Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Abebe, Tsehay; Mahadevan, Jana; Bogachus, Lindsey D.; Hahn, Stephanie; Black, M Stephen; Oseid, Elizabeth; Urano, Fumihiko; Cirulli, Vincenzo; Robertson, R. Paul

doi:10.1172/jci.insight.92854

Cited by 39 publications

(35 citation statements)

References 45 publications

(39 reference statements)

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“…MDA levels were 0.018±0.005 nmol/g protein for O group; 0.016±0.005 nmol/g protein for N group; 0.01±0.005 nmol/g protein for L group for spleen and 0.031±0.004 nmol/g protein for O group; 0.02±0.004 nmol/g protein for N group; 0.017±0.004 nmol/g protein for L group for liver. This study was based on the premise that a hypercaloric diet induce oxidative stress in rats causing hepatic steatosis and cellular hypertrophy as shown in previous studies [34,35]. Our working hypothesis was that PLGA NP's loaded with lutein increase the antioxidant defenses due to lutein antioxidant potential [25].…”

Section: Resultsmentioning

confidence: 96%

The Antioxidant Effect of PLGA Nanoparticles Encapsulated with Lutein in Rats Treated with Hypercaloric Diet

Radulescu¹,

Miricescu²,

Calenic³

et al. 2018

Mat.Plast.

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Poly lactic-co-glycolic acid (PLGA) is a biodegradable polymer that has been the focus of intense research due to its potential applications in medical research. Its uses in nanotechnology are underlined by its capability of targeting various cells and delivering active compounds to different human tissues. To date, PLGA nanoparticles are employed in areas such as vaccination therapy, diagnostic imaging procedure and various applications in various anticancer therapies. The aim of the present study is to measure and evaluate different correlations between oxidative stress parameters in spleen and liver following administration of nanoparticles encapsulated with lutein in an animal model. Our results show that acute oral administration of PLGA NPs induces a change in the oxidative stress status in both liver and spleen of rats, but does not induce oxidative stress damage to cell structures such as lipids or proteins.

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Section: Resultsmentioning

confidence: 96%

The Antioxidant Effect of PLGA Nanoparticles Encapsulated with Lutein in Rats Treated with Hypercaloric Diet

Radulescu¹,

Miricescu²,

Calenic³

et al. 2018

Mat.Plast.

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“…Pancreatic β-cells are vulnerable to oxidative stress due to very low levels of antioxidant enzymes expression (Tiedge et al, 1997). Nuclear factor erythroid 2related factor 2 (Nfe2l2/Nrf2) is the master regulator of antioxidant gene transcription (Abebe et al, 2017). Activation of Nrf2 can regulate gene transcription of superoxide dismutase (Sod1 and Sod2), catalase, and glutathione peroxide 1 (Gpx1) along with many other (Zhu et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

Cytoprotective effects of combination of gypenosides andCostus pictusD.Don extract in BRIN-BD11 β-cells

Patibandla

Campbell

Bennett

et al. 2020

Preprint

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Ethnopharmacological Relevance: Gypenosides and Costus pictus D.Don are used as an anti-diabetic herbal remedy in China and India respectively. However, the synergistic effect of these two extracts on β-cell protection is not yet elucidated. Introduction: In Type 2 diabetes mellitus (T2DM), pro-inflammatory cytokines and lipotoxicity are known causes of pancreatic β-cell dysfunction and impaired insulin secretion and eventually β-cell death. Thus, any cytoprotective drug supplements can protect the β-cell and may help in T2DM treatment. Gypenosides, extracted from the Chinese medicinal herb Gynostemma pentaphyllum and the leaf extract from an Indian medicinal herb Costus pictus D. Don are used in traditional medicine due to their insulin secretory properties. In our previous studies, both extracts have shown significant cytoprotective effects in insulin-secreting BRIN-BD11 cells. In the present study, we aim to investigate the synergistic effects of a combination of these extracts on BRIN-BD11 β-cell protection. Methods Combination of extracts was prepared by adding Gypenosides with Costus pictus at 2:1 to a concentration of 18.75mg/ml. Cell viability was determined by MTT assay following treatment with combination and/or palmitate and cytokine cocktail for 24-48h. Following 24h treatment, proliferation was measured by Ki67 staining and cytoprotective gene expression was quantified by qPCR. Results: Combination treatment of 25μg/ml enhanced cell viability both at 24h (n=8; P<0.05) and 48h (n=8; P<0.0001) treatment. Over 24h, combination treatment (25&12.5 μg/ml) showed a significant protective effect against 125μM and 250μM palmitate induced (P<0.0001) and cytokine cocktail- (TNFα 1000U, IL-1β 50U & IFNγ 1000U) (P<0.0001 & P<0.01 respectively) induced toxicity. Combination treatment over 24h increased expression of antioxidant genes Nrf2 (P<0.001), Cat (P<0.001) and Sod1 (P<0.05) along with pro-proliferative Erk1 (P<0.01) while pro-inflammatory Nfkb1 expression was reduced(P<0.001). Conclusion: The results suggest that a combination of gypenosides and costus pictus may protect β-cells against inflammatory cytokines and lipotoxicity caused by saturated free fatty acids associated with obesity and diabetes.

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“…Recently, Yagishita and colleagues presented detailed in vivo evidence to demonstrate that Nrf2 induction prevents reactive species damage including oxidative DNAadduct formation, impaired insulin secretion, and apoptosis in pancreatic β-cells (38). Furthermore, activation of the Nrf2antioxidant pathway is reported to be a possible mechanism mediating self-repair of β-cells after a short-term exposure to a high fat diet feeding (48). Our present findings identify Plin5 as a positive regulator of Nrf2 in β-cells under lipid stress.…”

Section: Discussionmentioning

confidence: 99%

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

et al. 2020

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Oxidative stress induced by free fatty acid overload in pancreatic β-cells is a potential contributory factor to dysfunction of insulin secretion and apoptotic cell death. Perilipin 5 (Plin5) has been reported to ameliorate oxidative stress-mediated damage in non-insulin-secreting tissues. We tested the hypothesis that Plin5 plays a similar role in pancreatic β-cells, which are extremely sensitive to oxidative stress. Here, our in vitro data showed that Plin5-mediated alleviation of palmitate-triggered apoptosis involves the mitochondrial pathway. And the protective role of Plin5 on β-cells was partially dependent on its modulation in oxidative stress. Upregulation of Plin5 in INS-1 cells decreased reactive oxygen species production, enhanced cellular glutathione levels, and induced expression of antioxidant enzymes glutamate-cysteine ligase catalytic subunit and heme oxygenase-1. However, knocking out of Plin5 abolished all of these beneficial effects. Furthermore, by using the O 2− scavenger MnTMPyP, we verified that altering Plin5 expression impacted lipotoxic cell death partially via modulating oxidative stress. Mechanistic experiments revealed that Plin5 induced Nrf2-ARE system, a master regulator in the cellular adaptive response to oxidative stress, by activating PI3K/Akt and ERK signal pathways, contributing to the increase of antioxidant defense and consequently improving β-cell function and survival in the presence of lipotoxic oxidative stress. Overall, our findings indicate that Plin5 abrogates oxidative damage in INS-1 β-cells during lipotoxic stress partially through the enhancement of antioxidant defense involving the PI3K/Akt and ERK mediated Nrf2-ARE system.

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Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Cited by 39 publications

References 45 publications

The Antioxidant Effect of PLGA Nanoparticles Encapsulated with Lutein in Rats Treated with Hypercaloric Diet

The Antioxidant Effect of PLGA Nanoparticles Encapsulated with Lutein in Rats Treated with Hypercaloric Diet

Cytoprotective effects of combination of gypenosides andCostus pictusD.Don extract in BRIN-BD11 β-cells

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

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