Metformin modulates mitochondrial autophagy in renal tubular epithelial injury induced by high glucose via the Keap1/Nrf2 pathway.

The current study aimed to explore the role and underpinning molecular mechanisms of metformin in renal cellular injury induced by high glucose levels. Male C57BL/KsJ (db/db) and (db/m +) mice were utilized in this study. The experimental group was administered 1 mg/mL of metformin through drinking water. Renal tissues were harvested for hematoxylin and eosin (HE) staining, superoxide dismutase (SOD) activity detection, biochemical indices analysis, Western blotting, and qRT-PCR. HK-2 cells were utilized for Nrf2 siRNA transfection and to establish a high level of glucose-induced cell models. Metformin was administered at a concentration of 1 mmol/L in the experimental group. Cellular viability was assessed using CCK-8, whereas acridine orange (AO) staining and LC3-mitotracker co-localization staining were employed to evaluate autophagy. The expression of Nrf2, P21, LC3, PTEN-induced putative kinase 1 (PINK1), translocase of outer mitochondrial membrane 20 (TOMM20), and Kelch-like ECH-associated protein 1 (Keap1) were determined through Western blotting and qRT-PCR. Metformin mitigated renal tissue inflammatory damage in diabetic mice, as indicated by upregulated expression of Nrf2, PINK1, LC3, and TOMM20, and downregulated expression of Keap1 and P21. High level of glucose treatment in HK-2 cells resulted in decreased autophagy, and reduced expression of Nrf2, PINK1, LC3, and TOMM20 alongside elevated the expression of Keap1 and P21. Notably, metformin treatment partially counteracted these effects. Nrf2 knockdown intensified these phenomena in the high level of glucose-induced model. Protein-protein interaction network analysis indicated that Nrf2 could regulate the majority autophagy-related proteins via Keap1. Metformin modulates mitochondrial autophagy in high glucose-induced renal tubular epithelial senescence via the Keap1/Nrf2 pathway.

Comparative mathematical modeling of causal association between metal exposure and development of chronic kidney disease.

Background: Previous studies have identified several genetic and environmental risk factors for chronic kidney disease (CKD). However, little is known about the relationship between serum metals and CKD risk. Methods: We investigated associations between serum metals levels and CKD risk among 100 medical examiners and 443 CKD patients in the medical center of the First Hospital Affiliated to China Medical University. Serum metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). We analyzed factors influencing CKD, including abnormalities in Creatine and Cystatin C, using univariate and multiple analysis such as Lasso and Logistic regression. Metal levels among CKD patients at different stages were also explored. The study utilized machine learning and Bayesian Kernel Machine Regression (BKMR) to assess associations and predict CKD risk based on serum metals. A chained mediation model was applied to investigate how interventions with different heavy metals influence renal function indicators (creatinine and cystatin C) and their impact on diagnosing and treating renal impairment. Results: Serum potassium (K), sodium (Na), and calcium (Ca) showed positive trends with CKD, while selenium (Se) and molybdenum (Mo) showed negative trends. Metal mixtures had a significant negative effect on CKD when concentrations were all from 30th to 45th percentiles compared to the median, but the opposite was observed for the 55th to 60th percentiles. For example, a change in serum K concentration from the 25th to the 75th percentile was associated with a significant increase in CKD risk of 5.15(1.77,8.53), 13.62(8.91,18.33) and 31.81(14.03,49.58) when other metals were fixed at the 25th, 50th and 75th percentiles, respectively. Conclusions: Cumulative metal exposures, especially double-exposure to serum K and Se may impact CKD risk. Machine learning methods validated the external relevance of the metal factors. Our study highlights the importance of employing diverse methodologies to evaluate health effects of metal mixtures.

Characterization and evolutionary analysis of phosphate starvation response genes in wheat and other major gramineous plants.

Developing cultivars with improved Pi use efficiency is essential for the sustainability of agriculture as well as the environment. Phosphate starvation response (PHR) regulators have not yet been systematically studied in wheat. This study provides the detailed characteristics of PHRs in hexaploid wheat as well as other major gramineous plants at the genome-wide level. The identified PHR proteins were divided into six subfamilies through phylogeny analysis, and a total of 63 paralogous TaPHR pairs were designated as arising from duplication events, with strong purifying selection. The promoters of TaPHRs were identified as stations for many transcription factors. Protein-protein interaction network and gene ontology enrichment analysis indicated a core biological process of cellular response to phosphate starvation. The three-dimensional structures of core PHR proteins showed a high phylogenetic relationship, but amino acid deletions in core protein domains may cause functional differentiation between rice and wheat. TaPHR3 could interact with TaSPX1 and TaSPX5 proteins, which is regarded as a novel interaction mode. Under different Pi gradient treatments, TaPHRs showed low inducible expression patterns among all subfamilies. Our study is the first to comprehensively clarify the basic properties of TaPHR proteins and might accumulate basic data for improving grain yield and environmental homeostasis.

Multifactorial analysis of renal anemia-associated substandard hemoglobin levels and prevalence of anemia in patients on maintenance hemodialysis in Liaoning Province: a cross-sectional study.

BACKGROUND: In hemodialysis (HD) patients, anemia is greatly improved due to regular weekly use of iron and erythropoietin (EPO), but a large number of patients still show persistent anemia. We do a survey to elucidate the influencing factors that contribute to the failure of hemoglobin (Hb) to meet the standard and provide epidemiological data reference for promoting the recognition of renal anemia and improving the treatment effect of renal anemia. METHODS: The clinical data of End-Stage Renal Disease (ESRD) HD patients in 22 tertiary hospital HD centers in Liaoning Province from September 2021 to June 2022 were collected by convenient sampling. According to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) anemia diagnostic criteria. The standard of Hb compliance: Hb ≥110 g/L is considered as Hb compliant, and Hb <110 g/L as Hb non-compliant. The factors influencing Hb up-to-standard in ESRD HD patients and their correlations were analyzed by comparison between the two groups. RESULTS: The results of this study showed that among the 1,652 ESRD patients investigated in Liaoning Province, the prevalence rate of anemia was 89.29% (1,475/1,652), and the Hb compliance rate was 46.25% (764/1,652). The Hb compliance rate in maintenance hemodialysis (MHD) patients with different primary diseases was statistically significant (P<0.05). Compared with the Hb non-standard group, the gender, dialysis access, HD frequency, concurrent infection, primary disease of ESRD patients, red blood cell (RBC) count, hematocrit (HCT), mean RBC Hb concentration, mean RBC Hb content, platelet (PLT), albumin (ALB), total protein (TP), serum creatinine (Cr), serum calcium (Ca), serum potassium (K), ferritin (Fer), serum iron (SI), and transferrin (TRE) saturation were significantly different between both groups (P<0.05). Adrenaline was an independent risk factor affecting Hb failure in ESRD patients (OR =1.001, 95% CI: 1.000-1.002); dialysis frequency (OR =0.726, 95% CI: 0.601-0.878), ALB (OR =0.959, 95% CI: 0.929-0.990), TP (OR =0.982, 95% CI: 0.968-0.996), serum Cr (OR =0.959, 95% CI: 0.929-0.999), and SI (OR =0.961, 95% CI: 0.940-0.982) were protective factors affecting Hb failure in ESRD patients (P<0.05). Pearson correlation analysis showed that ALB, TP, serum Cr, serum Ca, serum K, SI, and TRE saturation were positively correlated with Hb (P<0.05). CONCLUSIONS: The anemia rate of ESRD patients treated with MHD in Liaoning Province is high. Based on the results, increasing the frequency of dialysis can improve anemia. Parathyroid hormone levels need to be controlled.

OGT-Mediated KEAP1 Glycosylation Accelerates NRF2 Degradation Leading to High Phosphate-Induced Vascular Calcification in Chronic Kidney Disease.

Unraveling the complex regulatory pathways that mediate the effects of phosphate on vascular smooth muscle cells (VSMCs) may provide novel targets and therapies to limit the destructive effects of vascular calcification (VC) in patients with chronic kidney disease (CKD). Our previous studies have highlighted several signaling networks associated with VSMC autophagy, but the underlying mechanisms remain poorly understood. Thereafter, the current study was performed to characterize the functional relevance of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) in high phosphate-induced VC in CKD settings. We generated VC models in 5/6 nephrectomized rats in vivo and VSMC calcification models in vitro. Artificial modulation of OGT (knockdown and overexpression) was performed to explore the role of OGT in VSMC autophagy and VC in thoracic aorta, and in vivo experiments were used to substantiate in vitro findings. Mechanistically, co-immunoprecipitation (Co-IP) assay was performed to examine interaction between OGT and kelch like ECH associated protein 1 (KEAP1), and in vivo ubiquitination assay was performed to examine ubiquitination extent of nuclear factor erythroid 2-related factor 2 (NRF2). OGT was highly expressed in high phosphate-induced 5/6 nephrectomized rats and VSMCs. OGT silencing was shown to suppress high phosphate-induced calcification of VSMCs. OGT enhances KEAP1 glycosylation and thereby results in degradation and ubiquitination of NRF2, concurrently inhibiting VSMC autophagy to promote VSMC calcification in 5/6 nephrectomized rats. OGT inhibits VSMC autophagy through the KEAP1/NRF2 axis and thus accelerates high phosphate-induced VC in CKD.

Case Report: A Patient With COVID-19 Who Benefited From Hemoadsorption.

In December 2019, the 2019 novel coronavirus disease (COVID-19), which has been identified to be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China and spread across the world. Higher plasma levels of cytokines, including interleukin (IL)-6, IL-2, IL-7, IL-10, and tumor necrosis factor-α, were found in patients with COVID-19, which implies the occurrence of a cytokine storm and its association with disease severity. Extracorporeal blood purification has been proven to effectively remove the released inflammatory cytokines. In this study, we report on a patient with COVID-19 who benefited from hemoadsorption.