Improvement of the Mitochondrial Antioxidant Defense Status Prevents Cytokine-Induced Nuclear Factor-κB Activation in Insulin-Producing Cells

Azevedo-Martins, Anna Karenina; Lortz, Stephan; Lenzen, Sigurd; Curi, Rui; Eizirik, Décio L.; Tiedge, Markus

doi:10.2337/diabetes.52.1.93

Cited by 155 publications

(105 citation statements)

References 43 publications

(62 reference statements)

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“…This led us to speculate that HIIT-related improvements to lipid markers may have partially explained the non-significant differences in post-intervention SBP in HIIT (227.12 mmHg), compared to SED (239.77 mmHg, +5.28% v. HIIT) and LIT (241.63 mmHg, +6.01% v. HIIT). In the present study, significant HIITrelated increases in the mRNA expression of Sod1 (compared to SED) and Cat (compared to SED and LIT) may further explain the non-significant differences in post-intervention SBP in HIIT, via eAO-mediated increases in molecular-level protection [10,35]. Research indicates that radical-mediated damage is a primary contributor to the development of hypertension [36] as superoxide can stimulate NFκB transcription factors that eventually lead to endothelial dysfunction and reduced vasodilation, resulting in increased peripheral resistance and elevated blood pressure [37].…”

Section: Ckd) Is Timelymentioning

confidence: 50%

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High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

Tucker

Briskey

Scanlan

et al. 2015

Free Radical Biology and Medicine

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Increased levels of oxidative stress and inflammation have been linked to the progression of chronic kidney disease. To reduce oxidative stress and inflammation related to chronic kidney disease, chronic aerobic exercise is often recommended. Data suggests high intensity interval training may be more beneficial than traditional aerobic exercise. However, appraisals of differing modes of exercise, along with explanations of mechanisms responsible for observed effects, are lacking. This study assessed effects of eight weeks of high intensity interval training (85% VO 2 max), versus low intensity exercise (45-50% VO 2 max) and sedentary behaviour, in an animal model of early-stage chronic kidney disease. We examined kidney-specific mRNA expression of genes related to endogenous antioxidant enzyme activity (glutathione peroxidase 1; Gpx1, superoxide dismutase 1; Sod1, and catalase; Cat) and inflammation (kidney injury molecule 1; Kim1 and tumour necrosis factor receptor super family 1b; Tnfrsf1b), as well as plasma F2-isoprostanes, a marker of lipid peroxidation.Compared to sedentary behaviour, high intensity interval training resulted in increased mRNA expression of Sod1 (p=0.01) and Cat (p<0.001). Compared to low intensity exercise, high intensity interval training resulted in increased mRNA expression of Cat (p<0.001) and Tnfrsf1b (p=0.047). In this study, high intensity interval training was superior to sedentary behaviour and low intensity exercise as high intensity interval training beneficially influenced expression of genes related to endogenous antioxidant enzyme activity and inflammation.

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Section: Ckd) Is Timelymentioning

confidence: 50%

“…Regulating NFκB-mediated INF is one beneficial effect of endogenous antioxidant enzymes (eAO). Specifically, superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) quench radicals while simultaneously inhibiting nuclear translocation of NFκB [10], thereby reducing systemic INF and INF-related radical generation.…”

Section: Introductionmentioning

confidence: 99%

High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

Tucker

Briskey

Scanlan

et al. 2015

Free Radical Biology and Medicine

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“…Activation of the transcription factor NF-κB has a pro-apoptotic role in beta cells exposed either to IL-1β + IFN-γ [58,59] or to dsRNA + IFN-γ [22]. MnSOD and IκBα are two genes that might participate in beta-cell defence against apoptosis by decreasing NF-κB activation [60,61], and both mRNAs were induced by dsRNA. MnSOD is a NF-κB dependent [52] mitochondrial antioxidant enzyme, and overexpression of MnSOD protects beta cells against immune-mediated damage [62].…”

Section: Discussionmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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“…Given the importance of maintaining normal redox potential in beta cells, it is not surprising that experimental overexpression of free radical dissipating enzymes such as catalase, glutathione peroxidase and the cytoplasmic copper-zinc superoxide dismutase protects cultured rodent beta cells from deleterious combinations of cytokines (interferon gamma [IFN-γ], tumor necrosis factor α [TNF-α] and interleukin 1 [IL-1]) [13]. However, it is unusual to find a mouse with systemically upregulated antioxidant defences that include increased expression at the beta cell level as well.…”

Section: Introductionmentioning

confidence: 99%

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

et al. 2005

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Aims/hypothesis: ALR/Lt, a mouse strain with strong resistance to type 1 diabetes, is closely related to autoimmune type 1 diabetes-prone NOD/Lt mice. ALR pancreatic beta cells are resistant to the beta cell toxin alloxan, combinations of cytotoxic cytokines, and diabetogenic NOD T-cell lines. Reciprocal F1 hybrids between either ALR and NOD or ALR and NON/Lt, showed that alloxan resistance was transmitted to F1 progeny only when ALR was the maternal parent. Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes. Methods: When F1 progeny from reciprocal outcrosses between ALR and NOD were backcrossed to NOD, a four-fold lower frequency of spontaneous type 1 diabetes development occurred when ALR contributed the mtDNA. Because of the apparent interaction between nuclear and mtDNA, the mitochondrial genomes were sequenced. Results: An ALR-specific sequence variation in the mt-Nd2 gene producing a leucine to methionine substitution at amino acid residue 276 in the NADH dehydrogenase 2 was discovered. An isoleucine to valine mutation in the mt-Co3 gene encoding COX3 distinguished ALR and NOD from NON and ALS. All four strains were distinguished by variation in a mt-encoded arginyl tRNA polyadenine tract. Shared alleles of mt-Co3 and mt-Tr comparing NOD and ALR allowed for exclusion of these two genes as candidates, implicating the mt-Nd2 variation as a potential ALR-derived type 1 diabetes protective gene. Conclusions/interpretation: The unusual resistance of ALR mice to both ROS-mediated and autoimmune type 1 diabete stresses reflects an interaction between the nuclear and mt genomes. The latter contribution is most likely via a single nucleotide polymorphism in mt-Nd2.

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Improvement of the Mitochondrial Antioxidant Defense Status Prevents Cytokine-Induced Nuclear Factor-κB Activation in Insulin-Producing Cells

Abstract: Proinflammatory cytokines (interleukin-1␤ [IL-1␤], tumor necrosis factor-␣ [TNF-␣], and ␥-interferon [IFN-

Cited by 155 publications

References 43 publications

High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

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