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Our study aimed to evaluate change in sarcopenia, its defining components over 1 year follow-up and investigate associations with subsequent cognitive decline, incident mild cognitive impairment (MCI) and dementia among patients undergoing haemodialysis (HD). In the multicentre, longitudinal study, 1117 HD patients aged 56.8 ± 14.3 years (654 men; and 463 women) from 17 dialysis centres in Guizhou Province, China, were recruited in 2019 and followed up for 1 year in 2020. Sarcopenia was diagnosed with Asian Working Group for Sarcopenia criteria using appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS). Body composition was measured using body composition monitor; body water, weight, and height were corrected to calculate ASMI. HGS was measured by mechanical handgrip dynamometer. Cognitive function was measured with Mini Mental State Examination. Multivariate linear, logistic regression models and subgroup analyses were employed to examine the associations of changes in sarcopenia, ASMI, and HGS with Mini Mental State Examination score change, and incident MCI, dementia. Four hundred fourteen (37.1%) patients had sarcopenia at baseline; during 1 year follow-up, 257 (23.0%) developed MCI and 143 (12.8%) developed dementia. According to changes in sarcopenia, patients were stratified into four groups: non-sarcopenia; non-sarcopenia to sarcopenia; sarcopenia; and sarcopenia to non-sarcopenia. HD patients in sarcopenia and non-sarcopenia to sarcopenia groups had higher risk of MCI (34.8%, 32.0%, vs. 17.4%) and dementia (20.6%, 19.8%, vs. 8.7%), compared non-sarcopenia group (P < 0.001). Multivariate linear regression analyses showed that sarcopenia [regression coefficients (β) -1.098, 95% confidence interval (CI) -1.872, -0.324, P = 0.005] and non-sarcopenia to sarcopenia (β -1.826, -2.441, -1.212, P < 0.001) were associated with faster cognitive decline compared to non-sarcopenia. HGS decline (β 0.046, 0.027-0.064, P < 0.001) and ASMI decline (β 0.236, 0.109-0.362, P < 0.001) were both positively associated with cognitive decline. Multivariate logistic regression analyses demonstrated that patients with sarcopenia and non-sarcopenia to sarcopenia were both at increased risk of developing MCI [odds ratio (OR) 1.788, 95% CI 1.115-2.870, P = 0.016 and OR 1.589, 95% CI 1.087-2.324, P = 0.017, respectively], but only non-sarcopenia to sarcopenia was at increased risk of dementia (OR 1.792, 95% CI 1.108-2.879, P = 0.017). Both greater change of ASMI and HGS had lower risk of MCI with adjusted ORs of 0.857 (0.778-0.945, P = 0.002) and 0.976 (0.963-0.989, P < 0.001). Robust associations were found among female individuals, aged >60 years, and with low educational level. Longitudinal associations were observed between new-onset, persistent sarcopenia, and cognitive impairment. Early detection and intervention should be implemented to delay the onset of sarcopenia and improve cognitive health among HD patients.

Acteoside (Act), a phenylethanoid compound that was first isolated from mullein, has been widely used for the investigation of anti-inflammatory and anti-fibrotic effect. However, the mechanism of Act against unilateral ureteral obstruction (UUO)-mediated renal injury is largely unknown. Therefore, this study aimed to explore the effects of Act on UUO rats and possible mechanisms. A total of 20 Sprague-Dawley (SD) rats were divided randomly into three groups (  ≥ 6): (i) sham-operated group (Sham); (ii) UUO group (UUO+Saline); and (iii) UUO + Act 40 mg/kg/day, (UUO+Act); Continuous gavage administration for 2 weeks postoperatively, while the rats in Sham and UUO+saline groups were given equal amounts of saline. All rats were sacrificed after 14 days, the urine and blood samples were collected for biochemical analysis, the renal tissues were collected for pathological staining and immunohistochemistry. Correlations between individual proteins were analyzed by Pearson correlation analysis. The results of renal function indexes and histopathological staining showed that Act could improve renal function by reducing serum creatinine, blood urea nitrogen and urine protein at the same time, Act could alleviate renal inflammation and fibrosis. In addition, the results of immunohistochemistry showed that Act could reduce the expression of inflammation and kidney injury-related proteins F4/80, Mcp-1, KIM-1 proteins, as well as the expression of fibrosis-related protein -SMA and -catenin. More importantly, Act can also reduce the expression of HMGN1, TLR4 and TREM-1 proteins. These data demonstrate that Act can ameliorate UUO-induced renal inflammation and fibrosis in rats probably through triggering HMGN1/TLR4/TREM-1 pathway.

Background Gut microbiota alterations have been implicated in sepsis and related infectious diseases, but the causal relationship and underlying mechanisms remain unclear. Methods We evaluated the association between gut microbiota composition and sepsis using two-sample Mendelian randomization (MR) analysis based on published genome-wide association study (GWAS) summary statistics. Sensitivity analyses were conducted to validate the robustness of the results. Reverse MR analysis and integration of GWAS and expression quantitative trait loci (eQTL) data were performed to identify potential genes and therapeutic targets. Results Our analysis identified 11 causal bacterial taxa associated with sepsis, with increased abundance of six taxa showing positive causal relationships. Ten taxa had causal effects on the 28-day survival outcome of septic patients, with increased abundance of six taxa showing positive associations. Sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis did not provide evidence of reverse causality. Integration of GWAS and eQTL data revealed 76 genes passing the summary data-based Mendelian randomization (SMR) test. Differential expression of these genes was observed between sepsis patients and healthy individuals. These genes represent potential therapeutic targets for sepsis. Molecular docking analysis predicted potential drug-target interactions, further supporting their therapeutic potential. Conclusion Our study provides insights for the development of personalized treatment strategies for sepsis and offers preliminary candidate targets and drugs for future drug development.

Background Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. Methods A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. Results Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. Conclusion This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.

Cognitive dysfunction caused by diabetes has become a serious global medical issue. Diabetic kidney disease (DKD) exacerbates cognitive dysfunction in patients, although the precise mechanism behind this remains unclear. Here, we conducted an investigation using RNA sequencing data from the Gene Expression Omnibus (GEO) database. We analyzed the differentially expressed genes in DKD and three types of neurons in the temporal cortex (TC) of diabetic patients with cognitive dysfunction. Through our analysis, we identified a total of 133 differentially expressed genes (DEGs) shared between DKD and TC neurons (62 up-regulated and 71 down-regulated). To identify potential common biomarkers, we employed machine learning algorithms (LASSO and SVM-RFE) and Venn diagram analysis. Ultimately, we identified 8 overlapping marker genes (ZNF564, VPS11, YPEL4, VWA5B1, A2ML1, KRT6A, SEC14L1P1, SH3RF1) as potential biomarkers, which exhibited high sensitivity and specificity in ROC curve analysis. Functional analysis using Gene Ontology (GO) revealed that these genes were primarily enriched in autophagy, ubiquitin/ubiquitin-like protein ligase activity, MAP-kinase scaffold activity, and syntaxin binding. Further enrichment analysis using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicates that these biomarkers may play a crucial role in the development of cognitive dysfunction and diabetic nephropathy. Building upon these biomarkers, we developed a diagnostic model with a reliable predictive ability for DKD complicated by cognitive dysfunction. To validate the 8 biomarkers, we conducted RT-PCR analysis in the cortex, hippocampus and kidney of animal models. The results demonstrated the up-regulation of SH3RF1 in the cortex, hippocampus and kidney of mice, which was further confirmed by immunofluorescence and Western blot validation. Notably, SH3RF1 is a scaffold protein involved in cell survival in the JNK signaling pathway. Based on these findings, we support that SH3RF1 may be a common gene expression feature that influences DKD and cognitive dysfunction through the apoptotic pathway.

Kidney functions, including electrolyte and water reabsorption and secretion, could be influenced by circulating hormones. The pituitary gland produces a variety of hormones and cytokines; however, the influence of these factors on the kidney has not been well explained and explored. To provide more in-depth information and insights to support the pituitary–kidney axis connection, we used mouse pituitary and kidney single-cell transcriptomics data from the GEO database for further analysis. Based on a ligand–receptor pair analysis, cell–cell interaction patterns between the pituitary and kidney cell types were described. Key ligand–receptor pairs, such as GH-GHR, PTN-SDC2, PTN-SDC4, and DLK1-NOTCH3, were relatively active in the pituitary–kidney axis. These ligand–receptor pairs mainly target proximal tubule cells, principal cells, the loop of Henle, intercalated cells, pericytes, mesangial cells, and fibroblasts, and these cells are related to physiological processes, such as substance reabsorption, angiogenesis, and tissue repair. Our results suggested that the pituitary gland might directly regulate kidney function by secreting multiple hormones or cytokines and indicated that the above ligand–receptor pairs might represent a new research focus for studies on kidney function or kidney disease.

Background Diabetic kidney disease (DKD) is one of the most pervasive complications of diabetes worldwide. However, the pathogenesis of DKD remains poorly understood, due to limitations of the models. The hPSC-derived kidney organoids may offer a new possibility to solve the problem. Methods We generated human pluripotent stem cells (hPSCs) derived kidney organoids to model DKD injury by glucose intervention for 24 and 72 h, respectively. RT-qPCR was used to assess gene expression, while immunofluorescence was performed to evaluate protein expression. PAS staining was applied to examine organoid morphology, and Sirius Red staining was used to assess fibrosis. Results Firstly, qPCR results showed that glucose and lipid metabolism-related genes such as LDH , HK2 , SGLT2 , PLIN2 , PPARA , PGC1A , and HSL mRNA expression were upregulated after glucose intervention. Secondly, qPCR and immunofluorescence staining results revealed that the expression of pro-inflammatory cytokines IL6, IL1B, TNFA, VCAM1 and IL-10 were increased, which suggested kidney organoids possess inflammatory responses in high glucose environments. Thirdly, KIM1, a kidney injury maker was upregulated after glucose intervention, and increased apoptosis cells in kidney organoids were confirmed by TUNEL assay. Finally, qPCR and immunofluorescence staining results revealed that the expression of fibrosis-related molecules TGF-β1 and COL4 were increased. Conclusion In general, diabetic kidney disease organoid models provide a valuable model for studying the onset, progression, and injury of DKD. Clinical trial number Not applicable.

Introduction: Cognitive impairment is prevalent in patients undergoing hemodialysis (HD), which is related to the nutritional and inflammatory status of this population. Malnutrition-inflammation score (MIS) has been identified as a useful tool to evaluate nutrition and inflammation status. The aim of this study is to investigate the association between MIS and cognitive impairment in HD patients. Methods: This was a multicenter observational cohort study with 1,591 patients undergoing HD. Nutritional and inflammatory status was evaluated with MIS, anthropometric measurements, and body composition assessments. Cognitive function was evaluated with the Mini Mental State Examination (MMSE). The associations between MIS and cognitive impairment were analyzed by multivariable logistic regression models. Results: Among 1,591 HD patients, the mean MIS was 6.0 ± 2.6. Patients with higher MIS had significantly lower MMSE scores. 311 patients had cognitive impairment. After adjusting clinical confounders, higher MIS was independently associated with increased rate of cognitive impairment both as a categorized variable (OR, 1.358; 95% CI, 1.010–1.825; p = 0.045) and as a continuous variable (OR, 1.113; 95% CI, 1.053–1.178; p < 0.001). Subgroup analysis showed a stronger association between MIS and cognitive impairment in males, the population with age 41–60 years, and 61–80 years, no smoker, living by oneself, HD combined with or without hemoperfusion as dialysis modality. ROC curve analysis of MIS showed 60.1% sensitivity and 52.0% specificity in predicting cognitive impairment (AUC 0.604; 95% CI 0.567–0.640, p < 0.001). Conclusions: MIS was independently associated with cognitive impairment in HD patients.

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague–Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.

Malnutrition and inflammation are prevalent in hemodialysis (HD) patients and linked to cognitive impairment (CI). Naples prognostic score (NPS) is a comprehensive measure of patients' inflammation and nutritional status. This study is to evaluate the association of NPS and CI risk in HD patients. Two thousand seven hundred twenty-five HD patients were recruited and NPS score obtained based on albumin, total cholesterol (TC), lymphocytes, neutrophils, and monocytes. Cognitive function was assessed with Mini-Mental State Examination score (MMSE). Logistic regression models, interactive analyses were conducted. Among 2725 HD patients, the prevalence of CI is 33.8%, the mean MMSE score was 26.9 ± 3.9. After adjusting clinical confounders, NPS showed a positive associated with CI both as a continuous variable (OR = 1.120, 95% CI 1.029-1.221,  = 0.009) and as a categorical variable (OR = 1.552, 95%CI: 1.146-2.110,  = 0.005). The analysis revealed a negative correlation between NPS and MMSE scores, observed both as a continuous variable ( = -0.178, 95% CI -0.321 to -0.035,  = 0.015) and as a categorical variable. Higher NPS was significantly associated with increased dementia risk (adjusted OR = 1.153, 95% CI 1.035-1.286,  = 0.010). Among CI patients, the proportion of males was higher than that of females. Subgroup analysis showed that the effect of NPS on CI was more pronounced in individuals under 65 years, without diabetes and cerebrovascular disease (CVD). Except for males, low education level, non-CVD, and HD frequency less than three times per week, the association between NPS and dementia was more significant. NPS was associated with cognitive impairment in HD patients with a positive dose-response effect.