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Beta Cells and Diabetes
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nutraceuticals and Dietary Supplements, 2020
Shivani Srivastava, Durgavati Yadav, Kumar Sandeep, Harsh Pandey, Surya Kumar Singh, Yamini Bhusan Tripathi
Ceramide, a central molecule of sphingolipid (bioactive lipid messengers) metabolism, has shown to trigger autophagy through signaling pathways involving mTOR and the dissociation of Beclin 1:Bcl 2 complex via JNK-1-mediated Bcl 2 phosphorylation in a dependent manner. More precisely, ceramide-synthase plays a vital role in inducing autophagy through the conversion of short-chain ceramide (C2 and C6) into long-chain ceramide (Pattingre et al., 2009).
Endotoxic Shock and the Sphingomyelin Pathway
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Cecil K. Joseph, Richard N. Kolesnick
Ceramide may also be generated from anabolic reactions. De novo synthesis of ceramide involves the condensation of serine and palmitoyl-CoA to form ketosphinganine (22). The latter is reduced to dihydrosphingosine, acylated to dihydroceramide by the enzyme ceramide synthase, and finally oxidized to ceramide by dihydroceramide reductase. Treatment of P388 and U937 cells with the chemotherapeutic agent daunorubicin results in elevated levels of ceramide (23). Ceramide elevation in this instance did not result from activation of a sphingomyelinase but rather from stimulation of ceramide synthase. The fungal toxin fumonisin Bl, a specific inhibitor of ceramide synthase, was shown to block both daunorubicin-induced cer-amide generation and apoptosis, suggesting that cer-amide synthase activation was obligatory for the death response.
Role of Vitamin C in Chronic Wound Healing
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Juliet M. Pullar, Margreet C.M. Vissers
Cell culture studies demonstrate that vitamin C can promote the differentiation of keratinocytes, which is critical for reepithelialization in wound healing [93]. In an organotypic culture model, vitamin C enhanced differentiation of rat epidermal keratinocytes, increasing filaggrin expression, a differentiation marker, and the number of keratohyalin granules [94]. It also improved the ultrastructural organization of the stratum corneum, enhancing the characteristic basket-weave pattern of this layer, and promoting extracellular lipid deposition. Finally, vitamin C markedly increased the barrier function of the epidermis, as demonstrated by reductions in transepidermal water loss and permeation rates of corticosterone and mannitol. In support of these findings, others have also shown that vitamin C promotes the synthesis and organization of barrier lipids, increases cornified envelope formation during differentiation, and promotes barrier function [95–99]. More specifically, vitamin C has been shown to enhance ceramide synthesis, which is the major lipid component of the stratum corneum [95,97,99]. It particularly increases formation of ceramides 6 and 7 [95], which are hydroxylated derivatives. The increased synthesis seems to be related to upregulation of ceramide synthetic enzymes including serine palmitoyltransferase and ceramide synthase [97,99].
Radiation-induced neuropathological changes in the oligodendrocyte lineage with relevant clinical manifestations and therapeutic strategies
Published in International Journal of Radiation Biology, 2022
Additionally, ceramide and protein kinase B (PKB)/Akt were found to also be implicated in radiation-induced apoptosis of oligodendrocytes. Irradiated primary cultures of neonatal rat oligodendrocytes exhibited a dose-dependent downregulation of PKB activity. This decrease occurred prior to the onset of oligodendroglial apoptosis, suggesting that the PKB/Akt pathway may be implicated in radiation-induced apoptosis. The irradiated cells also had increased ceramide levels that preceded the onset of apoptosis 4 hours after a single dose of 10 Gy (Lu and Wong 2004). Endogenous ceramide can be generated via the activation of acid sphingomyelinase (ASMase) and subsequent hydrolysis of sphingomyelin, as well as de novo synthesis by ceramide synthase. Both pathways were shown to be required for radiation-induced apoptosis in B lymphocytes and lymphoblast’s (Vit and Rosselli 2003). However, inhibition of ASMase and ceramide synthase activities did not alter the apoptotic response of irradiated oligodendrocytes (Lu and Wong 2004). A recent study in irradiated Jurkat T cells revealed that a single dose of 10 Gy physically disrupted lysosomal membrane integrity, which led to the release of ASMase and subsequent increase in ceramide levels as well as cellular apoptosis (Ferranti et al. 2020). Hence, it is possible that similar mechanisms may also be involved in radiation-induced apoptosis of oligodendrocytes which warrant further investigations.
Fungal sphingolipids: role in the regulation of virulence and potential as targets for future antifungal therapies
Published in Expert Review of Anti-infective Therapy, 2020
Caroline Mota Fernandes, Maurizio Del Poeta
The inhibition of ceramide synthesis can also lead to increased levels of DHS and PHS. These sphingoid bases inhibit Aspergillus growth and induce death by apoptosis [66]. Therefore, drugs targeting the ceramide synthases might be potent antifungals, showing a dual mechanism of action: depletion of the sphingolipids content and accumulation of toxic sphingoid bases. So far, two inhibitors of fungal ceramide synthase have been reported. Fumonisin B1 is a mycotoxin produced by Fusarium that competes with the sphingoid base as an enzyme substrate and also affects the binding of the fatty acid chain [67,68]. Although fumonisin B1 inhibits the ceramide synthases, this compound apparently showed poor antifungal activity [68]. In contrast, australifungin, a compound isolated from Sporormiella australis, inhibits the ceramide production and show a broad-spectrum activity against Candida, Aspergillus and Cryptococcus [69]. The use of these mycotoxins in the antifungal therapy has been limited due to their high reactivity and lack of specificity toward the fungal ceramide synthase, also inhibiting the mammalian enzyme [68,69]. In fact, fumonisin B1 is toxic to animals and causes hepato and nephrotoxicity in rodents [70,71]. A fluorescent assay to detect ceramide synthase activity has been reported [72], enabling the screen of chemical libraries for more selective compounds, active against the fungal but not the mammalian enzyme.
Validation of urinary sphingolipid metabolites as biomarker of effect for fumonisins exposure in Kenyan children
Published in Biomarkers, 2019
Ruth Nabwire Wangia, David Peter Githanga, Kathy Siyu Xue, Lili Tang, Omu Aggrey Anzala, Jia-Sheng Wang
The mechanism of FB1 toxicity is attributed to its structural similarity to sphingoid bases, which consists of twenty-carbon backbone as shown in Figure 1 (Wang et al.1991). Due to its structural similarity to sphingoid bases, fumonisin B1 acts as a competitive inhibitor of ceramide synthase (Marasas et al. 2004, Riley et al.2012). The de novo pathway of sphingolipid synthesis is highly dependent on the action of ceramide synthase. The process begins with the condensation of serine and palmitoyl-CoA. This condensation is catalyzed by serine palmitoyl transferase to generate 3-ketodihydrosphingosine which is subsequently reduced to sphinganine (Sa). Sa is then N-acylated by ceramide synthase to produce dihydroceramide (dhc) that through the action of dhc-desaturase is reduced to ceramide. In the presence of fumonisin exposure, FB1 inhibits the N-acylation process by blocking ceramide synthase (Turner et al.1999, Voss et al.2002, 2006, Zitomer et al.2009). Ultimately, this inhibition results in accumulation of intracellular Sa that can eventually lead to oxidatively generated DNA damage, sphingomyelin depletion and altered function of sphingolipids as second messengers