[Effect of traditional Chinese medicine in attenuating chronic kidney disease and its complications by regulating gut microbiota-derived metabolite trimethylamine N-oxide: a review].

Trimethylamine N-oxide(TMAO), a metabolite of gut microbiota, is closely associated with chronic kidney disease(CKD). It can aggravate the kidney injury and promote the occurrence of complications of CKD mainly by inducing renal fibroblast activation, vascular endothelial inflammation, macrophage foaming, platelet hyperreactivity, and inhibition of reverse cholesterol transport. Thus it is of great significance for clinical treatment of CKD to regulate circulating TMAO and alleviate its induced body damage. Currently, therapeutic strategies for TMAO regulation include dietary structure adjustment, lifestyle intervention, intestinal microflora regulation, and inhibition of intestinal trimethylamine synthesis and liver trimethylamine oxidation. Chinese medicinal herbs have the clinical advantage of multi-component and multi-target effects, and application of traditional Chinese medicine(TCM) to synergistically regulating TMAO and improving CKD via multiple pathways has broad prospects. This study systematically reviewed the clinical relevance and mechanism of TMAO in aggravating CKD renal function deterioration and complication progression. In addition, the effect and mechanism of TCM in improving TMAO-induced kidney injury, cardiovascular disease, hyperlipidemia, thrombosis and osteoporosis were summarized. The results provided a theoretical basis for TCM in attenuating gut microbiota-derived metabolite TMAO and improving CKD, as well as a basis and direction for in-depth clinical development and mechanism research in the future.

Causal Effects of Specific Gut Microbiota on Chronic Kidney Diseases and Renal Function-A Two-Sample Mendelian Randomization Study.

BACKGROUND: Targeting the gut microbiota may become a new therapeutic to prevent and delay the progression of chronic kidney disease (CKD). Nonetheless, the causal relationship between specific intestinal flora and CKD is still unclear. MATERIALS AND METHOD: To identify genetically predicted microbiota, we used summary data from genome-wide association studies on gut microbiota in 18340 participants from 24 cohorts. Furthermore, we genetically predicted the causal relationship between 211 gut microbiotas and six phenotypes (outcomes) (CKD, estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (UACR), dialysis, rapid progress to CKD, and rapid decline of eGFR). Four Mendelian randomization (MR) methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode were used to investigate the casual relationship between gut microbiotas and various outcomes. The result of IVW was deemed as the primary result. Then, Cochrane's Q test, MR-Egger, and MR-PRESSO Global test were used to detect heterogeneity and pleiotropy. The leave-one method was used for testing the stability of MR results and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS: Through the MR analysis of 211 microbiotas and six clinical phenotypes, a total of 36 intestinal microflora were found to be associated with various outcomes. Among them, Class Bacteroidia (=-0.005, 95% CI: -0.001 to -0.008, p = 0.002) has a strong causality with lower eGFR after the Bonferroni-corrected test, whereas phylum Actinobacteria (OR = 1.0009, 95%CI: 1.0003-1.0015, p = 0.0024) has a strong causal relationship with dialysis. The Cochrane's Q test reveals that there is no significant heterogeneity between various single nucleotide polymorphisms. In addition, no significant level of pleiotropy was found according to MR-Egger and MR-PRESSO Global tests. CONCLUSIONS: Through the two-sample MR analysis, we identified the specific intestinal flora that has a causal relationship with the incidence and progression of CKD at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for CKD.

Perilla frutescens L. alleviates trimethylamine N-oxide-induced apoptosis in the renal tubule by regulating ASK1-JNK phosphorylation.

Trimethylamine N-oxide (TMAO) is associated with overall mortality in patients with chronic kidney disease (CKD). Previous findings suggest that P. frutescens (L.) can alleviate renal injury, but its effects and mechanisms underlying alleviation of TMAO-induced kidney damage remain unclear. In this study, a TMAO injury model, in vivo and in vitro, was established to clarify the effects and mechanisms of P. frutescens in alleviating TMAO-induced kidney injury. The results show that TMAO (60 mM/L) can induce the activation of apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK), thus aggravating downstream cell apoptosis in vitro. The study also found that P. frutescens aqueous extract (PFAE) (5 mg/mL) can inhibit TMAO-induced apoptosis by downregulating ASK1-JNK phosphorylation. In the in vivo experiments, it was demonstrated that TMAO can increase the levels of blood urea nitrogen and cystatin C, aggravating renal tubular epithelial apoptosis. The results also show that PFAE can reduce TMAO-induced renal damage by inhibiting ASK1-JNK phosphorylation in vivo. Our findings confirmed that P. frutescens can alleviate TMAO-induced renal tubule apoptosis by regulating ASK1-JNK phosphorylation, indicating that P. frutescens may be an effective treatment for alleviating TMAO damage in CKD.

Total extract of Abelmoschus manihot L. alleviates uric acid-induced renal tubular epithelial injury via inhibition of caspase-8/caspase-3/NLRP3/GSDME signaling.

Purpose: The incidence of uric acid (UA)-induced kidney injury is increasing owing to the high incidence of hyperuricemia in recent years. The flower of Abelmoschus manihot (Linneus) Medik is a traditional Chinese medicinal herb widely used in the treatment of some kidney diseases. In our previous study, we reported that the total extract of A. manihot L. flower (TEA) attenuated adriamycin-induced renal tubular cell injury. In this study, we aimed to evaluate the role of TEA in UA-induced tubular cell injury. Methods: Normal rat proximal epithelial NRK-52E cells were incubated with UA to mimic hyperuricemia conditions. The role of TEA in the renal tubular cells was also assessed. The cellular morphology was observed using phase-contrast microscopy, and cell viability was analyzed using the Cell Counting kit-8. Living and dead cells were stained using a Calcein-AM/PI double stain kit. The release of lactate dehydrogenase (LDH) was analyzed by LDH cytotoxicity Assay Kit. The expression of target proteins was analyzed using western blot analysis. Results: UA triggered NRK-52E cell injury, as evidenced by morphological changes, detachment of cells from the bottom, cell swelling, large bubbles blowing from cell membrane and loss of cell viability. UA increased release of LDH. UA induced the expression of p-ERK1/2 and the subsequent activation of caspase-8, caspase-3, and NLRP3 inflammasomes. Pyroptosis was elicited by UA after gasdermin E N-terminal (GSDME-NT) was cleaved from gasdermin E (GSDME). Z-DEVD-FMK, a caspase-3 inhibitor, suppressed the expression of both NLRP3 and GSDME-NT, but not that of caspase-8. INF39, an NLRP3 inhibitor, altered the expression of GSDME-NT expression, but not that caspase-3 and caspase-8. TEA alleviated UA-induced cell injury by suppressing ERK1/2/caspase-8/caspase-3/NLRP3/GSDME signaling. Conclusion: GSDME-mediated pyroptosis was involved in UA-induced renal tubular cell injury. This is the first study to report that TEA protects renal tubular epithelial cells against UA by inhibiting the ERK/1/2/caspase-8/caspase-3/NLRP3/GSDME pathway.

A Novel Nomogram Based on a Competing Risk Model Predicting Cardiovascular Death Risk in Patients With Chronic Kidney Disease.

Objective: Chronic kidney disease (CKD) patients are more likely to die from cardiovascular disease (CVD) than develop renal failure. This study aimed to develop a new nomogram for predicting the risk of cardiovascular death in CKD patients. Methods: This study enrolled 1656 CKD patients from NHANES 2003 to 2006 survey. Data sets from 2005 to 2006 survey population were used to build a nomogram for predicting the risk of cardiovascular death, and the nomogram was validated using data from 2003 to 2004 survey population. To identify the main determinants of cardiovascular death, we performed univariate analysis and backward-stepwise regression to select the key factors. The probability of cardiovascular death for each patient in 5, 7, and 9 years was calculated using a nomogram based on the predictors. To assess the nomogram's performance, the area under receiver operating characteristic curve (AUC) and the calibration curve with 1,000 bootstraps resamples were utilized. The prediction model's discrimination was examined using cumulative incidence function (CIF). Results: Age, homocysteine, potassium levels, CKD stage, and anemia were included in the nomogram after screening risk factors using univariate analysis and backward-stepwise regression. Internal validation revealed that this nomogram possesses high discrimination and calibration (AUC values of 5-, 7-, and 9-years were 0.79, 0.81, and 0.81, respectively). External validation confirmed the same findings (AUC values of 5-, 7- and 9-years were 0.76, 0.73, and 0.73, respectively). According to CIF, the established nomogram effectively differentiates patients at a high risk of cardiovascular death from those at low risk. Conclusion: This work develops a novel nomogram that integrates age, homocysteine, potassium levels, CKD stage, and anemia and can be used to more easily predict cardiovascular death in CKD patients, highlighting its potential value in clinical application.

Development and validation of a novel nomogram to predict overall survival of patients with moderate to severe chronic kidney disease.

INTRODUCTION: The risk of death significantly increased from stage 3 chronic kidney disease (CKD) onward. We aimed to construct a novel nomogram to predict the overall survival (OS) of patients afflicted with CKD from stage 3-5. METHODS: A total of 882 patients with stage 3-5 CKD were enrolled from the NHANES 2001-2004 survey. Data sets from the 2003-2004 survey population were used to develop a nomogram that would predict the risk of OS. The 2001-2002 survey population was used to validate the nomogram. Least absolute shrinkage and selection operator (Lasso) regression was conducted to screen the significant predictors relative to all-cause death. The multivariate Cox regression based on the screened factors was applied to effectively construct the nomogram. The performance of the nomogram was evaluated according to the C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve with 1000 bootstraps resample. Kaplan-Meier's curves were used for testing the discrimination of the prediction model. RESULTS: Five variables (age, urinary albumin-to-creatinine ratio (UACR), potassium, cystatin C (Cys C), and homocysteine) were screened by the Lasso regression. The nomogram was constructed using these factors, as well as the CKD stage. The included factors (age, CKD stage, UACR, potassium, Cys C, and homocysteine) were all significantly related to the death of CKD patients, according to the multivariate Cox regression analysis. The internal validation showed that this nomogram demonstrates good discrimination and calibration (adjusted C-index: 0.70; AUC of 3-, 5-, and 10-year OS were 0.75, 0.78, and 0.77, respectively). External validation also demonstrated exceedingly similar results (C-index: 0.72, 95% CI: 0.69-0.76; AUC of 3-, 5-, and 10-year OS were 0.76, 0.79, and 0.80, respectively). CONCLUSIONS: This study effectively constructed a novel nomogram that incorporates CKD stage, age, UACR, potassium, Cys C, and homocysteine, which can be conveniently used to facilitate the individualized prediction of survival probability in patients with stage 3-5 CKD. It displays valuable potential for clinical application.

Effects of SGLT2 inhibitors on cardiovascular outcomes in patients with stage 3/4 CKD: A meta-analysis.

INTRODUCTION: After stage 3 CKD, the risk of adverse cardiovascular events increased significantly. Therefore, we performed a meta-analysis to investigate the cardiovascular protective effect of SGLT2 inhibitors in patients with stage 3/4 CKD with different baseline kidney function or underlying diseases. METHOD: To identify eligible trials, we systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021. The primary cardiovascular outcome was defined as a combination of cardiovascular mortality and hospitalization due to heart failure. Baseline kidney functions (stage 3a CKD: eGFR45-59mL/min per 1.73m2, stage 3b CKD: eGFR30-44mL/min per 1.73m2, stage 4 CKD: eGFR<30mL/min per 1.73m2) and underlying diseases (Type 2 diabetes, heart failure (Preserved ejection fraction or reduced ejection fraction), atherosclerotic cardiovascular disease) were used to stratify efficacy and safety outcomes. The results were subjected to a sensitivity analysis to ensure that they were reliable. RESULTS: In the present study, a total of eleven trials were included that involved a total of 27,823 patients with stage 3/4 CKD. The treatment and control groups contained 14,451 and 13,372 patients, respectively. In individuals with stage 3/4 CKD, SGLT2 inhibitors reduced the risk of primary cardiovascular outcomes by 26% (HR 0.74, [95% CI 0.69-0.80], I2 = 0.00%), by 30% in patients with stage 3a CKD (HR 0.70, [95% CI 0.59-0.84], I2 = 18.70%), by 23% in patients with stage 3b CKD (HR 0.77, [95% CI 0.66-0.90], I2 = 2.12%), and by 29% in patients with stage 4 CKD (HR 0.71, [95% CI 0.53-0.96], I2 = 0.00%). The risk of primary outcomes was reduced by 29% (HR 0.71, [95% CI 0.63-0.80], I2 = 0.00%) in patients with type 2 diabetes, by 28% (HR 0.72, [95% CI 0.56-0.93], I2 = 37.23%) in patients with heart failure with preserved ejection fraction, by 21% (HR 0.79, [95% CI 0.70-0.89], I2 = 0.00%) in patients with heart failure with reduced ejection fraction, and by 25% (HR 0.75, [95% CI 0.64-0.88], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease. CONCLUSIONS: For stage 3/4 CKD, SGLT2 inhibitors significantly decreased the risk of primary cardiovascular outcomes, and these benefits were consistent throughout the spectrum of different kidney functions, even in stage 4 CKD. There was no evidence of increased adverse outcomes across different baseline clinical complications, such as type 2 diabetes, heart failure, or atherosclerotic cardiovascular disease.

Artemisia capillaris Thunb. water extract attenuates adriamycin-induced renal injury by regulating apoptosis through the ROS/MAPK axis.

Artemisia capillaris Thunb. is widely used in the treatment of kidney diseases, but the underlying mechanism remain elusive. Therefore, this study aimed to elucidate the mechanism of Artemisia capillaris Thunb. in alleviating renal injury. And renoprotective effects of freeze-dried powder of Artemisia capillaris Thunb. water extract (WAC) were assessed using adriamycin (ADR)-induced renal injury to the NRK-52E cells and ADR-induced renal injury Sprague-Dawley rats (SD rats) models. The results show that WAC could alleviate ADR-induced renal injury in SD rats and the NRK-52E cell line, improved renal function (BUN 9.73 ± 0.35 vs 7.13 ± 0.15, SCR 80.60 ± 1.68 vs 60.50 ± 1.42, ACR 11.50 ± 0.50 vs 8.526 ± 0.15) or cell viability (IC50 = 1.08 µg/ml (ADR), cell viability increase 36.38% ± 6.74% (added 4 mg/ml WAC)), and reduced the apoptosis. Moreover, WAC inhibited the MAPK signal transduction, increased the expression of superoxide dismutase 1 (SOD1), and decreased the production of ROS. The treatment of N-acetylcysteine (NAC, antioxidant) in vitro showed that NAC inhibited apoptosis and alleviated renal injury by inhibiting oxidative stress and reducing the phosphorylation of proteins related to the MAPK signaling pathway. Therefore, these results suggested that WAC can alleviate ADR-induced renal injury and apoptosis by regulating the ROS/MAPK axis and has potential to be used as a renoprotective drug. PRACTICAL APPLICATIONS: Artemisia capillaris Thunb., which is a medicinal and edible plant, is widely used to treat kidney diseases in traditional Chinese medicine. The present research examined the renal protective effect of Artemisia capillaris Thunb. The results show that Artemisia capillaris Thunb. can effectively reduce renal tubular cell apoptosis through the ROS/MAPK axis in vivo and in vitro. In general, Artemisia capillaris Thunb. can be used as a potential herb to attenuate renal injury and further research can be conducted to explore its renoprotective mechanisms.

The Association between Leisure-Time Physical Activity Intensity and Duration with the Risk of Mortality in Patients with Chronic Kidney Disease with or without Cardiovascular Diseases.

Introduction: For chronic kidney disease (CKD) patients with or without cardiovascular diseases, the associations between leisure-time physical activity intensity (LTPA) and daily exercise time with mortality risk remain unclear. Method: This study enrolled 3279 CKD patients from National Health and Nutrition Examination Survey (NHANES) 2007-2014 survey. Patients were grouped into different groups according to LTPA intensity (none, moderate, vigorous) and duration (0 min, 0-30 min, 30-60 min, > 60 min). We selected the confounders based on their connections with the outcomes of interest or a change in effect estimate of more than 10%. Multivariable-adjusted Cox proportional hazards models were used to examine the associations between LTPA and mortality. The three-knot cubic spline (10, 50, and 90%) was employed to investigate the relationship between the dose of LTPA duration and all-cause death. Patients were divided into different groups according to cardiovascular diseases (CVD). Results: A total of 564 all-cause death were recorded in this study. Multivariable Cox regression showed that moderate LTPA was associated with a reduced risk of mortality by 38% (hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.44-0.88) in CKD patients, while vigorous LTPA did not have evident survival benefits (HR: 0.91, 95% CI: 0.46-2.64). Subgroups analysis demonstrated that those who engaged in moderate LTPA have a significantly lower risk of mortality (HR: 0.67, 95% CI: 0.47-0.95) in patients without CVD, while patients complicated with CVD did not benefit from the practice (HR: 0.61, 95% CI: 0.37-1.02). Physical exercise for more than 30 minutes was associated with a lower risk of mortality in general CKD patients (30-60 min: HR: 0.23, 95% CI: 0.09-0.58, > 60 min: HR: 0.23, 95% CI: 0.08-0.63) and those without CVD (30-60 min/d: HR: 0.32, 95% CI: 0.12-0.83, > 60 min/d: HR: 0.20, 95% CI: 0.06-0.71); however, this positive outcome was not seen in patients complicated with CVD (30-60 min/d: HR: 0.67, 95% CI: 0.11-4.04, > 60 min/d: HR: 1.14, 95% CI: 0.14-9.11). Conclusions: Moderate LTPA for more than 30 minutes is associated with a reduced risk of mortality in general CKD patients and those without CVD. However, LTPA did not reduce the risk of mortality in CKD patients complicated with CVD.

Exploring the Critical Components and Therapeutic Mechanisms of Perilla frutescens L. in the Treatment of Chronic Kidney Disease via Network Pharmacology.

Chronic kidney disease (CKD) is a chronic progressive disease that seriously threatens human health. Some patients will continue to progress into the CKD stage 3-5 (also called chronic renal failure), which is mainly manifested by a decline in renal function and multi-system damage. Perilla frutescens (L.) Britton. (Lamiaceae) is one of the most widely used traditional Chinese medicine (TCM) herbs in CKD, especially in CKD stage 3-5. But its active components and mechanisms are still unclear. In this study, we used network pharmacology to analyze the active components of P. frutescens and the main therapeutic targets for intervention in CKD stage 3-5. Then, the key components were selected for enrichment analysis and identified by high performance liquid chromatograph (HPLC). Finally, we verified the critical components through molecular docking, and in vitro experiments. The results show that 19 main active components of P. frutescens were screened, and 108 targets were intersected with CKD stage 3-5. The PPI network was constructed and found that the core nodes AKT1, TP53, IL6, TNF, and MAPK1 may be key therapeutic targets. Enrichment analysis shows that related targets may be involved in regulating various biological functions, and play a therapeutic role in CKD stage 3-5 by regulating apoptosis, T cell receptor, and PI3K-AKT signaling pathways. Molecular docking indicates that the key active components were well docked with its corresponding targets. Five active components were identified and quantified by HPLC. According to the results, luteolin was selected as the critical component for further verification. In vitro experiments have shown that luteolin can effectively alleviate adriamycin (ADR)-induced renal tubular apoptosis and suppress AKT and p53 phosphorylation. The effects of luteolin to reduce apoptosis may be mediated by inhibiting oxidative stress and downregulating the mitogen-activated protein kinase (MAPK) and p53 pathways. In general, we screened and analyzed the possible active components, therapeutic targets and pathways of P. frutescens for treating CKD. Our findings revealed that luteolin can reduce renal tubular epithelial cell apoptosis and may be the critical component of P. frutescens in the treatment of CKD. It provides references and direction for further research.

Chinese Herbal Medicine Suyin Detoxification Granule Inhibits Pyroptosis and Epithelial-Mesenchymal Transition by Downregulating MAVS/NLRP3 to Alleviate Renal Injury.

PURPOSE: Proteinuria is an independent risk factor of chronic kidney disease (CKD). Albumin-induced tubulointerstitial inflammation and epithelial-mesenchymal transition (EMT) via the activation of NLRP3 inflammasome is a potential therapeutic target for CKD. Suyin Detoxification Granule (SDG) improves proteinuria and postpones renal failure. However, the underlying mechanism is still unknown. METHODS: Firstly, the rat model of renal failure was established using intragastric administration of adenine. Renal function, proteinuria, inflammatory indicators in serum, and renal pathology were assessed, and renal immunohistochemical staining of NLRP3 inflammasomes was performed after intervention with low and high concentrations of SDG. Secondly, the model of renal tubular epithelial HK-2 cells was established using albumin in vitro, and the cell viability, EMT phenotype, and the expression of proteins in the NLRP3 inflammasome signaling pathway were measured after the freeze-dried powder of Suyin Detoxification Prescription (SDP) and CY-09, which is a selective and direct NLRP3 inhibitor, were co-incubated with albumin. ATP, SOD, mitochondrial membrane potential, and ROS were further measured in vitro, and changes in the mitochondrial function after SDP intervention were observed. The mitochondrial antiviral signaling protein (MAVS) was knocked down using siRNA, and the interaction between MAVS and NLRP3 was verified using Western blotting, polymerase chain reaction (PCR), and immunofluorescence. RESULTS: SDG improved renal function and proteinuria, alleviated renal fibrosis, and reduced serum inflammation and the expression of the components of the NLRP3 inflammasome in the kidney. In vitro, SDP and CY-09 enhanced cell viability after injury with albumin and inhibited pyroptosis induced by the NLRP3 inflammatory signaling pathway and expression of proteins involved in EMT. It was further found that SDP alleviated the mitochondrial dysfunction caused by albumin. The knockdown of MAVS reduced the expression of NLRP3 pathway proteins and their mRNA levels and also weakened the co-localization of NLRP3, thus, reducing cell pyroptosis. CONCLUSION: SDP protected renal tubular epithelial cells from cell pyroptosis and EMT by regulating the albumin-induced mitochondrial dysfunction/ MAVS/ NLRP3-ASC-caspase-1 inflammasome signaling pathway.

Effects of SGLT2 Inhibitors on Renal Outcomes in Patients With Chronic Kidney Disease: A Meta-Analysis.

Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear. Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function. Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) >300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR<60 mL/min/1.73 m2 (HR 0.70, [95% CI 0.58-0.83], I2 = 0.00%) and by 43% in patients with UACR > 300 mg/g (HR 0.57, [95% CI 0.48-0.67], I2 = 16.59%). A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR<60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease (HR 0.74, [95% CI 0.51-1.06], I2 = 0.00%). However, they reduced the risk of major renal outcomes by 46% (HR 0.54, [95% CI 0.38-0.76], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure (eGFR<60 mL/min/1.73 m2: HR 0.81, [95% CI 0.47-1.38], I2 = 0.00%; UACR > 300 mg/g: HR 0.66, [95% CI 0.41-1.07], I2 = 0.00%). SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48). Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect.

Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation.

BACKGROUND AND OBJECTIVE: Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its applicability, with nephrotoxicity considered a major dose-limiting adverse effect. Apigenin (APG), a flavonoid widely distributed in natural plants, has been reported to have antioxidant, anti-inflammatory, and mild tumor-suppressive properties. In this study, we investigated the role of APG in DOX-induced nephrotoxicity and chemotherapeutic efficacy. METHODS: Male BALB/c mice were administered DOX (11.5 mg/kg) via the tail vein to establish the DOX nephropathy model. After treatment with or without APG (125, 250, and 500 mg/kg) for two weeks, urine, serum, and tissue samples were collected to evaluate proteinuria, serum albumin, serum creatinine (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD) activity, malondialdehyde (MDA), glutathione (GSH), and pathological changes. Rat renal tubular epithelial cells (NRK52E), murine podocyte cells (MPC5), and murine breast cancer cells (4T1) were utilized to verify the effect of APG on DOX-induced cell injury. An MTT assay was employed to analyze cell viability. Apoptosis was evaluated using a colorimetric TUNEL staining and cleaved caspase-3 protein analysis by western blotting. A reactive oxygen species (ROS)/superoxide (O2-) fluorescence probe was employed to determine oxidative injury. Western blotting was used to analyze nephrin, α-smooth muscle actin (α-SMA), collagen I (Col1), fibronectin (FN), and SOD2 expression. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18), IL-6, NACHT, LRR, PYD domain-containing protein 3 (NLRP3), caspase-1, and IL-1ß were tested by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: APG ameliorated DOX-elicited renal injuries in both the glomeruli and tubules. The DOX + APG groups had much lower tissue MDA, IL-6, TNF-α, NLRP3, caspase-1, and IL-1ß levels and generation of intracellular ROS, but significantly higher SOD activity and GSH levels compared to those of the DOX group. Additionally, APG attenuated DOX-induced morphological changes, loss of cellular viability, and apoptosis in NRK-52E and MPC-5 cells, but not in 4T1 cells. CONCLUSION: APG has a protective role against DOX-induced nephrotoxicity, without weakening DOX cytotoxicity in malignant tumors. Thus, APG may serve as a potential protective agent against renal injury and inflammatory diseases and may be a promising candidate to attenuate renal toxicity in cancer patients treated with DOX.

Efficacy and Safety of Chinese Herbal Formula Granules in Treating Chronic Kidney Disease Stage 3: A Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

BACKGROUND: It is generally considered that traditional Chinese medicine (TCM) therapy postpones the progression of some chronic kidney diseases (CKDs). Chinese medicine herbs are widely applied in TCM therapy. We aimed to evaluate clinical efficacy and safety of Chinese herbal formula granules in patients with CKD stage 3 through a prospective randomized controlled study. METHODS: A total of 343 participants with CKD stage 3 were recruited from 9 hospitals in Jiangsu Province between April 2014 and October 2016. Participants were randomly assigned to a treatment or control group. Patients in the treatment group orally took Chinese herbal formula granules twice a day, while controls received placebo granules. The duration of intervention was 24 weeks. Primary outcomes were 24-hour proteinuria, serum creatinine, and eGFR, which were measured every 4 weeks. RESULTS: There was no statistical difference in 24-hour proteinuria between the two groups (0.97 ± 1.14 g/d vs. 0.97 ± 1.25 g/d). Patients in the treatment group had significantly lower serum creatinine level (130.78 ± 32.55 µmol/L versus 149.12 ± 41.27 µmol/L) and significantly higher eGFR level (55.74 ± 50.82 ml/min/1.73·m2 versus 44.46 ± 12.60 ml/min/1.73·m2) than those in the control group (P < 0.05). There was no significant difference between two groups in the incidence of adverse events. CONCLUSION: The treatment adopting Chinese herbal formula granules for 24 weeks improved kidney function of patients with CKD stage 3.

Sodium Butyrate-Modulated Mitochondrial Function in High-Insulin Induced HepG2 Cell Dysfunction.

The liver plays a pivotal role in maintaining euglycemia. Biogenesis and function of mitochondria within hepatocytes are often the first to be damaged in a diabetic population, and restoring its function is recently believed to be a promising strategy on inhibiting the progression of diabetes. Previously, we demonstrated that the gut microbiota metabolite butyrate could reduce hyperglycemia and modulate the metabolism of glycogen in both db/db mice and HepG2 cells. To further explore the mechanism of butyrate in controlling energy metabolism, we investigated its influence and underlying mechanism on the biogenesis and function of mitochondria within high insulin-induced hepatocytes in this study. We found that butyrate significantly modulated the expression of 54 genes participating in mitochondrial energy metabolism by a PCR array kit, both the content of mitochondrial DNA and production of ATP were enhanced, expressions of histone deacetylases 3 and 4 were inhibited, beta-oxidation of fatty acids was increased, and oxidative stress damage was ameliorated at the same time. A mechanism study showed that expression of GPR43 and its downstream protein beta-arrestin2 was increased on butyrate administration and that activation of Akt was inhibited, while the AMPK-PGC-1alpha signaling pathway and expression of p-GSK3 were enhanced. In conclusion, we found in the present study that butyrate could significantly promote biogenesis and function of mitochondria under high insulin circumstances, and the GPR43-ß-arrestin2-AMPK-PGC1-alpha signaling pathway contributed to these effects. Our present findings will bring new insight on the pivotal role of metabolites from microbiota on maintaining euglycemia in diabetic population.

Data Mining-Based Analysis of Chinese Medicinal Herb Formulae in Chronic Kidney Disease Treatment.

BACKGROUND: Traditional Chinese medicine (TCM) has long been used to treat chronic kidney disease (CKD) in Asia. Its effectiveness and safety for CKD treatment have been confirmed in documented studies. However, the prescription rule of formulae for Chinese medicinal herbs is complicated and remains uncharacterized. Thus, we used data mining technology to evaluate the treatment principle and coprescription pattern of these formulae in CKD TCM treatment. METHODS: Data on patients with CKD were obtained from the outpatient system of a TCM hospital. We established a Chinese herb knowledge base based on the Chinese Pharmacopoeia and the Chinese Materia Medica. Then, following extraction of prescription information, we deweighted and standardized each prescribed herb according to the knowledge base to establish a database of CKD treatment formulae. We analyzed the frequency with which individual herbs were prescribed, as well as their properties, tastes, meridian tropisms, and categories. Then, we evaluated coprescription patterns and assessed medication rules by performing association rule learning, cluster analysis, and complex network analysis. RESULTS: We retrospectively analyzed 299 prescriptions of 166 patients with CKD receiving TCM treatment. The most frequently prescribed core herbs for CKD treatment were Rhizoma Dioscoreae (Shanyao), Spreading Hedyotis Herb (Baihuasheshecao), Root of Snow of June (Baimagu), Radix Astragali (Huangqi), Poria (Fulin), Rhizoma Atractylodis Macrocephalae (Baizhu), Radix Pseudostellariae (Taizishen), and Fructus Corni (Shanzhuyu). The TCM properties of the herbs were mainly being warm, mild, and cold. The tastes of the herbs were mainly sweet, followed by bitter. The main meridian tropisms were Spleen Meridian of Foot-Taiyin, Liver Meridian of Foot-Jueyi, Lung Meridian of Hand-Taiyin, Stomach Meridian of Foot-Yangming, and Kidney Meridian of Foot-Shaoyin. The top three categories were deficiency-tonifying, heat-clearing, and dampness-draining diuretic. CONCLUSION: Using an integrated analysis method, we confirmed that the primary TCM pathogeneses of kidney disease were deficiency and dampness-heat. The primary treatment principles were tonifying deficiency and eliminating dampness-heat.

Total Extracts of Abelmoschus manihot L. Attenuates Adriamycin-Induced Renal Tubule Injury via Suppression of ROS-ERK1/2-Mediated NLRP3 Inflammasome Activation.

Abelmoschus manihot (L.) Medik. (Malvaceae) is a herb used in traditional Chinese medicine to treat some kidney diseases. To date, the detailed mechanisms by which A. manihot improves some kinds of renal disease are not fully understood. In this study, we established Adriamycin-induced NRK-52E cells, the normal rat kidney epithelial cell line, injury, and Sprague-Dawley rats with Adriamycin-induced nephropathy to evaluate the role and mechanisms of total extracts of A. manihot flower (TEA) both in vitro and in vivo. We found that TEA ameliorated Adriamycin-induced cellular morphological changes, cell viability, and apoptosis through the suppression of protein oxidation and ERK1/2 signaling. However, this anti-oxidative stress role of TEA was independent of ROS inhibition. Adriamycin activated ERK1/2 signaling followed by activation of NLRP3 inflammasomes. TEA suppressed NLRP3 inflammasomes via inhibition of ERK1/2 signal transduction; decreased proteinuria and attenuated renal tubule lesions; and inhibited the expression of NLRP3 in tubules in rats with Adriamycin nephropathy. Collectively, TEA protects renal tubular cells against Adriamycin-induced tubule injury via inhibition of ROS-ERK1/2-NLRP3 inflammasomes.