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Polycystic Ovary Syndrome (PCOS) is characterized by a self-perpetuating vicious cycle between insulin resistance (IR) and hyperandrogenism (HA). While lifestyle management remains the internationally recommended first-line treatment, current clinical management, primarily relying on combined oral contraceptives and metformin, offers symptomatic relief or “masking” of the phenotype but fails to adequately disrupt this core pathophysiological loop, while also carrying potential intergenerational safety concerns. This review systematically evaluates the paradigm shift toward mechanism-based precision medicine. First, we analyze emerging precision-targeted therapies that intervene in specific pathological nodes: (1) metabolic regulators (e.g., GLP-1RAs, SGLT2i, and brown adipose tissue (BAT) activators) that target systemic glucotoxicity and the novel “BAT-Ovarian axis”; (2) neuroendocrine modulators (e.g., NK3R antagonists) that act as negative modulators of the hyperactive GnRH pulse generator; and (3) innovative androgen synthesis inhibitors (e.g., Artemisinins) that utilize a degradation-at-source mechanism. Complementing these, we explore the strategic value of Natural Products through the lens of “Network Pharmacology”, highlighting their ability to restore systemic homeostasis via multi-target modulation. Finally, we address critical translational challenges, specifically the need to establish long-term reproductive and offspring safety, providing a roadmap for developing true disease-modifying treatments for PCOS. Distinct from reviews limited to isolated therapeutic modalities, this article uniquely bridges current clinical management with emerging organ-specific precision targets and natural product networks.

Background Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks’ gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. Methods Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals ( n  = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals ( n  = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals ( n  = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals ( n  = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. Results Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration (“Prion Disease”, “Alzheimer’s Disease”, “Arachidonic Acid metabolism”). Adverse changes were independent of respiratory function during ventilation. Conclusions Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.

An ideal DNA‐encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on‐DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a “Mask & Release” strategy to streamline the challenging on‐DNA core skeleton synthesis. N‐phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA‐compatible C‐H functionalization, introducing the 1st‐dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA‐conjugated drug‐like core skeletons such as ortho‐alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on‐DNA core skeleton synthetic method development. A “Mask & Release” strategy is disclosed herein to streamline the challenging on‐DNA core skeleton synthesis including ortho‐alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran, in which N‐phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA‐compatible C–H functionalization, introducing the 1st‐dimensional diversity at a defined site, and simultaneously releasing the phenol functionality to realize the 2nd diversity.

Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among women of reproductive age. It is characterized by hyperandrogenism, ovulatory dysfunction, and the presence of polycystic ovarian morphology (PCOM) on ultrasound, often accompanied by metabolic disturbances such as insulin resistance and obesity. Current treatments, including oral contraceptives and anti-androgen medications, often yield limited efficacy and undesirable side effects. This study investigates the role of UGT2B15, an essential enzyme for androgen metabolism, in PCOS pathogenesis and its potential as a therapeutic target. Methods We used RNA sequencing to examine the effects of UGT2B15 knockdown in KGN cells. To modulate UGT2B15 expression, we employed siRNA and (R)/(S) -NAF (naftopidil), a chemical inducer of UGT2B15 identified in our previous studies on a prostate hyperplasia model. The effects of siRNA and (R)/(S) -NAF on dihydrotestosterone (DHT) levels, cell apoptosis, and the expression of apoptosis-related proteins in KGN cells were evaluated. In a PCOS mouse model, we assessed the effects of (R) -NAF and (S) -NAF on serum androgen levels, menstrual cycles, ovarian morphology, and UGT2Bs expression. Additionally, luciferase reporter and ChIP assays were utilized to study UGT2B15 regulation by NR1H4. Results Elevated androgens were found to suppress UGT2B15 expression in ovarian granulosa cells, leading to DHT accumulation and apoptosis. (R) -NAF and (S) -NAF treatments reversed these effects, alleviating PCOS symptoms in mice such as hyperandrogenism, irregular menstrual cycles, and the presence of ovarian cysts. NR1H4 negatively regulated the transcription of UGT2B15 in KGN cells. (R) -NAF and (S) -NAF disrupted NR1H4 binding to the UGT2B15 promoter without affecting its protein levels, indicating direct interference with its regulation. Conclusions UGT2B15 represents a promising target for novel PCOS therapies by modulating androgen metabolism and protecting ovarian granulosa cells from apoptosis. (R) -NAF and (S) -NAF regulate UGT2B15 by disrupting NR1H4's binding to its promoter, implying potential therapeutic compounds for PCOS treatment.

Background Antenatal steroids (ANS) are routinely administered to women at risk of preterm birth to accelerate fetal lung maturation. Despite extensive clinical use, dosing and route of ANS administration remain unoptimized beyond intramuscular (IM) injection. We aimed to undertake a proof-of-principle assessment of transdermal ANS administration for accelerated fetal lung maturation. Methods We formulated and tested a transdermal ANS (betamethasone) patch in ex vivo studies. To confirm in vivo transdermal distribution of the ANS patch, we undertook a 24-h pharmacokinetic study in non-pregnant cynomolgus macaques (NHP). To assess the efficacy of transdermal betamethasone on fetal lung maturation, we used a preterm sheep model of pregnancy comparing postnatal ventilation outcomes. Date mated ewes received either of the following: (i) IM normal saline (Saline Control, n  = 13); (ii) IM ANS (betamethasone) delivery 2 or 8 days post-treatment (2-Day IM ANS, n  = 14; 8-day IM ANS Group, n  = 6); (iii) IM saline + 2 × transdermal ANS (Betamethasone) patches delivery 2 days post-treatment (2-Day ANS Patch, n  = 10); or (iv) IM saline + 2 × transdermal ANS (betamethasone) patches replaced with 2 × new patches after 48 h, delivery 8 days post-treatment (8-Day ANS Patch, n  = 11). Lambs were delivered at 123 ± 1 dGA (term 150 days), then ventilated for 30 min to assess lung maturation status. Arterial blood gas, delivery, and ventilation data were analyzed ( p  < 0.05 significant). Results Transdermal administration of ANS in NHPs achieved rapid plasma accumulation, with a plasma half-life of 8.9 h, similar to that achieved with IM dosing in clinical practice. In preterm sheep, all 2- and 8-day IM and transdermal ANS patch groups had clinically important and statistically significant improvements in ventilation parameters (umbilical PaCO 2 , pH, tidal volume) compared to saline control. Conclusions We demonstrate, for the first time, the potential for using transdermal ANS for preterm fetal lung maturation. Transdermal ANS administration eliminates the need for injections, pain, and infection risk. Moreover, transdermal ANS delivery demonstrates advantages in dose control, continuity of exposure, and potential to remove drug exposure should the risk of preterm birth resolve. Further development of this technology may improve preterm outcomes through delivery of a low dose, constant fetal steroid exposure.

Human Wharton’s jelly stem cells (hWJSCs) are multipotent stem cells that are extensively employed in biotechnology applications. However, the impact of simulated lunar microgravity (sμG) on the growth, differentiation, and viability of this cell population is incompletely characterized. We aimed to determine whether acute (72 h) exposure to sμG elicited changes in growth and lineage differentiation in hWJSCs and if putative changes were maintained once exposure to terrestrial gravity (1.0 G) was restored. hWJSCs were cultured under standard 1.0 G conditions prior to being passaged and cultured under sμG (0.16 G) using a random positioning machine. Relative to control, hWJSCs cultured under sμG exhibited marked reductions in growth but not viability. Cell population expression of characteristic stemness markers (CD 73, 90, 105) was significantly reduced under sμG conditions. hWJSCs had 308 significantly upregulated and 328 significantly downregulated genes when compared to 1.0 G culture conditions. Key markers of cell replication, including MKI67 , were inhibited. Significant upregulation of osteocyte–chondrocyte lineage markers, including SERPINI1, MSX2, TFPI2, BMP6, COMP, TMEM119, LUM, HGF, CHI3L1 and SPP1 , and downregulation of cell fate regulators, including DNMT1 and EZH2 , were detected in sμG-exposed hWJSCs. When returned to 1.0 G for 3 days, sμG-exposed hWJSCs had accelerated growth, and expression of stemness markers increased, approaching normal (i.e. 95%) levels. Our data support earlier findings that acute sμG significantly reduces the cell division potential of hWJSCs and suggest that acute sμG-exposure induces reversible changes in cell growth accompanied by osteocyte–chondrocyte changes in lineage differentiation.

The management and prevention of key inflammatory-associated pregnancy complications such as chorioamnionitis and pre-eclampsia is hampered by a lack of early gestation risk screening tools. In a proof-of-principle study we used targeted cell-free RNA analyses of maternal plasma samples from large animal (sheep) and human pregnancy cohorts to develop a minimally invasive screening test for inflammatory markers. This study utilised a preterm sheep model of sterile and bacterial chorioamnionitis. Date-mated ewes received either intraamniotic Saline Control ( n  = 10) or E.Coli LPS (Sterile chorioamnionitis) with 2 days ( n  = 9) or 8 days exposure( n  = 6). Preterm lambs were delivered at 124 ± 1d gestation. Findings were validated in a bacterial model of chorioamnionitis where ewes were exposed to 7 days of intraamniotic M.Hominis with delivery at 98 d gestion( n  = 8) or 128d gestation( n  = 8). Maternal blood was collected prior to intervention and at delivery in each group. Random Forest algorithm was used to analyse 8 cell-free RNA(cfRNA) targets related to inflammation in maternal plasma at baseline and delivery, identifying genes that separated animals with or without intrauterine inflammation. Plasma cfRNA data was compared to mRNA expression in placental tissue. Haematological and placental mRNA comparisons were analysed with ANOVA/Tukey HSD/Dunnett T3 tests. Maternal plasma cfRNA findings of intrauterine inflammation were then validated in human plasma samples from a cohort of patients with late onset pre-eclampsia ( n  = 10) or uncomplicated pregnancies ( n  = 10). We present data showing that targeted maternal cfRNA assays can accurately identify chorioamnionitis of sterile (AUC 1.0) and infectious (AUC 0.84) origin in a sheep model of pregnancy. Findings were then validated in human maternal plasma samples from patients with late-onset pre-eclampsia in the 1st (AUC = 0.85), 2nd (AUC = 0.90) and 3rd (AUC = 0.82) trimesters. In both sheep and human model systems, cfRNA tests offered high levels of sensitivity and specificity in the absence of overt clinical symptoms. We suggest that further development of this technology may serve as a scalable, rapidly deployed and cost-effective means for predicting major inflammatory conditions in pregnancy.

Tetrastigma hemsleyanum , a traditional Chinese medicinal plant with anti-inflammatory, anti-cancer, and anti-tumor properties, faces increasing abiotic stress due to climate change, agricultural chemicals, and industrialization. This study investigated how three abiotic stress factors influence antioxidant enzyme activity, MDA levels, DPPH free radical scavenging capacity, chlorophyll, carotenoids, active compounds, and gene expression in different T. hemsleyanum strains. The comprehensive evaluation indicates that the ZJWZ strain holds potential as a preferred parental material for future resistance breeding. Furthermore, PAL gene expression was strongly positively correlated with flavonoid and phenol contents, highlighting its role in the stress response through the phenylpropanoid-flavonoid pathway. This study contributes to the standardization of the production and breeding of superior strains of T. hemsleyanum . It also lays the foundation for investigating how plants react to environmental stressors.

Despite substantial improvement in air quality in China, winter PM2.5 concentrations particularly in January show limited decline, especially in the central region. This study used statistical analysis and WRF-CMAQ to examine how typical meteorological years affect transport and pollution processes in Henan. The mean effect difference ranged from −22 to 33%. In January 2020, weak winds and a low planetary boundary layer increased PM2.5 by 3–33%, whereas in January 2023, stronger northerly winds and a higher boundary layer reduced PM2.5 by 12–22%. These differences altered transport pathways, leading to a shift in dominant source regions from Beijing–Tianjin–Hebei and Shandong to Anhui and Hubei, with primary PM2.5 showing high sensitivity to transport pathways, whereas secondary PM2.5 remained relatively stable due to its dependence on regional chemical formation. Typical meteorological years in Henan exhibit two distinct pollution regimes: The local accumulation regime (2020) showed faster growth (20–30 μg m−3 d−1), a higher peak (107 μg m−3), longer persistence, and slower dissipation and was dominated by near-range transport. In contrast, the regional transport regime (2023) exhibited slower growth (<20 μg m−3 d−1), a lower peak (99 μg m−3), shorter persistence, and more rapid dissipation and was sustained by multi-regional input from Anhui, Shandong, and Hubei. In both episodes, primary PM2.5 dominated during the growth and peak stages, whereas secondary PM2.5 played a more prominent role during dissipation.