Benzene ring bisphenol A substitutes potently inhibit human, rat, and mouse gonadal 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a chemical used in the production of certain plastics and resins. Recent research has found that BPA can inhibit the activity of 3ß-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3ß-HSDs). Whether benzene ring BPA substitutes can inhibit human, rat, and mouse gonadal 3ß-HSDs, the structure-activity relationship and the underlying mechanism remain unclear. In this study, we compared 6 benzene ring BPA substitutes to BPA in the inhibition of human, rat, and mouse gonadal 3ß-HSDs and conducted structure-activity relationship and in silico docking analysis. The inhibitory activity (IC50) of human 3ß-HSD2 in KGN cells ranged from about 0.02 µM for bisphenol H to 8.75 µM for BPA, that of rat 3ß-HSD1 in testicular microsomes ranged from 0.099 µM for bisphenol H to 31.32 µM for BPA, and that of mouse 3ß-HSD6 ranged from 0.021 µM for BPH to ineffectiveness for 100 µM BPA. These compounds acted as mixed inhibitors with LogP inversely correlated with IC50 and ΔG positively correlated with IC50 value. Docking analysis showed that these compounds bind to the steroid active site of the 3ß-HSD enzymes. In conclusion, some benzene ring BPA substitutes potently inhibit gonadal 3ß-HSD in various species, and lipophilicity and binding affinity determine their inhibitory strength.

Curcuminoids inhibit human and rat placental 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, curcuma longa L has been applied to treat pain and tumour-related symptoms for over thousands of years. Curcuminoids, polyphenolic compounds, are the main pharmacological component from the rhizome of Curcuma longa L. Pharmacological investigations have found that curcuminoids have many pharmacological activities of anti-inflammatory, anti-tumour, and anti-metastasis. AIM OF THE STUDY: 3ß-Hydroxysteroid dehydrogenase (3ß-HSD1) catalyses the production of steroid precursors for androgens and estrogens, which play an essential role in cancer metastasis. We explored the potency and mode of action of curcuminoids and their metabolites of inhibiting 3ß-HSD1 activity and compared the species difference between human and rat. MATERIALS AND METHODS: In this study, we investigated the direct inhibition of 6 curcuminoids on human placental 3ß-HSD1 activity and compared the species-dependent difference in human 3ß-HSD1 and rat placental homolog 3ß-HSD4. RESULTS: The inhibitory potency of curcuminoids on human 3ß-HSD1 was demethoxycurcumin (IC50, 0.18 µM) > bisdemethoxycurcumin (0.21 µM)>curcumin (2.41 µM)> dihydrocurcumin (4.13 µM)>tetrahydrocurcumin (15.78 µM)>octahydrocurcumin (ineffective at 100 µM). The inhibitory potency of curcuminoids on rat 3ß-HSD4 was bisdemethoxycurcumin (3.34 µM)>dihydrocurcumin (5.12 µM)>tetrahydrocurcumin (41.82 µM)>demethoxycurcumin (88.10 µM)>curcumin (137.06 µM)> octahydrocurcumin (ineffective at 100 µM). Human choriocarcinoma JAr cells with curcuminoid treatment showed that these chemicals had similar potency to inhibit progesterone secretion under basal and 8bromo-cAMP stimulated conditions. Docking analysis showed that all chemicals bind pregnenolone-binding site with mixed/competitive mode for 3ß-HSD. CONCLUSION: Some curcuminoids are potent human placental 3ß-HSD1 inhibitors, possibly being potential drugs to treat prostate cancer and breast cancer.

The Immune Subtypes and Landscape of Advanced-Stage Ovarian Cancer.

Immunotherapy has played a significant role in the treatment of a variety of hematological and solid tumors, but its application in ovarian cancer (OC) remains unclear. This study aimed to identify immune subtypes of OC and delineate an immune landscape for selecting suitable patients for immunotherapy, thereby providing potent therapeutic targets for immunotherapy drug development. Three immune subtypes (IS1-IS3) with distinctive molecular, cellular, and clinical characteristics were identified from the TCGA and GSE32062 cohorts. Compared to IS1, IS3 has a better prognosis and exhibits an immunological "hot". IS3, in contrast, exhibits an immunological "cold" and has a worse prognosis in OC patients. Moreover, gene mutations, immune modulators, CA125, CA199, and HE4 expression, along with sensitivity either to immunotherapy or chemotherapy, were significantly different among the three immune subtypes. The OC immune landscape was highly heterogeneous between individual patients. Poor prognosis was correlated with low expression of the hub genes CD2, CD3D, and CD3E, which could act not only as biomarkers for predicting prognosis, but also as potential immunotherapy targets. Our study elucidates the immunotyping and molecular characteristics of the immune microenvironment in OC, which could provide an effective immunotherapy stratification method for optimally selecting patients, and also has clinical significance for the development of new immunotherapy as well as rational combination strategies for the treatment of OC patients.