ROLE OF DIHYDROCERAMIDE IN CELL SIGNALING

Sphingolipids are a class of bioactive lipids. Ceramide is the hub molecule of the intricate sphingolipid biosynthetic pathway. It is a bioactive lipid, regulating a number of physiological functions such as apoptosis, cell growth arrest, differentiation, senescence, migration and adhesion. The dihydroceramide is the precursor of ceramide along the de novo biosynthetic pathway. Several groups considered the dihydroceramide an inactive molecule. Recent studies associated dihydroceramide with the induction of cellular processes such as cell cycle arrest and programmed cell death. On the other hand this molecule also showed antiapoptotic properties. The goal of my doctorate project is to demonstrate the dihydroceramide implication in the regulation of a pro-survival cell response to stress. Hence, the human gastric carcinoma HGC-27 cells were treated with resveratrol, a molecule that induces dihydroceramide accumulation. Resveratrol is a polyphenol with well known anti-oxidant and anti-tumoral properties. On the other hand it is a calorie restriction mimetic, thus it activates sirtuins, promoting cell survival. A number of studies demonstrated that resveratrol modulates the biosynthetic de novo pathway of ceramide. Here we demonstrated that resveratrol, similarly to the specific inhibitor XM462, inhibits DEGS-1 desaturase activity, inducing dihydroceramide accumulation. This accumulation results in autophagy induction without affecting cell viability. We also obtained this response treating different cell lines with several drugs or conditions known to induce dihydroceramide accumulation. Although autophagy did not affect cell viability, however it causes a delay in cell proliferation. In fact we demonstrated that dihydroceramide accumulation in HGC-27 cells induces a temporary arrest in G0/G1 phase resulting in the delayed cell cycle phases progression. Moreover, we demonstrated that both autophagy activation and cell cycle arrest are temporally subsequent to the unfolded protein response (UPR) which is due to the dihydroceramide accumulation-mediated ER stress. All these results give an important contribute to the understanding of the metabolic role of sphingolipid mediators and their targeting in the anti-tumoral therapy

PP178—Antiepileptic Drugs: Prescribing Patterns and Interaction Risk in General Practice

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Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARα epigenetic mechanism of mammary epithelial cell fate

A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RAR\u3b1 (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

Late-onset non-familial acrokeratosis verruciformis of Hopf: a case report.

Acrokeratosis verruciformis of Hopf is a rare heritable autosomal dominant genodermatosis and keratinization disorder, first described in 1931 by Hopf. It presents with multiple flat skin colored papules, mainly localized at the dorsal region of the hands and feet. AKV is an allelic disorder, associated with heterozygous missense mutation in ATP2A2 gene, which is involved in Darier's disease. Usually, it arises in early life but rare sporadic cases with adult onset have been reported. We report a case of late-onset non-familial AKV in a 52-year old patient

Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells

Resveratrol has both apoptosis and autophagy-promoting activities in different cancer cells. Dihydroceramide is the immediate precursor of the apoptotic mediator ceramide in the de novo sphingolipid synthesis pathway. Here we demonstrate that resveratrol induces autophagy in HGC-27 cells, with no sign of cell death. Autophagy occurs after an increase in dihydroceramides by inhibition of dihydroceramide desaturase. The effects of resveratrol are mimicked by a dihydroceramide desaturase inhibitor. These results demonstrate that resveratrol-induced autophagy occurs with a rise in intracellular dihydroceramide levels as the result of inhibition of dihydroceramide desaturases activity and that dihydroceramide accumulation is responsible for autophagy promotion

Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena

Sphingolipids are a wide family of lipids that share common sphingoid backbones, including (2S,3R)-2-amino-4-octadecane-1,3-diol (dihydrosphingosine) and (2S,3R,4E)-2-amino-4-octadecene-1,3-diol (sphingosine). The metabolism and biological functions of sphingolipids derived from sphingosine have been the subject of many reviews. In contrast, dihydrosphingolipids have received poor attention, mainly due to their supposed lack of biological activity. However, the reported biological effects of active site directed dihydroceramide desaturase inhibitors and the involvement of dihydrosphingolipids in the response of cells to known therapeutic agents support that dihydrosphingolipids are not inert but are in fact biologically active and underscore the importance of elucidating further the metabolic pathways and cell signaling networks involved in the biological activities of dihydrosphingolipids. Dihydroceramide desaturase is the enzyme involved in the conversion of dihydroceramide into ceramide and it is crucial in the regulation of the balance between sphingolipids and dihydrosphingolipids. Furthermore, given the enzyme requirement for O\u2082 and the NAD(P)H cofactor, the cellular redox balance and dihydroceramide desaturase activity may reciprocally influence each other. In this review both dihydroceramide desaturase and the biological functions of dihydrosphingolipids are addressed and perspectives on this field are discussed