Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3β phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3β/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.

This study investigated the hypoglycemic and renal protective effects of scutellarin (SCU) in db/db mice and elucidated the underlying mechanisms. The oral administration of metformin hydrochloride (Met) at 120 mg/kg and SCU at 25, 50, and 100 mg/kg over an eight-week period had hypoglycemic effects, demonstrated by decreases in body weight, blood glucose, food and water intake, and glycated hemoglobin activity and by augmented insulin levels and pyruvate kinase activity in the serum of db/db mice. SCU alleviated dyslipidemia by decreasing the levels of triglycerides and total cholesterol and enhancing the levels of high-density lipoprotein cholesterol in the serum of db/db mice. SCU reversed the overexpression of mRNA of renal damage markers (receptor for advanced glycation end products, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1), macrophage marker CD11b, and T cell marker CD3 in kidney of db/db mice. Pathological examination confirmed that SCU improved the organ structures of hyperglycemia-damaged livers, kidneys, and pancreas islets. Antibody array assay and enzyme-linked immunosorbent assay were combined to screen and analyze the regulatory effects of SCU on inflammatory factors and oxidative enzymes. SCU exerted anti-inflammatory effects by inhibiting the levels of proinflammatory cytokines (glycogen synthase kinase, intercellular adhesion molecule 2, and interleukin 1βand 2) and promoting anti-inflammatory cytokines (interleukin 4). SCU decreased the reactive oxygen species and malondialdehyde concentrations and increased the activity levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) in serum and kidneys. Furthermore, SCU upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which in turn improved heme oxygenase 1 (HO-1), superoxide dismutase 1 and 2, and catalase expression levels in kidneys. The study showed that SCU has at least partial hypoglycemic and renal protective effects in db/db mice, and the mechanism is the modulation of the Nrf2/HO-1 signaling pathway.

Introduction: Verticillium wilt is the most devastating soil-borne disease affecting Cotinus coggygria in the progress of urban landscape construction in China.Methods: To assess the variability of the rhizosphere-associated soil microbiome in response to Verticillium wilt occurrence, we investigated the microbial diversity, taxonomic composition, biomarker species, and co-occurrence network of the rhizosphere-associated soil in Verticillium wilt-affected C. coggygria using Illumina sequencing.Results: The alpha diversity indices of the rhizosphere bacteria in Verticillium wilt-affected plants showed no significant variability compared with those in healthy plants, except for a moderate increase in the Shannon and Invsimpson indices, while the fungal alpha diversity indices were significantly decreased. The abundance of certain dominant or crucial microbial taxa, such as Arthrobacter, Bacillus, Streptomyces, and Trichoderma, displayed significant variations among different soil samples. The bacterial and fungal community structures exhibited distinct variability, as evidenced by the Bray–Curtis dissimilarity matrices. Co-occurrence networks unveiled intricate interactions within the microbial community of Verticillium wilt-affected C. coggygria, with greater edge numbers and higher network density. The phenomenon was more evident in the fungal community, showing increased positive interaction, which may be associated with the aggravation of Verticillium wilt with the aid of Fusarium. The proportions of bacteria involved in membrane transport and second metabolite biosynthesis functions were significantly enriched in the diseased rhizosphere soil samples.Discussion: These findings suggested that healthy C. coggygria harbored an obviously higher abundance of beneficial microbial consortia, such as Bacillus, while Verticillium wilt-affected plants may recruit antagonistic members such as Streptomyces in response to Verticillium dahliae infection. This study provides a theoretical basis for understanding the soil micro-ecological mechanism of Verticillium wilt occurrence, which may be helpful in the prevention and control of the disease in C. coggygria from the microbiome perspective.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and poses significant threats to individuals with diabetes. The concept of gut–kidney axis has gained increasing attention in recent years and the in the occurrence and development of DN, alterations in the gut microbiota also plays a crucial and indispensable role. However, the specific causal relationships between various gut microbial communities and DN, as well as the underlying molecular mechanisms, remains unclear. This study utilized data from genome-wide association studies. After screening for qualified instrumental variables, mendelian randomization causal analyses were performed by inverse variance weighting, MR-Egger, weighted median, weighted mode and MR-RAPS methods. Additionally, sensitivity analyses such as heterogeneity, multiplicity, and the direction of the causal effect were carried out to ensure that the results were robust. After identifying significant gut microbiota, protein-proteomics mediation analysis was conducted on potential 3282 plasma proteins to determine those with mediating effects. Finally, Reactome enrichment analysis was performed to ascertain metabolic or signaling pathways with mediating effects. Mendelian randomization analysis indicated associations between 21 gut microbiota and DN. After adjusting significance levels, Catenibacterium and Parasutterella were found to have causal effects on the onset of DN. Subsequently, we identified 22 plasma proteins with mediating effects, along with 27 metabolic or signaling pathways including activated propionic acid metabolism. Increased in the abundance of Catenibacterium and Parasutterella intestinal bacteria are causative factors for DN. More importantly, the underlying mechanism by which the increased abundance of Catenibacterium and Parasutterella intestinal bacteria lead to DN were revealed, providing a blueprint for the involvement of gut–kidney axis in the pathogenesis of DN and paving the way for future studies.

Background: Patients with diabetic kidney disease (DKD) often have gastrointestinal dysfunction such as inflammatory bowel disease (IBD). This study aims to investigate the genetic mechanism leading to IBD in DKD patients through data mining and bioinformatics analysis.Methods: The disease-related genes of DKD and IBD were searched from the five databases of OMIM, GeneCards, PharmGkb, TTD, and DrugBank, and the intersection part of the two diseases were taken to obtain the risk genes of DKD complicated with IBD. A protein–protein interaction (PPI) network analysis was performed on risk genes, and three topological parameters of degree, betweenness, and closeness of nodes in the network were used to identify key risk genes. Finally, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the risk genes to explore the related mechanism of DKD merging IBD.Results: This study identified 495 risk genes for DKD complicated with IBD. After constructing a protein–protein interaction network and screening for three times, six key risk genes were obtained, including matrix metalloproteinase 2 (MMP2), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), interleukin (IL)-18, IL-13, and C–C motif chemokine ligand 5 (CCL5). Based on GO enrichment analysis, we found that DKD genes complicated with IBD were associated with 3,646 biological processes such as inflammatory response regulation, 121 cellular components such as cytoplasmic vesicles, and 276 molecular functions such as G-protein-coupled receptor binding. Based on KEGG enrichment analysis, we found that the risk genes of DKD combined with IBD were associated with 181 pathways, such as the PI3K-Akt signaling pathway, advanced glycation end product–receptor for AGE (AGE-RAGE) signaling pathway and hypoxia-inducible factor (HIF)-1 signaling pathway.Conclusion: There is a genetic mechanism for the complication of IBD in patients with CKD. Oxidative stress, chronic inflammatory response, and immune dysfunction were possible mechanisms for DKD complicated with IBD.

Background: Immunoglobulin A nephropathy (IgAN), recognized as the leading cause of primary glomerular disease worldwide, continues to present unresolved complexities in its underlying pathogenic mechanisms. Emerging evidence underscores ferroptosis, an iron-mediated regulated cell death pathway driven by the accumulation of lipid peroxides, as a potential contributor to various pathological conditions. Despite growing interest in this field, the exact molecular pathways governing ferroptosis activation in IgAN progression remain incompletely understood and require systematic investigation. The aim of this study was to identify ferroptosis-related feature gene (FFG) for the potential diagnosis of IgAN and to investigate its relationship with renal immune cell infiltration.Methods: Renal tissue microarray datasets (GSE93798, GSE104948, GSE99339) from IgAN patients and normal controls were retrieved from GEO database. The ferroptosis-related genes were obtained from the Ferrb database. Machine learning algorithms (LASSO, SVM-RFE, random forest) were employed to screen FFGs. The findings were validated in an IgAN mouse model using immunohistochemistry and western blotting. Gene set enrichment analysis (GSEA) was conducted to explore the underlying mechanism of FFG in IgAN. Immune cell infiltration characteristics were also analyzed vis CIBERSORT algorithm.Results: A total of 180 ferroptosis-related differentially expressed genes were identified in IgAN. Among them, dual specificity phosphatase 1 (DUSP1) was screened as FFG by three machine learning algorithms. DUSP1 exhibited significant downregulation in renal tissues of both IgAN patients and mice. Enhanced transcriptional abundance demonstrated significant positive associations with ferroptosis-associated biomarkers glutathione peroxidase-4 (GPX4) and cystine/glutamate antiporter (SLC7A11/xCT), while displaying an inverse relationship with acyl-CoA synthetase long-chain isoform 4 (ACSL4) expression. GSEA further identified DUSP1’s functional enrichment in critical signaling networks, particularly mitogen-activated protein kinase (MAPK) cascades, ERBB receptor tyrosine kinase pathways, and Janus kinase-signal transducer (JAK–STAT) transduction mechanisms. Immunoinfiltration analysis demonstrated increased infiltration of T follicular helper cells, activated NK cells, and M1 macrophages in the renal tissues of IgAN patients, with DUSP1 expression showing negative correlations with these proinflammatory cell types.Conclusion: Our research successfully identified DUSP1 as a ferroptosis-related biomarker in IgAN patients, and explored its potential mechanism in the pathogenesis of IgAN and its potential relationship with immune cell infiltration. These findings are of great significance for the diagnosis and prospective treatment strategies for IgAN patients.