Metformin protects primary rat hepatocytes against oxidative stress‐induced apoptosis

Rosa, Laura Conde de la; Vrenken, Titia E.; Buist‐Homan, Manon; Faber, Klaas Nico; Moshage, Han

doi:10.1002/prp2.125

Cited by 52 publications

(35 citation statements)

References 68 publications

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“…45) A recent study has indicated that the protective effect of metformin, an antihyperglycemic agent used in type 2 diabetes, on oxidative stress is in part dependent on the induction of HO-1. 46) In this study, we showed that EPS induced HO-1 expression in Schwann cells, suggesting the beneficial effect of EPS. Analysis of SOD1 and catalase revealed that EPS induced their antioxidant protein expression via the Nrf2-mediated pathway.…”

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confidence: 50%

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases. Key words epalrestat; heme oxygenase (HO)-1; superoxide dismutase (SOD); catalaseHeme oxygenase (HO)-1 is a stress-responsive enzyme that has anti-inflammatory, antioxidant, and cytoprotective functions. Expectations are high that the regulation and amplification of HO-1 by pharmacological approaches would lead to the discovery of novel drugs for the treatment of a variety of diseases.1) HO-1 has emerged as an anti-inflammatory therapeutic target.2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported.3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.3) However, such metalloporphyrins as cobalt protoporphyrin IX, which are prototypical inducers of HO-1 and commonly used in experimental cell culture and animal models, are not applicable to clinical interventions because of their high toxicity.2) It is expected that the upregulation of HO-1 by currently available pharmacological agents, whose safety and pharmacokinetics have already been confirmed clinically, would be useful for the treatment of a variety of diseases.The biochemical activities of heme degradation products and their metabolic derivatives contribute to the cytoprotective function of HO-1. HO-1 catalyzes the degradation of heme to produce ferrous iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted into bilirubin. Carbon monoxide is involved in inflammation regulation.4) Bilirubin and biliverdin, which can scavenge peroxyl radicals, are cytoprotec...

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confidence: 50%

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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“…No treatment strategies targeting patients with NAFLD and T2DM have been established, indicating that etiological treatments (aimed at ameliorating visceral obesity, hyperlipidemia, and diabetes mellitus/insulin resistance) have a high priority. Therefore, insulin-sensitizing agents have been evaluated for the treatment of NAFLD and T2DM, and metformin is an attractive treatment due to its favorable safety profile and potential therapeutic effect [13, 32–34]. It is reported in the literature [35] that metformin not only increases glucose utilization in peripheral tissues, but also inhibits the production of glucose, triglycerides, and cholesterol and stimulates fatty acid oxidation, preventing the progression of NAFLD [18, 36].…”

Section: Discussionmentioning

confidence: 99%

Metformin and Diammonium Glycyrrhizinate Enteric-Coated Capsule versus Metformin Alone versus Diammonium Glycyrrhizinate Enteric-Coated Capsule Alone in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus

Zhang

Cheng

et al. 2017

Gastroenterology Research and Practice

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Objective. The present study was conducted to compare the efficacy of metformin combined with diammonium glycyrrhizinate enteric-coated capsule (DGEC) versus metformin alone versus DGEC alone for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods. 163 patients with NAFLD and T2DM were enrolled in this 24-week study and were randomized to one of three groups: group 1 was treated with metformin alone; group 2 was treated with DGEC alone; group 3 received metformin plus DGEC combination therapy. Anthropometric parameters, liver function, lipid profile, serum ferritin (SF), metabolic parameters, liver/spleen computed tomography (CT) ratio, and fibroscan value were evaluated at baseline and after 8, 16, and 24 weeks of treatment. Results. After 24 weeks, significant improvements in all measured parameters were observed in three groups (P < 0.05) except for the improvements in low density lipoprotein cholesterol (LDL-C) and metabolic parameters in group 2 which did not reach statistical significance (P > 0.05). Compared with group 1 and group 2, the patients in group 3 had greater reductions in observed parameters apart from CB and TB (P < 0.05). Conclusions. This study showed that metformin plus DGEC was more effective than metformin alone or DGEC alone in reducing liver enzymes, lipid levels, and metabolic parameters and ameliorating the degree of hepatic fibrosis in patients with NAFLD and T2DM.

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“…MET at a dose of 125 mg/kg restored the levels of ALAT, ASAT and ALP in rats chemically induced hepatocarcinogenesis (Afzal et al, 2012). A novel mechanism reported about MET may protect against apoptosis, involving the induction of hemeoxygenase-1 (HO-1) and bcl-xl expression and the reduction of mitogen-activated protein kinase (JNK) activation and the modulation of JNK activity represents a target for the treatment of these disorders (de la Rosa et al, 2015). MET ameliorates functional defects, activation of caspases and apoptosis in pancreatic islets from type 2 diabetic patients (Marchetti et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of canagliflozin or metformin on metabolic disorders in obese diabetic rats

Marie¹,

Arafa²,

Alazimi³

2015

Afr. J. Pharm. Pharmacol.

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This study aimed to investigate the effect of canagliflozin (CAN) or metformin (MET) on investigated biochemical parameters in obese diabetic rat model. Obesity induced by melted butter administration and hyperlipidemic rats were subjected to streptozotocin (STZ; 35 mg/kg i.p) to develop the diabetic model (D). Animals were grouped as control (C), D none treated and diabetic treated with CAN (10 mg/kg) or MET (100 mg/kg) for two and four weeks. Both treated groups showed significant reduction in body weight and CAN group exhibited significant decrease in oral glucose tolerance test (OGTT) as compared to D or MET group in the experimental periods. Both drugs showed hypolipidemic activity by reducing total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and elevating high-density lipoprotein (HDL) as compared to D group values in the two intervals with advantage in MET effect. Both treatments achieved significant reduction in the diabetic elevated serum values for liver and kidney functions. These results indicate that butter high-fat diet and low dose of STZ makes normal male adult rat associated with hyperlipidemia, glucose intolerance and disturbed liver and kidney functions. Treatment by either CAN or MET resisted the metabolism disturbance of the butter high fat diet/STZ-induced obese type 2 diabetes mellitus rats.

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Metformin protects primary rat hepatocytes against oxidative stress‐induced apoptosis

Cited by 52 publications

References 68 publications

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Metformin and Diammonium Glycyrrhizinate Enteric-Coated Capsule versus Metformin Alone versus Diammonium Glycyrrhizinate Enteric-Coated Capsule Alone in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus

Effect of canagliflozin or metformin on metabolic disorders in obese diabetic rats

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