(2-Methylbutyryl)shikonin Naturally Occurring Shikonin Derivative Ameliorates the α-MSH-Induced Melanogenesis via ERK1/2 and p38 MAP Kinase-Mediated Down-Regulation of the MITF Transcription Factor.

Cutaneous pigmentation is an important phenotypic trait whose regulation, despite recent advances, has yet to be completely elucidated. Melanogenesis, a physiological process of melanin production, is imperative for organism survival as it provides protection against the environmental insults that majorly involve sunlight-induced skin photodamage. However, immoderate melanin synthesis can cause pigmentation disorders associated with a psychosocial impact. In this study, the hypopigmentation effect of (2-methylbutyryl)shikonin, a natural product present in the root extract of Lithospermum erythrorhizon, and the underlying mechanisms responsible for the inhibition of melanin synthesis in α-MSH-stimulated B16F10 cells and C57BL/6J mice was studied. Non-cytotoxic concentrations of (2-methylbutyryl)shikonin significantly repressed cellular tyrosinase activity and melanin synthesis in both in vitro and in vivo models (C57BL/6J mice). (2-Methylbutyryl)shikonin remarkably abolished the protein expression of MITF, tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2, thereby blocking the production of pigment melanin via modulating the phosphorylation status of MAPK proteins, viz., ERK1/2 and p38. In addition, specific inhibition of ERK1/2 attenuated the inhibitory effects of (2-methylbutyryl)shikonin on melanin synthesis, whereas selective inhibition of p38 augmented the inhibitory effect of BSHK on melanin synthesis. Moreover, topical application of (2-methylbutyryl)shikonin on C57BL/6J mouse tails remarkably induced tail depigmentation. In conclusion, with these findings, we, for the first time, report the hypopigmentation effect of (2-methylbutyryl)shikonin via inhibition of cellular tyrosinase enzyme activity, subsequently ameliorating the melanin production, thereby indicating that (2-methylbutyryl)shikonin is a potential natural therapy for hyperpigmentation disorders.

Glabridin ameliorates intracellular events caused by palmitic acid and alcohol in mouse hepatocytes and fast food diet and alcohol -induced steatohepatitis and fibrosis in C57BL/6J mice model.

Steatohepatitis is a significant risk factor for end-stage liver disease. In this study, the therapeutic potential of Glabridin (GBD), an isoflavan derived from Glycyrrhiza glabra, is investigated in in-vitro and in-vivo models against palmitic acid (PA) or fast food (FF) diet + alcohol (EtOH). Mouse hepatocytes (AML-12 cells) were treated with PA; 250 µM + EtOH; 250 µM ± GBD (10 µM and 25 µM) for 24 h. C57BL/6J mice fed with standard chow (SC) diet, fast food (FF) diet + intermittent oral ingestion of EtOH (10-50%v/v) ± GBD (20 mg/kg and 40 mg/kg) for eight (8) weeks, were analyzed for histological features of steatohepatitis and fibrosis, biochemical indexes, and protein and gene expression studies related to oxidative stress, inflammation, lipogenesis, fibrosis, and apoptosis. GBD therapy considerably reduced intracellular events in AML-12 cells exposed to PA + EtOH. GBD treatments significantly improved body metrics, biochemical indexes, and histological features in C57BL/6J mice compared to FF + EtOH. Moreover, protein and gene expression investigations revealed a strong therapeutic effects on oxidative stress, inflammation, steatosis, fibrosis, and apoptosis -related molecular signaling cascades. In conclusion, these findings suggest that GBD has a strong therapeutic potential to be developed as anti-steatohepatitis/fibrosis medicine.

A small animal model of NASH with progressive steatohepatitis -induced by fast food diet and alcohol in C57BL/6J mouse with high human pathophysiological proximity.

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) both can progress to end-stage liver disease (ESLD). No relevant animal models are available for studying the toxic consequences of concurrent fast food diet and alcohol usage in fibrosing NASH. As a result, dependable and short-term in-vivo models capable of recapitulating human disease pathophysiology are required for deciphering mechanistic insights and preclinical drug discovery programs. The current study aims to develop a mouse model for progressive steatohepatitis employing a fast food (FF) diet with intermittent oral alcohol (EtOH) administration. For eight (8) weeks, C57BL/6J mice were fed standard chow (SC) diet ± EtOH or FF ± EtOH. EtOH uses enhanced the histological characteristics of FF -induced steatohepatitis and fibrosis. A dysregulated molecular signaling cascade related to oxidative stress, steatosis, fibrosis, DNA damage, and apoptosis was evident at protein and gene expression levels in the FF + EtOH. The results from the in-vivo model were replicated in mouse hepatocyte cultures (AML-12) subjected to palmitic acid (PA) ± EtOH exposures. The results of the present study indicate that the clinical hallmarks of human progressive steatohepatitis and fibrosis were achieved in our mice model, showing its suitability for preclinical research.

Synthesis, molecular docking, and biological evaluation of [3,2-b]indole fused 18ß-glycyrrhetinic acid derivatives against skin melanoma.

Melanoma, the most serious yet uncommon type of cancer, originates in melanocytes. Risk factors include UV radiation, genetic factors, tanning lamps and beds. Here, we described the synthesis and selective anti melanoma activity of [3,2-b]indole fused 18ß-glycyrrhetinic acid, a derivative of 18ß-glycyrrhetinic acid in murine B16F10 and A375 human melanoma cell lines. Among the 14 molecules, GPD-12 showed significant selective cytotoxic activity against A375 and B16F10 cell lines with IC50 of 13.38 µM and 15.20 µM respectively. GPD 12 induced the formation of reactive oxygen species in A375 cells that could trigger oxidative stress mediated cell death as is evident from the increased expression of apoptosis related proteins such as caspase-9 and caspase-3 and the increased ratio of Bax to Bcl2. The results showed that GPD 12 can be used as an effective therapeutic agent against melanoma.

Herbal products as skincare therapeutic agents against ultraviolet radiation-induced skin disorders.

This paper aims to highlight the pharmacological aspects of listed herbal skincare products used for the treatment of various disorders caused due to ultraviolet radiation. The pharmacological aspects include safety and efficacy validation as per regulatory guidelines following internationally accepted scientific principles for their development of skincare products. Herbal products have always been used traditionally for the treatment of various skin ailments and have become more prevalent because of their safety and high efficacy benefits. The incorporation of synthetic molecules and chemical substances in the different medicinal and pharmaceutical formulations is the leading cause of the dermal toxicity. Therefore, the developments of herbal skincare products containing scientifically validated herbal ingredients have better acceptance, respect, and belief in the society. The listed herbal products in this review can help take forward the commercial development of skincare products for therapeutic as well as beauty care purposes from such plants.