Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia.

Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. Dihydrotestosterone (DHT) and androgen receptor (AR) levels are increased in patients with AGA, and DHT-AR signaling correlates strongly with AGA pathogenesis. In this study, treatment with self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticle-type siRNA selectively suppressed AR expression in vitro. Clinical studies with application of SAMiRNA to the scalp and massaging to deliver it to the hair follicle confirmed its efficacy in AGA. For identification of a potent SAMiRNA for AR silencing, 547 SAMiRNA candidates were synthesized and screened. SAMiRNA-AR68 (AR68) was the most potent and could be efficiently delivered to human follicle dermal papilla cells (HFDPCs) and hair follicles, and this treatment decreased the AR mRNA and protein levels. We confirmed that 10 µM AR68 elicits no innate immune response in human PBMCs and no cytotoxicity up to 20 µM with HFDP and HaCaT cells. Clinical studies were performed in a randomized and double-blind manner with two different doses and frequencies. In the low-dose (0.5 mg/ml) clinical study, AR68 was applied three times per week for 24 weeks, and through quantitative analysis using a phototrichogram, we confirmed increases in total hair counts. In the high-dose (5 mg/ml) clinical study, AR68 was given once per week for 24 weeks and showed 83% efficacy in increasing hair counts compared with finasteride. No side effects were observed. Therefore, SAMiRNA targeting AR mRNA is a potential novel topical treatment for AGA.

Deletion of liver-specific STAT5 gene alters the expression of bile acid metabolism genes and reduces liver damage in lithogenic diet-fed mice.

Signal transducers and activators of transcription 5 (STAT5) mediates growth hormone signals, which may control hepatic cholesterol uptake and bile acid metabolism. Deregulation of liver cholesterol homeostasis and bile acid metabolism may cause liver damage and cholesterol gallstone development. The purpose of this study was to understand the role of local STAT5 signaling in cholesterol and bile acid metabolism using liver-specific STAT5 knock-out (STAT5 LKO) mice on a normal diet and a cholesterol- and bile acid-containing lithogenic diet. STAT5 LKO mice showed significant down-regulation of STAT5 and insulin-like growth factor-1 genes. STAT5 gene deletion had a minor effect on cholesterol metabolism, as evidenced by a minor change in circulating cholesterol levels and no changes in expression of hepatic low-density lipoprotein receptor and cholesterol synthesis genes in STAT5 LKO mice. In contrast, bile acid synthesis and uptake genes were profoundly down-regulated and bile acid detoxification genes were up-regulated in STAT5 LKO mice. In STAT5 fl/fl mice, a lithogenic diet induced liver damage, as evidenced by moderate increases in liver ballooning, inflammation and fibrosis. However, STAT5 deletion ameliorated the degree of liver damage induced by the lithogenic diet. In STAT5 LKO mice, a lithogenic diet did not alter the incidence or severity of cholesterol gallstones. In conclusion, local STAT5 signaling does not have a significant role in cholesterol metabolism. In contrast, hepatic STAT5 signaling has significant roles in regulating transcription of genes for synthesis, transport and detoxification of bile acids, but it has only a minor role in bile acid metabolism.

Inhibitory effects of Leonurus sibiricus on weight gain after menopause in ovariectomized and high-fat diet-fed mice.

Leonurus sibiricus, also called motherwort, is a well-known functional food and medicinal herb. It has been known to possess beneficial properties for women's health, especially for aged women. Estrogen deficiency in the menopause could induce lipid metabolic abnormalities in body fat, resulting in obesity. In this study, the inhibitory effects of L. sibiricus on obesity after the menopause were investigated. Female C57BL/6 mice were ovariectomized and fed high-fat diet (HFD) for 12 weeks. Following an induction period, aqueous extracts of L. sibiricus (LS) were orally administrated for 6 weeks. The body, uterine, and visceral fat weights were measured immediately after the animals were killed. Histological analysis was performed to monitor fat and liver. Serum levels of glucose, triglyceride, total cholesterol, and LDL-cholesterol were evaluated. In addition, the expression of lipases was analyzed. Total body weight was significantly decreased by LS treatment. Histological changes in adipocyte size were shown along with a decrease of visceral fat weight in the LS-treated group. In addition, the fat infiltration of liver was reduced by LS administration. LS-treated mice experienced decreases of serum triglyceride, total cholesterol, and LDL-cholesterol levels. The expression of HSL and ATGL was significantly increased by LS treatment. These results suggest that LS could regulate the lipid metabolism via an increase of lipases expression in ovariectomized and HFD-fed mice. LS might be a novel candidate for a functional food to inhibit weight gain after the menopause.