Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters

Zhou, Shanshan; Jin, Jingpeng; Bai, Tao; Sachleben, Leroy R.; Cai, Lu; Zheng, Yang

doi:10.1016/j.lfs.2015.05.015

Cited by 18 publications

(13 citation statements)

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“…In the present study, hyperglycemia‐induced oxidative stress decreases Nrf2, HO‐1, and γ‐GCS with increases Keap1 mRNA levels. The alterations were effectively reversed by the DC + ISO + KF10 and DC + ISO + KF20 rats (Zhou, Jin et al, ). Our results are in agreement with recent study which suggests that KF treatment attenuates hyperglycemia‐induced cardiac injuries through the activation of Nrf‐2 (Chen et al, ).…”

Section: Discussionmentioning

confidence: 99%

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

Zhang

Guo

Wang

et al. 2019

Drug Development Research

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This study was designed to delineate the effect of kaempferol (KF) on heart failure (HF) in diabetic rats. Streptozotocin‐induced male diabetic rats received KF orally at 10 and 20 mg/kg for 42 consecutive days. In last 2 days of the experimental period, isoproterenol was subcutaneously injected at 85 mg/kg to induce HF. The hearts were processed for hemodynamic, biochemical, molecular, and histological investigations. Systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were elevated in KF‐treated HF‐induced diabetic rats. Moreover, KF treatment resulted in decreased fasting blood glucose and glycosylated hemoglobin levels with increased serum insulin levels. Besides, serum cardiac injury markers like troponin‐I, creatine kinase‐muscle/brain, lactate dehydrogenase, and brain natriuretic peptide levels were significantly reduced in KF treatment. KF treatment has shown decrease in cardiac heme oxygenase‐1, nuclear factor erythroid 2–related factor 2 (Nrf‐2), and γ‐glutamylcysteine synthetase with increased Keap1 mRNA levels. The cardioprotection of KF was improved by inhibition of apoptosis via blocking phosphorylation of Akt/glycogen synthase kinase (GSK)‐3β and p38 mitogen‐activated protein‐kinase/extracellular signal‐regulated kinases signaling pathways in HF‐induced diabetic rats. Moreover, reduced cardiac apoptosis in KF treatment was confirmed by decreased terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) positive cells, histopathological changes in HF‐induced diabetic rats. Therefore, the cardioprotective effect of KF is attributed to the regulation of Nrf2, nuclear factor kappa‐light‐chain‐enhancer of activated B cells, and Akt/GSK‐3β signaling pathways in HF‐induced diabetic rats.

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Section: Discussionmentioning

confidence: 99%

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

Zhang

Guo

Wang

et al. 2019

Drug Development Research

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“…[15][16][17][18] Synthetic small molecule activators of the Nrf2/Keap1 pathway include bardoxolone methyl, which belongs to the antioxidant inflammation modulator class of drugs. Although preclinical studies showed a reduction in kidney disease with bardoxolone methyl, 19,20 this treatment was associated with heart failure in at risk patients.…”

mentioning

confidence: 99%

Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy

Deliyanti

Alrashdi

Tan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Deliyanti D, Alrashdi SF, Tan SM, et al. Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy. Invest Ophthalmol Vis Sci. 2018;59:815-825. https:// doi.org/10.1167/iovs.17-22920 PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the bloodretinal barrier (BRB) and associated damage to macroglial Müller cells.METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Müller cells exposed to hyperglycemia. RESULTS.In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-a and IL-6. Müller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase-1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-2 0 -deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Müller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress.CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetesinduced damage and potentially prevent vision loss.

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“…Neste sentido, em 2013 a primeira droga ativadora do Nrf2, o Dimetilfumarato, foi aprovada pela Agência de controle de alimentos e medicamentos dos Estados Unidos (FDA) e está em uso clínico no tratamento da esclerose múltipla. Tal fato enche de expectativa os pesquisadores, pois pode ser aberta uma ampla gama de possibilidades de tratamento para outras doenças como o DM 78 .…”

Section: Potencial Terapêuticounclassified

O papel do fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2) no diabetes mellitus

Hahn¹,

Oliveira²,

Bock³

2017

Clin. Biomed. Res.

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RESUMOO diabetes mellitus (DM) é uma doença metabólica complexa. Sua etiologia é atribuída a uma combinação entre fatores genéticos, ambientais e de estilo de vida. Contudo, sabe-se que o estresse oxidativo desempenha papel crucial na patogênese do DM, acarretando em disfunção das células β pancreáticas e resistência à insulina. Neste contexto, o fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2) é considerado o regulador mestre da resposta antioxidante do organismo, sendo um mecanismo de importância crítica para a manutenção da homeostase e sobrevivência celular. Todavia, a função do Nrf2 não se limita somente à resposta antioxidante. Ao interagir com outras vias metabólicas, o Nrf2 possui importante papel na regulação do metabolismo, atuando no metabolismo dos lipídios, manutenção da glicemia, resposta inflamatória, entre outros. Entretanto, a exata relação do Nrf2 com outras vias metabólicas ainda não é totalmente conhecida. Contudo, sabe-se que o comprometimento da função do Nrf2 é evidente na fisiopatologia do DM bem como no desenvolvimento de suas complicações clínicas. A ativação do Nrf2 protege contra os danos mediados pelo DM, podendo ser adequada uma intervenção exógena para aumentar a sua atividade. Palavras-chave: Complicações do diabetes; estresse oxidativo; antioxidantes; inflamação; obesidade ABSTRACTDiabetes mellitus (DM) is a complex metabolic disease. Its etiology is attributed to a combination of genetic, environmental, and lifestyle factors. However, it is known that oxidative stress plays a crucial role in the pathogenesis of DM, leading to pancreatic β-cell dysfunction and insulin resistance. In this context, the nuclear factor-erythroid 2-related factor 2 (Nrf2) is considered the main regulator of the body's antioxidant response, being a mechanism of critical importance in the maintenance of homeostasis and cell survival. However, the role of Nrf2 is not limited to the antioxidant response alone. When interacting with other metabolic pathways, Nrf2 plays an important role in regulating metabolism, acting on lipid metabolism, in the maintenance of glycemia, and in inflammatory response, among others. However, the exact relationship of Nrf2 with other metabolic pathways is not yet fully understood. Nevertheless, impairment of Nrf2 function is known to be evident in the pathophysiology of DM as well as in the development of its clinical complications. Activation of the Nrf2 protects against damage mediated by DM, and an exogenous intervention may be adequate to increase its activity. Keywords: Diabetes complications; oxidative stress; antioxidants; inflammation; obesityO diabetes mellitus (DM) é uma doença metabólica crônica e progressiva que apresenta severas complicações. A sua principal característica clínica é a hiperglicemia crônica resultante de defeitos na secreção e/ou ação da insulina. De tal modo, a exposição crônica à hiperglicemia conduz a danos, disfunção e falência de diversos órgãos, afetando especialmente o coração, rins, olhos, nervos, ilhotas pancreáticas e vasos sanguí...

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Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters

Cited by 18 publications

References 73 publications

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy

O papel do fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2) no diabetes mellitus

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