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Activin and inhibin are both dimeric proteins sharing the same β subunits that belong to the TGF-β superfamily. They are well known for stimulating and inhibiting pituitary FSH secretion, respectively, in mammals. In addition, activin also acts as a mesoderm-inducing factor in frogs. However, their functions in development and reproduction of other species are poorly defined. In this study, we disrupted all three activin/inhibin β subunits (βAa, inhbaa ; βAb, inhbab ; and βB, inhbb ) in zebrafish using CRISPR/Cas9. The loss of βAa/b but not βB led to a high mortality rate in the post-hatching stage. Surprisingly, the expression of fshb but not lhb in the pituitary increased in the female βA mutant together with aromatase ( cyp19a1a ) in the ovary. The single mutant of βAa/b showed normal folliculogenesis in young females; however, their double mutant ( inhbaa-/- ; inhbab-/- ) showed delayed follicle activation, granulosa cell hypertrophy, stromal cell accumulation and tissue fibrosis. The ovary of inhbaa-/- deteriorated progressively after 180 dpf with reduced fecundity and the folliculogenesis ceased completely around 540 dpf. In addition, tumor- or cyst-like tissues started to appear in the inhbaa-/- ovary after about one year. In contrast to females, activin βAa/b mutant males showed normal spermatogenesis and fertility. As for activin βB subunit, the inhbb-/- mutant exhibited normal folliculogenesis, spermatogenesis and fertility in both sexes; however, the fecundity of mutant females decreased dramatically at 270 dpf with accumulation of early follicles. In summary, the activin-inhibin system plays an indispensable role in fish reproduction, in particular folliculogenesis and ovarian homeostasis.

Colon adenocarcinoma (COAD) is a malignancy with a high mortality rate and complex biological characteristics and heterogeneity, which poses challenges for clinical treatment. Anoikis is a type of programmed cell death that occurs when cells lose their attachment to the extracellular matrix (ECM), and it plays a crucial role in tumor metastasis. However, the specific biological link between anoikis and COAD, as well as its mechanisms in tumor progression, remains unclear, making it a potential new direction for therapeutic strategy research. We employed transcriptomic data and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to pinpoint differentially expressed anoikis-related genes (ARGs) in COAD. Using Cox proportional hazards models and Lasso regression analysis, we developed a prognostic signature derived from these ARGs. We also investigated the roles and interactions of these genes in the tumor microenvironment by analyzing single-cell RNA sequencing data. Additionally, we employed molecular docking techniques to evaluate the potential of inhibin subunit beta B (INHBB) as therapeutic targets and to assess the binding affinity of candidate drugs. Finally, we used gene knockout techniques to silence the key gene INHBB and explored its biological functions . In our study, by analyzing the expression differences of ARGs, we successfully classified patients with COAD. Kaplan-Meier survival analysis demonstrated that patients with elevated risk scores experienced poorer prognosis, a finding that was confirmed in both the training and validation cohorts. Additionally, immune infiltration analysis revealed a notable increase in immune cell presence within the tumor microenvironment of high-risk patients. Molecular docking identified potential drug candidates with high binding affinity to INHBB, including risperidone. Furthermore, experiments with INHBB showed that downregulation of its expression in COAD cell lines significantly reduced cellular viability and migration capacity. In summary, our research, based on the expression characteristics of ARGs, provides new insights into the precise classification, prognosis assessment, and identification of potential therapeutic targets in COAD. It also validates the key role of INHBB in the progression of COAD, establishing the foundation for future personalized treatment strategies.

Abstract Background Clinicians have long been struggling to find an effective tool to predict onset of puberty. Objective To explore stimulability of inhibin B after exogenous FSH and its potential role for prediction of onset of puberty. Design and participants Study subjects were enrolled into “exploratory cohort” (n = 42) and “validation cohort” (n = 19). The exploratory cohort was further divided into group 1 (healthy children with spontaneous puberty [SP], n = 26) and group 2 (patients with hypogonadotropic hypogonadism [HH], n = 16). The validation cohort included children who presented with complaints of delayed puberty. Intervention and outcome Participants were subjected to FSH stimulation test and GnRH analogue stimulation test. Cutoffs derived from the exploratory cohort for basal and FSH stimulated inhibin B (FSH-iB) were applied on the validation cohort. Basal LH, GnRH analogue-stimulated LH, basal inhibin B, and FSH-iB were compared with clinical outcomes on a prospective follow-up for prediction of onset of puberty. Results There was statistically significant increment in inhibin B after exogenous FSH in group 1 (SP) in both male (188.8 pg/mL; P = 0.002) and female (1065 pg/mL; P = 0.023) subjects. The increment was not statistically significant in group 2 (HH) in both sexes. FSH-iB at a cutoff of 116.14 pg/mL in males and 116.50 pg/mL in females had 100% sensitivity and specificity for labelling entry into puberty. On application of these cutoffs on the validation cohort, FSH-iB had 100% positive predictive value, negative predictive value, and diagnostic accuracy for prediction of pubertal onset. Conclusion Inhibin B was stimulable in both male and female subjects. FSH-iB can be considered a novel and promising investigation for prediction of onset of puberty. Future studies are required for further validation.

Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.

Inhibin, β, which is also known as INHBA, encodes a protein that belongs to the Transforming Growth factor-β (TGF-β) superfamily, which plays a pivotal role in cancer. Gastrointestinal tract (GI tract) cancer refers to the cancers that develop in the colon, liver, esophagus, stomach, rectum, pancreas, and bile ducts of the digestive system. The role of INHBA in all GI tract cancers remains understudied. By utilizing GEPIA2, which uses transcriptomic data from TCGA, we examined the expression of INHBA across different GI tract cancers. The results revealed consistent upregulation of INHBA in all TCGA GI tract cancers, except for liver hepatocellular carcinoma, where it showed downregulation compared to normal tissues, along with GTEx normal samples. Significant differences in INHBA expression were noted in adenocarcinomas of the colon, pancreas, rectum, and stomach, while no such differences were observed in cholangiocarcinoma and liver cancer. Moreover, a comprehensive bioinformatics analysis has been done to demonstrate that the differences in expression levels are significantly related to pathological tumor stages and prognosis in different GI tract cancers. Mucinous adenocarcinoma, esophageal squamous cell carcinoma, and stomach adenocarcinoma show a higher frequency of INHBA alteration and are primarily linked to mutations and amplifications. DNA methylation, immune infiltration, functional enrichment analysis, the genes associated with INHBA, and survival analysis in all TCGA GI tract cancers have been extensively analyzed. In colon and stomach cancers, increased INHBA expression significantly correlates with poorer overall survival (OS). However, in colon and pancreatic adenocarcinoma, higher expression is significantly associated with worse disease-free survival (DFS). Additionally, INHBA expression exhibited a positive correlation with cancer-associated fibroblasts across all gastrointestinal (GI) tract cancers. The KEGG pathway analysis revealed that INHBA and its interacting proteins are involved in several pathways, including TGF-beta signaling, Signalling pathways regulating pluripotency of stem cells, colorectal cancer, pancreatic cancer, AGE-RAGE signaling, and so on as major pathways. These findings demonstrate that INHBA could serve as a potential biomarker therapeutic target for GI tract cancer.

Anna Köttgen and colleagues report genome-wide association studies for serum urate in over 140,000 individuals from the Global Urate Genetics Consortium (GUGC). They identify 18 loci newly associated with serum urate concentrations and confirm 10 known loci, characterize their associations with gout and include a network analysis suggesting a role for inhibins-activins pathways in regulating urate homeostasis. Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46 , INHBB , SFMBT1 , TMEM171 , VEGFA , BAZ1B , PRKAG2 , STC1 , HNF4G , A1CF , ATXN2 , UBE2Q2 , IGF1R , NFAT5 , MAF , HLF , ACVR1B - ACVRL1 and B3GNT4 ). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or [beta]-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of [beta]-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing [beta]-catenin downstream of WNT4. In the absence of Wnt4 or [beta]-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin [beta]B (Inhbb), a subunit of activins, was upregulated in the Wnt4 and [beta]-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via [beta]-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and [beta]-catenin) and negative (activin [beta]B) regulators derived from the somatic cells in the fetal ovary.