KEY POINTS:Integrated stress response promotes drug-induced AKI. Activating transcription factor 4 promoted tubular epithelial cell pyroptosis in drug-induced AKI by activating signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling. BACKGROUND:Pyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases, such as AKI, which currently lacks specific treatment options. METHODS:Changes in tubular epithelial cells (TEC) after drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, coimmunoprecipitation, and Western blotting. TEC fate was further evaluated using transgenic mouse models and pharmacological interventions. RESULTS:We identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in TECs significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited signal transducer and activator of transcription 1 phosphorylation and disrupted its interaction with guanylate-binding protein 2, thereby attenuating NLR family pyrin domain-containing 3 inflammasome activation, preventing TECs' pyroptosis, and improving kidney function. Notably, inhibition of ATF4-either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of TECs-significantly reduced renal inflammation and injury. CONCLUSIONS:ATF4 promoted pyroptosis in drug-induced AKI through signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling.

Emerging insights into lactate‑mediated protein lactylation illuminate novel regulatory axes in the pathogenesis of diabetic nephropathy (DN). While histone lactylation has established epigenetic associations with metabolic memory, expanding proteomic evidence reveals dynamic lactylation landscapes across extracellular matrix components, inflammatory mediators and redox regulators in renal compartments. The present review systematically catalogues DN‑relevant histones and non‑histone substrates undergoing functional lactylation, while mechanistically dissecting how hyperglycemia‑fueled lactate flux drives DN through lactate‑mediated protein modification landscapes. The present review further delineates the progress of research on the potential regulatory mechanisms involved in DN and delve into the possible functions and related mechanisms. This mechanistic reappraisal establishes lactylation topology mapping as a prerequisite for developing precision modulation approaches in DN management.

Key PointsIntegrated stress response promotes drug-induced AKI.Activating transcription factor 4 promoted tubular epithelial cell pyroptosis in drug-induced AKI by activating signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling.BackgroundPyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases, such as AKI, which currently lacks specific treatment options.MethodsChanges in tubular epithelial cells (TEC) after drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, coimmunoprecipitation, and Western blotting. TEC fate was further evaluated using transgenic mouse models and pharmacological interventions.ResultsWe identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in TECs significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited signal transducer and activator of transcription 1 phosphorylation and disrupted its interaction with guanylate-binding protein 2, thereby attenuating NLR family pyrin domain-containing 3 inflammasome activation, preventing TECs' pyroptosis, and improving kidney function. Notably, inhibition of ATF4-either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of TECs-significantly reduced renal inflammation and injury.ConclusionsATF4 promoted pyroptosis in drug-induced AKI through signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling.

Epigenetic regulation in disease development has been witnessed within this decade. RNA methylation is the predominant form of epigenetic regulation, and the most prevalent modification in RNA is N6-methyladenosine (m6A). Recently, RNA modification has emerged as a potential target for disease treatment. RNA modification is a posttranscriptional gene expression regulation that is involved in both physiological and pathological processes. Evidence suggests that m6A methylation significantly affects RNA metabolism, and its abnormal changes have been observed in a variety of diseases. Metabolic diseases are a series of diseases caused by abnormal metabolic processes of the body, the common metabolic diseases include diabetes mellitus, obesity, and nonalcoholic fatty liver disease, etc.; although the pathogenesis of these diseases differs from each other to the current understanding, most recent studies suggested pivotal role m6A in modulating these metabolic diseases, and m6A-based drug development has been on the agenda. This paper reviewed recent understanding of RNA modification in metabolic diseases, hoping to provide systematic information for those in this area.

Diabetic kidney disease (DKD), affecting 20-40% of individuals with diabetes, is the leading cause of end-stage renal disease and represents a considerable global public health challenge owing to its high morbidity and mortality rates. Although traditional DKD management has focused on renin-angiotensin system blockade, the residual risk of renal failure persists despite optimised therapy. New therapeutic drugs, including glucagon-like peptide-1 receptor agonists, have triggered a paradigm shift in DKD treatment. Sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and selective endothelin receptor antagonists have shown notable efficacy in improving renal outcomes in patients with type 2 diabetes mellitus. Furthermore, traditional Chinese medicine (TCM), with its holistic approach and evidence-based refinements, has shown considerable promise in DKD treatment, particularly as its theoretical framework continues to evolve. This study highlighted the transformative potential of multitargeted strategies in mitigating DKD progression, improving cardiovascular outcomes, and alleviating healthcare burdens. Future research should prioritise standardised trials, long-term safety assessments of TCM and personalised therapeutic regimens to optimise clinical management and patient quality of life.

Background: The aim of this study was twofold: (1) to explore risk factors contributing to the progression of diabetic kidney disease (DKD) and the occurrence of renal and cardiovascular endpoint events in a real-world setting, and (2) to evaluate the effectiveness of Shenyuan Granules, a Chinese herbal medicine. Methods: This cohort study was performed on 298 DKD patients from June 2020 to June 2024. The patients were divided into risk groups based on Kidney Disease: Improving Global Outcomes (KDIGO) 2024 guidelines. Cox proportional hazards regression models were employed to identify the risk factors that contribute to renal and cardiovascular events. Propensity score matching (PSM) was used as the statistical method to compare 36 treatment-group patients, who were treated with Shenyuan Granules along with standard treatment, with 36 control-group patients, who received standard treatment alone. Furthermore, clinical biochemical indicators, traditional Chinese medicine (TCM) syndrome scores, and cardiovascular and renal endpoints of the two groups were assessed and compared. Results: This study helped identify the risk factors associated with renal and cardiovascular endpoint events in 298 DKD patients. The independent risk factors identified to be associated with renal endpoint events in DKD patients ( P < 0.05) were as follows: advanced age, elevated serum creatinine (Scr), elevated uric acid, elevated platelet lymphocyte ratio (PLR), abdominal aortic calcification (AAC), cardiac valve calcification (CVC), increased left ventricular mass index (LVMI), and left ventricular hypertrophy (LVH). However, the independent risk factors identified to be associated with cardiovascular endpoint events in DKD patients ( P < 0.05) were as follows: hypertension, AAC, CVC, increased LVMI, LVH, and left ventricle ejection fraction (LVEF) < 55.0%. According to the findings, Shenyuan Granules significantly improved TCM syndrome scores (83.3% and 44.4%, for treatment and control groups, respectively, with P < 0.05 each) in terms of key clinical indicators, including hemoglobin, estimated glomerular filtration rate (eGFR), Scr, 24-hour urinary protein, LVEF, and LVMI. Conclusion: Factors such as AAC, CVC, LVH, and increased LVMI can continue to deteriorate kidneys and increase the risk of cardiovascular diseases. However, Shenyuan Granules offer promising results in significantly improving renal and cardiac function and alleviating the clinical symptoms of DKD patients.

BACKGROUND:Inflammation and oxidative stress are important pathological processes of contrast-induced acute renal injury (CIAKI). This study explored whether DMF had therapeutic effects and investigated the underlying mechanism in CIAKI. METHODS:A CIAKI animal model was established in C57BL/6J mice with iohexol, and DMF was used as an intervention. In vitro, HK-2 cells were treated with iohexol and DMF. RNA-seq analysis was performed on the renal tissue of the mice. Protein-protein interaction (PPI), and enrichment analysis were subsequently conducted. In addition, endoplasmic reticulum stress (ERS) activation and STAT3 inhibition were used to study the relationships among ERS, the JAK2-STAT3 pathway and pyroptosis. RESULTS:DMF improved the renal function of CIAKI model mice. Enrichment analysis revealed that the differentially expressed genes (DEGs) were enriched mostly in the acute phase response and the JAK-STAT pathway. The results revealed that inflammation, ERS and pyroptosis increased in the CIAKI group but decreased after DMF treatment. Further study revealed that the JAK2-STAT3 pathway was overactivated in vivo and in vitro and that DMF inhibited the JAK2-STAT3 pathway. In addition, ERS activation could increase the JAK2-STAT3 pathway and pyroptosis, while STAT3 knockdown could reverse pyroptosis, indicating that ERS could activate the JAK2-STAT3 pathway, further triggering pyroptosis. DMF ameliorated pyroptosis through regulating ERS and the JAK2-STAT3 pathway in CIAKI. CONCLUSION:This study demonstrated that DMF had renoprotective effects on CIAKI. DMF ameliorated pyroptosis through the inhibition of ERS and the JAK2-STAT3 pathway.

Abstract Background The treatment options to delay the progression of diabetic nephropathy (DN), a key contributor to chronic kidney disease (CKD), are urgently needed. Previous studies reported that traditional Chinese medicine Panax notoginseng (PNG) exerted beneficial effects on DN. However, the renoprotective effects of Notoginsenoside R2 (NR2), an active component of PNG, on DN have not been investigated. This study aimed to assess the therapeutic potential of NR2 in DN and explore its underlying mechanisms. Methods In vivo models were developed using db/db mice, while in vitro models utilized HK-2 cells exposed to high glucose and palmitic acid (HGPA). Online databases and Cytoscape software were employed to predict the potential targets of NR2. The expression of associated proteins was measured using immunohistochemistry and western blot. Lipid accumulation, oxidative stress levels, mitochondrial function and cell apoptosis were also assessed. Small interfering RNA was used in in vitro experiments to examine the effect of c-Src. Results NR2 ameliorated albuminuria, renal function and renal pathology in db/db mice. The activation of c-Src was suppressed in db/db mice and in HK-2 cells exposed to HGPA. NR2 inhibited JNK/STAT1 phosphorylation and CD36 overexpression. NR2 also ameliorated lipid accumulation, oxidative stress, mitochondrial dysfunction and cell apoptosis in vivo and in vitro. By inhibiting c-Src, HK-2 cells exposed to HGPA experienced less lipid deposition and mitochondrial damage, indicating the renoprotective effects of NR2 were correlated with the inhibition of c-Src. Conclusion NR2 ameliorated mitochondrial dysfunction and delayed the progression of DN partly through suppression of c-Src. The protective effects of NR2 might be related to a reduction in lipid accumulation. Graphical Abstract

Diabetic kidney disease (DKD) is one of the most common and severe chronic microvascular complications of diabetes mellitus (DM). The pathogenesis of DKD is complex, and lipid metabolism disorders play an important role in the pathogenesis of DKD. DKD belongs to the category of “kidney deficiency”, “edema”, “guan ge” and other pathological factors secondary to “thirst quenching disease” in traditional Chinese medicine. The pathological factors mainly focus on blood stasis and toxicity, which is consistent with modern medical theory. At present, the efficacy and safety of integrated traditional Chinese and Western medicine in treating lipid metabolism disorders in patients with DKD have been extensively studied and confirmed. In this review, the application and possible mechanism of traditional Chinese patent medicines (Bailing Capsule, Shenyan Kangfu Tablets, Jinshuibao Capsule, Huangkui Capsule, Yi-Shen-Hua-Shi granule, Shenmai injection), Chinese medicine compound (Tangshen Formula, Danggui Buxue Decoction, Tangshenkang), single Chinese medicine (Astragalus membranaceus, Panax notoginseng, Salvia miltiorrhiza) combined with Western medicine in the treatment of DKD with lipid metabolism disorder were discussed, in order to provide ideas for clinical diagnosis and treatment of patients with DKD with lipid metabolism disorder.

Diabetic foot ulcer (DFU), a severe complication of diabetes mellitus, presents significant clinical challenges due to its rapid deterioration and high morbidity rates. While conventional therapies exist kinds of limitations, their clinical utility is frequently constrained. Recent advancements in biomedical engineering have introduced innovative therapeutic modalities, particularly nanomaterials and hydrogels. However, emerging technologies face translational barriers including immature manufacturing processes leading to elevated costs, and insufficient long-term safety data due to limited clinical validation periods. Current clinical studies remain constrained by small cohort sizes and preliminary-stage investigations. The purpose of this study was to review traditional primary treatment and simultaneously combine clinical data to increase the speed of innovative safety, cost, and effectiveness indicator testing.

Background: Diabetic nephropathy (DN) is the primary cause of end-stage renal disease (ESRD), and the therapeutic strategies for DN are limited. Notoginsenoside Fc (Fc), a novel saponin isolated from Panax Notoginseng (PNG), has been reported to alleviate vascular injury in diabetic rats. However, the protective effects of Fc on DN remain unclear. Purpose: To investigate the beneficial effects and mechanisms of Fc on DN. Methods: Db/db mice were treated with 2.5, 5 and 10 mg center dot kg(-1)center dot d(-1) of Fc for 8 weeks. High glucose (HG) induced mouse glomerular endothelial cells (GECs) were treated with 2.5, 5 and 10 mu M of Fc for 24 h. Results: Our data found that Fc ameliorated urinary microalbumin level, kidney dysfunction and histopathological damage in diabetic mice. Moreover, Fc alleviated the accumulation of oxidative stress, the collapse of mitochondrial membrane potential and the expression of mitochondrial fission proteins, such as Drp-1 and Fis1, while increased the expression of mitochondrial fusion protein Mfn2. Fc also decreased pyroptosis-related proteins levels, such as TXNIP, NLRP3, cleaved caspase-1, and GSDMD-NT, indicating that Fc ameliorated GECs pyroptosis. In addition, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) expression was increased in diabetic group, which was partially abrogated by Fc. Our data further proved that knockdown of HMGCS2 could restrain HG-induced GECs mitochondrial dysfunction and pyroptosis. These results indicated that the inhibitory effects of Fc on mitochondrial damage and pyroptosis were associated with the suppression of HMGCS2. Conclusion: Taken together, this study clearly demonstrated that Fc ameliorated GECs pyroptosis and mitochondrial dysfunction partly through regulating HMGCS2 pathway, which might provide a novel drug candidate for DN.

Objective: This meta-analysis evaluated the beneficial and potential adverse effects of Astragalus in the treatment of patients with type 2 diabetes mellitus (T2DM). Methods: The authors searched for randomized controlled trials of Astragalus treatment for patients with T2DM in the following databases: PubMed, Embase, Cochrane Library, China Knowledge Resource Integrated Database (CNKI), Wanfang Data, China Science and Technology Journal Database (CQVIP), and SinoMed. Two reviewers conducted independent selection of studies, data extraction, and coding, as well as the assessment of risk of bias in the studies included. Standard meta-analysis and, if appropriate, meta-regression were performed using the STATA, v.15.1, software. Results: This meta-analysis encompasses 20 studies and a total of 953 participants. Compared to the control group (CG), the observation group (OG) decreased fasting plasma glucose (FPG) (WMD = -0.67, 95% CI: -1.13∼-0.20, P = 0.005), 2 hours postprandial plasma glucose (2hPG) (WMD = -0.67 (95% CI: -1.13∼-0.20, P=0.005), glycated hemoglobin A1C (HbA1c) (WMD = -0.93, 95% CI: -1.22∼-0.64, P = 0.000), homeostatic model assessment for insulin resistance (HOMA-IR) (WMD = -0.45, 95% CI: -0.99∼0.99, P = 0.104), insulin sensitive index (WMD = 0.42, 95% CI: 0.13-0.72, P = 0.004). The total effective ratio of the OG is more effective than CG (RR = 1.33, 95% CI: 1.26-1.40, P = 0.000), the significant effective ratio (RR = 1.69, 95% CI: 1.48-1.93, P = 0.000). Conclusions: Astragalus may provide specific benefits for T2DM patients as an adjuvant treatment. Nonetheless, the certainty of the evidence and risk of bias fell short of optimal performance, indicating the need for additional clinical research to ascertain potential effects. PROSPERO REGISTRATION NUMBER CRD42022338491.

BACKGROUND:In diabetic liver injury, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Rutin is a bioflavonoid produced by the hydrolysis of glucosidases to quercetin. Its biological activities include lowering blood glucose, regulating insulin secretion, regulating dyslipidemia, and exerting anti-inflammatory effects have been demonstrated. However, its effect on diabetic NAFLD is rarely reported.PURPOSE:Our study aimed to investigate the protective effects of Rutin on diabetic NAFLD and potential pharmacological mechanism.METHODS:We used db/db mice as the animal model to investigate diabetic NAFLD. Oleic acid-treated (OA) HeLa cells were examined whether Rutin had the ability to ameliorate lipid accumulation. HepG2 cells treated with 30 mM/l d-glucose and palmitic acid (PA) were used as diabetic NAFLD in vitro models. Total cholesterol (TC) and Triglycerides (TG) levels were determined. Oil red O staining and BODIPY 493/503 were used to detect lipid deposition within cells. The indicators of inflammation and oxidative stress were detected. The mechanism of Rutin in diabetic liver injury with NAFLD was analyzed using RNA-sequence and 16S rRNA, and the expression of fat-synthesizing proteins in the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway was investigated. Compound C inhibitors were used to further verify the relationship between AMPK and Rutin in diabetic NAFLD.RESULTS:Rutin ameliorated lipid accumulation in OA-treated HeLa. In in vitro and in vivo models of diabetic NAFLD, Rutin alleviated lipid accumulation, inflammation, and oxidative stress. 16S analysis showed that Rutin could reduce gut microbiota dysregulation, such as the ratio of Firmicutes to Bacteroidetes. RNA-seq showed that the significantly differentially genes were mainly related to liver lipid metabolism. And the ameliorating effect of Rutin on diabetic NAFLD was through AMPK/SREBP1 pathway and the related lipid synthesis proteins was involved in this process.CONCLUSION:Rutin ameliorated diabetic NAFLD by activating the AMPK pathway and Rutin might be a potential new drug ingredient for diabetic NAFLD.

Background Evidence regarding the effect of Panax notoginseng saponins (PNS) on treating elderly stroke patients is scare and inconsistent. This study investigated the efficacy and safety of PNS by means of meta-analysis so as to provide an evidence-based reference for the treatment of elderly patients with stroke. Methods We searched the PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, Wanfang, and China Biomedical Database to identify the eligible randomized controlled trials (RCTs) concerning using PNS to treat elderly people with stroke from their inception to first, May 2022. Meta-analysis was used for pool analysis of the included studies, whose quality was assessed via Cochrane Collaboration's RCT risk of bias tool. Results Altogether 206 studies published between 1999 and 2022 with a low risk of bias were included, covering 21,759 participants. The results showed that the improved neurological status shown in the intervention group with PNS alone was statistically significant (SMD = −0.826, 95% CI: −0.946 to −0.707) in contrast to the control group. The total clinical efficacy (Relative risk (RR) = 1.197, 95% Confidence interval (CI): 1.165 to 1.229) and daily living activities (SMD = 1.675, 95% C: 1.218 to 2.133) of elderly stroke patients were significantly improved as well. In addition, the invention group using PNS combined with WM/TAU displayed significant improvement in neurological status (SMD = −1.142, 95% CI: −1.295 to −0.990) and the total clinical efficacy (RR = 1.191, 95% CI: 1.165 to 1.217) compared with the control group. Conclusion Single PNS intervention or PNS combined with WM/TAU significantly improves the neurological status, the overall clinical efficacy and daily living activities of elderly stroke patients. However, more multicenter RCT research with high quality is required in the future to verify the results in this study. The trial registration number: Inplasy protocol 202330042. doi:10.37766/inplasy2023.3.0042.

Objective . This meta-analysis evaluated the curative effect of the compatibility of Astragalus membranaceus and Panax notoginseng (ARPN) as main components on diabetic nephropathy. Methods . We used various Chinese and English databases, including the Cochrane Library, PubMed, Embase, Web of Science, the China National Knowledge Infrastructure (CNKI), China Biology Medicine Disc (SinoMed), VIP, and Wanfang, to search for randomized controlled trials on the compatibility of Astragalus membranaceus and Panax notoginseng as main components. After data extraction, meta-analysis was performed with Review Manager 5.4.0 and Stata 15, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the quality of the evidence. Result . A total of 17 studies involving 1342 patients with diabetic nephropathy were included. Compared with the control group, ARPN can significantly improve the clinical effective rate of diabetic nephropathy (OR 5.12, 95% CI 3.42 to 7.66, P < 0.00001), and the curative effect of reducing UAER (MD −26.67, 95% CI −31.30 to −22.04, P < 0.00001) and 24 h urinary protein (SMD −0.58, 95% CI −0.75 to −0.41, P < 0.00001) is also significantly better than that of the control group, and it can also improve the renal function(Scr: MD −13.78, 95% CI −25.39 to −2.17, P = 0.02; BUN: MD −0.74, 95% CI −1.27 to −0.20, P = 0.007). In addition, it can also reduce glycosylated hemoglobin (SMD −1.30, 95% CI −2.33 to −0.27, P = 0.01) and blood lipid(TC: SMD −0.62, 95% CI −0.95 to −0.29, P = 0.0002; TG: SMD −0.47, 95% CI −0.75 to −0.19, P = 0.0009; LDL: SMD −0.43, 95% CI −0.68 to −0.18, P = 0.0008), and improve the TCM syndrome score (MD −4.87, 95% CI −6.17 to −3.57, P < 0.00001). Subgroup analysis suggested that the treatment plan of the control group could be the sources of heterogeneity. All the included studies had no obvious adverse effects. Conclusions . The compatibility of Radix Astragali and Radix notoginseng as the main components can effectively improve the renal function of patients with diabetic nephropathy and delay the progress of diabetic nephropathy. However, the results of this study need further research to be confirmed because of the uncertainty of the evidence and the suboptimal risk bias.

胰高血糖素样肽-1受体激动剂(glucagon-like peptide-1 receptor agonist,GLP-1RA)是一种新型降糖药物,作用靶点多样,可改善氧化应激、抗炎、减轻晚期糖基化终末产物损害、调节肾素-血管紧张素-醛固酮系统、改善内皮功能以及减轻肾纤维化等,并发挥肾脏保护作用,在临床上被应用于糖尿病肾病(diabetic nephropathy,DN)的治疗.现就近年来发表的关于GLP-1RA治疗DN的临床应用和作用机制的文献进行综述,为临床提供参考.

Abstract Acute kidney injury (AKI) is a disease with high morbidity and mortality and ischemia-reperfusion (IR) injury is the main cause of AKI. It has been reported that hyperglycemia was a crucial risk factor for renal IRI in diabetes patients with renal IR-induced AKI. Whereas there is no effective treatment. Here, we explored the nephroprotective effects of combination of Astragaloside II and Notoginsenoside Fc on diabetes with IR-induced AKI and its potential mechanisms. We established hyperglycemia with renal hypoxia reoxygenation (H/R) injury model in vivo and in vitro. We first found that combination of Astragaloside II and Notoginsenoside Fc could improve biochemical indexes and renal histologic injury in model mice. We provided relevant evidence that combination of Astragaloside II and Notoginsenoside Fc significantly reduced apoptosis level. In addition, our data suggested that combination of Astragaloside II and Notoginsenoside Fc could have inhibited effects on oxidative stress and NLRP3 activation, further suppressing inflammatory cell aggregation and inflammatory factor secretion. Further studies found that the combination of Astragaloside II and Notoginsenoside Fc could prevent SHP-1-induced VEGF inhibition and activate PDGFB to ameliorate renal tubular epithelial cells (TECs) function. In conclusion, our study indicated that combined treatment of Astragaloside II and Notoginsenoside Fc exerted beneficial protective effects on renal tubular injury and mitochondrial oxidative stress in diabetes with ischemia-reperfusion induced AKI via activating PDGFB and inhibiting SHP-1/VEGFA signaling pathway. Therefore, combination of Astragaloside II and Notoginsenoside Fc may be a potential therapeutic strategy to treat diabetes with IR-induced AKI.

Introduction Mitochondria dysfunction is one of the primary causes of tubular injury in acute kidney injury (AKI). Notoginsenoside Fc (Fc), a new saponin isolated from Panax notoginseng, exhibited numerous pharmacological actions. However, the beneficial effects of Fc on renal tubular impairment and mitochondrial dysfunction in AKI have not been fully studied. Methods In this study, we established acetaminophen (APAP)-induced AKI model in mice to examine the therapeutic impacts of Fc on AKI. Results Our results showed that Fc could decrease the levels of the serum creatinine (Scr), blood urea nitrogen (BUN) and Cystatin C in mice with AKI. Fc also ameliorated renal histopathology, renal tubular cells apoptosis and restored expression of apoptosis-related proteins such as Bax, Bcl-2 and caspase3 (C-caspase3). Additionally, Fc increased the protein expression of SIRT3 and SOD2 in kidneys from mice with AKI. In vitro studies further showed Fc reduced the apoptosis of HK-2 cells exposure to APAP, attenuated the loss of mitochondrial membrane potential and decreased the formation of mitochondrial superoxide. Fc also partly restored the protein expression of Bax, Bcl-2, C-Caspase3, SIRT3, and SOD2 in HK-2 cells exposure to APAP. Conclusion In summary, Fc might reduce renal tubular injury and mitochondrial dysfunction in AKI partly through the regulation of SIRT3/SOD2 pathway.

Review question / Objective: Population: The symptoms of the population were in line with the relevant diagnostic criteria for stroke both at home and abroad, and were confirmed as ischemic stroke by medical imaging tests such as MRI or CT.The subject groups were older adults with an average age of over 60, regardless of gender or race. Intervention: Intervention involves single use of PNS or combined use of PNS and WM or PNS and Treatment as usual (TAU). Comparator: All the patients in the controlled group underwent conventional routine treatment to improve their cerebral blood supply and drug treatment. Outcomes: Measurement for the outcomes should be clearly defined and includes at least one of the below items: neurological deficit score, the clinical response rate and assessment of Activities of daily living (ADLs). Study design: All the included studies were RCTs or clinical controlled trials. The study design adopted RCT.

Background: Diabetic kidney disease (DKD) is a primary microvascular complication of diabetes. However, a complete cure for DKD has not yet been found. Although there is evidence that Rutin can delay the onset of DKD, the underlying mechanism remains unclear. Purpose: To investigate the renoprotective effect of Rutin in the process of DKD and to explore its potential molecular mechanisms. Methods: Db/db mice and high glucose (HG)-induced human renal glomerular endothelial cells (GEnCs) were used as in vivo and in vitro models, respectively. Western blot (WB), Immunohistochemistry (IHC)and Immu-nofluorescence (IF) staining were used to identify the expression level of proteins associated with endothelial-to-mesenchymal transition (EndMT) and autophagy. Tandem Mass Tag (TMT)-based proteomics analysis was uti-lized to reveal the mechanism of Rutin in DKD. Transfection with small interfering RNA (siRNA) to reveal the role of histone deacetylase 1 (HDAC1) in HG-induced GEnCs. Results: Following 8 weeks of Rutin administration, db/db mice's kidney function and structure significantly improved. In HG-induced GEnCs, activation of autophagy attenuates cellular EndMT. Rutin could alleviate EndMT and restore autophagy in vivo and in vitro models. Proteomics analysis results showed that HDAC1 significantly downregulated in the 200 mg/kg/d Rutin group compared with the db/db group. Transfection with si-HDAC1 in GEnCs partially blocked HG-induced EndMT and restored autophagy. Furthermore, Rutin inhibits the phosphorylation of the PI3K / AKT/ mTOR pathway. HDAC1 overexpression was suppressed in HG-induced GEnCs after using Rapamycin, a specific mTOR inhibitor, verifying the correlation between mTOR and HDAC1. Conclusion: Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via the PI3K/AKT/mTOR pathway in DKD.