BACKGROUND:Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by reproductive dysfunction and endocrine-metabolic abnormalities. However, its precise pathogenesis remains unclear. Increasing evidence indicates that ovarian granulosa cells (GCs) dysfunction and metabolic imbalance play critical roles in the initiation and progression of PCOS. This study investigated the regulatory role of the sulfite oxidase (SUOX)-AMP-activated protein kinase (AMPK) signaling axis in the development and function of ovarian GCs in PCOS. METHODS:PCOS-associated gene variants were identified using high-throughput sequencing and subsequently validated using dual-luciferase reporter assays. SUOX expression was modulated in ovarian KGN cells using gene knockdown and overexpression approaches combined with pharmacological interventions to assess alterations in SUOX-AMPK signaling and its downstream effects. A mouse model of PCOS was established to further evaluate the biological role of SUOX in vivo. RESULTS:SUOX expression was significantly reduced in follicular fluid samples from patients with PCOS. SUOX knockdown was associated with suppression of AMPK signaling, mitochondrial dysfunction, impaired autophagy, and increased lipid synthesis in KGN cells. Conversely, SUOX overexpression or AMPK pharmacological activation effectively reversed these pathological changes. Restoration of SUOX expression partially reduced ovarian metabolic dysfunction in PCOS mouse models. CONCLUSION:These findings demonstrate that the SUOX-AMPK signaling axis plays an important role in the pathogenesis of PCOS. Reduced SUOX expression may contribute to disease progression by promoting oxidative stress, worsening mitochondrial damage, and impairing ovarian function, suggesting that SUOX may represent a potential molecular target for the diagnosis and treatment of PCOS.

Abstract Objective The interplay between chronic sleep deprivation and drug‐resistant epilepsy (DRE) has gained increasing attention. Brain and muscle Arnt‐like protein 1 (BMAL1), which is implicated in sleep disturbance, has an unclear role in DRE. We aimed to investigate the role of BMAL1 in sleep deprivation‐induced DRE. Methods A pentylenetetrazole (PTZ) kindling epilepsy model was established to explore the impact of chronic sleep deprivation on pharmacoresistance and related molecular expression. BMAL1 was either overexpressed or knocked down in epileptic rats using adeno‐associated viral vectors, and pharmacoresistance together with hippocampal protein levels were assessed. Complementary in vitro experiments in brain endothelial cells and astrocytes further evaluated the effects of BMAL1 on Per2, P‐S6, and P‐gp. Results Chronic sleep deprivation significantly increased pharmacoresistance, accompanied by reduced BMAL1 and Per2, elevated P‐S6, and increased P‐glycoprotein (P‐gp) expression in the hippocampus. In vitro experiments confirmed that BMAL1 regulates P‐gp through the mTOR pathway. In vivo, BMAL1 overexpression attenuated chronic sleep deprivation‐induced pharmacoresistance, restoring Per2, inhibiting the mTOR pathway, and reducing P‐gp levels. Conversely, BMAL1 knockdown promoted pharmacoresistance in epileptic rats with normal sleep, with decreased Per2, increased P‐S6, and elevated P‐gp. Significance These findings indicate that BMAL1 is an important mediator linking chronic sleep deprivation to pharmacoresistance in epilepsy, and suggest the BMAL1–mTOR–P‐gp axis as a potential therapeutic target for drug‐resistant epilepsy. Plain Language Summary Drug‐resistant epilepsy remains a major clinical challenge, and sleep loss increases its risk. We found that chronic sleep loss reduces BMAL1, a protein that helps regulate sleep. In experiments with rats and brain cells, altering BMAL1 levels changed P‐glycoprotein via the mTOR pathway. These changes in P‐glycoprotein then influenced the response to anti‐seizure medicines. The study showed that targeting BMAL1 may be a new treatment for drug‐resistant epilepsy.

Polycystic ovary syndrome (PCOS) is currently recognized as a condition that affects several systems in the body, including the reproductive, endocrine, and cardiovascular systems. Prevalent among teenagers and women of reproductive age. Prior research has demonstrated an elevation of miR-34a-5p within the follicular fluid (FF) of women of PCOS. Despite this, the precise mechanisms through which miR-34a-5p influences granulosa cells (GC) development and function remain poorly characterized. Therefore, this study investigates the involvement and pathogenic mechanisms of miR-34a-5p within GCs in the context of PCOS. The human granulosa-like tumor cell line (KGN) got transfected at a control, as well as a miR-34a-5p mimic and inhibitor, respectively. Monitor cellular proliferation in each experimental group. The experimental methods included RT-qPCR, CCK8, flow cytometry and western blotting. Also, the interaction between miR-34a-5p and the particular sequence of JAG1 has been verified using the dual luciferase assay. Further investigation of the connection involving miR-34a-5p and the Notch signaling pathway was conducted using bioinformatics analysis and experimental methods. The results demonstrated that miR-34a-5p expression was significantly elevated in the serum(p<0. 0001)and FF (p = 0. 0402) of PCOS, whereas its expression in GCs (p = 0. 5522) showed no significant variation. Overexpressing miR-34a-5p caused a decrease in the rate at which KGN cells multiplied and an increase in programmed cell death. Conversely, inhibiting miR-34a-5p resulted in an increase in cell growth and a decrease in programmed cell death. Bioinformatics analysis and experimental results further demonstrated thatmiR-34a-5p interacts with the 3’UTR region of JAG1, leading to a negative regulation of the Jagged1-Notch signaling pathway. In summary, the miR-34a-5p molecule inhibits the growth of GCs as well as triggers programmed cell death by regulating the Jagged1-Notch signaling pathway. Silencing miR-34a-5p prevents dysfunction in GCs. Our analysis implies that miR-34a-5p is a new molecular site to treat PCOS.

OBJECTIVES:Medroxyprogesterone acetate (MPA), a steroid progesterone, is widely used to treat endometriosis, menstrual disorders, and uterine bleeding in clinical practice. However, the safety profile of MPA requires comprehensive evaluation. METHODS:This study performed a retrospective analysis using real-world data extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Case reports from 2003 to 2023 were analyzed using methods like reporting advantage ratio (ROR), proportional report ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and empirical Bayes geometric mean (EBGM). RESULTS:In the case reports spanning from 2003 to 2023, showed 26,437 adverse events (AEs) related to MPA, mostly in females (25,639). Disproportionality analysis identified 116 ADRs across 19 system organ class (SOC) levels, including expected AEs like 'female breast cancer'(n = 8717) and 'ovarian cancer' (n = 459). Unexpected AEs, such as 'acquired diaphragmatic eventration'(n = 3), were also noted. CONCLUSION:Our study identifies potential new and unexpected ADR signals linked to MPA, which align with clinical observations. Additional research is necessary to confirm these associations and address previously unrecognized safety concerns. This research provides a novel and distinctive approach to exploring drug-related AEs.

BACKGROUND:Polycystic ovary syndrome (PCOS) commonly impacts fertile females with potentially severe effects on fertility and metabolism. Blood ghrelin levels are lower in PCOS patients, and exogenous supplements have been proposed for their potential to trigger anti-inflammatory effects at the cellular level. This study aimed to investigate whether pretreatment with ghrelin reduced inflammation, insulin resistance, and reproductive abnormalities in PCOS and the underlying mechanism of this disorder. METHODS:Ghrelin supplementation was first tested in an inflammation model using human ovarian granulosa cells (KGN cells) that were built by treated with Lipolyaccharide. KGN cells were pretreated with ghrelin and exposed to lipopolysaccharide (LPS). Inflammatory gene expression and cytokine production were analyzed by Enzyme-linked immunosorbent assay (ELISA). Based on these results, the PCOS mice model was built with Dehydroepiandrosterone (DHEA) and a high-fat diet. The mRNA and protein expressions of inflammatory factors including Toll-like receptor 4 (TLR4), nuclear factor kappa-B-p65 (NF-κB-p65), Phospho-NF-κB-p65 (p-NF-κB-p65) and myeloid differentiation factor 88 (MYD88) related to the TLR4/NF-κB signaling pathway were evaluated in KGN cells and mouse ovarian tissues using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and western blot, respectively. Lipid metabolism was quantified via an automated biochemical analyzer. RESULTS:The mRNA and protein expressions of interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) in ghrelin pretreated KGN cells were lower than the LPS group (p < 0.05). Protein expression was reduced for TLR4, NF-κB-p65, and MYD88 within KGN cells of ghrelin groups compared to the LPS group (p < 0.05). Ghrelin treatment restored the estrous cycle and slowed weight gain and abdominal fat weight of PCOS mice (p < 0.05). Ghrelin treatment decreased the serum concentrations of testosterone, luteinizing hormone, insulin, IL-6, IL-1β, and TNF-α compared to the PCOS group (p < 0.05). Estradiol concentrations of mice treated with ghrelin were higher than the PCOS group (p < 0.05). The concentrations of low and high-density lipoprotein, triglyceride, and cholesterol in mice treated with ghrelin were lower than in the PCOS mice (p < 0.05). Inflammatory gene expression for IL-6, IL-1β, TNF-α, TLR4, NF-κB-p65, and MYD88 decreased in the ovarian tissues of ghrelin-treated mice compared to the PCOS group (p < 0.05), along with reduced protein expression of TLR4, p-NF-κB-p65, and MYD88 (p < 0.05). CONCLUSIONS:In the present study, ghrelin treatment effectively reduced inflammation in vitro, and attenuated insulin resistance and reproductive abnormalities in PCOS mice through the TLR4/NF-κB signaling pathway, highlighting potential therapeutic avenues for future PCOS treatments and research directions.

BackgroundAlterations in metabolites and metabolic pathways are thought to be important triggers of idiopathic pulmonary fibrosis (IPF), but our lack of a comprehensive understanding of this process has hampered the development of IPF-targeted drugs.MethodsTo fully understand the metabolic profile of IPF, C57BL/6 J male mice were injected intratracheally with bleomycin so that it could be used to construct a mouse model of IPF, and lung tissues from 28-day and control IPF mice were analyzed by pathology and immunohistochemistry. In addition, serum metabolites from IPF mice were examined using LC-ESI-MS/MS, and the differential metabolites were analyzed for KEGG metabolic pathways and screened for biomarkers using machine learning algorithms.ResultsIn total, the levels of 1465 metabolites were detected, of which 104 metabolites were significantly altered after IPF formation. In IPF mouse serum, 52% of metabolite expression was downregulated, with lipids (e.g., GP, FA) and organic acids and their derivatives together accounting for more than 70% of the downregulated differentially expressed metabolites. In contrast, FA and oxidised lipids together accounted for 60% of the up-regulated differentially expressed metabolites. KEGG pathway enrichment analyses of differential metabolites were mainly enriched in the biosynthesis of unsaturated fatty acids, pentose phosphate pathway, and alanine, aspartate, and glutamate metabolism. Seven metabolites were screened by machine learning LASSO models and evaluated as ideal diagnostic tools by receiver operating characteristic curves (ROCs).DiscussionIn conclusion, the serum metabolic disorders found to be associated with pulmonary fibrosis formation will help to deepen our understanding of the pathogenesis of pulmonary fibrosis.

Preeclampsia (PE) is a common complication of pregnancy, usually accompanied by symptoms such as hyper-tension and proteinuria. It can induce severe conditions that may result in maternal and fetal morbidity and fatality. In this study, we use bioinformatics analysis to compare microRNA microassay in decidual stromal cells from PE patients and healthy donors. Our result indicated that placentas from PE patients had a higher CCL1/ CXCL2 expression, compared with those from healthy donors. Bioinformatics analysis confirmed that decidual stromal cells derived from PE patients expressed significantly lower miR-455-3p than those derived from healthy donors. Transfection of miR-455-3p inhibitors enhanced the CCL2/CXCL8 expression in decidual stromal cells, and luciferase activity assay confirmed that nuclear factor of activated T cells 5 (NFAT5) mRNA was the direct target of miR-455-3p; NFAT5 also promoted cytokine secretion. In the flow cytometry study, higher M1 macrophage infiltration was observed in placentas from PE patients than in those from healthy donors. We also observed that condition medium (CM) derived from decidual stromal cells could significantly promote M1 po-larization of macrophages after transfection with miR-455-3p inhibitor; further, transwell invasion assay confirmed that decidual stromal cells-CM educated macrophages suppressed trophoblast invasion. Taken together, our result demonstrates that downregulation of miR-455-3p in decidual stromal cells can promote macrophage polarization and suppress trophoblasts invasion.

Abstract Background Altered metabolic pathways have recently been considered as potential drivers of idiopathic pulmonary fibrosis (IPF) for the study of drug therapeutic targets. However, our understanding of the metabolite profile during IPF formation is lacking. Methods To comprehensively characterize the metabolic disorders of IPF, a mouse IPF model was constructed by intratracheal injection of bleomycin into C57BL/6J male mice, and lung tissues from IPF mice at 7 days, 14 days, and controls were analyzed by pathology, immunohistochemistry, and Western Blots. Meanwhile, serum metabolite detections were conducted in IPF mice using LC–ESI–MS/MS, KEGG metabolic pathway analysis was applied to the differential metabolites, and biomarkers were screened using machine learning algorithms. Results We analyzed the levels of 1465 metabolites and found that more than one-third of the metabolites were altered during IPF formation. There were 504 and 565 metabolites that differed between M7 and M14 and controls, respectively, while 201 differential metabolites were found between M7 and M14. In IPF mouse sera, about 80% of differential metabolite expression was downregulated. Lipids accounted for more than 80% of the differential metabolite species with down-regulated expression. The KEGG pathway enrichment analysis of differential metabolites was mainly enriched to pathways such as the metabolism of glycerolipids and glycerophospholipids. Eight metabolites were screened by a machine learning random forest model, and receiver operating characteristic curves (ROC) assessed them as ideal diagnostic tools. Conclusions In conclusion, we have identified disturbances in serum lipid metabolism associated with the formation of pulmonary fibrosis, contributing to the understanding of the pathogenesis of pulmonary fibrosis.

Background : Pulmonary fibrosis (PF) is a chronic progressive disease whose pathogenesis is thought to be associated with activation of the immune system and consequent metabolic changes. Recent studies suggested that gut microbes are closely related with host's immune response and metabolic changes in fibrotic hosts. However, the dynamic changes of the gut microbiome and the interaction profiles with host metabolism during the development of pulmonary fibrosis remain inconclusive. Results : We collected serum and fecal samples from bleomycin-induced fibrotic mice at 0, 7, 14, and 28 days and performed UPLC-MS analysis on serum metabolites and metagenomic sequencing on fecal samples. It is found that the serum metabolic profile and gut microbiome were significantly altered in mice during the progression of fibrosis. Among the serum metabolites, the levels of three major types of lipids, i.e ., glycerolipids, glycerophospholipids, and fatty acids exhibit significant time-dependent changes. The glycerolipid TG and multiple glycerophospholipids (3 PG, 6 PE, and 1 PC) decreased in the early stage of fibrosis and increased in the late stage. The other two types of glycerolipids MG and DG and the fatty acids Cartinine and Punicic acid decreased through the development of fibrosis. In the meantime, we detected significantly elevated abundance of gut microbiome taxa, including Prevotella sp. from Bacteroidetes , Lactobacillus from Firmicutes, and Bifidobacterium from Actinobacteria in mice with pulmonary fibrosis. When compared to the dynamic profiles of serum metabolites, the abundances of gut microbiome show a high level of correlation with that of serum metabolites. The taxa from Bacteroides , such as Butyricimonas_synergistica and Muribaculaceae, show positive correlation with the cluster of glycerophospholipids, while taxa from Firmicutes , such as Clostridioides difficile and Enterococcus faecium exhibit negative correlation. Further functional classification suggested that those taxa are involved in multiple functional modules, such as Transporters, Secretion system, and Metabolism. Conclusions : The results reveal the synergistic changes between the gut microbiome and host metabolism and the dynamic responses of gut microbiome to host fibrosis during the progression of fibrosis.

BACKGROUND Myocardial infarction (MI) is one of the most common cardiovascular diseases, inducing severe myocardial injury and leading to high mortality. Bromodomain-containing protein 7 (BRD7), a member of bromodomain-containing protein family, is involved in multiple cellular processes, such as cell cycle, transcriptional regulation, and chromatin remodeling, but the functions of BRD7 in regulating MI-associated myocardial injury are still obscure. In this work, we investigated the effect of BRD7 on MI-induced myocardial injury in vitro and in vivo. METHODS The MI model was established by ligating the left anterior descending coronary artery (LAD) of rats which were then injected with BRD7 short hairpin RNA (shRNA). The rat H9C2 cardiomyocytes were treated with hypoxia and injected with BRD7 shRNA. The expression of BRD7 in MI rat model, and hypoxia-treated H9C2 cells was detected by quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemical staining. The effect of BRD7 was analyzed using western blot, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, echocardiography, and flow cytometry analysis. The expressions of Wnt/β-catenin signaling relative proteins were determined by western blot. RESULTS Significantly, BRD7 was highly expressed in MI patients, MI rat models, and hypoxia treated rat H9C2 cardiomyocytes. Echocardiography analysis demonstrated that the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were repressed in the MI rats relative to sham group rats, while the silencing of BRD7 rescued the dysfunction in the model. We also found that BRD7 silencing reduced cardiomyocyte apoptosis in both MI rats and H9C2 cells under the treatment of hypoxia. BRD7 silencing inhibited the activation of Wnt/β-catenin signaling in H9C2 cells under the treatment of hypoxia. Moreover, Wnt agonist BML294 reversed the anti-apoptosis effect of BRD7 silencing in hypoxia-induced H9C2 cells. CONCLUSIONS Collectively, we concluded that BRD7 contributed to MI-induced myocardial injury through activating Wnt/β-catenin signaling. Targeting BRD7 may become a promising therapeutic strategy for the treatment of MI-induced myocardial injury.

Background Emerging evidence has implied that the GABRG2 gene play a role in the mechanism of febrile seizure (FS), however, the relationship between GABRG2 rs211037 polymorphism and the risk of FS remains controversial. This meta-analysis was conducted to investigate the relationship of GABRG2 rs211037 polymorphism with the susceptibility to FS. Methods MEDLINE, Embase, Cochrane Library and CNKI databases were searched (until April 6, 2019) for eligible studies on the relationship between GABRG2 rs211037 polymorphism and FS. We calculated the odds ratios (ORs) by a fixed or random model with the STATA 15.0 software. Subgroup analyses for the ethnicity, the source of the control, and age and sex matching of controls were conducted. Results A total of 8 studies consisting of 775 FS patients and 5162 controls were included in this study. Based on the overall data, he GABRG2 rs211037 polymorphism was not significantly associated with the risk of FS (TT + CT vs CC: OR = 0.95, 95%CI 0.64–1.41, P = 0.80). Notably, the GABRG2 rs211037 variant was significantly associated with decreased risk of FS in Asian populations (TT vs CT + CC: OR = 0.63, 95%CI 0.45–0.88, P = 0.006), but increased risk in Caucasian populations (CT vs CC: OR = 1.56, 95%CI 1.14–2.15, P = 0.006). Significant associations were also detected when healthy controls out of the whole controls were employed for comparison (TT vs CT + CC: OR = 0.59, 95% CI 0.45–0.77, P < 0.001) and when data from studies with age- and sex-matched controls were used (TT + CT vs CC: OR = 0.60, 95% CI 0.43–0.86, P = 0.001). Conclusion The GABRG2 rs211037 polymorphism may decrease the risk of FS in Asian populations, while increasing the risk in Caucasian populations. Further well-designed studies with large sample sizes are essential to verify the conclusions in other ethnicities.

Background We performed this meta-analysis to investigate the association between GABRG2 rs211037polymorphism and the risk for idiopathic generalized epilepsies (IGEs). Methods Medline, Embase, Cochrane Library and Chinese National Knowledge Infrastructure (CNKI) databases were searched for eligible studies (until May 5, 2020) on the association between GABRG2 rs211037 polymorphism and IGE. The odds ratios were calculated using a fixed or random model in STATA 15.0 software. Subgroup analyses for ethnicity, age, source of controls, type of seizure syndrome and therapeutic responses were conducted. Results We found no significant associations between GABRG2 rs211037 polymorphism and the susceptibility to IGEs. In addition, no significant association was detected between GABRG2 rs211037 polymorphism and drug resistance in IGE patients. The results did not change after stratification by Asian population, healthy controls, children, juvenile myoclonic epilepsy, and childhood absence epilepsy. Conclusion The current studies indicated that the GABRG2 rs211037 polymorphism was not related to susceptibility or drug resistance of IGE. Further well-designed studies are needed to verify the results.

Background: Observational studies have shown a link between elevated body mass index (BMI) and the risk of polycystic ovary syndrome (PCOS). While Mendelian randomization (MR) studies in Europeans have suggested a causal role of increased BMI in PCOS, whether the same role is suggested in Asians has yet to be investigated. We used MR studies to infer causal effects using genetic data from East Asian populations. Methods and Findings: We performed a 2-sample bidirectional MR analysis using summary statistics from genome-wide association studies (GWAS) of BMI (with up to 173 430 individuals) and PCOS (4386 cases and 8017 controls) in East Asian populations. Seventy-eight single nucleotide polymorphisms (SNPs) correlated with BMI were selected as genetic instrumental variables to estimate the causal effect of BMI on PCOS using the inverse-variance weighted (IVW) method. To test the reliability of the results, further sensitivity analyses included MR-Egger regression, weighted median estimates, and leave-one-out analysis. The IVW analysis indicated a significant association between high BMI and the risk of PCOS (odds ratio per standard deviation higher BMI, 2.208; 95% confidence interval 1.537 to 3.168, P = 1.77 x 10(-5)). In contrast, the genetic risk of PCOS had no significant effect on BMI. Conclusions: The results of our bidirectional MR study showed that an increase in BMI causes PCOS, while PCOS does not cause an increased BMI. This study provides further genetic support for a link between BMI and PCOS. Further research is needed to interpret the potential mechanisms of this association.

BACKGROUND:Reversible splenial lesion syndrome (RESLES) is known to cause severe psychiatric symptoms but is also a very rare clinical disease in which the specific aetiology is unknown. According to current reports, there are major causes of the disease, including viral or bacterial infection, epilepsy, anti-epileptic drug withdrawal, high-altitude cerebral oedema, and metabolic disorders such as hypoglycaemia and hypernatraemia. In this article, we report a patient with thrombotic thrombocytopenic purpura (TTP) who presented with RESLES.CASE PRESENTATION:A 34-year-old female patient who presented with fever and progression of disorder of consciousness was eventually diagnosed with RESLES based on brain imaging. Moreover, clinical features and peripheral smears demonstrating schistocytes and thrombocytopenia confirmed a diagnosis of TTP. RESLES can be improved by plasma exchange therapy.CONCLUSION:This rare case highlights the occurrence of RESLES as a presenting feature of the expanding list of unusual neurological manifestations of TTP.

Abstract Association of single-nucleotide polymorphisms (SNPs) of the ghrelin gene with polycystic ovary syndrome (PCOS)is unclear. However, their correlation with PCOS-related obesity has been observed. The objective of this study was to evaluate the effects of ghrelin gene SNPs on PCOS-related obesity in Chinese women. The full-length sequence of the ghrelin gene was determined to explore the relationship of the SNPs with PCOS-related obesity in Chinese women. The gene was sequenced, including all exons, introns and exon–intron boundaries in 230 Han Chinese women with PCOS and 162 normal women. Significant genotypic and allelic differences were observed between the obese PCOS group and obese control group at rs35681 locus (p = .013 and .017). The genotypic analysis of obese and non-obese people in the PCOS group showed that the proportion of A allele in the obese PCOS group (10.9%) was higher than that of the G allele (3.6%). This study revealed that ghrelin rs35681 might be related to the occurrence of obesity associated with PCOS, and allele A was found to increase the risk of obesity in PCOS.