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Ceramides and Ceramide Synthases in Cancer: Focus on Apoptosis and Autophagy - [v1]
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.tap\:transition-transform{transition-duration:.15s;transition-property:transform;transition-timing-function:cubic-bezier(.4,0,.2,1)}.slider-tap .tap\:duration-300{transition-duration:.3s}.slider-tooltip-focus:not(.slider-focused) .tt-focus\:hidden{display:none!important}.slider-tooltip-focus.slider-focused:not(.slider-tooltip-hidden) .tt-focused\:block{display:block!important}.slider-tooltip-drag:not(.slider-state-drag) .tt-drag\:hidden{display:none!important}.slider-tooltip-drag.slider-state-drag .tt-dragging\:block\:not\(\.slider-tooltip-hidden\){display:block!important}@media not all and (min-width:1280px){.max-xl\:w-full{width:100%}}@media not all and (min-width:1024px){.max-lg\:items-center{align-items:center}.max-lg\:gap-x-6{-moz-column-gap:1.5rem;column-gap:1.5rem}.max-lg\:pt-lg{padding-top:1.5rem;padding-top:var(--spacing-lg)}}@media 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inline-block"><!--[--><a href="https://orcid.org/0000-0001-9082-3083" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/2622522" target="_blank" rel="noopener noreferrer">Simone C. Da Silva Rosa</a></span><!----><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0002-3732-3781" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/eVpFcFlBUVdlakhFcHcyekhqdDNaaGRiZlRqR21CamNCTkhneHV5UWtyMD0=" target="_blank" rel="noopener noreferrer">Xiaohui Weng</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/MmVhMk0ySVlZeEtkSHgwNGVrRmVtbitmU3NhRHVibUxWSkxsMDRpMTF5bz0=" target="_blank" rel="noopener noreferrer">Joadi Jacobs</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/2589198" target="_blank" rel="noopener noreferrer">Shahrokh Lorzadeh</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/554890" target="_blank" rel="noopener noreferrer">Amir Ravandi</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/MzBsLzBzK05rTTUwd2RFSWRiNVZ0TUxRZ2VZNzRESkVtcTdoUGZmcXlUND0=" target="_blank" rel="noopener noreferrer">Rui Vitorino</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/999674" target="_blank" rel="noopener noreferrer">Stevan Pecic</a></span><!----><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0002-3706-8768" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/Q2tzaThsZzFFZWIwREhtL1FBQmNwcGR5dWRYRk1UMWxFWEx4ckZDMTZIcz0=" target="_blank" rel="noopener noreferrer">Shahla Shojaei</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/img/user_image/134198/Saeid_Ghavami.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/134198" target="_blank" rel="noopener noreferrer">Saeid Ghavami</a></span><sup> *</sup><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0001-5948-508X" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><!----><!--]--></span></span><!--]--><!--]--></div><div class="invisible absolute"><!--[--><!--[--><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/1344513" target="_blank" rel="noopener noreferrer">Javad Alizadeh</a></span><!----><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0001-9082-3083" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/2622522" target="_blank" rel="noopener noreferrer">Simone C. Da Silva Rosa</a></span><!----><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0002-3732-3781" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/eVpFcFlBUVdlakhFcHcyekhqdDNaaGRiZlRqR21CamNCTkhneHV5UWtyMD0=" target="_blank" rel="noopener noreferrer">Xiaohui Weng</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/MmVhMk0ySVlZeEtkSHgwNGVrRmVtbitmU3NhRHVibUxWSkxsMDRpMTF5bz0=" target="_blank" rel="noopener noreferrer">Joadi Jacobs</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/2589198" target="_blank" rel="noopener noreferrer">Shahrokh Lorzadeh</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/554890" target="_blank" rel="noopener noreferrer">Amir Ravandi</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/MzBsLzBzK05rTTUwd2RFSWRiNVZ0TUxRZ2VZNzRESkVtcTdoUGZmcXlUND0=" target="_blank" rel="noopener noreferrer">Rui Vitorino</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/statics/img/design/default-user.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/999674" target="_blank" rel="noopener noreferrer">Stevan Pecic</a></span><!----><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0002-3706-8768" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><!----><span><a href="https://sciprofiles.com/profile/author/Q2tzaThsZzFFZWIwREhtL1FBQmNwcGR5dWRYRk1UMWxFWEx4ckZDMTZIcz0=" target="_blank" rel="noopener noreferrer">Shahla Shojaei</a></span><!----><!----><span>,</span><!--]--></span></span><span class="pr-sm"><span class="m-text text-sm"><!--[--><div class="m-avatar flex items-center justify-center overflow-hidden rounded-full bg-brand-bold font-medium text-color-on-brand h-5 w-5 min-w-5 text-[0.575rem] !inline-block align-middle mr-xs" data-testid="m-avatar"><!--[--><img src="/img/user_image/134198/Saeid_Ghavami.png"><!--]--><span class="sr-only"></span></div><span><a href="https://sciprofiles.com/profile/134198" target="_blank" rel="noopener noreferrer">Saeid Ghavami</a></span><sup> *</sup><div class="m-icon-custom text-color-inherit pl-xs inline-block"><!--[--><a href="https://orcid.org/0000-0001-5948-508X" rel="noopener noreferrer" target="_blank"><img src="/_ipx/_/img/articleorcid.webp" onerror="this.setAttribute('data-error', 1)" data-nuxt-img srcset="/_ipx/_/img/articleorcid.webp 1x, /_ipx/_/img/articleorcid.webp 2x" class="w-4"></a><!--]--></div><!----><!--]--></span></span><!--]--><!--]--></div></div><div style="display:none;" class="mt-sm"><!----><button class="m-button m-button--sm m-button--tertiary rounded !inline-flex after:hidden bg-white" type="button"><!----><span class="inline-flex h-full w-full items-center gap-2 whitespace-nowrap justify-center"><!--[--><!----><!--]--><!--[-->Show more <!--]--><!----><!----><!--[--><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" aria-hidden="true" role="img" data-testid="keyboard_arrow_down" style="" width="16" height="16" viewBox="0 0 16 16"></svg><!--]--></span></button></div></div><!----><p class="m-text text-sm text-color-error pt-sm"><!--[-->This version is not peer-reviewed<!--]--></p></div><div class="m-accordion mx-auto flex w-full flex-col gap-3 rounded-2xl bg-white"><!--[--><div class="m-accordion__item border-b border-color-default"><button id="accordion-button-expand-0" aria-controls="accordion-panel-0" class="relative mb-xs flex w-full cursor-pointer py-md text-sm outline-offset-2" aria-expanded="true"><!--[--><span class="text-sm">This preprints belongs to the Topic</span><!--]--><div class="absolute right-0 top-1/2 -translate-y-1/2"><!--[--><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" aria-hidden="true" role="img" data-testid="keyboard_arrow_down" class="origin-center transition 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id="headlessui-listbox-button-mui-11728" type="button" aria-haspopup="listbox" aria-expanded="false" data-headlessui-state data-testid="select-activator" class="common-field__dropdown-input [&>span]:overflow-hidden h-10"><span class="flex w-full items-center gap-1 [&>span]:truncate"><!----><span>Version 1</span></span><div class="flex"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" aria-hidden="true" role="img" data-testid="keyboard_arrow_down" class="duration-400 transition-transform" style="" width="24" height="24" viewBox="0 0 16 16"></svg></div></button><!----></div><!----></div></div><!--]--><!----></div><div class="pt-sm"><div class="flex"><p class="m-text text-xs"><!--[-->Submitted:<!--]--></p><p class="m-text text-xs pl-xs"><!--[-->14 January 2023<!--]--></p></div><div class="flex pt-sm"><p class="m-text text-xs"><!--[-->Posted: <!--]--></p><p class="m-text text-xs pl-xs"><!--[-->16 January 2023<!--]--></p></div><!----></div><div class="pt-sm"><div><p class="m-text text-xs"><!--[-->You are already at the latest version <!--]--></p></div></div><div><!----></div></div><!--[--><div class="py-md border-b border-color-default flex items-center justify-between" data-v-d8c082ee><div class="flex-none flex items-center" data-v-d8c082ee><span class="m-text text-xs pr-xs font-semibold flex-none" data-v-d8c082ee><!--[-->Alerts<!--]--></span><span data-v-d8c082ee></span></div><div class="m-switch flex items-center gap-2" data-v-d8c082ee><!----><!--[--><!----><button class="relative inline-flex h-[1.4rem] w-[2.75rem] shrink-0 cursor-pointer items-center rounded-full border-2 border-color-transparent transition-colors duration-150 ease-out ui-focus-visible:ring-2 ui-focus-visible:ring-brand-bold ui-focus-visible:ring-opacity-75 bg-content-default hover:bg-content-bold active:bg-content-bolder" aria-label="Switch on" id="headlessui-switch-mui-11729" role="switch" type="button" tabindex="0" aria-checked="false" data-headlessui-state><span aria-hidden="true" class="pointer-events-none inline-block h-[1rem] w-[1rem] transform rounded-full bg-white shadow-lg ring-0 transition duration-200 ease-in-out translate-x-0.5"></span></button><!--]--></div></div><div data-v-d8c082ee data-v-03f1a75d><!----></div><!--]--><div><h6 class="m-heading text-inherit m-h6 font-semibold pt-lg"><!--[-->Abstract<!--]--></h6><div class="">Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides’ fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest methods to analyze the lipids in biological samples. Finally, we discuss the drug development strategies focusing on the ceramide synthases and ceramides as future therapeutic approaches in cancer therapy.</div><!--[--><!--]--></div><div data-v-3ce94018><div class="pt-lg" data-v-3ce94018><span class="m-text text-body font-semibold" data-v-3ce94018><!--[-->Keywords: <!--]--></span><span class="m-text text-body pt-sm" data-v-3ce94018><!--[--><!--]--></span></div></div><div class="flex-1 pt-lg mr-lg lg:pt-0" data-v-6afb3413><div class="pt-md" data-v-6afb3413><div class="flex flex-wrap lg:flex-nowrap items-center" data-v-6afb3413><span class="m-text text-body font-semibold" data-v-6afb3413><!--[-->Subject: <!--]--></span><span class="m-text text-body" data-v-6afb3413><!--[-->Biology and Life Sciences<!--]--></span><span class="" data-v-6afb3413> - </span><span class="m-text text-body" data-v-6afb3413><!--[-->Biochemistry and Molecular Biology<!--]--></span></div></div><div class="content-container" id="articleRef" data-v-6afb3413><script type="text/x-mathjax-config"> MathJax.Hub.Config({ menuSettings: { CHTMLpreview: false }, "CHTML-preview":{ disabled: true }, "HTML-CSS": { scale: 90, availableFonts: [], preferredFont: null, preferredFonts: null, webFont:"Gyre-Pagella", imageFont:'TeX', undefinedFamily:"'Arial Unicode MS',serif", linebreaks: { automatic: false } }, "TeX": { extensions: ["noErrors.js"], noErrors: { inlineDelimiters: ["",""], multiLine: true, style: { "font-size": "90%", "text-align": "left", "color": "black", "padding": "1px 3px", "border": "1px solid" } } } }); </script><script type="text/javascript" async="" src="https://www.mdpi.com/bundles/mathjax/MathJax.js?config=TeX-AMS-MML_HTMLorMML"></script> <section id="Introduction" type="intro"><h2 data-nested="1" id="preprints-h2-1"> Introduction</h2> <div class="html-p">Ceramide is a crucial intermediate in sphingolipid metabolism in mammalian cells (1). Ceramide is synthesized by ceramide synthases (CerS) with different acyl chain lengths. CerS share some biochemical features like their structure, intracellular localization and their catalytic mechanism (1). Additionally, different CerS display significant variability in their biological properties (2). All CerS are associated with the endoplasmic reticulum (ER), and they all contain a crucial TRAM–Lag1p–CLN8 (TLC) domain: a CerS catalytic domain necessary for ceramide synthesis (3). Originally, CerS were known as Longevity Assurance (Lass) genes due to their homology to the longevity assurance gene 1 (LAG1p) in yeast, however their name was changed after characterization of their biochemical features (4). It was found that LAG genes result in the prolonged life span of <span class="html-italic">S. cerevisiae</span> and extend the lifespan of a cell, hence the name LAG1. The most remarkable characteristic of CerS is that each of the CerS has a specificity for an acyl CoA chain length despite all catalyzing the same reaction. It can thus be seen that CerS determine the fatty acid composition of ceramides (2). <a href="#preprints-67418-t001" class="html-table">Table 1</a> displays ceramides with different acyl chain lengths as synthesized by these six CerS.</div> <div class="html-p">Multiple investigations have been performed to determine the role of CerS in different pathologies. Although no longer true, ceramides were classically known to induce cancer cells’ growth inhibition, cell death, and senescence (11). Recent reports found that ceramides with various fatty acid chain lengths might have different functions in the pathogenesis of cancer, indicating the critical importance of CerS in sphingolipid metabolism (12-14). There are various functions of ceramides that are context dependent and are modulated by their localization in the cell and presence or absence of their targets. For instance, ceramides with various fatty-acid chain lengths have been shown to play a role in cancer cell proliferation like C16-ceramide (synthesized by CerS6) whereas C18-ceramide (synthesized by CerS1) is involved in cell death (11). Based on C18-ceramide downregulation in most head and neck squamous cell carcinoma (HNSCC) tissues compared to adjacent normal tissue, CerS1 has been found to play a role in the growth regulation of HNSCC (15). Furthermore, the balance between C16-and C18-ceramides levels could be associated with HNSCC tumor development (15, 16) related to the clinical progression of this cancer (17). CerS2 have been shown to play a role in breast cancer. In an initial study (18), it was found that the levels of total ceramide (especially C16-, C24:1- and C24:0-ceramides) were significantly increased in aggressive tumors. This was consistent with an increases in CerS2, CerS4 and CerS6 mRNA levels. In the subsequent study (19), mRNA levels of CerS2 and CerS6 were highly increased in breast tumors compared to the normal tissue, where almost half of the patients showed increased levels of CerS2 and CerS6 mRNA. Notably, there was a significant relationship between the expression of CerS6 and CerS2, and between CerS2/CerS6 and CerS4. Moreover, the sensitivity of breast cancer cells to chemotherapeutic drugs was not affected by CerS4 (unlike CerS1 and CerS5) (20). It has been suggested that CerS6 is involved in the etiology of cancer. For example, using microarray studies, CerS6 has been found to be implicated in early embryonic development and cancer differentiation (21). In contrast to this, another study showed that mRNA levels of CerS6 were increased in breast cancer tissues and regulation of CerS6 expression was dependent on estrogen receptor (18, 19, 22). This double-edge role of ceramides in cancer highlights the potential targeting of some of the enzymes in the ceramide metabolism pathway as novel therapeutic methods. For example CerS6 can be targeted in order to hamper cancer cell growth in head and neck and breast cancers while activation of CerS1 could be harnessed to develop new treatments against lung and head and neck cancers (11).</div> <div class="html-p">Therefore, in the current review paper we summarize different types of CerS and their products. Then, we discuss the impact of CerS and ceramides in apoptosis and autophagy which play an important role in cancer. We later explain the current methods that is being used for evaluation of lipids including ceramides in biological samples. Finally, we will provide over view for future therapeutic approaches to target CerS for developing potential new therapeutic approaches in cancer. </div></section><section id="CeramideSynthesis" type><h2 data-nested="1" id="preprints-h2-2"> Ceramide Synthesis</h2> <div class="html-p">Sphingolipids are one of the main lipid types in eukaryotic cells. Ceramides are the building block of all sphingolipids. This has made ceramide the focus of recent enormous attention due to its suggested role as a crucial signaling lipid involved in the regulation of different cellular processes (23). As shown in <a href="#preprints-67418-f001" class="html-fig">Figure 1</a>, ceramide is synthesized via different pathways in the cell. Ceramide is made of a sphingosine backbone, which is a fatty acyl chain with an amide linked to it, with different lengths (24). Ceramides are used as a precursor for more complex sphingolipids, for example: glucosylceramide, ceramide-1-phosphate (C1P), sphingomyelin, and galactosyl ceramide. Ceramide is also produced through the breakdown of these complex sphingolipids using various enzymes. This type of ceramide can be used as a substrate by ceramidases to release sphingosine, which is phosphorylated to make sphingosine 1-phosphate (S1P) (11). Endogenous ceramides are synthesized <span class="html-italic">de novo</span> in the ER through a pathway beginning with condensation of L-serine and palmitoyl-CoA followed by more enzymatic reactions leading to the production of ceramide (25, 26) (<a href="#preprints-67418-f001" class="html-fig">Figure 1</a>). D<span class="html-italic">e novo</span> synthesis of ceramide occurs in the ER, however, the synthesis of complex sphingomyelin and glycosphingolipids occurs in the Golgi apparatus (27). During this process the ceramide is transported to Golgi apparatus from the ER via vesicular trafficking or non-vesicular transport (i.e. by ceramide transfer protein (CERT)) (28). Lastly, the salvage pathway can also generate ceramides through hydrolyzing ceramide into sphingosine which is then reacylated by CerS to regenerate ceramides (29). </div></section><section id="CerSActivityRegulation" type><h2 data-nested="1" id="preprints-h2-3"> CerS Activity Regulation</h2> <div class="html-p">Mechanisms involved in the regulation of CerS activity are not fully known. Recent studies reveal that the formation of CerS dimers can regulate the ceramide synthesis which may be dependent on the interaction of CerS with each other (30). CerS is expressed in various levels in different tissues (31), however the acyl chain composition of the sphingolipid does not always correlate with CerS expression (31, 32). This has prompted the possibility of cross-regulation of CerS expression and activity (33). In fact, heterocomplexes of CerS2, -5, and -6 was recently reported in HeLa cells (34). Moreover, the activity of either monomers in this dimer form depend on, and can be regulated by, the other monomer, suggesting dimer formation as a mechanism of regulating CerS activity (30). Specifically, it was suggested that the highest level of CerS2 activity is dependent on its interaction with other CerS. CerS2 has the least activity among all CerS <span class="html-italic">in vitro</span> (35, 36), yet it has the widest tissue distribution (31). In fact, CerS monomers and dimers are in equilibrium in the ER and dimers formation and/or dissociation could be a major factor in their regulation. Dimer formation occurs rapidly which is an efficient way of increasing the ceramide levels under different conditions. This is of utmost importance in situations when <span class="html-italic">de novo</span> ceramide synthesis plays a crucial role in other signaling pathways requiring a quick mechanism of ceramide synthesis (30). The mechanisms of post translational modifications of CerS, if any, are not fully elucidated yet. There is some evidence that suggests a role for CerS phosphorylation. For example, an increase in the <span class="html-italic">de novo</span> ceramide synthesis is linked to activation of protein kinase C (PKC) and consequently up-regulation of CerS5 activity (37). It has been shown from high performance mass spectrometry that CerS might be phosphorylated (38, 39) and glycosylated (40). The rapid changes in CerS activity might be facilitated by the post-translational regulation of CerS under different conditions (41, 42)<b>.</b> </div></section><section id="CerSTissueDistribution" type><h2 data-nested="1" id="preprints-h2-4"> CerS Tissue Distribution</h2> <div class="html-p">CerS1 is mainly expressed in brain, testes, and skeletal muscle at low levels (31, 40, 43). It was shown by in situ-hybridization of brain tissue that CerS1 is expressed in most neurons and in very low levels in white matter cells (44). CerS1 is upregulated at a low level postnatally, possibly supporting the synthesis of neuronal cell membranes. The high level of CerS1 is in line with the composition of acyl chain of the neuronal sphingolipids (mainly C18-fatty acids) in neurons (44). CerS2 is more widely expressed in different human tissues compared to CerS1 with lowest expression in spleen, small intestine, colon, thymus, and peripheral blood leukocytes, moderate expression in heart, brain, placenta and lung, skeletal muscle, and highest expression in liver and kidney (31). It has been shown that CerS2 is highly expressed during active myelination in oligodendrocytes and Schwann cells in mouse brain (44). CerS3 is highly expressed in testes and skin (40, 45). The expression of CerS3 is very high in keratinocytes (46). CerS4, which is probably the least studied CerS, is highly expressed in leukocytes, heart, skin, and liver (31). CerS5 is highly expressed in lung epithelia and is likely the most studied CerS because it can synthesize C16-ceramide which is an important pro-apoptotic ceramide (47). It was found that down regulation of CerS5 in lung epithelium by siRNA or using fumonisin B1 decreased the total CerS activity (48). This shows that CerS5 is indeed involved in the ceramide synthesis in lung tissue. Lastly<b>,</b> CerS6 is highly expressed in intestine and immune system (2). </div></section><section id="RoleofCerSandceramidesinRegulationofApoptosis" type><h2 data-nested="1" id="preprints-h2-5"> Role of CerS and ceramides in Regulation of Apoptosis</h2> <div class="html-p">Apoptosis is a programmed process whereby cells are committed to death (49). There are two main apoptosic pathways namely intrinsic or extrinsic (50). Mitochondria play a crucial role in intrinsic apoptosis as the outer membrane integrity loss results in a cascade of events that leads to apoptotic death (51). Different proteins are connected to apoptosis initiation leading to the permeabilization of the mitochondrial outer membrane by the formation of different pores (52, 53), mitochondrial apoptosis-induced channel (54), Bax oligomerization into channels (55, 56), mitochondrial permeability transition pore (57, 58), and Bax/Bak hybrid channels (56, 59). Ceramides are also involved in the formation of channels in the mitochondrial outer membrane (60-62). Moreover, these events <span class="html-italic">in vivo</span> can occur at the same time resulting in a regulated and coordinated outcome. </div> <div class="html-p">A recent study highlighted the role of ceramides in regulation of apoptosis. It found that C16-ceramide is needed for germ cell apoptosis induced by gamma radiation in <span class="html-italic">C. elegans</span> (63). C16-ceramide-mediated apoptosis was detected by acridine orange (AO) staining, involvement of MAPK pathway (<span class="html-italic">mpk-1</span>; homologue of mammalian <span class="html-italic">erk</span> and <span class="html-italic">sek-1;</span> homologue of mammalian JNK), production of ROS and reduction in mitochondrial outer membrane potential (MOMP). Most studies thus far have shown that ceramides regulate apoptosis mainly through ceramide channel formation and regulation of anti-apoptotic Bcl2 family proteins (Bcl2 and Bcl-xL), and pro-apoptotic Bcl2 family proteins (Bax and Bak) as discussed below and briefly illustrated in <a href="#preprints-67418-f002" class="html-fig">Figure 2</a>. </div></section><section id="RegulationofApoptosisbyCeramideChannels" type><h2 data-nested="1" id="preprints-h2-6"> Regulation of Apoptosis by Ceramide Channels </h2> <div class="html-p">Ceramides have the special ability to perforate the cell lipid bilayers through forming water-filled channels (typically 10 nm in diameter) (64, 65). Levels of mitochondrial ceramide elevates during apoptosis initiation and resulting in mitochondrial outer membrane integrity loss (66). Pro-apoptotic proteins such as cytochrome c are released from the intermembrane space into the cytosol upon the permeabilization of the mitochondrial outer membrane and at this point the cell is irreversibly committed to death (67, 68). The most recent model for the ceramide channel comprises of layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure in lipid bilayer membranes (69, 70). Ceramides with various fatty acyl chain lengths such as C2-, C8-, C16- and C24-ceramides are capable of perforating the mitochondrial outer membranes (27, 71). This ceramide channel formation strongly depends on ceramide molecule structure (72). For example, dihydroceramide does not possess the 4–5 double bond in ceramide and therefore it cannot induce cell death. Furthermore, dihydroceramide cannot form ceramide channels <span class="html-italic">in vitro</span> (73). It is unsurprising that ceramides can influence each other since ceramides production with various chain lengths invariably changes the biophysical properties of membranes (74, 75). Furthermore, membranes biophysical properties alter due to the depletion of very long chain ceramides (76). Ceramide channels in the mitochondrial outer membrane are large enough to permit the release of apoptotic proteins into the cytosol (77). Previous study findings show that various ceramide species induce membrane permeability independently from one another (60). In a recent study, the egress of two intermembrane space proteins were evaluated to investigate the mechanisms by which ceramides perforate the mitochondria (78). Sulfite oxidase is a 120 KD enzyme and adenylate kinase is a 26 KD protein and both localize in the mitochondrial intermembrane space. Upon mixing C16- and C22- ceramide with isolated mitochondria, it was found that C16-ceramide induced the SOX release whereas C22-ceramide showed no release of SOX indicating that the C22-ceramide channels are significantly smaller than the ones made by C16-ceramide. Interestingly, both C16-ceramide and C22-ceramide resulted in the release of both SOX and AK. This release was possibly due to the formation of either C16-ceramide channels or C16–C22-hybrid channels as C22-ceramide channels did not release SOX. In short, these findings agree with the theory that various ceramides can form channels of varied sizes and quantities in isolated mitochondria (78). In another study by Laviad <span class="html-italic">et al.</span>, it was found that CerS overexpression results in the high production of specific ceramides in HEK cells. For example, CerS2 overexpression led to the enrichment of C22-, C24- and C24:ceramide (31) while CerS5 overexpression resulted in the enrichment of C16-ceramide. Additionally, cytochrome c release was measured to examine the impact of exogenous ceramides on the membrane permeability of isolated mitochondria from HEK cells. Interestingly, C16-ceramide addition to isolated mitochondria from CerS5-transfected cells (enriched with C16-ceramide) elevated the levels of cytochrome c release while it was significantly decreased in isolated mitochondria from CerS2-transfected cells. On the other hand, C24-ceramide addition to isolated mitochondria from CerS2-transfected cells increased the release of cytochrome c whereas it was significantly reduced in isolated mitochondria from CerS5-transfected cells highlighting the existing competition <span class="html-italic">ex vivo</span> (78). </div></section><section id="RegulationofApoptosisbyCeramidesthroughantiapoptoticBcl2familyproteinsBcl2andBclXL" type><h2 data-nested="1" id="preprints-h2-7"> Regulation of Apoptosis by Ceramides through anti-apoptotic Bcl-2 family proteins, Bcl2 and Bcl-XL</h2> <div class="html-p">Bcl2 phosphorylation at serine 70 is needed for its total and optimal anti-apoptotic function (79). It has been suggested that ceramide might influence the Bcl2 phosphorylation and therefore its function, since ceramide activates protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) (80). In fact, C2-ceramide (and not C2-dihydroceramide) specifically activates mitochondrial PP2A that induces Bcl2 dephosphorylation and consequently ceramide-induced apoptosis in HL-60 cell line (a human leukemia cell line). These results show that ceramide-induced apoptosis might involve mitochondrial PP2A which dephosphorylates and inactivates Bcl2 in Bcl2 expressing cells (81). The fatty acyl chain lengths of the ceramide are critical in regulating the ceramide channels by Bcl-xL (82). Bcl-xL prevents the formation of ceramide channel and therefore ceramide-induced apoptosis (83). Interestingly, this prevention of ceramide channel formation is disrupted when ceramide has a truncated fatty acyl chain which shows a crucial role for the acyl chain length in binding to the Bcl-xL. Bcl-xL binding to ceramide greatly depends on the acyl chain length of ceramide due to the hydrophobic pocket in Bcl-xL structure. Bcl-xL efficiently inhibits the formation of ceramide channels formed by 16-, 18- and, 20-ceramides (82). Moreover, BH3 peptide mimetics bind to the hydrophobic grove on Bcl-xL and thus prevent its binding to Bax, inhibiting the ceramide channel formation (84). </div></section><section id="RegulationofApoptosisbyceramidesthroughproapoptoticBcl2familyproteinsBaxandBak" type><h2 data-nested="1" id="preprints-h2-8"> Regulation of Apoptosis by ceramides through pro-apoptotic Bcl2 family proteins, Bax and Bak: </h2> <div class="html-p">Bax has a crucial role in regulation of apoptosis (85). Bax translocates to mitochondria, after a variety of apoptotic stimuli, to form pores in mitochondrial outer membrane by potentiating the ceramide channels and thus inducing loss of mitochondrial membrane potential (85). This leads to the cytochrome c release from mitochondrial intermembrane spaces into the cytosol. </div> <div class="html-p">As opposed to Bcl-xL, formation of Bax is not dependent on nor influenced by acyl chain length of ceramide (86). It has been found that Bax, Bak, and ceramide are dependent on one another when forming ceramide channels (84). Additionally,Bak is crucial for the synthesis of long-chain ceramide by CerS during apoptosis (87). Moreover, evidence suggests that Bax and ceramide act together in a synergistic manner in the permeabilization of mitochondrial outer membrane (88, 89). It has also been reported that in Bax-transfected DU-145 cells and HL-60 cells the exogenous C2- and C6-ceramides leads to the Bax redistribution to mitochondria and causes mitochondrial permeability transition followed by cytochrome c release, then activation of caspase-3 and DNA fragmentation (90). It was found that ceramides capable of permeabilizing into the cells can promote the conformational change in the Bax N-terminus in Bax-expressing cells (91). Interestingly, loss of Bax inhibits the C2-ceramide-induced apoptosis in colorectal cancer HCT116 cells, highlighting again the role of ceramide in the regulation of apoptosis induction (92).</div></section><section id="EndoplasmicReticulumERandRegulationofApoptosisviaCeramides" type><h2 data-nested="1" id="preprints-h2-9"> Endoplasmic Reticulum (ER) and Regulation of Apoptosis via Ceramides</h2> <div class="html-p">The ER plays an important role in different cellular processes such as lipid metabolism, protein folding, protein synthesis, and calcium homeostasis and is therefore a crucial organelle within eukaryotic cells (93). When newly synthesized proteins in the ER are improperly folded or when the Ca<sup>2+</sup> sequestration is perturbed, it leads to ER stress (94, 95). To mitigate this stress, a complicated homeostatic mechanism is activated in the ER known as the unfolded protein response (UPR) (95). Three transmembrane proteins in the ER mediate UPR namely; inositol-requiring enzyme 1 (IRE1), pancreatic ER kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6), each of which have specific functions and targets (96, 97). </div> <div class="html-p">Elevated levels of ceramide in the mitochondria are linked to the induction of apoptosis. It has been found that synthesized ceramides in isolated ER vesicles transfer to the isolated mitochondria where they perforate the outer membrane leading to the release of cytochrome <span class="html-italic">c</span> and adenylate kinase (98). Interestingly, the ER-like membranes that are closely connected to mitochondria (known as mitochondria-associated membranes) synthesize ceramide that can transfer and permeabilize the mitochondrial outer membrane (98). Therefore, this mechanism of ceramide exchange between the two organelle obviates the need for a <span class="html-italic">de novo</span> pathway to synthesize the ceramide in mitochondria required for the formation of ceramide channel followed by protein release (98). In HNSCC cell lines, CerS6 overexpression followed by increased C<sub>16</sub>-ceramide has pro-survival roles whereas CerS6 knockdown induces apoptosis via activation of ATF6-CHOP arm of the UPR (99). Senkal <span class="html-italic">et al.</span> found that the induction of wild type CerS6 and not the inactive/mutant CerS6, increased the tumor growth in Severe Combined Immuno Deficient (SCID) mice. Similarly, induction of wild type-CerS (and not mutant CerS6) or expression of the mutant ATF-6 protected cells from undergoing apoptosis in response to CerS6 knockdown. Conversely, CerS6 knockdown by siRNA induced ATF-6 activation and subsequently apoptosis in multiple human squamous cell carcinomas cells (HNSCC, A549, H157, and H1650).. Altogether, this data revealed an underlying mechanism of how the alteration of CerS6 (and by extension C16-ceramide) induces the activation of ATF6 leading to the ER-stress-mediated apoptosis in human squamous cell carcinomas cells (100). Another study showed that cell-permeable C2-ceramide induces an apoptotic ER stress response in salivary adenoid cystic carcinoma cells (ACCs). Findings from this study illustrated that C2-ceramide activates pro-apoptotic factors downstream of ER stress and therefore induces apoptosis in ACCs. They found that ceramide induces CHOP which is the key transcription factor highly expressed during ER stress and is known as a crucial inducer of ER stress-mediated apoptosis. The same study found that the mRNA expression of CHOP was upregulated upon treatment with ceramide in ACC-M and ACC-2 cells (101).</div></section><section id="RoleofCerSandceramidesinRegulationofApoptosisinCancer" type><h2 data-nested="1" id="preprints-h2-10"> Role of CerS and ceramides in Regulation of Apoptosis in Cancer</h2> <div class="html-p">Owing to their regulatory role on apoptosis, CerS and ceramides have been implicated in the pathogenesis of various cancers. Ceramides are produced in response to a variety of stressors to initiate apoptosis. For example, levels of C16-ceramide were elevated after celecoxib (a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug for the treatment of arthritis) treatment in human colon carcinoma cells thereby mediating the anti-proliferative effects (102, 103). In another study, it was shown that overexpression of different CerS led to varied outcomes of apoptosis induced radiation in HeLa cells: overexpression of CerS5 resulted in higher levels of apoptosis in cells while overexpression of CerS2 inhibited cells from undergoing apoptosis (104). CerS1 also plays a crucial role in regulation of the sensitivity to chemotherapeutic agents. It was shown that CerS1 sensitizes human embryonic kidney cells to different anti-cancer agents such as carboplatin, cisplatin, vincristine, and doxorubicin while CerS5 sensitizes these cells to only doxorubicin and vincristine and CerS4 has no effects on the sensitivity to any of these anti-cancer agents (20). Similarly, CerS1 has a critical role in regulating apoptosis in HNSCC cells through caspase activation induced by gemcitabine/doxorubicin (105). They found that CerS1 downregulation by siRNA inhibited apoptosis about 50% in response to gemcitabine/doxorubicin. Also, CerS1 (and not CerS5) siRNA modulated caspase-3 and caspase-9, but not caspase-8, activation in response to gemcitabine/doxorubicin treatment. Moreover, gemcitabine/doxorubicin treatment led to a remarkable reduction in the growth of HNSCC tumor in severe combined immunodeficiency mice with UM-SCC-22A (a HNSCC cell line) xenografts. Interestingly, liquid chromatography and mass spectroscopy analysis showed that only the levels of C18-ceramide (synthesized by CerS1) were significantly increased in response to gemcitabine/doxorubicin in these tumors. These findings highlight a key role for C18-ceramide in gemcitabine/doxorubicin-induced apoptosis through caspase-9/3 activation in HNSCC (105). In another study on CerS1, it was found that treatment of K562 cells (a chronic myeloid leukemia cell line) with imatinib induced C18-ceramide synthesis via CerS1, which plays a role in imatinib-induced apoptosis in these cells (106). CerS1 downregulation using siRNA partly inhibited the imatinib-induced apoptosis in drug-sensitive K562 cells. Also, CerS1 overexpression (but not CerS6) triggered a significant increase in the synthesis of C18-ceramide induced by imatinib and promoted apoptosis. These results propose the involvement of C18-ceramide (synthesized by CerS1) in imatinib-induced apoptosis in K562 cells (106). As mentioned previously, d<span class="html-italic">e novo</span> synthesis of ceramide is an important inducer of Bax. It has been found that localization of Bax to the mitochondria was decreased after CerS5 knockdown in NT-2 cells (a testicular embryonal carcinoma cell line) (107) indicating that CerS5 is critical in the synthesis of ceramide that leads to apoptosis in these cancer cells. CD95 (Fas) and its ligand (CD95L) are death receptors and ligands, which induce apoptosis (108). CerS6 modulates the activation of CD95 and therefore the induction of apoptosis (109). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family able to initiate apoptosis via its death receptors (DR4 and DR5) (110, 111). This leads to caspase 8, and -10 activation. It has been found that normal cells are resistant to TRAIL-induced apoptosis because of low levels of TRAIL receptors expressed on their membrane (112). The CD95 activation and cancer cell killing were both increased after CerS6 overexpression while CerS6 knockdown abrogated CD95 activation in colon adenocarcinoma cell lines (DLD1, SW620 and SW480). Role of ceramides in the CD95-induced apoptosis in different types of cancer was investigated in another study by the same research group. Findings showed that fumonisin B1 (an inhibitor of CerS activity) inhibited the C16-ceramide increase in SW480 cells (113). Also, TRAIL-resistant SW620 cells had a lower levels of CerS6 expressed. CerS6 downregulation by siRNA led to a specific and significant reduction of C16-ceramide - enough to abrogate the TRAIL-induced apoptosis. Furthermore, only a slight increase in CerS6 expression was enough to reverse the TRAIL resistance in SW620 cells. These findings show that regulation of the CerS6 expression could potentially be a novel therapeutic approach to alter colon cancer cells’ sensitivity to apoptosis (113). In another study, it was found that the mRNA levels of CerS2 and CerS6 were highly increased in about half of the tissues obtained from patients with breast cancer in comparison to normal tissues. Findings from this study suggested that C16-ceramide (synthesized by CerS6) and C24:1- and C24-ceramide (synthesized by CerS2) may have an unusual pro-survival role and thus resist apoptosis in breast cancer pathogenesis (19). lncRNA ceramide synthase 6 antisense RNA 1 (CERS6-AS1) is a novel RNA that modulates the gene expression of ceramide synthesis 6 and is significantly overexpressed in various cancers such as gastric, hepatocellular, pancreatic and breast cancer (114). A study found that LncRNA CERS6-AS1 promotes proliferation and migration while inhibiting apoptosis of breast cancer cell lines <span class="html-italic">in vitro</span> (115). In agreement with this, flow cytometry findings on CERS6-AS1 knockdown revealed high rate of apoptosis (115). A very interesting research study showed that C16-ceramide directly binds to voltage-dependent anion channel VDAC2, a mitochondrial platform for Bax/Bak translocation, to mediate apoptosis in Human colon carcinoma HCT116 cells (91). VDAC channels are a platform for the recruitment of pro-apoptotic Bak and Bax into mitochondria, leading to cytochrome c release and permeabilization of the OMM (116). Moreover, C2-cermide has been found to induce apoptosis in lung adenocarcinoma cells (A549 and PC9) via regulation of the thioredoxin-interacting protein (Txnip) (117). Treatment of these cells with C2-ceramide caused an increase in the activity of caspase-3. Txnip has a crucial role in redox signal transmission in the cell (118). The expression of CerS6 which synthesizes C16-ceramide is significantly upregulated in breast cancer (19) and non-small-cell lung cancer (119) cells. CerS6 is a regulator of apoptosis and contributes to the metastasis and progression of cancer cells (120). Using siCerS6, Shi <span class="html-italic">et al.</span> showed that CerS6 knockdown prevented the migration and metastasis of ovarian cancer cells while inducing apoptosis in these cells (121). C6-ceramide also induces apoptosis in salivary adenoid cystic carcinoma (SACC) SACC-83 and SACC-LM cell lines in a dose dependent manner as shown by the upregulation of caspase-3, PUMA, and CHOP (122). </div></section><section id="RoleofCerSandceramidesinRegulationofAutophagy" type><h2 data-nested="1" id="preprints-h2-11"> Role of CerS and ceramides in Regulation of Autophagy</h2> <div class="html-p">Autophagy is a self-recycling mechanism in the cell that targets nonfunctional or misfolded proteins or damaged organelles and degrades them via lysosomes (123-127). There are three types of autophagy; macroautophagy (hereafter autophagy), microautophagy and chaperone-mediated autophagy all of which differ from one another in terms of their mechanism and function (128, 129). Autophagy not only leads to the elimination of misfolded proteins and damaged organelles, it also modulates the recycling of components within the cell thereby ensuring the cellular quality control (130-132). The primary function of autophagy is survival under stress conditions, such as starvation (133). This is accomplished through self-eating that provides the cell with required energy and metabolic precursors (134-137). Consequently, dysregulated or prolonged autophagy activation can result in cell death (138-140). Ceramides have been shown to regulate autophagy (141). Class I PI3K and Akt are two well-known regulators of autophagy. C2 or C6-ceramide have the ability to activate PP2A blocking the Akt activation thereby inducing autophagy in HT-29 (human colon) and MCF-7 (breast cancer) cell lines (142, 143). Furthermore, amino acid deprivation leads to an increase in ceramide levels. This results in inhibition of the mTOR activity and therefore autophagy induction in a PP1/PP2A dependent manner. It was shown by Edinger <span class="html-italic">et al.</span> that ceramide rapidly and significantly downregulates amino acid transporter proteins (103). Likewise, C2-ceramide inhibited the protein expression of nutrient transporter leading to starvation and consequentlyAMPK-dependent autophagy induction in murine prolymphocytic cells (FL5. 12) (144). Beclin1 is a crucial mediator in autophagy pathway. Beclin1 expression is increased under stress and its gene is mutated or deleted in different types of cancers (145). Scarlatti <span class="html-italic">et al</span>. demonstrated that exogenous C2-ceramide increases the expression of Beclin1 and thus autophagy induction. This effect is inhibited after using myriocin (a CerS inhibitor) which shows that ceramide regulation of Beclin1 expression occurs at either transcriptional or post-transcriptional level (143). In CNE2 and Hep3B cancer cell lines, C2-ceramide can also activate JNK and consequently c-Jun phosphorylation. C-Jun then upregulates the expression of Beclin1 mRNA (146). Moreover, elevated levels of Beclin1 could stem from the Beclin1-Bcl2 dissociation (147). In fact, ceramide triggers the JNK1 activation which leads to the phosphorylation of Bcl2 that in turn releases Beclin1 from the Beclin1-Bcl2 complex (148, 149). Also, ceramide is involved in the activation of Forkhead box protein O3 (FOXO3) that can increase the expression levels of BNIP3 (150). The increased expression of BNIP3 competitively binds to Bcl2 and Bcl-xL thereby dissociating Beclin1 from binding to Bcl2 (151). Ceramide-induced ER stress can play a role in the induction of autophagy (141). In fact, downregulation of CerS2 triggers significant accumulation of C14 and C16-ceramides and induces ER-stress-mediated autophagy (152). It should be mentioned that ER stress is also interconnected with the autophagy flux. Autophagy flux is defined as the rate of the degradation of cargos by autophagy process which shows autophagic degradation activity (153). One of the UPR arms is the dimerization of the IRE1 (154). IRE1 enhances autophagy flux through its interaction with adapter proteins such as apoptosis signal-regulating kinase 1 and tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). This results in the formation of IRE1/TRAF2/ASK1 complex that activates JNK that will subsequently phosphorylates c-Jun, which increases Beclin1 expression (155, 156). It should be mentioned that despite the fact that IRE1 induces the protective autophagy, this could switch to autophagy-dependent cell death during prolonged ER stress (156, 157). The PERK/eIF2α arm of UPR also plays an important role in regulation of autophagy. This arm is particularly active after ER stress that leads to autophagy induction. ATF4 and CHOP (C/EBP homologous protein, a transcription factor induced by ATF4) are essential for downstream effects of PERK where they can modulate the expression of different ATG genes. <a href="#preprints-67418-f003" class="html-fig">Figure 3</a> shows how ceramide can regulate autophagy. </div></section><section id="LifeorDeathDichotomyofAutophagyAutophagyParadox" type><h2 data-nested="1" id="preprints-h2-12"> Life-or-Death Dichotomy of Autophagy (Autophagy Paradox)</h2> <div class="html-p">There is a basal level of autophagy activity the cells in the human body (158-161). This basal activity is involved in the recycling of proteins and organelles destined for degradation and highlights the antiaging role of autophagy (162, 163). Autophagy can also be induced via different stimulus like nutrient withdrawal (164). Autophagy provides the cell with required building blocks to maintain the homeostasis and metabolism for survival (165, 166). Autophagy-dependent cell death is also known as the type II programmed cell death which is defined as a highly regulated cell death that does not involve other cell death pathways but is solely dependent on the central machinery of autophagy pathway (167, 168). </div> <div class="html-p">Owing to its double-edged role of cell survival and death, autophagy is unsurprisingly involved in the pathology of different diseases including but not limited to cancer, liver diseases, and neurodegenerative diseases (169-171). Autophagy has advantageous and detrimental effects in all these situations (172). Furthermore, accumulating evidence implicates ceramides in the regulation of these two opposing roles of autophagy that regulate cell death and cell survival, known as the autophagy paradox (173, 174). </div></section><section id="RegulationofAutophagybyCeramides" type><h2 data-nested="1" id="preprints-h2-13"> Regulation of Autophagy by Ceramides</h2> <div class="html-p">Bioactive sphingolipids regulate autophagy by exerting their effect in different steps of the autophagy pathway. Research on the role of ceramides in elongation phase of autophagy is very limited and majority of studies have revealed different roles for ceramides on the initiation and degradation phases of autophagy (<a href="#preprints-67418-f003" class="html-fig">Figure 3</a>). </div></section><section id="Ceramidesregulateinductionampnucleationstepsofautophagy" type><h2 data-nested="1" id="preprints-h2-14"> Ceramides regulate induction & nucleation steps of autophagy</h2> <div class="html-p">Autophagy is regulated at the initiation step via different mechanisms. It has been demonstrated that ceramide induces the activation of JNK leading to the phosphorylation of Bcl-2 (175). Bcl-2 phosphorylation leads to its dissociation from Beclin1 and therefore lifts its inhibitory role on autophagy. Interestingly, treatments (for example glucosylceramide synthase inhibitor PDMP or tamoxifen) that elevate the long-chain ceramides levels significantly potentiate this effect of autophagy. Moreover, it was shown that treatment of nasopharyngeal carcinoma and hepatocellular carcinoma cells with ceramide enhances the Beclin1 expression through activation of JNK thereby inducing autophagy (146). Also, levels of S1P may greatly influence the formation of autophagosomes through their effect on the LC3 lipidation and thus its anchoring to the autophagosomal membrane. S1P can also modulate aBeclin1 complex although the underlying mechanism remains unknown. Additionally, it has been revealed that Sphk overexpression increases the S1P levels thereby enhancing the preautophagosomal formation in primary neurons. This remarkably enhances the overall autophagosomes formation (176). The mitochondria-associated ER membranes can be the membrane source for phagophore formation. Lipid rafts within the mitochondria-associated ER membranes are particularly important for this process. During formation of autophagosomes, ganglioside GD3 which is a component of lipid rafts and a downstream product of ceramides binds to Beclin1 complex (177, 178). GD3 contributes to the recruitment of components of the autophagic pathway. It also regulates the membrane fluidity, thus playing a role in the formation of phagophore curved membranes. Golgi-derived ATG9 vesicles donate material to the forming phagophore (179). The availability of the phosphorylated form of ceramide, ceramide-1-phosphate, (180) potentiates the formation of these vesicles which subsequently fuse to the forming phagophore (181). </div></section><section id="Ceramidesregulatefusionampdegradationstepsofautophagy" type><h2 data-nested="1" id="preprints-h2-15"> Ceramides regulate fusion & degradation steps of autophagy</h2> <div class="html-p">A direct role for sphingolipids in promoting the autophagosomes-lysosome fusion have not yet been demonstrated. It has recently been reported that C1P synthesis from sphingomyelin induces the Ca<sup>2+</sup>-dependent liposomal fusion that increases the vesicle fusion (182). Furthermore, a role for C1P has been proposed in the exocytotic and endocytic pathways (182) that are connected to the autophagic pathway (183, 184). It has also been reported that C18-ceramides regulates the degradation step of the autophagy. C18-ceramides can induce the selective targeting and degradation of mitochondria by autophagy, and mitophagy (185, 186). As stated above, localized ceramide on mitochondria binds to the lipidated LC3 on the autolysosomes and induce mitophagy (187). Interestingly, aside from their role in regulation of degradation step of autophagy, ceramides can also serve as autophagic substrates (188). </div></section><section id="Ceramideregulatesautophagyflux" type><h2 data-nested="1" id="preprints-h2-16"> Ceramide regulates autophagy flux </h2> <div class="html-p">Sphingolipids are also involved in the regulation of transporters which direct nutrients into the cell. These lipids are important in autophagic flux (144, 189) however, studies on their exact mechanism of actions are limited. As mentioned earlier, autophagosome fuses with lysosome to form autolysosome, thereby degrading the proteins and organelles via the acidic hydrolases in the lysosomes. Interestingly, it has been shown that the efficiency of autophagosome-lysosome fusion depends on the lipid composition in the cell such as the ceramide levels (190). Moreover, it has previously been reported that myristate enhances the autophagic flux in cardiomyocytes which is dependent on C14-ceramide and CerS5. This indicates that ceramide plays a role in the modulation of autophagic flux (189). </div></section><section id="CytoprotectiveautophagyinductionbyCerSandceramide" type><h2 data-nested="1" id="preprints-h2-17"> Cytoprotective autophagy induction by CerS and ceramide</h2> <div class="html-p">Ceramides, and in particular long chain ceramides, are involved in regulating the cell death signaling (191). Ceramides can however trigger cytoprotective autophagy to inhibit cell death under certain conditions (192). Ceramide is involved in the down regulation of amino acid and nutrient transporters. This results in starvation which triggers survival autophagy through activating AMPK and then inhibition of mTOR signaling (193, 194). Changes in the nutrient transporters’ expression impacts cell growth and survival because these transporters regulate fuel for the cell. Moreover, survival autophagy is decreased upon downregulation of CerS2 that alters normal ceramide trafficking in the ER. This leads to the accumulation of long chain ceramides and IRE1 activation, thereby inhibiting cell death induction (152). Guenther <span class="html-italic">et al</span>. showed that C2-ceramide led to downregulation of nutrient transporters and consequently restricted the levels of nutrients in the cell leading to cell starvation and cell death (144). C2-ceramide also induced cytoprotective autophagy to inhibit cell death since autophagy inhibition by chloroquine sensitized cells to ceramide (144). In another study it was found that CerS2 downregulation led to no remarkable reduction of very long chain ceramide such as C24 ceramide. However, it increased the levels of long chain ceramide in such as C14 or C16-ceramide (~3-fold) (152). Also, a report showed that accumulation of long chain ceramide induced autophagy but not apoptosis in neuroblastoma cells (SMS-KCNR) (152). From a mechanistic standpoint, downregulation of CerS2 induced the cytoprotective autophagy and UPR. This led to the IRE1 activation which prevented the cell death induction (152). Moreover, vorinostat and sorafenib, two chemotherapeutic agents, have the ability to induce the CD95 activation through via acid sphingomyelinase activation and synthesis of C12, C22 and C26-ceramide (195). C14 and C16 ceramide activated CD95 triggered autophagy which was dependent to PERK. This indicated the cytoprotective effects since ATG5 downregulation increased the lethal effects of sorafenib and vorinostat in HEPG2 cells (195). Some studies have found that dehydroceramide (DHC) could induce protective autophagy, however its exact role is not fully elucidated (196-199). It was shown that XM462 (DHC desaturase inhibitor) delays G1/S transition in the cell cycle by ER stress activation and autophagy induction in HCG27 cells (gastric carcinoma) (196). Also, the inhibition of XM462-induced autophagy leads to a remarkable decrease in cell viability, emphasizing the role of DHC-induced autophagy in promoting cell survival (196). Interestingly, studies have shown that cytoprotective autophagy could be connected to apoptosis. It has been shown that caspases can regulate the autophagy-apoptosis crosstalk (200). Upon activation, caspases can cleave important autophagic proteins like Atg3, Atg4D, Atg5, Atg7, Beclin-1, and p62 leading to their inactivation. (201-205).It was also found that caspase-9 binds Atg7, promoting the lipidation of LC3B-I and formation of LC3B-II. This increases the autophagy activity. On the other hand, interaction between caspase-9 and Atg7 inhibits caspase-9 recruitment to the apoptosome. This inhibits caspase-9 activation and thus apoptosis (94). It was reported that in MCF-7 breast cancer cells caspase-9 knockout inhibits autophagic flux and promotes apoptosis via inhibition of cytoprotective autophagy (206). These finding highlight the intricate interconnection between autophagy and apoptosis. </div></section><section id="LethalautophagyinductionbyCerSandceramide" type><h2 data-nested="1" id="preprints-h2-18"> Lethal autophagy induction by CerS and ceramide:</h2> <div class="html-p">The role of ceramides in inducing apoptosis is well-known. Ceramides can induce apoptosis in response to different stimuli such as death receptor ligation, hypoxia, growth factor withdrawal, and chemotherapeutic drugs (144). Various studies have established the critical role of ceramides in regulation of lethal autophagy, however the exact mechanisms are still not fully understood. Ceramide triggers lethal autophagy through its effect on the Beclin1 expression. In fact, exogenous C2-ceramide enhances the expression of Beclin1 followed by induction of lethal autophagy in HT-29 colon cancer cells (143). This effect was inhibited when the <span class="html-italic">de novo</span> ceramide synthesis was inhibited by myriocin, suggesting the observed effects are due to C2-ceramide conversion to long chain ceramide (143). Other findings have shown that the mechanism by which C2-ceramide enhances the expression of Becloin1 is through JNK activation. JNK subsequently activates c-Jun which is a transcription factor capable of regulating Beclin1 expression (146). Additionally, chemotherapeutic drugs increase the ceramide synthesis which in turn enhances the expression of Beclin1 and therefore lethal autophagy (207). Other drugs can also result in an increase in the synthesis of ceramides. It was reported that cannabinoids trigger the production of ceramide leading to mTOR inhibition and lethal autophagy in human glioma cells (208).</div> <div class="html-p">Mitophagy is a selective autophagy that targets and removes damaged mitochondria. Mitophagy is therefore critical for the cell to maintain the proper homeostasis. Mitophagy involves two main steps; first the activation of general autophagy and second the selective targeting of the damaged mitochondria via different mediators (209). </div> <div class="html-p">Mitophagy plays an important role in tumor suppression via lethal mitophagy. Lethal mitophagy is defined as the process through which mitochondria are eliminated to the extent that cell undergoes cell death independent of the apoptosic pathway. Prolonged mitophagy results in caspase-dependent apoptosis via release of cathepsin proteases from lysosomes into the cytosol (210, 211). Lethal mitophagy is also induced by CerS1 (and also its product C18-ceramide) and is not dependent on Bax, Bak and caspase 3. It was reported that C18-ceramide synthesized by CerS1 was accumulated on the outer mitochondrial membrane. The exogenous C18-pyridinium ceramide was also localized on the outer mitochondrial membrane due to the pyridinium positive charge. This accumulated C18-ceramide interacts with LC3B-II on the forming autophagosmoe thereby facilitating the engulfment of the mitochondria into the autophagosome (212).</div></section><section id="RoleofCerSandCeramidesinRegulationofAutophagyinCancer" type><h2 data-nested="1" id="preprints-h2-19"> Role of CerS and Ceramides in Regulation of Autophagy in Cancer </h2> <div class="html-p">CerS and Ceramides have been implicated in the pathogenesis of various cancers due to their regulatory role in autophagy. Recent reports demonstrated that under starvation condition, Bcl-2 expression inhibits autophagy (13), while C2 and C6-ceramide could trigger autophagy in HT-29 colon carcinoma cell line (8). In fact, C2-ceramide increased the BNIP3 accumulation (213) which induced autophagy via interfering with the Beclin1:Bcl2 complex and dissociating Beclin1 (151). The Beclin1:Bcl-2 dissociation is independent of Bcl-2 phosphorylation (214). Therefore, there could be two mechanisms through which ceramide dissociates this complex: 1) JNK1 activation and subsequent Bcl2 phosphorylation or 2) BNIP3 accumulation on mitochondria which interferes with the Beclin1:Bcl2 complex and dissociates Beclin1. It was previously shown that treatment of human HNSCC cells (UM-SCC 22A) with CerS1-mediated generation of C18-ceramide and C18-pyridinium-ceramide induced lethal autophagy was independent of apoptosis (212). The lethal autophagy induced by C18-ceramide was modulated by LC3B-II followed by the selective engulfment of mitochondria via the interaction between ceramide and LC3B-II (212). Dbaibo <span class="html-italic">et al</span>. reported that arsenic trioxide (As2O3) triggered cytotoxic accumulation of overall ceramide in leukemia cells (HuT-102, C91-Pl and MT-2 cells) by inhibiting the activity of GluCeramide synthase (215). Additionally, As2O3 induced both apoptosis and autophagic cell death in these cells. The lethal autophagy was associated with an increase in the Beclin1 expression. Also, this lethal autophagy was inhibited when cells were treated with 3-MA (216). C2-ceramide triggers lethal autophagy (LC3B-II lipidation, formation of autophagosomes, and acidic lysosomes) in U373-MG and T98G cells (malignant glioma) (213). It was found that the mechanism involved was the reduction of mitochondrial membrane potential and BNIP3 activation by C2- ceramide (213). Moreover, the lethal autophagy was mediated by C2-ceramide and triggers the activation of c-Jun by JNK which increases the expression of Beclin-1 in human nasopharyngeal carcinoma (CNE2) and hepatocellular carcinoma (Hep3B) cell lines (146). Treatment of cells with SP600125 (JNK inhibitor) or Beclin1 knockdown by siRNA rescued these cancer cells from C2-ceramide-induced lethal autophagy (146). Also, in leukemia cells (HL-60) and Chinese hamster ovary cells (CHO) ceramide activated protein phosphatases (CAPPs) inhibit mTOR which induces lethal autophagy. However, S1P induces mTOR thereby suppressing lethal autophagy in these cells (217). In another study, it was shown that overexpression of CerS1 triggers lethal autophagy in brain cancer cells (U251 and A172) (204). LC3B-I to LC3B-II conversion and p62 degradation indicated autophagy induction in both cells. CerS1 overexpression and exogenous C18-ceramide greatly enhanced the occurrence of LC3 punctate and formation of autophagosomes in both cells. Additionally, CerS1 induced autophagy via inhibiting the PI3K/AKT pathway in these cells (218). </div> <div class="html-p">A role for CerS has also been described on the outcome of patients with cancer via the regulation of autophagy. The results from a study by Hartmann <span class="html-italic">et al.</span> displayed a correlation between strong CerS5 staining and poor prognosis in colorectal patients. Consistent with this observation, patients with a weak CerS5 staining had a better prognosis. These findings highlight that overexpression of CerS5 is connected to a more aggressive cancer that could be modulated through ceramide levels by currently unknown mechanisms. Changes in the CerS5 expression can interfere with the ceramides balance in colon cancer and therefore promote cancer progression (219). In this study, the proteomic network analysis showed a shift from apoptosis (patients with CerS5 low expression) to autophagy (patients with CerS5 high expression), indicating an association between high CerS5 expression and poor survival (220). Altogether these findings show that altering the ceramide-mediated apoptosis and autophagy activation in patients with high CerS5 expression could possibly be responsible for the link between strong CerS5 expression and poor survival (220). <a href="#preprints-67418-t002" class="html-table">Table 2</a> summarizes the roles of various molecules in the ceramide metabolism pathway in regulation of autophagy in different types of cancer discussed in this section.</div></section><section id="OverallViewonLipidAnalysis" type><h2 data-nested="1" id="preprints-h2-20"> Overall View on Lipid Analysis</h2> <div class="html-p">Over the last decades, the detection of early cancer stages has been the focus of intensive investigation in medical research, especially non-invasive cancer screening methods based on blood analysis (225). Lipids serve a plethora of roles in human metabolism (226), acting as: cell membrane constituents, signaling molecules, energy supply, and energy storage. Changes in lipid concentrations have been reported in various types of cancer (227-233) and lipid metabolic reprogramming has become a hallmark of cancer (228, 233). However, despite the evidence highlighting its relevance to cancer, lipid metabolism remains difficult to analyze due to the lack of standard systematic quantitation methods, lipidome nomenclature, and analysis applied to cancer research (234-236). </div> <div class="html-p">Lipidomics is the study that statistically profiles and quantitates lipid molecules on a large scale (237). The development of lipidomics followed the advances in techniques such as: mass spectrometry (MS), nuclear magnetic resonance spectrometry (NMR), and chromatography. Mass spectrometry uses mass spectrometers to study the mass-to-charge (m/z) ratio of single analytes allowing structural elucidation and quantitation, which includes steps of molecular ions and related fragment generation, ion separation based on their m/z, signal detection, and the intensity of individual ion measurement. Typically, a mass spectrometer consists of an ion source, a mass analyzer system, a detector, and a data processing system. Among the lipid separation methods, liquid high-performance chromatography (HPLC), or simply LC, combined with mass spectrometry (MS), is the primary choice for lipidomics studies due to the sensitivity and selectivity of the analysis (238). MS-based lipidomics can be categorized as non-targeting or targeted lipidomics. The former identifies and quantifies all detected lipids, whereas the latter focuses only on specified lipid classes (239). Notably, the HPLC-MS technique has been reported back to the 1970s (240, 241) as a powerful method for sphingolipids, such as ceramides, detection.. Additionally, numerous other studies have validated this method of ceramides detection over the last decades for humans, animals and plants (242-250). </div> <div class="html-p">Prior to LC-MS analysis, biological samples are prepared through different methods, including liquid-liquid extraction, organic solvent precipitation, and solid phase extraction, separating cellular or fluid lipids from the other constituents and preserving these lipids for further analyses (251). Most procedures extract high solubility lipids in organic solvents (252), such as Folch, Bligh and Dyer, methyl tert-butyl ether, and Butanol:Methanol. </div> <div class="html-p">Once lipids are extracted, samples are ready to undergo mass spectrometry lipid separation (253). A typical workflow of lipidomics analysis of biological samples consists of sample collection and storage, homogenization, internal standard addition for calibration, analysis of lipids with and without separation, data processing and lipid identification, and biomedical application, summarized in (<a href="#preprints-67418-f004" class="html-fig">Figure 4</a>).</div> <div class="html-p">The generation of lipid databases and the tools to cross-compare them with experimentally obtained lipidomics data has been an important development. Examples are LipidMaps, LipidBank, LipidHome, LipidBlast, and LipidSearch (254). Moreover, comprehensive mass spectrometry determination of a great range of serum lipids can reveal significant differences between studied groups of diseases, such as cancer, where selected lipid species may indicate potential prognostic biomarkers. For instance, a study by Wolrab et al., 2022, conducted lipidomic profiling of serum to screen for pancreatic cancer in 830 samples. They demonstrated differences in serum versus plasma lipidome concentrations between samples of pancreatic cancer patients and healthy controls using mass spectrometry (MS) based approaches, followed by statistical analysis. They concluded that lipid concentrations in serum were mildly higher than in plasma, yielding an enhanced sensitivity (255).</div> <div class="html-p">After lipidomics and identification of key targets, the next critical step in modern bioinformatics is the integration of systems biology for proteomics, genomics, regulatory genomics, and metabolomics data to provide a further systems-level overview of phenotypic responses of living systems to stimuli, (<a href="#preprints-67418-f005" class="html-fig">Figure 5</a>)<b>.</b> The conventional statistical methods can be applied to each type of data, such as gene expression, proteomics or lipidomics; however, the integration across these data types, to provide mechanistically meaningful models, remains challenging (256).</div> <div class="html-p">To overcome this integration challenge, a new pipeline strategy developed by Lima et al., 2022, could be an interesting alternative method to validate the altered lipid levels in the samples under study. For example, the automatic text-mining feature of VOSviewer can be used to create coincidence networks of terms associated with the disease of interest, e.g., prostate cancer. These results will be complemented with DisGENET data, a repository of disease associations, and a recent bioinformatics analysis integrating all differentially expressed lipids identified in tumor tissue and serum samples from patients to improve VOSviewer's limited term selection. Later, the results can be integrated with gene expression data from the Gene Expression Omnibus database to correlate gene and protein levels (257). Additional lipid tools and resources for bioinformatic analysis are listed in <a href="#preprints-67418-t003" class="html-table">Table 3</a>.</div> <div class="html-p">Despite the technological advances in lipidomics, there are still limitations to this approach. Not only does the diversity and structural complexity of many lipidomes remain a challenge, but understanding, interpreting, and integrating large data sets in conjunction with classical toxicological parameters is a major task. An integrative approach is needed to understand the principles underlying metabolic regulation of a system and how their combined interactions, in conjunction with variations in clinical phenotype, lead to pathophysiology. This challenge requires new data exploration strategies such as analysis workflows, statistical and computational algorithms for data integration, filtering, and network analysis, if we are to be able to truly transform the large multivariate data collected in such metabolomic experiments into new biological insights.</div> <div class="html-p">Artificial intelligence (AI) methods are advancing rapidly, and breakthrough technologies are changing the landscape of health research with high diagnostic and prognostic value. Machine learning methods (also referred to as complex AI), supervised and unsupervised, are used by AI systems to account for complex interactions, either by collecting input data, including biofluids and tissues, to predict output values based on new input samples, or by finding underlying patterns in an unlabeled data set to identify subclusters and outliers in the data.</div> <div class="html-p">Although AI methods have been well described in other areas of healthcare, there is little information on the value of using AI methods to understand the complex nature of phlebotomy. Machine learning has enabled the discovery of more robust biomarkers that have been approved by the Food and Drug Administration (FDA) to guide treatment, which can be very valuable in disease. Additionally, biomarkers serve as powerful clinical predictors that can be used to individualize treatment options for patients to achieve desired outcomes. The machine learning approach called Random Forest (RF) can integrate multiple data types and combine classical clinical chemistry and toxicology test results with multivariate metabolomic and lipidomic data. Several authors have previously adapted RF methods for data integration (also referred to as data fusion) that developed and evaluated a fuzzy logic combination with RF to prioritize the discriminative features of gene expression data.</div> <div class="html-p">In summary, to move towards standardization, minimum requirements for lipid studies should become routine. As described by McDonald et al., 2022, the nine major categories for conducting lipidomics research are 1) overall study design, 2) pre-analytics, 3) lipid extraction, 4) analytical platform, 5) lipid identification, 6) lipid quantification, 7) quality control, 8) method validation, and 9) data reporting (235). </div></section><section id="ConclusionandFutureDirections" type><h2 data-nested="1" id="preprints-h2-21"> Conclusion and Future Directions</h2> <div class="html-p">As we discussed ceramides may play essential roles response to different cancer therapy strategies through apoptosis and autophagy pathways, therefore targeting ceramides and their biosynthesis pathway could be beneficial for developing new cancer therapy methods. It can be seen that the development of new therapeutics that interact with novel pharmacological targets is urgently needed. All anti-cancer drugs can be classified into two major categories: small molecules and monoclonal antibodies (258). Small-molecule drugs are preferable in drug development compared to antibodies due to better pharmacokinetic properties, lower preclinical and clinical costs, and large-scale production and purification (259, 260).</div> <div class="html-p">Modulation of the sphingolipid/ceramide-controlled apoptosis with small molecules represents an important tool and addition to the current anticancer therapies. Currently, there have been only five clinical trials of different phases that involved ceramide as the active drug for the treatment of various cancers (<a href="#preprints-67418-t004" class="html-table">Table 4</a>). However, none of these studies explore the new small molecules as modulators of ceramide pathways. </div> <div class="html-p">The biosynthesis of ceramides has been done via two pathways: de novo sphingolipid pathway and sphingolipid-salvage pathway (<a href="#preprints-67418-f006" class="html-fig">Figure 6</a>) (261). Several different CerS have been identified in both pathways, and modulation of these enzymes is reported in many mechanisms including apoptosis and protein kinase inhibition (262-264). Several studies showed that decreased levels of ceramides are reported in many malignancies and tumor progression, while ceramide levels are observed to be increased by chemotherapies (265-268). Additionly, several tyrosine kinase inhibitors (TKI) increase production of CerS on a nuclear level, which in turn leads to upregulation of ceramide biosynthesis (269, 270). Recently it has been reported that the combination of a novel sphingosine kinase 2 inhibitor ABC294640, and TKI displays synergistic anti-cancer effects in multiple myeloma and cholangiocarcinoma (271, 272). Thus, the small molecules that can modulate ceramide pathways represent valid targets for anticancer drug discovery, especially in combination with currently available TKI-based anti-cancer therapies (<a href="#preprints-67418-f007" class="html-fig">Figure 7</a>) since previous studies suggests that there may be functional crosstalk between inhibiting tyrosine kinases overexpressed in certain tumors and dysregulation of ceramide synthesis in malignancies. </div> <div class="html-p">It should be noted, however, that the co-administration of a tyrosine kinase inhibitor and a ceramide modulator would have many drawbacks, including the possibility of drug-drug interactions <span class="html-italic">in vivo</span> which complicates preclinical/clinical studies and the drug development process in the long term. One novel drug design strategy is the use of multi-target designed ligands (MTDLs), i.e. a polypharmacology approach. MTDLs are small molecules designed to simultaneously interact with multiple biological targets relevant for a given pathology (273). Furthermore, they have several advantages including a potential for higher efficacy and fewer side-effects compared to cocktail drugs and could avoid unpredictable pharmacokinetic and pharmacodynamics relationships (274). To develop new anticancer MTDL therapeutics, the first step will be to determine the similarities and potential overlap in the structures of already existing TKIs and ceramide modulators for targets of interest (<a href="#preprints-67418-f008" class="html-fig">Figure 8</a>). In the case that the target does not have any known modulators, drug design can be achieved using knowledge of characterized active and/or allosteric binding sites by X-ray crystallography in combination with virtual-ligand screening (VLS). A general scaffold, or core of a chemical structure, or even particular chemical groups can be used for this purpose. Once the specific structures important for the activity at the targets of interests are identified, the pharmacophore - the area responsible for the biological activity for these targets, can be defined. Next, the pharmacophores can be combined in three different fashions; they can be linked, fused or merged (275). Linked MTDLs are designed by simple linking (anchoring) of two or more individual pharmacophores via a linking group. Fused MTDLs are similar, but the pharmacophores are connected directly, without a linking group. Both, linked and fused types of multitarget compounds usually have molecular weights above 500 and increased lipophilicity, which are important for drug design but could lead to poor solubility and permeability according to Lipinski Rule of Five.(276) However, these two types of conjugated pharmacophores are a valuable tool in the early structure-activity relationship studies and the discovery of the multitarget activity. Merged pharmacophores, on the other hand, are of the greatest interest in the multitarget drug discovery and there are many successful applications of this method reported.(277-279) </div> <div class="html-p">Here we propose that the key pharmacophoric elements required to interact with each target of interest are combined (merged) into one single pharmacophore. Once pharmacophores are identified and combined, the next step is to preform extensive SAR studies in order to determine the best possible groups that can be tolerated on the particular pharmacophores. Next, the standard structure-based drug design approach can be followed: a) Using computer drug design tools, several additional compounds that could interact with the amino acid residues present in the binding site can be designed; b) Synthesize the second generation of lead compound(s) and test them for activity; c) Crystallographic determination of the lead compound with both targets which should identify the actual binding interactions and provide better insight in the other possible interactions. d) Finally, another more specific SAR study that will optimize the drug-target interactions should be performed. </div> <div class="html-p">In summary, one new rational approach is to design a single drug that would be able to interact simultaneously as an inhibitor of specific protein kinases and a modulator of certain ceramides involved in the cancer pathology. Based on the previous studies mentioned above, the novel drug should target the allosteric-binding site of the protein kinases, since the gene sequences of the allosteric sites consist of fewer homologues than those of the active sites, these drugs will be more specific. One way to identify the ceramides target involved in the cancer pathogenesis is to perform lipidomics analysis and compare lipid distribution between cancer and wild-type cells, i.e., the up- or down-regulated lipids that could represent a novel target for the MTDLs.</div></section> <section class="html-notes"><h2 id="preprints-h2-22">Author Contributions</h2> <div class="html-p">Javad Alizadeh, Shahla Shojaei, Joadi Jacobs and Shahrokh Lorzadeh prepared the draft of general ceramide synthases, ceramides and apoptosis and autophagy. Simone C da Silva Rosa, Amir Ravandi, and Rui Vitorino participated in preparation of lipid analysis and lipidomic section. Xiaohui Weng, and Stevan Pecic prepared the drug development part. Saeid Ghavami designed and lead the whole project, and finalize the whole manuscript. .</div></section><section id="html-references_list"><h2 id="preprints-h2-23">References</h2> <ol class="html-xxx"> <li id="B1-preprints-67418" class="html-x" data-content="1.">Field BC, Gordillo R, Scherer PE. The Role of Ceramides in Diabetes and Cardiovascular Disease Regulation of Ceramides by Adipokines. Frontiers in Endocrinology. 2020;11. [<a href="https://doi.org/10.3389/fendo.2020.569250" class="cross-ref" target="_blank" rel="noopener noreferrer">CrossRef</a>]</li> <li id="B2-preprints-67418" class="html-x" data-content="2.">Levy M, Futerman AH. Mammalian ceramide synthases. IUBMB Life. 2010;62(5):347-56. 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[<a href="https://doi.org/10.1016/j.bmc.2021.116507" class="cross-ref" target="_blank" rel="noopener noreferrer">CrossRef</a>]</li> </ol></section><section id="FiguresandTables" type="display-objects"><div class="html-fig-wrap" id="preprints-67418-f001"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f001"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png" alt="Preprints 67418 g001" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f001"></a> </div> </div> <div class="html-fig_description"> <b>Figure 1.</b> Main metabolic pathways of ceramide metabolism. Three pathways help synthesize ceramide in the cell namely, sphingomyelin hydrolysis pathway, de novo pathway, and salvage pathway. De novo sphingolipid biosynthesis begins with the condensation of serine and palmitoyl-CoA, which then is catalyzed by serine palmitoyltransferase enzyme. Its product, 3-ketosphinganine, is reduced to sphinganine by 3-ketosphinganine reductase. Next, dihydroceramide synthases contribute in synthesis of dihydroceramides using sphinganine and fatty acyls, which are then reduced by dihydroceramide desaturase to produce ceramides with different acyl chain lengths. Ceramide is also synthesized by other metabolic pathways (salvage and sphingomyelin hydrolysis). The ceramide produced via these pathways will be used as a mediator in the regulation of subsequent downstream pathways (enzymes shown in red italics). <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f001"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f001"> <div class="html-caption"> <b>Figure 1.</b> Main metabolic pathways of ceramide metabolism. Three pathways help synthesize ceramide in the cell namely, sphingomyelin hydrolysis pathway, de novo pathway, and salvage pathway. De novo sphingolipid biosynthesis begins with the condensation of serine and palmitoyl-CoA, which then is catalyzed by serine palmitoyltransferase enzyme. Its product, 3-ketosphinganine, is reduced to sphinganine by 3-ketosphinganine reductase. Next, dihydroceramide synthases contribute in synthesis of dihydroceramides using sphinganine and fatty acyls, which are then reduced by dihydroceramide desaturase to produce ceramides with different acyl chain lengths. Ceramide is also synthesized by other metabolic pathways (salvage and sphingomyelin hydrolysis). The ceramide produced via these pathways will be used as a mediator in the regulation of subsequent downstream pathways (enzymes shown in red italics).</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png" alt="Preprints 67418 g001" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f002"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f002"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png" alt="Preprints 67418 g002" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f002"></a> </div> </div> <div class="html-fig_description"> <b>Figure 2.</b> Role of ceramide in regulation of apoptosis via different mechanisms. Figure shows how ceramides regulate the apoptosis via formation of ceramide channels and interaction with anti-apoptotic proteins like Bcl-xL and pro-apoptotic proteins such as Bax. Ceramides with various fatty acyl chain lengths can perforate into the mitochondrial outer membranes. These channels are layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure. Ceramide channels contribute to the permeabilization of the mitochondrial outer membrane. This leads to the release of pro-apoptotic proteins such as cytochrome c from the intermembrane space into the cytosol and thus apoptosis. Additionally, ceramides help in the oligomerization of Bax molecules during apoptosis. Furthermore, ceramide can influence the Bcl2 phosphorylation and therefore its anti-apoptotic function. Ceramide activates mitochondrial protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) that induces Bcl2 dephosphorylation and therefore ceramide-induced apoptosis. <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f002"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f002"> <div class="html-caption"> <b>Figure 2.</b> Role of ceramide in regulation of apoptosis via different mechanisms. Figure shows how ceramides regulate the apoptosis via formation of ceramide channels and interaction with anti-apoptotic proteins like Bcl-xL and pro-apoptotic proteins such as Bax. Ceramides with various fatty acyl chain lengths can perforate into the mitochondrial outer membranes. These channels are layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure. Ceramide channels contribute to the permeabilization of the mitochondrial outer membrane. This leads to the release of pro-apoptotic proteins such as cytochrome c from the intermembrane space into the cytosol and thus apoptosis. Additionally, ceramides help in the oligomerization of Bax molecules during apoptosis. Furthermore, ceramide can influence the Bcl2 phosphorylation and therefore its anti-apoptotic function. Ceramide activates mitochondrial protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) that induces Bcl2 dephosphorylation and therefore ceramide-induced apoptosis.</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png" alt="Preprints 67418 g002" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f003"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f003"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png" alt="Preprints 67418 g003" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f003"></a> </div> </div> <div class="html-fig_description"> <b>Figure 3.</b> Role of ceramide in regulation of autophagy by different mechanisms. Ceramide activates JNK which leads to the phosphorylation of BCL2 resulting in the dissociation of Beclin1 from the Beclin1-Bcl2 complex. Beclin1 then can participate in the formation of autophagosomes. Also, localized ceramide on the outer mitochondrial membrane can act as a LC3II-receptor, thereby bringing the mitochondria into the forming autophagosome. Figure also shows the cross talk between ER and autophagy pathway. Ceramide activates the ATF6 in the ER membrane which subsequently activates CHOP. Activation of CHOP inhibits the phosphorylation of BCL2 by JNK. . <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f003"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f003"> <div class="html-caption"> <b>Figure 3.</b> Role of ceramide in regulation of autophagy by different mechanisms. Ceramide activates JNK which leads to the phosphorylation of BCL2 resulting in the dissociation of Beclin1 from the Beclin1-Bcl2 complex. Beclin1 then can participate in the formation of autophagosomes. Also, localized ceramide on the outer mitochondrial membrane can act as a LC3II-receptor, thereby bringing the mitochondria into the forming autophagosome. Figure also shows the cross talk between ER and autophagy pathway. Ceramide activates the ATF6 in the ER membrane which subsequently activates CHOP. Activation of CHOP inhibits the phosphorylation of BCL2 by JNK. .</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png" alt="Preprints 67418 g003" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f004"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f004"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png" alt="Preprints 67418 g004" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f004"></a> </div> </div> <div class="html-fig_description"> <b>Figure 4.</b> Major steps in lipid preparation and analysis involve 1) sample collection (serum, plasma, urine, cell, organ/tissue); 2) lipid extraction (folch method, blingh-dyer method, MTBE method, BUME method); 3) Lipid separation (TLC, GC, LC, SFC); 4) mass spectrometry data acquisition (MS combined with chromatography, shot gun MS, MS imaging); 5) data analysis (identification, quantification, pathway analysis); 6) interpretation (biomarkers, therapeutic targets). <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f004"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f004"> <div class="html-caption"> <b>Figure 4.</b> Major steps in lipid preparation and analysis involve 1) sample collection (serum, plasma, urine, cell, organ/tissue); 2) lipid extraction (folch method, blingh-dyer method, MTBE method, BUME method); 3) Lipid separation (TLC, GC, LC, SFC); 4) mass spectrometry data acquisition (MS combined with chromatography, shot gun MS, MS imaging); 5) data analysis (identification, quantification, pathway analysis); 6) interpretation (biomarkers, therapeutic targets).</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png" alt="Preprints 67418 g004" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f005"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f005"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png" alt="Preprints 67418 g005" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f005"></a> </div> </div> <div class="html-fig_description"> <b>Figure 5.</b> Bioinformatics guide to lipidomics integrative analysis. <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f005"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f005"> <div class="html-caption"> <b>Figure 5.</b> Bioinformatics guide to lipidomics integrative analysis.</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png" alt="Preprints 67418 g005" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f007"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f007"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png" alt="Preprints 67418 g006" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f007"></a> </div> </div> <div class="html-fig_description"> <b>Figure 7.</b> Drug design strategies summary and potential binding sites on Bcr-Abl tyrosine kinase. Tyrosine kinases use ATP as a source of phosphate group for the phosphorylation reaction of the phenol groups on the tyrosine residues. A) Substrate (orange) binding to substrate binding site. Huang et al. used peptide inhibitors that binds to the substrate-binding region and were able to inhibit in vitro Bcr-Abl kinase in the micromolar range.<sup>Ref</sup> However, peptides have several disadvantages to be used as the therapeutics in the clinical settings, and the small molecule drug that binds and significantly inhibits substrate-based region for Bcr-Abl kinase has not yet been reported. B) The binding site for ATP is usually located close to the substrate binding site. Imatinib (shown in red) binds to ATP-binding region. A known T315I mutation, located in ATP-binding site, causes a drug resistance to imatinib, and makes this binding site less attractive target for drug design. C) Allosteric-binding site with asciminib shown in blue. The first discovered allosteric site on Bcr-Abl has been named myristoyl-binding region, since myristoyl acid binds in this binding region and produce inactivation of the kinase. This highly hydrophobic pocket represents a novel target for the site-specific drug design strategy. More drug-like small molecules that could mimic myristate could theoretically bind there and inhibit the kinase. D) A potential, novel dual inhibitor strategy: substrate-binding ligand (L1) is anchored to the ATP-binding ligand (L2) – a potential small molecule drug could bind simultaneously to the allosteric site and ATP-binding region. <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f007"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f007"> <div class="html-caption"> <b>Figure 7.</b> Drug design strategies summary and potential binding sites on Bcr-Abl tyrosine kinase. Tyrosine kinases use ATP as a source of phosphate group for the phosphorylation reaction of the phenol groups on the tyrosine residues. A) Substrate (orange) binding to substrate binding site. Huang et al. used peptide inhibitors that binds to the substrate-binding region and were able to inhibit in vitro Bcr-Abl kinase in the micromolar range.<sup>Ref</sup> However, peptides have several disadvantages to be used as the therapeutics in the clinical settings, and the small molecule drug that binds and significantly inhibits substrate-based region for Bcr-Abl kinase has not yet been reported. B) The binding site for ATP is usually located close to the substrate binding site. Imatinib (shown in red) binds to ATP-binding region. A known T315I mutation, located in ATP-binding site, causes a drug resistance to imatinib, and makes this binding site less attractive target for drug design. C) Allosteric-binding site with asciminib shown in blue. The first discovered allosteric site on Bcr-Abl has been named myristoyl-binding region, since myristoyl acid binds in this binding region and produce inactivation of the kinase. This highly hydrophobic pocket represents a novel target for the site-specific drug design strategy. More drug-like small molecules that could mimic myristate could theoretically bind there and inhibit the kinase. D) A potential, novel dual inhibitor strategy: substrate-binding ligand (L1) is anchored to the ATP-binding ligand (L2) – a potential small molecule drug could bind simultaneously to the allosteric site and ATP-binding region.</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png" alt="Preprints 67418 g006" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f006"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f006"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png" alt="Preprints 67418 g007" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f006"></a> </div> </div> <div class="html-fig_description"> <b>Figure 6.</b> De novo and Salvage pathways of ceramide synthesis. Enzyme ceramide synthase (CerS) is involved in both pathways and represents a valid target for drug design of ceramide synthesis modulators. <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f006"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f006"> <div class="html-caption"> <b>Figure 6.</b> De novo and Salvage pathways of ceramide synthesis. Enzyme ceramide synthase (CerS) is involved in both pathways and represents a valid target for drug design of ceramide synthesis modulators.</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png" alt="Preprints 67418 g007" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png"></div> </div> <div class="html-fig-wrap" id="preprints-67418-f008"> <div class="html-fig_img"> <div class="html-figpopup html-figpopup-link" href="#fig_body_display_preprints-67418-f008"> <img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png" alt="Preprints 67418 g008" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png"> <a class="html-expand html-figpopup" href="#fig_body_display_preprints-67418-f008"></a> </div> </div> <div class="html-fig_description"> <b>Figure 8.</b> Polypharmacological approach. Two or more biological targets are selected, and small molecule modulators are identified. Upon determining the pharmacophores, the multi-target designed ligands (MTDLs) are created by linking, fusing or merging pharmacophores. The merged pharmacophores are of the particular interest in the drug discovery due to several pharmacokinetic and pharmacodynamic advantage properties. Once MTDL is designed, synthesized and preliminary structure-activity relationship study is established, the computer-based drug design should follow up in order to create the second generation of lead compounds. Next should follow the crystallographic determination of the lead compound with both targets to better understand the binding interactions of MTDLs with both targets. More specific SAR study that will optimize the drug-target interactions should follow up. . <!-- <p><a class="html-figpopup" href="#fig_body_display_preprints-67418-f008"> Click here to enlarge figure </a></p> --> </div> </div> <div class="html-fig_show mfp-hide" id="fig_body_display_preprints-67418-f008"> <div class="html-caption"> <b>Figure 8.</b> Polypharmacological approach. Two or more biological targets are selected, and small molecule modulators are identified. Upon determining the pharmacophores, the multi-target designed ligands (MTDLs) are created by linking, fusing or merging pharmacophores. The merged pharmacophores are of the particular interest in the drug discovery due to several pharmacokinetic and pharmacodynamic advantage properties. Once MTDL is designed, synthesized and preliminary structure-activity relationship study is established, the computer-based drug design should follow up in order to create the second generation of lead compounds. Next should follow the crystallographic determination of the lead compound with both targets to better understand the binding interactions of MTDLs with both targets. More specific SAR study that will optimize the drug-target interactions should follow up. .</div> <div class="html-img"><img data-large="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png" data-original="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png" alt="Preprints 67418 g008" src="https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png"></div> </div> <div class="html-table-wrap" id="preprints-67418-t001"> <div class="html-table_wrap_td"> <div class="html-tablepopup html-tablepopup-link" href="#table_body_display_preprints-67418-t001"> <img src="https://pub.mdpi-res.com/img/table.png"> <a class="html-expand html-tablepopup" href="#table_body_display_preprints-67418-t001"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 1.</b> Different CerS synthesize ceramides with various acyl chain lengths. </div> </div> <div class="html-table_show mfp-hide " id="table_body_display_preprints-67418-t001"> <div class="html-caption"> <b>Table 1.</b> Different CerS synthesize ceramides with various acyl chain lengths.</div> <table> <thead><tr> <th align="left" valign="top" style="border:solid thin" class="html-align-left">CerS</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Synthesized ceramide</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Ref</th> </tr></thead> <tbody> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C18</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(5)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS2</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C20, <br>C22, <br>C24, <br>C26</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(6)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS3</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C22, <br>C24, <br>C26</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(7)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS4</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C18, <br>C20</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(8)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS5</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C16</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(9)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CerS6</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C14, <br>C16</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(10)</td> </tr> </tbody> </table> </div> <div class="html-table-wrap" id="preprints-67418-t002"> <div class="html-table_wrap_td"> <div class="html-tablepopup html-tablepopup-link" href="#table_body_display_preprints-67418-t002"> <img src="https://pub.mdpi-res.com/img/table.png"> <a class="html-expand html-tablepopup" href="#table_body_display_preprints-67418-t002"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 2.</b> Summary of the role of ceramides and enzymes involved in ceramide metabolism in autophagy regulation in different cancers. </div> </div> <div class="html-table_show mfp-hide " id="table_body_display_preprints-67418-t002"> <div class="html-caption"> <b>Table 2.</b> Summary of the role of ceramides and enzymes involved in ceramide metabolism in autophagy regulation in different cancers.</div> <table> <thead><tr> <th align="left" valign="top" style="border:solid thin" class="html-align-left">Ceramide</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Mechanism of Action</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Effect on Autophagy</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Cancer Type</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">Ref</th> </tr></thead> <tbody> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C2-ceramide</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">BNIP3 accumulation, Beclin1:Bcl-2 dissociation</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Colon carcinoma cell line (HT-29)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(151, 213)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C18-ceramide </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">ceramide and LC3B-II interaction </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">HNSCC cells (UM-SCC 22A)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(212)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">As2O3 induced accumulation of overall ceramide </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">upregulation of Beclin-1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Leukemia cells (HuT-102, C91-Pl, MT-2)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(215)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C2-ceramide</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">mitochondrial membrane potential decrease, BNIP3 activation</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Glioma cells (U373-MG and T98G)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(213)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C2-ceramide</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">c-Jun activation through JNK signaling</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Nasopharyngeal carcinoma cells (CNE2), hepatocellular carcinoma cells (Hep3B)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(146)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">CAPPs (ceramide activated protein phosphatases)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Akt-mTOR pathway inhibition </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Leukemia cells (HL-60), Chinese hamster ovary cells (CHO)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(221)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">S1P</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Akt-mTOR pathway activation</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy inhibition</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Leukemia cells (HL-60), Chinese hamster ovary cells (CHO)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(221)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C6-ceramide </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">mitochondrial permeabilization</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Breast cancer cells (MCF-7)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(222)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">C18-ceramide</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">increased the formation of autophagosomes, PI3K/AKT pathway inhibition</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">brain cancer cells (U251 and A172)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(218)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">inhibition of SphK1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">ATG5 and Beclin-1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">HCT116 human colon cancer cells</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(223)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">inhibition of SphK2 by ABC294640</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">accumulation of intracellular ceramides</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">lethal autophagy induction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">herpes virus-related tumors </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">(224)</td> </tr> </tbody> </table> </div> <div class="html-table-wrap" id="preprints-67418-t003"> <div class="html-table_wrap_td"> <div class="html-tablepopup html-tablepopup-link" href="#table_body_display_preprints-67418-t003"> <img src="https://pub.mdpi-res.com/img/table.png"> <a class="html-expand html-tablepopup" href="#table_body_display_preprints-67418-t003"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 3.</b> Publicly available lipid tools and resources for bioinformatic analysis. </div> </div> <div class="html-table_show mfp-hide " id="table_body_display_preprints-67418-t003"> <div class="html-caption"> <b>Table 3.</b> Publicly available lipid tools and resources for bioinformatic analysis.</div> <table> <thead><tr> <th align="left" valign="top" style="border:solid thin;background:#D9D9D9" class="html-align-left">Name</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin;background:#D9D9D9" class="html-align-left">Description</th> <th align="left" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin;background:#D9D9D9" class="html-align-left">URL</th> </tr></thead> <tbody> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidMaps</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">The web portal gateway to Lipidomics resources; classification of biological lipids, dividing them into eight general categories</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://www.lipidmaps.org/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidFinder</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">An open-source Python workflow which searches several different databases to obtain putative identification of lipids</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://www.lipidmaps.org/resources/tools/lipidfinder/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidSig</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Allows the exploration of the quality and the clustering of samples, correlation between lipids and samples, and the expression and composition of lipids</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">http://www.chenglab.cmu.edu.tw/lipidsig/Profiling/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidSuite</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Workflow for preprocessing, exploration, differential analysis, and enrichment of untargetted and targeted lipidomics</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://suite.lipidr.org/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidPedia</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Lipid encyclopedia; provides associated biomedical information through text-mining strategy in literatures</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://lipidpedia.cmdm.tw/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidBank</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">The official database of Japanese Conference on the Biochemistry of Lipids (JCBL)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://lipidbank.jp/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidHome</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Database of theoretical lipid structures derived from a seed set of lipid sub classes and some lipid chemical space constraints </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://apps.lifs.isas.de/lipidhome/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidBlast</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">In silico tandem mass spectrometry database for lipid identification</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://fiehnlab.ucdavis.edu/projects/lipidblast</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LipidMatch</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">An automated workflow for rule-based lipid identification using untargeted high-resolution tandem mass spectrometry data</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">http://secim.ufl.edu/secim-tools/lipidmatch/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">ONION</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Functional approach for integration of lipidomics and transcriptomics data</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://github.com/wjurkowski/ONION</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">LINT-Web</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Web-based Lipidomic data mining tool using intra-omic integrative correlation strategy</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">http://www.lintwebomics.info/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">MetaboAnalyst</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Platform dedicated for metabolomics data analysis via user-friendly, web-based interface.</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://www.metaboanalyst.ca/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">SwissTarget Prediction</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Estimate the most probable macromolecular targets of a small molecule, assumed as bioactive</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">http://www.swisstargetprediction.ch/predict.php</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">String</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Protein-Protein interaction networks functional enrichment analysis</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://string-db.org/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">Stitch</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Resource to explore known and predicted interactions of chemicals and proteins</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">http://stitch.embl.de/</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">DisGeNET</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Integrative database with human gene-disease associations (GDAs) and variant-disease associations (VDAs) from various repositories including Mendelian, complex and environmental diseases</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://www.disgenet.org/search</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" class="html-align-left">VosViewer</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Software tool for constructing and visualizing bibliometric networks</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">https://www.vosviewer.com/</td> </tr> </tbody> </table> </div> <div class="html-table-wrap" id="preprints-67418-t004"> <div class="html-table_wrap_td"> <div class="html-tablepopup html-tablepopup-link" href="#table_body_display_preprints-67418-t004"> <img src="https://pub.mdpi-res.com/img/table.png"> <a class="html-expand html-tablepopup" href="#table_body_display_preprints-67418-t004"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 4.</b> Studies in adults with ceramide as treatment for cancer. </div> </div> <div class="html-table_show mfp-hide " id="table_body_display_preprints-67418-t004"> <div class="html-caption"> <b>Table 4.</b> Studies in adults with ceramide as treatment for cancer.</div> <table> <tbody> <tr> <td align="center" valign="top" style="border:solid thin" class="html-align-center">#</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Status</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Title</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Conditions</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Drug(s) used</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Phase</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Eligible</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Location</td> <td align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-center">Reference (NCT)</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Completed</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Topical Ceramide Lipids As Treatment For Cutaneous Breast Cancer</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Breast cancer</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">• Drug: ceramide</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">2</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">≥ 18, female</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">9 states in USA</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NCT00008320</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">2</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Unknown</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C6 Ceramide NanoLiposome in Patients With Advanced Solid Tumors</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Cancer; carcinoma; solid tumors; tumor</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">• Drug: Ceramide NanoLiposome</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">≥ 18</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">3 states in USA</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NCT02834611</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">3</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Withdrawn</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Detection of Acid Sphingomyelinase/Ceramide Pathway Activation in Radiotherapy Patients Using Intravoxel Incoherent Motion (IVIM) Diffusion-weighted Magnetic Resonance Imaging and Serum Biomarkers</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Metastatic disease to bone; metastatic disease to soft tissue<br> </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">• Device: MRI with IVIM DW-MRI <br>• Other: Blood draw<br> </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">N/A</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">≥ 18</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NY, USA</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NCT02465723</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">4</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Not yet recruiting</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (RR-AML)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Acute Myeloid Leukemia, in Relapse Acute;<br>Myeloid Leukemia, Refractory<br> </td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">• Drug: Ceramide NanoLiposome (Ceraxa)</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">≥ 18</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">3 states in USA</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NCT04716452</td> </tr> <tr> <td align="left" valign="top" style="border-left:solid thin;border-bottom:solid thin;border-right:solid thin" class="html-align-left">5</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Completed</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Combination of Lenalidomide (Revlimid, LEN) and Autologous Mature Dendritic Cells Pulsed With α-galactosyl Ceramide (α-GalCer; KRN7000) in Myeloma</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">Myeloma</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">• Drug: Lenalidomide Biological: Monocyte derived DCs loaded with KRN7000</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">1</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">≥ 18</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">CT, USA</td> <td align="left" valign="top" style="border-bottom:solid thin;border-right:solid thin" class="html-align-left">NCT00698776</td> </tr> </tbody> </table> </div> </section><section class="html-fn_group"><table><tr id> <td></td> <td><div class="html-p"> <b>Disclaimer/Publisher’s Note:</b> The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). 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Stay engaged with research that explores social issues, cultural dynamics, and economic systems, enriching our understanding of human interactions.","social-sciences",{"code":41,"msg":42,"data":124},{"temp_id":125,"version":7,"id":126,"hash_key":127,"doi":128,"article_abstract":129,"article_title":130,"keywords":131,"is_registering_doi":132,"mdpi_topic":133,"preprints_collections":138,"subject":139,"top_subject":142,"article_type":143,"submitted_at":145,"published_at":146,"last_edited_at":50,"authors":147,"ethical_approval":132,"ethical_approval_number":50,"ethical_approval_body":50,"ethical_approval_for_publication":132,"article_supplementary":50,"final_file":206,"graphic_abstract":210,"statistics":211,"is_peer_reviewed":6,"peer_reviewed_article_url":214,"almetric":215,"preserved_by_portico":6,"ms_xml":217,"versions":219,"citation":221,"peer_reviewed_citation":222,"version_changes":223,"updating_alert_registered":132,"preprints_process_url":50,"comments_count":41,"latest_version":7,"author_notes":224,"withdrawed_at":50,"is_withdrwan":132},67418,"202301.0264","421f15bb4029d40b83f5bd0d34dd7658","10.20944/preprints202301.0264.v1","Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides’ fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest methods to analyze the lipids in biological samples. Finally, we discuss the drug development strategies focusing on the ceramide synthases and ceramides as future therapeutic approaches in cancer therapy.","Ceramides and Ceramide Synthases in Cancer: Focus on Apoptosis and Autophagy","mitochondrial cell death; autophagy cell death; lipidomic analysis; drug development",false,{"id":134,"name":135,"converted_name_system":136,"mdpi_url":137},452,"Cancer Cell Metabolism","Cancer-Cell-Metabolism","https://www.mdpi.com/topics/Cancer_Cell_Metabolism",[],{"id":140,"name":141},23,"Biochemistry and Molecular Biology",{"id":55,"name":56},{"id":55,"name":144},"Review","2023-01-14 16:26:51","2023-01-16 03:37:34",[148,156,162,167,172,177,182,187,193,198],{"id":149,"name":150,"email":151,"is_corresponding":132,"orcid_link":152,"author_mark":153,"sp_link":154,"avatar":155},311016,"Javad Alizadeh","alizadej@myumanitoba.ca","https://orcid.org/0000-0001-9082-3083","","https://sciprofiles.com/profile/1344513","/statics/img/design/default-user.png",{"id":157,"name":158,"email":159,"is_corresponding":132,"orcid_link":160,"author_mark":153,"sp_link":161,"avatar":155},311017,"Simone C. Da Silva Rosa","simone.dasilvarosa@umanitoba.ca","https://orcid.org/0000-0002-3732-3781","https://sciprofiles.com/profile/2622522",{"id":163,"name":164,"email":165,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":166,"avatar":50},311018,"Xiaohui Weng","xweng5@csu.fullerton.edu","https://sciprofiles.com/profile/author/eVpFcFlBUVdlakhFcHcyekhqdDNaaGRiZlRqR21CamNCTkhneHV5UWtyMD0=",{"id":168,"name":169,"email":170,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":171,"avatar":50},311019,"Joadi Jacobs","jacobsj1@myumanitoba.ca","https://sciprofiles.com/profile/author/MmVhMk0ySVlZeEtkSHgwNGVrRmVtbitmU3NhRHVibUxWSkxsMDRpMTF5bz0=",{"id":173,"name":174,"email":175,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":176,"avatar":155},311020,"Shahrokh Lorzadeh","shahrokh.lorzadeh@umanitoba.ca","https://sciprofiles.com/profile/2589198",{"id":178,"name":179,"email":180,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":181,"avatar":155},311021,"Amir Ravandi","amir.ravandi@umanitoba.ca","https://sciprofiles.com/profile/554890",{"id":183,"name":184,"email":185,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":186,"avatar":50},311022,"Rui Vitorino","ruimpvitorino@gmail.com","https://sciprofiles.com/profile/author/MzBsLzBzK05rTTUwd2RFSWRiNVZ0TUxRZ2VZNzRESkVtcTdoUGZmcXlUND0=",{"id":188,"name":189,"email":190,"is_corresponding":132,"orcid_link":191,"author_mark":153,"sp_link":192,"avatar":155},311023,"Stevan Pecic","specic@fullerton.edu","https://orcid.org/0000-0002-3706-8768","https://sciprofiles.com/profile/999674",{"id":194,"name":195,"email":196,"is_corresponding":132,"orcid_link":50,"author_mark":153,"sp_link":197,"avatar":50},311024,"Shahla Shojaei","shahla.shojaei@umanitoba.ca","https://sciprofiles.com/profile/author/Q2tzaThsZzFFZWIwREhtL1FBQmNwcGR5dWRYRk1UMWxFWEx4ckZDMTZIcz0=",{"id":199,"name":200,"email":201,"is_corresponding":6,"orcid_link":202,"author_mark":203,"sp_link":204,"avatar":205},311025,"Saeid Ghavami","saeid.ghavami@umanitoba.ca","https://orcid.org/0000-0001-5948-508X","*","https://sciprofiles.com/profile/134198","/img/user_image/134198/Saeid_Ghavami.png",{"filename":207,"url":208,"filesize":209},"final_file.pdf","/frontend/manuscript/421f15bb4029d40b83f5bd0d34dd7658/download_pub",1617399,[],{"viewed":212,"downloaded":213},"263","488","https://doi.org/10.1016/j.ejcb.2023.151337",{"score":41,"detail_url":216},"https://preprints.altmetric.com/details/doi/10.20944/preprints202301.0264.v1",{"html_content":218},"\u003Cscript type=\"text/x-mathjax-config\">\n MathJax.Hub.Config({\n menuSettings: {\n CHTMLpreview: false\n },\n \"CHTML-preview\":{\n disabled: true\n },\n \"HTML-CSS\": {\n scale: 90,\n availableFonts: [],\n preferredFont: null,\n preferredFonts: null,\n webFont:\"Gyre-Pagella\",\n imageFont:'TeX',\n undefinedFamily:\"'Arial Unicode MS',serif\",\n linebreaks: { automatic: false }\n },\n \"TeX\": {\n extensions: [\"noErrors.js\"],\n noErrors: {\n inlineDelimiters: [\"\",\"\"],\n multiLine: true,\n style: {\n \"font-size\": \"90%\",\n \"text-align\": \"left\",\n \"color\": \"black\",\n \"padding\": \"1px 3px\",\n \"border\": \"1px solid\"\n }\n }\n }\n });\n \u003C/script>\u003Cscript type=\"text/javascript\" async=\"\" src=\"https://www.mdpi.com/bundles/mathjax/MathJax.js?config=TeX-AMS-MML_HTMLorMML\">\u003C/script>\n \u003Csection id=\"Introduction\" type=\"intro\">\u003Ch2 data-nested=\"1\" id=\"preprints-h2-1\"> Introduction\u003C/h2>\n\u003Cdiv class=\"html-p\">Ceramide is a crucial intermediate in sphingolipid metabolism in mammalian cells (1). Ceramide is synthesized by ceramide synthases (CerS) with different acyl chain lengths. CerS share some biochemical features like their structure, intracellular localization and their catalytic mechanism (1). Additionally, different CerS display significant variability in their biological properties (2). All CerS are associated with the endoplasmic reticulum (ER), and they all contain a crucial TRAM–Lag1p–CLN8 (TLC) domain: a CerS catalytic domain necessary for ceramide synthesis (3). Originally, CerS were known as Longevity Assurance (Lass) genes due to their homology to the longevity assurance gene 1 (LAG1p) in yeast, however their name was changed after characterization of their biochemical features (4). It was found that LAG genes result in the prolonged life span of \u003Cspan class=\"html-italic\">S. cerevisiae\u003C/span> and extend the lifespan of a cell, hence the name LAG1. The most remarkable characteristic of CerS is that each of the CerS has a specificity for an acyl CoA chain length despite all catalyzing the same reaction. It can thus be seen that CerS determine the fatty acid composition of ceramides (2). \u003Ca href=\"#preprints-67418-t001\" class=\"html-table\">Table 1\u003C/a> displays ceramides with different acyl chain lengths as synthesized by these six CerS.\u003C/div>\n\u003Cdiv class=\"html-p\">Multiple investigations have been performed to determine the role of CerS in different pathologies. Although no longer true, ceramides were classically known to induce cancer cells’ growth inhibition, cell death, and senescence (11). Recent reports found that ceramides with various fatty acid chain lengths might have different functions in the pathogenesis of cancer, indicating the critical importance of CerS in sphingolipid metabolism (12-14). There are various functions of ceramides that are context dependent and are modulated by their localization in the cell and presence or absence of their targets. For instance, ceramides with various fatty-acid chain lengths have been shown to play a role in cancer cell proliferation like C16-ceramide (synthesized by CerS6) whereas C18-ceramide (synthesized by CerS1) is involved in cell death (11). Based on C18-ceramide downregulation in most head and neck squamous cell carcinoma (HNSCC) tissues compared to adjacent normal tissue, CerS1 has been found to play a role in the growth regulation of HNSCC (15). Furthermore, the balance between C16-and C18-ceramides levels could be associated with HNSCC tumor development (15, 16) related to the clinical progression of this cancer (17). CerS2 have been shown to play a role in breast cancer. In an initial study (18), it was found that the levels of total ceramide (especially C16-, C24:1- and C24:0-ceramides) were significantly increased in aggressive tumors. This was consistent with an increases in CerS2, CerS4 and CerS6 mRNA levels. In the subsequent study (19), mRNA levels of CerS2 and CerS6 were highly increased in breast tumors compared to the normal tissue, where almost half of the patients showed increased levels of CerS2 and CerS6 mRNA. Notably, there was a significant relationship between the expression of CerS6 and CerS2, and between CerS2/CerS6 and CerS4. Moreover, the sensitivity of breast cancer cells to chemotherapeutic drugs was not affected by CerS4 (unlike CerS1 and CerS5) (20). It has been suggested that CerS6 is involved in the etiology of cancer. For example, using microarray studies, CerS6 has been found to be implicated in early embryonic development and cancer differentiation (21). In contrast to this, another study showed that mRNA levels of CerS6 were increased in breast cancer tissues and regulation of CerS6 expression was dependent on estrogen receptor (18, 19, 22). This double-edge role of ceramides in cancer highlights the potential targeting of some of the enzymes in the ceramide metabolism pathway as novel therapeutic methods. For example CerS6 can be targeted in order to hamper cancer cell growth in head and neck and breast cancers while activation of CerS1 could be harnessed to develop new treatments against lung and head and neck cancers (11).\u003C/div>\n\u003Cdiv class=\"html-p\">Therefore, in the current review paper we summarize different types of CerS and their products. Then, we discuss the impact of CerS and ceramides in apoptosis and autophagy which play an important role in cancer. We later explain the current methods that is being used for evaluation of lipids including ceramides in biological samples. Finally, we will provide over view for future therapeutic approaches to target CerS for developing potential new therapeutic approaches in cancer. \u003C/div>\u003C/section>\u003Csection id=\"CeramideSynthesis\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-2\"> Ceramide Synthesis\u003C/h2>\n\u003Cdiv class=\"html-p\">Sphingolipids are one of the main lipid types in eukaryotic cells. Ceramides are the building block of all sphingolipids. This has made ceramide the focus of recent enormous attention due to its suggested role as a crucial signaling lipid involved in the regulation of different cellular processes (23). As shown in \u003Ca href=\"#preprints-67418-f001\" class=\"html-fig\">Figure 1\u003C/a>, ceramide is synthesized via different pathways in the cell. Ceramide is made of a sphingosine backbone, which is a fatty acyl chain with an amide linked to it, with different lengths (24). Ceramides are used as a precursor for more complex sphingolipids, for example: glucosylceramide, ceramide-1-phosphate (C1P), sphingomyelin, and galactosyl ceramide. Ceramide is also produced through the breakdown of these complex sphingolipids using various enzymes. This type of ceramide can be used as a substrate by ceramidases to release sphingosine, which is phosphorylated to make sphingosine 1-phosphate (S1P) (11). Endogenous ceramides are synthesized \u003Cspan class=\"html-italic\">de novo\u003C/span> in the ER through a pathway beginning with condensation of L-serine and palmitoyl-CoA followed by more enzymatic reactions leading to the production of ceramide (25, 26) (\u003Ca href=\"#preprints-67418-f001\" class=\"html-fig\">Figure 1\u003C/a>). D\u003Cspan class=\"html-italic\">e novo\u003C/span> synthesis of ceramide occurs in the ER, however, the synthesis of complex sphingomyelin and glycosphingolipids occurs in the Golgi apparatus (27). During this process the ceramide is transported to Golgi apparatus from the ER via vesicular trafficking or non-vesicular transport (i.e. by ceramide transfer protein (CERT)) (28). Lastly, the salvage pathway can also generate ceramides through hydrolyzing ceramide into sphingosine which is then reacylated by CerS to regenerate ceramides (29). \u003C/div>\u003C/section>\u003Csection id=\"CerSActivityRegulation\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-3\"> CerS Activity Regulation\u003C/h2>\n\u003Cdiv class=\"html-p\">Mechanisms involved in the regulation of CerS activity are not fully known. Recent studies reveal that the formation of CerS dimers can regulate the ceramide synthesis which may be dependent on the interaction of CerS with each other (30). CerS is expressed in various levels in different tissues (31), however the acyl chain composition of the sphingolipid does not always correlate with CerS expression (31, 32). This has prompted the possibility of cross-regulation of CerS expression and activity (33). In fact, heterocomplexes of CerS2, -5, and -6 was recently reported in HeLa cells (34). Moreover, the activity of either monomers in this dimer form depend on, and can be regulated by, the other monomer, suggesting dimer formation as a mechanism of regulating CerS activity (30). Specifically, it was suggested that the highest level of CerS2 activity is dependent on its interaction with other CerS. CerS2 has the least activity among all CerS \u003Cspan class=\"html-italic\">in vitro\u003C/span> (35, 36), yet it has the widest tissue distribution (31). In fact, CerS monomers and dimers are in equilibrium in the ER and dimers formation and/or dissociation could be a major factor in their regulation. Dimer formation occurs rapidly which is an efficient way of increasing the ceramide levels under different conditions. This is of utmost importance in situations when \u003Cspan class=\"html-italic\">de novo\u003C/span> ceramide synthesis plays a crucial role in other signaling pathways requiring a quick mechanism of ceramide synthesis (30). The mechanisms of post translational modifications of CerS, if any, are not fully elucidated yet. There is some evidence that suggests a role for CerS phosphorylation. For example, an increase in the \u003Cspan class=\"html-italic\">de novo\u003C/span> ceramide synthesis is linked to activation of protein kinase C (PKC) and consequently up-regulation of CerS5 activity (37). It has been shown from high performance mass spectrometry that CerS might be phosphorylated (38, 39) and glycosylated (40). The rapid changes in CerS activity might be facilitated by the post-translational regulation of CerS under different conditions (41, 42)\u003Cb>.\u003C/b> \u003C/div>\u003C/section>\u003Csection id=\"CerSTissueDistribution\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-4\"> CerS Tissue Distribution\u003C/h2>\n\u003Cdiv class=\"html-p\">CerS1 is mainly expressed in brain, testes, and skeletal muscle at low levels (31, 40, 43). It was shown by in situ-hybridization of brain tissue that CerS1 is expressed in most neurons and in very low levels in white matter cells (44). CerS1 is upregulated at a low level postnatally, possibly supporting the synthesis of neuronal cell membranes. The high level of CerS1 is in line with the composition of acyl chain of the neuronal sphingolipids (mainly C18-fatty acids) in neurons (44). CerS2 is more widely expressed in different human tissues compared to CerS1 with lowest expression in spleen, small intestine, colon, thymus, and peripheral blood leukocytes, moderate expression in heart, brain, placenta and lung, skeletal muscle, and highest expression in liver and kidney (31). It has been shown that CerS2 is highly expressed during active myelination in oligodendrocytes and Schwann cells in mouse brain (44). CerS3 is highly expressed in testes and skin (40, 45). The expression of CerS3 is very high in keratinocytes (46). CerS4, which is probably the least studied CerS, is highly expressed in leukocytes, heart, skin, and liver (31). CerS5 is highly expressed in lung epithelia and is likely the most studied CerS because it can synthesize C16-ceramide which is an important pro-apoptotic ceramide (47). It was found that down regulation of CerS5 in lung epithelium by siRNA or using fumonisin B1 decreased the total CerS activity (48). This shows that CerS5 is indeed involved in the ceramide synthesis in lung tissue. Lastly\u003Cb>,\u003C/b> CerS6 is highly expressed in intestine and immune system (2). \u003C/div>\u003C/section>\u003Csection id=\"RoleofCerSandceramidesinRegulationofApoptosis\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-5\"> Role of CerS and ceramides in Regulation of Apoptosis\u003C/h2>\n\u003Cdiv class=\"html-p\">Apoptosis is a programmed process whereby cells are committed to death (49). There are two main apoptosic pathways namely intrinsic or extrinsic (50). Mitochondria play a crucial role in intrinsic apoptosis as the outer membrane integrity loss results in a cascade of events that leads to apoptotic death (51). Different proteins are connected to apoptosis initiation leading to the permeabilization of the mitochondrial outer membrane by the formation of different pores (52, 53), mitochondrial apoptosis-induced channel (54), Bax oligomerization into channels (55, 56), mitochondrial permeability transition pore (57, 58), and Bax/Bak hybrid channels (56, 59). Ceramides are also involved in the formation of channels in the mitochondrial outer membrane (60-62). Moreover, these events \u003Cspan class=\"html-italic\">in vivo\u003C/span> can occur at the same time resulting in a regulated and coordinated outcome. \u003C/div>\n\u003Cdiv class=\"html-p\">A recent study highlighted the role of ceramides in regulation of apoptosis. It found that C16-ceramide is needed for germ cell apoptosis induced by gamma radiation in \u003Cspan class=\"html-italic\">C. elegans\u003C/span> (63). C16-ceramide-mediated apoptosis was detected by acridine orange (AO) staining, involvement of MAPK pathway (\u003Cspan class=\"html-italic\">mpk-1\u003C/span>; homologue of mammalian \u003Cspan class=\"html-italic\">erk\u003C/span> and \u003Cspan class=\"html-italic\">sek-1;\u003C/span> homologue of mammalian JNK), production of ROS and reduction in mitochondrial outer membrane potential (MOMP). Most studies thus far have shown that ceramides regulate apoptosis mainly through ceramide channel formation and regulation of anti-apoptotic Bcl2 family proteins (Bcl2 and Bcl-xL), and pro-apoptotic Bcl2 family proteins (Bax and Bak) as discussed below and briefly illustrated in \u003Ca href=\"#preprints-67418-f002\" class=\"html-fig\">Figure 2\u003C/a>. \u003C/div>\u003C/section>\u003Csection id=\"RegulationofApoptosisbyCeramideChannels\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-6\"> Regulation of Apoptosis by Ceramide Channels \u003C/h2>\n\u003Cdiv class=\"html-p\">Ceramides have the special ability to perforate the cell lipid bilayers through forming water-filled channels (typically 10 nm in diameter) (64, 65). Levels of mitochondrial ceramide elevates during apoptosis initiation and resulting in mitochondrial outer membrane integrity loss (66). Pro-apoptotic proteins such as cytochrome c are released from the intermembrane space into the cytosol upon the permeabilization of the mitochondrial outer membrane and at this point the cell is irreversibly committed to death (67, 68). The most recent model for the ceramide channel comprises of layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure in lipid bilayer membranes (69, 70). Ceramides with various fatty acyl chain lengths such as C2-, C8-, C16- and C24-ceramides are capable of perforating the mitochondrial outer membranes (27, 71). This ceramide channel formation strongly depends on ceramide molecule structure (72). For example, dihydroceramide does not possess the 4–5 double bond in ceramide and therefore it cannot induce cell death. Furthermore, dihydroceramide cannot form ceramide channels \u003Cspan class=\"html-italic\">in vitro\u003C/span> (73). It is unsurprising that ceramides can influence each other since ceramides production with various chain lengths invariably changes the biophysical properties of membranes (74, 75). Furthermore, membranes biophysical properties alter due to the depletion of very long chain ceramides (76). Ceramide channels in the mitochondrial outer membrane are large enough to permit the release of apoptotic proteins into the cytosol (77). Previous study findings show that various ceramide species induce membrane permeability independently from one another (60). In a recent study, the egress of two intermembrane space proteins were evaluated to investigate the mechanisms by which ceramides perforate the mitochondria (78). Sulfite oxidase is a 120 KD enzyme and adenylate kinase is a 26 KD protein and both localize in the mitochondrial intermembrane space. Upon mixing C16- and C22- ceramide with isolated mitochondria, it was found that C16-ceramide induced the SOX release whereas C22-ceramide showed no release of SOX indicating that the C22-ceramide channels are significantly smaller than the ones made by C16-ceramide. Interestingly, both C16-ceramide and C22-ceramide resulted in the release of both SOX and AK. This release was possibly due to the formation of either C16-ceramide channels or C16–C22-hybrid channels as C22-ceramide channels did not release SOX. In short, these findings agree with the theory that various ceramides can form channels of varied sizes and quantities in isolated mitochondria (78). In another study by Laviad \u003Cspan class=\"html-italic\">et al.\u003C/span>, it was found that CerS overexpression results in the high production of specific ceramides in HEK cells. For example, CerS2 overexpression led to the enrichment of C22-, C24- and C24:ceramide (31) while CerS5 overexpression resulted in the enrichment of C16-ceramide. Additionally, cytochrome c release was measured to examine the impact of exogenous ceramides on the membrane permeability of isolated mitochondria from HEK cells. Interestingly, C16-ceramide addition to isolated mitochondria from CerS5-transfected cells (enriched with C16-ceramide) elevated the levels of cytochrome c release while it was significantly decreased in isolated mitochondria from CerS2-transfected cells. On the other hand, C24-ceramide addition to isolated mitochondria from CerS2-transfected cells increased the release of cytochrome c whereas it was significantly reduced in isolated mitochondria from CerS5-transfected cells highlighting the existing competition \u003Cspan class=\"html-italic\">ex vivo\u003C/span> (78). \u003C/div>\u003C/section>\u003Csection id=\"RegulationofApoptosisbyCeramidesthroughantiapoptoticBcl2familyproteinsBcl2andBclXL\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-7\"> Regulation of Apoptosis by Ceramides through anti-apoptotic Bcl-2 family proteins, Bcl2 and Bcl-XL\u003C/h2>\n\u003Cdiv class=\"html-p\">Bcl2 phosphorylation at serine 70 is needed for its total and optimal anti-apoptotic function (79). It has been suggested that ceramide might influence the Bcl2 phosphorylation and therefore its function, since ceramide activates protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) (80). In fact, C2-ceramide (and not C2-dihydroceramide) specifically activates mitochondrial PP2A that induces Bcl2 dephosphorylation and consequently ceramide-induced apoptosis in HL-60 cell line (a human leukemia cell line). These results show that ceramide-induced apoptosis might involve mitochondrial PP2A which dephosphorylates and inactivates Bcl2 in Bcl2 expressing cells (81). The fatty acyl chain lengths of the ceramide are critical in regulating the ceramide channels by Bcl-xL (82). Bcl-xL prevents the formation of ceramide channel and therefore ceramide-induced apoptosis (83). Interestingly, this prevention of ceramide channel formation is disrupted when ceramide has a truncated fatty acyl chain which shows a crucial role for the acyl chain length in binding to the Bcl-xL. Bcl-xL binding to ceramide greatly depends on the acyl chain length of ceramide due to the hydrophobic pocket in Bcl-xL structure. Bcl-xL efficiently inhibits the formation of ceramide channels formed by 16-, 18- and, 20-ceramides (82). Moreover, BH3 peptide mimetics bind to the hydrophobic grove on Bcl-xL and thus prevent its binding to Bax, inhibiting the ceramide channel formation (84). \u003C/div>\u003C/section>\u003Csection id=\"RegulationofApoptosisbyceramidesthroughproapoptoticBcl2familyproteinsBaxandBak\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-8\"> Regulation of Apoptosis by ceramides through pro-apoptotic Bcl2 family proteins, Bax and Bak: \u003C/h2>\n\u003Cdiv class=\"html-p\">Bax has a crucial role in regulation of apoptosis (85). Bax translocates to mitochondria, after a variety of apoptotic stimuli, to form pores in mitochondrial outer membrane by potentiating the ceramide channels and thus inducing loss of mitochondrial membrane potential (85). This leads to the cytochrome c release from mitochondrial intermembrane spaces into the cytosol. \u003C/div>\n\u003Cdiv class=\"html-p\">As opposed to Bcl-xL, formation of Bax is not dependent on nor influenced by acyl chain length of ceramide (86). It has been found that Bax, Bak, and ceramide are dependent on one another when forming ceramide channels (84). Additionally,Bak is crucial for the synthesis of long-chain ceramide by CerS during apoptosis (87). Moreover, evidence suggests that Bax and ceramide act together in a synergistic manner in the permeabilization of mitochondrial outer membrane (88, 89). It has also been reported that in Bax-transfected DU-145 cells and HL-60 cells the exogenous C2- and C6-ceramides leads to the Bax redistribution to mitochondria and causes mitochondrial permeability transition followed by cytochrome c release, then activation of caspase-3 and DNA fragmentation (90). It was found that ceramides capable of permeabilizing into the cells can promote the conformational change in the Bax N-terminus in Bax-expressing cells (91). Interestingly, loss of Bax inhibits the C2-ceramide-induced apoptosis in colorectal cancer HCT116 cells, highlighting again the role of ceramide in the regulation of apoptosis induction (92).\u003C/div>\u003C/section>\u003Csection id=\"EndoplasmicReticulumERandRegulationofApoptosisviaCeramides\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-9\"> Endoplasmic Reticulum (ER) and Regulation of Apoptosis via Ceramides\u003C/h2>\n\u003Cdiv class=\"html-p\">The ER plays an important role in different cellular processes such as lipid metabolism, protein folding, protein synthesis, and calcium homeostasis and is therefore a crucial organelle within eukaryotic cells (93). When newly synthesized proteins in the ER are improperly folded or when the Ca\u003Csup>2+\u003C/sup> sequestration is perturbed, it leads to ER stress (94, 95). To mitigate this stress, a complicated homeostatic mechanism is activated in the ER known as the unfolded protein response (UPR) (95). Three transmembrane proteins in the ER mediate UPR namely; inositol-requiring enzyme 1 (IRE1), pancreatic ER kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6), each of which have specific functions and targets (96, 97). \u003C/div>\n\u003Cdiv class=\"html-p\">Elevated levels of ceramide in the mitochondria are linked to the induction of apoptosis. It has been found that synthesized ceramides in isolated ER vesicles transfer to the isolated mitochondria where they perforate the outer membrane leading to the release of cytochrome \u003Cspan class=\"html-italic\">c\u003C/span> and adenylate kinase (98). Interestingly, the ER-like membranes that are closely connected to mitochondria (known as mitochondria-associated membranes) synthesize ceramide that can transfer and permeabilize the mitochondrial outer membrane (98). Therefore, this mechanism of ceramide exchange between the two organelle obviates the need for a \u003Cspan class=\"html-italic\">de novo\u003C/span> pathway to synthesize the ceramide in mitochondria required for the formation of ceramide channel followed by protein release (98). In HNSCC cell lines, CerS6 overexpression followed by increased C\u003Csub>16\u003C/sub>-ceramide has pro-survival roles whereas CerS6 knockdown induces apoptosis via activation of ATF6-CHOP arm of the UPR (99). Senkal \u003Cspan class=\"html-italic\">et al.\u003C/span> found that the induction of wild type CerS6 and not the inactive/mutant CerS6, increased the tumor growth in Severe Combined Immuno Deficient (SCID) mice. Similarly, induction of wild type-CerS (and not mutant CerS6) or expression of the mutant ATF-6 protected cells from undergoing apoptosis in response to CerS6 knockdown. Conversely, CerS6 knockdown by siRNA induced ATF-6 activation and subsequently apoptosis in multiple human squamous cell carcinomas cells (HNSCC, A549, H157, and H1650).. Altogether, this data revealed an underlying mechanism of how the alteration of CerS6 (and by extension C16-ceramide) induces the activation of ATF6 leading to the ER-stress-mediated apoptosis in human squamous cell carcinomas cells (100). Another study showed that cell-permeable C2-ceramide induces an apoptotic ER stress response in salivary adenoid cystic carcinoma cells (ACCs). Findings from this study illustrated that C2-ceramide activates pro-apoptotic factors downstream of ER stress and therefore induces apoptosis in ACCs. They found that ceramide induces CHOP which is the key transcription factor highly expressed during ER stress and is known as a crucial inducer of ER stress-mediated apoptosis. The same study found that the mRNA expression of CHOP was upregulated upon treatment with ceramide in ACC-M and ACC-2 cells (101).\u003C/div>\u003C/section>\u003Csection id=\"RoleofCerSandceramidesinRegulationofApoptosisinCancer\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-10\"> Role of CerS and ceramides in Regulation of Apoptosis in Cancer\u003C/h2>\n\u003Cdiv class=\"html-p\">Owing to their regulatory role on apoptosis, CerS and ceramides have been implicated in the pathogenesis of various cancers. Ceramides are produced in response to a variety of stressors to initiate apoptosis. For example, levels of C16-ceramide were elevated after celecoxib (a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug for the treatment of arthritis) treatment in human colon carcinoma cells thereby mediating the anti-proliferative effects (102, 103). In another study, it was shown that overexpression of different CerS led to varied outcomes of apoptosis induced radiation in HeLa cells: overexpression of CerS5 resulted in higher levels of apoptosis in cells while overexpression of CerS2 inhibited cells from undergoing apoptosis (104). CerS1 also plays a crucial role in regulation of the sensitivity to chemotherapeutic agents. It was shown that CerS1 sensitizes human embryonic kidney cells to different anti-cancer agents such as carboplatin, cisplatin, vincristine, and doxorubicin while CerS5 sensitizes these cells to only doxorubicin and vincristine and CerS4 has no effects on the sensitivity to any of these anti-cancer agents (20). Similarly, CerS1 has a critical role in regulating apoptosis in HNSCC cells through caspase activation induced by gemcitabine/doxorubicin (105). They found that CerS1 downregulation by siRNA inhibited apoptosis about 50% in response to gemcitabine/doxorubicin. Also, CerS1 (and not CerS5) siRNA modulated caspase-3 and caspase-9, but not caspase-8, activation in response to gemcitabine/doxorubicin treatment. Moreover, gemcitabine/doxorubicin treatment led to a remarkable reduction in the growth of HNSCC tumor in severe combined immunodeficiency mice with UM-SCC-22A (a HNSCC cell line) xenografts. Interestingly, liquid chromatography and mass spectroscopy analysis showed that only the levels of C18-ceramide (synthesized by CerS1) were significantly increased in response to gemcitabine/doxorubicin in these tumors. These findings highlight a key role for C18-ceramide in gemcitabine/doxorubicin-induced apoptosis through caspase-9/3 activation in HNSCC (105). In another study on CerS1, it was found that treatment of K562 cells (a chronic myeloid leukemia cell line) with imatinib induced C18-ceramide synthesis via CerS1, which plays a role in imatinib-induced apoptosis in these cells (106). CerS1 downregulation using siRNA partly inhibited the imatinib-induced apoptosis in drug-sensitive K562 cells. Also, CerS1 overexpression (but not CerS6) triggered a significant increase in the synthesis of C18-ceramide induced by imatinib and promoted apoptosis. These results propose the involvement of C18-ceramide (synthesized by CerS1) in imatinib-induced apoptosis in K562 cells (106). As mentioned previously, d\u003Cspan class=\"html-italic\">e novo\u003C/span> synthesis of ceramide is an important inducer of Bax. It has been found that localization of Bax to the mitochondria was decreased after CerS5 knockdown in NT-2 cells (a testicular embryonal carcinoma cell line) (107) indicating that CerS5 is critical in the synthesis of ceramide that leads to apoptosis in these cancer cells. CD95 (Fas) and its ligand (CD95L) are death receptors and ligands, which induce apoptosis (108). CerS6 modulates the activation of CD95 and therefore the induction of apoptosis (109). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family able to initiate apoptosis via its death receptors (DR4 and DR5) (110, 111). This leads to caspase 8, and -10 activation. It has been found that normal cells are resistant to TRAIL-induced apoptosis because of low levels of TRAIL receptors expressed on their membrane (112). The CD95 activation and cancer cell killing were both increased after CerS6 overexpression while CerS6 knockdown abrogated CD95 activation in colon adenocarcinoma cell lines (DLD1, SW620 and SW480). Role of ceramides in the CD95-induced apoptosis in different types of cancer was investigated in another study by the same research group. Findings showed that fumonisin B1 (an inhibitor of CerS activity) inhibited the C16-ceramide increase in SW480 cells (113). Also, TRAIL-resistant SW620 cells had a lower levels of CerS6 expressed. CerS6 downregulation by siRNA led to a specific and significant reduction of C16-ceramide - enough to abrogate the TRAIL-induced apoptosis. Furthermore, only a slight increase in CerS6 expression was enough to reverse the TRAIL resistance in SW620 cells. These findings show that regulation of the CerS6 expression could potentially be a novel therapeutic approach to alter colon cancer cells’ sensitivity to apoptosis (113). In another study, it was found that the mRNA levels of CerS2 and CerS6 were highly increased in about half of the tissues obtained from patients with breast cancer in comparison to normal tissues. Findings from this study suggested that C16-ceramide (synthesized by CerS6) and C24:1- and C24-ceramide (synthesized by CerS2) may have an unusual pro-survival role and thus resist apoptosis in breast cancer pathogenesis (19). lncRNA ceramide synthase 6 antisense RNA 1 (CERS6-AS1) is a novel RNA that modulates the gene expression of ceramide synthesis 6 and is significantly overexpressed in various cancers such as gastric, hepatocellular, pancreatic and breast cancer (114). A study found that LncRNA CERS6-AS1 promotes proliferation and migration while inhibiting apoptosis of breast cancer cell lines \u003Cspan class=\"html-italic\">in vitro\u003C/span> (115). In agreement with this, flow cytometry findings on CERS6-AS1 knockdown revealed high rate of apoptosis (115). A very interesting research study showed that C16-ceramide directly binds to voltage-dependent anion channel VDAC2, a mitochondrial platform for Bax/Bak translocation, to mediate apoptosis in Human colon carcinoma HCT116 cells (91). VDAC channels are a platform for the recruitment of pro-apoptotic Bak and Bax into mitochondria, leading to cytochrome c release and permeabilization of the OMM (116). Moreover, C2-cermide has been found to induce apoptosis in lung adenocarcinoma cells (A549 and PC9) via regulation of the thioredoxin-interacting protein (Txnip) (117). Treatment of these cells with C2-ceramide caused an increase in the activity of caspase-3. Txnip has a crucial role in redox signal transmission in the cell (118). The expression of CerS6 which synthesizes C16-ceramide is significantly upregulated in breast cancer (19) and non-small-cell lung cancer (119) cells. CerS6 is a regulator of apoptosis and contributes to the metastasis and progression of cancer cells (120). Using siCerS6, Shi \u003Cspan class=\"html-italic\">et al.\u003C/span> showed that CerS6 knockdown prevented the migration and metastasis of ovarian cancer cells while inducing apoptosis in these cells (121). C6-ceramide also induces apoptosis in salivary adenoid cystic carcinoma (SACC) SACC-83 and SACC-LM cell lines in a dose dependent manner as shown by the upregulation of caspase-3, PUMA, and CHOP (122). \u003C/div>\u003C/section>\u003Csection id=\"RoleofCerSandceramidesinRegulationofAutophagy\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-11\"> Role of CerS and ceramides in Regulation of Autophagy\u003C/h2>\n\u003Cdiv class=\"html-p\">Autophagy is a self-recycling mechanism in the cell that targets nonfunctional or misfolded proteins or damaged organelles and degrades them via lysosomes (123-127). There are three types of autophagy; macroautophagy (hereafter autophagy), microautophagy and chaperone-mediated autophagy all of which differ from one another in terms of their mechanism and function (128, 129). Autophagy not only leads to the elimination of misfolded proteins and damaged organelles, it also modulates the recycling of components within the cell thereby ensuring the cellular quality control (130-132). The primary function of autophagy is survival under stress conditions, such as starvation (133). This is accomplished through self-eating that provides the cell with required energy and metabolic precursors (134-137). Consequently, dysregulated or prolonged autophagy activation can result in cell death (138-140). Ceramides have been shown to regulate autophagy (141). Class I PI3K and Akt are two well-known regulators of autophagy. C2 or C6-ceramide have the ability to activate PP2A blocking the Akt activation thereby inducing autophagy in HT-29 (human colon) and MCF-7 (breast cancer) cell lines (142, 143). Furthermore, amino acid deprivation leads to an increase in ceramide levels. This results in inhibition of the mTOR activity and therefore autophagy induction in a PP1/PP2A dependent manner. It was shown by Edinger \u003Cspan class=\"html-italic\">et al.\u003C/span> that ceramide rapidly and significantly downregulates amino acid transporter proteins (103). Likewise, C2-ceramide inhibited the protein expression of nutrient transporter leading to starvation and consequentlyAMPK-dependent autophagy induction in murine prolymphocytic cells (FL5. 12) (144). Beclin1 is a crucial mediator in autophagy pathway. Beclin1 expression is increased under stress and its gene is mutated or deleted in different types of cancers (145). Scarlatti \u003Cspan class=\"html-italic\">et al\u003C/span>. demonstrated that exogenous C2-ceramide increases the expression of Beclin1 and thus autophagy induction. This effect is inhibited after using myriocin (a CerS inhibitor) which shows that ceramide regulation of Beclin1 expression occurs at either transcriptional or post-transcriptional level (143). In CNE2 and Hep3B cancer cell lines, C2-ceramide can also activate JNK and consequently c-Jun phosphorylation. C-Jun then upregulates the expression of Beclin1 mRNA (146). Moreover, elevated levels of Beclin1 could stem from the Beclin1-Bcl2 dissociation (147). In fact, ceramide triggers the JNK1 activation which leads to the phosphorylation of Bcl2 that in turn releases Beclin1 from the Beclin1-Bcl2 complex (148, 149). Also, ceramide is involved in the activation of Forkhead box protein O3 (FOXO3) that can increase the expression levels of BNIP3 (150). The increased expression of BNIP3 competitively binds to Bcl2 and Bcl-xL thereby dissociating Beclin1 from binding to Bcl2 (151). Ceramide-induced ER stress can play a role in the induction of autophagy (141). In fact, downregulation of CerS2 triggers significant accumulation of C14 and C16-ceramides and induces ER-stress-mediated autophagy (152). It should be mentioned that ER stress is also interconnected with the autophagy flux. Autophagy flux is defined as the rate of the degradation of cargos by autophagy process which shows autophagic degradation activity (153). One of the UPR arms is the dimerization of the IRE1 (154). IRE1 enhances autophagy flux through its interaction with adapter proteins such as apoptosis signal-regulating kinase 1 and tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). This results in the formation of IRE1/TRAF2/ASK1 complex that activates JNK that will subsequently phosphorylates c-Jun, which increases Beclin1 expression (155, 156). It should be mentioned that despite the fact that IRE1 induces the protective autophagy, this could switch to autophagy-dependent cell death during prolonged ER stress (156, 157). The PERK/eIF2α arm of UPR also plays an important role in regulation of autophagy. This arm is particularly active after ER stress that leads to autophagy induction. ATF4 and CHOP (C/EBP homologous protein, a transcription factor induced by ATF4) are essential for downstream effects of PERK where they can modulate the expression of different ATG genes. \u003Ca href=\"#preprints-67418-f003\" class=\"html-fig\">Figure 3\u003C/a> shows how ceramide can regulate autophagy. \u003C/div>\u003C/section>\u003Csection id=\"LifeorDeathDichotomyofAutophagyAutophagyParadox\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-12\"> Life-or-Death Dichotomy of Autophagy (Autophagy Paradox)\u003C/h2>\n\u003Cdiv class=\"html-p\">There is a basal level of autophagy activity the cells in the human body (158-161). This basal activity is involved in the recycling of proteins and organelles destined for degradation and highlights the antiaging role of autophagy (162, 163). Autophagy can also be induced via different stimulus like nutrient withdrawal (164). Autophagy provides the cell with required building blocks to maintain the homeostasis and metabolism for survival (165, 166). Autophagy-dependent cell death is also known as the type II programmed cell death which is defined as a highly regulated cell death that does not involve other cell death pathways but is solely dependent on the central machinery of autophagy pathway (167, 168). \u003C/div>\n\u003Cdiv class=\"html-p\">Owing to its double-edged role of cell survival and death, autophagy is unsurprisingly involved in the pathology of different diseases including but not limited to cancer, liver diseases, and neurodegenerative diseases (169-171). Autophagy has advantageous and detrimental effects in all these situations (172). Furthermore, accumulating evidence implicates ceramides in the regulation of these two opposing roles of autophagy that regulate cell death and cell survival, known as the autophagy paradox (173, 174). \u003C/div>\u003C/section>\u003Csection id=\"RegulationofAutophagybyCeramides\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-13\"> Regulation of Autophagy by Ceramides\u003C/h2>\n\u003Cdiv class=\"html-p\">Bioactive sphingolipids regulate autophagy by exerting their effect in different steps of the autophagy pathway. Research on the role of ceramides in elongation phase of autophagy is very limited and majority of studies have revealed different roles for ceramides on the initiation and degradation phases of autophagy (\u003Ca href=\"#preprints-67418-f003\" class=\"html-fig\">Figure 3\u003C/a>). \u003C/div>\u003C/section>\u003Csection id=\"Ceramidesregulateinductionampnucleationstepsofautophagy\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-14\"> Ceramides regulate induction & nucleation steps of autophagy\u003C/h2>\n\u003Cdiv class=\"html-p\">Autophagy is regulated at the initiation step via different mechanisms. It has been demonstrated that ceramide induces the activation of JNK leading to the phosphorylation of Bcl-2 (175). Bcl-2 phosphorylation leads to its dissociation from Beclin1 and therefore lifts its inhibitory role on autophagy. Interestingly, treatments (for example glucosylceramide synthase inhibitor PDMP or tamoxifen) that elevate the long-chain ceramides levels significantly potentiate this effect of autophagy. Moreover, it was shown that treatment of nasopharyngeal carcinoma and hepatocellular carcinoma cells with ceramide enhances the Beclin1 expression through activation of JNK thereby inducing autophagy (146). Also, levels of S1P may greatly influence the formation of autophagosomes through their effect on the LC3 lipidation and thus its anchoring to the autophagosomal membrane. S1P can also modulate aBeclin1 complex although the underlying mechanism remains unknown. Additionally, it has been revealed that Sphk overexpression increases the S1P levels thereby enhancing the preautophagosomal formation in primary neurons. This remarkably enhances the overall autophagosomes formation (176). The mitochondria-associated ER membranes can be the membrane source for phagophore formation. Lipid rafts within the mitochondria-associated ER membranes are particularly important for this process. During formation of autophagosomes, ganglioside GD3 which is a component of lipid rafts and a downstream product of ceramides binds to Beclin1 complex (177, 178). GD3 contributes to the recruitment of components of the autophagic pathway. It also regulates the membrane fluidity, thus playing a role in the formation of phagophore curved membranes. Golgi-derived ATG9 vesicles donate material to the forming phagophore (179). The availability of the phosphorylated form of ceramide, ceramide-1-phosphate, (180) potentiates the formation of these vesicles which subsequently fuse to the forming phagophore (181). \u003C/div>\u003C/section>\u003Csection id=\"Ceramidesregulatefusionampdegradationstepsofautophagy\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-15\"> Ceramides regulate fusion & degradation steps of autophagy\u003C/h2>\n\u003Cdiv class=\"html-p\">A direct role for sphingolipids in promoting the autophagosomes-lysosome fusion have not yet been demonstrated. It has recently been reported that C1P synthesis from sphingomyelin induces the Ca\u003Csup>2+\u003C/sup>-dependent liposomal fusion that increases the vesicle fusion (182). Furthermore, a role for C1P has been proposed in the exocytotic and endocytic pathways (182) that are connected to the autophagic pathway (183, 184). It has also been reported that C18-ceramides regulates the degradation step of the autophagy. C18-ceramides can induce the selective targeting and degradation of mitochondria by autophagy, and mitophagy (185, 186). As stated above, localized ceramide on mitochondria binds to the lipidated LC3 on the autolysosomes and induce mitophagy (187). Interestingly, aside from their role in regulation of degradation step of autophagy, ceramides can also serve as autophagic substrates (188). \u003C/div>\u003C/section>\u003Csection id=\"Ceramideregulatesautophagyflux\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-16\"> Ceramide regulates autophagy flux \u003C/h2>\n\u003Cdiv class=\"html-p\">Sphingolipids are also involved in the regulation of transporters which direct nutrients into the cell. These lipids are important in autophagic flux (144, 189) however, studies on their exact mechanism of actions are limited. As mentioned earlier, autophagosome fuses with lysosome to form autolysosome, thereby degrading the proteins and organelles via the acidic hydrolases in the lysosomes. Interestingly, it has been shown that the efficiency of autophagosome-lysosome fusion depends on the lipid composition in the cell such as the ceramide levels (190). Moreover, it has previously been reported that myristate enhances the autophagic flux in cardiomyocytes which is dependent on C14-ceramide and CerS5. This indicates that ceramide plays a role in the modulation of autophagic flux (189). \u003C/div>\u003C/section>\u003Csection id=\"CytoprotectiveautophagyinductionbyCerSandceramide\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-17\"> Cytoprotective autophagy induction by CerS and ceramide\u003C/h2>\n\u003Cdiv class=\"html-p\">Ceramides, and in particular long chain ceramides, are involved in regulating the cell death signaling (191). Ceramides can however trigger cytoprotective autophagy to inhibit cell death under certain conditions (192). Ceramide is involved in the down regulation of amino acid and nutrient transporters. This results in starvation which triggers survival autophagy through activating AMPK and then inhibition of mTOR signaling (193, 194). Changes in the nutrient transporters’ expression impacts cell growth and survival because these transporters regulate fuel for the cell. Moreover, survival autophagy is decreased upon downregulation of CerS2 that alters normal ceramide trafficking in the ER. This leads to the accumulation of long chain ceramides and IRE1 activation, thereby inhibiting cell death induction (152). Guenther \u003Cspan class=\"html-italic\">et al\u003C/span>. showed that C2-ceramide led to downregulation of nutrient transporters and consequently restricted the levels of nutrients in the cell leading to cell starvation and cell death (144). C2-ceramide also induced cytoprotective autophagy to inhibit cell death since autophagy inhibition by chloroquine sensitized cells to ceramide (144). In another study it was found that CerS2 downregulation led to no remarkable reduction of very long chain ceramide such as C24 ceramide. However, it increased the levels of long chain ceramide in such as C14 or C16-ceramide (~3-fold) (152). Also, a report showed that accumulation of long chain ceramide induced autophagy but not apoptosis in neuroblastoma cells (SMS-KCNR) (152). From a mechanistic standpoint, downregulation of CerS2 induced the cytoprotective autophagy and UPR. This led to the IRE1 activation which prevented the cell death induction (152). Moreover, vorinostat and sorafenib, two chemotherapeutic agents, have the ability to induce the CD95 activation through via acid sphingomyelinase activation and synthesis of C12, C22 and C26-ceramide (195). C14 and C16 ceramide activated CD95 triggered autophagy which was dependent to PERK. This indicated the cytoprotective effects since ATG5 downregulation increased the lethal effects of sorafenib and vorinostat in HEPG2 cells (195). Some studies have found that dehydroceramide (DHC) could induce protective autophagy, however its exact role is not fully elucidated (196-199). It was shown that XM462 (DHC desaturase inhibitor) delays G1/S transition in the cell cycle by ER stress activation and autophagy induction in HCG27 cells (gastric carcinoma) (196). Also, the inhibition of XM462-induced autophagy leads to a remarkable decrease in cell viability, emphasizing the role of DHC-induced autophagy in promoting cell survival (196). Interestingly, studies have shown that cytoprotective autophagy could be connected to apoptosis. It has been shown that caspases can regulate the autophagy-apoptosis crosstalk (200). Upon activation, caspases can cleave important autophagic proteins like Atg3, Atg4D, Atg5, Atg7, Beclin-1, and p62 leading to their inactivation. (201-205).It was also found that caspase-9 binds Atg7, promoting the lipidation of LC3B-I and formation of LC3B-II. This increases the autophagy activity. On the other hand, interaction between caspase-9 and Atg7 inhibits caspase-9 recruitment to the apoptosome. This inhibits caspase-9 activation and thus apoptosis (94). It was reported that in MCF-7 breast cancer cells caspase-9 knockout inhibits autophagic flux and promotes apoptosis via inhibition of cytoprotective autophagy (206). These finding highlight the intricate interconnection between autophagy and apoptosis. \u003C/div>\u003C/section>\u003Csection id=\"LethalautophagyinductionbyCerSandceramide\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-18\"> Lethal autophagy induction by CerS and ceramide:\u003C/h2>\n\u003Cdiv class=\"html-p\">The role of ceramides in inducing apoptosis is well-known. Ceramides can induce apoptosis in response to different stimuli such as death receptor ligation, hypoxia, growth factor withdrawal, and chemotherapeutic drugs (144). Various studies have established the critical role of ceramides in regulation of lethal autophagy, however the exact mechanisms are still not fully understood. Ceramide triggers lethal autophagy through its effect on the Beclin1 expression. In fact, exogenous C2-ceramide enhances the expression of Beclin1 followed by induction of lethal autophagy in HT-29 colon cancer cells (143). This effect was inhibited when the \u003Cspan class=\"html-italic\">de novo\u003C/span> ceramide synthesis was inhibited by myriocin, suggesting the observed effects are due to C2-ceramide conversion to long chain ceramide (143). Other findings have shown that the mechanism by which C2-ceramide enhances the expression of Becloin1 is through JNK activation. JNK subsequently activates c-Jun which is a transcription factor capable of regulating Beclin1 expression (146). Additionally, chemotherapeutic drugs increase the ceramide synthesis which in turn enhances the expression of Beclin1 and therefore lethal autophagy (207). Other drugs can also result in an increase in the synthesis of ceramides. It was reported that cannabinoids trigger the production of ceramide leading to mTOR inhibition and lethal autophagy in human glioma cells (208).\u003C/div>\n\u003Cdiv class=\"html-p\">Mitophagy is a selective autophagy that targets and removes damaged mitochondria. Mitophagy is therefore critical for the cell to maintain the proper homeostasis. Mitophagy involves two main steps; first the activation of general autophagy and second the selective targeting of the damaged mitochondria via different mediators (209). \u003C/div>\n\u003Cdiv class=\"html-p\">Mitophagy plays an important role in tumor suppression via lethal mitophagy. Lethal mitophagy is defined as the process through which mitochondria are eliminated to the extent that cell undergoes cell death independent of the apoptosic pathway. Prolonged mitophagy results in caspase-dependent apoptosis via release of cathepsin proteases from lysosomes into the cytosol (210, 211). Lethal mitophagy is also induced by CerS1 (and also its product C18-ceramide) and is not dependent on Bax, Bak and caspase 3. It was reported that C18-ceramide synthesized by CerS1 was accumulated on the outer mitochondrial membrane. The exogenous C18-pyridinium ceramide was also localized on the outer mitochondrial membrane due to the pyridinium positive charge. This accumulated C18-ceramide interacts with LC3B-II on the forming autophagosmoe thereby facilitating the engulfment of the mitochondria into the autophagosome (212).\u003C/div>\u003C/section>\u003Csection id=\"RoleofCerSandCeramidesinRegulationofAutophagyinCancer\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-19\"> Role of CerS and Ceramides in Regulation of Autophagy in Cancer \u003C/h2>\n\u003Cdiv class=\"html-p\">CerS and Ceramides have been implicated in the pathogenesis of various cancers due to their regulatory role in autophagy. Recent reports demonstrated that under starvation condition, Bcl-2 expression inhibits autophagy (13), while C2 and C6-ceramide could trigger autophagy in HT-29 colon carcinoma cell line (8). In fact, C2-ceramide increased the BNIP3 accumulation (213) which induced autophagy via interfering with the Beclin1:Bcl2 complex and dissociating Beclin1 (151). The Beclin1:Bcl-2 dissociation is independent of Bcl-2 phosphorylation (214). Therefore, there could be two mechanisms through which ceramide dissociates this complex: 1) JNK1 activation and subsequent Bcl2 phosphorylation or 2) BNIP3 accumulation on mitochondria which interferes with the Beclin1:Bcl2 complex and dissociates Beclin1. It was previously shown that treatment of human HNSCC cells (UM-SCC 22A) with CerS1-mediated generation of C18-ceramide and C18-pyridinium-ceramide induced lethal autophagy was independent of apoptosis (212). The lethal autophagy induced by C18-ceramide was modulated by LC3B-II followed by the selective engulfment of mitochondria via the interaction between ceramide and LC3B-II (212). Dbaibo \u003Cspan class=\"html-italic\">et al\u003C/span>. reported that arsenic trioxide (As2O3) triggered cytotoxic accumulation of overall ceramide in leukemia cells (HuT-102, C91-Pl and MT-2 cells) by inhibiting the activity of GluCeramide synthase (215). Additionally, As2O3 induced both apoptosis and autophagic cell death in these cells. The lethal autophagy was associated with an increase in the Beclin1 expression. Also, this lethal autophagy was inhibited when cells were treated with 3-MA (216). C2-ceramide triggers lethal autophagy (LC3B-II lipidation, formation of autophagosomes, and acidic lysosomes) in U373-MG and T98G cells (malignant glioma) (213). It was found that the mechanism involved was the reduction of mitochondrial membrane potential and BNIP3 activation by C2- ceramide (213). Moreover, the lethal autophagy was mediated by C2-ceramide and triggers the activation of c-Jun by JNK which increases the expression of Beclin-1 in human nasopharyngeal carcinoma (CNE2) and hepatocellular carcinoma (Hep3B) cell lines (146). Treatment of cells with SP600125 (JNK inhibitor) or Beclin1 knockdown by siRNA rescued these cancer cells from C2-ceramide-induced lethal autophagy (146). Also, in leukemia cells (HL-60) and Chinese hamster ovary cells (CHO) ceramide activated protein phosphatases (CAPPs) inhibit mTOR which induces lethal autophagy. However, S1P induces mTOR thereby suppressing lethal autophagy in these cells (217). In another study, it was shown that overexpression of CerS1 triggers lethal autophagy in brain cancer cells (U251 and A172) (204). LC3B-I to LC3B-II conversion and p62 degradation indicated autophagy induction in both cells. CerS1 overexpression and exogenous C18-ceramide greatly enhanced the occurrence of LC3 punctate and formation of autophagosomes in both cells. Additionally, CerS1 induced autophagy via inhibiting the PI3K/AKT pathway in these cells (218). \u003C/div>\n\u003Cdiv class=\"html-p\">A role for CerS has also been described on the outcome of patients with cancer via the regulation of autophagy. The results from a study by Hartmann \u003Cspan class=\"html-italic\">et al.\u003C/span> displayed a correlation between strong CerS5 staining and poor prognosis in colorectal patients. Consistent with this observation, patients with a weak CerS5 staining had a better prognosis. These findings highlight that overexpression of CerS5 is connected to a more aggressive cancer that could be modulated through ceramide levels by currently unknown mechanisms. Changes in the CerS5 expression can interfere with the ceramides balance in colon cancer and therefore promote cancer progression (219). In this study, the proteomic network analysis showed a shift from apoptosis (patients with CerS5 low expression) to autophagy (patients with CerS5 high expression), indicating an association between high CerS5 expression and poor survival (220). Altogether these findings show that altering the ceramide-mediated apoptosis and autophagy activation in patients with high CerS5 expression could possibly be responsible for the link between strong CerS5 expression and poor survival (220). \u003Ca href=\"#preprints-67418-t002\" class=\"html-table\">Table 2\u003C/a> summarizes the roles of various molecules in the ceramide metabolism pathway in regulation of autophagy in different types of cancer discussed in this section.\u003C/div>\u003C/section>\u003Csection id=\"OverallViewonLipidAnalysis\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-20\"> Overall View on Lipid Analysis\u003C/h2>\n\u003Cdiv class=\"html-p\">Over the last decades, the detection of early cancer stages has been the focus of intensive investigation in medical research, especially non-invasive cancer screening methods based on blood analysis (225). Lipids serve a plethora of roles in human metabolism (226), acting as: cell membrane constituents, signaling molecules, energy supply, and energy storage. Changes in lipid concentrations have been reported in various types of cancer (227-233) and lipid metabolic reprogramming has become a hallmark of cancer (228, 233). However, despite the evidence highlighting its relevance to cancer, lipid metabolism remains difficult to analyze due to the lack of standard systematic quantitation methods, lipidome nomenclature, and analysis applied to cancer research (234-236). \u003C/div>\n\u003Cdiv class=\"html-p\">Lipidomics is the study that statistically profiles and quantitates lipid molecules on a large scale (237). The development of lipidomics followed the advances in techniques such as: mass spectrometry (MS), nuclear magnetic resonance spectrometry (NMR), and chromatography. Mass spectrometry uses mass spectrometers to study the mass-to-charge (m/z) ratio of single analytes allowing structural elucidation and quantitation, which includes steps of molecular ions and related fragment generation, ion separation based on their m/z, signal detection, and the intensity of individual ion measurement. Typically, a mass spectrometer consists of an ion source, a mass analyzer system, a detector, and a data processing system. Among the lipid separation methods, liquid high-performance chromatography (HPLC), or simply LC, combined with mass spectrometry (MS), is the primary choice for lipidomics studies due to the sensitivity and selectivity of the analysis (238). MS-based lipidomics can be categorized as non-targeting or targeted lipidomics. The former identifies and quantifies all detected lipids, whereas the latter focuses only on specified lipid classes (239). Notably, the HPLC-MS technique has been reported back to the 1970s (240, 241) as a powerful method for sphingolipids, such as ceramides, detection.. Additionally, numerous other studies have validated this method of ceramides detection over the last decades for humans, animals and plants (242-250). \u003C/div>\n\u003Cdiv class=\"html-p\">Prior to LC-MS analysis, biological samples are prepared through different methods, including liquid-liquid extraction, organic solvent precipitation, and solid phase extraction, separating cellular or fluid lipids from the other constituents and preserving these lipids for further analyses (251). Most procedures extract high solubility lipids in organic solvents (252), such as Folch, Bligh and Dyer, methyl tert-butyl ether, and Butanol:Methanol. \u003C/div>\n\u003Cdiv class=\"html-p\">Once lipids are extracted, samples are ready to undergo mass spectrometry lipid separation (253). A typical workflow of lipidomics analysis of biological samples consists of sample collection and storage, homogenization, internal standard addition for calibration, analysis of lipids with and without separation, data processing and lipid identification, and biomedical application, summarized in (\u003Ca href=\"#preprints-67418-f004\" class=\"html-fig\">Figure 4\u003C/a>).\u003C/div>\n\u003Cdiv class=\"html-p\">The generation of lipid databases and the tools to cross-compare them with experimentally obtained lipidomics data has been an important development. Examples are LipidMaps, LipidBank, LipidHome, LipidBlast, and LipidSearch (254). Moreover, comprehensive mass spectrometry determination of a great range of serum lipids can reveal significant differences between studied groups of diseases, such as cancer, where selected lipid species may indicate potential prognostic biomarkers. For instance, a study by Wolrab et al., 2022, conducted lipidomic profiling of serum to screen for pancreatic cancer in 830 samples. They demonstrated differences in serum versus plasma lipidome concentrations between samples of pancreatic cancer patients and healthy controls using mass spectrometry (MS) based approaches, followed by statistical analysis. They concluded that lipid concentrations in serum were mildly higher than in plasma, yielding an enhanced sensitivity (255).\u003C/div>\n\u003Cdiv class=\"html-p\">After lipidomics and identification of key targets, the next critical step in modern bioinformatics is the integration of systems biology for proteomics, genomics, regulatory genomics, and metabolomics data to provide a further systems-level overview of phenotypic responses of living systems to stimuli, (\u003Ca href=\"#preprints-67418-f005\" class=\"html-fig\">Figure 5\u003C/a>)\u003Cb>.\u003C/b> The conventional statistical methods can be applied to each type of data, such as gene expression, proteomics or lipidomics; however, the integration across these data types, to provide mechanistically meaningful models, remains challenging (256).\u003C/div>\n\u003Cdiv class=\"html-p\">To overcome this integration challenge, a new pipeline strategy developed by Lima et al., 2022, could be an interesting alternative method to validate the altered lipid levels in the samples under study. For example, the automatic text-mining feature of VOSviewer can be used to create coincidence networks of terms associated with the disease of interest, e.g., prostate cancer. These results will be complemented with DisGENET data, a repository of disease associations, and a recent bioinformatics analysis integrating all differentially expressed lipids identified in tumor tissue and serum samples from patients to improve VOSviewer's limited term selection. Later, the results can be integrated with gene expression data from the Gene Expression Omnibus database to correlate gene and protein levels (257). Additional lipid tools and resources for bioinformatic analysis are listed in \u003Ca href=\"#preprints-67418-t003\" class=\"html-table\">Table 3\u003C/a>.\u003C/div>\n\u003Cdiv class=\"html-p\">Despite the technological advances in lipidomics, there are still limitations to this approach. Not only does the diversity and structural complexity of many lipidomes remain a challenge, but understanding, interpreting, and integrating large data sets in conjunction with classical toxicological parameters is a major task. An integrative approach is needed to understand the principles underlying metabolic regulation of a system and how their combined interactions, in conjunction with variations in clinical phenotype, lead to pathophysiology. This challenge requires new data exploration strategies such as analysis workflows, statistical and computational algorithms for data integration, filtering, and network analysis, if we are to be able to truly transform the large multivariate data collected in such metabolomic experiments into new biological insights.\u003C/div>\n\u003Cdiv class=\"html-p\">Artificial intelligence (AI) methods are advancing rapidly, and breakthrough technologies are changing the landscape of health research with high diagnostic and prognostic value. Machine learning methods (also referred to as complex AI), supervised and unsupervised, are used by AI systems to account for complex interactions, either by collecting input data, including biofluids and tissues, to predict output values based on new input samples, or by finding underlying patterns in an unlabeled data set to identify subclusters and outliers in the data.\u003C/div>\n\u003Cdiv class=\"html-p\">Although AI methods have been well described in other areas of healthcare, there is little information on the value of using AI methods to understand the complex nature of phlebotomy. Machine learning has enabled the discovery of more robust biomarkers that have been approved by the Food and Drug Administration (FDA) to guide treatment, which can be very valuable in disease. Additionally, biomarkers serve as powerful clinical predictors that can be used to individualize treatment options for patients to achieve desired outcomes. The machine learning approach called Random Forest (RF) can integrate multiple data types and combine classical clinical chemistry and toxicology test results with multivariate metabolomic and lipidomic data. Several authors have previously adapted RF methods for data integration (also referred to as data fusion) that developed and evaluated a fuzzy logic combination with RF to prioritize the discriminative features of gene expression data.\u003C/div>\n\u003Cdiv class=\"html-p\">In summary, to move towards standardization, minimum requirements for lipid studies should become routine. As described by McDonald et al., 2022, the nine major categories for conducting lipidomics research are 1) overall study design, 2) pre-analytics, 3) lipid extraction, 4) analytical platform, 5) lipid identification, 6) lipid quantification, 7) quality control, 8) method validation, and 9) data reporting (235). \u003C/div>\u003C/section>\u003Csection id=\"ConclusionandFutureDirections\" type>\u003Ch2 data-nested=\"1\" id=\"preprints-h2-21\"> Conclusion and Future Directions\u003C/h2>\n\u003Cdiv class=\"html-p\">As we discussed ceramides may play essential roles response to different cancer therapy strategies through apoptosis and autophagy pathways, therefore targeting ceramides and their biosynthesis pathway could be beneficial for developing new cancer therapy methods. It can be seen that the development of new therapeutics that interact with novel pharmacological targets is urgently needed. All anti-cancer drugs can be classified into two major categories: small molecules and monoclonal antibodies (258). Small-molecule drugs are preferable in drug development compared to antibodies due to better pharmacokinetic properties, lower preclinical and clinical costs, and large-scale production and purification (259, 260).\u003C/div>\n\u003Cdiv class=\"html-p\">Modulation of the sphingolipid/ceramide-controlled apoptosis with small molecules represents an important tool and addition to the current anticancer therapies. Currently, there have been only five clinical trials of different phases that involved ceramide as the active drug for the treatment of various cancers (\u003Ca href=\"#preprints-67418-t004\" class=\"html-table\">Table 4\u003C/a>). However, none of these studies explore the new small molecules as modulators of ceramide pathways. \u003C/div>\n\u003Cdiv class=\"html-p\">The biosynthesis of ceramides has been done via two pathways: de novo sphingolipid pathway and sphingolipid-salvage pathway (\u003Ca href=\"#preprints-67418-f006\" class=\"html-fig\">Figure 6\u003C/a>) (261). Several different CerS have been identified in both pathways, and modulation of these enzymes is reported in many mechanisms including apoptosis and protein kinase inhibition (262-264). Several studies showed that decreased levels of ceramides are reported in many malignancies and tumor progression, while ceramide levels are observed to be increased by chemotherapies (265-268). Additionly, several tyrosine kinase inhibitors (TKI) increase production of CerS on a nuclear level, which in turn leads to upregulation of ceramide biosynthesis (269, 270). Recently it has been reported that the combination of a novel sphingosine kinase 2 inhibitor ABC294640, and TKI displays synergistic anti-cancer effects in multiple myeloma and cholangiocarcinoma (271, 272). Thus, the small molecules that can modulate ceramide pathways represent valid targets for anticancer drug discovery, especially in combination with currently available TKI-based anti-cancer therapies (\u003Ca href=\"#preprints-67418-f007\" class=\"html-fig\">Figure 7\u003C/a>) since previous studies suggests that there may be functional crosstalk between inhibiting tyrosine kinases overexpressed in certain tumors and dysregulation of ceramide synthesis in malignancies. \u003C/div>\n\u003Cdiv class=\"html-p\">It should be noted, however, that the co-administration of a tyrosine kinase inhibitor and a ceramide modulator would have many drawbacks, including the possibility of drug-drug interactions \u003Cspan class=\"html-italic\">in vivo\u003C/span> which complicates preclinical/clinical studies and the drug development process in the long term. One novel drug design strategy is the use of multi-target designed ligands (MTDLs), i.e. a polypharmacology approach. MTDLs are small molecules designed to simultaneously interact with multiple biological targets relevant for a given pathology (273). Furthermore, they have several advantages including a potential for higher efficacy and fewer side-effects compared to cocktail drugs and could avoid unpredictable pharmacokinetic and pharmacodynamics relationships (274). To develop new anticancer MTDL therapeutics, the first step will be to determine the similarities and potential overlap in the structures of already existing TKIs and ceramide modulators for targets of interest (\u003Ca href=\"#preprints-67418-f008\" class=\"html-fig\">Figure 8\u003C/a>). In the case that the target does not have any known modulators, drug design can be achieved using knowledge of characterized active and/or allosteric binding sites by X-ray crystallography in combination with virtual-ligand screening (VLS). A general scaffold, or core of a chemical structure, or even particular chemical groups can be used for this purpose. Once the specific structures important for the activity at the targets of interests are identified, the pharmacophore - the area responsible for the biological activity for these targets, can be defined. Next, the pharmacophores can be combined in three different fashions; they can be linked, fused or merged (275). Linked MTDLs are designed by simple linking (anchoring) of two or more individual pharmacophores via a linking group. Fused MTDLs are similar, but the pharmacophores are connected directly, without a linking group. Both, linked and fused types of multitarget compounds usually have molecular weights above 500 and increased lipophilicity, which are important for drug design but could lead to poor solubility and permeability according to Lipinski Rule of Five.(276) However, these two types of conjugated pharmacophores are a valuable tool in the early structure-activity relationship studies and the discovery of the multitarget activity. Merged pharmacophores, on the other hand, are of the greatest interest in the multitarget drug discovery and there are many successful applications of this method reported.(277-279) \u003C/div>\n\u003Cdiv class=\"html-p\">Here we propose that the key pharmacophoric elements required to interact with each target of interest are combined (merged) into one single pharmacophore. Once pharmacophores are identified and combined, the next step is to preform extensive SAR studies in order to determine the best possible groups that can be tolerated on the particular pharmacophores. Next, the standard structure-based drug design approach can be followed: a) Using computer drug design tools, several additional compounds that could interact with the amino acid residues present in the binding site can be designed; b) Synthesize the second generation of lead compound(s) and test them for activity; c) Crystallographic determination of the lead compound with both targets which should identify the actual binding interactions and provide better insight in the other possible interactions. d) Finally, another more specific SAR study that will optimize the drug-target interactions should be performed. \u003C/div>\n\u003Cdiv class=\"html-p\">In summary, one new rational approach is to design a single drug that would be able to interact simultaneously as an inhibitor of specific protein kinases and a modulator of certain ceramides involved in the cancer pathology. Based on the previous studies mentioned above, the novel drug should target the allosteric-binding site of the protein kinases, since the gene sequences of the allosteric sites consist of fewer homologues than those of the active sites, these drugs will be more specific. One way to identify the ceramides target involved in the cancer pathogenesis is to perform lipidomics analysis and compare lipid distribution between cancer and wild-type cells, i.e., the up- or down-regulated lipids that could represent a novel target for the MTDLs.\u003C/div>\u003C/section>\n \n \u003Csection class=\"html-notes\">\u003Ch2 id=\"preprints-h2-22\">Author Contributions\u003C/h2>\n\u003Cdiv class=\"html-p\">Javad Alizadeh, Shahla Shojaei, Joadi Jacobs and Shahrokh Lorzadeh prepared the draft of general ceramide synthases, ceramides and apoptosis and autophagy. Simone C da Silva Rosa, Amir Ravandi, and Rui Vitorino participated in preparation of lipid analysis and lipidomic section. Xiaohui Weng, and Stevan Pecic prepared the drug development part. Saeid Ghavami designed and lead the whole project, and finalize the whole manuscript. .\u003C/div>\u003C/section>\u003Csection id=\"html-references_list\">\u003Ch2 id=\"preprints-h2-23\">References\u003C/h2>\n\u003Col class=\"html-xxx\">\n\u003Cli id=\"B1-preprints-67418\" class=\"html-x\" data-content=\"1.\">Field BC, Gordillo R, Scherer PE. The Role of Ceramides in Diabetes and Cardiovascular Disease Regulation of Ceramides by Adipokines. Frontiers in Endocrinology. 2020;11. [\u003Ca href=\"https://doi.org/10.3389/fendo.2020.569250\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B2-preprints-67418\" class=\"html-x\" data-content=\"2.\">Levy M, Futerman AH. Mammalian ceramide synthases. IUBMB Life. 2010;62(5):347-56. 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[\u003Ca href=\"https://doi.org/10.3389/fendo.2020.00483\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B263-preprints-67418\" class=\"html-xxx\" data-content=\"263.\">Park JW, Park WJ, Futerman AH. Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta. 2014;1841(5):671-81. [\u003Ca href=\"https://doi.org/10.1016/j.bbalip.2013.08.019\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B264-preprints-67418\" class=\"html-xxx\" data-content=\"264.\">Mullen TD, Hannun YA, Obeid LM. Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J. 2012;441(3):789-802. [\u003Ca href=\"https://doi.org/10.1042/bj20111626\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B265-preprints-67418\" class=\"html-xxx\" data-content=\"265.\">Coant N, Sakamoto W, Mao C, Hannun YA. Ceramidases, roles in sphingolipid metabolism and in health and disease. Adv Biol Regul. 2017;63:122-31. [\u003Ca href=\"https://doi.org/10.1016/j.jbior.2016.10.002\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B266-preprints-67418\" class=\"html-xxx\" data-content=\"266.\">Wang K, Wei Y, Xu R, Li Y, Mao C. Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer. Adv Exp Med Biol. 2022;1372:157-68.\u003C/li>\n\u003Cli id=\"B267-preprints-67418\" class=\"html-xxx\" data-content=\"267.\">Xu R, Antwi Boasiako P, Mao C. Alkaline ceramidase family: The first two decades. Cell Signal. 2021;78:109860. 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[\u003Ca href=\"https://doi.org/10.1007/s00277-011-1212-5\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B270-preprints-67418\" class=\"html-xxx\" data-content=\"270.\">Camgoz A, Gencer EB, Ural AU, Avcu F, Baran Y. Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloid leukemia cells. Leuk Lymphoma. 2011;52(8):1574-84.\u003C/li>\n\u003Cli id=\"B271-preprints-67418\" class=\"html-xxx\" data-content=\"271.\">Sundaramoorthy P, Gasparetto C, Kang Y. The combination of a sphingosine kinase 2 inhibitor (ABC294640) and a Bcl-2 inhibitor (ABT-199) displays synergistic anti-myeloma effects in myeloma cells without a t(11;14) translocation. Cancer Med. 2018;7(7):3257-68. [\u003Ca href=\"https://doi.org/10.1002/cam4.1543\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B272-preprints-67418\" class=\"html-xxx\" data-content=\"272.\">Ding X, Zhang Y, Huang T, Xu G, Peng C, Chen G, et al. Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma. Am J Cancer Res. 2019;9(3):546-61.\u003C/li>\n\u003Cli id=\"B273-preprints-67418\" class=\"html-xxx\" data-content=\"273.\">Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51(3):347-72.\u003C/li>\n\u003Cli id=\"B274-preprints-67418\" class=\"html-xxx\" data-content=\"274.\">Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W, et al. Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms. Journal of Medicinal Chemistry. 2019;62(20):8881-914. [\u003Ca href=\"https://doi.org/10.1021/acs.jmedchem.9b00017\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B275-preprints-67418\" class=\"html-xxx\" data-content=\"275.\">Proschak E, Stark H, Merk D. Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds. Journal of Medicinal Chemistry. 2019;62(2):420-44. [\u003Ca href=\"https://doi.org/10.1021/acs.jmedchem.8b00760\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B276-preprints-67418\" class=\"html-xxx\" data-content=\"276.\">Benet LZ, Hosey CM, Ursu O, Oprea TI. BDDCS, the Rule of 5 and drugability. Adv Drug Deliv Rev. 2016;101:89-98. [\u003Ca href=\"https://doi.org/10.1016/j.addr.2016.05.007\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B277-preprints-67418\" class=\"html-xxx\" data-content=\"277.\">Ma H, Huang B, Zhang Y. Recent advances in multitarget-directed ligands targeting G-protein-coupled receptors. Drug Discov Today. 2020;25(9):1682-92. [\u003Ca href=\"https://doi.org/10.1016/j.drudis.2020.07.004\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B278-preprints-67418\" class=\"html-xxx\" data-content=\"278.\">Stelitano G, Sammartino JC, Chiarelli LR. Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis. Molecules. 2020;25(5):1239. [\u003Ca href=\"https://doi.org/10.3390/molecules25051239\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003Cli id=\"B279-preprints-67418\" class=\"html-xxx\" data-content=\"279.\">Wilt S, Kodani S, Valencia L, Hudson PK, Sanchez S, Quintana T, et al. Further exploration of the structure-activity relationship of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors. Bioorganic & Medicinal Chemistry. 2021;51:116507. [\u003Ca href=\"https://doi.org/10.1016/j.bmc.2021.116507\" class=\"cross-ref\" target=\"_blank\" rel=\"noopener noreferrer\">CrossRef\u003C/a>]\u003C/li>\n\u003C/ol>\u003C/section>\u003Csection id=\"FiguresandTables\" type=\"display-objects\">\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f001\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f001\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\" alt=\"Preprints 67418 g001\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f001\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 1.\u003C/b>\n Main metabolic pathways of ceramide metabolism. Three pathways help synthesize ceramide in the cell namely, sphingomyelin hydrolysis pathway, de novo pathway, and salvage pathway. De novo sphingolipid biosynthesis begins with the condensation of serine and palmitoyl-CoA, which then is catalyzed by serine palmitoyltransferase enzyme. Its product, 3-ketosphinganine, is reduced to sphinganine by 3-ketosphinganine reductase. Next, dihydroceramide synthases contribute in synthesis of dihydroceramides using sphinganine and fatty acyls, which are then reduced by dihydroceramide desaturase to produce ceramides with different acyl chain lengths. Ceramide is also synthesized by other metabolic pathways (salvage and sphingomyelin hydrolysis). The ceramide produced via these pathways will be used as a mediator in the regulation of subsequent downstream pathways (enzymes shown in red italics).\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f001\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f001\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 1.\u003C/b>\n Main metabolic pathways of ceramide metabolism. Three pathways help synthesize ceramide in the cell namely, sphingomyelin hydrolysis pathway, de novo pathway, and salvage pathway. De novo sphingolipid biosynthesis begins with the condensation of serine and palmitoyl-CoA, which then is catalyzed by serine palmitoyltransferase enzyme. Its product, 3-ketosphinganine, is reduced to sphinganine by 3-ketosphinganine reductase. Next, dihydroceramide synthases contribute in synthesis of dihydroceramides using sphinganine and fatty acyls, which are then reduced by dihydroceramide desaturase to produce ceramides with different acyl chain lengths. Ceramide is also synthesized by other metabolic pathways (salvage and sphingomyelin hydrolysis). The ceramide produced via these pathways will be used as a mediator in the regulation of subsequent downstream pathways (enzymes shown in red italics).\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\" alt=\"Preprints 67418 g001\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g001.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f002\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f002\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\" alt=\"Preprints 67418 g002\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f002\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 2.\u003C/b>\n Role of ceramide in regulation of apoptosis via different mechanisms. Figure shows how ceramides regulate the apoptosis via formation of ceramide channels and interaction with anti-apoptotic proteins like Bcl-xL and pro-apoptotic proteins such as Bax. Ceramides with various fatty acyl chain lengths can perforate into the mitochondrial outer membranes. These channels are layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure. Ceramide channels contribute to the permeabilization of the mitochondrial outer membrane. This leads to the release of pro-apoptotic proteins such as cytochrome c from the intermembrane space into the cytosol and thus apoptosis. Additionally, ceramides help in the oligomerization of Bax molecules during apoptosis. Furthermore, ceramide can influence the Bcl2 phosphorylation and therefore its anti-apoptotic function. Ceramide activates mitochondrial protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) that induces Bcl2 dephosphorylation and therefore ceramide-induced apoptosis.\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f002\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f002\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 2.\u003C/b>\n Role of ceramide in regulation of apoptosis via different mechanisms. Figure shows how ceramides regulate the apoptosis via formation of ceramide channels and interaction with anti-apoptotic proteins like Bcl-xL and pro-apoptotic proteins such as Bax. Ceramides with various fatty acyl chain lengths can perforate into the mitochondrial outer membranes. These channels are layers of ceramide molecules that are stacked in an anti-parallel way on top of each other forming ceramide columns in a barrel-like structure. Ceramide channels contribute to the permeabilization of the mitochondrial outer membrane. This leads to the release of pro-apoptotic proteins such as cytochrome c from the intermembrane space into the cytosol and thus apoptosis. Additionally, ceramides help in the oligomerization of Bax molecules during apoptosis. Furthermore, ceramide can influence the Bcl2 phosphorylation and therefore its anti-apoptotic function. Ceramide activates mitochondrial protein phosphatase 2A (PP2A) (a physiologic Bcl2 phosphatase) that induces Bcl2 dephosphorylation and therefore ceramide-induced apoptosis.\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\" alt=\"Preprints 67418 g002\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g002.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f003\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f003\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\" alt=\"Preprints 67418 g003\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f003\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 3.\u003C/b>\n Role of ceramide in regulation of autophagy by different mechanisms. Ceramide activates JNK which leads to the phosphorylation of BCL2 resulting in the dissociation of Beclin1 from the Beclin1-Bcl2 complex. Beclin1 then can participate in the formation of autophagosomes. Also, localized ceramide on the outer mitochondrial membrane can act as a LC3II-receptor, thereby bringing the mitochondria into the forming autophagosome. Figure also shows the cross talk between ER and autophagy pathway. Ceramide activates the ATF6 in the ER membrane which subsequently activates CHOP. Activation of CHOP inhibits the phosphorylation of BCL2 by JNK. .\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f003\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f003\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 3.\u003C/b>\n Role of ceramide in regulation of autophagy by different mechanisms. Ceramide activates JNK which leads to the phosphorylation of BCL2 resulting in the dissociation of Beclin1 from the Beclin1-Bcl2 complex. Beclin1 then can participate in the formation of autophagosomes. Also, localized ceramide on the outer mitochondrial membrane can act as a LC3II-receptor, thereby bringing the mitochondria into the forming autophagosome. Figure also shows the cross talk between ER and autophagy pathway. Ceramide activates the ATF6 in the ER membrane which subsequently activates CHOP. Activation of CHOP inhibits the phosphorylation of BCL2 by JNK. .\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\" alt=\"Preprints 67418 g003\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g003.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f004\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f004\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\" alt=\"Preprints 67418 g004\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f004\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 4.\u003C/b>\n Major steps in lipid preparation and analysis involve 1) sample collection (serum, plasma, urine, cell, organ/tissue); 2) lipid extraction (folch method, blingh-dyer method, MTBE method, BUME method); 3) Lipid separation (TLC, GC, LC, SFC); 4) mass spectrometry data acquisition (MS combined with chromatography, shot gun MS, MS imaging); 5) data analysis (identification, quantification, pathway analysis); 6) interpretation (biomarkers, therapeutic targets).\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f004\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f004\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 4.\u003C/b>\n Major steps in lipid preparation and analysis involve 1) sample collection (serum, plasma, urine, cell, organ/tissue); 2) lipid extraction (folch method, blingh-dyer method, MTBE method, BUME method); 3) Lipid separation (TLC, GC, LC, SFC); 4) mass spectrometry data acquisition (MS combined with chromatography, shot gun MS, MS imaging); 5) data analysis (identification, quantification, pathway analysis); 6) interpretation (biomarkers, therapeutic targets).\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\" alt=\"Preprints 67418 g004\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g004.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f005\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f005\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\" alt=\"Preprints 67418 g005\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f005\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 5.\u003C/b>\n Bioinformatics guide to lipidomics integrative analysis.\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f005\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f005\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 5.\u003C/b>\n Bioinformatics guide to lipidomics integrative analysis.\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\" alt=\"Preprints 67418 g005\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g005.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f007\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f007\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\" alt=\"Preprints 67418 g006\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f007\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 7.\u003C/b>\n Drug design strategies summary and potential binding sites on Bcr-Abl tyrosine kinase. Tyrosine kinases use ATP as a source of phosphate group for the phosphorylation reaction of the phenol groups on the tyrosine residues. A) Substrate (orange) binding to substrate binding site. Huang et al. used peptide inhibitors that binds to the substrate-binding region and were able to inhibit in vitro Bcr-Abl kinase in the micromolar range.\u003Csup>Ref\u003C/sup> However, peptides have several disadvantages to be used as the therapeutics in the clinical settings, and the small molecule drug that binds and significantly inhibits substrate-based region for Bcr-Abl kinase has not yet been reported. B) The binding site for ATP is usually located close to the substrate binding site. Imatinib (shown in red) binds to ATP-binding region. A known T315I mutation, located in ATP-binding site, causes a drug resistance to imatinib, and makes this binding site less attractive target for drug design. C) Allosteric-binding site with asciminib shown in blue. The first discovered allosteric site on Bcr-Abl has been named myristoyl-binding region, since myristoyl acid binds in this binding region and produce inactivation of the kinase. This highly hydrophobic pocket represents a novel target for the site-specific drug design strategy. More drug-like small molecules that could mimic myristate could theoretically bind there and inhibit the kinase. D) A potential, novel dual inhibitor strategy: substrate-binding ligand (L1) is anchored to the ATP-binding ligand (L2) – a potential small molecule drug could bind simultaneously to the allosteric site and ATP-binding region.\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f007\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f007\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 7.\u003C/b>\n Drug design strategies summary and potential binding sites on Bcr-Abl tyrosine kinase. Tyrosine kinases use ATP as a source of phosphate group for the phosphorylation reaction of the phenol groups on the tyrosine residues. A) Substrate (orange) binding to substrate binding site. Huang et al. used peptide inhibitors that binds to the substrate-binding region and were able to inhibit in vitro Bcr-Abl kinase in the micromolar range.\u003Csup>Ref\u003C/sup> However, peptides have several disadvantages to be used as the therapeutics in the clinical settings, and the small molecule drug that binds and significantly inhibits substrate-based region for Bcr-Abl kinase has not yet been reported. B) The binding site for ATP is usually located close to the substrate binding site. Imatinib (shown in red) binds to ATP-binding region. A known T315I mutation, located in ATP-binding site, causes a drug resistance to imatinib, and makes this binding site less attractive target for drug design. C) Allosteric-binding site with asciminib shown in blue. The first discovered allosteric site on Bcr-Abl has been named myristoyl-binding region, since myristoyl acid binds in this binding region and produce inactivation of the kinase. This highly hydrophobic pocket represents a novel target for the site-specific drug design strategy. More drug-like small molecules that could mimic myristate could theoretically bind there and inhibit the kinase. D) A potential, novel dual inhibitor strategy: substrate-binding ligand (L1) is anchored to the ATP-binding ligand (L2) – a potential small molecule drug could bind simultaneously to the allosteric site and ATP-binding region.\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\" alt=\"Preprints 67418 g006\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g006.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f006\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f006\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\" alt=\"Preprints 67418 g007\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f006\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 6.\u003C/b>\n De novo and Salvage pathways of ceramide synthesis. Enzyme ceramide synthase (CerS) is involved in both pathways and represents a valid target for drug design of ceramide synthesis modulators.\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f006\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f006\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 6.\u003C/b>\n De novo and Salvage pathways of ceramide synthesis. Enzyme ceramide synthase (CerS) is involved in both pathways and represents a valid target for drug design of ceramide synthesis modulators.\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\" alt=\"Preprints 67418 g007\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g007.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig-wrap\" id=\"preprints-67418-f008\">\n \u003Cdiv class=\"html-fig_img\">\n \u003Cdiv class=\"html-figpopup html-figpopup-link\" href=\"#fig_body_display_preprints-67418-f008\">\n \u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\" alt=\"Preprints 67418 g008\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\">\n \u003Ca class=\"html-expand html-figpopup\" href=\"#fig_body_display_preprints-67418-f008\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-fig_description\">\n \u003Cb>Figure 8.\u003C/b>\n Polypharmacological approach. Two or more biological targets are selected, and small molecule modulators are identified. Upon determining the pharmacophores, the multi-target designed ligands (MTDLs) are created by linking, fusing or merging pharmacophores. The merged pharmacophores are of the particular interest in the drug discovery due to several pharmacokinetic and pharmacodynamic advantage properties. Once MTDL is designed, synthesized and preliminary structure-activity relationship study is established, the computer-based drug design should follow up in order to create the second generation of lead compounds. Next should follow the crystallographic determination of the lead compound with both targets to better understand the binding interactions of MTDLs with both targets. More specific SAR study that will optimize the drug-target interactions should follow up. .\n\u003C!-- \u003Cp>\u003Ca class=\"html-figpopup\" href=\"#fig_body_display_preprints-67418-f008\">\n Click here to enlarge figure\n \u003C/a>\u003C/p> -->\n\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-fig_show mfp-hide\" id=\"fig_body_display_preprints-67418-f008\">\n \u003Cdiv class=\"html-caption\"> \u003Cb>Figure 8.\u003C/b>\n Polypharmacological approach. Two or more biological targets are selected, and small molecule modulators are identified. Upon determining the pharmacophores, the multi-target designed ligands (MTDLs) are created by linking, fusing or merging pharmacophores. The merged pharmacophores are of the particular interest in the drug discovery due to several pharmacokinetic and pharmacodynamic advantage properties. Once MTDL is designed, synthesized and preliminary structure-activity relationship study is established, the computer-based drug design should follow up in order to create the second generation of lead compounds. Next should follow the crystallographic determination of the lead compound with both targets to better understand the binding interactions of MTDLs with both targets. More specific SAR study that will optimize the drug-target interactions should follow up. .\u003C/div>\n \u003Cdiv class=\"html-img\">\u003Cimg data-large=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\" data-original=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\" alt=\"Preprints 67418 g008\" src=\"https://www.preprints.org/frontend/picture/ms_xml/manuscript/421f15bb4029d40b83f5bd0d34dd7658/preprints-67418-g008.png\">\u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-table-wrap\" id=\"preprints-67418-t001\">\n \u003Cdiv class=\"html-table_wrap_td\">\n \u003Cdiv class=\"html-tablepopup html-tablepopup-link\" href=\"#table_body_display_preprints-67418-t001\">\n \u003Cimg src=\"https://pub.mdpi-res.com/img/table.png\">\n \u003Ca class=\"html-expand html-tablepopup\" href=\"#table_body_display_preprints-67418-t001\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-table_wrap_discription\">\n \u003Cb>Table 1.\u003C/b>\n Different CerS synthesize ceramides with various acyl chain lengths.\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-table_show mfp-hide \" id=\"table_body_display_preprints-67418-t001\">\n \n\n \u003Cdiv class=\"html-caption\">\n\u003Cb>Table 1.\u003C/b>\n Different CerS synthesize ceramides with various acyl chain lengths.\u003C/div>\n \u003Ctable>\n \u003Cthead>\u003Ctr>\n\u003Cth align=\"left\" valign=\"top\" style=\"border:solid thin\" class=\"html-align-left\">CerS\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Synthesized ceramide\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Ref\u003C/th>\n\u003C/tr>\u003C/thead>\n\u003Ctbody>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C18\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(5)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS2\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C20, \u003Cbr>C22, \u003Cbr>C24, \u003Cbr>C26\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(6)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS3\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C22, \u003Cbr>C24, \u003Cbr>C26\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(7)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS4\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C18, \u003Cbr>C20\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(8)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS5\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C16\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(9)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CerS6\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C14, \u003Cbr>C16\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(10)\u003C/td>\n\u003C/tr>\n\u003C/tbody>\n \u003C/table>\n\n\n\n\u003C/div>\n\u003Cdiv class=\"html-table-wrap\" id=\"preprints-67418-t002\">\n \u003Cdiv class=\"html-table_wrap_td\">\n \u003Cdiv class=\"html-tablepopup html-tablepopup-link\" href=\"#table_body_display_preprints-67418-t002\">\n \u003Cimg src=\"https://pub.mdpi-res.com/img/table.png\">\n \u003Ca class=\"html-expand html-tablepopup\" href=\"#table_body_display_preprints-67418-t002\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-table_wrap_discription\">\n \u003Cb>Table 2.\u003C/b>\n Summary of the role of ceramides and enzymes involved in ceramide metabolism in autophagy regulation in different cancers.\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-table_show mfp-hide \" id=\"table_body_display_preprints-67418-t002\">\n \n\n \u003Cdiv class=\"html-caption\">\n\u003Cb>Table 2.\u003C/b>\n Summary of the role of ceramides and enzymes involved in ceramide metabolism in autophagy regulation in different cancers.\u003C/div>\n \u003Ctable>\n \u003Cthead>\u003Ctr>\n\u003Cth align=\"left\" valign=\"top\" style=\"border:solid thin\" class=\"html-align-left\">Ceramide\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Mechanism of Action\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Effect on Autophagy\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Cancer Type\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Ref\u003C/th>\n\u003C/tr>\u003C/thead>\n\u003Ctbody>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C2-ceramide\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">BNIP3 accumulation, Beclin1:Bcl-2 dissociation\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Colon carcinoma cell line (HT-29)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(151, 213)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C18-ceramide \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">ceramide and LC3B-II interaction \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">HNSCC cells (UM-SCC 22A)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(212)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">As2O3 induced accumulation of overall ceramide \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">upregulation of Beclin-1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Leukemia cells (HuT-102, C91-Pl, MT-2)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(215)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C2-ceramide\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">mitochondrial membrane potential decrease, BNIP3 activation\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Glioma cells (U373-MG and T98G)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(213)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C2-ceramide\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">c-Jun activation through JNK signaling\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Nasopharyngeal carcinoma cells (CNE2), hepatocellular carcinoma cells (Hep3B)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(146)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CAPPs (ceramide activated protein phosphatases)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Akt-mTOR pathway inhibition \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Leukemia cells (HL-60), Chinese hamster ovary cells (CHO)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(221)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">S1P\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Akt-mTOR pathway activation\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy inhibition\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Leukemia cells (HL-60), Chinese hamster ovary cells (CHO)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(221)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C6-ceramide \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">mitochondrial permeabilization\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Breast cancer cells (MCF-7)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(222)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C18-ceramide\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">increased the formation of autophagosomes, PI3K/AKT pathway inhibition\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">brain cancer cells (U251 and A172)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(218)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">inhibition of SphK1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">ATG5 and Beclin-1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">HCT116 human colon cancer cells\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(223)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">inhibition of SphK2 by ABC294640\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">accumulation of intracellular ceramides\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">lethal autophagy induction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">herpes virus-related tumors \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">(224)\u003C/td>\n\u003C/tr>\n\u003C/tbody>\n \u003C/table>\n\n\n\n\u003C/div>\n\u003Cdiv class=\"html-table-wrap\" id=\"preprints-67418-t003\">\n \u003Cdiv class=\"html-table_wrap_td\">\n \u003Cdiv class=\"html-tablepopup html-tablepopup-link\" href=\"#table_body_display_preprints-67418-t003\">\n \u003Cimg src=\"https://pub.mdpi-res.com/img/table.png\">\n \u003Ca class=\"html-expand html-tablepopup\" href=\"#table_body_display_preprints-67418-t003\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-table_wrap_discription\">\n \u003Cb>Table 3.\u003C/b>\n Publicly available lipid tools and resources for bioinformatic analysis.\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-table_show mfp-hide \" id=\"table_body_display_preprints-67418-t003\">\n \n\n \u003Cdiv class=\"html-caption\">\n\u003Cb>Table 3.\u003C/b>\n Publicly available lipid tools and resources for bioinformatic analysis.\u003C/div>\n \u003Ctable>\n \u003Cthead>\u003Ctr>\n\u003Cth align=\"left\" valign=\"top\" style=\"border:solid thin;background:#D9D9D9\" class=\"html-align-left\">Name\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin;background:#D9D9D9\" class=\"html-align-left\">Description\u003C/th>\n\u003Cth align=\"left\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin;background:#D9D9D9\" class=\"html-align-left\">URL\u003C/th>\n\u003C/tr>\u003C/thead>\n\u003Ctbody>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidMaps\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">The web portal gateway to Lipidomics resources; classification of biological lipids, dividing them into eight general categories\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://www.lipidmaps.org/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidFinder\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">An open-source Python workflow which searches several different databases to obtain putative identification of lipids\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://www.lipidmaps.org/resources/tools/lipidfinder/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidSig\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Allows the exploration of the quality and the clustering of samples, correlation between lipids and samples, and the expression and composition of lipids\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">http://www.chenglab.cmu.edu.tw/lipidsig/Profiling/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidSuite\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Workflow for preprocessing, exploration, differential analysis, and enrichment of untargetted and targeted lipidomics\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://suite.lipidr.org/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidPedia\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Lipid encyclopedia; provides associated biomedical information through text-mining strategy in literatures\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://lipidpedia.cmdm.tw/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidBank\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">The official database of Japanese Conference on the Biochemistry of Lipids (JCBL)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://lipidbank.jp/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidHome\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Database of theoretical lipid structures derived from a seed set of lipid sub classes and some lipid chemical space constraints \u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://apps.lifs.isas.de/lipidhome/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidBlast\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">In silico tandem mass spectrometry database for lipid identification\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://fiehnlab.ucdavis.edu/projects/lipidblast\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LipidMatch\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">An automated workflow for rule-based lipid identification using untargeted high-resolution tandem mass spectrometry data\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">http://secim.ufl.edu/secim-tools/lipidmatch/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">ONION\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Functional approach for integration of lipidomics and transcriptomics data\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://github.com/wjurkowski/ONION\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">LINT-Web\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Web-based Lipidomic data mining tool using intra-omic integrative correlation strategy\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">http://www.lintwebomics.info/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">MetaboAnalyst\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Platform dedicated for metabolomics data analysis via user-friendly, web-based interface.\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://www.metaboanalyst.ca/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">SwissTarget Prediction\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Estimate the most probable macromolecular targets of a small molecule, assumed as bioactive\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">http://www.swisstargetprediction.ch/predict.php\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">String\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Protein-Protein interaction networks functional enrichment analysis\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://string-db.org/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">Stitch\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Resource to explore known and predicted interactions of chemicals and proteins\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">http://stitch.embl.de/\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">DisGeNET\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Integrative database with human gene-disease associations (GDAs) and variant-disease associations (VDAs) from various repositories including Mendelian, complex and environmental diseases\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://www.disgenet.org/search\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin;background:#F2F2F2\" class=\"html-align-left\">VosViewer\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Software tool for constructing and visualizing bibliometric networks\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">https://www.vosviewer.com/\u003C/td>\n\u003C/tr>\n\u003C/tbody>\n \u003C/table>\n\n\n\n\u003C/div>\n\u003Cdiv class=\"html-table-wrap\" id=\"preprints-67418-t004\">\n \u003Cdiv class=\"html-table_wrap_td\">\n \u003Cdiv class=\"html-tablepopup html-tablepopup-link\" href=\"#table_body_display_preprints-67418-t004\">\n \u003Cimg src=\"https://pub.mdpi-res.com/img/table.png\">\n \u003Ca class=\"html-expand html-tablepopup\" href=\"#table_body_display_preprints-67418-t004\">\u003C/a>\n \u003C/div>\n\n \u003C/div>\n \u003Cdiv class=\"html-table_wrap_discription\">\n \u003Cb>Table 4.\u003C/b>\n Studies in adults with ceramide as treatment for cancer.\n \u003C/div>\n\u003C/div>\n\u003Cdiv class=\"html-table_show mfp-hide \" id=\"table_body_display_preprints-67418-t004\">\n \n\n \u003Cdiv class=\"html-caption\">\n\u003Cb>Table 4.\u003C/b>\n Studies in adults with ceramide as treatment for cancer.\u003C/div>\n \u003Ctable>\n \u003Ctbody>\n\u003Ctr>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border:solid thin\" class=\"html-align-center\">#\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Status\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Title\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Conditions\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Drug(s) used\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Phase\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Eligible\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Location\u003C/td>\n\u003Ctd align=\"center\" valign=\"top\" style=\"border-top:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-center\">Reference (NCT)\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Completed\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Topical Ceramide Lipids As Treatment For Cutaneous Breast Cancer\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Breast cancer\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">• Drug: ceramide\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">2\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">≥ 18, female\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">9 states in USA\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NCT00008320\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">2\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Unknown\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C6 Ceramide NanoLiposome in Patients With Advanced Solid Tumors\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Cancer; carcinoma; solid tumors; tumor\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">• Drug: Ceramide NanoLiposome\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">≥ 18\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">3 states in USA\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NCT02834611\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">3\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Withdrawn\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Detection of Acid Sphingomyelinase/Ceramide Pathway Activation in Radiotherapy Patients Using Intravoxel Incoherent Motion (IVIM) Diffusion-weighted Magnetic Resonance Imaging and Serum Biomarkers\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Metastatic disease to bone; metastatic disease to soft tissue\u003Cbr>\n\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">• Device: MRI with IVIM DW-MRI \u003Cbr>• Other: Blood draw\u003Cbr>\n\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">N/A\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">≥ 18\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NY, USA\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NCT02465723\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">4\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Not yet recruiting\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (RR-AML)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Acute Myeloid Leukemia, in Relapse Acute;\u003Cbr>Myeloid Leukemia, Refractory\u003Cbr>\n\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">• Drug: Ceramide NanoLiposome (Ceraxa)\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">≥ 18\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">3 states in USA\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NCT04716452\u003C/td>\n\u003C/tr>\n\u003Ctr>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-left:solid thin;border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">5\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Completed\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Combination of Lenalidomide (Revlimid, LEN) and Autologous Mature Dendritic Cells Pulsed With α-galactosyl Ceramide (α-GalCer; KRN7000) in Myeloma\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">Myeloma\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">• Drug: Lenalidomide Biological: Monocyte derived DCs loaded with KRN7000\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">1\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">≥ 18\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">CT, USA\u003C/td>\n\u003Ctd align=\"left\" valign=\"top\" style=\"border-bottom:solid thin;border-right:solid thin\" class=\"html-align-left\">NCT00698776\u003C/td>\n\u003C/tr>\n\u003C/tbody>\n \u003C/table>\n\n\n\n\u003C/div>\n\u003C/section>\u003Csection class=\"html-fn_group\">\u003Ctable>\u003Ctr id>\n\u003Ctd>\u003C/td>\n\u003Ctd>\u003Cdiv class=\"html-p\">\n\u003Cb>Disclaimer/Publisher’s Note:\u003C/b> The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.\u003C/div>\u003C/td>\n\u003C/tr>\u003C/table>\u003C/section>\n \u003Csection id=\"html-copyright\">\u003Cbr>© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (\u003Ca href=\"http://creativecommons.org/licenses/by/4.0/\" target=\"_blank\">http://creativecommons.org/licenses/by/4.0/\u003C/a>).\u003C/section>\n ",[220],{"version":7,"hash_key":127,"id":126,"change":50},"Alizadeh, J.; Da Silva Rosa, S. C.; Weng, X.; Jacobs, J.; Lorzadeh, S.; Ravandi, A.; Vitorino, R.; Pecic, S.; Shojaei, S.; Ghavami, S. Ceramides and Ceramide Synthases in Cancer: Focus on Apoptosis and Autophagy. \u003Cem>Preprints\u003C/em> \u003Cb>2023\u003C/b>, 2023010264. https://doi.org/10.20944/preprints202301.0264.v1","Alizadeh, J.; da Silva Rosa, S.C.; Weng, X.; Jacobs, J.; Lorzadeh, S.; Ravandi, A.; Vitorino, R.; Pecic, S.; Zivkovic, A.; Stark, H.; et al. Ceramides and Ceramide Synthases in Cancer: Focus on Apoptosis and Autophagy. European Journal of Cell Biology 2023, 151337, doi:10.1016/j.ejcb.2023.151337.",[],[],["Reactive",226],{"$scookieConsent":227,"$stoast-ui":228,"$ssite-config":230},{"necessary":6,"functional":132,"statistic":132,"marketing":132,"unclassified":132},{"showToast":132,"toastMessage":153,"toastVariant":229},"neutral",{"env":231,"name":232,"url":233},"production","nuxt-app","http://frontend.preprints.org/",["Set"],["ShallowReactive",236],{"lENb9jbRai":50,"mgOlEjP40X":50,"Ya7hZzqdE7":50},"/manuscript/202301.0264/v1",["Reactive",239],{"auth":240,"share-modal":242,"useHeader":243},{"userInfo":241,"isLogin":132},{},{"isShareModalOpen":132,"item":50},{"height":41}]</script> <script>window.__NUXT__={};window.__NUXT__.config={public:{turnstile:{siteKey:"0x4AAAAAAAeRafIKjAzYS6R5"},strapiUrl:"",blog:"https://preprintsblog.wordpress.sciforum.net",envData:{USER:"www-data",SSH_CLIENT:"10.10.0.129 40222 22",npm_config_user_agent:"npm/8.19.2 node/v18.10.0 linux x64 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