Dihydroceramide Desaturase-1 Inhibitors (Centaurus)

Introduction: The outermost layer of the skin, the epidermis, is directly exposed to external stress (e.g., irradiation, allergens, and chemicals). Changes in epidermal conditions/environment in response to this stress could also influence conditions of the dermis, located directly beneath the epidermis. Yet, whether/how any epidermal environment changes in response to external stress affect dermal functions has not been completely clarified. Methods: We employed ultraviolet irradiation B (UVB) (which hardly reaches the dermis) as a model of external stress. Human keratinocytes and human dermal fibroblasts were treated with UVB and conditioned medium of keratinocytes exposed to UVB (UVB-keratinocyte-M), respectively. We assessed (1) inflammatory cytokines and lipid mediators in keratinocytes; (2) matrix metalloprotease (MMP) levels and collagen degradation in fibroblasts; (3) ex vivo organ-cultured human skin was treated with UVB. MMP levels and collagen degradation were examined; (4) test whether the mixture of agent (agent cocktail) consisting of dihydroceramide, niacin amide, resveratrol, glucosyl hesperidin, and phytosterol ester that has been shown to improve skin barrier integrity can mitigate influence of UVB in skin; and (5) a pilot one-arm human clinical test to assess efficacy of formulation containing agent cocktail on stratum corneum hydration, skin elasticity, and wrinkle index. Results: Inflammatory-cytokine and -lipid mediator production were increased in cultured keratinocytes treated with UVB, while matrix MMP-1, -3, and -9 production and collagen degradation were increased in fibroblasts incubated with UVB-keratinocyte-M. mRNA expression of COL1A1 (that codes type 1 collagen) levels was decreased in fibroblasts incubated with UVB-keratinocyte-M. The study using ex vivo organ-cultured human skin showed both MMP-1 and MMP-9 expression were increased in both epidermis and dermis and increased dermal collagen degradation following UVB irradiation. Increased MMP production and collagen degradation were attenuated by application of an agent cocktail. Finally, a pilot clinical study demonstrated that the formulation containing our agent cocktail likely has the ability to improve skin hydration, increase skin elasticity, and reduce the appearance of wrinkles. Conclusion: Epidermal changes in epidermal environment and conditions in response to external stress affect dermal conditions, and these negative effects of external stress on various skin layers can be pharmacologically mitigated.

Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol‐associated liver disease (ALD) remain unknown.

To explore the links between intestinal T cells, microbial translocation and ALD

Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non‐alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18‐M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC–MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS‐sorted cells. Mechanisms for T‐cell alterations were assessed in vitro.

Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose‐dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short‐term abstinence did not reverse TRM cell death in patients with ALD.

Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.