11β-hydroxysteroid dehydrogenase types 1 and 2. in postnatal development of rat testis： gene express,on, localization and regulation by luteinizing hormone and androgens

11β-hydroxysteroid dehydrogenase type 1 （11β-HSD1） and type 2 （11β-HSD2） are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone （LH） and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day （PND） 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone （MENT） and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.

Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient

Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of < 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.

Synergistic control of sex hormones by 17β-HSD type 7: a novel target for estrogen-dependent breast cancer

17β-hydroxysteroid dehydrogenase(17β-HSD)type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer.Recent confirmation of the role of dyhydroxytestosterone(DHT)in counteracting estrogeninduced cell growth prompted us to study the reductive 17β-HSD type 7(17β-HSD7),which activates estrone while markedly inactivatingDHT.The role ofDHTin breast cancer cell proliferation isdemonstratedby its independent suppression of cell growthin the presence of a physiological concentration of estradiol(E2).Moreover,an integral analysis of a large number of clinical samples in Oncomine datasets demonstrated the overexpression of 17β-HSD7 in breast carcinoma.Inhibition of 17β-HSD7 in breast cancer cells resulted in a lower level of E2 and a higher level of DHT,successively induced regulation of cyclinD1,p21,Bcl-2,and Bik,consequently arrested cell cycle in the G0/G1 phase,and triggered apoptosis and auto-downregulation feedback of the enzyme.Such inhibition led to significant shrinkage of xenograft tumors with decreased cancer cell density and reduced 17β-HSD7 expression.Decreased plasma E2 and elevated plasma DHT levels were also found.Thus,the dual functional 17β-HSD7 is proposed as a novel target for estrogen-dependent breast cancer by regulating the balance of E2 andDHT.Thisdemonstrates aconceptual advance on the general belief that the major role of this enzyme is in cholesterol metabolism.

Estrogen Biosynthesis and Its Regulation in Endometriosis

Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis.It affects approximately 10%women of reproductive age.Although its etiology and pathogenesis remain poorly understood,it is characterized by the elevated local production of estrogen in the endometriotic tissues.In this paper,we review the mechanisms of estrogen biosynthesis and its regulation in endometriosis.