Hui Wang

Background: Endometriosis is an estrogen-dependent disorder with limited treatment options. The precise molecular targets of curcumin and its effects on local estrogen synthesis in this disease remain unclear. Methods: We investigated curcumin’s efficacy and mechanism via network pharmacology, in vitro functional assays in ectopic endometrial cells, an allogeneic mouse model, and target validation through molecular docking, thermal shift, and hydrolysis stability assays. Results: Curcumin significantly inhibited ectopic cell malignant phenotypes, reducing migration distance by 55.60 ± 7.32%, 80.34 ± 11.19%, and 82.88 ± 13.67% at 5, 10, and 15 μM, respectively, and decreasing invasive cell numbers by 40.38 ± 7.67%, 58.33 ± 12.70%, and 60.18 ± 9.07%, respectively (all p < 0.05). In a mouse model, curcumin (200 mg/kg/day) reduced lesion number by 38.46% (2.167 ± 0.752 vs. 1.333 ± 0.516, p = 0.0493) and lesion volume by 59.73% (0.0497 ± 0.0173 vs. 0.0200 ± 0.0130 mm³, p = 0.00732). It also suppressed de novo estrogen synthesis and modulated the estrogen receptor α (ERα) and β (ERβ) ratio. Mechanistically, curcumin directly bound to and inhibited protein kinase A (PKA), a key kinase in the cAMP signaling pathway. Conclusions: We first demonstrate that curcumin alleviates endometriosis by targeting PKA to inhibit local estrogen synthesis, identifying PKA as a novel therapeutic target and curcumin as a promising treatment candidate.

Metabolic determinants of oocyte quality and embryonic development remain incompletely understood. Here, we profiled metabolites in human cumulus cells (CCs) and follicular fluid (FF), validated in two mouse models, and integrated transcriptomics with receptor blockade to define mechanisms. In human CCs, adenosine was higher in cycles yielding fewer high-quality embryos and discriminated embryo quality (ROC AUC = 0.75). Conversely, FF adenosine was reduced in the same context. In mice, low-quality oocytes and their associated CCs accumulated adenosine, revealing an intra- vs extracellular disequilibrium. The imbalance aligned with reduced expression of the adenosine transporters ENT1/ENT2 and the gap-junction component CX37. Functionally, supplementation with exogenous adenosine restored early embryonic development from low-quality oocytes, lowering oxidative stress and spindle/chromosome errors via adenosine receptors. Smart-seq2 transcriptomic analysis and functional experiments showed partial normalization of programs governing meiosis and cellular stress responses, including correction of CycB1/Cdc27 (MPF/APC/C) and JNK-linked pathways. Together, we identify adenosine disequilibrium as a metabolic fingerprint of poor oocyte competence and show that receptor-mediated adenosine signaling tunes MPF-related and oxidative stress pathways to rescue developmental potential. These findings provide a mechanistic and translational basis for early prediction and culture optimization in ART.

Changes in fatty acid composition caused by diet or exposure to diets that promote obesity can impact the quality of eggs and embryos, as well as the health of the resulting offspring. Palmitoylcarnitine, as an important intermediate for fatty acid transport across the inner mitochondrial membrane, undergoes a substantial increase during oocyte maturation. However, its impact on oocyte/embryo development remains unknown. In the present study, by establishing a high-fat diet (HFD)-induced model of obesity, we systematically evaluated the effects of palmitoylcarnitine supplementation on oocyte competence and embryo quality derived from obese mice. We found that palmitoylcarnitine supplement during in vitro culture markedly ameliorates the meiotic defects and genomic instability in HFD oocytes. The abnormal mitochondrial distribution and the lowered mitochondrial membrane potential in HFD oocytes are also prevented simultaneously, indicative of the improved mitochondrial function. Moreover, palmitoylcarnitine administration is capable of suppressing blastocyst apoptosis and promoting early embryo development from HFD mice. Taken together, our results suggest that palmitoylcarnitine has beneficial effects on oocyte quality exposed to maternal obesity via modulating meiotic structure and energy metabolism.

Although Myo‐Inositol/D‐Chiro‐Inositol (Ins) and berberine (BBR) have each shown beneficial effects in polycystic ovary syndrome (PCOS), their combined therapeutic potential has not been systematically evaluated. Here, we demonstrate that Ins/BBR exerts superior efficacy compared with single treatments by targeting multiple pathogenic pathways in PCOS. In a DHEA+HFD‐induced mouse model, Ins/BBR restored systemic sex steroid balance, normalized LH/FSH ratio, and improved estrous cyclicity. It also reduced ovarian cysts and enhanced fertility, accompanied by partial normalization of steroidogenic enzyme expression. At the cellular level, Ins/BBR alleviated mitochondrial defects and broadly reprogrammed metabolic landscape in granulosa cells, in specific, restoring nucleotide pools and amino acid turnover and preventing abnormal long‐chain fatty acid accumulation. Together, these findings provide preclinical evidence that Ins/BBR acts through coordinated endocrine, ovarian and metabolic mechanisms, supporting its promise as a safe and effective therapeutic strategy for PCOS.

Background: Undescended Testis, the most common congenital male reproductive disorder in children, demonstrates complex pathogenesis with genetic predisposition. While early surgical intervention (before 18 months) remains standard care, pharmacological options are limited.Purpose: Explore the therapeutic potential of Traditional Chinese Medicine for Undescended Testis.Study design: This study employs multiple bioinformatics approaches to search for potential Traditional Chinese Medicines for Undescended Testis treatment and investigate their therapeutic mechanisms.Methods: This study integrated medication regularity analysis, network pharmacology, Mendelian randomization, and molecular docking, with exploration conducted through cellular and animal models.Results: Our analysis identified 27 bioactive Epimedium compounds, with Quercetin, Kaempferol, and Icariin showing particular promise. Protein interaction networks revealed AKT1, PARP1, and PGR as key targets. Functional enrichment analysis primarily focused on biological processes including response to stress-induced damage (such as reactive oxygen species, chemical toxins, and other stressors), steroid signaling and receptor activation, transmembrane signal transduction, as well as cellular proliferation and apoptosis regulation. Molecular docking demonstrated Yinyanghuo B’s strong binding affinity with PARP1 (-7.2 kcal/mol). Mendelian randomization confirmed PARP1 reduction’s causal relationship with lower Undescended Testis risk. We constructed animal and cellular heat stress models to simulate Undescended Testis, and subsequent experiments observed significant DNA damage. Thermally stressed TM4 cells showed significant PARP1 upregulation, suggesting its critical role in testicular heat stress response by accelerating DNA damage repair.Conclusion: These findings potentially provide mechanistic evidence supporting Epimedium’s traditional use while advancing Traditional Chinese Medicine modernization through contemporary pharmacological validation.

Background: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women of reproductive age, is mainly ameliorated through drugs or lifestyle changes, with limited treatment options. To date, numerous researchers have found that fertility nutrient supplements may benefit female reproductive health, but their direct impact on polycystic ovary syndrome risk remains unclear.Methods: Our research employs Mendelian Randomization to assess how fertility nutrients affect PCOS risk. Initially, we reviewed 49 nutrients and focused on 10: omega-3 fatty acids, calcium, dehydroepiandrosterone, vitamin D, betaine, D-Inositol, berberine, curcumin, epigallocatechin gallate, and metformin. Using methodologies of Inverse Variance Weighting and Mendelian Randomization-Egger regression, we examined their potential causal relationships with PCOS risk.Results: Our findings indicate omega-3 fatty acids reduced PCOS risk (OR=0.73, 95% CI: 0.57-0.94, P=0.016), whereas betaine increased it (OR=2.60, 95% CI: 1.09-6.17, P=0.031). No definitive causal relations were observed for calcium, dehydroepiandrosterone, vitamin D, D-Inositol, and metformin (P>0.05). Drug target Mendelian Randomization analysis suggested that increased expression of the berberine target gene BIRC5 in various tissues may raise PCOS risk (OR: 3.00-4.88; P: 0.014-0.018), while elevated expressions of curcumin target gene CBR1 in Stomach and epigallocatechin gallate target gene AHR in Adrenal Gland were associated with reduced PCOS risk (OR=0.48, P=0.048; OR=0.02, P=0.018, respectively).Conclusions: Our research reveals that specific fertility nutrients supplementation, such as omega-3 fatty acids, berberine, and curcumin, may reduce the risk of PCOS by improving metabolic and reproductive abnormalities associated with it.

Are taurine and its transporter TAUT associated with spermiogenesis and early embryo development? Morphologically abnormal spermatozoa increased after local functional interference by intratesticular injection, and taurine depletion significantly reduced the normal embryo numbers in vivo and blastocyst formation rate in vitro. Taurine is one of the most abundant amino acids in the male reproductive system and it has been demonstrated that taurine can efficiently improve spermatogenic function in rat models of testicular injury. However, limited information is known about the role of taurine and its transporter TAUT in spermatogenesis and early embryo development. Clinical characteristics from 110 couples who have experienced recurrent pregnancy loss (RPL) were collected from December 2014 to March 2018. According to whether a fetal heartbeat was seen in the previous pregnancy under ultrasonic monitoring, patients with RPL were divided into two groups: an RPL without heartbeat (pregnancy with no fetal heartbeat, ROH) group, and an RPL with heartbeat (one or more pregnancies with fetal heartbeat, RWH) group. Semen samples (21 ROH and 20 RWH) were finally used for metabolomic analysis. Furthermore, semen samples were obtained from 30 patients with teratozoospermia (normal sperm morphology in vitro. N/A The sample size was low and larger cohorts are needed to confirm the positive effect of taurine on human sperm quality. A comprehensive safety examination should be performed to evaluate whether taurine is a possible treatment for teratozoospermia. Furthermore, the specific molecular mechanism of TAUT involvement in spermiogenesis remains to be clarified. The study provides new insights into the role of taurine and its transporter TAUT in male reproduction and embryo development. The results also indicate that TAUT is a promising molecular candidate for the assessment of sperm quality, which may contribute to the diagnosis and treatment for teratozoospermia. This work was supported by grants from the National Natural Science Foundation of China (no. 81774075, 31900605, 81971451), Jiangsu Science and Technology Program Grant (BK20190654) and Maternal and child health scientific research of Jiangsu Province (F202121). The authors declare no competing financial interests.

Oxidative stress (OS) is one of the primary factors leading to male infertility. Oral administration of antioxidants has thus far been found to significantly improve the quality of human sperm. Therefore, antioxidant treatment has become the consensus among international experts on male infertility. In this study, peroxisomal biogenesis factor 3 (Pex3)-knockout (KO, −/−) mice were used as a model to compare the efficacy of three types of traditional Chinese medicine (TCM) granules (Epimedium [YYH], Cuscuta [TSZ], and Rhodiola [HJT]) for male reproductive function rescue. YYH was revealed to be the best and exerted a rescue effect on Pex3−/− mice with spermatogenesis defects. In addition, YYH prominently reduced ROS levels in the testes, inhibited DNA oxidative damage in spermatogenic cells, promoted the proliferation of spermatogenic cells, and inhibited apoptosis in Pex3−/− male mice. Furthermore, the mechanism by which YYH ameliorated dyszoospermia was confirmed via the establishment of cyclin-dependent kinase inhibitor 2 A (P16Ink4a)-KO mice. Specifically, Pex3−/− mice produced elevated amounts of ROS, which damaged germ cell DNA and further activated the signaling pathway of the cell senescence regulatory protein P16-CDK6, resulting in cell cycle arrest and eventually contributing to spermatogenesis dysfunction. YYH supplementation partially corrected the associated phenotype in gene KO mice by affecting P16 expression levels, thus improving the reproductive outcome to a certain extent.