Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation.

Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.

Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.

BACKGROUND: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. RESULTS: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression. CONCLUSIONS: Our findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression. Video Abstract.

Targeting autophagy to counteract neuroinflammation: A novel antidepressant strategy.

Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease.

Clinical outcome of percutaneous angioplasty and covered stent placement for treatment of left brachiocephalic vein obstruction in hemodialysis patients.

BACKGROUND: Left brachiocephalic vein (LBV) obstruction is a common complication in patients undergoing hemodialysis. This study aimed to compare the clinical characteristics and outcomes of patients with LBV obstruction who underwent percutaneous angioplasty or stenting. METHODS: We performed a retrospective study of 67 hemodialysis patients with LBV stenosis or occlusion who underwent percutaneous transluminal angioplasty (PTA; n = 25) or percutaneous transluminal stenting (PTS; n = 42). We compared the clinical characteristics, lesion features, and patency between the two groups of patients. RESULTS: The average age, sex, smoking history, body mass index, obstruction period, comorbidities, and clinical manifestations were comparable between the PTA and PTS groups. Prior ipsilateral catheterization was less common in the PTS group than in the PTA group (14.3% vs 36.0%, p < 0.05). Smaller sized balloons were used in the PTS group than in the PTA group (p < 0.05). The overall primary patency rates were similar between the two groups, whereas the secondary patency rate in the PTS group was higher than that in the PTA group (p < 0.05). The average age, sex, smoking history, body mass index, obstruction period, prior ipsilateral catheterization, comorbidities, and types of lesions were comparable between patients with or without restenosis, while patients with restenosis had a higher percentage of high venous pressure than those without restenosis (87.5% vs 60.5%, p < 0.05). CONCLUSION: The primary patency rates were similar in the angioplasty and the stenting groups. Stenting has a significantly higher secondary patency rate than angioplasty alone for treating LBV obstruction and is required more commonly in patients without prior ipsilateral catheterization.

Predicting Osteoporotic Fracture in Patients With Early-Stage Diabetic Kidney Disease Using a Radiomic Model: A Longitudinal Cohort Study.

OBJECTIVE: There is an urgent need for effective predictive strategies to accurately evaluate the risk of fragility fractures in elderly patients in the early stages of diabetic kidney disease (DKD). METHODS: This longitudinal cohort study included 715 older patients in the early stages of DKD diagnosed between January 2015 and August 2019. Patients were randomly allocated to a training cohort (n = 499) and a validation cohort (n = 216). The least absolute shrinkage and selection operator method was used to select key features for dual-energy x-ray absorptiometry-based radiomic analysis. A radiomic model was constructed using Cox proportional hazards regression. The performance of the radiomic model was compared with that of traditional fracture assessment tools through a receiver operating characteristic curve, calibration curve, and decision curve analysis. RESULTS: Over a mean follow-up period of 4.72 ± 1.60 years, 65 participants (9.09%) experienced incident fragility fractures. Seventeen features were ultimately selected to create the radiomic model. The calibration plots of this model demonstrated satisfactory agreement between the observed and predicted outcomes. Moreover, the radiomic model outperformed traditional fracture assessment tools in both the training and validation cohorts according to the area under the receiver operating characteristic curve and decision curve analysis. CONCLUSIONS: The novel radiomic model has demonstrated a more effective prediction of fragility fracture in elderly patients in the early stages of DKDcompared to traditional fracture assessment tools.

Hidden in the mediastinum: a case of extramedullary hematopoiesis unveiled through thoracoscopy.

Extramedullary hematopoiesis (EMH) is a rare condition characterized by proliferation of hematopoietic stem cells outside the bone marrow, usually as a compensatory response to hematological disease. Although EMH primarily occurs in the liver and spleen, it can manifest in atypical locations, such as the mediastinum. We herein describe an asymptomatic 66-year-old man with incidentally discovered posterior mediastinal EMH. A 28- × 32-mm mass was detected during a routine examination. Laboratory findings were within normal limits. Computed tomography revealed a well-defined enhancing mass with a density of 60 Hounsfield units, suggestive of a neurogenic tumor. Surgical resection confirmed EMH, characterized by megakaryocytes and hematopoietic precursors. The patient recovered smoothly and was discharged 5 days postoperatively. Accurate preoperative diagnosis of EMH is challenging, as illustrated by this case. Although typically associated with anemia or hematological abnormalities, EMH can present without such signs. Surgical resection and histopathological examination are essential for diagnosis. This case emphasizes the diagnostic complexity of posterior mediastinal EMH, even in patients without overt hematological disorders. Posterior mediastinal EMH is exceedingly rare and diagnostically demanding. A high index of suspicion and histological tissue analysis are crucial for optimal management. Video-assisted thoracoscopic surgery enables both diagnosis and treatment through mass excision.

Zic family member 3 attenuates oxidative stress-induced vascular smooth muscle cell apoptosis in patients with chronic kidney disease.

Neointimal hyperplasia is reportedly essential for arteriovenous fistulas (AVF) in patients undergoing hemodialysis. Oxidative stress is vital in the progression of uremic venous intimal hyperplasia. Studies have suggested that zinc ions obstruct vascular calcification in patients with chronic kidney disease (CKD). Recent studies have shown that the zinc finger protein, Zic family member 3 (ZIC3), is crucial for the earliest cardiovascular progenitors. ZIC3 mutations are associated with congenital heart disease. However, the mechanism of action of ZIC3 in vascular intimal hyperplasia in CKD remains unelucidated. Venous specimens were collected during primary AVF surgery and traumatic amputation, and serum samples were collected from patients with CKD and healthy controls. Mouse vascular smooth muscle cells (VSMCs) were treated with hydrogen peroxide (H2O2) to clarify the role of ZIC3 in CKD. ZIC3 expression was reduced in the veins of patients with uremia and the serum of those with CKD. Zic3 and Bcl2 levels were significantly decreased in mouse VSMCs treated with H2O2·H2O2 inhibited mouse VSMC activity, upregulated Bax, and cleaved caspase 3 expression. Following Zic3 overexpression, Bcl2 expression level and cell viability were elevated, whereas Bax and cleaved caspase 3 expression levels were downregulated. In contrast, Zic3 knockdown yielded the opposite results. Therefore, ZIC3 could be a new therapeutic target in venous neointimal hyperplasia of CKD.

Analysis and Verification of Glycosylation Characteristics of Septic Acute Kidney Injury.

Background: Septic acute kidney injury (S-AKI) results from an imbalance in the regulation of systemic inflammatory responses. Glycosylation plays an important role in inflammatory responses. However, the relationship between S-AKI and glycosylation is unclear. Methods: The datasets of the public platform were analyzed using R language to obtain glycosylation-related differentially expressed genes (GRDEGs) in S-AKI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed for GRDEGs. Hub genes were obtained using three machine learning algorithms and their diagnostic values were evaluated using receiver operating characteristic (ROC) curves. The relationships between the hub genes, immune cells, and signaling pathways were analyzed, and the upstream miRNAs, transcription factors, and compounds of the hub genes were predicted. Mouse models of AKI with sepsis were constructed and the expression of the hub genes was verified. Results: We obtained 45 GRDEGs that were mainly enriched in glycoprotein metabolism and immune inflammatory response, such as "O-glycan biosynthesis", "phagosome", "pathogenic Escherichia coli infection", "glycosyltransferase activity", etc. Seven hub genes that have potential diagnostic value were identified and were associated with the regulation of immune cells. Through gene set enrichment analysis (GSEA) of hub genes, it was found that these genes may be involved in metabolism, signaling transduction, and inflammation-related signaling pathways, such as "metabolism of amino and derivatives", "RHO GTPase cycle", "transport of small molecules", "neutrophil degranulation", "immune system", etc. We then predicted 100 miRNAs, 60 TFs, and 23 compounds of the hub genes using forecasting tools. Finally, animal experiments confirmed the differential expression of ASGR1, UMOD, SPTBN1, and ADAMTS17. Conclusion: This study identified and validated four biomarkers associated with abnormal glycosylation that could be potential targets for AKI in sepsis.

Effect of sodium bicarbonate infusion on hospital mortality in acute kidney injury patients with metabolic acidosis.

Background: Physicians usually consider that sodium bicarbonate (SB) infusion can be used for metabolic acidosis; however, there is little evidence available to assess its effect on hospital mortality in large AKI cohorts. Here, we investigated the effect of SB infusion in patients with AKI complicated by metabolic acidosis. Method: Patients with AKI complicated by metabolic acidosis were screened from the MIMIC-IV database. A propensity score analysis (PSA) was used to decrease baseline differences in the probability of receiving SB. The marginal structural Cox model (MSCM) was employed to adjust for both baseline and time-varying confounding factors. Results: A total of 1853 patients with AKI complicated with metabolic acidosis were included in our study. A total of 390 pairs of patients were divided into an SB infusion group and a non-SB infusion group. The SB infusion group had more serious and worse laboratory indicators, including lower pH [7.19 (0.11) vs. 7.26 (0.07)] and bicarbonate concentration (BC) [12.36 (4.26) vs. 15.96 (3.25) mmol/l]. While there was no significant effect on overall hospital mortality in AKI patients complicated with metabolic acidosis (p = 0.056), SB infusion was observed to have beneficial correlation on hospital mortality in patients with high AG acidosis (AG > 18 mmol/L) (p = 0.012). Similar results were replicated with the MSCM. Conclusion: We found that SB infusion in AKI patients with metabolic acidosis is not beneficial for hospital mortality. However, SB infusion for AKI patients and high AG metabolic acidosis significantly improved hospital mortality. Further larger randomized controlled trials are needed to confirm these results.

Impact of Hemodialysis on Left Ventricular-Arterial Coupling in End-Stage Renal Disease Patients.

INTRODUCTION: As a key determinant of cardiovascular performance, vascular-arterial coupling (VAC) has been reported to be a predictor of clinical outcomes in various clinical scenarios. However, few studies have explored how acute fluid removal during hemodialysis (HD) impacts the interaction between cardiac function and the arterial system. METHODS: We recruited 317 HD patients from an established renal dialysis unit for this cross-sectional study and a total of 285 were included in the final analyses. We measured left ventricle end-systolic elastance (Ees), the effective arterial elastance (Ea), and VAC before and after HD using noninvasive echocardiographic measurements. We also compared echocardiographic and hemodynamic parameters in ventriculo-arterial coupling and ventriculo-arterial uncoupling patients. RESULTS: HD significantly altered partial ventricular and vascular function parameters such as blood pressure, left ventricular end-diastolic volume, stroke volume, left ventricular ejection fraction, and systemic vascular resistance index. Ea increased following HD from 3.5 ± 1.4 to 4.2 ± 1.8 mm Hg/mL (p < 0.0001), Ees increased following HD from 7.9 ± 5.5 to 9.2 ± 6.9 mm Hg/mL (p = 0.04), whereas VAC did not markedly alter as a result of HD. Ventriculo-arterial uncoupling was found to be related to abnormal cardiac structure and worse systolic function. CONCLUSIONS: VAC obtained from echocardiography is likely to be load-independent and useful as a reliable index for stratifying the risk of cardiovascular diseases in HD patients. Further investigations on larger patient cohorts are needed to further validate our findings.

Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.

The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Long non-coding RNA MALAT1 sponges miR-30c to promote the calcification of human vascular smooth muscle cells by regulating Runx2.

OBJECTIVES: Recent evidence suggested that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in the pathogenesis of vascular calcification (VC). In this study, we tried to explore the expression and role of a lncRNA, i.e., metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and a miRNA, i.e., miR-30c, in VC. METHODS: In vitro VC model was induced in human vascular smooth muscle cells (VSMCs) after 10 days culture in calcifying medium containing 2 mM Na2HPO4. Alizarin red S staining, calcium assay and western blot analysis of runt-related transcription factor 2 (Runx2) and alpha smooth muscle actin (α-SMA) were performed to evaluate VC. Knockdown of MALAT1 and up-regulation of MALAT1, miR-30c and Runx2 was performed to determine the impact of these molecules on VSMCs calcification. Dual-luciferase report assay was performed to confirm the relationship between MALAT1 and miR-30c or miR-30c and Runx2. In addition, quantitative reverse transcription PCR and western blot were used to determine gene and protein expression. RESULTS: MALAT1 was increased, while miR-30c was decreased in calcified VSMCs. Knockdown of MALAT1 suppressed VSMCs calcification; on the contrary, up-regulation of MALAT1 promoted VSMCs calcification. The effect of MALAT1 over-expression on VSMCs calcification was reversed by upregulation of miR-30c, which was reversed again by upregulation of Runx2. Dual-luciferase report assay confirmed that there is a direct interaction between MALAT1 and miR-30c, and Runx2 is a direct target of miR-30c. CONCLUSION: MALAT1 over-expression promoted VSMCs calcification, which was at least partially through regulating the miR-30c/Runx2 axis.

Corrigendum to "Establishment and functional characterization of the reversibly immortalized mouse glomerular podocytes (imPODs)" [Genes & Diseases 5 (2018) 137-149].

[This corrects the article DOI: 10.1016/j.gendis.2018.04.003.].

Identification of prognostic and therapeutic biomarkers in type 2 papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential prognostic and therapeutic biomarkers in PRCC2. METHODS: A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker. RESULTS: PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). CONCLUSIONS: TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.

RNA analysis of diet-induced sarcopenic obesity in rats.

Obesity has been suggested as a risk factor for sarcopenia. Sarcopenic obesity (SO), as a new category of obesity, is a high-risk geriatric syndrome in elderly individuals. However, knowledge about the molecular pathomechanisms of SO is still sparse. In the present study, starting at 13 months, male Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) and normal diet (ND) for 28 weeks to establish a rodent animal model of SO with an identical protocol, which was further assessed and verified as a successful SO model. Through RNA-seq analysis of gastrocnemius muscle in SO rats, we found that differentially expressed genes (DEGs) and alternative splicing events (ASEs) focused mainly on inflammatory, immune-response, skeletal muscle cell differentiation, fat cell differentiation and antigen processing and presentation. Furthermore, as the core regulation factor of skeletal muscle, the mef2c (myocyte enhancer Factor 2C) gene also has a significant alternative 3' splice site (A3SS) and down-regulated expression in HFD-induced SO. The alternative genes targeted by mef2c identified by GO analysis were enriched in transcript regulation of RNA polymerase II promoter. In conclusion, these explorative findings in aging high-fat-fed rats might serve as a firm starting point for understanding the pathway and mechanism of sarcopenic obesity.

Radiomics based on biparametric MRI for the detection of significant residual prostate cancer after androgen deprivation therapy: using whole-mount histopathology as reference standard.

We aimed to study radiomics approach based on biparametric magnetic resonance imaging (MRI) for determining significant residual cancer after androgen deprivation therapy (ADT). Ninety-two post-ADT prostate cancer patients underwent MRI before prostatectomy (62 with significant residual disease and 30 with complete response or minimum residual disease [CR/MRD]). Totally, 100 significant residual, 52 CR/MRD lesions, and 70 benign tissues were selected according to pathology. First, 381 radiomics features were extracted from T2-weighted imaging, diffusion-weighted imaging, and apparent diffusion coefficient (ADC) maps. Optimal features were selected using a support vector machine with a recursive feature elimination algorithm (SVM-RFE). Then, ADC values of significant residual, CR/MRD lesions, and benign tissues were compared by one-way analysis of variance. Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues. Third, the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve (AUC). The ADC value (mean ± standard deviation [s.d.]) of significant residual lesions ([1.10 ± 0.02] × 10-3 mm2 s-1) was significantly lower than that of CR/MRD ([1.17 ± 0.02] × 10-3 mm2 s-1), which was significantly lower than that of benign tissues ([1.30 ± 0.02] × 10-3 mm2 s-1; both P < 0.05). The SVM feature models were comparable to ADC value in distinguishing CR/MRD from benign tissue (AUC: 0.766 vs 0.792) and distinguishing residual from benign tissue (AUC: 0.825 vs 0.835) (both P > 0.05), but superior to ADC value in differentiating significant residual from CR/MRD (AUC: 0.748 vs 0.558; P = 0.041). Radiomics approach with biparametric MRI could promote the detection of significant residual prostate cancer after ADT.

Diagnosis, prevalence, and outcomes of sarcopenia in kidney transplantation recipients: A systematic review and meta-analysis.

The prevalence of sarcopenia and its clinical predictors and clinical impact vary among kidney transplant recipients (KTRs), in part because of different diagnostic criteria. This study aimed to assess the reported diagnosis criteria of sarcopenia and compare them in terms of prevalence, clinical predictors, and impact of sarcopenia. The Medline, Embase, and Cochrane Library were searched for the full-length reports published until 28 January 2022. The subgroup analysis, meta-regression, and sensitivity analysis were performed and heterogeneity was assessed using the I2 . A total of 681 studies were retrieved, among which only 23 studies (including 2535 subjects, 59.7% men, mean age 49.8 years) were eventually included in the final analysis. The pooled prevalence in these included studies was 26% [95% confidence interval (95% CI): 20-34%, I2  = 93.45%], including 22% (95% CI: 14-32%, I2  = 88.76%) in men and 27% (95% CI: 14-41%, I2  = 90.56%) in women (P = 0.554 between subgroups). The prevalence of sarcopenia diagnosed using low muscle mass was 34% (95% CI: 21-48%, I2  = 95.28%), and the prevalence of using low muscle mass in combination with low muscle strength and/or low physical performance was 21% (95% CI: 15-28%, I2  = 90.37%) (P = 0.08 between subgroups). In meta-regression analyses, the mean age (regression coefficient: 1.001, 95% CI: 0.991-1.011) and percentage male (regression coefficient: 0.846, 95% CI: 0.367-1.950) could not predict the effect size. Lower body mass index (odds ratio (OR): 0.57, 95% CI: 0.39-0.84, I2  = 61.5%), female sex (OR: 0.31, 95% CI: 0.16-0.61, I2  = 0.0%), and higher age (OR: 1.08, 95% CI: 1.05-1.10, I2  = 10.1%) were significantly associated with a higher risk for sarcopenia in KTRs, but phase angle (OR: 0.81, 95% CI: 0.16-4.26, I2  = 84.5%) was not associated with sarcopenia in KTRs. Sarcopenia was not associated with rejections (risk ratio (RR): 0.67, 95% CI: 0.23-1.92, I2  = 12.1%), infections (RR: 1.03, 95% CI: 0.34-3.12, I2  = 87.4%), delayed graft functions (RR: 0.81, 95% CI: 0.46-1.43, I2  = 0.0%), and death (RR: 0.95, 95% CI: 0.32-2.82, I2  = 0.0%) in KRTs. Sarcopenia was found to be very common in KRTs. However, we have not found that sarcopenia had a negative impact on clinical health after kidney transplantation. Large study cohorts and multicentre longitudinal studies in the future are urgently needed to explore the prevalence and prognosis of sarcopenia in kidney transplant patients.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy.

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF), causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H2O2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy.

Inhibition of MAPK pathway-induced apoptosis in renal cancer cells by ethanol extraction of Dysosma versipellis / 中国药理学通报

Aim To explore the effects of ethanol extraction of Dysosma versipellis on the proliferation and apoptosis of renal clear cell carcinoma OS-RC-2 cells and the underlying mechanism. Methods After treated with Dysosma versipellis, the proliferation of OS-RC-2 cells was detected by the CCK-8 assay and clone formation assay. The migration rate of cells was detected by thewound healing assay and Transwell assay. The level of ROS was detected by the reactive oxygen detection kit. The common targets between Dysosma versipellis and ROS were obtained by the network pharmacology. The above common targets were analyzed by KEGG. The apoptosis rate and cell cycle were detected by the flow cytometry, and the key proteins of MAPK signaling pathway and the levels of apoptosis related proteins were measured by Western blot. Results The results showed that Dysosma versipellis significantly inhibited the cell viability and migration ability of 0S-RC-2 cells, and up-regulated the level of ROS. Network pharmacology analysis showed a total of 165 common targets between Dysosma versipellis and ROS. KEGG analysis of the common targets revealed that there were significant changes in the MAPK signaling pathway. The results of Western blot showed that after treated with Dysosma versipellis, the protein level of JNK and the ratio of p-ERK/ERK were down-regulated. Besides, the protein level of caspase-9 and Bcl-2 declined, while the levels of cleaved caspase-9 and Bax were promoted. The flow cytometry results showed that Dysosma versipellis could significantly promote the apoptosis rate,down-regulate the cells in Gl-phase,while up-regulate the cells in G2/M-phase. The results of the rescue experiment showed that co-administration of NAC and Dysosma versipellis could significantly reverse the cell viability and apoptosis rate, the level of apop-totic related proteins, as well as the protein levels of MAPK pathway,when compared to treated with Dysosma versipellis alone in OS-RC-2. Conclusion In summary, Dysosma versipellis may inhibit the MAPK signaling pathway via the changes in ROS,further promoting apoptosis rate and decline cell proliferation in OS-RC-2 cell line.

Increased expression of the P2Y12 receptor is involved in the failure of autogenous arteriovenous fistula caused by stenosis.

OBJECTIVE: This study investigated the role of the P2Y12 receptor in autogenous arteriovenous fistula (AVF) failure resulting from stenosis. METHODS: Stenotic venous tissues and blood samples were obtained from patients with end-stage renal disease (ESRD) together with AVF stenosis, while venous tissues and blood samples were collected from patients with ESRD undergoing initial AVF surgery as controls. Immunohistochemistry and/or immunofluorescence techniques were utilized to assess the expression of P2Y12, transforming growth factor-ß1 (TGF-ß1), monocyte chemotactic protein 1 (MCP-1), and CD68 in the venous tissues. The expression levels of P2Y12, TGFß1, and MCP-1 were quantified using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Double and triple immunofluorescence staining was performed to precisely localize the cellular localization of P2Y12 expression. RESULTS: Expression levels of P2Y12, TGFß1, MCP-1, and CD68 were significantly higher in stenotic AVF venous tissues than in the control group tissues. Double and triple immunofluorescence staining of stenotic AVF venous tissues indicated that P2Y12 was predominantly expressed in α-SMA-positive vascular smooth muscle cells (VSMCs) and, to a lesser extent, in CD68-positive macrophages, with limited expression in CD31-positive endothelial cells. Moreover, a subset of macrophage-like VSMCs expressing P2Y12 were observed in both stenotic AVF venous tissues and control venous tissues. Additionally, a higher number of P2Y12+/TGF-ß1+ double-positive cells were identified in stenotic AVF venous tissues than in the control group tissues. CONCLUSION: Increased expression of P2Y12 in stenotic AVF venous tissues of patients with ESRD suggests its potential involvement in the pathogenesis of venous stenosis within AVFs.