Polycystic ovary syndrome (PCOS) is a prevalent chronic disorder characterized by reproductive, endocrine, and metabolic abnormalities in women worldwide. Increasing evidence has implicated the gut microbiota in the pathogenesis of PCOS, raising the possibility that probiotic interventions could offer therapeutic benefits. Akkermansia muciniphila (AKK), known for its metabolic and immunomodulatory properties, remains underexplored in the context of PCOS. In this study, we utilized a dehydroepiandrosterone (DHEA)-induced PCOS model in Sprague-Dawley (SD) rats to investigate the therapeutic potential of a novel AKK strain, PROBIO (referred to as AP). Treatment with AP significantly alleviated multiple PCOS-related phenotypes, including hyperandrogenism, elevated luteinizing hormone to follicle-stimulating hormone (LH/FSH) ratio, disrupted estrous cycle, abnormal ovarian morphology, and impaired glucose metabolism. Mechanistically, 16S rRNA gene sequencing and untargeted metabolomics revealed that AP partially exerted its beneficial effects by modulating DHEA-induced gut microbiota dysbiosis. Notably, metabolomic profiling indicated enhanced arginine biosynthesis and increased serum L-arginine levels in AP-treated rats. Consistently, in vivo supplementation with L-arginine reproduced the therapeutic effects of AP, ameliorating hyperandrogenism, LH/FSH imbalance, ovarian abnormalities, and estrous cycle irregularities in DHEA-induced PCOS rats. Taken together, these findings suggest that AP ameliorates PCOS phenotypes by restoring gut microbial composition, modulating host metabolism, and promoting L-arginine biosynthesis. This study highlights the potential of AP as a novel probiotic-based intervention for PCOS and underscores the therapeutic relevance of L-arginine in managing this disorder.

Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited. Here, aortic-arch, vagus-nodose slice, and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve, spontaneous/evoked membrane depolarizations under different pharmacological interventions. Strikingly, profiles of A-fiber's instantaneous firing frequency (IFF), including pressure threshold, rate, and sensitivity, were significantly reduced by 10 µmol/L flufenamic acid (FAA) and further suppressed by 3 µmol/L GsMTx4. Conversely, 3 µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA, consistent with step depolarization-evoked action potentials (APs). In < 10% of A-type neurons, spontaneous APs accompanied by major (Ma-STPs) and minor sub-threshold depolarizations (Mi-STPs) were abolished by nanomolar tetrodotoxin. FAA only blocked spontaneous APs, while GsMTx4 suppressed both APs and Ma-STPs. The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs. Further, single-cell transcriptomic analysis revealed significant Piezo1 and TRPM4 co-expression in neurons. Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways, validated by gene expression data. These findings demonstrate that TTX-sensitive Na (TTX-S), Piezo1, and TRPM4 channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.

As a life-threatening respiratory syndrome, epidemiological data from China has shown that the mortality rate of neonatal acute respiratory distress syndrome (ARDS) is as high as 12.5%. Nevertheless, studies on the influencing factors of this mortality remain limited. This research enrolled newborns with ARDS who initiated invasive mechanical ventilation (IMV) within 72 hours after birth. A Cox regression model with hazard ratio (HR) was constructed using the least absolute shrinkage and selection operator analysis with the lambda.1se screening criterion. Four characteristic variables were identified: inhaled nitric oxide (iNO), high frequency ventilation (HFV), gestational age (GA), and IMV duration. The Kaplan-Meier curve indicated that infants with a higher GA, receiving iNO, or undergoing HFV had a higher risk of death. Restricted cubic spline analysis further revealed that GA ⩾ 38.785 weeks and IMV duration < 117 hours were associated with a significant mortality risk. A linear trend test confirmed a significant linear relationship between GA and mortality risk. Significant interaction effects were observed between "iNO" and "IMV" as well as between "HFV" and "GA". This study underscores that neonates with advanced GA who require concomitant HFV and iNO therapy are associated with a significantly heightened mortality risk.

Increasing evidence suggests an association between Sjögren's syndrome (SS) and multiple cancers; however, the causal relationships and regulatory mechanisms remain unclear. Using European genome-wide association study data, we employed Mendelian randomisation (MR) and meta-analysis to explore the SS-cancer causality. Bidirectional two-sample MR revealed that SS increased the risk of colorectal (odds ratio (OR) = 1.08) and lung cancers (OR = 1.15), whereas lung (OR = 3.03) and female genital cancers (OR = 6.59) were found to elevate the risk of SS. Co-localisation analysis confirmed bidirectional causality between SS and lung cancer. Summary data-based MR identified HLA-DPB2 as a hub gene, with single-cell RNA and mRNA analyses suggesting its role in memory B cells regulation via MHC-II ligands and lung carcinogenesis. This study demonstrates a mutually positive association between SS and lung cancer, implicating HLA-DPB2 as a potential regulatory gene and offering novel insights into the relationship between SS and cancer, especially lung cancer.

Early diagnosis is vitally important for effective treatment of nasopharyngeal carcinoma (NPC). Nevertheless, the exact pathogenic mechanisms of NPC remain unclear, and early diagnosis of NPC is still limited. Herein, we showed that a specific tsRNA for NPC, 5'tiRNA-32-ValAAC-2, is a novel pathogenic factor and has potential diagnostic value for NPC screening. In this study, small RNA microarray profiling and array hybridization were used to detect expression spectrums of tsRNAs in the sera of newly diagnosed NPC patients. The upregulated tsRNAs were validated using RT-qPCR, and their clinical significance in NPC diagnosis was analyzed. Furthermore, the most highly expressed tsRNA, was further investigated. 5'tiRNA-32-ValAAC-2 could serve as a potential diagnostic biomarker for NPC. Subsequently, the effect of 5'tiRNA-32-ValAAC-2 on the growth and invasion of NPC cells was investigated. The results indicated that overexpression of 5'tiRNA-32-ValAAC-2 promoted NPC cells proliferation, migration, and invasion. In contrast, the inhibition of 5'tiRNA-32-ValAAC-2 suppressed NPC cells proliferation, migration and invasion. TargetScan and miRanda analyses revealed that UGT2B7, SYNPO2, ZNF44, PDHB, and UFM1 might serve as downstream target-genes of 5'tiRNA-32-ValAAC-2. In conclusion, 5'tiRNA-32-ValAAC-2 could potentially be a novel pathogenic factor for NPC, and it functions as a diagnostic biomarker in the primary diagnosis of NPC.

The immunosuppressive tumor microenvironment (TME) undermines the efficacy of many cancer therapies. This study investigated the immunomodulatory and anti-tumor activity of Azvudine (FNC), alone or in combination with anti-PD-1 blockade. We established syngeneic tumor models in immunocompetent mice. Single-cell RNA sequencing, flow cytometry, and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration. FNC demonstrated dose- and time-dependent tumor inhibition. It significantly expanded memory T cells, natural killer (NK) cells, and CD8 cytotoxic T lymphocytes, while reducing the abundance of myeloid-derived suppressor cells (MDSCs). Flow cytometry confirmed these immunological shifts, showing enhanced infiltration of effector immune cells within the TME. Moreover, FNC induced hallmark features of immunogenic cell death (ICD), including the release of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1) and calreticulin. When combined with anti-PD-1 therapy, FNC produced a synergistic anti-tumor effect, leading to durable tumor remission in all treated mice. FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity, offering a promising strategy to augment existing immunotherapies. Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.

Renal ischemia-reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI), leading to substantial morbidity and mortality. Spexin (SPX), a 14-amino acid endogenous peptide involved in metabolic regulation and immune modulation, has not yet been studied in the context of chronic treatment and renal IRI. This study evaluated the effects of exogenous SPX on renal function, histopathological changes, and molecular pathways in both IRI-induced injured and healthy kidneys. Twenty-eight male BALB/c mice were divided into four groups: control, SPX, IRI, and SPX+IRI. IRI was induced by 30 minutes of bilateral renal ischemia followed by 6 hours of reperfusion. Renal injury markers, histopathological changes, inflammatory mediators, apoptotic markers, and fibrosis-related proteins were analyzed. SPX significantly exacerbated IRI-induced kidney injury by activating the Wnt/β-catenin signaling pathway and promoting the upregulation of pro-inflammatory, pro-apoptotic, and pro-fibrotic mediators. It is noteworthy that SPX exerted more severe deleterious nephrotoxic effects in the healthy kidney compared to those observed in the IRI-induced injured kidney. These findings indicate that chronic treatment with SPX administration may have intrinsic pro-inflammatory, pro-apoptotic and fibrotic properties, raising concerns about its therapeutic potential. Further research is needed to clarify its physiological role and therapeutic implications in kidney diseases.

The introduction of PD-1 blockades to chemotherapy and radiotherapy has shown promising outcomes in patients with nasopharyngeal carcinoma, but anti-PD-1 therapies are only effective in a small proportion of patients, indicating the need for reliable predictive biomarkers of benefit from immunotherapy. Here, we summarized recent advances in immunotherapy for nasopharyngeal carcinoma and studies on potential predictors that correlated with treatment response or long-term survival after immunotherapy, including biomarkers in both the tumor microenvironment and the tumor macroenvironment. Some of these biomarkers have been validated as truly predictive of immunotherapy benefit using cohorts from randomized controlled trials, while others still require further validation of their predictive value. We also summarized the challenges and future directions of biomarker studies, hopefully facilitating the development of predictive biomarkers for immunotherapy that can eventually enter clinical practice.

Congenital musculoskeletal and limb deformities (CMLD) seriously affect the physical and mental health of patients, and pose great challenges to healthcare systems worldwide. We explored the specific situation and changes of incidence, prevalence, disability-adjusted life years rates, and mortality of CMLD in under-5 children from 1990 to 2021 in different groups, including different regions, periods, genders and socio-demographic indices (SDI), through corresponding analytical models. Overall, the global disease burden of CMLD in under-5 children has decreased from 1990 to 2021. The disease burden of CMLD in under-5 children varied significantly among different regions and countries, and there was a strong correlation between the corresponding burden of disease and the level of SDI. In addition, cross-country inequality analysis showed that while absolute inequalities in the disease burden of CMLD in under-5 children have improved, relative inequalities have worsened. It is essential to reduce the global health impact of CMLD by implementing targeted interventions to improve health care in underdeveloped areas.

Long-term exposure to particulate matter has been increasingly implicated in the progression of chronic kidney disease (CKD). However, its impact on IgA nephropathy (IgAN), a leading cause of end-stage renal disease (ESRD), remains unclear. A total of 1768 IgAN patients, confirmed by renal biopsy were included in this cohort study. Long-term exposure to PM and PM was assessed using high-resolution satellite-based data from the China High Air Pollutants (CHAP) dataset. Cox proportional hazards models were used to estimate the associations between PM or PM and ESRD risk, adjusting for demographic, clinical, and biochemical covariates. Over a median follow-up of 3.63 years, 209 participants progressed to ESRD. Higher exposure to both PM and PM was significantly associated with an increased risk, with hazard ratios of 1.62 and 1.36 per 10 µg/m increase, respectively. A nonlinear dose-response relationship was observed, with risk increasing markedly beyond threshold levels. Trajectory modeling of prebaseline exposure identified a subgroup with persistently high and fluctuating particulate matter exposure that showed the highest risk. This study provides strong evidence that prolonged exposure to ambient particulate matter contributes to renal disease progression in individuals with IgAN.

The primary clinical manifestation of osteoarthritis (OA) is pain, yet considerable variability exists in the pain experience among OA patients. This narrative review aims to explore the mechanisms driving OA pain heterogeneity to inform the development of targeted interventions that improve treatment efficacy and patient outcomes. A comprehensive literature search was conducted across multiple databases (PubMed, Scopus, and Google Scholar) for papers published between January 1, 2020, and December 31, 2024. Inclusion criteria focused on studies addressing pain mechanisms and therapeutic interventions in OA. This review identifies key mechanisms of OA pain, including joint alterations, angiogenesis, nervous system involvement, peripheral and central sensitization, and psychosocial factors. It highlights the underlying distinct mechanisms in OA pain, which contribute to the variability in individuals' responses to treatment. It was suggested that interactions between neuroimmune and neurovascular systems are key contributors to chronic pain in OA. This narrative review emphasizes the complexity of OA pain, highlighting the importance of thoroughly understanding the underlying mechanisms for developing personalized and effective pain management strategies. Additional research is required to refine treatment approaches and explore long-term effects.

Biliary tract cancer (BTC) is a rare group of malignancies that develop from the epithelial lining of the biliary tree and have a poor prognosis. Although chemotherapy is the standard of care for patients with advanced BTC in China, its clinical benefits are moderate. In recent years, the approval of targeted therapies and immunotherapies has provided new avenues for the management of advanced BTC. Nonetheless, the increasing number of personalized medicine approaches has created a challenge for clinicians choosing individualized treatment strategies based on tumor characteristics. In this article, we discuss recent progress in implementing precision medicine approaches for advanced BTC in China and examine genomic profiling studies in Chinese patients with advanced BTC. We also discuss the challenges and opportunities of using precision medicine approaches, as well as the importance of considering population-specific factors and tailoring treatment approaches to improve outcomes for patients with BTC. In addition to providing a comprehensive overview of current and emerging precision medicine approaches for the management of advanced BTC in China, this review article will support clinicians outside of China by serving as a reference regarding the role of patient- and population-specific factors in clinical decision-making for patients with this rare malignancy.

Acute ischemic stroke (AIS) is a cerebrovascular disease characterized by high morbidity, disability, and mortality, posing a significant threat to human health. Endovascular treatment has now been established as a key method for AIS management, in which stent retrievers that can mechanically remove blood clots play a key role in this technique. In recent years, stent retrievers have evolved in complexity and functionality to improve the ability of clot removing and surgical safety. However, the present instruments still have limitations on treatment efficiency, vascular adaptability, and operational precision, posing an urgent need for innovation in the design of stent retrievers. This paper systematically reviewed the structural features and working principles of AIS stent retrievers from the perspective of efficacy evaluation metrics, historical development, recent advancements in stent retrieval technology, and future prospects.

Trophoblast cells serve as the foundation for placental development. We analyzed published multiomics sequencing data and found that trophoblast cells highly expressed RRS1 compared to primitive endoderm and epiblast. We used HTR-8/SVneo cells for further investigation, and Western blot and immunofluorescence staining confirmed that HTR-8/SVneo cells highly expressed RRS1. RRS1 was successfully knocked down in HTR-8/SVneo cells using siRNA. Using IncuCyte S3 live-cell analysis system based on continuous live-cell imaging and real-time data, we observed that proliferation, migration, and invasion abilities were all significantly decreased in RRS1-knockdown cells. RNA-seq revealed that knockdown of RRS1 affected the gene transcription, and upregulated pathways in extracellular matrix organization, DNA damage response, and intrinsic apoptotic signaling, downregulated pathways in embryo implantation, trophoblast cell migration, and wound healing. Differentially expressed genes were enriched in diseases related to placental development. Consistent with these findings, human chorionic villus samples collected from spontaneous abortion cases exhibited significantly reduced RRS1 expression compared to normal controls. Our results highlight the functional importance of RRS1 in human trophoblasts and suggest that its deficiency contributes to early pregnancy loss.

The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

This study aimed to evaluate the efficacy and safety of combining albumin-bound paclitaxel (abpaclitaxel) and anlotinib for ovarian cancer. In this study, 44 patients diagnosed with platinum-resistant ovarian cancer were enrolled. Patients received ab-paclitaxel along with anlotinib until disease progression or intolerable toxicity. Efficacy was assessed according to RECIST 1.1 criteria or Rustin's criteria. The primary endpoint was the investigator-evaluated objective response rate (ORR). 44 patients were enrolled between January 2021 and March 2023 with a median age of 49 years. Twenty-nine had measurable lesions and 15 had non-measurable lesions. Overall, the investigator-evaluated ORR was 56.8% (25/44; 95% CI 0.411-0.713) in intention-to-treat population and 58.1% (25/43; 95% CI 0.422-0.726) in per-protocol population. The median progression-free survival was 9.8 months, and the median duration of response was 7.4 months. For safety, grade 3/4 adverse events (AEs) included leukopenia, gum pain, hypertension, and hand-foot syndrome. The response rates were 55.0% (11/20) in patients with previous use of antiangiogenic reagents and who had previous use of PARP inhibitors. The combination of ab-paclitaxel and anlotinib showed promising anti-tumor activity and a manageable safety profile in platinum-resistant ovarian cancer. Patients with previous use of antiangiogenic drugs or PARP inhibitors still benefited from this protocol.

Effective axon regeneration is essential for the successful restoration of nerve functions in patients suffering from axon injury-associated neurological diseases. Certain self-regeneration occurs in injured peripheral axonal branches of dorsal root ganglion (DRG) neurons but does not occur in their central axonal branches. By performing rat sciatic nerve or dorsal root axotomy, we determined the expression of the dysbindin domain containing 2 (DBNDD2) in the DRGs after the regenerative peripheral axon injury or the non-regenerative central axon injury, respectively, and found that DBNDD2 is down-regulated in the DRGs after peripheral axon injury but up-regulated after central axon injury. Furthermore, we found that DBNDD2 expression differs in neonatal and adult rat DRGs and is gradually increased during development. Functional analysis through DBNDD2 knockdown revealed that silencing DBNDD2 promotes the outgrowth of neurites in both neonatal and adult rat DRG neurons and stimulates robust axon regeneration in adult rats after sciatic nerve crush injury. Bioinformatic analysis data showed that transcription factor estrogen receptor 1 (ESR1) interacts with DBNDD2, exhibits a similar expression trend as DBNDD2 after axon injury, and may targets DBDNN2. These studies indicate that reduced level of DBNDD2 after peripheral axon injury and low abundance of DBNDD2 in neonates contribute to axon regeneration and thus suggest the manipulation of DBNDD2 expression as a promising therapeutic approach for improving recovery after axon damage.