NADPH oxidase: A membrane-bound enzyme and its inhibitors in diabetic complications

Laddha, Ankit P.; Kulkarni, Yogesh A.

doi:10.1016/j.ejphar.2020.173206

Cited by 44 publications

(71 citation statements)

References 95 publications

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“…Overexpression of Rac1 is related to the high levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) can form a VEGF-VEGFR signaling pathway, which participates in the regulation of angiogenesis (83,84). The role of Rac1 in retinal angiogenesis has been well documented (85,86). IQ-guanosine triphosphatase activating protein 1 (IQGAP1) is a scaffold protein with Rac1 binding domain, and its knock-out can significantly inhibit choroidal neovascularization induced by the VEGFR2-Rac1 signal axis (87).…”

Section: Rac1 Promotes Tumor Angiogenesismentioning

confidence: 99%

Rac1, A Potential Target for Tumor Therapy

et al. 2021

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RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.

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Section: Rac1 Promotes Tumor Angiogenesismentioning

confidence: 99%

Rac1, A Potential Target for Tumor Therapy

et al. 2021

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“…In the back drop of the above discussion about the unique situation the islet beta cell faces, namely poor antioxidant defense, and a high degree of intracellular oxidative stress, which is created under diabetogenic conditions, I have overviewed our current understanding of the roles of NADPH oxidases (Noxs) in the onset of metabolic dysfunction of the beta cell under the duress of exposure to pro-inflammatory cytokines. The Nox superfamily represents a class of flavocytochromes that promote transport electrons through biological membranes and catalyze the cytosolic NADPH-dependent reduction of molecular oxygen to superoxide radicals [25][26][27][28][29][30][31][32][33][34][35]. Interestingly, however, despite a considerable degree of similarity in their ability to generate high levels of superoxide radicals under metabolic stress conditions, they significantly differ in structural composition, subcellular distribution, and response to specific external stimuli (Figure 1).…”

Section: Nadph Oxidases Play Key Roles In Islet Function In Health Anmentioning

confidence: 99%

“…Lastly, it is noteworthy that the Nox5 gene is not expressed in mice and rats [32]. The reader is referred to recent reviews that highlight subunit composition, regulation of individual subunit function via post-translational modifications, translocation to the membrane, holoenzyme assembly, and functional activation of individual members of the Nox superfamily [25][26][27][28][29][30][31][32][33][34]. It may be germane to point out that investigations from multiple laboratories have reported expression of Nox1 [37][38][39], Nox2 [26,[40][41][42][43], Nox4 [41,44], and Nox5 [45] in human islets, thus making these oxidases potential regulators of islet function and dysfunction in health and disease.…”

Section: Nadph Oxidases Play Key Roles In Islet Function In Health Anmentioning

confidence: 99%

Oxidative Stress in Cytokine-Induced Dysfunction of the Pancreatic Beta Cell: Known Knowns and Known Unknowns

Kowluru

2020

Metabolites

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Compelling evidence from earlier studies suggests that the pancreatic beta cell is inherently weak in its antioxidant defense mechanisms to face the burden of protecting itself against the increased intracellular oxidative stress following exposure to proinflammatory cytokines. Recent evidence implicates novel roles for nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) as contributors to the excessive intracellular oxidative stress and damage under metabolic stress conditions. This review highlights the existing evidence on the regulatory roles of at least three forms of Noxs, namely Nox1, Nox2, and Nox4, in the cascade of events leading to islet beta cell dysfunction, specifically under the duress of chronic exposure to cytokines. Potential crosstalk between key signaling pathways (e.g., inducible nitric oxide synthase [iNOS] and Noxs) in the generation and propagation of reactive molecules and metabolites leading to mitochondrial damage and cell apoptosis is discussed. Available data accrued in investigations involving small-molecule inhibitors and antioxidant protein expression methods as tools toward the prevention of cytokine-induced oxidative damage are reviewed. Lastly, current knowledge gaps in this field, and possible avenues for future research are highlighted.

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“…The duration of diabetes and treatments to high glucose could not influence the retinal antioxidant capacity of mitochondrial enzymes in the disposal of H 2 O 2 , suggesting that mitochondria may not be a major source of oxidative stress in the diabetic retina. Nevertheless, an increased level of ROS was found under in vivo conditions in the diabetic retinas that indicate the possibility of non-mitochondrial sources of ROS generation, which may include activation of NADPH and NADH oxidases [27,48,49], activation of endothelial cells by paracrine mediators [25], activation of microglia [50], and glutamate excitotoxicity [51,52]. Thus, metabolic abnormalities by hyperglycemia per se, especially through mitochondrial stress may not be the sole basis of retinal damage in diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 99%

Does Hyperglycemia Cause Oxidative Stress in the Diabetic Rat Retina?

Ola

2021

Cells

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Diabetes, being a metabolic disease dysregulates a large number of metabolites and factors. However, among those altered metabolites, hyperglycemia is considered as the major factor to cause an increase in oxidative stress that initiates the pathophysiology of retinal damage leading to diabetic retinopathy. Diabetes-induced oxidative stress in the diabetic retina and its damaging effects are well known, but still, the exact source and the mechanism of hyperglycemia-induced reactive oxygen species (ROS) generation especially through mitochondria remains uncertain. In this study, we analyzed precisely the generation of ROS and the antioxidant capacity of enzymes in a real-time situation under ex vivo and in vivo conditions in the control and streptozotocin-induced diabetic rat retinas. We also measured the rate of flux through the citric acid cycle by determining the oxidation of glucose to CO2 and glutamate, under ex vivo conditions in the control and diabetic retinas. Measurements of H2O2 clearance from the ex vivo control and diabetic retinas indicated that activities of mitochondrial antioxidant enzymes are intact in the diabetic retina. Short-term hyperglycemia seems to influence a decrease in ROS generation in the diabetic retina compared to controls, which is also correlated with a decreased oxidation rate of glucose in the diabetic retina. However, an increase in the formation of ROS was observed in the diabetic retinas compared to controls under in vivo conditions. Thus, our results suggest of diabetes/hyperglycemia-induced non-mitochondrial sources may serve as major sources of ROS generation in the diabetic retina as opposed to widely believed hyperglycemia-induced mitochondrial sources of excess ROS. Therefore, hyperglycemia per se may not cause an increase in oxidative stress, especially through mitochondria to damage the retina as in the case of diabetic retinopathy.

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NADPH oxidase: A membrane-bound enzyme and its inhibitors in diabetic complications

Cited by 44 publications

References 95 publications

Rac1, A Potential Target for Tumor Therapy

Rac1, A Potential Target for Tumor Therapy

Oxidative Stress in Cytokine-Induced Dysfunction of the Pancreatic Beta Cell: Known Knowns and Known Unknowns

Does Hyperglycemia Cause Oxidative Stress in the Diabetic Rat Retina?

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