Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11β-HSD1 were investigated. The potencies of inhibition on human 11β-HSD1 were bisphenol H (IC₅₀, 0.75 µM) > bisphenol G (IC₅₀, 5.06 µM) > diallyl bisphenol A (IC₅₀, 13.36 µM) > dimethyl bisphenol A (IC₅₀, 30.18 µM) > bisphenol A dimethyl ether (IC₅₀, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11β-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11β-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC₅₀ values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC₅₀ values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11β-HSD isoforms.

This study investigated the multifaceted effects of 4,4'-thiodiphenol (TDP) on male reproductive health, focusing on its toxicity, hormonal modulation, and impact on steroidogenesis. Male rats were exposed to TDP at varying doses (0, 1, 10, and 100 mg/kg) from day 35-56 postpartum. Overt toxicity was evident as TDP significantly reduced inhibited spermatogenesis at 10 and 100 mg/kg. TDP exhibited anti-androgenic properties by inhibiting testosterone biosynthesis at 10 and 100 mg/kg, correlating with increased LH levels at 10 mg/kg and altered T/LH ratios at ≥ 1 mg/kg. Immunohistochemical analysis revealed a dose-dependent increase in Leydig cell (LC) numbers, particularly at 100 mg/kg, attributed to enhanced LC proliferation as evidenced by elevated PCNA labeling. RNA-seq and qPCR analyses demonstrated the impact of TDP on LC gene expression, notably downregulating steroidogenesis-related genes such as Lhcgr, Star, Cyp11a1, and Hsd3b1, and inducing oxidative stress pathway genes. Protein expression studies confirmed reduced levels of key steroidogenic proteins and increased oxidative stress, evidenced by elevated malondialdehyde levels and reduced SOD1 expression. In vitro studies further elucidated the inhibition of TDP on steroidogenesis and induction of reactive oxygen species (ROS), independent of cytotoxicity. Additionally, the modulation of m6A RNA methylation was explored, showing an increase in m6A levels and a reduction in FTO and ALKBH5 expression and overexpression of Fto reversed TDP-mediated suppression of testosterone and steroidogenic and antioxidative genes, suggesting a novel regulatory mechanism involving RNA modification. Collectively, these findings underscore the potential of TDP as an endocrine disruptor with significant implications for male reproductive health.