This study aimed to explore the mechanisms by which Astragaloside IV (AS-IV), a major bioactive component of Astragalus membranaceus, mitigates high-glucose-induced peritoneal fibrosis (PF) in peritoneal dialysis (PD). Using both in vivo (uremic rat model) and in vitro (human peritoneal mesothelial cells) approaches, we observed that AS-IV treatment was associated with a significant attenuation of PF. This effect was mediated through the inhibition of epithelial-mesenchymal transition (EMT) and fibrosis. In vivo, AS-IV reduced extracellular matrix deposition and collagen accumulation, downregulated EMT and fibrosis markers (α-SMA, collagen IV), and restored E-cadherin levels. Notably, these changes correlated with the downregulation of ENKUR, pPI3K, and pAkt. The in vitro results corroborated these findings, showing that AS-IV suppressed EMT without cytotoxic effects. Our data indicate that AS-IV may exert antifibrotic effects via modulation of the ENKUR/PI3K/Akt signaling pathway, suggesting a potential target for the prevention of PF.

BACKGROUND:Chronic kidney disease (CKD) is driven by inflammation, fibrosis, and metabolic dysfunction. While circadian rhythm dysregulation is well documented in chronic disorders, its specific impact on CKD pathogenesis remains elusive. METHODS:We performed four-hour interval time-series RNA sequencing on renal tissues from control and CKD mice. We used the JTK_CYCLE algorithm to identify rhythmic genes and categorize them as lost, acquired, or sustained in CKD; we subsequently performed focused bioinformatic analyses. RESULTS:The renal circadian profile was substantially altered; acquired rhythmicity emerged as the dominant pattern, and core clock gene expression was disrupted. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that upregulated acquired-rhythmic genes in CKD were enriched in immune-inflammatory pathways; the expression of these genes peaked at Zeitgeber time (ZT) 12-16, consistent with a higher level of renal macrophage infiltration at ZT16 than at ZT0. Conversely, genes associated with nutrient and energy metabolism pathways were downregulated but acquired rhythmicity in CKD. Dapagliflozin improved renal function and restored the circadian expression rhythms of NR1D1 and p-BMAL1. CONCLUSIONS:CKD profoundly remodels the renal circadian transcriptome, driving immune-inflammatory and metabolic pathways into maladaptive rhythmicity. Furthermore, dapagliflozin can partially restore the expression of renal core clock genes.

Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease. However, its pathological mechanism remains incompletely understood. Ribonucleotide reductase M2 (RRM2) is a small subunit of ribonucleotide reductases, which is involved in nucleotide metabolism and catalyzes the conversion of nucleotides to deoxynucleotides, thereby maintaining the deoxyribonucleoside triphosphate pools required for DNA biosynthesis, repair, and replication. This study establishes a novel connection between the enzyme RRM2-traditionally recognized for its role in DNA synthesis-and the pathological progression of DKD, thereby filling the gap in identifying the "bridge molecule" between ferroptosis and the PI3K/Akt/Nrf2 pathway.

Short-chain chlorinated paraffins (SCCPs), as persistent organic pollutants, pose potential health threats, yet their toxicological mechanisms remain incompletely elucidated. This study demonstrates that exposure to SCCPs can induce liver injury in mice. Specifically, SCCPs interfere with the expression of intestinal tight junction proteins in a gut microbiota-dependent manner, leading to increased intestinal permeability and a subsequent elevation of serum lipopolysaccharide (LPS) levels. LPS activates the Toll-like Receptor 4 (TLR4)/Nuclear Factor kappa-B (NF-κB) signaling pathway and influences macrophage polarization, thereby inducing pyroptosis-related signaling in the liver. Further investigation reveals that the gut microbiota dysbiosis induced by SCCPs exposure disrupts the intestinal barrier and induces hepatotoxicity in association with downregulating the Wnt/β-catenin pathway. In summary, this study provides evidence that SCCPs contribute to gut-liver axis disruption through gut microbiota dysbiosis and suppression of the Wnt/β-catenin pathway, providing new insights into their toxicological effects.

Karst reservoirs with high dissolved inorganic carbon (DIC) concentration exhibit an efficient biological carbon pump (BCP) effects driven by phytoplankton photosynthesis; however, the biogeochemical interaction effect between DIC dynamics and phytoplankton community succession on the regulation of BCP remains to be elucidated. To address this issue, we conducted seasonal surveys across 11 karst reservoirs in the Wujiang River Basin and analyzed phytoplankton species composition, nutrients, DIC and its stable carbon isotopes (δ13CDIC). The results showed that reservoirs dominated by non-diatoms exhibited faster seasonal community succession rates, particularly those with algal bloom such as cyanobacteria or dinoflagellates. Random Forest regression and Mantel-tests identified non-diatoms as the primary predictor of community dissimilarity, with temperature, Chl-a, and CO₂(aq) depletion ranking as the most influential environmental filters. Non-diatoms exhibit enhanced dominance under CO2(aq)-limited conditions and increasing primary productivity and BCP efficiency, a process closely linked to dynamic shifts in DIC speciation (e.g., CO₂(aq) and HCO₃−). Furthermore, reservoirs with low hydraulic loads (Hydr-L) demonstrated pronounced seasonal vertical stratification that intensified CO2 limitation within the euphotic zone, which promoted non-diatom growth and resulted in a stronger BCP effect than reservoirs with high Hydr-L. Overall, our findings demonstrate that the phytoplankton community succession co-varies robustly with DIC dynamic speciation, with their synergistic interaction influencing the BCP efficiency in karst reservoirs. This framework enhances predictive understanding of carbon source–sink functioning in karst cave reservoirs under the context of biome community shifts driven by global warming and eutrophication.

The relationship between uric acid and chronic kidney disease (CKD) progression remains unclear. To study the association between the serum uric acid-to-24-hour-urinary urate excretion ratio (SUER) and kidney events in patients experiencing chronic kidney disease (CKD) progression. A retrospective cohort study involving 165 CKD patients with estimated glomerular filtration rates (eGFRs) between 15 and 150 mL/min/1.73 m2 was conducted at Huadong Hospital, Fudan University (Shanghai, P. R. China). The exposure variable was the SUER, whereas the outcome was a renal endpoint event, defined as a 50

Introduction Although the impact of air pollutants on infectious diseases is well-known, there is limited evidence regarding its effects on peritoneal dialysis (PD) patients. This study aimed to investigate the association between air pollutants and PD-related peritonitis. Methods This is an observational study affiliated to the PD Telemedicine-assisted Platform Cohort Study (PDTAP study), which is a national-level cohort study in China. The primary outcome was PD-related peritonitis, and the secondary outcomes were peritonitis-related death and transfer to hemodialysis. The pollution data were obtained from China High Air Pollutants according to the patients' place of residence. The association between pollutants and outcomes was evaluated by cause-specific Cox proportional hazard regression model. The patients were divided into the high-pollution group and low-pollution group according to the median value of PM2.5 (53.90 mu g/m(3)) and the WHO standard of PM2.5 (35.00 mu g/m(3)). Results A total of 7439 PD patients from all 7 geographical regions across China were enrolled between June 2016 and April 2019. There were 1585 patients who developed peritonitis during follow-up. The pollution was most severe in the north and central regions of China. Patients in the high-pollution group were characterized by older age, higher BMI, lower income, from rural and non-university affiliated hospitals, and had more comorbidities and better residual renal function. In multivariate analysis, PM2.5 and its components (SO4, NO3, NH4, OM, and BC), PM10, NO2, and CO were associated with increased peritonitis risk (P < 0.001-0.027). Additionally, following the propensity score matching to control for key individual-level covariates, the association between PM2.5 and its components, NO2, and CO with elevated peritonitis risk remained significant (P < 0.001). Conclusion In this national large-scale Chinese PD cohort study, air pollutants were found to be associated with increased risk for peritonitis.

Continuous damming in karst rivers fragmented the longitudinal structure of river systems, disrupting plankton habitats, limiting dispersal, and reducing biodiversity. This study examined variations in zooplankton functional diversity in a dammed river system during dry and wet seasons. Sampling across both seasons yielded 44 samples, with 64 zooplankton taxa categorized into seven functional groups based on their traits. Functional diversity indices were calculated. Results revealed significant differences in nutrient concentrations between upstream and downstream sections, particularly during the dry season (R2 = 0.11, p < 0.01). Zooplankton functional diversity decreased from upstream to downstream, with more pronounced differences in the dry season (R2 = 0.94, p < 0.05), driven by reduced dispersal stochasticity (βBC close to −1). Continuous damming primarily affected smaller zooplankton, such as rotifers, while dissolved oxygen, water temperature, and pH influenced distribution patterns related to habitat depth, breeding season, life span, and reproduction. These findings underscored the impact of damming on zooplankton functional diversity and informed dam management strategies for biodiversity conservation.

INTRODUCTION:Unwanted glucose exposure and absorption during peritoneal dialysis (PD) remain clinical challenges. Recent studies have attempted to reduce glucose absorption in PD via use of selective sodium-glucose cotransporter 2 (SGLT2) inhibitors, but results have been inconsistent and even paradoxical. We aimed to (i) explore whether both SGLT1 and SGLT2 are expressed and their respective anatomical localizations and proportions in the peritoneum and (ii) elucidate whether dual SGLT1/SGLT2 inhibition could reduce glucose absorption and improve ultrafiltration using a uremia chronic PD rat model. METHODS:Twenty-four male Sprague-Dawley rats were randomly divided into four groups (each n = 6): the sham operation group, uremia group, uremia PD group, and sotagliflozin-treated group (a dual SGLT1+2 inhibitor). The expression levels of both SGLT1 and SGLT2 were determined by immunohistochemistry and Western blot analysis. Peritoneal transport function was monitored via a peritoneal equilibration test. RESULTS:Both SGLT1 and SGLT2 are comparably expressed in the rat peritoneum and are prominently located in the vascular endothelium and peritoneal mesothelium. Compared with sham controls, uremia rats presented significantly increased expressions of both SGLT1 and SGLT2, and their expressions were further significantly increased after high-glucose PDF exposure for 5 weeks but markedly reversed by sotagliflozin cotreatment. Compared with the sham controls, uremia rats were characterized by greater glucose absorption, increased blood glucose levels, a lower D/D0 glucose ratio, a higher D/P cr ratio, a higher D/P urea ratio, and less net ultrafiltration. After infusion of high-glucose PDF for 5 weeks, these changes were more marked and were substantially ameliorated by sotagliflozin cotreatment. CONCLUSIONS:High-glucose PDF significantly increased the peritoneal expressions of both SGLT1 and SGLT2, which in turn facilitated more glucose absorption, eventually leading to a vicious cycle. Sotagliflozin may emerge as a novel strategy in PD to reduce glucose diffusion and enhance ultrafiltration.

Background:Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide, whose pathogenesis involves immune dysregulation and inflammatory response. Glycosylation plays key roles in numerous biological processes. This study aims to interrogate the role of glycosylation-related genes in tubulointerstitial immunoinflammatory injury in DN. Methods:We utilized two tubulointerstitial transcriptome datasets from DN patients and normal individuals. Glycosylation-related hub genes were identified by integrating differential expression analysis, glycosylation-related gene sets, and machine learning. Immune cell infiltration was assessed using single-sample GSEA (ssGSEA), and functional enrichment analysis was performed via GO and KEGG. The expression levels of hub genes were validated in STZ-induced diabetic mouse model (n=5/group) followed by the evaluation of diagnostic efficiency and clinical significance. Results:Six glycosylation-related hub genes (HEXB, B4GALT5, GALNT7, GCNT3, CGA, and VCAN) were identified, all closely associated with immune cell infiltration in DN. Enrichment analysis indicated their involvement in immune and inflammatory processes. CGA was significantly downregulated, while the other genes were upregulated in DN, which was experimentally validated in diabetic mice. ROC curve analysis revealed high diagnostic accuracy for all genes: HEXB (AUC = 0.892), B4GALT5 (AUC = 0.909), GALNT7 (AUC = 0.931), GCNT3 (AUC = 0.929), CGA (AUC = 0.898), and VCAN (AUC = 0.967). Elevated VCAN, GCNT3, and GALNT7 exhibited a positive association with renal function decline or proteinuria, providing valuable prognostic insights. Conclusion:This study highlights the significant role of glycosylation-related genes in DN pathogenesis, likely mediated through immune and inflammatory mechanisms. VCAN, GCNT3, and GALNT7 show particular promise as novel biomarkers for clinical diagnosis and immunotherapeutic targets, supporting their future clinical translation for DN management.

Dapagliflozin (DAPA), an SGLT-2 inhibitor, shows peritoneal protection and can alleviate high glucose-induced peritoneal fibrosis. Yet, its precise molecular mechanism is unknown. This study aims to explore DAPA’s protective effect on the peritoneum and its underlying mechanism. In vitro, human peritoneal mesothelial cells (HPMCs) were isolated from peritoneal dialysate and cultured. HMrSV5 cells were stimulated with 2.5% D-Glucose (high glucose, HG) for 48 h, then cultured in D-glucose DMEM medium with or without DAPA. To assess SGLT2i-induced ENKUR down-regulation, HMrSV5 cells were treated with DAPA for 24 h while overexpressing ENKUR. In vivo, six-week-old male Sprague-Dawley rats were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of DAPA. Changes in SGLT2, ENKUR, PI3K/AKT pathways, and EMT markers were evaluated in HPMCs and the rat model. As dialysis duration increases the morphology of the cells transitioned from a cobblestone appearance to a spindle shape. Immunofluorescence analysis confirmed the mesothelial cell origin and revealed an upregulation of ENKUR and the PI3K/AKT signaling pathway, which are associated with the occurrence of EMT. DAPA was found to decrease the expression of ENKUR and inhibit the activation of the PI3K/AKT pathway induced by high glucose in HMrSV5 cells. In rats subjected to PD, we observed a reduction in ultrafiltration capacity, an increase in peritoneal thickness, and elevated levels of SGLT2, ENKUR, PI3K/AKT and EMT markers. Notably, these alterations were mitigated by intragastric administration of DAPA. DAPA effectively ameliorates high glucose-induced peritoneal fibrosis through downregulation of ENKUR/PI3K/AKT signaling pathway.

Osteoporosis (OP) , a degenerative condition defined by osteopenia, is strongly influenced by peak bone mass (PBM) . However, the early diagnosis of osteoporosis remains incompletely understood. This study aims to identify early diagnostic biomarkers in populations with low PBM and to validate their clinical significance in the diagnosis, treatment, and prevention of osteoporosis. We obtained three microarray datasets (GSE2208, GSE97 498, and GSE64 433) from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the limma package. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Protein-protein interaction network (PPI) analysis and visualization were conducted with String and Cytoscape. CytoHubba was used to identify hub genes, and relevant miRNAs were predicted using CyTargetLinker in Cytosc ape. Finally, the hub genes and predicted mi RNA expression were confirmed via RT-qPCR experiments in peripheral blood monocytes of ovariectomy (OVX) mice. We identified 747 DEGs from GSE2208 and 1238 DEGs from GSE9 7498 and identified 58 overlapping DGEs between these two datasets. The enriched GO terms and pathways were determined, including " TNF signaling pathway, plasma membrane, protease binding, and positive regulation o f I-kappa B kinase/NF-kappa B signaling." Ten hub genes (TNF, FN-1, CCR2, HB-EGF, MMP14, NOD2, SOCS 3, IFNAR1, IRA K3, PRKACB) were selected from the overlapping DEGs. Additionally, 42 target miRNAs were identified for the ten hub genes using CyTargetLinker. Eight miRNAs were selected after cross-validation with the osteoporosis miRNA expression profiling dataset (GSE64433 In RT-qPCR experiments, the ten hub genes and eight predicted miRNAs in the blood monocytes of OVX mice were further validated. The study found that the hub genes and predicted miRNAs are potentially linked to OP development and may serve as biomarkers for the early screening of individuals at high risk of OP, thus playing a pivotal role in OP prevention and treatment. This provides a valuable foundation for further experimental studies and clinical applications. )

BackgroundThere are inequalities in resource allocation and services across peritoneal dialysis (PD) centers in China. This study aimed to explore the association between hospital type (university-affiliated vs. non-university-affiliated hospitals) and clinical outcomes in PD patients.MethodsData from the Peritoneal Dialysis Telemedicine-assisted Platform cohort was analyzed. The primary outcome was all-cause mortality, while secondary outcomes included hemodialysis transfer and first-episode PD-related peritonitis. Univariable and multivariable Fine-Gray models were used to calculate subdistribution hazard ratios (SHRs). Propensity-score matched analyses and sensitivity analyses restricted to incident patients were also performed.ResultsA total of 7416 PD patients were enrolled (June 2016 to April 2019), with a median follow-up of 29.0 months. University-affiliated hospitals' patients (n = 4806) were younger, had better nutritional status, and higher socio-economic status than those in non-university-affiliated hospitals (n = 2610). University-affiliated hospitals exhibited a lower risk for all-cause mortality (SHR: 0.72, 95% confidence interval (CI): 0.61-0.85, p < 0.001), higher hemodialysis transfer (SHR: 1.31, 95% CI: 1.08-1.60, p < 0.01), but no association with first-episode peritonitis in multivariable analyses. After propensity-score matching, university-affiliated hospitals were still associated with lower all-cause mortality (SHR: 0.74, 95% CI: 0.61-0.91, p < 0.01) and a higher risk of hemodialysis transfer (SHR: 1.52, 95% CI: 1.19-1.94, p < 0.01). Comparable results for all-cause mortality and first-episode peritonitis also found in incident patients.ConclusionIn China, PD patients in university-affiliated hospitals had lower mortality but a higher risk of hemodialysis transfer. Further studies are needed to understand these findings and inform future practices and resource allocations.

This study investigates the role of water level fluctuations (WLF) in shaping phytoplankton community structure and gross primary productivity (GPP) in Hongfeng Reservoir, a karst reservoir in Southwest China, through long-term monitoring (2016-2023) across seven sampling sites. Results revealed substantial seasonal and interannual variations in water levels (maximum fluctuation range: 9.78 m) and nutrient concentrations, with total nitrogen (TN) and phosphorus (TP) peaking during wet seasons. Chlorophyta dominated species diversity (42-48%), while Cyanophyta exhibited the highest relative abundance. GPP fluctuated markedly between the dry (586.09 mg C/m²/d) and wet seasons (3018.66 mg C/m²/d), driven by phytoplankton abundance and community stability. The Bray-Curtis (BC) dissimilarity index declined over time, showing a negative correlation with WLF (r = -0.03) and a significant negative impact on GPP. WLF indirectly enhanced GPP by altering community dynamics. Findings highlight WLF as a critical regulator of phytoplankton structure and productivity, emphasizing the importance of hydrological management in mitigating algal blooms and balancing ecological stability. This study provides actionable insights for optimizing water level regulation to sustain reservoir ecosystem health in karst regions.

Background Osteoblast differentiation is essential for fracture healing and bone regeneration. miR-324-5p has been implicated in osteoporosis, but its precise role in osteogenic differentiation remains unclear. We investigated the function and regulatory mechanisms of miR-324-5p in bone marrow mesenchymal stem cells (BMSCs). Methods RT-qPCR was used to assess miR-324-5p expression during osteogenic differentiation of BMSCs. ALP, Alizarin Red S (ARS), Oil Red O, and TRAP staining were performed to evaluate osteoblast, adipocyte, and osteoclast differentiation. Rat femoral fracture and calvarial bone defect models were established to assess in vivo bone regeneration. Methylated RNA immunoprecipitation (MeRIP) and luciferase reporter assays were used to investigate METTL3-mediated m6A modification of pri-miR-324-5p and its regulation of ELAVL1. Results miR-324-5p expression increased during osteogenic differentiation, and ALP and ARS staining confirmed enhanced osteoblast activity and mineralization following miR-324-5p overexpression. Meanwhile, Oil Red O staining showed reduced adipogenic differentiation, and TRAP staining demonstrated suppressed osteoclast formation. In vivo, miR-324-5p promoted bone healing, bone mass, and bone regeneration. Mechanistically, METTL3-mediated m6A modification facilitated pri-miR-324-5p maturation, positively regulating its expression. Additionally, miR-324-5p directly targeted ELAVL1, and ELAVL1 overexpression reversed the osteogenic effects of miR-324-5p. Conclusion The METTL3/miR-324-5p/ELAVL1 axis plays a crucial role in osteogenic differentiation and bone regeneration, providing new insights into m6A modification-driven osteogenesis.

Peritoneal dialysis (PD)-related peritonitis is a common complication with high morbidity and mortality, and empirical antibiotic regimens vary across countries. Despite some research, inconsistent results and design limitations highlight the need to reassess the association between these regimens and outcomes. This study was affiliated with the PD Telemedicine-assisted Platform (PDTAP) study. The primary outcome was peritonitis-associated death, and the secondary outcomes were peritonitis-associated hemodialysis transfer and subsequent peritonitis within 6 months. Propensity score matching and logistic regression were used to access the relationship between empirical antibiotic administration and outcomes. Altogether, 1431 patients experienced a first episode of peritonitis from June 1, 2016, to April 30, 2019. Among them, 1203 patients were assigned to the cefazolin-based group (n = 637) or to the vancomycin-based group (n = 566) based on administration of empirical antibiotics against Gram-positive bacteria. Compared to the cefazolin-based group, patients in the vancomycin-based group were older, had a longer PD duration, and reported higher income, along with a greater prevalence of diabetes, cardiovascular disease, and peritonitis history (P < 0.05 for all). Both groups exhibited similar rates of peritonitis-associated death and subsequent peritonitis within 6 months (P > 0.05 for all), however, the vancomycin-based group was more prone to to hemodialysis transfer (11.00

Decreased renal uric acid excretion is a major contributor to hyperuricemia (HUA), but its underlying mechanism remains unclear. Here, we identify cathepsin B (CTSB) as a key regulator of urate handling in HUA. Urinary CTSB levels were elevated in HUA patients, and renal CTSB expression was increased in HUA mice. In CTSBtecKOmice, the expression of reabsorptive urate transporters URAT1 and GLUT9 was decreased, while the secretory transporter ABCG2 was upregulated, leading to enhanced renal uric acid excretion and reduced serum uric acid (SUA). CTSB deficiency also reduced serum IL-1β, IL-6, and TNF-α levels. In vitro and transcriptomic analyses revealed that CTSB inhibition suppressed glycolysis-marked by reduced HK2 and PKM2 expression-downregulated URAT1 and GLUT9, and upregulated ABCG2. Conversely, CTSB overexpression enhanced glycolysis and reversed these effects. These findings suggest that CTSB promotes urate retention via glycolysis and may serve as a novel target for HUA treatment.