Wnt/ß-catenin Pathway Aggravates Renal Fibrosis by Activating PUM2 Transcription to Repress YME1L-mediated Mitochondrial Homeostasis.

Chronic kidney disease (CKD) affects more than 10% of people worldwide and is a leading cause of death. However, the pathogenesis of CKD remains elusive. The oxidative stress and mitochondrial membrane potential were detected using Enzyme-linked immunosorbent assay and JC-1 assay. Co-immunoprecipitation, dual-luciferase assay, chromatin IP, RNA IP and RNA pull-down were used to validate the interactions among genes. Exploiting a H2O2-induced fibrosis model in vitro, PUM2 expression was upregulated in Human kidney 2 cell (HK-2) cells, along with reduced cell viability, enhanced oxidative stress, impaired mitochondrial potential, and upregulated expressions of fibrosis-associated proteins. While PUM2 knockdown reversed the H2O2-induced injury in HK-2 cells. Mechanically, Wnt/ß-catenin pathway activated PUM2 transcription via TCF4. It was further identified that Wnt/ß-catenin pathway inhibited YME1L expression through PUM2-mediated destabilizing of its mRNA. PUM2 aggravated H2O2-induced oxidative stress, mitochondrial dysfunction, and renal fibrosis in HK-2 cell via suppressing YME1L expression. Our study revealed that Wnt/ß-catenin aggravated renal fibrosis by activating PUM2 transcription to repress YME1L-mediated mitochondrial homeostasis, providing novel insights and potential therapeutic targets for the treatment of kidney fibrosis.

Decoding human in vitro terminal erythropoiesis originating from umbilical cord blood mononuclear cells and pluripotent stem cells.

Ex vivo red blood cell (RBC) production generates unsatisfactory erythroid cells. A deep exploration into terminally differentiated cells is required to understand the impairments for RBC generation and the underlying mechanisms. Here, we mapped an atlas of terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMN) and pluripotent stem cells (PSC) and observed their dynamic regulation of erythropoiesis at single-cell resolution. Interestingly, we detected a few progenitor cells and non-erythroid cells from both origins. In PSC-derived erythropoiesis (PSCE), the expression of haemoglobin switch regulators (BCL11A and ZBTB7A) were significantly absent, which could be the restraint for its adult globin expression. We also found that PSCE were less active in stress erythropoiesis than in UCBMN-derived erythropoiesis (UCBE), and explored an agonist of stress erythropoiesis gene, TRIB3, could enhance the expression of adult globin in PSCE. Compared with UCBE, there was a lower expression of epigenetic-related proteins (e.g., CASPASE 3 and UBE2O) and transcription factors (e.g., FOXO3 and TAL1) in PSCE, which might restrict PSCE's enucleation. Moreover, we characterized a subpopulation with high proliferation capacity marked by CD99high in colony-forming unit-erythroid cells. Inhibition of CD99 reduced the proliferation of PSC-derived cells and facilitated erythroid maturation. Furthermore, CD99-CD99 mediated the interaction between macrophages and erythroid cells, illustrating a mechanism by which macrophages participate in erythropoiesis. This study provided a reference for improving ex vivo RBC generation.

Disruption of mitochondrial energy metabolism is a putative pathogenesis of Diamond-Blackfan anemia.

Energy metabolism in the context of erythropoiesis and related diseases remains largely unexplored. Here, we developed a primary cell model by differentiating hematopoietic stem progenitor cells toward the erythroid lineage and suppressing the mitochondrial oxidative phosphorylation (OXPHOS) pathway. OXPHOS suppression led to differentiation failure of erythroid progenitors and defects in ribosome biogenesis. Ran GTPase-activating protein 1 (RanGAP1) was identified as a target of mitochondrial OXPHOS for ribosomal defects during erythropoiesis. Overexpression of RanGAP1 largely alleviated erythroid defects resulting from OXPHOS suppression. Coenzyme Q10, an activator of OXPHOS, largely rescued erythroid defects and increased RanGAP1 expression. Patients with Diamond-Blackfan anemia (DBA) exhibited OXPHOS suppression and a concomitant suppression of ribosome biogenesis. RNA-seq analysis implied that the substantial mutation (approximately 10%) in OXPHOS genes accounts for OXPHOS suppression in these patients. Conclusively, OXPHOS disruption and the associated disruptive mitochondrial energy metabolism are linked to the pathogenesis of DBA.

Optimized rituximab regimen versus recommended regimen for idiopathic membranous nephropathy: A single-center retrospective cohort study.

BACKGROUND: Rituximab (RTX) has become the first-line treatment for idiopathic membranous nephropathy (IMN). Compared with conventional therapy, rituximab therapy has a more favorable safety profile. However, the recommended RTX dose as a flux may have its limitations. The aim of this study was to investigate the clinical efficacy and safety of three regimens, including a cyclic corticosteroid-cyclophosphamide regimen and two different doses of RTX regimens, for the treatment of IMN. METHODS: We recruited 58 patients with IMN confirmed by renal biopsy. 20 patients were treated with a cycle regimen, 22 patients were received RTX with 500 mg per week, totaling a dose of 2000 mg (optimized RTX group), and 16 patients received RTX with 1000 mg at day 1 and day 15 (recommended RTX group). Treatment responses, including complete remission (CR) and partial remission (PR), and outcome adverse events such as steroid diabetes, infections and a drop in white blood cell count, were compared among the three groups after 9 months of follow-up. RESULTS: At 9-month follow-up, the composite remission rates (CR + PR) were 90 %, 72.7 %, and 75 % for the cycle regimen group, optimized RTX group, and recommended RTX group, respectively, with CR of 35 %, 22.7 %, and 25 %, respectively. There was no statistical difference between the three groups on CR and composite remission. Kaplan-Meier survival analyses showed no significant differences in cumulative CR rates and cumulative composite remission rates among the three groups (P = 0.632, P = 0.258). The cycle regimen group had a higher risk of steroid diabetes (35 %). Compared with the recommended RTX regimen, the optimized regimen reduced the incidence of adverse events of infection (9.1 % vs. 37.5 %, P = 0.049), especially in patients older than 60 years of age (P = 0.026). A lower anti-PLA2R at baseline may be associated with a higher risk of infection (P = 0.043). CONCLUSIONS: The efficiency of low-dose and long-course of RTX regiment is not inferior to the recommended treatment regimen, and this regimen can effectively reduce the incidence of infection in patients with IMN. Moreover, we recommend a low-dose, long course of RTX treatment for the elderly.

Bioinformatics reveals the pathophysiological relationship between diabetic nephropathy and periodontitis in the context of aging.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus. Periodontitis (PD) is a microbially-induced chronic inflammatory disease that is thought to have a bidirectional relationship with diabetes mellitus. DN and PD are recognized as models associated with accelerated aging. This study is divided into two parts, the first of which explores the bidirectional causal relationship through Mendelian randomization (MR). The second part aims to investigate the relationship between PD and DN in terms of potential crosstalk genes, aging-related genes, biological pathways, and processes using bioinformatic methods. MR analysis showed no evidence to support a causal relationship between DN and PD (P = 0.34) or PD and DN (P = 0.77). Using the GEO database, we screened 83 crosstalk genes overlapping in two diseases. Twelve paired genes identified by Pearson correlation and the four hub genes in the key cluster were jointly evaluated as key crosstalk-aging genes. Using support vector machine recursive feature elimination (SVM-RFE) and maximal clique centrality (MCC) algorithms, feature selection established five genes as the key crosstalk-aging genes. Based on five key genes, an ANN diagnostic model with reliable diagnosis of two diseases was developed. Gene enrichment analysis indicates that AGE-RAGE pathway signaling, the complement system, and multiple immune inflammatory pathways may be involved in common features of both diseases. Immune infiltration analysis reveals that most immune cells are differentially expressed in PD and DN, with dendritic cells and T cells assuming vital roles in both diseases. Overall, although there is no causal link, CSF1R, CXCL6, VCAM1, JUN and IL1B may be potential crosstalk-aging genes linking PD and DN. The common pathways and markers explored in this study could contribute to a deeper understanding of the common pathogenesis of both diseases in the context of aging and provide a theoretical basis for future research.

Identification of molecular mediators of renal sarcopenia risk: a mendelian randomization analysis.

BACKGROUND: Observational studies have shown an association between reduced renal function and the risk of sarcopenia. However, the causal relationship and the underlying biological mechanisms remain uncertain. Using a Mendelian randomization (MR) framework, we investigated the causal role of 27 hypothetical risk mediators, including metabolites, hormones, inflammation, and stress traits, on the risk of sarcopenia. METHODS: Instrumental variables (IVs) to proxy renal function were identified by selecting single nucleotide polymorphisms (SNPs) reliably associated with creatinine and cystatin C-based glomerular filtration rate (GFR) in CKDGen summary data. IVs for putative risk traits and sarcopenia traits were constructed from relevant genome-wide association studies (GWAS). MR estimated effects were obtained using an inverse-variance weighted effects model, and various sensitivity analyses were performed. The mediating role of hypothetical risk factors in the relationship between GFR and sarcopenia was assessed through multivariate MR. RESULTS: Genetically predicted reduced GFRcrea was associated with higher odds of appendicular lean mass (ALM) (odds ratio (OR): 0.64, 95% confidence interval (CI) 0.37 to 0.68) and grip strength (OR: 0.67; 95% CI 0.58 to 0.78). Likewise, GFRcys highlighted a causal relationship with ALM (OR: 0.52; 95% CI 0.42 to 0.65) and grip strength (OR: 0.66; 95% CI 0.59 to 0.74). Both estimated GFR (eGFR) were negatively associated with IGF-1, IL-16, 25(OH)D, triglycerides (range of effect size per standard deviation: -0.81 to -0.30), and positively correlated with HDL cholesterol (0.62, 0.31). There was a positive correlation between IGF-1, fasting insulin and ALM as well as grip strength (OR range: 1.04-1.67) and a negative correlation between serum CRP and ALM (OR: 0.95) as well as grip strength (OR: 0.98). Additionally, genetically predicted IL-1ß (OR: 0.95) and total cholesterol (OR: 0.96) were negatively associated with ALM. We found evidence that IGF-1 mediates the relationship between eGFR and risk for muscle mass and strength. CONCLUSIONS: This MR study provides insight into the potential causal mechanisms between renal function and the risk of sarcopenia and proposes IGF-1 as a potential target for the prevention of renal sarcopenia.

Identification and characterization of two immune-related subtypes in human chronic kidney disease.

BACKGROUND: Immune response plays a vital role in the initiation and development of chronic kidney disease (CKD). Detailed mechanisms and specific immune-related biomarkers of CKD need further clarification. We aimed to identify and characterize immune-related infiltrates that are implicated in the CKD development using a bioinformatics method. METHODS: The expression profiles of GSE66494 dataset were acquired from the Gene Expression Omnibus (GEO) database. Patients with CKD were divided into low- vs. high-immune subtypes based on their immune score. Based on such analysis, we identified differentially expressed genes (DEGs) of low- and high-immune subtypes. The weight gene co-expression network analysis (WGCNA) was used to identify immune-associated modules between two subtypes. The gene set enriched (GSEA) and variation (GSVA) analyses were correlated with their functional types using the molecular complex detection (MCODE) method. Finally, the immune infiltration landscape between subtypes was revealed using the xCell algorithm. RESULTS: The total number of 131 differentially expressed immune-related genes (DEIRGs) were identified between low- vs. high-immune subtypes. Out of them GSEA/GSVA results identified and enriched immune- and inflammation-related pathways. In particular, GSVA results indicated that immune-related pathways were activated in high-immune subgroups. The core DEIRG genes that were identified to be involved in CKD development included: the protein tyrosine phosphatase receptor type C (PTPRC; also known as CD45) regulating cell growth and differentiation, an early activation marker (CD69), co-receptor for T cell receptor (CD8A), and T cell co-stimulatory signal (CD28). These core DEIRD genes were further verified by the GSE96804 dataset. We also found a higher proportion of immune cells infiltrating the high-immune subgroup. Furthermore, the four core genes were positively correlated with most immune cell types. CONCLUSION: Among 131 DEIRG genes, four genes (PTPRC, CD69, CD8A, and CD28) were identified as potential biomarkers associated with the immune cell infiltration in CKD patients, which may provide a novel insight for immunotherapy for CKD.

Three-Dimensional Hydrogen-Bonded Porous Metal-Organic Framework for Natural Gas Separation with High Selectivity.

A 3D hydrogen-bonded metal-organic framework, [Cu(apc)2]n (TJU-Dan-5, Hapc = 2-aminopyrimidine-5-carboxylic acid), was synthesized via a solvothermal reaction. The activated TJU-Dan-5 with permanent porosity exhibits a moderate uptake of 1.52 wt% of hydrogen gas at 77 K. The appropriate BET surface areas and decoration of the internal polar pore surfaces with groups that form extensive hydrogen bonds offer a more favorable environment for selective C2H6 adsorption, with a predicted selectivity for C2H6/CH4 of around 101 in C2H6/CH4 (5:95, v/v) mixtures at 273 K under 100 kPa. The molecular model calculation demonstrates a C-H···π interaction and a van der Waals host-guest interaction of C2H6 with the pore walls. This work provides a strategy for the construction of 3D hydrogen-bonded MOFs, which may have great potential in the purification of natural gas.

Annexin A1 may contribute to the morphological changes in podocytes by mediating endocytic vesicle fusion and transport via promotion of SNARE assembly in idiopathic membranous nephropathy.

BACKGROUND: Annexin A1 is a membrane-associated calcium-binding protein that participates in the progression of many diseases by facilitating vesicle aggregation. It has been documented that reducing vesicle formation alleviates podocyte injury and albuminuria in idiopathic membranous nephropathy (IMN). However, the role of Annexin A1 (ANXA1) in IMN is unknown. METHODS: Electron microscopy was used to observe the numbers of vesicles in podocytes. The expression of ANXA1 in IMN was investigated by bioinformatics analysis. We validated the hub genes with the Nephroseq V5 online tool and microarray data from the GEO. Immunohistochemical staining and qPCR were performed to measure gene and protein expression. RESULTS: The numbers of vesicles in IMN podocytes were significantly increased. Bioinformatics analysis showed that ANXA1, one of the differentially expressed genes, was upregulated in glomeruli from IMN patients. In the validation database and dataset, we confirmed that ANXA1 expression was upregulated in the glomeruli of IMN patients. We revealed that the increased expression of ANXA1 was negatively correlated with the glomerular filtration rate (GFR) and proteinuria. Moreover, ANXA1 was enriched in the biological process of vesicle fusion, in which the expression of SNAREs and the SNARE complex was increased. Finally, the expression of ANXA1 and genes related to SNAREs and the SNARE complex was upregulated in glomeruli from IMN patients according to immunohistochemical staining and qPCR. CONCLUSION: We conclude that ANXA1 may mediate endocytic vesicle fusion and transport by promoting SNARE assembly, contributing to the morphological changes in podocytes and massive proteinuria in IMN.

CROST: a comprehensive repository of spatial transcriptomics.

The development of spatial transcriptome sequencing technology has revolutionized our comprehension of complex tissues and propelled life and health sciences into an era of spatial omics. However, the current availability of databases for accessing and analyzing spatial transcriptomic data is limited. In response, we have established CROST (https://ngdc.cncb.ac.cn/crost), a comprehensive repository of spatial transcriptomics. CROST encompasses high-quality samples and houses 182 spatial transcriptomic datasets from diverse species, organs, and diseases, comprising 1033 sub-datasets and 48 043 tumor-related spatially variable genes (SVGs). Additionally, it encompasses a standardized spatial transcriptome data processing pipeline, integrates single-cell RNA sequencing deconvolution spatial transcriptomics data, and evaluates correlation, colocalization, intercellular communication, and biological function annotation analyses. Moreover, CROST integrates the transcriptome, epigenome, and genome to explore tumor-associated SVGs and provides a comprehensive understanding of their roles in cancer progression and prognosis. Furthermore, CROST provides two online tools, single-sample gene set enrichment analysis and SpatialAP, for users to annotate and analyze the uploaded spatial transcriptomics data. The user-friendly interface of CROST facilitates browsing, searching, analyzing, visualizing, and downloading desired information. Collectively, CROST offers fresh and comprehensive insights into tissue structure and a foundation for understanding multiple biological mechanisms in diseases, particularly in tumor tissues.

Mendelian randomization reveals systemic lupus erythematosus and rheumatoid arthritis and risk of adverse pregnancy outcomes.

BACKGROUND: The effect of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) on adverse pregnancy outcomes is a controversial topic. This study aimed to use Mendelian randomization (MR) analysis to assess the causal relationship between SLE, RA and adverse pregnancy outcomes. METHODS: Genetic variants for SLE and RA, as well as adverse pregnancy outcomes, were derived from pooled statistics from large public genome-wide association studies. Several methods, such as inverse variance weighting (IVW), MR-Egger, weighted median and MR-Pleiotropic Residuals Sum and Outliers, were employed to estimate two-sample causality. RESULTS: Genetic prediction of SLE was associated with higher odds of preterm labour [odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.01-1.05; p = 0.008]. RA was associated with higher odds of preterm labour (OR 1.03, 95 % CI 1.01-1.06; p = 0.009), pre-eclampsia or eclampsia (OR 1.04, 95 % CI 1.01-1.07; p = 0.005), and poor fetal growth (OR 1.08, 95 % CI 1.04-1.12; p = 2.91 × 10-5). The results of bidirectional MR analysis did not indicate that SLE was associated with spontaneous abortion, pre-eclampsia or eclampsia, preterm rupture of membranes, or poor fetal growth (p-value for IVW 0.13-0.97). CONCLUSIONS: This study found a genetic association between SLE and the risk of preterm labour, and highlights the importance of perinatal care and monitoring for patients with SLE. Furthermore, RA was found to be associated with a wide range of adverse outcomes, including preterm labour, pre-eclampsia or eclampsia, and poor fetal growth; as such, there is a need for more intensive therapeutic interventions and prenatal monitoring.

Inverted U-shaped relationship between coffee consumption and serum uric acid in American chronic kidney disease population.

Objective: The objective of this study was to examine the contentious relationship between coffee consumption and serum uric acid (SUA) levels, specifically within American population with chronic kidney disease (CKD). Methods: A total of 23,381 participants from the 2001-2018 National Health and Nutrition Examination Survey (NHANES) were selected for inclusion in this investigation. Linear regression models and generalized additive models with smooth curve fitting were employed to analyze the association between log coffee consumption and serum uric acid levels. Furthermore, the robustness of the findings was assessed across diverse populations. Results: The results of the linear regression analysis indicate a positive and marginally statistically significant (p = 0.0307) association between log coffee consumption and SUA, even after controlling for other variables. Furthermore, the generalized additive model revealed a nonlinear relationship characterized by an inverted U-shape between log coffee consumption and SUA. The inflection point, identified as 11.43 g/day, marks the point at which this relationship changes direction. Moreover, this inverted U-shaped relationship was consistently observed across various subgroups, including gender, age (<60 and ≥ 60 years), hypertensive and non-hypertensive individuals, those with and without cardiovascular disease, non-diabetic individuals, and those who consumed coffee with or without caffeine or sugar. Conclusion: An inverse U-shaped correlation has been observed between log coffee consumption and SUA levels. This finding implies that once coffee consumption surpasses a specific threshold, it promotes a decline in SUA levels.

Clinical efficacy and safety of beraprost sodium in the treatment of nephrotic syndrome: A meta-analysis.

BACKGROUND: Beraprost sodium has been shown to have positive effects in the kidney; however, its efficacy and safety in the treatment of nephrotic syndrome (NS) are currently unknown. Therefore, the aim of this meta-analysis was to evaluate the clinical efficacy and safety of beraprost sodium in the treatment of NS. METHODS: We systematically searched EMBASE, PubMed, MEDLINE, China National Knowledge Internet (CNKI), Chinese Biomedical Database (CBM), and Wanfang database for articles from their inception to August 2022. RESULTS: A total of 12 randomized controlled trials (RCTs) involving 1200 subjects were collected for careful evaluation. The meta-analysis indicated that compared with the controls, combination therapy with berprost sodium could remarkably improve the total effective rate (odds ratio 4.21, 95% confidence interval [CI]: 2.87 to 7.25) and reduce 24 hours proteinuria (mean difference [MD] -1.03, 95% CI: -1.26 to -0.8), serum creatinine (MD -18.39; 95% CI: -27.81 to -8.98), blood urea nitrogen (MD -1.43,95% CI: -1.94 to -0.92), serum total cholesterol (MD -1.24; 95% CI: -1.36 to -1.11), and triglyceride (MD -0.69; 95% CI: -1.03 to -0.35), and increase serum albumin (MD 4.96, 95% CI: 2.98 to 6.93). But the adverse effects of dizziness and headache were higher (RD = 0.05. 95% CI: 0.02 to 0.08). CONCLUSION: For NS patients, combination therapy with beraprost sodium can achieve higher clinical efficacy and significant improvement in renal function than conventional therapy.

Copper-catalyzed nitration of electron-deficient BN-naphthalene.

Under Cu-catalysis, a regioselective nitration of 1,8-dihalogenated BN-naphthalene (ABN) compounds (4a-4c) has been established with the use of tert-butyl nitrite as the nitrating reagent. The syntheses of dihalo-ABN nitro products (6a-6c; halo = Cl, Br and I) were case-studied in conjunction with the first synthesis and characterization of diiodo-ABN compound 4c. The molecular structures of these compounds have been spectroscopically characterized and further confirmed by X-ray single crystal diffraction experiments. This method allows direct regioselective nitration of electron-deficient ABN systems, providing a step-economical entry to novel nitro-ABN structural motifs with potential applications in agrochemicals, materials sciences, and the medicinal and pharmaceutical industries.

Roles of interferon regulatory factor 4 in the AKI-CKD transition, glomerular diseases and kidney allograft rejection.

Interferon regulatory factor 4 (IRF4) is expressed in immune cells and is a member of the interferon regulatory factor family. Recently, it has been found that IRF4 plays important roles in the acute kidney injury (AKI)-chronic kidney disease (CKD) transition, glomerular diseases and kidney allograft rejection. In particular, the relationship between IRF4 and the AKI-CKD transition has attracted widespread attention. Furthermore, it was also found that the deficiency of IRF4 hindered the transition from AKI to CKD through the suppression of macrophage-to-fibroblast conversion, inhibition of M1-M2 macrophage polarization, and reduction in neutrophil inward flow. Additionally, an examination of the crucial role of IRF4 in glomerular disease was conducted. It was reported that inhibiting IRF4 could alleviate the progression of glomerular disease, and potential physiopathology mechanisms associated with IRF4 were postulated. Lastly, IRF4 was found to have detrimental effects on the development of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR).

Association of nocturia of self-report with estimated glomerular filtration rate: a cross-sectional study from the NHANES 2005-2018.

Nocturia is a manifestation of systemic diseases, in which chronic kidney disease (CKD) is an independent predictor of nocturia due to its osmotic diuretic mechanism. However, to our knowledge, previous studies have not examined the association between nocturia and estimated glomerular filtration rate (eGFR). The purpose of this study was to assess the association between nocturia exposure and eGFR in the general US population. This study presents a cross-sectional analysis of the general US population enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. To account for potential confounding factors, linear regression analysis was conducted to investigate the association between nocturia and eGFR. Stratified analyses and interaction tests were employed to examine the variables of interest. Additionally, sensitivity analyses were conducted across diverse populations. A total of 12,265 individuals were included in the study. After controlling for confounding factors, the results of the linear regression analysis indicated that a single increase in nocturnal voiding frequency was associated with a decrease in eGFR by 2.0 mL/min/1.73 m2. In comparison to individuals with a nocturnal urinary frequency of 0, those who voided 1, 2, 3, 4, and ≥ 5 times at night experienced a decrease in eGFR by 3.1, 5.4, 6.4, 8.6 and 4.0 mL/min/1.73 m2, respectively. Nocturia was found to be associated with a decreased eGFR of 4 mL/min/1.73 m2 when compared to individuals without nocturia. The sensitivity analysis yielded consistent findings regarding the association between nocturia and eGFR in both CKD and non-CKD populations, as well as in hypertensive and non-hypertensive populations. Nevertheless, inconsistent conclusions were observed across various prognostic risk populations within the CKD context. The presence of nocturia and heightened frequency of nocturnal urination have been found to be associated with a decline in eGFR.

Overview of multi-omics research in gout.

Gout is a self-limiting inflammation disease triggered by deposition of monosodium urate with a variety of comorbidities. With the improvement of living standards, the global incidence of gout is increasing year by year, which seriously affects people's health. As an effective tool to study diseases, omics technology has been widely used to discover potential biomarkers and risk factors of gout. The identified variation sites or different-expressed products provide different dimensions of insights for the study of the pathogenesis and disease progression of gout. In this review, the application and research results of multi-omics technology in gout were analyzed and summarized through PubMed literature retrieval. Meanwhile, the recent research progress of multi-omics technology in the field of gout was reviewed to understand the specific changes of gout patients at different molecular levels, and to provide ideas and directions for further research on gout in the future.

LncRNA SNHG1 knockdown inhibits hyperglycemia induced ferroptosis via miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy.

BACKGROUND: Hyperglycemia accelerates the development of diabetic nephropathy (DN) by inducing renal tubular injury. Nevertheless, the mechanism has not been elaborated fully. Here, the pathogenesis of DN was investigated to seek novel treatment strategies. METHODS: A model of diabetic nephropathy was established in vivo, the levels of blood glucose, urine albumin creatinine ratio (ACR), creatinine, blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione (GSH), and iron were measured. The expression levels were detected by qRT-PCR and Western blotting. H&E, Masson, and PAS staining were used to assess kidney tissue injury. The mitochondria morphology was observed by transmission electron microscopy (TEM). The molecular interaction was analyzed using a dual luciferase reporter assay. RESULTS: SNHG1 and ACSL4 were increased in kidney tissues of DN mice, but miR-16-5p was decreased. Ferrostatin-1 treatment or SNHG1 knockdown inhibited ferroptosis in high glucose (HG)-treated HK-2 cells and in db/db mice. Subsequently, miR-16-5p was confirmed to be a target for SNHG1, and directly targeted to ACSL4. Overexpression of ACSL4 greatly reversed the protective roles of SNHG1 knockdown in HG-induced ferroptosis of HK-2 cells. CONCLUSIONS: SNHG1 knockdown inhibited ferroptosis via the miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy, which provided some new insights for the novel treatment of diabetic nephropathy.

DKK3 promotes oxidative stress injury and fibrosis in HK-2 cells by activating NOX4 via ß-catenin/TCF4 signaling.

Oxidative stress and fibrosis may accelerate the progression of chronic kidney disease (CKD). DKK3 is related to regulating renal fibrosis and CKD. However, the molecular mechanism of DKK3 in regulating oxidative stress and fibrosis during CKD development has not been clarified, which deserves to be investigated. Human proximal tubule epithelial cells (HK-2 cells) were treated with H2O2 to establish a cell model of renal fibrosis. The mRNA and protein expressions were analyzed using qRT-PCR and western blot, respectively. Cell viability and apoptosis were evaluated using MTT assay and flow cytometry, respectively. ROS production was estimated using DCFH-DA. The interactions among TCF4, ß-catenin and NOX4 were validated using luciferase activity assay, ChIP and Co-IP. Herein, our results revealed that DKK3 was highly expressed in HK-2 cells treated with H2O2. DKK3 depletion increased H2O2-treated HK-2 cell viability and reduced cell apoptosis, oxidative stress, and fibrosis. Mechanically, DKK3 promoted formation of the ß-catenin/TCF4 complex, and activated NOX4 transcription. Upregulation of NOX4 or TCF4 weakened the inhibitory effect of DKK3 knockdown on oxidative stress and fibrosis in H2O2-stimulated HK-2 cells. All our results suggested that DKK3 accelerated oxidative stress and fibrosis through promoting ß-catenin/TCF4 complex-mediated activation of NOX4 transcription, which could lead to novel molecules and therapeutic targets for CKD.