Gypenoside IX Suppresses p38 MAPK/Akt/NFκB Signaling Pathway Activation and Inflammatory Responses in Astrocytes Stimulated by Proinflammatory Mediators

Wang, Xiaoshuang; Liu, Yang; Yang, Li; Xing, Faping; Yang, Hua; Qin, Liyue; Lan, Yunyi; Wu, Hui; Zhang, Beibei; Shi, Hailian; Cheng, Lü; Huang, Fei; Wu, Xiaojun; Wang, Zhengtao

doi:10.1007/s10753-017-0654-x

Cited by 46 publications

(23 citation statements)

References 37 publications

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“…During pathological conditions involving CNS inflammation, IL-1β is mainly released by activated macrophages and microglia, and astrocytes are regarded as the major target of IL-1β, as suggested by the presence of IL-1β receptors on the surfaces of astrocytes [ 27 ]. In astrocytes, IL-1β induces the expression of other cytokines, including IL-6 and TNF-α, as well as other inflammatory mediators that have been implicated in the CNS immune response to injury [ 28 ]. Interestingly, systemic LPS and IL-1β injections have been reported to induce excess COX-2 production within the rodent brain [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Nam

Yoon

et al. 2018

J Neuroinflammation

166

137

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BackgroundThe FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined.MethodsBV2 microglial cells were treated with ibrutinib (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry.ResultsIbrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1β proinflammatory cytokine levels.ConclusionsOur data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1308-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Nam

Yoon

et al. 2018

J Neuroinflammation

166

137

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“…Several hours later (6, 12, 24, 36 and 48 hours), the supernatant of H9C2 cells was obtained to detect cell vitality using LDH. MTS, TUNEL and FCM were used to analyse cell vitality and cell apoptosis, which have been described in previous publications …”

Section: Methodsmentioning

confidence: 99%

“…As a traditional Chinese medicine, Gynostemma pentaphylla ( Thunb .) Makino exerts anti‐hypertensive, anti‐ageing, anti‐hyperlipidemia, anti‐hyperglycaemia and anti‐inflammation effects . As a result, Gynostemma has been used to improve symptoms of several diseases for centuries, including hyperlipidemia, hepatitis, atherosis and diabetes.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Chen

Zong

et al. 2018

J Cellular Molecular Medi

115

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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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“…Gyp has various biological activities, including roles in anti-inflammatory reactions, insulin resistance, reducing memory deficits, and decreasing liver fibrosis [11,12]. Moreover, Gyp IX inhibits NFκB transcriptional activity and reduced the expression of several inflammatory factors, including nitric oxide synthase (iNOS), tumour necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) [11]. Qin and colleagues showed that Gyp influences lipid metabolism, reduces oxidative stress, inhibits mitochondrial damage, and prevents degeneration in fatty liver disease [13].…”

Section: Introductionmentioning

confidence: 99%

Gypenosides protect against cardiac ischemia-reperfusion injury by inhibiting mitochondria-dependent apoptosis

Qiao¹,

Liu²,

Chen³

2018

Trop. J. Pharm Res

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Purpose:To investigate the effect of gypenoside (Gyp) on myocardial ischemia-reperfusion (I/R), focusing on mitochondrial function and oxidative stress. Methods: A 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide methylthiazolyldiphenyltetrazolium bromide (MTT) assay was employed to measure the protective effect of Gyp pre-treatment against I/R injury. Flow cytometry was used to detect cellular reactive oxygen species (ROS) content and mitochondrial membrane potential (MMP) levels. Additionally, cytochrome C release was observed by laser scanning confocal microscopy. Finally, Annexin V staining and western blot were applied to analyse cell apoptosis. Results: MTT assay results showed that Gyp pre-treatment protected H9C2 cells against I/R injury in a Gyp concentration-dependent manner. Moreover, Gyp treatment inhibited intracellular ROS production, repressed cytochrome C transposition induced by I/R treatment, and recovered MMP to almost normal levels. Furthermore, the expression of apoptosis-related proteins included cleaved caspase-3, -9 and Bax which were decreased by Gyp treatment after I/R injury. Conclusion: These results suggest that Gyp treatment prior to injury can help maintain normal mitochondrial function and inhibit ROS production during I/R injury, ultimately leading to the suppression of I/R-induced cell apoptosis. Thus, Gyp may be a promising drug for the treatment of myocardial I/R. This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest

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Gypenoside IX Suppresses p38 MAPK/Akt/NFκB Signaling Pathway Activation and Inflammatory Responses in Astrocytes Stimulated by Proinflammatory Mediators

Cited by 46 publications

References 37 publications

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

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

Gypenosides protect against cardiac ischemia-reperfusion injury by inhibiting mitochondria-dependent apoptosis

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