RESUMEN
Gel electrophoresis (GE) is one of the most general tools in biomedicine. However, it suffers from low resolution, and its mechanism has not been fully revealed yet. Herein, we presented the dispersion model of w2 (t) â Tt, showing the band dispersion (w) via temperature (T) and running time (t) control. Second, we designed an efficient GE chip via the time control and rapid Joule heat self-dissipation by thermal conductive plastic (TCP) and electrode buffer. Third, we conducted the simulations on TCP and polymethylmethacrylate (PMMA) chips, unveiling that (i) the temperature of TCP was lower than the PMMA one, (ii) the temperature uniformity of TCP was better than the PMMA one, and (iii) the resolution of TCP was superior to the PMMA one. Fourth, we designed both TCP and PMMA chips for experimentally validating the dispersion model, TCP chip, and simulations. Finally, we applied the TCP chip to thalassemia and model urine protein assays. The TCP chip has merits of high resolution, rapid run of 6-10 min, and low cost. This work paves the way for greatly improving electrophoretic techniques in gel, chip, and capillary via temperature and time control for biologic study, biopharma quality control, clinical diagnosis, and so on.
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Calor , Carrera , Electroforesis , Polimetil Metacrilato , TemperaturaRESUMEN
Diabetic kidney disease (DKD) is an important diabetic microvascular complication, which has become the main cause of end-stage renal disease (ESRD) all over the world. It is of great significance to find effective therapeutic targets and improve the prognosis of the disease. Traditionally, it is believed that the activation of the renin-angiotensin-aldosterone system (RAAS) is the main reason for the progression of DKD, but with the progress of research, it is known that the production of proteinuria in patients with DKD is also related to podocyte injury and loss. Many studies have shown that mitochondrial dysfunction in podocytes plays an important role in the occurrence and development of DKD, and oxidative stress is also the main pathway and common hub of diabetes to the occurrence and development of microvascular and macrovascular complications. Thus, the occurrence and progression of DKD is correlated with not only the activation of the RAAS, but also the damage of mitochondria, oxidative stress, and inflammatory mediators. Besides, diabetes-related metabolic disorders can also cause abnormalities in mitochondrial dynamics, autophagy and cellular signal transduction, which are intertwined in a complex way. Therefore, in this review, we mainly explore the mechanism and the latest research progress of podocyte mitochondria in DKD and summarize the main signal pathways involved in them. Thus, it provides feasible clinical application and future research suggestions for the prevention and treatment of DKD, which has important practical significance for the later treatment of patients with DKD.
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Nefropatías Diabéticas/metabolismo , Fallo Renal Crónico/metabolismo , Mitocondrias/metabolismo , Podocitos/metabolismo , Proteinuria/metabolismo , Nefropatías Diabéticas/patología , Humanos , Fallo Renal Crónico/patología , Mitocondrias/patología , Podocitos/patología , Proteinuria/patologíaRESUMEN
BACKGROUND/AIMS: Hyperuricemia is an independent risk factor for chronic kidney disease and cardiovascular disease. Here, we examined the combined protective effects of Chinese herbal formula Si-Wu-Tang and Er-Miao-San on hyperuricemia and renal impairment in rats. METHODS: Rats were randomly divided into normal rats, hyperuricemic rats, and hyperuricemic rats orally administrated with benzbromarone (4.5 mg·kg⻹·d⻹), Si-Wu-Tang (3.78 g·kg⻹·d⻹) and Si-Wu-Tang plus Er-Miao-San (6.48 g·kg⻹·d⻹) for 4 weeks. Hyperuricemic rats were orally gavaged with adenine (0.1 g·kg⻹·d⻹) and potassium oxonate (1.5 g·kg⻹·d⻹) daily for 4 weeks. Serum uric acid, creatinine, total cholesterol (TCH), triglyceride and blood urea nitrogen (BUN) concentrations, as well as urinary uric acid and microalbuminuria were measured weekly. Serum xanthine oxidase (XOD) activity and renal histopathology were also evaluated. The renal expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) was detected by western blot. RESULTS: Si-Wu-Tang plus Er-Miao-San lowered serum uric acid, creatinine, triglyceride and BUN levels to a greater degree than did Si-Wu-Tang alone. Si-Wu-Tang plus Er-Miao-San ameliorated microalbuminuria and renal histopathology, as well as decreased serum TCH concentration and XOD activity in hyperuricemic rats. Combination of Si-Wu-Tang and Er-Miao-San also led to a greater increase in OAT1 and OAT3 expression than did Siwutang alone. CONCLUSION: Si-Wu-Tang and Er-Miao-San synergistically ameliorated hyperuricemia and renal impairment in rats through upregulation of OAT1 and OAT3.
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Medicamentos Herbarios Chinos/administración & dosificación , Hiperuricemia/tratamiento farmacológico , Adenina/toxicidad , Administración Oral , Animales , Benzbromarona/farmacología , Creatinina/sangre , Sinergismo Farmacológico , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/farmacología , Hiperuricemia/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ácido Oxónico/toxicidad , Exudados de Plantas/administración & dosificación , Exudados de Plantas/farmacología , Ratas , Ratas Sprague-Dawley , Ácido Úrico/sangre , Ácido Úrico/orina , Xantina Oxidasa/sangreRESUMEN
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. METHODS: Conditionally immortalized mouse podocytes were exposed to HG with 30 µg /ml of EMO and 1 µmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg(-1)· d(-1) and QLT0267 at 10 mg· kg(-1)· w(-1) p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. RESULTS: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. CONCLUSION: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD.
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Emodina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Sustancias Protectoras/farmacología , Albuminuria/patología , Albuminuria/orina , Animales , Compuestos Azo/farmacología , Glucemia/análisis , Desmina/genética , Desmina/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Glucosa/toxicidad , Riñón/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Podocitos/citología , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Estreptozocina/toxicidad , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Decreased expression of α3ß1 integrin may contribute to reduction in podocyte adhesion to glomerular basement membrane (GBM), which represents a novel early mechanism leading to diabetic kidney disease (DKD). Here, we examined the protective effects of Notoginsenoside R1 (NR1) on podocyte adhesion and α3ß1 integrin expression under diabetic condition in vitro and in vivo. METHODS: Conditionally immortalized mouse podocytes were exposed to high glucose (HG) with 10 and 100µg /ml of NR1 for 24 h. Podocyte adhesion, albuminuria, oxidative markers, renal histopathology, podocyte number per glomerular volume, integrin-linked kinase (ILK) activity and α3ß1 integrin expression were measured in vitro and in vivo. RESULTS: HG decreased podocyte adhesive capacity and α3ß1 integrin expression, the main podocyte anchoring dimer to the GBM. However, NR1 ameliorated impaired podocyte adhesive capacity and partially restored α3ß1 integrin protein and mRNA expression. These in vitro observations were confirmed in vivo. In streptozotocin(STZ)-induced diabetic rats, treatment with NR1 (5 and 10 mg· kg(-1)· d(-1)) for 12 weeks partially restored the number of podocytes per glomerular volume and glomerular α3ß1 integrin expression, as well as ameliorated albuminuria, histopathology and oxidative stress. NR1 also inhibited glomerular ILK activity in diabetic rats. CONCLUSION: NR1, a novel antioxidant, ameliorated glucose-induced impaired podocyte adhesive capacity and subsequent podocyte depopulation partly through α3ß1 integrin upregulation. These findings might provide a potential new therapeutic option for the treatment of DKD.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Ginsenósidos/administración & dosificación , Integrina alfa3beta1/biosíntesis , Animales , Adhesión Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Regulación de la Expresión Génica , Membrana Basal Glomerular/efectos de los fármacos , Membrana Basal Glomerular/patología , Ratones , Estrés Oxidativo/efectos de los fármacos , Podocitos/efectos de los fármacos , Podocitos/patología , RatasRESUMEN
BACKGROUND: Endoplasmic reticulum (ER) stress-induced podocyte apoptosis plays a critical role in the development of diabetic nephropathy (DN). Here, we tested the hypothesis that suppression of PERK-ATF4-CHOP pathway by Astragaloside IV (AS-IV) is associated with inhibition of ER stress-induced podocyte apoptosis in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetic rats were treated with AS-IV at 5 and 10 mg·kg-1·d-1, p.o., for 12 weeks. Albuminuria examination, hematoxylin & eosin staining and TUNEL analysis were performed. Immunohistochemistry, western blot, and real-time PCR were used to detect renal expression of ER chaperone GRP78 and ER-associated apoptosis proteins. RESULTS: Treatment with AS-IV ameliorated albuminuria and renal histopathology in diabetic rats. Diabetic rats had significant increment in podocyte apoptosis as well as phosphorylated PERK and eIF2α in the kidneys, which were attenuated by AS-IV treatment. Furthermore, diabetic rats were found to have increased protein and mRNA expressions of GRP78 and ER-associated apoptosis proteins, such as ATF4, CHOP and TRB3, which were also attenuated by AS-IV treatment. Increased Bax expression and decreased Bcl-2 expression were detected in diabetic rats, and these changes were partially restored by AS-IV treatment. CONCLUSION: The protective effect of AS-IV on ER stress-induced podocyte apoptosis is associated with inhibition of PERK-ATF4-CHOP pathway. Down-regulation of PERK- ATF4-CHOP pathway by AS-IV may be a novel strategy for the treatment of DN.
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Factor de Transcripción Activador 4/metabolismo , Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Podocitos/efectos de los fármacos , Saponinas/farmacología , Factor de Transcripción CHOP/metabolismo , Triterpenos/farmacología , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/genética , Animales , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucosa/farmacología , Proteínas de Choque Térmico/metabolismo , Masculino , Podocitos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Factor de Transcripción CHOP/genética , Proteína X Asociada a bcl-2/metabolismo , eIF-2 Quinasa/genéticaRESUMEN
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: -1.13â¼-0.20, P = 0.005), 2 hours postprandial plasma glucose (2hPG) (WMD = -0.67 (95% CI: -1.13â¼-0.20, P=0.005), glycated hemoglobin A1C (HbA1c) (WMD = -0.93, 95% CI: -1.22â¼-0.64, P = 0.000), homeostatic model assessment for insulin resistance (HOMA-IR) (WMD = -0.45, 95% CI: -0.99â¼0.99, 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.
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Diabetes Mellitus Tipo 2 , Humanos , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Insulina , Resistencia a la InsulinaRESUMEN
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·kg-1·d-1 of Fc for 8 weeks. High glucose (HG) induced mouse glomerular endothelial cells (GECs) were treated with 2.5, 5 and 10 µM 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.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ginsenósidos , Enfermedades Mitocondriales , Ratas , Ratones , Animales , Nefropatías Diabéticas/metabolismo , Células Endoteliales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Piroptosis , Enfermedades Mitocondriales/metabolismo , Hidroximetilglutaril-CoA Sintasa/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
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.
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Diabetes Mellitus , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Metabolismo de los Lípidos , Proteínas Quinasas Activadas por AMP/metabolismo , Rutina/farmacología , Células HeLa , ARN Ribosómico 16S , Hígado , Inflamación/metabolismo , Dieta Alta en Grasa/efectos adversos , Lípidos , Ratones Endogámicos C57BLRESUMEN
Oxidative stress and apoptosis play key role in the pathogenesis of acute kidney injury (AKI). We hypothesize that Astragaloside IV(AS-IV) prevents AKI through inhibiting oxidative stress and apoptosis. The rats were divided into sham control, saline-,vehicle-, or AS-IV-treated groups. AS-IV (20 mg/kg) was orally administered once daily to the rats for 7 consecutive days before terminating the experiments. In ischemia-induced AKI model, experimental rats were subjected to bilateral clamping of the renal arteries for 45 min, followed by reperfusion for 24 h. In contrast-induced AKI model, iopamidol (2.9 g iodine/kg) was administered intravenously into the rats. Renal function, histopathology, oxidative stress and apoptosis were evaluated in these models. Pretreatment with AS-IV significantly decreased blood urea nitrogen, serum creatinine, cystatin C and neutrophil gelatinase-associated lipocalin levels, as well as urinary kidney injury molecule-1 level and tubular injury. AS-IV also reduced oxidative stress and tubular cell apoptosis. The p38 mitogen-activated protein kinase phosphorylation and caspase-3 activity were elevated in kidney tissues from AKI rats, accompanied by an increase in Bax expression and a decrease in Bcl-2 expression at mRNA and protein levels. These changes were prevented by AS-IV pretreatment. Therefore, AS-IV can be developed as a novel therapeutic approach to prevent AKI through targeting inhibition of oxidative stress and apoptosis pathways.
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Lesión Renal Aguda/prevención & control , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Riñón/irrigación sanguínea , Estrés Oxidativo/efectos de los fármacos , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/cirugía , Proteínas de Fase Aguda , Animales , Caspasa 3/metabolismo , Moléculas de Adhesión Celular/orina , Cistatina C/sangre , Medicamentos Herbarios Chinos/farmacología , Isquemia/cirugía , Riñón/efectos de los fármacos , Riñón/cirugía , Pruebas de Función Renal , Lipocalina 2 , Lipocalinas/sangre , Masculino , Modelos Animales , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Arteria Renal/cirugía , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Saponinas/farmacología , Triterpenos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n=8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mgkg(-1)d(-1), p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n=8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF-κB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-α, MCP-1 and ICAM-1 in kidney tissues. The α1-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-α, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-κB mediated inflammatory genes expression.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Regulación de la Expresión Génica , Inflamación/genética , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , FN-kappa B/metabolismo , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Albuminuria/sangre , Albuminuria/complicaciones , Albuminuria/tratamiento farmacológico , Albuminuria/patología , Animales , Biomarcadores/sangre , Quimiocina CCL2/sangre , Quimiocina CCL2/genética , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/sangre , Inflamación/complicaciones , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/genética , Enfermedades Renales/sangre , Enfermedades Renales/complicaciones , Masculino , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Podocitos/ultraestructura , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Saponinas/farmacología , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
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.
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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.
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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 Immunofluorescence (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 utilized 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.
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Diabetes Mellitus , Nefropatías Diabéticas , Ratones , Animales , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Células Endoteliales/metabolismo , Histona Desacetilasa 1/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , AutofagiaRESUMEN
Objective: To investigate the protective effect and mechanism of astragaloside IV (AS-IV) on damage in human glomerular endothelial cells (GEnCs) stimulated by high glucose and high insulin. Methods: The transwell method was used to detect the integrity of the cell barrier after AS-IV intervention in a high glucose and high insulin environment for 24 h; immunofluorescence and Western blot methods were used to detect the tight junction protein ZO-1 and claudin-5 expression; intracellular and extracellular 1ß (IL-1ß) and tumor necrosis factor α (TNFα) were determined by ELISA; expression and activation of AKT, p-AKT, GSK3α/ß, and p-GSK3α/ß were evaluated by Western blot. Results: The results showed that AS-IV had a significant protective effect on the cell barrier of GEnCs. High glucose or insulin inhibited cell viability in a concentration-dependent manner. High glucose or insulin significantly inhibited glucose uptake and promoted release of reactive oxygen species in GEnCs. Administration with AS-IV dramatically preserved viability of the cells; moreover, the expression of intracellular tight junction proteins was upregulated, inflammatory cytokines including IL-1ß and TNFα were decreased, and the AKT-GSK3 pathway participated in modulation of AS-IV in GEnCs cells. Conclusion: We found in the present study that AS-IV can preserve filtration barrier integrity in glomerular endothelial cells under diabetic settings, its effects on increasing the cell energy metabolism and cell viability, inhibiting inflammation and oxidative stress damage, and enhancing tight junction between cells play a role in it; and the intracellular signaling pathway AKT-GSK modulated the above function. Our present finding supplied a new understanding towards development of DN and provided an alternative method on ameliorating DN.
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Objective: This meta-analysis evaluated the effects and potential harms of Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone for the treatment of population with a chronic kidney disease (CKD). Methods: We searched for the randomized clinical trials (RCTs) through databases including the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR). Meta-analysis was performed with STATA 16 software after data extraction. The risk of bias was assessed with the Cochrane risk-of-bias tool (RoB 2.0), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence. Result: A total of 32 studies were included involving 2264 participants. Compared to the control group, the treatment group significantly decreased serum creatinine (SCr) (SMD -0.60, 95% CI -0.79 to -0.41, P < 0.0001), blood urea nitrogen (BUN) (SMD -0.66, 95% CI -0.81 to -0.50, P < 0.0001), Cystatin C (CysC) (SMD -5.16, 95% CI -14.84 to 4.53, P=0.297), 24 hour urine protein (24 h UPE) (SMD -0.70, 95% CI -1.21 to -0.19, P=0.008), time to initiation of dialysis (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089), serum total cholesterol (TC) (SMD -0.53, 95% CI -0.88 to -0.17, P=0.0042, P=0.0035), plasma fibrinogen (FIB) (SMD -0.79, 95% CI -1.12 to -0.46, P < 0.0001), C-reactive protein (CRP) (SMD -0.56, 95% CI -0.93 to -0.19, P=0.0029); increased creatinine clearance (Ccr) (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002), glomerular filtration rate (GFR) (SMD 0.56, 95% CI 0.30 to 0.83, P < 0.001), effective rate (Log RR 0.30, 95% CI 0.23 to 0.37, P < 0.0001), and hemoglobin (Hb) (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042). Moreover, the incidences of adverse effects were similar between the two groups. Conclusions: Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone, as a complementary therapy to conventional medicine, presents potential impacts to improve kidney functions and delay the progression of CKD without obvious adverse effects. However, the certainty of the evidence and the risk of bias are suboptimal and further clinical studies are still required to determine the underlying effects.
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Mitochondrial abnormality is one of the main factors of tubular injury in diabetic nephropathy (DN). Formononetin (FMN), a novel isoflavonoid isolated from Astragalus membranaceus, has diverse pharmacological activities. However, the beneficial effects of FMN on renal tubular impairment and mitochondrial dysfunction in DN have yet to be studied. In this study, we performed in vivo tests in Streptozotocin (STZ) -induced diabetic rats to explore the therapeutic effects of FMN on DN. We demonstrated that FMN could ameliorate albuminuria and renal histopathology. FMN attenuated renal tubular cells apoptosis, mitochondrial fragmentation and restored expression of mitochondrial dynamics-associated proteins, such as Drp1, Fis1 and Mfn2, as well as apoptosis-related proteins, such as Bax, Bcl-2 and cleaved-caspase-3. Moreover, FMN upregulated the protein expression of Sirt1 and PGC-1α in diabetic kidneys. In vitro studies further demonstrated that FMN could inhibit high glucose-induced apoptosis of HK-2 cells. FMN also reduced the production of mitochondrial superoxide and alleviated mitochondrial membrane potential (MMP) loss. Furthermore, FMN partially restored the protein expression of Drp1, Fis1 and Mfn2, Bax, Bcl-2, cleaved-caspase-3, Sirt1 and PGC-1α in HK-2 cells exposure to high glucose. In conclusion, FMN could attenuate renal tubular injury and mitochondrial damage in DN partly by regulating Sirt1/PGC-1α pathway.
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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.
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BACKGROUND: Brain impairment is one of a major complication of diabetes. Dietary flavonoids have been recommended to prevent brain damage. Astragalus membranaceus is a herbal medicine commonly used to relieve the complications of diabetes. Flavonoids is one of the major ingredients of Astragalus membranaceus, but its function and mechanism on diabetic encepholopathy is still unknown. METHODS: Type 2 diabetes mellitus (T2DM) model was induced by high fat diet and STZ in C57BL/6J mice, and BEnd.3 and HT22 cell lines were applied in the in vitro study. Quality of flavonoids was evaluated by LC-MS/MS. Differential expressed proteins in the hippocampus were evaluated by proteomics; influence of the flavonoids on composition of gut microbiota was analyzed by metagenomics. Mechanism of the flavonoids on diabetic encepholopathy was analyzed by Q-PCR, Western Blot, and multi-immunological methods et al. RESULTS: We found that flavonoids from Astragalus membranaceus (TFA) significantly ameliorated brain damage by modulating gut-microbiota-brain axis: TFA oral administration decreased fasting blood glucose and food intake, repaired blood brain barrier, protected hippocampus synaptic function; improved hippocampus mitochondrial biosynthesis and energy metabolism; and enriched the intestinal microbiome in high fat diet/STZ-induced diabetic mice. In the in vitro study, we found TFA increased viability of HT22 cells and preserved gut barrier integrity in CaCO2 monocellular layer, and PGC1α/AMPK pathway participated in this process. CONCLUSION: Our findings demonstrated that flavonoids from Astragalus membranaceus ameliorated brain impairment, and its modulation on gut-brain axis plays a pivotal role. Our present study provided an alternative solution on preventing and treating diabetic cognition impairment.
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Astragaloside II (AS II), a novel saponin purified from Astragalus membranes, has been reported to modulate the immune response, repair tissue injury, and prevent inflammatory response. However, the protective effects of AS II on podocyte injury in diabetic nephropathy (DN) have not been investigated yet. In this study, we aimed to investigate the beneficial effects of AS II on podocyte injury and mitochondrial dysfunction in DN. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg in rats. Diabetic rats were randomly divided into four groups, namely, diabetic rats and diabetic rats treated with losartan (10 mg·kg-1·d-1) or AS II (3.2 and 6.4 mg·kg-1·d-1) for 9 weeks. Normal Sprague-Dawley rats were chosen as nondiabetic control group. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology and podocyte apoptosis, and morphological changes were evaluated. Expressions of mitochondrial dynamics-related and autophagy-related proteins, such as Mfn2, Fis1, P62, and LC3, as well as Nrf2, Keap1, PINK1, and Parkin, were examined by immunohistochemistry, western blot, and real-time PCR, respectively. Our results indicated that AS II ameliorated albuminuria, renal histopathology, and podocyte foot process effacement and podocyte apoptosis in diabetic rats. AS II also partially restored the renal expression of mitochondrial dynamics-related and autophagy-related proteins, including Mfn2, Fis1, P62, and LC3. AS II also increased the expression of PINK1 and Parkin associated with mitophagy in diabetic rats. Moreover, AS II facilitated antioxidative stress ability via increasing Nrf2 expression and decreasing Keap1 protein level. These results suggested that AS II ameliorated podocyte injury and mitochondrial dysfunction in diabetic rats partly through regulation of Nrf2 and PINK1 pathway. These important findings might provide an innovative therapeutic strategy for the treatment of DN.