Unfolding Nrf2 in diabetes mellitus

Behl, Tapan; Kaur, Ishnoor; Sehgal, Aayush; Sharma, Eshita; Kumar, Arun; Grover, Madhuri; Bungău, Simona

doi:10.1007/s11033-020-06081-3

Cited by 28 publications

(17 citation statements)

References 68 publications

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“…Of note, emerging evidence suggests that oxidative stress plays a vital role in the pathogenesis of T2DM (Yaribeygi et al, 2020). Nrf2 is a key transcription factor in regulating oxidative stress responses, and the activation of the Nrf2/ARE signaling pathway is important in resisting oxidative stress (Behl et al, 2021). In general, Nrf2 binds to keap1 in the cytoplasm and can be degraded by ubiquitin in an inactivated status.…”

Section: Discussionmentioning

confidence: 99%

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

et al. 2022

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Oxidative stress and aberrant insulin signaling transduction play vital roles in type 2 diabetes mellitus (T2DM). Our previous research has demonstrated that trilobatin (TLB), derived from the leaves of Lithocarpus Polystachyus (Wall.), exhibits a potent antioxidative profile. In the current study, we investigated the anti-T2DM effect of TLB on KK-Ay diabetic mice and further explored the potential mechanisms. Our results showed that TLB significantly reduced the high fasting blood glucose level and insulin resistance and promoted the tolerances to exogenous glucose and insulin in KK-Ay mice. Moreover, TLB reduced the content of reactive oxygen species; enhanced antioxidant enzymes activities, including serum catalase, glutathione peroxidase, and superoxide dismutase; and regulated the abnormal parameters of lipid metabolism, including triglyceride, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and free fatty acid, as evidenced by enzyme-linked immunosorbent assay. Additionally, TLB markedly ameliorated the pancreatic islet morphology near normal and increased the insulin expression of the islet. Whereafter, TLB promoted Nrf2 that was translocated from cytoplasm to nucleus. Moreover, it increased the protein expressions of HO-1, NQO-1, and GLUT-2, and phosphorylation levels of Akt and GSK-3βSer 9 and decreased the protein expressions of keap1 and phosphorylation levels of IRS-1Ser 307 and GSK-3βTyr 216. Taken together, our findings reveal that TLB exhibits an anti-T2DM effect in KK-Ay mice by activating the Nrf2/ARE signaling pathway and regulating insulin signaling transduction pathway, and TLB is promising to be developed into a novel candidate for the treatment of T2DM in clinic due to its favorable druggability.

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Section: Discussionmentioning

confidence: 99%

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

et al. 2022

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“… 31 Recent studies have reported that upregulating the AMPK pathway can activate the NRF2/KEAP1 pathway, which leads to the alleviation of insulin resistance and diabetes-related complications induced by oxidative stress and inflammation. 32 , 33 TXNIP, also known as vitamin D3-upregulated gene 1 (VDUP1), plays a critical role in diabetes. Various epidemiological studies have demonstrated that the levels of TXNIP in patients with hyperlipidemia and hyperglycemia are significantly higher than those in healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Qihu Preparation Ameliorates Diabetes by Activating the AMPK Signaling Pathway in db/db Mice

Zeng

Zhou

et al. 2021

DMSO

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To examine the pharmacological effects of Qihu on type 2 diabetes mellitus using db/db mice. Materials and Methods: Thirty-seven db/db mice were randomly divided into the following 5 groups: diabetes model control group (DM group; n = 7), administered with the adjuvant 0.3% carboxymethyl cellulose-Na; positive control group (Met group; n = 8), administered with metformin (0.13 g/kg bodyweight); Qihu-L group (n = 7), administered with a low dose of Qihu (0.75 g/kg bodyweight), Qihu-M group (n = 7), administered with a medium dose of Qihu (1.5 g/kg bodyweight); Qihu-H group (n = 8), administered with a high dose of Qihu (3.0 g/kg bodyweight). BKS mice (n = 8) were used as the negative control group. The db/db mice were administered with drugs through oral gavage for 28 days. The random blood glucose levels, glucose tolerance test, bodyweight, food intake, and blood lipid levels of the mice were measured during the experimental period. The liver and pancreas tissues were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses. Results: Compared with the DM group, the Qihu groups exhibited decreased bodyweight gain. The blood glucose levels in the Qihu-L, Qihu-M, and Qihu-H were 31.46%, 43.73%, and 51.83%, respectively, lower than those in the DM group. The triglyceride levels were significantly downregulated and the swelling and steatosis of the hepatocytes were significantly lower in the Qihu-M and Qihu-H groups than in the DM group. Qihu downregulated the expression of IL-1β, IL-6, and TXNIP and upregulated the AMP-activated protein kinase (AMPK) signaling pathway in the pancreas and liver tissues of db/db mice. Conclusion:The anti-diabetic effects of Qihu are mediated through the activation of the AMPK/Txnip signaling and the downregulation of the secretion of inflammatory factors in db/db mice.

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“…In response, ROS are attenuated by Nrf2 [ 199 ] and β-cells are protected from oxidative stress. However, chronic exposure to hyperglycemia leads to accumulation of ROS due to incomplete reduction of oxygen during glucose metabolism [ 200 , 201 ]. In addition, aberrant glucose metabolism generates ROS through activation of protein kinase C, glucose auto-oxidation, generation of excessive superoxide, increased hexosamine metabolism, and increased islet amyloid deposition [ 202 , 203 , 204 ].…”

Section: Nrf2 Agonism In Diabetes and Its Complicationsmentioning

confidence: 99%

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

Kim

Jeon

2022

IJMS

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Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.

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Unfolding Nrf2 in diabetes mellitus

Cited by 28 publications

References 68 publications

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

Qihu Preparation Ameliorates Diabetes by Activating the AMPK Signaling Pathway in db/db Mice

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

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