scholarly journals Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc

2019 ◽  
Vol 20 (4) ◽  
pp. 985 ◽  
Author(s):  
Stefano Ciciliot ◽  
Gian Fadini
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Metabolic Pathways ◽  
Adaptor Protein ◽  
Oxygen Species ◽  
Related Protein ◽  
Redox Enzyme ◽  
Obesity And Diabetes ◽  
Promising Therapeutic Target

Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66Shc has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66Shc in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66Shc may represent a promising therapeutic target with enormous implications for human health.

scholarly journals Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3769
Author(s):  
Katerina Hadrava Hadrava Vanova ◽  
Chunzhang Yang ◽  
Leah Meuter ◽  
Jiri Neuzil ◽  
Karel Pacak
Keyword(s):  
Reactive Oxygen Species ◽  
Tumor Cells ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Ros Scavenging ◽  
Promising Therapeutic Target ◽  
Ros Accumulation ◽  
Intracellular Ros

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.

scholarly journals The Role of Reactive Oxygen Species in the Pathogenesis of Adipocyte Dysfunction in Metabolic Syndrome. Prospects of Pharmacological Correction

2017 ◽  
Vol 72 (1) ◽  
pp. 11-16 ◽  
Author(s):  
E. S. Prokudina ◽  
L. N. Maslov ◽  
V. V. Ivanov ◽  
I. D. Bespalova ◽  
D. S. Pismennyi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Metabolic Syndrome ◽  
Positive Impact ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Tnf Α ◽  
The One

It is established that oxidative stress induces insulin resistance of adipocytes, increases secretion leptin, IL-6, TNF-α by adipocytes. Adiponectin secretion by adipocytes is reduced after the action of reactive oxygen species. Metabolic syndrome contributes to oxidative stress in adipose tissue, on the one hand due to the activation of production of reactive oxygen species by adipocyte NADPH-oxidase, and on the other hand by reducing the antioxidant defense adipocytes. It is found that obesity itself can induce oxidative stress. Chronic stress, glucocorticoids, mineralocorticoids, angiotensin-II, TNF-α play an important role in the pathogenesis of oxidative stress of adipocytes. Metformin remains the cure for the treatment of insulin resistance. The positive results in the treatment of metabolic syndrome by losartan were obtained. Antioxidants and flavonoids exhibit a positive impact on the course of the experimental metabolic syndrome.

scholarly journals The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
W. A. García-Suástegui ◽  
L. A. Ramos-Chávez ◽  
M. Rubio-Osornio ◽  
M. Calvillo-Velasco ◽  
J. A. Atzin-Méndez ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Free Radical ◽  
Metabolic Pathways ◽  
The Body ◽  
Oxygen Species ◽  
Brain Disorders ◽  
Toxic Agents ◽  
Major Organ ◽  
The Brain

Organisms have metabolic pathways that are responsible for removing toxic agents. We always associate the liver as the major organ responsible for detoxification of the body; however this process occurs in many tissues. In the same way, as in the liver, the brain expresses metabolic pathways associated with the elimination of xenobiotics. Besides the detoxifying role of CYP2E1 for compounds such as electrophilic agents, reactive oxygen species, free radical products, and the bioactivation of xenobiotics, CYP2E1 is also related in several diseases and pathophysiological conditions. In this review, we describe the presence of phase I monooxygenase CYP2E1 in regions of the brain. We also explore the conditions where protein, mRNA, and the activity of CYP2E1 are induced. Finally, we describe the relation of CYP2E1 in brain disorders, including the behavioral relations for alcohol consumption via CYP2E1 metabolism.

scholarly journals Role of Reactive Oxygen Species in Injury-Induced Insulin Resistance

2011 ◽  
Vol 25 (3) ◽  
pp. 492-502 ◽  
Author(s):  
Lidong Zhai ◽  
Scott W. Ballinger ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Superoxide Dismutase ◽  
Critical Illness ◽  
Intracellular Signaling ◽  
Hepatic Insulin Resistance ◽  
Stress Signaling ◽  
Oxygen Species ◽  
Superoxide Dismutase 2

Abstract Acute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury.

scholarly journals Role of Reactive Oxygen Species in Injury-Induced Insulin Resistance

2011 ◽  
Vol 96 (2) ◽  
pp. 558-558
Author(s):  
Lidong Zhai ◽  
Scott W. Ballinger ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals Role of adaptor protein p66Shc in renal pathologies

2018 ◽  
Vol 314 (2) ◽  
pp. F143-F153 ◽  
Author(s):  
Kevin D. Wright ◽  
Alexander Staruschenko ◽  
Andrey Sorokin
Keyword(s):  
Reactive Oxygen Species ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Review Article ◽  
Oxygen Species ◽  
Kidney Physiology ◽  
Signaling Mechanisms ◽  
Wide Range ◽  
Key Questions

p66Shc is one of the three adaptor proteins encoded by the Shc1 gene, which are expressed in many organs, including the kidney. Recent studies shed new light on several key questions concerning the signaling mechanisms mediated by p66Shc. The central goal of this review article is to summarize recent findings on p66Shc and the role it plays in kidney physiology and pathology. This article provides a review of the various mechanisms whereby p66Shc has been shown to function within the kidney through a wide range of actions. The mitochondrial and cytoplasmic signaling of p66Shc, as it relates to production of reactive oxygen species (ROS) and renal pathologies, is further discussed.

scholarly journals Role of Reactive Oxygen Species in Injury-Induced Insulin Resistance

2011 ◽  
Vol 32 (1) ◽  
pp. 154-154
Author(s):  
Lidong Zhai ◽  
Scott W. Ballinger ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species

Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species

2007 ◽  
Vol 293 (5) ◽  
pp. E1311-E1319 ◽  
Author(s):  
Edward R. Duncan ◽  
Simon J. Walker ◽  
Vivienne A. Ezzat ◽  
Stephen B. Wheatcroft ◽  
Jian-Mei Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Wild Type

Insulin resistance is well established as an independent risk factor for the development of type 2 diabetes and cardiovascular atherosclerosis. Most studies have examined atherogenesis in models of severe insulin resistance or diabetes. However, by the time of diagnosis, individuals with type 2 diabetes already demonstrate a significant atheroma burden. Furthermore, recent studies suggest that, even in adolescence, insulin resistance is a progressive disorder that increases cardiovascular risk. In the present report, we studied early mechanisms of reduction in the bioavailability of the antiatheroscerotic molecule nitric oxide (NO) in very mild insulin resistance. Mice with haploinsufficiency for the insulin receptor (IRKO) are a model of mild insulin resistance with preserved glycemic control. We previously demonstrated that 2-mo-old (Young) IRKO mice have preserved vasorelaxation responses to ACh. This remained the case at 4 mo of age. However, by 6 mo, despite no significant deterioration in glucose homeostasis (Adult), IRKO mice had marked blunting of ACh-mediated vasorelaxation [IRKO maximum contraction response (Emax) 66 ± 5% vs. wild type 87 ± 4%, P < 0.01]. Despite the endothelial dysfunction demonstrated, aortic endothelial nitric oxide synthase (eNOS) mRNA levels were similar in Adult IRKO and wild-type mice, and, interestingly, aortic eNOS protein levels were increased, suggesting a compensatory upregulation in the IRKO. We then examined the potential role of reactive oxygen species in mediating early endothelial dysfunction. The superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) restored ACh relaxation responses in the Adult IRKO (Emax to ACh with MnTMPyP 85 ± 5%). Dihydroethidium fluorescence of aortas and isolated coronary microvascular endothelial cells confirmed a substantial increase in endothelium-derived reactive oxygen species in IRKO mice. These data demonstrate that mild insulin resistance is a potent substrate for accelerated endothelial dysfunction and support a role for endothelial cell superoxide production as a mechanism underlying the early reduction in NO bioavailability.

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