Identification of the shared genes in type 2 diabetes mellitus and osteoarthritis and the role of quercetin.

This study investigated the underlying comorbidity mechanism between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA), while also assessing the therapeutic potential of quercetin for early intervention and treatment of these two diseases. The shared genes were obtained through GEO2R, limma and weighted gene co-expression network analysis (WGCNA), and validated using clinical databases and the area under the curves (ROC). Functional enrichment analysis was conducted to elucidate the underlying mechanisms of comorbidity between T2DM and OA. The infiltration of immune cells was analysed using the CIBERSORT algorithm in conjunction with ESTIMATE algorithm. Subsequently, transcriptional regulation analysis, potential chemical prediction, gene-disease association, relationships between the shared genes and ferroptosis as well as immunity-related genes were investigated along with molecular docking. We identified the 12 shared genes (EPHA3, RASIP1, PENK, LRRC17, CEBPB, EFEMP2, UBAP1, PPP1R15A, SPEN, MAFF, GADD45B and KLF4) across the four datasets. Our predictions suggested that targeting these shared genes could potentially serve as therapeutic interventions for both T2DM and OA. Specifically, they are involved in key signalling pathways such as p53, IL-17, NF-kB and MAPK signalling pathways. Furthermore, the regulation of ferroptosis and immunity appears to be interconnected in both diseases. Notably, in this context quercetin emerges as a promising drug candidate for treating T2DM and OA by specifically targeting the shared genes. We conducted a bioinformatics analysis to identify potential therapeutic targets, mechanisms and drugs for T2DM and OA, thereby offering novel insights into molecular therapy for these two diseases.

The influence of genetic predisposition to oxidative stress on painful diabetic peripheral neuropathy: A mendelian randomization study.

Genetic predisposition to oxidative stress (OS) may influence the risk of Painful Diabetic Peripheral Neuropathy (PDPN). This study employed a Mendelian Randomization (MR) approach to investigate the causal relationship between genetic predisposition to OS and PDPN. Genetic instruments associated with OS biomarkers were selected as exposures. Summary-level data on PDPN was obtained from the largest available genome-wide association study (GWAS). MR analyses were conducted using the inverse-variance weighted (IVW) method, with sensitivity analyses employing the MR-Egger, weighted median, and MR-PRESSO approaches. Genetic predisposition to increased glutathione S-transferase (GST) activity was associated with a reduced risk of PDPN (OR=0.66, 95%CI: 0.49-0.89, P=0.006). Higher ascorbate levels conferred a protective effect against PDPN (OR=0.83, 95%CI: 0.71-0.97, P=0.018). No significant association was observed between genetic predisposition to OS biomarkers and PDPN severity. Genetic predisposition to increased GST activity and higher ascorbate levels protect against the development of PDPN, suggesting a causal relationship.

Causal relationship between 731 immune cells and the risk of diabetic nephropathy: a two­sample bidirectional Mendelian randomization study.

OBJECTIVE: Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis. METHOD: The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran's Q test, MR-Egger intercept's P-value, MR-PRESSO, and Leave-One-Out (LOO) method. RESULT: The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells. CONCLUSION: This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

Sex- and reproductive status-specific relationships between body composition and non-alcoholic fatty liver disease.

BACKGROUND: Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different sex and reproductive status populations. METHODS: This cross-sectional study included 880 patients (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively, and the following parameters were obtained: liver stiffness measurement (LSM), controlled attenuation parameter (CAP), waist circumference (WC), body mass index (BMI), percent body fat (PBF), visceral fat area (VFA), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat mass (FM), fat free mass (FFM), and FFM to FM ratio (FFM/FM). Multiple ordinal logistic regression (MOLR) was used to analyze the independent correlation between body composition indicators and liver steatosis grade and fibrosis stage in different sex and menopausal status populations. RESULTS: Men had higher WC, ASM, ASMI, FFM, and FFM/FM than pre- or post-menopausal women, while pre-menopausal women had higher PBF, VFA, and FM than the other two groups (p < 0.001). Besides, men had greater CAP and LSM values (p < 0.001). For MOLR, after adjusting for confounding factors, WC (OR, 1.07; 95% CI, 1.02-1.12; P = 0.011) and FFM/FM (OR, 0.52; 95% CI, 0.31-0.89; P = 0.017) in men and visceral obesity (OR, 4.16; 95% CI, 1.09-15.90; P = 0.037) in post-menopausal women were independently associated with liver steatosis grade. WC and visceral obesity were independently associated with liver fibrosis stage in men (OR, 1.05; 95% CI, 1.01-1.09, P = 0.013; OR, 3.92; 95% CI, 1.97-7.81; P < 0.001, respectively). CONCLUSIONS: Increased WC and low FFM/FM in men and visceral obesity in post-menopausal women were independent correlates of more severe liver steatosis. In addition, increased WC and visceral obesity were independent correlates of worse liver fibrosis in men. These data support the sex- and reproductive status-specific management of NAFLD.

C, F co-doping Ag/TiO2 with visible light photocatalytic performance toward degrading Rhodamine B.

The organic pollutants in industrial wastewater continuously endanger human health. Therefore, effective treatment of organic pollutants is very urgent. Photocatalytic degradation technology is an excellent solution to remove it. TiO2 photocatalysts are easy to prepare and have high catalytic activity, unfortunately, TiO2 only absorbs ultraviolet light limiting its utilization of visible light. In this study, a facile environmentally friendly synthesis of Ag-coated on micro-wrinkled TiO2-based catalysts in order to extend the absorption of Visible light. Firstly, a fluorinated titanium dioxide precursor was prepared by a one-step solvothermal method, and the precursor was calcined at high temperature in a nitrogen atmosphere to form a carbon dopant, and then a surface silver-deposited carbon/fluorine co-doped TiO2 photocatalyst C/F-Ag-TiO2 was prepared by a hydrothermal method The results showed that the Ag was coated on the wrinkled TiO2 layer and C/F-Ag-TiO2 photocatalyst was synthetized successfully. Benefit from the synergistic effect of doped carbon and fluorine atoms in combination with the quantum size effect of the surface silver nanoparticles, the band gap energy of C/F-Ag-TiO2 (2.56 eV) is obviously lower than anatase (3.2eV). The photocatalyst achieved an impressive degradation rate of 84.2% for Rhodamine B in 4 h, with a degradation rate constant of 0.367 h-1, which was 17 times higher than that of P25 under visible light. Therefore, the C/F-Ag-TiO2 composite is a promising candidate as a highly efficient photocatalyst for environmental remediation.

Hyperoside ameliorates diabetic nephropathy induced by STZ via targeting the miR-499-5p/APC axis.

Diabetic nephropathy is a serious complication of diabetes. Hyperoside has been widely reported to ameliorate diabetes-associated disease. The current study is designed to explore the mechanism of hyperoside in diabetic nephropathy. In the present study, high glucose was used to treat podocytes. Diabetic nephropathy mice models were established by high-fat feeding followed by multiple low dose injections of streptozocin. Western blot analysis was conducted for detection of extracellular matrix accumulation, inflammatory response and cell apoptosis. We found out that hyperoside improved high glucose-induced cell injury. Additionally, hyperoside prevented mice with diabetic nephropathy from diabetic symptoms and renal dysfunction. Mechanistically, hyperoside inhibited the mRNA and protein expression of APC. MiR-499-5p was found to be an upstream negative mediator of APC, and hyperoside induced the upregulation of miR-499-5p. MiR-499-5p bound with the 3' untranslated region of APC to inhibit its expression. Finally, rescue assays revealed that the suppressive effects of miR-499-5p overexpression on renal dysfunction were rescued by upregulation of APC in mice with diabetic nephropathy. In conclusion, these findings indicated that hyperoside ameliorates diabetic nephropathy via targeting the miR-499-5p/APC axis, suggesting that hyperoside may offer a potential tactic for diabetic nephropathy treatment.

Paeoniflorin ameliorates ulcerative colitis by modulating the dendritic cell-mediated TH17/Treg balance.

Immunological tolerance is critical for maintaining gut homeostasis. An imbalance between interleukin-17 (IL-17)-producing T helper 17 (TH17) cells and regulatory T cells (Treg cells) is involved in ulcerative colitis (UC) pathogenesis. Dendritic cells (DCs) are able to induce T cell differentiation. Paeoniflorin (PF) is a monoterpene glucoside that is commonly used for treatment of autoimmune disease. However, the immunological mechanism of PF involvement in UC treatment is unclear. The present study aimed to explore whether PF can restore the TH17/Treg balance by modulating DCs. The effects of PF on DCs, TH17 cells and Treg cells were measured. Furthermore, PF-treated DCs were injected into mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. PF inhibited MHC-II and CD86 expression on the DC surface (P < 0.05), decreased interleukin (IL)-12 secretion in vitro and in vivo (P < 0.05), and restored the TH17/Treg ratio in the mouse model of colitis (P < 0.05). PF-treated DCs diminished TH17 differentiation (4.26% in vitro and 1.64% in vivo) and decreased IL-17 expression (P < 0.05) while inducing CD4+CD25+Foxp3+ Treg differentiation (7.82% in vitro and 6.85% in vivo) and increasing Foxp3 and IL-10 production (P < 0.05). Additionally, both PF and PF-treated DCs improved colonic histopathology in the mouse model of colitis (P < 0.05). In conclusion this study suggested that PF can ameliorate TNBS-induced colitis by modulating the DC-mediated TH17/Treg balance.

Ameliorative effect of polydatin on hyperglycemia and renal injury in streptozotocin-induced diabetic rats.

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1ß, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.

Plasma heparanase is associated with blood glucose levels but not urinary microalbumin excretion in type 2 diabetic nephropathy at the early stage.

AIM: To explore the possible correlations between plasma heparanase and albuminuria, glucose and lipid metabolism in the type 2 diabetic nephropathy patients at the early stage. METHODS: One hundred and forty patients with type 2 diabetic nephropathy at early stage were recruited into the study. Plasma heparanase and the characterized advanced glycation end products (AGEs), carboxymethyllysine (CML) were measured by enzyme-linked immunosorbent assay. RESULTS: Plasma heparanase was positively associated with fasting blood glucose (R = 0.24, p = .01) while heparanase was not significantly correlated with the urinary microalbumin to creatinine ratio (urinary mAlb/Cr) (R = 0.05, p = .58) and CML (R = 0.16, p = .26). On stepwise linear regression analysis, fasting blood glucose was the main independent determinants of plasma heparanase concentration. CONCLUSION: Plasma heparanase is not significantly associated with urinary mAlb/Cr while it is correlated positively with blood glucose levels in the early stage of diabetic nephropathy. Plasma heparnase might be regarded as a marker for vascular endothelial cells injury in diabetic patients.

Total flavones of Abelmoschus manihot improve diabetic nephropathy by inhibiting the iRhom2/TACE signalling pathway activity in rats.

CONTEXT: Total flavones extracted from Abelmoschus manihot L. (Malvaceae) medic (TFA) have been proven clinically effective at improving renal inflammation and glomerular injury in chronic kidney disease (CKD). OBJECTIVE: This study evaluated the function of TFA as an inhibitor of iRhom2/TACE (tumour necrosis factor-α converting enzyme) signalling and investigated its anti-DN (diabetic nephropathy) effects in a DN rat model. MATERIALS AND METHODS: In vitro, cells were treated with 200 µg/mL advanced glycation end products (AGEs), and then co-cultured with 20 µg/mL TFA for 24 h. Real time PCR, western blotting and co-immunoprecipitation assays were performed. In vivo, DN was induced in 8 week old male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin, then TFA were administered to rats by gavage for 12 weeks at three different doses (300, 135 and 75 mg/kg/d). 4-Phenylbutanoic acid (2.5 mg/kg/d) was used as a positive control. RESULTS: IC50 of TFA is 35.6 µM in HK2 and 39.6 µM in HRMC. TFA treatment (20 µM) inhibited the activation of iRhom2/TACE signalling in cultured cells induced by AGEs. LD50>26 g/kg and ED50=67 mg/kg of TFA in rat by gavage, TFA dose-dependently downregulated the expression of proinflammatory cytokines and exerted anti-inflammatory effects significantly though inhibiting the activation of iRhom2/TACE signalling. DISCUSSION AND CONCLUSIONS: Our results show that TFA could dose-dependently ameliorate renal inflammation by inhibiting the activation of iRhom2/TACE signalling and attenuating ER stress. These results suggest that TFA has potential therapeutic value for the treatment of DN in humans.

[Treatment of Early Diabetic Retinopathy by Liuwei Dihuang Pill Combined Ginkao Leaf Tablet].

OBJECTIVE: To observe the prevention and clinical efficacy of combination of Liuwei Dihuang Pill (LDP) and Ginkgo Leaf Tablet (GLT) for early diabetic retinopathy (DR). METHODS: Using randomized, double-blind, double simulation, parallel controlled clinical trial, 140 type 2 diabetes mellitus (T2DM) outpatients were recruited and assigned to the treatment group and the control group, 70 in each group. All patients received basic Western medicine treatment (such as blood glucose and pressure control). Patients in the treatment group took LDP (8 pills each time, 3 times per day) and GLT (19.2 mg each time, 3 times per day), while those in the control group took LDP placebos and GLT placebos. All treatment lasted for 24 consecutive months. All subjects were followed-up every month. The general clinical data as sex, age, and metabolic data such as blood glucose, blood pressure, blood lipid, and DR prevalence rate were collected and statistically analyzed. RESULTS: There was no significant difference in levels of blood glucose, blood pressure, or blood lipid between the two groups (P > 0.05). After treatment the DR incidence rate was significantly lower in the treatment group than in the control group [3.1% (2/64) vs 18.6% (11/59), P < 0.05)]. Meanwhile, the DR prevalence rate of the treatment group was also significantly lower than that of the control group [6.3% (4/64) vs 20.0% (13/59), P < 0.05]. CONCLUSION: Combination of LDP and GLT could effectively prevent and treat the development of DR in T2DM patients.

A mendelian randomization study investigating the causal relationships between 1400 serum metabolites and autoimmune diseases.

Objective: This study aims to explore the causal relationships between 1400 serum metabolites (SMs) and five autoimmune diseases (Myasthenia gravis [MG], Multiple sclerosis [MS], Systemic lupus erythematosus [SLE], Type 1 diabetes mellitus [T1DM], and Ulcerative colitis [UC]) through Mendelian randomization analysis. Method: Data on MG, MS, SLE, T1DM, and UC were obtained from the IEU OpenGWAS Project database, while information on 1400 SMs was extracted from GWAS summary statistics provided by Chen et al. Causal relationships were assessed using the inverse variance weighted (IVW), MR-Egger, Weighted Median (WME), and Simple median (SME) methods. The robustness of instrumental variables was verified through computation of the F-statistic. Heterogeneity was evaluated using Cochran's Q test and the leave-one-out (LOO) method. Horizontal pleiotropy was assessed using MR-Egger regression and MR-PRESSO. Result: Following correction of the IVW P values using the False Discovery Rate (FDR) method, it was found that increased levels of 5-methyluridine (ribothymidine) (OR = 1.191, 95%CI 1.086-1.307, FDR-P = 0.000) and 2'-deoxyuridine (OR = 1.337, 95%CI 1.127-1.586, FDR-P = 0.001) were found to be correlated with a higher risk of MS. Conversely, the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) (OR = 0.771, 95%CI 0.649-0.916, FDR-P = 0.007) was linked to a decreased risk of MS. Levels of 1,2-dilinoleoyl-GPE (18:2/18:2) (OR = 0.877, 95%CI 0.791-0.974, FDR-P = 0.003) appear to be a protective factor for T1DM. No notable correlations between SMs and MG, SLE, or UC. The study detected no heterogeneity or horizontal pleiotropy. Conclusion: Levels of 5-methyluridine (ribothymidine), 2'-deoxyuridine, and the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) can serve as predictors for MS. Similarly, 1,2-dilinoleoyl-GPE (18:2/18:2) levels can be used to predict T1DM. However, no significant causal relationships were found between SMs and MG, SLE, or UC. This observation holds significant clinical implications for crafting tailored preventive and therapeutic approaches for ADs.

Pan-Cancer Analysis of ART1 and its Potential Value in Gastric Cancer.

Objective: To comprehensively explore the impact of Mono-ADP-ribosyltransferases-1 expression on both prognosis and the intricate landscape of the tumor immune microenvironment across diverse cancer types, our study seeks to delve into the multifaceted interplay between Mono-ADP-ribosyltransferases-1 expression levels and their implications for clinical outcomes and the dynamic milieu of immune responses within tumors. Methods: Genomic, transcriptomic, and clinical datasets spanning diverse cancer types were meticulously curated from The Cancer Genome Atlas and Genotypic Tissue Expression repositories. Initially, our inquiry focused on discerning the prognostic significance and immunological implications of Mono-ADP-ribosyltransferases-1 expression across this heterogeneous spectrum of malignancies. Subsequently, we scrutinized the relationships between Mono-ADP-ribosyltransferases-1 expression levels and a spectrum of factors including RNA modification genes, genetic mutations, and the emergent concept of tumor stemness. Employing functional enrichment analyses, we endeavored to unravel the underlying mechanistic pathways modulated by Mono-ADP-ribosyltransferases-1. Leveraging Bayesian co-localization analysis, we sought to discern the spatial convergence of Mono-ADP-ribosyltransferases-1 expression particularly within the context of digestive tract tumors. Lastly, to corroborate our findings, we conducted in vitro experiments, specifically focusing on Gastric Cancer, thus corroborating the putative oncogenic role attributed to Mono-ADP-ribosyltransferases-1 in this malignancy. Results: Across diverse tumor types, Mono-ADP-ribosyltransferases-1 expression exhibits distinctive patterns compared to normal and adjacent tissues, thereby intertwining with the prognostic outcomes of numerous cancer patients. Noteworthy findings from our immune role identification underscore the pivotal involvement of Mono-ADP-ribosyltransferases-1 in the landscape of tumor immunotherapy. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis elucidates the enrichment of Mono-ADP-ribosyltransferases-1-associated genes predominantly within the NF-kB, Foxo, and PI3K-Akt signaling cascades, shedding light on potential mechanistic pathways underlying its influence. Bayesian co-localization analysis unveils a compelling genetic correlation between Mono-ADP-ribosyltransferases-1 and digestive tract tumors, accentuating its relevance within this specific oncological domain. Importantly, experimental validation attests to the therapeutic promise of targeting Mono-ADP-ribosyltransferases-1 in the treatment paradigm of gastric cancer, thereby underscoring its potential as a viable therapeutic target deserving of further exploration and clinical translation. Conclusion: This comprehensive pan-cancer analysis unveils crucial insights into the intricate role played by Mono-ADP-ribosyltransferases-1 in the tumorigenesis of diverse malignancies, thereby establishing a robust theoretical framework for subsequent in-depth investigations. Leveraging these insights, targeting Mono-ADP-ribosyltransferases-1-related signaling pathways within the dynamic tumor microenvironment emerges as a promising avenue for novel therapeutic interventions in the realm of tumor immunotherapy. By delineating the interplay between Mono-ADP-ribosyltransferases-1 expression and tumorigenic processes across various cancer types, this study paves the way for innovative therapeutic strategies aimed at disrupting oncogenic signaling cascades and bolstering immune-mediated antitumor responses.

A two-sample bidirectional Mendelian randomization analysis investigates associations between gut microbiota and type 2 diabetes mellitus.

Objective: This study sought to elucidate the causal association between gut microbiota (GM) composition and type 2 diabetes mellitus (T2DM) through a comprehensive two-sample bidirectional Mendelian randomization analysis. Method: T2DM data were sourced from the IEU OpenGWAS Project database, complemented by 211 gut microbiota (GM) datasets from the MiBioGen Federation. The primary analytical approach employed was inverse variance weighted (IVW), supplemented by MR-Egger regression and weighted median (WME) methods to investigate their potential interplay. Results were assessed using odds ratios (OR) and 95% confidence intervals (CI). The robustness and reliability of the findings were confirmed through leave-one-out analysis, heterogeneity testing, and assessment of horizontal pleiotropy. Furthermore, we explored the potential mediating role of metabolites in the pathway linking GM to T2DM. Result: A set of 11 Single Nucleotide Polymorphisms (SNPs) linked to GM were identified as instrumental variables (IVs). The IVW analysis revealed that increased abundance of the genus Actinomyces, genus Bilophila, genus Lachnoclostridium, genus Ruminococcus gnavus group, and genus Streptococcus corresponded to a heightened risk of T2DM. Conversely, higher levels of genus Eubacterium oxidoreducens group, genus Oscillospira, genus Ruminococcaceae UCG003, genus Ruminococcaceae UCG010, and genus Sellimonas were associated with a reduced risk of T2DM. However, following false discovery rate (FDR) correction, only the abundance of genus Lachnoclostridium retained a significant positive correlation with T2DM risk (OR = 1.22, q value = 0.09), while the other ten GM showed suggestive associations with T2DM. Reverse MR analysis did not reveal any causal relationship between T2DM and the increased risk associated with the identified GM. Additionally, metabolites did not exhibit mediating effects in this context. Conclusion: This study effectively pinpointed specific GM associated with T2DM, potentially paving the way for novel biomarkers in the prevention and treatment of this condition. The findings suggested that probiotics could emerge as a promising avenue for managing T2DM in the future. Furthermore, the analysis indicated that metabolites do not appear to act as mediators in the pathway from GM to T2DM.

Identification of disulfidptosis-associated genes and characterization of immune cell infiltration in thyroid carcinoma.

OBJECTIVE: The primary objective of this study is to conduct a comprehensive screening and analysis of differentially expressed genes related to disulfidoptosis (DEDRGs) in thyroid carcinoma (THCA). This entails delving into the intricate characterization of immune cell infiltration within the THCA context and subsequently formulating and validating a novel prognostic model. METHOD: To achieve our objectives, we first delineated two distinct subtypes of disulfidoptosis-related genes (DRGs) via consensus clustering methodology. Subsequently, employing the limma R package, we identified the DEDRGs critical for our investigation. These DEDRGs underwent meticulous validation across various databases, alongside an in-depth analysis of gene regulation. Employing functional enrichment techniques, we explored the potential molecular mechanisms underlying disulfidoptosis in THCA. Furthermore, we scrutinized the immune landscape within the two identified subtypes utilizing CIBERSORT and ESTIMATE algorithms. The construction of the prognostic model for THCA entailed intricate methodologies including univariate, multivariate Cox regression, and LASSO regression algorithms. The validity and efficacy of our prognostic model were corroborated through Kaplan-Meier survival curves and ROC curves. Additionally, a nomogram was meticulously formulated to facilitate the prediction of patient prognosis. To fortify our findings, we conducted a comprehensive Bayesian co-localization analysis coupled with rigorous in vitro experimentation, aimed at unequivocally establishing the validity of the identified DEDRGs. RESULT: Our analyses unveiled Cluster C1, characterized by elevated expression levels of DEDRGs, as harboring a favorable prognosis accompanied by abundant immune cell infiltration. Correlation analyses underscored predominantly positive associations among the DEDRGs, further affirming their significance in THCA. Differential expression patterns of DEDRGs between tumor samples and normal tissues were evident across the GEPIA and HPA databases. Insights from the TIMER database underscored a robust correlation between DEDRGs and immune cell infiltration. KEGG analysis elucidated the enrichment of DEDRGs primarily in pivotal pathways including MAPK, PPAR signaling pathway, and Proteoglycans in cancer. Furthermore, analyses using CIBERSORT and ESTIMATE algorithms shed light on the crucial role played by DEDRGs in shaping the immune microenvironment. The prognostic model, anchored by five genes intricately associated with THCA prognosis, exhibited commendable predictive accuracy and was intricately linked to the tumor immune microenvironment. Notably, patients categorized with low-risk scores stood to potentially benefit more from immunotherapy. The validation of DEDRGs unequivocally underscores the protective role of INF2 in THCA. CONCLUSION: In summary, our study delineates two discernible subtypes intricately associated with DRGs, revealing profound disparities in immune infiltration and survival prognosis within the THCA milieu. The implications of our findings extend to potential treatment strategies for THCA patients, which could entail targeted interventions directed towards DEDRGs and prognostic genes, thereby influencing disulfidptosis and the immune microenvironment. Moreover, the robust predictive capability demonstrated by our prognostic model, based on the five genes (ANGPTL7, FIRRE, ODAPH, PROKR1, SFRP5), underscores its potential clinical utility in guiding personalized therapeutic approaches for THCA patients.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway.

BACKGROUND: Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain. AIM: To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism. METHODS: Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA. RESULTS: In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1ß induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002. CONCLUSION: This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Effects of Niaoduqing granules on inflammatory response of diabetic kidney disease: A meta­analysis.

Diabetic kidney disease (DKD) is one of the most severe chronic microvascular complications of diabetes and the leading cause of end-stage kidney disease worldwide. The mechanism of inflammation underlying DKD has been attracting attention over recent years, but effective therapeutic strategies have remained elusive. Niaoduqing (NDQ) granules are one of the most commonly used drugs for the treatment of DKD in China, and it has therapeutic effects against inflammation in DKD. Therefore, the aim of the present analysis was to evaluate the inflammatory response outcomes and safety of NDQ granules for the treatment of DKD. The following databases were searched from their inception to 31st of May 2023 to obtain published accounts of relevant randomized controlled trials: China National Knowledge Infrastructure, China Science and Technology Journal, Wanfang, The Chinese Biomedicine, PubMed, Web of Science and Cochrane Library. The 'risk of bias' evaluation tool produced by the Cochrane Collaboration Handbook was used for evaluating the quality, whereas Revman software (version 5.3) was used for meta-analysis. In total, 16 studies were included into the present study according to criteria, with a total of 1,526 patients. Compared with those in the control group, the results of the meta-analysis revealed that the combination of conventional treatment and NDQ granules may further decrease C-reactive protein [standardized mean difference (SMD), -1.33; 95% confidence interval (CI), -1.76, -0.91; P<0.00001], TNF-α (SMD, -1.90; 95% CI, -2.35,-1.45; P<0.00001) and IL-6 (SMD, -1.72; 95% CI, -2.52,-0.91; P<0.0001) levels, whilst increasing the clinical effective rate (risk ratio, 1.22; 95% CI, 1.14,1.29; P<0.00001), in patients with DKD. In terms of safety, a total of 34 and 39 patients included in the intervention and in the control group, respectively, developed adverse reactions. Results from the present analysis suggest that NDQ granules may be beneficial in suppressing inflammation caused by DKD when used in combination with conventional treatment, potentially guiding future directions in clinical practice. However, further high-quality studies are needed to confirm the anti-inflammation response in the future.

Hyperuricemia Predicts the Progression of Type 2 Diabetic Kidney Disease in Chinese Patients.

INTRODUCTION: Diabetic kidney disease (DKD) has a high global disease burden and substantially increases the risk of end-stage renal disease and cardiovascular events. High levels of serum uric acid (SUA), or hyperuricemia, may indicate patients with type 2 diabetes (T2D) at risk for kidney disease. METHODS: This study explored the association between SUA levels and progression of kidney disease among patients with T2D. A cross-sectional study of 993 Chinese patients aged 20-75 years with T2D and DKD was conducted. Patients were stratified by progression risk of kidney disease based on estimated glomerular filtration rate and ratio of urinary albumin to creatinine, according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Ordinal logistic regression was used to assess associations between SUA and different KDIGO risk categories. RESULTS: Among 768 patients in the final analysis, those with hyperuricemia and higher SUA were more likely to be assigned to higher KDIGO risk categories. Patients with SUA > 420 µmol/L were ninefold more likely to be in a higher KDIGO risk category than those with SUA < 300 µmol/L (odds risk 9.74, 95% confidence interval 5.47-17.33, P < 0.001). CONCLUSIONS: Hyperuricemia may be associated with higher risk of DKD progression in individuals with T2D.

Effects of SGLT2 inhibitors on hepatic fibrosis and steatosis: A systematic review and meta-analysis.

Objective: Clinical trials have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) are closely associated with hepatic fibrosis and steatosis by FibroScan. This paper aimed at evaluating the effects of SGLT2i on hepatic fibrosis and steatosis, which are presented as liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Methods: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, China Science and Technology Journal Database, and Wanfang Database were searched for randomized clinical trials from database establishment to 30 November 2022 with no language restrictions. The risk of bias was evaluated by Collaboration Handbook. Software Stata 17 and Review Manager (version 5.3) were used for meta-analysis. Results: A total of eight articles including 686 patients were included. Compared with the control group, our results showed that SGLT2i could lower levels of LSM [MD = -0.82, 95%CI (-1.38, -0.25), p = 0.005] and CAP [MD = -12.80, 95%CI (-20.57, -5.03), p = 0.001]. Further subgroup analyses indicated that SGLT2i presented more advantages on longer treatment duration and more serious steatosis in decreasing LSM. For CAP, SGLT2i exhibited a clear advantage in subgroup analyses of longer treatment duration, younger people, dapagliflozin, worse fibrosis, and steatosis. Conclusion: SGLT2i could reduce LSM and CAP in contrast to other antihyperglycemic drugs. However, the included studies are not definitive, and well-designed, more multi-centered, blinded randomized clinical trials are warranted to definitively establish reliable evidence.

Corrigendum: The value of functional magnetic resonance imaging in the evaluation of diabetic kidney disease: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1226830.].