Inhibition of JNK Phosphorylation by a Novel Curcumin Analog Prevents High Glucose–Induced Inflammation and Apoptosis in Cardiomyocytes and the Development of Diabetic Cardiomyopathy

Pan, Yunlong; Wang, Y; Zhao, Ying‐Zheng; Peng, Kesong; Li, Wei; Zhang, J; Zhou, Shanshan; Q, Liu; X, Li; Cai, Liang; Liang, Guang

doi:10.2337/db13-1577

Cited by 173 publications

(138 citation statements)

References 41 publications

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“…Importantly, a recent clinical trial demonstrated that curcumin intervention in pre-diabetic human subjects lowered the number of individuals who eventually progressed to T2D [18] . Numerous in vitro investigations [17,[20][21][22][23][24][25][26] . For example, Pan et al investigated the protective effects of the curcumin derivative C66 on diabetic cardiomyopathy.…”

Section: Dietary Polyphenol and Dietary Polyphenol Interventionmentioning

confidence: 99%

“…In the H9c2 cell line (a cardiomyocyte model) and in rat neonatal cardiomyocytes, C66 pretreatment reduced high glucose-induced overexpression of the inflammatory cytokines, possibly via the inactivation of nuclear factor-κB (NF-κB) and the inhibition of Jun NH 2 -terminal kinase (JNK) phosphorylation. In mice with type 1 diabetes, C66 administration decreased the levels of plasma and cardiac tumor necrosis factor-α (TNFα), which is associated with a decreased risk of cardiac cell death [22] . Weisberg et al assessed the effect of native curcumin intervention in HFD fed C57BL/6J mice and the leptin-deficient (ob/ob) obesity mouse model.…”

Section: Dietary Polyphenol and Dietary Polyphenol Interventionmentioning

confidence: 99%

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Curcumin and dietary polyphenol research: beyond drug discovery

Jin

2018

Acta Pharmacol Sin

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Numerous natural products available over the counter are commonly consumed by healthy, sub-healthy or ill people for the treatment and prevention of various chronic diseases. Among them, a few dietary polyphenols, including the curry compound curcumin, have been attracting the most attention from biomedical researchers and drug developers. Unlike many so-called "good drug candidates", curcumin and several other dietary polyphenols do not have a single known therapeutic target or defined receptor. In addition, the bioavailability of these polyphenols is usually very low due to their poor absorption in the gut. These recently debated features have created enormous difficulties for drug developers. In this review, I do not discuss how to develop curcumin, other dietary polyphenols or their derivatives into pharmaceutical agents. Instead, I comment on how curcumin and dietary polyphenol research has enriched our knowledge of insulin signaling, including the presentation of my perspectives on how these studies will add to our understanding of the famous hepatic insulin function paradox.

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Section: Dietary Polyphenol and Dietary Polyphenol Interventionmentioning

confidence: 99%

Section: Dietary Polyphenol and Dietary Polyphenol Interventionmentioning

confidence: 99%

Curcumin and dietary polyphenol research: beyond drug discovery

Jin

2018

Acta Pharmacol Sin

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“…Increased cardiomyocyte apoptosis was a predominant cause of loss of contractile tissue, cardiac remodeling and, eventually, dysfunction [8]. Our previous study showed that inhibition of cardiomyocyte apoptosis improved cardiac function in diabetic mice [9].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that sustained activation of the NF-кB signaling pathway initiated apoptosis in HG-cultured cardiomyocytes [8, 10] and inhibition of this pathway improved cardiac dysfunction in diabetic mice [8]. Thus, targeted inhibition of persistent NF-κB signaling activation might effectively treat DCM.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

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Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway.

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“…Compound C66, a JNK inhibitor, was synthesized and purified (>98.4%) as described in our previous studies515253. PF00915275 and C66 were dissolved in DMSO for in vitro experiments and in CMC-Na (1%) for in vivo experiments.…”

Section: Methodsmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase Type 1(11β-HSD1) mediates insulin resistance through JNK activation in adipocytes

Peng

Pan

et al. 2016

Sci Rep

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Glucocorticoids are used to treat a number of human diseases but often lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Despite the known role of 11β-HSD1 and active glucocorticoid in causing insulin resistance, the molecular mechanisms by which insulin resistance is induced remain elusive. The aim of this study is to identify these mechanisms in high fat diet (HFD) experimental models. Mice on a HFD were treated with 11β-HSD1 inhibitor as well as a JNK inhibitor. We then treated 3T3-L1-derived adipocytes with prednisone, a synthetic glucocorticoid, and cells with 11β-HSD1 overexpression to study insulin resistance. Our results show that 11β-HSD1 and JNK inhibition mitigated insulin resistance in HFD mice. Prednisone stimulation or overexpression of 11β-HSD1 also caused JNK activation in cultured adipocytes. Inhibition of 11β-HSD1 blocked the activation of JNK in adipose tissue of HFD mice as well as in cultured adipocytes. Furthermore, prednisone significantly impaired the insulin signaling pathway, and these effects were reversed by 11β-HSD1 and JNK inhibition. Our study demonstrates that glucocorticoid-induced insulin resistance was dependent on 11β-HSD1, resulting in the critical activation of JNK signaling in adipocytes.

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Inhibition of JNK Phosphorylation by a Novel Curcumin Analog Prevents High Glucose–Induced Inflammation and Apoptosis in Cardiomyocytes and the Development of Diabetic Cardiomyopathy

Cited by 173 publications

References 41 publications

Curcumin and dietary polyphenol research: beyond drug discovery

Curcumin and dietary polyphenol research: beyond drug discovery

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

11β-Hydroxysteroid Dehydrogenase Type 1(11β-HSD1) mediates insulin resistance through JNK activation in adipocytes

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