ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function

Pi, Jingbo; Zhang, Qiang; Fu, Jingqi; Woods, Courtney G.; Hou, Yongyong; Corkey, Barbara E.; Collins, Sheila; Andersen, Melvin E.

doi:10.1016/j.taap.2009.05.025

Cited by 304 publications

(213 citation statements)

References 110 publications

(147 reference statements)

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“…Atg7 Δpan pancreata contained high amounts of Ucp2 mRNA (Fig. S3B), encoding a mitochondrial protein located on the inner mitochondrial membrane, involved in adaptive response to mitochondria-derived ROS and oxidative damage (31).…”

Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

207

182

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

207

182

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“…1); however, there were some unique differences. The commonly used MPC inhibitor ␣-CHC has been shown to inhibit insulin secretion in some studies (29 -31), stimulate in others (33,34), and do nothing in other studies (32). For most of these studies in ␤-cells, they have used a 1 mM ␣-CHC concentration, which is also known to inhibit PC (44).…”

Section: Pharmacological Inhibition Of the Mpc Reduces Gsis In 832/13mentioning

confidence: 99%

“…This inhibitor has facilitated experiments to determine the contribution of mitochondrial pyruvate transport to GSIS, yielding inconsistent results. Studies in rat islets (29), HIT cells (30), and MIN6 cells (31) showed that inhibition of pyruvate transport blocked GSIS, whereas a study with 832/13 cells showed no effect (32), and two other studies showed in mouse (33) and rat islets (34) that pyruvate transport inhibition leads to a stimulation of insulin secretion. A more potent mitochondrial pyruvate carrier inhibitor, ␣-cyano-␤-(1-phenylindol-3-yl)-acrylate (UK5099), which is now commercially available, has not yet been tested in ␤-cells (28).…”

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confidence: 99%

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Patterson

Cousteils

Lou

et al. 2014

Journal of Biological Chemistry

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Background: Pyruvate metabolism plays an essential role in pancreatic ␤-cells. Results: Pharmacological and siRNA-mediated inhibition of mitochondrial pyruvate carrier-1 and -2 inhibit ␤-cell metabolism and insulin secretion. Conclusion: Pyruvate entry into ␤-cell mitochondria is critical for regulating insulin release. Significance: Mitochondrial metabolism of pyruvate plays a key role in generating signals in response to nutrients that control insulin release.

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“…In this special context, the disruption of the uncoupling mitochondrial protein-2 (UC-2) into the inner membrane has been associated with a phenotype of massive and chronic free radical release [67].…”

Section: Molecular Pathways Of Diabetes Mellitus Pathogenesismentioning

confidence: 99%

“…In the same context, beta cells can adapt against free radical damage by expressing the nuclear-factor E2-related factor (Nrf-2) which triggers the expression of many different antioxidant genes, helping to rescue beta cells from the genotoxic free radical insults [67]. The Nrf-2 induction leads to expression of antioxidant genes and attenuation of the NFkB inflammatory pathway protecting endothelium, the nephron, and other structures against hyperglicemic-load induced toxicity [83][84][85][86].…”

Section: Molecular Pathways Of Diabetes Mellitus Pathogenesismentioning

confidence: 99%

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Ferrari¹

2017

Integr Obesity Diabetes

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Oxidative and nitrosative stress reactions are implicated in cell and organ damage due to diabetes mellitus. In both type 1 and type 2 DM there is a massive oxidative and nitrosative stresses which have been associated with intensive changes on both antioxidant enzyme systems (SOD, CAT, GPx, GSH) and total antioxidant capacity (TAC) causing peroxidative damage to lipids, proteins, nucleic acids and carbohydrates which can be used as DM biomarkers. Molecular pathophysiology of diabetes mellitus envolves induction of the the NFkB and p38-MAPK cell signaling pathways by Rac, TNF-α, TLR4, decrease of antioxidant defenses, and direct mitochondrial damage. Knowledge of molecular pathways is essential for research of newer preventive and therapeutic approaches in diabetes mellitus complications (atherosclerosis, myocardial damage, endothelial dysfunction, and renal failure).urine, feces, tissue sample), vegetable or fruit extract or even foods or pharmaceuticals [14][15][16].This article review and update the clinical, cellular, and molecular knowledge of free radicals and antioxidant defenses in diabetes mellitus. Ethiopathogenesis of diabetes mellitus I and IIDiabetes mellitus has been conceptualized as a group of metabolic disorders characterized by hyperglicemia as a result of insulin secretion failure and/or lacking of insulin action on target cells. The chronic diabetic hyperglicemic state has been related to long-term organ damage especially to the heart, endothelium and blood vessels, nerves, kidney, and eyes [17][18][19].

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ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function

Cited by 304 publications

References 110 publications

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

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