Senolytic combination of dasatinib and quercetin attenuates renal damage in diabetic kidney disease.

BACKGROUND: Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain. PURPOSE: To investigate the functions and potential mechanisms of the senolytics DQ on DKD. METHODS: Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector. RESULTS: DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD. CONCLUSION: For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.

Renal aging and mitochondrial quality control.

Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Myocardial Injury in Peritoneal Dialysis Patients Assessed by Multiparametric MRI: Relationship With Left Ventricular Phenotypes.

BACKGROUND: Myocardial injury is common in end-stage renal disease (ESRD) patients, but the presence and severity of myocardial injury in different left ventricular (LV) phenotypes were still not fully explored. PURPOSE: To evaluate myocardial tissue characteristics and deformation in ESRD patients on peritoneal dialysis separated into normal geometry, concentric remodeling, concentric left ventricular hypertrophy (LVH) and eccentric LVH patterns by multiparametric cardiac MRI. STUDY TYPE: Prospective. POPULATION: A total of 142 subjects, including 102 on peritoneal dialysis (69 males) and 40 healthy controls (27 males). FIELD STRENGTH/SEQUENCE: At 3.0 T, cine sequence, T1 mapping and T2 mapping. ASSESSMENT: LV mass index and LV remodeling index were used to create four subgroups with normal geometry, concentric remodeling, concentric LVH, and eccentric LVH. LV function, strain and strain rate, myocardial native T1 and T2 were measured. STATISTICAL TESTS: Descriptive statistics, analysis of variance and analysis of covariance, Pearson/Spearman correlation, stepwise regression, and intraclass correlation coefficient. P-value <0.05 was considered statistically significant. RESULTS: Even in normal geometry, LV strain parameters still diminished compared with the controls (global radial strain: 30.5 ± 7.7% vs. 37.1 ± 7.9%; global circumferential strain: -18.2 ± 2.6% vs. -20.6 ± 2.2%; global longitudinal strain: -13.3 ± 2.5% vs. -16.0 ± 2.8%). Eccentric LVH had significantly lower global circumferential systolic strain rate than concentric LVH (-0.82 ± 0.21%/- second vs. -0.96 ± 0.20%/- second). Compared with the controls, the four subgroups all revealed elevated native T1 and T2, especially in eccentric LVH, while concentric remodeling had the least changes including native T1, T2, and LV ejection fraction. After adjusting for covariates, there was no statistically significant difference in T2 between the four subgroups (P = 0.359). DATA CONCLUSIONS: Eccentric LVH is associated with the most pronounced evidence of myocardial tissue characteristics and function impairment, while as a benign remodeling, the concentric remodeling subgroup had the least increase in native T1. This study further confirms that native T1 and strain indicators can reflect the severity of myocardial injury in ESRD, providing better histological and functional basis for future grouping treatments. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Three-Dimensional Porous Indium Single-Atom Catalysts with Improved Accessibility for CO2 Reduction to Formate.

Single-atom catalysts (SACs) present substantial potential in electrocatalytic CO2 reduction reactions; however, inferior accessibility of single-atom sites to CO2 limits the overall CO2RR performances. Herein, we propose to improve the accessibility between In sites and CO2 through the construction of a three-dimensional (3D) porous indium single-atom catalyst (In1/NC-3D). The NaCl template-mediated synthesis strategy generates the unique 3D porous nanostructure of In1/NC-3D. Multiple characterizations validate that In1/NC-3D exhibits increased exposure of active sites and enhanced CO2 transport/adsorption capacity compared to the bulk In1/NC, thus improving accessibility of active sites to CO2. As a result, the In1/NC-3D presents superior CO2RR performance to the bulk In1/NC, with a partial current density of formate of 67.24 mA cm-2 at -1.41 V, relative to a reversible hydrogen electrode (vs RHE). The CO2RR performances with high formate selectivity at a large current density also outperform most reported In-based SACs. Importantly, the In1/NC-3D is demonstrated to maintain an FEformate of >82% at -66.83 mA·cm-2 over 21 h. This work highlights the design of a 3D porous single-atom catalyst for efficient CO2RR, promoting the development of advanced catalysts toward advanced energy conversion.

Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway.

The senolytics dasatinib and quercetin (DQ) alleviate age­related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin­creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid­Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation­related proteins. In addition, mouse podocytes were administered with high­glucose, DQ and 3­methyladenine (3­MA), and the expression levels of autophagic and podocyte differentiation­related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation­related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation­related proteins. Administration of 3­MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation in vitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.

The efficacy and safety of hydroxychloroquine versus leflunomide in patients with IgA nephropathy: a single-center experience.

PURPOSE: To date, our understanding of IgA nephropathy (IgAN) pathophysiology has remained incomplete; therefore, treatment remains largely empiric, and the efficacy and safety of immunosuppressants remain controversial. We aimed to assess the efficacy and safety of hydroxychloroquine and leflunomide therapy in a retrospective cohort of patients with IgAN. METHODS: We screened the IgAN registration database in our department, and a total of 159 kidney patients with biopsy-confirmed IgAN were enrolled, with 57 patients receiving hydroxychloroquine plus a renin-angiotensin system inhibitor (hydroxychloroquine group), 52 patients receiving leflunomide plus a renin-angiotensin system inhibitor (leflunomide group), and 50 patients receiving only a renin-angiotensin system inhibitor (renin-angiotensin system inhibitor-only group). Changes in proteinuria, hematuria, and the estimated glomerular filtration rate (eGFR), as well as adverse events, were analyzed during the follow-up period. RESULTS: At the end of 6-month follow-up, proteinuria significantly decreased by 70.36 (57.54, 79.33)%, 57.29 (46.79, 67.29)% and 41.20 (25.76, 48.94)% in the hydroxychloroquine, leflunomide and renin-angiotensin system inhibitor-only groups, respectively, compared to baseline (all P values < 0.001). Hematuria significantly decreased by 71.07 (56.48, 82.47)% in the leflunomide group (P < 0.001). The eGFR improved by 3.72 ± 2.97%, 3.16 ± 2.00% and 1.91 ± 2.41%, respectively, in the hydroxychloroquine, leflunomide and renin-angiotensin system inhibitor-only groups, but without statistical significance. No serious adverse events occurred during the follow-up period. CONCLUSION: Both hydroxychloroquine combined with a renin-angiotensin system inhibitor and leflunomide combined with a renin-angiotensin system inhibitor were more effective than a renin-angiotensin system inhibitor alone in improving proteinuria in IgAN patients. Hydroxychloroquine was more effective in reducing proteinuria, and leflunomide showed superiority in reducing hematuria. Our results need to be verified in large-scale randomized controlled trials.

Mn Single-Atom Tuning Fe-N-C Catalyst Enables Highly Efficient and Durable Oxygen Electrocatalysis and Zinc-Air Batteries.

Fe-N-C catalyst is one of most promising candidates for oxygen electrocatalysis reaction in zinc-air batteries (ZABs), but achieving sustained high activity is still a challenging issue. Herein, we demonstrate that introducing Mn single atoms into Fe-N-C (Mn1@Fe-N-C/CNTs) enables the realization of highly efficient and durable oxygen electrocatalysis performance and application in ZABs. Multiple characterizations confirm that Mn1@Fe-N-C/CNTs is equipped with Mn-N2O2 and Fe-N4 sites and Fe nanoparticles. The Mn-N2O2 sites not only tune the electron structure of Fe-Nx sites to enhance intrinsic activity, but also scavenge the attack of radicals from Fe-Nx sites for improvement in ORR durability. As a result, Mn1@Fe-N-C/CNTs exhibits enhanced ORR performance to traditional Fe-N-C catalysts with high E1/2 of 0.89 V vs reversible hydrogen electrode (RHE) and maintains ORR activity after 15 000 CV. Impressively, Mn1@Fe-N-C/CNTs also presents excellent OER activity and the difference (ΔE) between E1/2 of ORR and OER potential at 10 mA cm-2 (Ej10) is only 0.59 V, outperforming most reported catalysts. In addition, the maintainable bifunctional activity of Mn1@Fe-N-C/CNTs is demonstrated in ZABs with almost unchanged cycle voltage efficiency up to 200 h. This work highlights the critical role of Mn single atoms in enhancing ORR activity and stability, promoting the development of advanced catalysts.

Enhanced Electron Confinement of p-Block Indium Site in Extended Macrocyclic Conjugation Boosting Oxygen Reduction to Hydrogen Peroxide.

The electrocatalytic oxygen reduction reaction via a two-electron pathway (2e- ORR) is a promising route for hydrogen peroxide (H2O2) production. However, the strong electron interaction between the metal site and oxygen-containing intermediates usually generates 4-electron ORR, limiting H2O2 selectivity. Here, combining theoretical and experimental studies, we propose to enhance the electron confinement of the indium (In) center in an extended macrocyclic conjugation system toward high-efficiency H2O2 production. The extended macrocyclic conjugation in indium polyphthalocyanine (InPPc) evokes the attenuated transfer electron ability of the In center and weakens the interaction between the s orbital of In and the p obital of OOH*, favoring protonation of OOH* to H2O2. Experimentally, the prepared InPPc catalyst exhibits a noticeable H2O2 selectivity above 90% in 0.1-0.6 V vs RHE, outperforming the counterpart InPc. Importantly, the InPPc displays a high average H2O2 production rate of 23.77 mg/cm2/h in a flow cell. This study proposes a novel strategy to engineer molecular catalysts and provides new insights into the ORR mechanism.

Efficacy of roxadustat in treatment of peritoneal dialysis patients with renal anaemia.

BACKGROUND: There are no studies on the use of roxadustat in patients on regular peritoneal dialysis in China. AIM: To observe the efficacy and safety of roxadustat in treating renal anaemia in peritoneal dialysis patients. METHODS: Patients with renal anaemia who were regularly followed at the Peritoneal Dialysis Center of the First Affiliated Hospital of China Medical University from November 1, 2019 to June 30, 2020 were selected. A before-and-after self-control design was performed to retrospectively analyse the treatment effects on anaemia in patients treated with recombinant human erythropoietin (EPO) and roxadustat. RESULTS: A total of 31 patients with renal anaemia on long-term peritoneal dialysis treated with roxadustat were included. Haemoglobin (Hb) levels were maintained or increased in all patients (100%), and no patients had a decrease in Hb compared with the previous phase. Patients had a mean Hb of 86.2 ± 14.8 g/L with Hb compliance (Hb ≥ 110 g/L) of 16.1% during the EPO phase and a mean Hb of 112.4 ± 18.5 g/L with Hb compliance of 67.7% during the roxadustat phase. No major adverse cardiovascular events occurred in any patient. CONCLUSION: The application of roxadustat in peritoneal dialysis patients with renal anaemia can effectively improve the Hb compliance rate.

IL-6/STAT3-mediated autophagy participates in the development of age-related glomerulosclerosis.

The standard of age-related glomerulosclerosis is unclear. Both signal transducer and activator of transcription 3 (STAT3) and autophagy are involved in age-related kidney disease. Therefore, we aimed to explore the standard, as well as the potential mechanism(s). A total of 44 patients who underwent radical nephrectomy were enrolled. Pearson analysis was performed to investigate the parameters with ages. The patients were divided into the young- and aged-kidney groups. Kidney morphological changes were evaluated by histology staining, senescence was evaluated by senescence-associated-ß-galactosidase (SA-ß-gal) staining, and autophagosome was measured by transmission electron microscopy. Moreover, Western blot and/or immunohistochemistry were accomplished to assess the expression of p16, STAT3, and glycoprotein130 (GP130) and autophagy-related proteins. Furthermore, human glomerular mesangial cells were administrated with tocilizumab (TCZ) and/or IL-6, and then the above indexes were tested again. Sclerotic glomerular density and glomerular sclerosis rate were significantly higher in individuals more than 40 years old, and they were strongly correlated with ages. Moreover, the expression of p16, STAT3, GP130, and p62 was significantly increased, while LC3II and autophagosome were statistically decreased in the aged-kidney. Glomeruli were hardly to stain with SA-ß-gal. For the in vitro experiments, we observed that IL-6 significantly increased p16, STAT3, GP130, and p62, induced higher SA-ß-gal staining, while downregulated LC3II and autophagosome. Furthermore, TCZ statistically reversed the effects of IL-6 on the above expression of proteins. Glomerular sclerosis rate might be one standard for natural renal aging, and IL-6/STAT3-mediated autophagy may participate in the development of age-related glomerulosclerosis.

LncRNA ARAP1-AS2 promotes high glucose-induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1.

The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF-ß/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non-coding RNA (lncRNA), ARAP1-AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1-AS2 was significantly up-regulated in high glucose-induced human proximal tubular epithelial cells (HK-2 cells). Moreover, we found that overexpression or knockdown of ARAP1-AS2 could regulate fibrosis and HK-2 cell proliferation through EGFR/TGF-ß/Smad3 signalling. RNA pulldown assays revealed that ARAP1-AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual-immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1-AS2 may promote high glucose-induced proximal tubular cell injury via persistent EGFR/TGF-ß/Smad3 pathway activation by interacting with ARAP1.

A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation. METHODS: To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1ß expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1ß expression in the glomerular mesangial cells were measured. RESULTS: The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1ß pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1ß in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-ß1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells. CONCLUSION: MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1ß pathway, which may be a potential therapeutic strategy to prevent the progression of DN.

The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells.

Renal aging and associated functional decline are associated with an increase in cellular senescence. Previous studies show a direct correlation between advanced glycation end products (AGEs) accumulation and renal aging, chronic kidney disease (CKD) and other nephropathies, although the underlying molecular mechanisms remain largely unclear. We found elevated levels of the receptor of advanced glycation end product (RAGE) as well as STAT5 in aged human kidneys, as well as in human mesangial cells aged artificially through AGEs. Furthermore, genetic and pharmacological ablation of STAT5 significantly downregulated p16 levels and the percentage of ß-Gal-positive senescent cells in mesangial cells and kidneys of SD rats, indicating that AGEs-induced senescence depends on STAT5 signaling. The aged kidney tissues (both in patients and SD rats) and mesangial cells show low levels of LC3 (both LC3-II and LC3-II/I), and cultured mesangial cells also show fewer autolysosomes, autophagosomes, and autophagic vacuoles, which can be partially restored upon STAT5 inhibition. This indicates that AGEs accumulation also obliterates the protective effects of autophagy against aging via the RAGE/STAT5 axis. Direct inhibition of autophagy via 3-methyladenine (3-MA) increases the phenotype of renal aging without activating RAGE, it is inhibition of autophagy caused by RAGE/STAT5 that leads to mesangial aging. In conclusion, we found AGEs induced inhibition of autophagy and cellular senescence in mesangial cells via the RAGE/STAT5 pathway. Moreover, we found that RAGE/STAT5 acts as a key link between autophagy and senescence in the process of mesangial aging in vivo and in vitro.

Prevalence and associated factors of depression and anxiety among doctoral students: the mediating effect of mentoring relationships on the association between research self-efficacy and depression/anxiety.

PURPOSE: Although the mental health status of doctoral students deserves attention, few scholars have paid attention to factors related to their mental health problems. We aimed to investigate the prevalence of depression and anxiety in doctoral students and examine possible associated factors. We further aimed to assess whether mentoring relationships mediate the association between research self-efficacy and depression/anxiety. METHODS: A cross-sectional study was conducted among 325 doctoral students in a medical university. The Patient Health Questionnaire 9 and Generalized Anxiety Disorder 7 scale were used to assess depression and anxiety. The Research Self-Efficacy Scale was used to measure perceived ability to fulfill various research-related activities. The Advisory Working Alliance Inventory-student version was used to assess mentoring relationships. Linear hierarchical regression analyses were performed to determine if any factors were significantly associated with depression and anxiety. Asymptotic and resampling methods were used to examine whether mentoring played a mediating role. RESULTS: Approximately 23.7% of participants showed signs of depression, and 20.0% showed signs of anxiety. Grade in school was associated with the degree of depression. The frequency of meeting with a mentor, difficulty in doctoral article publication, and difficulty in balancing work-family-doctoral program was associated with both the level of depression and anxiety. Moreover, research self-efficacy and mentoring relationships had negative relationships with levels of depression and anxiety. We also found that mentoring relationships mediated the correlation between research self-efficacy and depression/anxiety. CONCLUSION: The findings suggest that educational experts should pay close attention to the mental health of doctoral students. Active strategies and interventions that promote research self-efficacy and mentoring relationships might be beneficial in preventing or reducing depression and anxiety.

circHLA-C Plays an Important Role in Lupus Nephritis by Sponging miR-150.

Circular RNAs (circRNAs) participate in the pathogenesis of various diseases by sponging microRNAs (miRs). However, the roles of circRNAs remain unreported in glomerular diseases. We previously reported that miR-150 positively correlated with renal chronicity index in patients with lupus nephritis (LN). We aimed to investigate renal circRNA profiling and the interaction between circRNAs and miR-150 in LN patients. Six renal biopsies from untreated female patients with LN class IV and five normal kidney tissues from urology patients were used for circRNA sequencing. 171 circRNAs with 2-fold differential expression were identified in LN compared with normal control. Ten selected circRNAs were validated by real-time qPCR, and seven circRNAs showed the same significant increases as the sequencing results. circHLA-C positively correlated with proteinuria (R = 0.92, p < 0.01), serum creatinine (R = 0.76, p = 0.08), renal activity index (R = 0.88, p < 0.05), and crescentic glomeruli (R = 0.93, p < 0.01). Renal circHLA-C increased 2.72-fold, and miR-150 decreased 66% in LN compared with normal control (p < 0.05). Bio-informatic analysis predicted miR-150 was regulated by circHLA-C and displayed one perfect match seed between circHLA-C and miR-150. The renal miR-150 showed a tendency of negative correlation with circHLA-C in LN patients. In conclusion, circHLA-C may play an important role in the pathogenesis of lupus nephritis by sponging miR-150.

Prevalence and related factors of depressive symptoms in hemodialysis patients in northern China.

BACKGROUND: To determine the prevalence of depressive symptoms and to explore related factors of depressive symptoms in hemodialysis (HD) patients in northern China. METHODS: We used a cross-sectional research design to recruit 227 chronic kidney disease (CKD) patients who were undergoing HD treatment in northern China during December, 2012 to March, 2013. The Chinese edition of the Center for Epidemiologic Studies Depression (CES-D) was used to measure depressive symptoms. Information on quality of life (QOL), activities of daily living (ADL), social support status, coping style, self-efficacy, ego resiliency and demographic characteristics was all collected by face to face interview. Multivariate logistic regression analysis was used to explore related factors of depressive symptoms. RESULTS: The prevalence of depressive symptoms among HD patients was 29.1%. Patients with a lower mood have worse ADL and QOL than patients with better mood. Patients with a lower mood have got less social support than patients with better mood, including both family support and outside family support. For coping style, patients with a lower mood were more inclined to choose "acceptance-resignation" coping style than patients with better mood, while the result is opposite in "avoidance" coping style. And patients with a better mood have better self-efficacy and ego resiliency than patients with lower mood. Multivariate logistic regression analyses revealed that ADL (OR = 1.124, p = 0.002), family support (OR = 0.867, p = 0.021), "acceptance-resignation" coping style (OR = 1.228, p = 0.022), and ego resiliency (OR = 0.944, p = 0.021) were associated with low mood independently. CONCLUSIONS: The prevalence of depressive symptoms is high in CKD patients on HD in northern China. activities of daily living, family support, "acceptance-resignation" coping style and ego resiliency were independently associated with depressive symptoms.

Inhibiting MicroRNA-503 and MicroRNA-181d with Losartan Ameliorates Diabetic Nephropathy in KKAy Mice.

BACKGROUND Diabetic nephropathy (DN) is the most lethal diabetic microvascular complication; it is a major cause of renal failure, and an increasingly globally prominent healthcare problem. MATERIAL AND METHODS To identify susceptible microRNAs for the pathogenesis of DN and the targets of losartan treatment, microRNA arrays were employed to survey the glomerular microRNA expression profiles of KKAy mice treated with or without losartan. KKAy mice were assigned to either a losartan-treated group or a non-treatment group, with C57BL/6 mice used as a normal control. Twelve weeks after treatment, glomeruli from the mice were isolated. MicroRNA expression profiles were analyzed using microRNA arrays. Real-time PCR was used to confirm the results. RESULTS Losartan treatment improved albuminuria and the pathological lesions of KKAy mice. The expression of 10 microRNAs was higher, and the expression of 12 microRNAs was lower in the glomeruli of the KKAy untreated mice than that of the CL57BL/6 mice. The expression of 4 microRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared to that of the untreated mice. The expression of miRNA-503 and miRNA-181d was apparently higher in the glomeruli of the KKAy untreated mice, and was inhibited by losartan treatment. CONCLUSIONS The over-expression of miR-503 and miR-181d in glomeruli of KKAy mice may be responsible for the pathogenesis of DN and are potential therapeutic targets for DN.

Effect of breviscapine injection on clinical parameters in diabetic nephropathy: A meta-analysis of randomized controlled trials.

Diabetic nephropathy (DN) is currently a major public health problem worldwide. The objective of the present study was to evaluate the clinical effect of breviscapine injections in patients with DN. A meta-analysis was performed using the following databases to obtain published reports in any language: PubMed/MEDLINE, Embase, China National Knowledge Infrastructure, Chinese Evidence-Based Medicine, Wanfang Digital Periodicals, Chinese Academic Journals Full-text Database, Chinese Biological and Medical Database, China Doctoral and Masters Dissertations Full-text Database and the Chinese Proceedings of Conference Full-text Database. Two assessors independently reviewed each trial. A total of 35 randomized controlled trials, which performed studies on a total of 2,320 patients (1,188 in treatment groups and 1,132 in control groups), were included in the present meta-analysis. Data were analyzed using Stata version 11.0 for Windows. The results from the analysis demonstrated that breviscapine injections have greater therapeutic effects in patients with DN in comparison with the control group, including renal protective effects (reducing urine protein, serum creatinine and blood urea nitrogen) and adjustment for dyslipidemia (affecting levels of cholesterol, triglycerides and high density lipoproteins). These effects indicate that breviscapine injections are beneficial to patients with DN. Further studies are required to determine the mechanisms underlying the therapeutic effects of breviscapine.

TL1-A can engage death receptor-3 and activate NF-kappa B in endothelial cells.

BACKGROUND: Death receptors (DRs) play an important role in renal pathology. We have shown that DR3 is inducibly expressed on renal tubular epithelial cells in the setting of inflammatory injuries. In this study we investigate the expression of DR3 in renal endothelial cells and their response to TL1A, the only known ligand of DR3. METHODS: We did RT-PCR, flow cytometry and subcellular immunoblotting to examine the expression and function of DR3 in cells in vitro. We did organ culture of human and mouse tissue to examine expression and signal of DR3 in vivo. RESULTS: DR3 is expressed in some interstitial vascular endothelial cells (EC) in human kidney in situ; these EC also respond to its ligand TL1A by activating NF-κB. Very low levels of DR3 can be detected on the cell surface of cultured human umbilical vein (HUV) EC, which do not respond to TL1A. HUVEC transfected to overexpress DR3 become responsive to TL1A, assessed by IκBα degradation and E-selectin induction, indicating that the signaling components needed for DR3 responsiveness are expressed. TL1A induces NF-κB activation in EC in renal and cardiac tissue from wild type but not DR3 knock-out mice. CONCLUSION: TL1A and DR3 activate NF-κB in vascular endothelial cells, and can be an important regulator of renal interstitial vascular injury.

Role of the CASP-9 Ex5+32 G>A polymorphism in susceptibility to cancer: A meta-analysis.

Failure of apoptosis is one of the hallmarks of cancer. As an execution-phase caspase, caspase-9 plays a crucial role during apoptosis. To examine whether the Ex5+32 G>A (rs1052576) polymorphism in the CASP-9 gene alters cancer risk, we conducted a comprehensive meta-analysis of 7 case-control studies consisting of a total of 1668 cancer cases and 2294 healthy controls. All studies considered, A allele and A allele carriers of Ex5+32 G>A in the CASP-9 gene had significant associations with cancer risk (OR=0.72, 95% CI, 0.58-0.89, P= 0.003; OR= 0.76, 95% CI, 0.63-0.92, P= 0.004; respectively). In the subgroup analysis, we found that the A allele of Ex5+32 G>A was a protective factor for cancer risk in Chinese and American populations (OR=0.60, 95% CI, 0.44-0.81, P<0.001; OR= 0.80, 95% CI, 0.69-0.94, P= 0.005; respectively). Similarly, we also found positive associations between A allele carriers of Ex5+32 G>A and cancer risk in Chinese and American populations (OR=0.63, 95% CI, 0.44-0.90, P= 0.01; OR= 0.78, 95% CI, 0.62-0.98, P=0.03; respectively). In addition, we identified that A allele and A allele carriers of Ex5+32 G>A may decrease the risk of cancer in the Asian population (OR=0.60, 95% CI, 0.44-0.81, P<0.001; OR= 0.63, 95% CI, 0.44-0.90, P= 0.01; respectively). In conclusion, this meta-analysis demonstrated that A allele and A allele carriers of the Ex5+32 G>A polymorphism in the CASP-9 gene may be protective factors for cancer risk.