Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

Objective To investigate the potential mechanism of action of polygonatum odoratum in treating Alzheimer's disease through the utilization of network pharmacology and molecular docking techniques.Methods The methods employed include target screening,Gene Ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,and molecular docking simulations to assess the binding interactions between the active compounds in polygonatum odoratum(POD)and the key target proteins associated with Alzheimer's disease.Subsequently,lipopolysaccharide(LPS)was used to induce an inflammatory cell model in BV2 microglial cells.After treating the cell model with POD extract for 24 hours,the cells were collected,and the expression of the target genes were detected by Real-time PCR.Results Eight active ingredients and 172 targets of POD were screened.The biological processes such as protein phosphorylation and signal transduction,protein binding and ATP binding were obtained by GO functional analysis.KEGG enrichment yielded PI3K/Akt,cAMP and other signaling pathways.The molecular docking result showed that the active ingredient of POD had well binding activity with epidermal growth factor receptor(EGFR),proto-oncogene tyrosine-protein kinase Src(SRC),tumor necrosis factor(TNF),STAT3.Through Real-time PCR experiments,the gene expressions of inducible nitric oxide synthase(iNOS),prostaglandin G/H synthase 2(PTGS2),interleukin(IL)-6,and IL-1β in the LPS-induced inflammatory cell model were significantly upregulated.After treating the inflammatory model with POD extract for 24 hours,the expression of TNF-α was significantly reduced,the expression of STAT3 was upregulated,there were no significant changes in the expressions of SRC and EGFR.Conclusion Network pharmacology suggests polygonatum odoratum's potential anti-Alzheimer's effects may be mediated through its interaction with targets such as EGFR,TNF,SRC,and STAT3.The experimental results suggest that polygonatum odoratum exerts an anti-inflammatory effect by acting on TNF-α,which may further alleviate the symptoms of Alzheimer's disease.

Di-(2-ethylhexyl)phthalate(DEHP)is an environmental pollutant commonly found in plastic products and has toxic effects on female reproductive system.DEHP can interfere with the synthesis of progesterone,testosterone and estradiol through female hypothalamic-pituitary-ovarian axis,aggravate insulin resistance and obesity by affecting glucose and lipid metabolism,and cause ovarian damage through inducing oxidative stress,excessive autophagy and pyroptosis of oocyte or granulosa cells.It can also alter epigenetic genes relating to follicular development and prevent follicles from mature.These factors are closely contribute to the pathogenesis of polycystic ovary syndrome.We systematically summarizes the mechanism of DEHP interfering with ovarian function and inducing polycystic ovary syndrome,in order to provide help for the prevention and treatment of female reproductive injury from environmental pollutant.

ObjectiveTo explore the effectiveness of traditional Chinese medicine （TCM） chronic disease management programme in preventing postoperative recurrence of colorectal polyps. MethodsThe clinical data of 447 postoperative colorectal polyp patients were retrospectively collected， and the patients were divided into an exposure group and a control group taking the acceptance of TCM chronic disease management programme as exposure factor， and the polyp recurrence rate as the main outcome indicator， comparing the differences in baseline characteristics， outcome events， and safety assessment between the two groups， and conducting correlation analysis between the length of medication and polyp recurrence. Multifactorial logistic regression was used to analyse the effects of receiving the TCM chronic disease management programme （TCM treatment and life management for spleen deficiency and dampness stasis syndrome， dampness and stasis obstruction in collaterals syndrome， and intestinal dampness and heat syndrome）， gender， age， co-morbidities， TCM syndrome， and dietary and exercise factors on the outcome events. ResultsAmong 257 postoperative patients with colorectal polyps， there were 172 in the exposure group and 85 in control group. The recurrence rate of polyps in exposure group was 22.7% （39/172）， while the recurrence rate in control group was 57.6% （49/85）， and the difference between groups was statistically significant （P＜0.01）. The diameter of recurrent polyps in exposure group （median= 4.0 mm） was smaller than that in control group （median= 5.0 mm， P＜0.01）. The correlation analysis between the duration of medication taking and the recurrence of polyps in the spleen deficiency and dampness stasis syndrome group showed Phi value as -0.345 （P＜0.001）； the correlation analysis within the group of dampness and stasis obstruction in collaterals syndrome showed Phi value as -0.361 （P＜0.05）， indicating a negative correlation between the duration of medication taking and polyp recurrence. The results of multivariate logistic regression analysis indicated that the positive effect of accepting TCM chronic disease management programme on preventing polyp recurrence is statistically significant （OR=0.224， P＜0.01）. ConclusionAccepting TCM chronic disease management programme for colorectal polyps can help reducing the recurrence rate after polyp surgery， which is a protective factor for patients to the outcome event.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting a substantial proportion of women of reproductive age. It is frequently associated with ovulatory dysfunction, infertility, and an increased risk of chronic metabolic diseases. A hallmark pathological feature of PCOS is the arrest of follicular development, closely linked to impaired intercellular communication between the oocyte and surrounding granulosa cells. Transzonal projections (TZPs) are specialized cytoplasmic extensions derived from granulosa cells that penetrate the zona pellucida to establish direct contact with the oocyte. These structures serve as essential conduits for the transfer of metabolites, signaling molecules (e.g., cAMP, cGMP), and regulatory factors (e.g., microRNAs, growth differentiation factors), thereby maintaining meiotic arrest, facilitating metabolic cooperation, and supporting gene expression regulation in the oocyte. The proper formation and maintenance of TZPs depend on the cytoskeletal integrity of granulosa cells and the regulated expression of key connexins, particularly CX37 and CX43. Recent studies have revealed that in PCOS, TZPs exhibit significant structural and functional abnormalities. Contributing factors—such as hyperandrogenism, insulin resistance, oxidative stress, chronic inflammation, and dysregulation of critical signaling pathways (including PI3K/Akt, Wnt/β‑catenin, and MAPK/ERK)—collectively impair TZP integrity and reduce their formation. This disruption in granulosa-oocyte communication compromises oocyte quality and contributes to follicular arrest and anovulation. This review provides a comprehensive overview of TZP biology, including their formation mechanisms, molecular composition, and stage-specific dynamics during folliculogenesis. We highlight the pathological alterations in TZPs observed in PCOS and elucidate how endocrine and metabolic disturbances—particularly androgen excess and hyperinsulinemia—downregulate CX43 expression and impair gap junction function, thereby exacerbating ovarian microenvironmental dysfunction. Furthermore, we explore emerging therapeutic strategies aimed at preserving or restoring TZP integrity. Anti-androgen therapies (e.g., spironolactone, flutamide), insulin sensitizers (e.g., metformin), and GLP-1 receptor agonists (e.g., liraglutide) have shown potential in modulating connexin expression and enhancing granulosa-oocyte communication. In addition, agents such as melatonin, AMPK activators, and GDF9/BMP15 analogs may promote TZP formation and improve oocyte competence. Advanced technologies, including ovarian organoid models and CRISPR-based gene editing, offer promising platforms for studying TZP regulation and developing targeted interventions. In summary, TZPs are indispensable for maintaining follicular homeostasis, and their disruption plays a pivotal role in the pathogenesis of PCOS-related folliculogenesis failure. Targeting TZP integrity represents a promising therapeutic avenue in PCOS management and warrants further mechanistic and translational investigation.

Objective:To analyze the clinical features and risk factors for renal injury in children with antineutrophil cytoplasmic antibody (ANCA)-positive IgA vasculitis (IgAV).Methods:A case-control study was conducted. Seventy-two ANCA-positive IgAV children hospitalized at the Children′s Hospital of Chongqing Medical University from January 2017 to October 2022 were enrolled as the ANCA-positive group. Propensity score matching (1∶4) using the nearest neighbor was performed with age and gender as covariate, and 288 cases ANCA-negative IgAV children were included as the ANCA-negative group. Patients with renal injury were named ANCA-positive IgAV nephritis (IgAVN) group and ANCA-negative IgAVN group, respectively. The ANCA-positive IgAVN group was further divided into myeloperoxidase (MPO) group and proteinase 3 (PR3) group based on the type of ANCA. Clinical data including manifestations, laboratory tests, renal injury, and prognosis were collected. Comparisons between groups were performed using independent sample t-tests, Mann-Whitney U tests, χ2 tests, or Fisher′s exact tests. Kaplan-Meier curves were used to assess differences in the time to renal injury onset, and multivariate logistic regression was performed to identify independent risk factors for renal injury. Results:Among the 72 ANCA-positive IgAV children (41 males, 31 females, age of 7.7 (5.3, 11.2) years), no significant difference in age or gender was observed compared to the ANCA-negative group (both P>0.05). The ANCA-positive group had higher IgM levels, a higher incidence of recurrent rash, and shorter thrombin time (all P<0.05). Among children with renal injury, the ANCA-positive group showed significant differences in the incidence of hematuria, clinical classification, and grade A prognosis compared to the ANCA-negative group (all P<0.05), but no difference was found in the time to renal involvement onest or renal pathology (all P>0.05). The MPO group had higher rates of microscopic hematuria, gross hematuria, acute renal insufficiency, glomerular sclerosis, and grade B prognosis compared to the ANCA-negative IgAVN group (all P<0.05), with a later onset of renal involvement ( P<0.05). Elevated serum creatinine ( OR=1.08, 95% CI 1.03-1.14) and shortened thrombin time ( OR=0.71, 95% CI 0.55-0.92) were independent risk factors for renal injury in ANCA-positive IgAV children (all P<0.05). Conclusions:Children with ANCA-positive IgAV are more likely to experience recurrent rash. MPO-ANCA-positive IgAVN children have higher risks of hematuria, acute kidney injury and glomerular sclerosis, with later-onset but poorer renal prognosis compared to ANCA-negative IgAVN children. Higher serum creatinine levels and shorter thrombin time may be associated with renal injury in children with ANCA-positive IgAV.

Objective:To analyze the clinical features and risk factors for renal injury in children with antineutrophil cytoplasmic antibody (ANCA)-positive IgA vasculitis (IgAV).Methods:A case-control study was conducted. Seventy-two ANCA-positive IgAV children hospitalized at the Children′s Hospital of Chongqing Medical University from January 2017 to October 2022 were enrolled as the ANCA-positive group. Propensity score matching (1∶4) using the nearest neighbor was performed with age and gender as covariate, and 288 cases ANCA-negative IgAV children were included as the ANCA-negative group. Patients with renal injury were named ANCA-positive IgAV nephritis (IgAVN) group and ANCA-negative IgAVN group, respectively. The ANCA-positive IgAVN group was further divided into myeloperoxidase (MPO) group and proteinase 3 (PR3) group based on the type of ANCA. Clinical data including manifestations, laboratory tests, renal injury, and prognosis were collected. Comparisons between groups were performed using independent sample t-tests, Mann-Whitney U tests, χ2 tests, or Fisher′s exact tests. Kaplan-Meier curves were used to assess differences in the time to renal injury onset, and multivariate logistic regression was performed to identify independent risk factors for renal injury. Results:Among the 72 ANCA-positive IgAV children (41 males, 31 females, age of 7.7 (5.3, 11.2) years), no significant difference in age or gender was observed compared to the ANCA-negative group (both P>0.05). The ANCA-positive group had higher IgM levels, a higher incidence of recurrent rash, and shorter thrombin time (all P<0.05). Among children with renal injury, the ANCA-positive group showed significant differences in the incidence of hematuria, clinical classification, and grade A prognosis compared to the ANCA-negative group (all P<0.05), but no difference was found in the time to renal involvement onest or renal pathology (all P>0.05). The MPO group had higher rates of microscopic hematuria, gross hematuria, acute renal insufficiency, glomerular sclerosis, and grade B prognosis compared to the ANCA-negative IgAVN group (all P<0.05), with a later onset of renal involvement ( P<0.05). Elevated serum creatinine ( OR=1.08, 95% CI 1.03-1.14) and shortened thrombin time ( OR=0.71, 95% CI 0.55-0.92) were independent risk factors for renal injury in ANCA-positive IgAV children (all P<0.05). Conclusions:Children with ANCA-positive IgAV are more likely to experience recurrent rash. MPO-ANCA-positive IgAVN children have higher risks of hematuria, acute kidney injury and glomerular sclerosis, with later-onset but poorer renal prognosis compared to ANCA-negative IgAVN children. Higher serum creatinine levels and shorter thrombin time may be associated with renal injury in children with ANCA-positive IgAV.

ObjectiveTo explore whether miR-375 regulates the malignant characteristics of osteosarcoma (OS) by influencing the expression of MMP13. MethodsPlasmid DNAs and miRNAs were transfected into OS cells and HEK293 cells using Lipofectamine 3000 reagent. Real-time quantitative polymerase chain reaction was performed to measure the expression of miR-375 and MMP13 in OS patients and OS cells. Western blot was performed to analyze the MMP13 protein in the patients with OS and OS cells. The targeting relationship between miR-375 and MMP13 was analyzed by luciferase assay. Migration and invasion were analysed by heal wound and transwell assays, respectively. ResultsmiR-375 expression in OS tissues was lower than that in normal tissues. The expression of MMP13 was upregulated in OS tissues. MMP13 expression was negatively correlated withmiR-375 expression in patients with OS. Migration and invasion were significantly inhibited in OS cells with the miR-375 mimic compared with OS cells with the miRNA control. MMP13 partially reversed the inhibition of migration and invasion induced by miR-375 in the OS cells. ConclusionmiR-375 attenuates migration and invasion by downregulating the expression of MMP13 in OS cells.