Genipin suppresses NLRP3 inflammasome activation through uncoupling protein-2

Rajanbabu, Venugopal; Galam, Lakshmi; Fukumoto, Jutaro; Enciso, Juan; Tadikonda, Pratima; Lane, Troy; Bandyopadhyay, Sayantani; Parthasarathy, Prasanna Tamarapu; Cho, Young; Cho, Seong Ho; Lee, Yong Chul; Lockey, Richard F.; Kolliputi, Narasaiah

doi:10.1016/j.cellimm.2015.06.002

Cited by 38 publications

(25 citation statements)

References 33 publications

(36 reference statements)

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“…The natural product genipin (GNP), an inhibitor of UCP2, was shown to enhance ATP production in isolated pancreatic islets and improve mitochondrial function in mice [27,28]. UCP2 also suppresses inflammation and inhibits NLRP3 expression [29,30]. In addition, UCP2 knockout mice were completely resistant to Toxoplasma gondii infection, suggesting that UCP2 has an antiinflammatory role [31].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Zhong

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver damage is a typical manifestation of nonalcoholic fatty liver disease (NAFLD). It originates from excessive fat accumulation, leading to hepatocyte death, inflammation, and fibrosis. Nonalcoholic steatohepatitis (NASH) is a type of NAFLD with a prevalence of 49% in morbidly obese patients. Pyroptosis plays an important role in the development of NASH; thus, it is important to elucidate the effect of lipid accumulation on pyroptosis. Genipin (GNP), a natural water-soluble cross-linking agent, has hepatoprotective effects and decreases lipid accumulation in the liver; however, the mechanisms underlying these effects are unknown. Methods: In this study, qPCR and Western blot were used to examine pyroptotic gene expression in high-fat diet (HFD) induced obese mice and free fatty acids (FFAs) treated hepatocytes. At the same time, relative lactate dehydrogenase (LDH) release and Hoechst & propidium iodide (PI) staining were done to verify cell death. To explore the molecular mechanism, cell transfection were constructed with siRNA or plasmid to obtain knockdown or overexpression hepatocytes. Results: We found that HFD-fed mice and FFAs-treated hepatocytes had obvious pyroptosis, and addition of GNP reversed liver damage and inhibited pyroptosis both in vitro and in vivo. Besides, UCP2 knockdown cells showed suppressed FFAs-mediated pyroptosis, as determined by decreased pyroptotic gene expression, reduced lactate dehydrogenase (LDH) release, and reduced cell death. Consistent with this, cells transfected with UCP2 had upregulated pyroptotic gene expression, increased LDH release, and increased cell death. Conclusion: GNP reverses HFD-induced liver damage and inhibits UCP2-mediated pyroptosis. Thus, GNP may serve as a potential therapeutic candidate for NAFLD.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Zhong

Liu

et al. 2018

Cell Physiol Biochem

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“…Inflammasomes are cytosolic, multiprotein complexes that are composed of a NOD‐like receptor (NLR) or the absent in melanoma (AIM2)‐like receptors, ASC and pro‐caspase‐1 . Among the NLRs, NLRP3 is best known for sensing the widest array of stimuli, such as nigericin, ATP, ROS, MSU and cholesterol . When the host receives a signal stimulus, NLRP3 itself can undergo oligomerization, increasing pro‐caspase‐1 through the adapter protein ASC, which activates caspase‐1 and then leads to the cleavage of the interleukin‐1β precursor (pro‐interleukin‐1β) and the interleukin‐18 precursor (pro‐interleukin‐18), causing corresponding inflammation factor IL‐1β and IL‐18 generation, thus inducing inflammation and necrosis (pyroptosis) and participating in the inflammatory response of cell and tissue …”

Section: Introductionmentioning

confidence: 99%

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

Zhang

Chen

Zong

et al. 2018

J Cellular Molecular Medi

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NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation.

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“…However, once excessive ROS overwhelms endogenous antioxidant defense systems, oxidative stress occurs in the lung tissue. Oxidative stress induces tissue damage and triggers inflammasome activation, resulting in severe inflammation in ALI [10]. Based on the underlying mechanisms of ALI, it is believed that antioxidant and anti-inflammatory agents may serve as effective therapeutic strategies for the treatment of ALI.…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Li-Fei-Xiao-Yan Prescription on Lipopolysaccharide-Induced Acute Lung Injury via Inhibition of Oxidative Stress and the TLR4/NF-κB Pathway

Gui

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Li-Fei-Xiao-Yan prescription (LFXY) has been clinically used in China to treat inflammatory and infectious diseases including inflammatory lung diseases. The present study was aimed at evaluating the potential therapeutic effects and potential mechanisms of LFXY in a murine model of lipopolysaccharide- (LPS-) induced acute lung injury (ALI). In this study, the mice were orally pretreated with LFXY or dexamethasone (positive drug) before the intratracheal instillation of LPS. Our data indicated that pretreatment with LFXY enhanced the survival rate of ALI mice, reversed pulmonary edema and permeability, improved LPS-induced lung histopathology impairment, suppressed the excessive inflammatory responses via decreasing the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and chemokine (MIP-2) and inhibiting inflammatory cells migration, and repressed oxidative stress through the inhibition of MPO and MDA contents and the upregulation of antioxidants (SOD and GSH) activities. Mechanistically, treatment with LFXY significantly prevented LPS-induced TLR4 expression and NF-κB (p65) phosphorylation. Overall, the present study suggests that LFXY protected mice from acute lung injury induced by LPS via inhibition of TLR4/NF-κB p65 activation and upregulation of antioxidative enzymes and it may be a potential preventive and therapeutic agent for ALI in the clinical setting.

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Genipin suppresses NLRP3 inflammasome activation through uncoupling protein-2

Cited by 38 publications

References 33 publications

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

Protective Effects of Li-Fei-Xiao-Yan Prescription on Lipopolysaccharide-Induced Acute Lung Injury via Inhibition of Oxidative Stress and the TLR4/NF-κB Pathway

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