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.

Consistency Analysis Between SUDOSCAN Examinations and Electromyography Results in Patients with Diabetes.

Objective: To evaluate the consistency between SUDOSCAN examinations and electromyography (EMG) results in patients with diabetes. Methods: A total of 326 patients with diabetes (201 males and 125 females) who were hospitalized in the endocrinology ward of the Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine) from June 2020 to February 2021 were selected as participants. All the patients were tested using a SUDOSCAN conductance analyzer for electrical skin conductivities and EMG for nerve conduction. The differences and consistencies between the results of the two examinations were analyzed. McNemar's test was used to analyze the differences between the results, and Cohen's kappa test was utilized to test the consistencies. Results: A total of 174 patients had abnormal SUDOSCAN results, and 152 patients had normal SUDOSCAN results. The EMG results of 299 patients were abnormal, and the EMG results of 27 patients were normal. The McNemar test result was P = 0.000, and the differences between the results of the SUDOSCAN and EMG examinations were statistically significant (P < 0.01). No significant consistency was found between the SUDOSCAN and EMG results, meaning that the consistency between the two examination results was not statistically significant (P = 0.868, P > 0.05). The difference between the results was statistically significant (P < 0.05), and the consistency was poor (kappa = 0.005). Conclusion: Differences existed between the SUDOSCAN examination and EMG results, and the results of the two examination methods were inconsistent, indicating that SUDOSCAN examinations cannot replace EMG examinations for DSPN.

Detection and Correlation Analysis of Serum Uric Acid in Patients with Thyroid-Associated Ophthalmopathy.

Purpose: To probe the property of serum uric acid in evaluating the activity of patients with thyroid-associated ophthalmopathy. Methods: A total of 443 patients with TAO admitted to our hospital from March 2016 to February 2021 were selected for the observation group. Simultaneously, 443 healthy subjects were selected for the control group. The observation group was divided into the active group (n = 254) and the inactive group (n = 189) according to the clinical activity score (CAS). Besides, the patients were divided into mild group (n = 201), moderate severe group (n = 133) and extremely severe group (n = 109) based on the severity of TAO. Serum uric acid, free triiodothyronine (FT3), free thyroid hormone (FT4), thyrotropin stimulating hormone (TSH) and glycosylated hemoglobin (HbA1c) levels were detected and analyzed in each group. Results: Serum UA, FT3, FT4, TSH and HbA1c in the active group were significantly enhanced than those in the other two groups (P < 0.05), and there was no significant difference between the inactive group and the control group (P > 0.05). In different disease severity groups, the serum UA level of patients in the active group was significantly promoted than that in the inactive group and control group (P < 0.05) and was decreased successively in extremely severe group, moderate severe group and mild group, with statistical significance (P < 0.05). Pearson's analysis showed that UA was positively correlated with FT3, FT4, and HbA1c (r = 0.652, P = 0.031; r = 0.571, P = 0.042; r = 0.737, P = 0.024), while was reversely correlated with TSH level (r = -0.137, P = 0.262). There was no correlation between UA and FT3, FT4, and HbA1c levels in the inactive group. UA detection showed the average sensitivity and specificity of TAO activity were 94.3% and 85.2%, respectively. There was no significant correlation between the severity of disease and serum UA in inactive patients (P = 0.135). There was a positive correlation between the severity of disease and serum UA in active patients (P = 0.005). Conclusion: UA may be used as a laboratory indicator for quantitative clinical diagnosis of thyroid-associated ophthalmopathy (TAO) and as a parameter for the presence of TAO activity.

Meta-Analysis of Naoxintong Capsule for Patients with Vascular Dementia.

Background: Vascular dementia (VaD) is the second most common form of dementia among the elderly. There is currently no unequivocal recommendation of an effective treatment option for VaD. Objective: The purpose of this study was to evaluate the efficacy and safety of Naoxintong capsule (NXT) in the treatment of VaD patients. Methods: We searched for randomized controlled trials (RCTs) published before September 2021 in PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, and Wanfang databases. The trials assessed the efficacy and/or safety of NXT in treating patients with VaD. A meta-analysis was then performed using Stata 14.0 software. Results: A total of 33 studies comprising 2,947 patients with VaD were included in this study. The meta-analysis revealed that NXT improved cognitive function in VaD patients, increased the mini-mental state examination (MMSE) score by 3.33 points (WMD = 3.33, 95% CI (2.72, 3.94)), the Montreal Cognitive Assessment (MoCA) score by 4.31 points (WMD = 4.31, 95% CI (2.72, 5.90)), and the Hasegawa dementia scale (HDS) by 2.71 points (WMD = 2.71, 95% CI (1.26, 4.17)). Furthermore, NXT significantly improved the daily lives of VaD patients, lowering the activities of daily living (ADL) score by 5.85 points (WMD = -5.85, 95% CI (-7.03, -4.66)). NXT improved the total effective rate (TER) (OR = 2.62, 95% CI (2.09, 3.29)) of the patients without increasing the occurrence of adverse events (AEs; OR = 0.72, 95% CI (0.43, 1.22)). Subgroup analysis revealed that whether NXT was used alone or in combination with western medicine, it could enhance the overall curative effect. Conclusions: NXT may be an effective and safe treatment option for VaD. However, because of the limited number and quality of articles included, this study's findings need to be validated by additional high-quality, large-sample, and multicenter RCTs (Systematic Review Registration Number: PROSPERO; https://clinicaltrials.gov/ct2/show/CRD42021233199).

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.

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway.

Background and Objective: Glucose fluctuation (GF) has been reported to induce renal injury and diabetic nephropathy (DN). However, the mechanism still remains ambiguous. Mitochondrial energy metabolism, especially aerobic glycolysis, has been a hotspot of DN research for decades. The activation of HIF-1α/miR210/ISCU/FeS axis has provided a new explanation for aerobic glycolysis. Our previous studies indicated quercetin as a potential therapeutic drug for DN. This study aims to evaluate levels of aerobic glycolysis and repressive effect of quercetin via HIF-1α/miR210/ISCU/FeS axis in a cell model of GF. Methods: The mouse glomerular mesangial cells (MCs) were exposed in high or oscillating glucose with or without quercetin treatment. Cell viability was measured by CCK8 assay. Aerobic glycolysis flux was evaluated by lactate acid, pH activity of PFK. Apoptosis level was confirmed by Annexin V-APC/7-AAD double staining and activity of caspase-3. TNF-α and IL-1ß were used to evaluate inflammation levels. Results: GF deteriorated inflammation damage and apoptosis injury in MCs, while quercetin could alleviate this GF-triggered cytotoxicity. GF intensified aerobic glycolysis in MCs and quercetin could inhibit this intensification in a dose-dependent manner. Quercetin prevented activities of two FeS-dependent metabolic enzymes, aconitase, and complex I, under GF injury in MCs. The mRNA expression and protein contents of HIF-1α were increased after GF exposure, and these could be alleviated by quercetin treatment. Knockdown of ISCU by siRNA and Up-regulating of miR-210 by mimic could weaken the effects of quercetin that maintained protein levels of ISCU1/2, improved cell viability, relieved inflammation injury, decreased apoptosis, and reduced aerobic glycolysis switch in MCs. Conclusion: Quercetin antagonizes GF-induced renal injury by suppressing aerobic glycolysis via HIF-1α/miR-210/ISCU/FeS pathway in MCs cell model. Our findings contribute to a new insight into understanding the mechanism of GF-induced renal injury and protective effects of quercetin.