Acteoside delays the fibrosis process of diabetic nephropathy by anti-oxidation and regulating the autophagy-lysosome pathway.

Renal fibrosis is the final pathological change of kidney disease, it has also been recognized to be critical for the final progression of diabetic nephropathy (DN) to kidney failure. Acteoside (ACT) is a phenylethanoid glycoside widely distributed in dicotyledonous plants. It has many pharmacological activities, such as anti-oxidation, anti-inflammation, anti-cancer, neuroprotection, cardiovascular protection, anti-diabetes, bone and cartilage protection, liver and kidney protection, and antibacterial activity. This study aims to investigate the protective effects of ACT on renal interstitial fibrosis in rats with DN induced by intraperitoneal injection of streptozocin (STZ) combined with unilateral nephrectomy and its mechanism. In vivo and in vitro, the effects of ACT on reactive oxygen species (ROS) level, oxidative tubular injury, as well as damage of autophagic flux and lysosome in the DN model were detected. Results indicate that administration of ACT delayed the progression of renal interstitial fibrosis in DN by anti-oxidation and regulating the autophagy-lysosome pathway, which may potentially be attributed to the regulatory influence of ACT on transcription factor EB (TFEB).

Elucidation of the anti-ß-cell dedifferentiation mechanism of a modified Da Chaihu Decoction by an integrative approach of network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Da Chaihu decoction (MDCH) is a traditional Chinese herbal prescription that has been used in the clinic to treat type 2 diabetes (T2D). Previous studies have confirmed that MDCH improves glycemic and lipid metabolism, enhances pancreatic function, and alleviates insulin resistance in patients with T2D and diabetic rats. Evidence has demonstrated that MDCH protects pancreatic ß cells via regulating the gene expression of sirtuin 1 (SIRT1) and forkhead box protein O1 (FOXO1). However, the detailed mechanism remains unclear. AIM OF THE STUDY: Dedifferentiation of pancreatic ß cells mediated by FOXO1 has been recognized as the main pathogenesis of T2D. This study aims to investigate the therapeutic effects of MDCH on T2D in vitro and in vivo to elucidate the potential molecular mechanisms. MATERIALS AND METHODS: To predict the key targets of MDCH in treating T2D, network pharmacology methods were used. A T2D model was induced in diet-induced obese (DIO) C57BL/6 mice with a single intraperitoneal injection of streptozotocin. Glucose metabolism indicators (oral glucose tolerance test, insulin tolerance test), lipid metabolism indicators (total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol), inflammatory factors (C-reactive protein, interleukin 6, tumor necrosis factor alpha), oxidative stress indicators (total antioxidant capacity, superoxide dismutase, malondialdehyde), and hematoxylin and eosin staining were analyzed to evaluate the therapeutic effect of MDCH on T2D. Immunofluorescence staining and quantification of FOXO1, pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), octamer-binding protein 4 (OCT4), neurogenin 3 (Ngn3), insulin, and SIRT1, and Western blot analysis of insulin, SIRT1, and FOXO1 were performed to investigate the mechanism by which MDCH inhibited pancreatic ß-cell dedifferentiation. RESULTS: The chemical ingredients identified in MDCH were predicted to be important for signaling pathways related to lipid metabolism and insulin resistance, including lipids in atherosclerosis, the advanced glycation end product receptor of the advanced glycation end product signaling pathway, and the FOXO signaling pathway. Experimental studies showed that MDCH improved glucose and lipid metabolism in T2D mice, alleviated inflammation and oxidative stress damage, and reduced pancreatic pathological damage. Furthermore, MDCH upregulated the expression levels of SIRT1, FOXO1, PDX1, and NKX6.1, while downregulating the expression levels of OCT4 and Ngn3, which indicated that MDCH inhibited pancreatic dedifferentiation of ß cells. CONCLUSIONS: MDCH has therapeutic effects on T2D, through regulating the SIRT1/FOXO1 signaling pathway to inhibit pancreatic ß-cell dedifferentiation, which has not been reported previously.

SIRT6's function in controlling the metabolism of lipids and glucose in diabetic nephropathy.

Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) and the main cause of excess mortality in patients with type 2 DM. The pathogenesis and progression of DN are closely associated with disorders of glucose and lipid metabolism. As a member of the sirtuin family, SIRT6 has deacetylation, defatty-acylation, and adenosine diphosphate-ribosylation enzyme activities as well as anti-aging and anticancer activities. SIRT6 plays an important role in glucose and lipid metabolism and signaling, especially in DN. SIRT6 improves glucose and lipid metabolism by controlling glycolysis and gluconeogenesis, affecting insulin secretion and transmission and regulating lipid decomposition, transport, and synthesis. Targeting SIRT6 may provide a new therapeutic strategy for DN by improving glucose and lipid metabolism. This review elaborates on the important role of SIRT6 in glucose and lipid metabolism, discusses the potential of SIRT6 as a therapeutic target to improve glucose and lipid metabolism and alleviate DN occurrence and progression of DN, and describes the prospects for future research.

The Effectiveness and Safety of Abelmoschus manihot in Treating IgA Nephropathy: A Systematic Review and Meta-Analysis.

Introduction: IgA nephropathy (IgAN) is a common issue. In China, Abelmoschus manihot (AM) is widely used in the treatment of IgAN. However, their combined effectiveness and safety for this purpose have not yet been explored. AM is an effective medicine for treating IgAN. This meta-analysis aimed to evaluate the effectiveness of AM for IgAN. Materials and Methods: The Cochrane Library, PubMed, EMBASE, Allied and Complementary Medicine Database (AMED), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure Database (CNKI), Chinese Science and Technique Journals Database (VIP), and the Wanfang Database were searched from their inceptions to June 2021. Random clinical trials (RCTs) comparing the effects of AM treatment in patients with IgAN were included. The study evaluated the efficacy or effectiveness of AM for IgAN and had clear outcome data, such as total effectiveness rate or proteinuria. Results: A total of 11 RCTs with 850 participants were included in this meta-analysis. The results of the meta-analysis showed that, compared with that of the conventional therapy alone, being combined with conventional treatment was significantly more effective for the total efficacy rate (OR = 4.33; 95% CI = 2.66, 7.04; P < 0.00001) and proteinuria (MD = -0.41 g/24 h; 95% CI = -0.44, -0.38; P < 0.00001) but had no effect on serum creatinine (Scr) (MD = -2.23 µmol/L; 95% CI = -5.90, 1.45; P=0.24), eGFR (MD = -0.45 mL/min·1.73 m2; 95% CI = -1.24, 2.13; P=0.60), Bun (MD = -0.22 mmol/L; 95% CI = -0.59, 0.14; P=0.23), systolic blood pressure (MD = -0.04 mmHg; 95% CI = -2.59, 2.51; P=0.98), diastolic blood pressure (MD = -0.34 mmHg, 95% CI = -1.65, 2.33; P=0.74), systolic blood pressure (MD = -0.04 mmHg, 95% CI = -2.59, 2.51; P=0.98), or serum albumin (MD = 1.70 g/L, 95% CI = -1.06, 4.45; P=0.23). Conclusions: AM provided additional benefits to proteinuria individuals with IgAN. However, due to the high clinical heterogeneity and small sample size of the included trials, future studies should conduct more rigorous RCTs on the clinical efficacy and safety of AM and RCTs with a larger sample size involving multicenters.

Effects of allopurinol on renal function in patients with diabetes: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: Diabetes mellitus is a common "non-gout" disease with high incidence. Several studies have shown that serum uric acid level in patients with diabetes is higher than that in healthy individuals, and is accompanied by severe albuminuria and high serum creatinine (Scr). Recent clinical studies have found that uric acid-lowering therapy (such as allopurinol) could reduce urinary albumin excretion rates (UAER) and Scr, increase eGFR, and thus reduce kidney damage in patients with diabetes. Therefore, this meta-analysis [PROSPERO CRD42021274465] intended to evaluate the efficacy and safety of allopurinol in patients with diabetes mellitus. METHODS: We thoroughly searched five electronic resource databases for randomized controlled trials (RCTs) that compared the efficacy and safety of allopurinol versus conventional treatment or placebo for the treatment of patients with diabetes mellitus. Predetermined outcomes were considered continuous variables, mean difference (MD) was used for the determination of effect size (standardized mean difference [SMD] was used to determine the effect size when there were different evaluation criteria in different articles), and the corresponding 95% confidence interval (CI) was calculated. All outcome measures were analyzed using a random-effects model for data analysis. RESULTS: Ten eligible trials with a total of 866 participants were included in the meta-analysis. Allopurinol was more effective in decreasing serum uric acid (SUA) levels compared with conventional treatment (p = 0.0001) or placebo (p < 0.00001). Moreover, the levels of 24-hour urine protein were significantly lower in the allopurinol group (p < 0.00001). The subgroup analysis of Scr showed that the Scr of patients with an allopurinol treatment duration of fewer than six months was significantly lower than that of the control group (p = 0.03). No significant difference in adverse events (AEs) was identified between the treatment and control groups. CONCLUSIONS: Our meta-analysis of RCTs showed that oral administration of allopurinol effectively reduced SUA levels in patients with diabetes, and patients' renal function was protected. More RCTs with larger sample sizes and higher quality are needed to clarify the role of allopurinol use in decreasing blood pressure, maintaining blood glucose levels, and improving renal function in patients with diabetes.

Renal Protective Effects of Melatonin in Animal Models of Diabetes Mellitus-Related Kidney Damage: A Systematic Review and Meta-Analysis.

Diabetic nephropathy (DN)-chronic kidney damage caused by hyperglycemia-eventually develops into end-stage renal disease (ESRD). Melatonin is a powerful antioxidant that has a wide range of biological activities. Potentially helpful effects of melatonin on diabetic kidney disease have been found in several studies. However, its protective mechanisms are not clear and remain to be explored. In this review (CRD42021285429), we conducted a meta-analysis to estimate the effects and relevant mechanisms of melatonin for diminishing renal injuries in diabetes mellitus models. The Cochrane Library, PubMed, and EMBASE databases up to September 2021 were used. Random- or fixed-effects models were used for calculating the standardized mean difference (SMD) or 90% confidence interval (CI). The risk of bias was estimated using the SYRCLE's RoB tool. Statistical analysis was conducted with RevMan. A total of 15 studies including 224 animals were included in the analysis. The experimental group showed a remarkable decrease in serum creatinine (P = 0.002), blood urea nitrogen (P = 0.02), and urinary albumin excretion rate (UAER) (P < 0.00001) compared with the control group, while the oxidative stress index improved. The experimental group also showed a remarkable increase in superoxide dismutase (P = 0.21), glutathione (P < 0.0001), and catalase (P = 0.04) and a remarkable decrease in MDA (P < 0.00001) content compared with the control group. We concluded that melatonin plays a role in renal protection in diabetic animals by inhibiting oxidative stress. Moreover, it should be noted that fasting blood glucose was reduced in the experimental group compared with the control group. The kidney and body weights of the animals were not decreased in the diabetic animal model compared with the control group.

Efficacy of Off-Label Therapy for Non-alcoholic Fatty Liver Disease in Improving Non-invasive and Invasive Biomarkers: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Objective: To evaluate the effects of vitamin E, pioglitazone, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with non-alcoholic fatty liver disease (NAFLD). Design: A network meta-analysis. Data Sources: PubMed, Embase, Cochrane Library, and Web of Science databases from their inception until September 1, 2021. Eligibility Criteria for Selecting Studies: Randomized controlled trials (RCTs) comparing the effects of four different drugs in patients with NAFLD were included. All superiority, non-inferiority, phase II and III, non-blinded, single-blinded, and double-blinded trials were included. Interventions of interest included vitamin E (α-tocopherol and δ-tocotrienol), pioglitazone, three kinds of GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide), four SGLT2 inhibitors (dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin), and comparisons of these different drugs, and placebos. Main Outcome Measures: The outcome measures included changes in non-invasive tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), controlled attenuation parameter (CAP), enhanced liver fibrosis (ELF) score, liver fat content (LFC), and keratin-18 (K-18)] and invasive tests [fibrosis score and resolution of non-alcoholic steatohepatitis (NASH)]. Results: Twenty-seven trials including 3,416 patients were eligible for inclusion in the study. Results refer to vitamin E, pioglitazone, GLP-1 receptor agonists, and SGLT2 inhibitors. First, placebos were used as a reference. δ-Tocotrienol was superior to placebo in decreasing the GGT level. Semaglutide, ipragliflozin, and pioglitazone induced a significantly higher decrease in the ALT level than a placebo. Semaglutide, pioglitazone, and dapagliflozin were superior to placebo in decreasing the AST level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than a placebo. Liraglutide was superior to placebo in decreasing CAP. Liraglutide, pioglitazone, and vitamin E induced a significantly higher increase in resolution of NASH than a placebo. As for pairwise comparisons, semaglutide and pioglitazone were superior to liraglutide in decreasing the ALT level. Semaglutide induced a significantly higher decrease in the ALT level than dulaglutide. Semaglutide was obviously superior to empagliflozin, liraglutide, dulaglutide, and tofogliflozin in decreasing the AST level. Pioglitazone induced a significantly higher decrease in the GGT level than ipragliflozin. δ-Tocotrienol was superior to liraglutide in decreasing the GGT level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than dulaglutide. Pioglitazone was superior to vitamin E in increasing the resolution of NASH. Furthermore, liraglutide treatment had the highest SUCRA ranking in decreasing CAP and ELF scores and increasing the resolution of NASH. Pioglitazone treatment had the highest SUCRA ranking in decreasing LFC and fibrosis scores. Tofogliflozin treatment had the highest SUCRA ranking in decreasing K-18, while dapagliflozin treatment had the highest SUCRA ranking in decreasing the GGT level. Semaglutide treatment had the highest SUCRA ranking in decreasing the levels of ALT and AST. Conclusion: The network meta-analysis provided evidence for the efficacy of vitamin E, pioglitazone, SGLT2 inhibitors, and GLP-1 receptor agonists in treating patients with NAFLD. To find the best guide-level drugs, it is necessary to include more RCTs with these off-label drugs, so that patients and clinicians can make optimal decisions together. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier: CRD42021283129.

Canagliflozin for Prevention of Cardiovascular and Renal Outcomes in type2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Objective: We aimed to evaluate the efficacy of canagliflozin for the treatment of specific cardiovascular and renal outcomes in Type 2 diabetes mellitus (T2DM) patients by means of a systematic review and meta-analysis. Methods: We performed comprehensive searches of PubMed, the Cochrane Library, and Embase for randomized, placebo-controlled trials of the treatment of T2DM with canagliflozin that were published to 28 September 2020. The cardiovascular outcomes recorded were cardiovascular mortality, heart failure, myocardial infarction, and stroke. The renal composite outcomes recorded were end-stage renal disease (ESRD), renal death. The data for the principal cardiovascular outcomes, ESRD, and renal death were pooled and expressed as Hazard ratios (HRs) with 95% confidence intervals (CIs). Two reviewers independently selected the trials and extracted the data. Results: We identified a total of 1,741 publications, leaving 96 for their titles, abstracts and full-text review. Of these, 10 trials met the inclusion criteria and were finally included in our meta-analysis. The meta-analysis showed that canagliflozin significantly reduced the risk of heart failure in T2DM by 36% (HR 0.64, 95% CI 0.53 to 0.77, p = 0.000). The effects of canagliflozin on non-fatal myocardial infarction or non-fatal stroke (HR 0.84, 95% CI: 0.76 to 0.93, p = 0.001), cardiovascular mortality (HR 0.84, 95% CI 0.72 to 0.97, p = 0.021), and myocardial infarction (HR 0.84, 95% CI 0.70 to 1.00, p = 0.045) in patients with T2DM were relatively small, reducing the risks by 16%. In addition, canagliflozin reduced the risk of stroke in T2DM patients by 13% (HR 0.87, 95% CI 0.71 to 1.06, p = 0.166). Moreover, canagliflozin significantly reduced the risk of the composite renal event of ESRD or renal death by 36% (HR 0.64, 95% CI 0.54 to 0.75, p = 0.000). Conclusion: This meta-analysis suggests that canagliflozin protects against cardiovascular and renal outcomes in patients with T2DM. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], identifier [CRD42020210315].

Cordyceps cicadae Ameliorates Renal Hypertensive Injury and Fibrosis Through the Regulation of SIRT1-Mediated Autophagy.

Hypertensive renal injury is a complication of hypertension. Cordyceps cicadae (C. cicadae) is a traditional Chinese medicine used to treat chronic kidney diseases especially renal fibrosis. Autophagy is described as a cell self-renewal process that requires lysosomal degradation and is utilized for the maintenance of cellular energy homeostasis. The present study explores the mechanism underlying C. cicadae's renoprotection on hypertensive nephropathy (HN). First, HN rat models were established on spontaneously hypertensive rats (SHRs). The expression of fibrosis-related protein and autophagy-associated protein was detected in vivo. NRK-52E cells exposed to AngII were chosen to observe the potential health benefits of C. cicadae on renal damage. The level of extracellular matrix accumulation was detected using capillary electrophoresis immunoquantification and immunohistochemistry. After treatment with lysosomal inhibitors (chloroquine) or an autophagy activator (rapamycin), the expression of Beclin-1, LC3II, and SQSTM1/p62 was further investigated. The study also investigated the change in sirtuin1 (SIRT1), fork head box O3a (FOXO3a), and peroxidation (superoxide dismutase (SOD) and malondialdehyde (MDA)) expression when intervened by resveratrol. The changes in SIRT1 and FOXO3a were measured in patients and the SHRs. Here, we observed that C. cicadae significantly decreased damage to renal tubular epithelial cells and TGFß1, α-smooth muscle actin (α-SMA), collagen I (Col-1), and fibronectin expression. Meanwhile, autophagy defects were observed both in vivo and in vitro. C. cicadae intervention significantly downregulated Beclin-1 and LC3II and decreased SQSTM1/p62, showing an inhibition of autophagic vesicles and the alleviation of autophagy stress. These functions were suppressed by rapamycin, and the results were just as effective as the resveratrol treatment. HN patients and the SHRs exhibited decreased levels of SIRT1 and FOXO3a. We also observed a positive correlation between SIRT1/FOXO3a and antifibrotic effects. Similar to the resveratrol group, the expression of SIRT1/FOXO3a and oxidative stress were elevated by C. cicadae in vivo. Taken together, our findings show that C. cicadae ameliorates tubulointerstitial fibrosis and delays HN progression. Renoprotection was likely attributable to the regulation of autophagic stress mediated by the SIRT1 pathway and achieved by regulating FOXO3a and oxidative stress.

Tong-Xie-Yao-Fang Regulates 5-HT Level in Diarrhea Predominant Irritable Bowel Syndrome Through Gut Microbiota Modulation.

Tong-Xie-Yao-Fang (TXYF) has been widely used for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in traditional Chinese medicine. However, its mechanism of action in the treatment of IBS-D remains to be fully understood. Recent reports have shown that Clostridium species in the gut can induce 5-HT production in the colon, which then contributes to IBS-D. Due to the wide use of TXYF in the clinical treatment of IBS-D and the close relationship between gut microbiota and IBS-D, we hypothesize that TXYF treats IBS-D by modulating gut microbiota and regulating colonic 5-HT levels. In this study, variation analysis of 16S rRNA was conducted to evaluate changes in the distribution of gut microbiota in IBS-D model rats after TXYF treatment. Moreover, we investigated whether TXYF could affect colonic 5-HT levels in IBS-D model rats. We then performed fecal transplantation experiments to confirm the effects of TXYF on gut microbiota and 5-HT levels. We found that TXYF treatment can ameliorate IBS-D and regulate 5-HT levels in colon tissue homogenates. TXYF treatment also affected the diversity of gut microbiota and altered the relative abundance of Akkermansia and Clostridium sensu stricto 1 in gut flora populations. Finally, we showed that fecal transplantation from TXYF-treated rats could relieve IBS-D and regulate 5-HT levels in colon tissue homogenates. In conclusion, the present study demonstrates that TXYF treatment diminishes colonic 5-HT levels and alleviates the symptoms of IBS-D by favorably affecting microbiota levels in gut flora communities.

Berberine Regulates Treg/Th17 Balance to Treat Ulcerative Colitis Through Modulating the Gut Microbiota in the Colon.

Berberine (BBR), an alkaloid isolated from Rhizoma Coptidis, Cortex Phellode, and Berberis, has been widely used in the treatment of ulcerative colitis (UC). However, the mechanism of BBR on UC is unknown. In this study, we investigated the activities of T regulatory cell (Treg) and T helper 17 cell (Th17) in a dextran sulfate sodium (DSS)-induced UC mouse model after BBR administration. We also investigated the changes of gut microbiota composition using 16S rRNA analysis. We also examined whether BBR could regulate the Treg/Th17 balance by modifying gut microbiota. The mechanism was further confirmed by depleting gut microbiota through a combination of antibiotic treatment and fecal transplantations. Results showed that BBR treatment could improve the Treg/Th17 balance in the DSS-induced UC model. BBR also reduced diversity of the gut microbiota and interfered with the relative abundance of Desulfovibrio, Eubacterium, and Bacteroides. Moreover, BBR treatment did not influence the Treg/Th17 balance after the depletion of gut microbiota. Our results also revealed that fecal transplantation from BBR-treated mice could relieve UC and regulate the Treg/Th17 balance. In conclusion, our study provides evidence that BBR prevents UC by modifying gut microbiota and regulating the balance of Treg/Th17.