Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

Weaver, Jessica L.; Holman, Theodore R.; Imai, Yumi; Jadhav, Ajit; Kenyon, Victor; Maloney, David J.; Nadler, Jerry L.; Rai, Ganesha; Simeonov, Anton; Taylor‐Fishwick, David A.

doi:10.1016/j.mce.2012.03.004

Cited by 114 publications

(103 citation statements)

References 53 publications

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“…Compounds 5 or 9 were added 30 min before stimuli and retained for the remainder of the experiment. cDNA was prepared from isolated RNA as previously reported [13,27,31]. Speciesspecific Taqman primers were used for ALOX12, IL-12p40 (also known as IL12B), IFNγ (IFNG), monocyte chemoattractant protein-1 (MCP1), actin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…Despite advances, key therapeutic targets leading to new drug-based strategies to prevent the loss of functional beta cell mass have not been clearly identified [12]. There is accumulating evidence that activation of 12-lipoxygenase is a key link between cytokinemediated inflammation and beta cell damage [13]. 12-Lipoxygenase is an oxygenase for arachidonic acid (AA) and other fatty acids, leading to proinflammatory lipids including 12-S-hydroperoxieicosatetraenoic acid (12-S-HPETE) and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE) [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…12-Lipoxygenase is expressed in rodent and human islets [11,[15][16][17][18] and is upregulated under conditions of metabolic and cytokine stress. Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22]. Recent evidence indicates that increased expression of 12-lipoxygenase in islets is a common feature of both rodent and human models of type 1 and type 2 diabetes [11,13,15,17,22].…”

Section: Introductionmentioning

confidence: 99%

“…Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22]. Recent evidence indicates that increased expression of 12-lipoxygenase in islets is a common feature of both rodent and human models of type 1 and type 2 diabetes [11,13,15,17,22]. Deletion of 12-lipoxygenase protects mice against hyperglycaemia induced with low dose streptozotocin.…”

Section: Introductionmentioning

confidence: 99%

“…Deletion of 12-lipoxygenase significantly inhibits the development of insulin resistance in mice fed a high-fat diet. Products of 12-lipoxygenase lead to ER stress, oxidative stress and generation of proinflammatory cytokines [11,13,14,26]. Very recent evidence has shown that 12-lipoxygenase can generate IL-12 production in the islet [23,27].…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

et al. 2014

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Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-Shydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Results Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Conclusions/interpretation Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

et al. 2014

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Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease

Zhang

Dalan

et al. 2022

Advanced Materials

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Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, and hypercholesterolemia, which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial‐based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on cell/molecule‐targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. Herein, the roles of ROS in both IHD and its risk factors are discussed, highlighting cardiovascular medications that have antioxidant properties, and summarizing the advantages, properties, and recent achievements of nanomedicines that have ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, the current challenges of nanomedicines for ROS‐scavenging treatment of IHD and possible future directions are discussed from a clinical perspective.

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Molecular insights of NADPH oxidases and its pathological consequences

Waghela

Vaidya

Agrawal

et al. 2020

Cell Biochemistry & Function

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Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. Significance of the study The NOXs are multi‐subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

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Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

Cited by 114 publications

References 53 publications

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease

Molecular insights of NADPH oxidases and its pathological consequences

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