The role of the cytochrome P450 superfamily in the skin.

In mammals, the skin acts as a barrier to prevent harmful environmental stimuli from entering the circulation. CYP450s are involved in drug biotransformation, exogenous and endogenous substrate metabolism, and maintaining the normal physiological function of the skin, as well as facilitating homeostasis of the internal environment. The expression pattern of CYP450s in the skin is tissue-specific and thus differs from the liver and other organs. The development of skin topical medications, and knowledge of the toxicity and side effects of these medications require a detailed understanding of the expression and function of skin-specific CYP450s. Thus, we summarized the expression of CYP450s in the skin, their function in endogenous metabolic physiology, aberrant CYP450 expression in skin diseases and the influence of environmental variables and medications. This information will serve as a crucial foundation for future studies on the skin, as well as for the design and development of new drugs for skin diseases including topical medications.

Alpinetin promotes hair regeneration via activating hair follicle stem cells.

BACKGROUND: Alopecia affects millions of individuals globally, with hair loss becoming more common among young people.  Various traditional Chinese medicines (TCM) have been used clinically for treating alopecia, however, the effective compounds and underlying mechanism are less known. We sought to investigate the effect of Alpinetin (AP), a compound extracted from Fabaceae and Zingiberaceae herbs, in hair regeneration. METHODS: Animal model for hair regeneration was mimicked by depilation in C57BL/6J mice. The mice were then topically treated with 3 mg/ml AP, minoxidil as positive control (PC), or solvent ethanol as vehicle control (VC) on the dorsal skin. Skin color changes which reflected the hair growth stages were monitored and pictured, along with H&E staining and hair shaft length measurement. RNA-seq analysis combined with immunofluorescence staining and qPCR analysis were used for mechanism study. Meanwhile, Gli1CreERT2; R26RtdTomato and Lgr5EGFP-CreERT2; R26RtdTomato transgenic mice were used to monitor the activation and proliferation of Gli1+ and Lgr5+ HFSCs after treatment. Furthermore, the toxicity of AP was tested in keratinocytes and fibroblasts from both human and mouse skin to assess the safety. RESULTS: When compared to minoxidil-treated and vehicle-treated control mice, topical application of AP promoted anagen initiation and delayed catagen entry, resulting in a longer anagen phase and hair shaft length. Mechanistically, RNA-seq analysis combined with immunofluorescence staining of Lef1 suggested that Lgr5+ HFSCs in lower bulge were activated by AP via Wnt signaling. Other HFSCs, including K15+, Lef1+, and Gli1+ cells, were also promoted into proliferating upon AP treatment. In addition, AP inhibited cleaved caspase 3-dependent apoptosis at the late anagen stage to postpone regression of hair follicles. More importantly, AP showed no cytotoxicity in keratinocytes and fibroblasts from both human and mouse skin. CONCLUSION: This study clarified the effect of AP in promoting hair regeneration by activating HFSCs via Wnt signaling. Our findings may contribute to the development of a new generation of pilatory that is more efficient and less cytotoxic for treating alopecia.

Premigratory neural crest stem cells generate enteric neurons populating the mouse colon and regulating peristalsis in tissue-engineered intestine.

Hirschsprung's disease (HSCR) is a common congenital defect. It occurs when bowel colonization by neural crest-derived enteric nervous system (ENS) precursors is incomplete during the first trimester of pregnancy. Several sources of candidate cells have been previously studied for their capacity to regenerate the ENS, including enteric neural crest stem cells (En-NCSCs) derived from native intestine or those simulated from human pluripotent stem cells (hPSCs). However, it is not yet known whether the native NCSCs other than En-NCSCs would have the potential of regenerating functional enteric neurons and producing neuron dependent motility under the intestinal environment. The present study was designed to determine whether premigratory NCSCs (pNCSCs), as a type of the nonenteric NCSCs, could form enteric neurons and mediate the motility. pNCSCs were firstly transplanted into the colon of adult mice, and were found to survive, migrate, differentiate into enteric neurons, and successfully integrate into the adult mouse colon. When the mixture of pNCSCs and human intestinal organoids was implanted into the subrenal capsule of nude mice and grown into the mature tissue-engineered intestine (TEI), the pNCSCs-derived neurons mediated neuron-dependent peristalsis of TEI. These results show that the pNCSCs that were previously assumed to not be induced by intestinal environment or cues can innervate the intestine and establish neuron-dependent motility. Future cell candidates for ENS regeneration may include nonenteric NCSCs.