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.

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 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.

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.

Corrigendum: GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: a system review and network meta-analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1149328.].

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.

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.

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.].

Huobahuagen tablet improves renal function in diabetic kidney disease: a real-world retrospective cohort study.

Objective: We aimed to explore the value of Huobahuagen tablet (HBT) in improving decreased renal function for patients with diabetic kidney disease (DKD) over time. Methods: This was a single-center, retrospective, real-world study on eligible 122 DKD patients who continued to use HBT + Huangkui capsule (HKC) therapy or HKC therapy without interruption or alteration in Jiangsu Province Hospital of Chinese Medicine from July 2016 to March 2022. The primary observation outcomes included estimated glomerular filtration rate (eGFR) at baseline and 1-, 3-, 6-, 9-, and 12-month follow-up visits and changes in eGFR from baseline (ΔeGFR). Propensity score (PS) and inverse probability treatment weighting (IPTW) were used to control for confounders. Results: eGFR was significantly higher in the HBT + HKC group than in the HKC alone group at the 6-, 9-, and 12-month follow-up visits (p = 0.0448, 0.0002, and 0.0037, respectively), indicating the superiority of HBT + HKC over HBT alone. Furthermore, the ΔeGFR of the HBT + HKC group was significantly higher than that of the HKC alone group at the 6- and 12-month follow-up visits (p = 0.0369 and 0.0267, respectively). In the DKD G4 patients, eGFR was higher in the HBT + HKC group at the 1-, 3-, 6-, 9-, and 12-month follow-up visits compared with baseline, with statistically significant differences at the 1-, 3-, and 6- month follow-up visits (p = 0.0256, 0.0069, and 0.0252, respectively). The fluctuations in ΔeGFR ranged from 2.54 ± 4.34 to 5.01 ± 5.55 ml/min/1.73 m2. Change in the urinary albumin/creatinine ratio from baseline did not exhibit a significant difference between the two groups at any of the follow-up visits (p > 0.05 for all). Adverse event incidence was low in both groups. Conclusion: The findings of this study based on real-world clinical practice indicate that HBT + HKC therapy exhibited better efficacy in improving and protecting renal function with a favorable safety profile than HKC therapy alone. However, further large-scale prospective randomized controlled trials are warranted to confirm these results.

GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: a system review and network meta-analysis.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework. Results: 64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center. Conclusion: Dulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346.

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

Background: The diversity of clinical trajectories in diabetic kidney disease (DKD) has made blood and biochemical urine markers less precise, while renal puncture, the gold standard, is almost impossible in the assessment of diabetic kidney disease, and the value of functional magnetic resonance imaging in the evaluation of diabetic pathological alterations is increasingly recognized. Methods: The literature on functional magnetic resonance imaging (fMRI) for the assessment of renal alterations in diabetic kidney disease was searched in PubMed, Web of Science, Cochrane Library, and Embase databases. The search time limit is from database creation to March 10, 2023. RevMan was used to perform a meta-analysis of the main parameters of fMRIs extracted from DKD patients and healthy volunteers (HV). Results: 24 publications (1550 subjects) were included in this study, using five functional MRIs with seven different parameters. The renal blood flow (RBF) values on Arterial spin labeling magnetic resonance imaging (ASL-MRI) was significantly lower in the DKD group than in the HV group. The [WMD=-99.03, 95% CI (-135.8,-62.27), P<0.00001]; Diffusion tensor imaging magnetic resonance imaging (DTI-MRI) showed that the fractional anisotropy (FA) values in the DKD group were significantly lower than that in HV group [WMD=-0.02, 95%CI (-0.03,-0.01), P<0.0001]. And there were no statistically significant differences in the relevant parameters in Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) or Intro-voxel incoherent movement magnetic resonance imaging (IVIM-DWI). Discussion: ASL and DWI can identify the differences between DKD and HV. DTI has a significant advantage in assessing renal cortical changes; IVIM has some value in determining early diabetic kidney disease from the cortex or medulla. We recommend combining multiple fMRI parameters to assess structural or functional changes in the kidney to make the assessment more comprehensive. We did not observe a significant risk of bias in the present study. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023409249.

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.

Corrigendum: Platelet abnormalities in autoimmune thyroid diseases: A systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fimmu.2022.1089469.].

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.

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.

Efficacy and safety of Abelmoschus manihot capsule combined with ACEI/ARB on diabetic kidney disease: a systematic review and meta analysis.

Background: Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes, with the incidence rate increasing yearly, which is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease. Abelmoschus Manihot capsule, as a proprietary Chinese patent medicine, is widely used for treating CKD in China. Currently, the combination of Abelmoschus Manihot (AM) capsule and renin-angiotensin-aldosterone system inhibitor (RASI) has gained popularity as a treatment option for DKD, with more and more randomized control trials (RCTs) in progress. However, the high-quality clinical evidence supporting its application in DKD is still insufficient. Aim of the study: To comprehensively and systematically evaluate the efficacy and safety of AM capsule combined with RASI in the treatment of DKD. Materials and methods: English and Chinese databases such as Pubmed, Cochrane Library, Embase, CNKI, SinoMed, WF, and VIP were searched to collect the RCTs of AM capsule in treatment of DKD. Then Two investigators independently reviewed and extracted data from the RCTs which met the inclusion criteria. The quality of the data was assessed using the Cochrane risk of bias assessment tool, and meta-analysis was performed using RevMan 5.4 software. Results: 32 RCTs with a total of 2,881 DKD patients (1,442 in the treatment group and 1,439 in the control group) were included. The study results showed that AM capsule combined with RASI could be more effective in decreasing 24h-UTP [MD = -442.05, 95% CI (-609.72, -274.38), p < 0.00001], UAER [MD = -30.53, 95% CI (-39.10, -21.96), p < 0.00001], UACR [MD = -157.93, 95% CI (-288.60, -27.25), p < 0.00001], Scr [MD = -6.80, 95% CI (-9.85, -3.74), p < 0.0001], and BUN [MD = -0.59, 95% CI (-1.07, -0.12), p = 0.01], compared to using RASI alone. According to the subgroup analyses, the combination of AM and ARB seems to be more effective in reducing UAER than the combination of ACEI, and the addition of AM may achieve a more significant clinical effect on decreasing Scr for DKD patients with 24h-UTP>2 g or Scr>110-133 µmol/L and >133 µmol/L. Furthermore, no additional adverse reactions were observed in the combination group [OR = 1.06; 95%CI: (0.66, 1.69), p = 0.82]. Conclusion: Combining AM with RASI may be a superior strategy for DKD treatment compared to RASI monotherapy. However, due to significant heterogeneity, the results should be interpreted with great caution, and more high-quality RCTs with multi-centers, different stages of DKD, large sample sizes, and long follow-up periods are still needed to improve the evidence quality of AM for DKD in the future. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails; Identifier CRD42022351422.

[Acupuncture mitigates ocular surface inflammatory response via α7nAChR/NF-κB p65 signaling in dry eye guinea pigs].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the ocular surface inflammation and α7 nicotinic acetylcholine receptor (α7nAChR) / nuclear factor kappa-B (NF-κB) p65 signal pathway in guinea pigs with dry eye, so as to explore its underlying mechanism. METHODS: A total of 32 male British tricolor short haired guinea pigs were randomized into blank control, model, EA and sham acupuncture groups, with 8 guinea pigs in each group. The dry eye model was established by subcutaneous injection of scopolamine hydrobromide solution (0.6 mg/0.2 mL each time, 4 times a day for 10 days). Guinea pigs of the EA group was treated with EA at bilateral "Cuanzhu" (BL2) and "Taiyang" (HN5), and manual acupuncture at bilateral "Jingming" (BL1), "Sizhukong" (SJ23), "Tongziliao" (GB1) for 15 min, once daily for 14 days. For animals of the sham acupuncture group, a blunt needle was used to prick the skin surface of the acupoints, the acupoint selection and stimulation time were the same as those in the EA group. Before and after modeling and after the intervention, the breakup time (BUT) of lacrimal film, sodium fluorescein coloring (Fl) state of corneal epithelium and phenol red thread (PRT) moist length were recorded for assessing the severity of dry eye. The density of activated immune cells around the corneal epithelial stromal cells was determined by corneal confocal microscopy. The contents of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in the cornea and lacri-mal gland tissues were determined by ELISA, and the expression levels of α7nAChR and NF-κB p65 in the cornea and lacrimal gland were detected by immunohistochemistry and Western blot, separately. RESULTS: Compared with the blank control group, the corneal Fl, density of activated immune cells of corneal epithelium, contents of IL-6, IL-10 and TNF-α in both corneal and lacrimal gland tissues, NF-κB p65 cell positive rate and protein expression of lacrimal gland and corneal tissues were significantly increased (P<0.01, P<0.05), while the BUT, PRT and lacrimal gland α7nAChR cell positive rate considerably decreased (P<0.01) in the model group. In comparison with the model group, the level of corneal Fl, density of the activated immune cells of corneal epithelium, contents of corneal and lacrimal IL-6 and TNF-α, and corneal and lacrimal NF-κB p65 cell positive rates and protein expressions were remarkably down-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except content of corneal IL-10, lacrimal NF-κB p65 cell positive rate and lacrimal α7nAChR protein expression, whereas the levels of BUT, PRT, corneal and lacrimal IL-10 and corneal and lacrimal α7nAChR cell positive rates and protein expressions significantly up-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except corneal TNF-α and corneal NF-κB p65 protein expression. CONCLUSION: EA can improve corneal and lacrimal function in dry eye guinea pigs, which may be associated with its actions in increasing the expression of α7nAChR, inhibiting the nuclear translocation of NF-κB, and reducing the activated immune cells and inflammatory reaction.

Integrated analysis of comprehensive metabolomics and network pharmacology to reveal the mechanisms of abelmoschus manihot (L.) medik. in the treatment of cisplatin-induced chronic kidney disease.

Background: Abelmoschus manihot (L.) Medik ("Huangkui" in Chinese, HK) has been widely used for the treatment of kidney diseases. Nephrotoxicity is the side effect of cisplatin (CDDP), which greatly limits its clinical application. Therefore, CDDP could be used to establish the chronic kidney disease (CKD) model. However, the protective effects of HK on CDDP-induced CKD have not been investigated. Purpose: To explore the protective effect and underlying mechanisms of HK on multiple low-dose CDDP-induced CKD in rats by the integrated analysis of serum, kidney, and urine metabolomics and network pharmacology. Methods: The CKD model was induced by multiple low-dose CDDP. Body weight, organ index, serum biochemical, and kidney histology were examined to evaluate the effect of HK. Serum, kidney, and urine were collected and profiled by HILIC/RPLC-Q-TOF/MS-based metabolomics. Potential biomarkers (PBs) were screened according to the criteria of VIP >1, p < 0.01, and FC > 2, and then identified or assigned. The pathway analysis and PBs enrichment were conducted by MetaboAnalyst and ChemRICH. Furthermore, network pharmacology was adopted to dig out the active components and targets. Finally, the results from metabolomics and network pharmacology were integrated to confirm each other. Results: HK could recover the CDDP-induced abnormal pharmacological and metabolic profile changes. A total of 187 PBs were screened and identified from the serum, kidney, and urine metabolomics. Pathway analysis showed that multiple metabolic pathways, mainly related to amino acid and lipid metabolisms, were involved in the nephroprotective effect of HK, and especially, HK could significantly alleviate the disorder of tryptophan metabolism pathway in serum, kidney, and urine. Meanwhile, network pharmacology analysis revealed that 5 components in HK and 4 key genes could be responsible for the nephroprotection of HK, which also indicated that the metabolism of tryptophan played an important role in HK against CKD. Conclusion: HK has a nephroprotection on CDDP-induced CKD, mainly by restoring the dysregulation of tryptophan metabolism. Integrated analysis of serum, kidney, and urine metabolomics and network pharmacology was a powerful method for exploring pharmacological mechanisms and screening active components and targets of traditional Chinese medicine.

Elevated serum uric acid is not an independent risk factor for the occurrence of Type 2 diabetic kidney disease in Chinese populations.

Previous studies suggested that increased serum uric acid (SUA) level is an independent risk factor for albuminuria in Type 2 diabetes (T2D) patients. However, the association between SUA and onset of Type 2 DKD (T2DKD) remained to be clarified. This was a cross-sectional clinical study in which 1210 Chinese T2D patients were enrolled. According to the urine albumin-to-creatinine ratio (UACR), the cohort was divided into normal-albuminuria (UACR < 30 mg/g), micro-albuminuria (UACR 30-300 mg/g) and macro-albuminuria (UACR > 300 mg/g). The micro- and macro-albuminuria groups were combined into albuminuria category. Results showed that T2D patients with macro-albuminuria have significantly higher SUA than the other 2 groups (P < .001). In the binary logistic regression model, the subjects with SUA higher than 420 µmol/L were associated with a 2-fold increase in the odds of albuminuria (odds ratio = 2.024, 95% confidence interval: 1.232-3.325, P = .005), as compared with those with SUA lower than 300 µmol/L. Moreover, the multinomial regression analysis revealed that the subjects with SUA higher than 420 µmol/L had about 3-fold increase in the odds of macro-albuminuria (odds ratio = 3.758, 95% confidence interval: 2.051-6.885, P < .001), as compared with those with SUA lower than 300 µmol/L. However, SUA was not significantly associated with the presence of micro-albuminuria. Although the SUAwas not independently risk factor for micro-albuminuria, it was closely correlated with the development of macro-albuminuria in Chinese T2DKD patients. Elevated SUA may be useful for predicting the occurrence of macro-albuminuria but not onset of micro-albuminuria at the early stage of T2DKD.

Efficacy and safety of Abelmoschus moschatus capsules combined with tripterygium glycoside tablets on diabetic nephropathy: A systematic review and meta-analysis.

Background: Diabetic nephropathy (DN) is one of the most serious chronic micro-vascular complications of diabetes and the leading cause of end-stage kidney disease (ESRD) worldwide, with reduced expectancy and quality of life and colossal financial and social burden worldwide. In spite of emerging treatments on DN, effective therapy on delaying the progression of DN is still lacking. In clinical practice, there are many studies focusing on Abelmoschus moschatus (AM) capsules together with Tripterygium glycoside (TG) tablets in the treatment of DN, and excellent results have been obtained. Objective: The study aimed to evaluate the efficacy and safety of AM combined with TG in the treatment of DN. Methods: Databases including PubMed, Web of Science, Cochrane Library, Embase, CNKI, WF, and VIP were searched from their inception to 1 March 2022. The "risk of bias" evaluation tool produced by the Cochrane Collaboration Handbook was used for evaluating the quality of the included studies. Revman 5.3 software was used for meta-analysis. Results: Here, 11 studies with a total of 1,072 participants were included for this meta-analysis. Our results showed that AM combined with TG plus basic treatment could lower levels of 24 h-UP [MD = -0.18; 95% CI: (-0.21, -0.14); p < 0.00001], Scr [MD = -15.29; 95% CI: (-28.69, -1.88); p = 0.03], and BUN [MD = -1.18; 95% CI: (-1.69, -0.68); p < 0.00001]. Meanwhile, the adverse reaction rate increased in the combination group [RR = 1.88; 95% CI (1.26, 2.82); p = 0.002]. Conclusion: Current evidence suggests that AM combined with TG may be more effective in the treatment of DN, which will be highly beneficial to further theoretical discussion and practical clinical applications. However, the safety cannot be ignored because of nearly increasing 2-fold adverse events, although they can be mitigated through systematic treatment. Meanwhile, due to low quality of the included studies, great possibility of publication bias, and large heterogeneity among different studies, the results of our review should be evaluated with more prudence and high-quality RCTs are warranted to confirm this in the future. Systematic review Registration: www.crd.york.ac.uk, identifier CRD42022344359.