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Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown. Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1. Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis. • The classical steroidogenic enzyme, Cyp17a1, is upregulated in liver during fasting. • CYP17a1 produces a hormone-ligand for the nuclear receptor PPARα and affects glucose and lipid handling in the liver. • Hepatic Cyp17a1 is essential for maintaining glycaemia and ketones during fasting. • Bile acids, via a nuclear receptor cascade, repress hepatic Cyp17a1 as part of the re-feeding response. [ABSTRACT FROM AUTHOR]

Drospirenone (DRO) is one of the most widely used progestins in contraceptive treatments and hormone replacement therapies. The pharmacokinetics and potential toxicological effects of DRO were investigated in juvenile sea bass ( Dicentrarchus labrax ) exposed through the diet (0.01–10 μg DRO/g) for up to 31 days. DRO was detected in the blood (4–27 ng/mL) of fish exposed to the highest concentration, with no significant bioaccumulation over time and no alteration of hepatic metabolizing enzymes, namely, CYP1A and CYP3A-catalysed activities and UDP-glucuronyltransferase (UGT). Pregnenolone (P5), progesterone (P4), 17α-hydroxyprogesterone (17P4), 17α-hydroxypregnenolone (17P5), androstenedione (AD) and testosterone (T) were determined in plasma and gene expression of cyp17a1 , cyp19a1a and cyp11β analysed by qRT-PCR in gonads. The significant increase in plasmatic levels of 17P5, 17P4 and AD detected after 31 days exposure to 10 ng DRO/g together with the increased expression of cyp17a1 in females evidence the ability of DRO to alter steroid synthesis at low intake concentrations (7 ng DRO/day). However, the potential consequences of this steroid shift for female reproduction remain to be investigated. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the deficiency of one of four steroidogenic enzymes involved in cortisol biosynthesis or in the electron donor enzyme P450 oxidoreductase (POR) that serves as electron donor to steroidogenic cytochrome P450 (CYP) type II enzymes. The biochemical and clinical phenotype depends on the specific enzymatic defect and the impairment of specific enzyme activity. Defects of steroid 21-hydroxylase (CYP21A2) and 11β-hydroxylase (CYP11B1) only affect adrenal steroidogenesis, whereas 17α-hydroxylase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency also impact on gonadal steroid biosynthesis. Inactivating POR gene mutations are the cause of CAH manifesting with apparent combined CYP17A1–CYP21A2 deficiency. P450 oxidoreductase deficiency (ORD) has a complex phenotype including two unique features not observed in any other CAH variant: skeletal malformations and severe genital ambiguity in both sexes. [Copyright &y& Elsevier]

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5α-reductase. All these events take place during weeks 8–12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation. [Copyright &y& Elsevier]

Colorectal cancer is one of the most common cancers worldwide, and it is also one of the major causes of mortality from cancer. Chemotherapy drugs are generally limited due to various complications, as well as the development of resistance and recurrence. The in silico docking investigation involved exploration of protein or nucleotide, 3D structural modeling, molecular docking, and binding energy calculation. Protein-protein interactions are significant to many biological processes, and their disruption is a leading cause of disease. The use of small molecules to modulate them is gaining popularity, but protein interfaces usually lack specific cavities for processing small molecules. MMP-2, PARP, iNOS, Chk1, proteins were used in the molecular docking analysis of kaempferitrin and 5-flurouracil. The compound kaempferitrin had the highest binding energy scores with most of the target proteins, according to molecular docking results. The findings suggest it could be used to develop new drugs for cancer therapy. [ABSTRACT FROM AUTHOR]