NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

Elumalai, Suma; Karunakaran, Udayakumar; Moon, Jun Sung; Won, Kyu Chang

doi:10.3390/cells10071573

Cited by 23 publications

(15 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NOX is considered one of the main resources for ROS production in endothelial cells. NOX is a multi-subunit complex, composed of the cytosolic components of regulatory subunits (p47phox, p67phox, p40phox, and small G-protein Rac1/2) and the membrane components of catalytic subunits (gp91phox and p22phox); the cytoplasmic subunits are translocated to the membrane and bind to the membrane subunits to assemble the active form of the NOX complex in response to stimulus [ 24 ]. Excessive assembly and activation of the NOX complex results in the induction of chronic inflammatory diseases, such as AS [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE−/− Mice

Liu

Teishima

Fu-jian

et al. 2022

Cells

View full text Add to dashboard Cite

Lipid rafts play important roles in signal transduction, particularly in responses to inflammatory processes. The current study aimed to identify whether lipid raft-mediated inflammation contributes to hyperhomocysteinemia (HHcy)-accelerated atherosclerosis (AS), and to investigate the underlying mechanisms. THP-1-derived macrophages were used for in vitro experiments. ApoE−/− mice were fed a high-fat diet for 12 weeks to establish an AS model, and a high-fat plus high-methionine diet was used to induce HHcy. We found that homocysteine (Hcy) increased the expression of p22phox and p67phox and promoted their recruitment into lipid rafts (indicating the assembly of the NOX complex), thereby increasing ROS generation and NOX activity, NLRP3 inflammasome activation, and pyroptosis. Mechanistically, Hcy activated the NOX-ROS-NLRP3 inflammasome pathway and induced pyroptosis by increasing the expression of acid sphingomyelinase (ASM) to promote the formation of lipid raft clustering. Importantly, lipid raft-mediated pyroptosis was confirmed in HHcy mice, and HHcy-promoted macrophage recruitment in atherosclerotic lesions and HHcy-aggravated AS were blocked by the lipid raft disruptor methyl-β-cyclodextrin. The study findings indicate that Hcy promotes lipid raft clustering via the upregulation of ASM, which mediates the assembly of the NOX complex, causing an increase in ROS generation, NLRP3 inflammasome activation, and pyroptosis, and contributes to HHcy-induced AS.

show abstract

Section: Discussionmentioning

confidence: 99%

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE−/− Mice

Liu

Teishima

Fu-jian

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…In skeletal muscle, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) enzymes are key producers of ROS and protagonists of redox homeostasis [ 12 , 13 ]. However, strong evidence suggests that NOX-generated ROS are a major contributor to oxidative damage in pathologic conditions, such as diabetes [ 14 , 15 , 16 ], and in muscle abnormalities in other settings [ 11 , 17 ]. The family of NOX enzymes consists of 7 members, NOX1–NOX5 and Duox1–2.…”

Section: Introductionmentioning

confidence: 99%

Apocynin Attenuates Diabetes-Induced Skeletal Muscle Dysfunction by Mitigating ROS Generation and Boosting Antioxidant Defenses in Fast-Twitch and Slow-Twitch Muscles

Sánchez-Duarte

Montoya‐Pérez

Márquez‐Gamiño

et al. 2022

Life

View full text Add to dashboard Cite

In response to diabetes mellitus, skeletal muscle is negatively affected, as is evident by reduced contractile force production, increased muscle fatigability, and increased levels of oxidative stress biomarkers. Apocynin is a widely used NADPH oxidase inhibitor, with antioxidant and anti-inflammatory potential. It has been effective for amelioration of a variety of disorders, including diabetic complications. Therefore, the present study was conducted to evaluate the effects and action mechanisms of apocynin in slow- and fast-twitch diabetic rat muscles. Male Wistar rats were rendered diabetic by applying intraperitoneally a single dose of streptozotocin (45 mg/kg). Apocynin treatment (3 mg/kg/day) was administered over 8 weeks. Fasting blood glucose (FBG), insulin tolerance and body weight gain were measured. Both slow (soleus) and fast (extensor digitorum longus, EDL) skeletal muscles were used for muscle function evaluation, oxidative stress markers, and evaluating gene expression using qRT-PCR. Treatment with apocynin significantly reduced FBG levels and enhanced insulin tolerance. Apocynin also prevented muscle contractile dysfunction in EDL muscle but had no significant effect on this parameter in soleus muscles. However, in both types of muscles, apocynin mitigated the oxidative stress by decreasing ROS levels and increasing total glutathione levels and redox state. Concomitantly, apocynin also statistically enhanced Nrf-2 and GLU4 mRNA expression and downregulated NOX2, NOX4, and NF-κB mRNA. Collectively, apocynin exhibits properties myoprotective in diabetic animals. These findings indicate that apocynin predominantly acts as an antioxidant in fast-twitch and slow-twitch muscles but has differential impact on contractile function.

show abstract

“…In DM, hyperglycemia is the main factor that induces oxidative stress, mainly via activation of NADPH oxidase in monocytes [ 7 ]. In type 2 DM, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to β-cell dysfunction and provides clues on the therapeutic benefits of NADPH oxidase inhibitors for the prevention of metabolic stress associated with β-cell failure [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update

Koniari

Velissaris

Kounis

et al. 2022

JCM

View full text Add to dashboard Cite

Diabetes mellitus (DM) and heart failure (HF) are two chronic disorders that affect millions worldwide. Hyperglycemia can induce excessive generation of highly reactive free radicals that promote oxidative stress and further exacerbate diabetes progression and its complications. Vascular dysfunction and damage to cellular proteins, membrane lipids and nucleic acids can stem from overproduction and/or insufficient removal of free radicals. The aim of this article is to review the literature regarding the use of antidiabetic drugs and their role in glycemic control in patients with heart failure and oxidative stress. Metformin exerts a minor benefit to these patients. Thiazolidinediones are not recommended in diabetic patients, as they increase the risk of HF. There is a lack of robust evidence on the use of meglinitides and acarbose. Insulin and dipeptidyl peptidase-4 (DPP-4) inhibitors may have a neutral cardiovascular effect on diabetic patients. The majority of current research focuses on sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. SGLT2 inhibitors induce positive cardiovascular effects in diabetic patients, leading to a reduction in cardiovascular mortality and HF hospitalization. GLP-1 receptor agonists may also be used in HF patients, but in the case of chronic kidney disease, SLGT2 inhibitors should be preferred.

show abstract

NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

Cited by 23 publications

References 110 publications

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE−/− Mice

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE−/− Mice

Apocynin Attenuates Diabetes-Induced Skeletal Muscle Dysfunction by Mitigating ROS Generation and Boosting Antioxidant Defenses in Fast-Twitch and Slow-Twitch Muscles

Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update

Contact Info

Product

Resources

About