Unlocking the potential of tranilast: Targeting fibrotic signaling pathways for therapeutic benefit.

Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-ß, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.

Knowledge of fertility and perception of fertility treatment among adults with sickle cell disease (KNOW FERTILITY).

Introduction: This study assessed fertility knowledge in adults with sickle cell disease using the Cardiff Fertility Knowledge Scale and Fertility Treatment Perception Survey and compared knowledge scores in respondents with sickle cell disease to previously reported unaffected cohorts. Methods: This cross-sectional study surveyed adults over age 18 with sickle cell disease at an adult sickle cell disease center using a 35-question survey addressing infertility risk factor knowledge and perceptions of fertility treatment. Analyses included summary statistics for continuous and categorical variables, univariate linear regression, and Mann-Whitney U tests for group comparisons of Fertility Knowledge Scale scores. Fertility Treatment Perception Survey scores were measured by medians of the two positive statements and four negative statements to generate separate positive and negative treatment belief scores. Statistical significance was set at p < 0.05 for all analyses. Results: Ninety-two respondents (71 female, 21 male) with median age of 32 years (IQR: 25.0, 42.5) completed the survey between October 2020-May 2021. Sixty-five percent of respondents reported taking sickle cell disease treatment and 18% reported refusing at least one sickle cell disease treatment due to fertility concerns. The mean Fertility Knowledge Score was 49% (SD: 5.2), lower than reported in an international cohort (57% vs. 49%, p = 0.001), and higher than in a cohort of reproductive-aged Black women in the USA (49% vs. 38%, p = 0.001). Less than 50% of respondents correctly identified common infertility risk factors including sexually transmitted infections, advanced age, and obesity. Mean positive fertility perception score was 3 (IQR 3, 4), and negative fertility perception score was 3.5 (IQR 3, 4). Factors associated with agreement with negative fertility perception statements included: trying to conceive, refusing sickle cell disease treatment, and undergoing fertility treatment. Discussion: Opportunities exist to improve knowledge of infertility risk factors among adults with sickle cell disease. This study raises the possibility that nearly one in five adults with sickle cell disease refuse SCD treatment or cure due to infertility concerns. Education about common infertility risks factors needs to be addressed alongside disease- and treatment- associated fertility risks.

AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells.

Granulosa cells (GCs) must respond appropriately to follicle-stimulating hormone (FSH) for proper follicle maturation. FSH activates protein kinase A (PKA) leading to phosphorylation of the cyclic AMP response element binding protein-1 (CREB1). We identified a unique A-kinase anchoring protein (AKAP13) containing a Rho guanine nucleotide exchange factor (RhoGEF) region that was induced in GCs during folliculogenesis. AKAPs are known to coordinate signaling cascades, and we sought to evaluate the role of AKAP13 in GCs in response to FSH. Aromatase reporter activity was increased in COV434 human GCs overexpressing AKAP13. Addition of FSH, or the PKA activator forskolin, significantly enhanced this activity by 1.5- to 2.5-fold, respectively (p < 0.001). Treatment with the PKA inhibitor H89 significantly reduced AKAP13-dependent activation of an aromatase reporter (p = 0.0067). AKAP13 physically interacted with CREB1 in co-immunoprecipitation experiments and increased the phosphorylation of CREB1. CREB1 phosphorylation increased after FSH treatment in a time-specific manner, and this effect was reduced by siRNA directed against AKAP13 (p = 0.05). CREB1 activation increased by 18.5-fold with co-expression of AKAP13 in the presence of FSH (p < 0.001). Aromatase reporter activity was reduced by inhibitors of the RhoGEF region, C3 transferase and A13, and greatly enhanced by the RhoGEF activator, A02. In primary murine and COV43 GCs, siRNA knockdown of Akap13/AKAP13 decreased aromatase and luteinizing hormone receptor transcripts in cells treated with FSH, compared with controls. Collectively, these findings suggest that AKAP13 may function as a scaffolding protein in FSH signal transduction via an interaction with CREB, resulting in phosphorylation of CREB.

Biomechanics and mechanical signaling in the ovary: a systematic review.

PURPOSE: Mammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis. METHODS: We performed a systematic review to assess and summarize the effects of mechanical signaling and mechanotransduction in oocyte maturation and folliculogenesis and to explore possible clinical applications. The review identified 2568 publications of which 122 met the inclusion criteria. RESULTS: The integration of mechanical and cell signaling pathways in gametogenesis is complex. Follicular activation or quiescence are influenced by mechanical signaling through the Hippo and Akt pathways involving the yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene, the mammalian target of rapamycin (mTOR), and forkhead box O3 (FOXO3) gene. CONCLUSIONS: There is overwhelming evidence that mechanical signaling plays a crucial role in development of the ovary, follicle, and oocyte throughout gametogenesis. Emerging data suggest the complexities of mechanotransduction and the biomechanics of oocytes and follicles are integral to understanding of primary ovarian insufficiency, ovarian aging, polycystic ovary syndrome, and applications of fertility preservation.