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    Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway. Wang Shiying,Zhao Xinxin,Yang Suxia,Chen Baoping,Shi Jun Chemico-biological interactions Diabetic nephropathy (DN) is a metabolic disease characterized by mesangial cell proliferation and extracellular matrix (ECM) accumulation. Salidroside (SAL) is the major ingredient in Rhodiola rosea and possesses beneficial effects on DN. This study aimed to evaluate the effect of SAL on high glucose (HG)-induced oxidative stress and ECM accumulation and the underlying mechanism. Rat glomerular mesangial cells HBZY-1 were induced by high glucose (HG) in the presence or absence of SAL. Cell proliferation was measured by CCK-8 assay. The reactive oxygen species (ROS) level, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected to evaluate oxidative stress. The expression levels of ECM proteins including fibronectin (FN) and type IV collagen (Coll IV) were detected by qRT-PCR and western blot analysis. The expressions of thioredoxin-interacting protein (TXNIP), nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 were assessed by western blot. Si-TXNIP or si-NC was transfected into HBZY-1 cells to inhibit TXNIP-NLRP3 inflammasome pathway. The results showed that SAL treatment alleviated HG-induced cell proliferation. SAL reduced the levels of ROS and MDA, and induced the SOD activity. Besides, the mRNA and protein expressions of FN and Coll IV were decreased by SAL. The expression levels of TXNIP, NLRP3, ASC, and caspase-1 were reduced in the SAL treated cells. In addition, TXNIP knockdown inhibited TXNIP-NLRP3 inflammasome activation and suppressed HG-induced cell proliferation, oxidative stress, and ECM accumulation. In conclusion, SAL alleviated HG-induced oxidative stress and ECM accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway. 10.1016/j.cbi.2017.10.012
    Targeting NLRP3 inflammasome as a promising approach for treatment of diabetic nephropathy: Preclinical evidences with therapeutic approaches. Ram Chetan,Jha Ankush Kumar,Ghosh Aparajita,Gairola Shobhit,Syed Abu Mohammad,Murty Upadhyayula Suryanarayana,Naidu V G M,Sahu Bidya Dhar European journal of pharmacology Diabetes mellitus is an increasingly prevalent disease around the globe. The epidemic of diabetes mellitus and its complications pretenses the foremost health threat globally. Diabetic nephropathy is the notable complication in diabetes, leading to end-stage renal disease (ESRD) and premature death. Abundant experimental evidence indicates that oxidative stress and inflammation are the important mediators in diabetic kidney diseases and interlinked with various signal transduction molecular mechanisms. Inflammasomes are the critical components of innate immunity and are recognized as a critical mediator of inflammation and autoimmune disorders. NOD-like receptor protein 3 (NLRP3) inflammasome is the well-characterized protein and it exhibits the sterile inflammation through the regulation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 production in tissues. In recent years, the role of NLRP3 inflammasome in the pathophysiology of diabetic kidney diseases in both clinical and experimental studies has generated great interest. In the current review, we focused on and discussed the role of NLRP3 inflammasome in diabetic nephropathy. A literature review was performed using online databases namely, PubMed, Scopus, Google Scholar and Web of science to explore the possible pharmacological interventions that blunt the NLRP3 inflammasome-caspase-1-IL-1β/IL-18 axis and shown to have a beneficial effect in diabetic kidney diseases. This review describes the inhibition of NLRP3 inflammasome activation as a promising therapeutic target for drug discovery in future. 10.1016/j.ejphar.2020.173503
    Cepharanthine and Piperine ameliorate diabetic nephropathy in rats: role of NF-κB and NLRP3 inflammasome. Samra Yara A,Said Heba S,Elsherbiny Nehal M,Liou Gregory I,El-Shishtawy Mamdouh M,Eissa Laila A Life sciences AIMS:Hyperglycemia leads to elevation of oxidative stress and proinflammatory cytokines which are the main causes of diabetic nephropathy (DN). NLRP3 inflammasome and thioredoxin-interacting protein (TXNIP) are recently assumed to participate in the development of DN. We aimed to investigate the effects of Cepharanthine (CEP), Piperine (Pip) and their combination in streptozotocin (STZ)-induced DN focusing on their role to modulate NLRP3 and TXNIP induced inflammation. MAIN METHODS:Diabetic rats were treated with intraperitoneal (i.p.) injection of CEP (10mg/kg/day), Pip (30mg/kg/day) or their combination for 8weeks. Nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA technique. TXNIP and NLRP3 genes expressions were evaluated by real time-PCR. KEY FINDINGS:Diabetic rats showed significant increase in renal TXNIP and NLRP3 expression. CEP, Pip or their combination significantly decreased TXNIP and NLRP3 expression in diabetic kidneys. Hyperglycemia induced NF-κB activation leading to increased IL-1β and TNF-α levels. CEP, Pip or their combination showed significant inhibition of NF-κB together with decreased IL-1β and TNF-α levels in diabetic rats. Also, diabetic rats showed significant decrease in creatinine clearance and increase in blood glucose, serum creatinine, blood urea nitrogen, malondialdehyde, proteinuria, and kidney weight to body Weight ratio. All of these changes were reversed by CEP, Pip or their combination. SIGNIFICANCE:The antioxidant and anti-inflammatory effects of CEP and Pip which were accompanied by inhibition of NF-κB and NLRP3 activation might be helpful mechanisms to halt the progression of DN. 10.1016/j.lfs.2016.06.002
    Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Song Wu,Wei Lin,Du Yanwei,Wang Yimei,Jiang Shuang International immunopharmacology Though the antidiabetic effect of ginsenoside compound K (CK) has been well studied, the effect of CK on diabetic nephropathy (DN) is not clear. Whether CK would have a protective effect against DN and it could exert the protective effect by inhibiting the oxidative stress, NLRP3 inflammasome and NF-κB/p38 signaling pathway were investigated in this study. Here, the HFD (high fat diet)/STZ (streptozotocin)-induced DN mice model was established to assess the CK effect in vivo. Parallel experiments uncovering the molecular mechanism by which CK prevents from DN was performed in rat glomerular mesangial cell line HBZY-1 exposed to high glucose. CK (10, 20, 40 mg/kg/day) were intragastrically administered for 8 weeks, the general status, biochemical parameters, renal pathological changes and oxidative stress-parameters were observed, and the NLRP3 inflammasome and NF-κB/p38 signaling pathway were evaluated. The results showed that the elevated fasting blood glucose, serum creatinine, blood urea nitrogen and 24-hour urine protein of the DN mice were significantly decreased, and the proliferation of glomerular mesangial matrix was alleviated by CK. In addition, the generation of ROS in the kidney was significantly decreased, and the expression of Nox1 and Nox4 proteins were down-regulated. Further, the expression of NLRP3 inflammasome components (NLRP3, ASC and Caspase-1) and the inflammatory cytokines IL-1β and IL-18 were also significantly down-regulated in vivo and in vitro. The phosphorylation of renal p38 MAPK was also inhibited by CK. MCC950 (an inhibitor of NLRP3 inflammasome) and VX-765 (a Caspase-1 Inhibitor) showed significant interaction with CK on the decrease of IL-1β concentration in HBZY-1 cells. In conclusion, our study provided evidence that the protective effect of CK on diabetes-induced renal injury is associated with down-regulating the expression of NADHP oxidase, and inhibition of ROS-mediated activation of NLRP3 inflammasome and NF-κB/p38 signaling pathway, suggesting its therapeutic implication for renal inflammation. 10.1016/j.intimp.2018.07.027
    Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways. Zhu Xiaoguang,Shi Jun,Li Huicong Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Oxidative stress, inflammation, and hyperglycemia are considered to play crucial roles in the pathogenesis and progression of diabetic nephropathy (DN). Liquiritigenin, one of the flavonoid compounds, has been shown to possess anti-inflammatory, anti-hyperlipidemic, and anti-oxidative properties. Our study aimed to explore the effects of liquiritigenin on high glucose (HG)-induced extracellular matrix (ECM) accumulation, oxidative stress and inflammatory response and delineate the underlying mechanism. In our study, glomerular mesangial cells (HBZY-1) were co-treated with various doses of liquiritigenin and HG. We found that HG, but not normal glucose or mannitol, promoted the proliferation of HBZY-1 cells, which was suppressed by liquiritigenin. Liquiritigenin inhibited HG-induced ECM accumulation in HBZY-1 cells by reducing the expressions and production of collagen IV (Col IV) and fibronectin (FN). Moreover, liquiritigenin attenuated HG-induced oxidative stress, as evidenced by the decreased MDA content and NADPH oxidase 4 (NOX4) expression, and the increased SOD activity in HBZY-1 cells. Liquiritigenin suppressed HG-induced inflammatory response, as demonstrated by the reduced expressions and secretion of interleukin (IL)-6 and IL-1β in HBZY-1 cells. Furthermore, we found that liquiritigenin inhibited HG-induced activation the nuclear factor-kappa B (NF-κB) and nod-like receptor protein 3 (NLRP3) inflammasome pathways. In conclusion, these results demonstrated that liquiritigenin attenuated HG-induced ECM accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways, suggesting that liquiritigenin might be a promising therapeutic agent for preventing the development of DN. 10.1016/j.biopha.2018.07.045
    Apocynin inhibited NLRP3/XIAP signalling to alleviate renal fibrotic injury in rat diabetic nephropathy. Xin Rui,Sun Xuhong,Wang Ziying,Yuan Wendan,Jiang Weidong,Wang Lin,Xiang Yanxiao,Zhang Hongqin,Li Xiaoyan,Hou Yun,Sun Wangnan,Du Pengchao Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie AIMS:In this animal study, we tried to test the hypothesis that apocynin could play an anti-inflammation role by inhibiting NLRP3/X-linked inhibitor of apoptosis protein (XIAP) signalling and have an effect on antifibrosis in rats with diabetic nephropathy. MAIN METHODS:Diabetic nephropathy rats were induced by tail-vein injection of streptozotocin at 60 mg/kg body weight in sodium citrate buffer (0.01 M, pH 4.5) with unrestricted access to food/water for 12 weeks, and rats with blood glucose levels above 18.0 mM were considered diabetic; the damage index for glomerular mesangial cells damage index was calculated by morphological examinations; protein and mRNA changes were analysed by western blotting immunohistochemistry and real-time quantitative polymerase chain reaction; interstitial fibrosis was assessed and scored using Masson's staining. KEY FINDINGS:In rats with diabetic nephropathy, apocynin (1) reduced renal injury and improved renal function; (2) downregulated the expression of NLRP3 in renal cortex; (3) downregulated the expression of XIAP in renal cortex; and (4) attenuated renal fibrosis. SIGNIFICANCE:As an inhibitor of reactive oxygen species (ROS), apocynin could downregulate the expression of NLRP3 and XIAP, and alleviate renal fibrosis, which meant not only that ROS was one type of ligands of NLRP3, but also that ROS mechanism and NLRP3 activation might be therapeutic targets in the treatment of diabetic nephropathy in the future. 10.1016/j.biopha.2018.07.036
    NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients. El-Horany Hemat El-Sayed,Abd-Ellatif Rania Nagi,Watany Mona,Hafez Yasser M,Okda Hanaa Ibrahim IUBMB life Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease. Nod-like receptors nucleotide-binding domain and leucine-rich repeat pyrin-3 domain (NLRP3) inflammasome displays a considerable role in the chronic inflammatory state observed in diabetic patients. Urinary heat shock protein 72 (uHSP72) is a sensitive and specific biomarker for the early detection of acute kidney injury. The aim of this study was to evaluate NLRP3 relative gene expression, its correlation with inflammatory and oxidative stress markers, and to assess the value of uHSP72 in the early detection of DN in type 2 diabetic patients with different degrees of DN. Forty-five type 2 diabetic patients: 15 normoalbuminuric, 15 microalbuminuric, 15 macroalbuminuric, in addition to 15 healthy controls were enrolled in this study. Clinical examination and routine laboratory investigations were performed. NLRP3 mRNA expression was assessed by real time polymerase chain reaction. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), interleukin 1β (IL-1β), and uHSP72 levels were estimated by enzyme-linked immunosorbent assay. Serum chitotriosidase (CHIT1) activity was examined. NLRP3 mRNA relative expression, serum levels of 8-OHdG, IL-1β, and uHSP72, in addition to CHIT 1 activity were significantly increased in the macroalbuminuric patient group as compared to control and the other two diabetic groups. Also, a significant positive correlation was documented between the previously mentioned parameters and urinary albumin/creatinine ratio, serum creatinine, and HbA1c. Multiple linear regression analysis using urinary albumin/creatinine ratio as dependent variable confirmed that uHSP72 and NLRP3 mRNA relative expression were the independent predictors of DN (β were 0.432 and 0.448 respectively, P < 0.001). Receiver operating characteristic analyses revealed that both NLRP3 mRNA relative expression and uHSP72 levels were useful biomarkers discriminating DN patients from patients with type 2 diabetes mellitus (AUC were 0.957 and 0.983, respectively). uHSP72 may be considered as a novel potential diagnostic biomarker for the early detection of DN. Moreover, these data support the pivotal role of NLRP3 in the development and progression of DN. © 2017 IUBMB Life, 69(8):623-630, 2017. 10.1002/iub.1645