Tibetan medicine Ershiwuwei Lvxue Pill attenuates collagen-induced arthritis via inhibition of JAK2/STAT3 signaling pathway

Liu, Chuan; Zhao, Qian; Zhong, Lina; Li, Qiuyue; Li, Rui; Li, Shuang; Li, Yangxin; Li, Ning; Su, Jinsong; Dhondrup, Wüntrang; Meng, Xianli; Zhang, Yi; Tu, Ya; Wang, Xiaobo

doi:10.1016/j.jep.2021.113820

Cited by 29 publications

(15 citation statements)

References 75 publications

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“…In previous studies, the levels of serum cytokines TNF-α and IL-1β are increased in RA patients. Meanwhile, activation of the JAK2-STAT3 pathway is regulated by inflammatory cytokine stimulation during the progression of RA [ 49 , 50 ]. Accumulating studies indicated that the MAPK signal transduction pathway can regulate the inflammatory cytokine and downstream cell transduction pathways, thereby affecting the inflammation and destruction of joints [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Elucidating the material basis and potential mechanisms of Ershiwuwei Lvxue Pill acting on rheumatoid arthritis by UPLC-Q-TOF/MS and network pharmacology

et al. 2022

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Ershiwuwei Lvxue Pill (ELP, མགྲིན་མཚལ་ཉེར་ལྔ།), a traditional Tibetan medicine preparation, has been used hundreds of years for the clinical treatment of rheumatoid arthritis (RA) in the highland region of Tibet, China. Nevertheless, its chemical composition and therapeutic mechanism are unclear. This study aimed to uncover the potentially effective components of ELP and the pharmacological mechanisms against RA by combing UPLC-Q-TOF/MS and network pharmacology. In this study, 96 compounds of ELP were identified or tentatively characterized based on UPLC-Q-TOF/MS analysis. Then, a total of 22 potential bioactive compounds were screened by TCMSP with oral bioavailability and drug-likeness. Preliminarily, 10 crucial targets may be associated with RA through protein-protein interaction network analysis. The functional enrichment analysis indicated that ELP exerted anti-RA effects probably by synergistically regulating many biological pathways, such as PI3K-Akt, Cytokine-cytokine receptor interaction, JAK-STAT, MAPK, TNF, and Toll-like receptor signaling pathway. In addition, good molecular docking scores were highlighted between five promising bioactive compounds (ellagic acid, quercetin, kaempferol, galangin, coptisine) and five core targets (PTGS2, STAT3, VEGFA, MAPK3, TNF). Overall, ELP can exert its anti-RA activity via multicomponent, multitarget, and multichannel mechanisms of action. However, further studies are needed to validate the biological processes and effect pathways of ELP.

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Section: Discussionmentioning

confidence: 99%

Elucidating the material basis and potential mechanisms of Ershiwuwei Lvxue Pill acting on rheumatoid arthritis by UPLC-Q-TOF/MS and network pharmacology

et al. 2022

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“…There is mounting evidence that the JAK2/STAT3 pathway exerts an important effect on the inflammatory reaction (19,20). Changes in the JAK2/STAT3 pathway affect the expression of many cytokines, such as TNF-a and IL-6 (20,21). Moreover, the JAK2/STAT3 pathway contributes to brain damage caused by ischemia/reperfusion (22).…”

Section: Introductionmentioning

confidence: 99%

Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

et al. 2021

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BackgroundInflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses via the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms.MethodsRux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice in vivo and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1β, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model in vitro.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.

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“…In addition, inflammatory factors that activate the JAK/STAT pathway, such as the IL-6 and TNF-α, can inhibit the expression of the cytokine signaling pathway (SOCS) protein and pro-apoptotic factor BAX, as well as stimulate the expression of anti-apoptotic factor Bcl-2. 40 , 41 This also proves that BA can play a role in reducing inflammation and apoptosis by activating the JAK2/STAT3 signaling pathway. However, down-regulation of the pathway has also been shown to have a protective effect on the liver, such as in the stage of liver fibrosis or liver cancer.…”

Section: Discussionmentioning

confidence: 71%

Protective effect of baicalin against arsenic trioxide-induced acute hepatic injury in mice through JAK2/STAT3 signaling pathway

Sun

Chu

et al. 2022

Int J Immunopathol Pharmacol

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Baicalin (BA) is a kind of flavonoid that is isolated from Scutellaria baicalensis Georgi, which has been verified to have hepatoprotective effects in some diseases. However, the role of BA in acute hepatic injury induced by arsenic trioxide (ATO) remains unclear. The aim of this study was to investigate the protective action of BA on acute hepatic injury induced by ATO and to probe its possible mechanism. Mice were pretreated with BA (50, 100 mg/kg) by gavage. After 7 h, ATO (7.5 mg/kg) was injected intraperitoneally to induce liver injury. After 7 days of treatment, serum and hepatic specimens were collected and assayed to evaluate the hepatoprotective effect of BA. Pathological sections and the liver function index indicated that ATO caused significant liver injury. The fluorescence of reactive oxygen species and oxidative stress indicators showed that ATO also increased oxidative stress. The inflammatory markers in ATO-induced mice also increased significantly. Staining of the terminal deoxynucleotidyl transferase dUTP nick end labeling and apoptotic factor assay showed that apoptosis increased. However, with BA pretreatment, these changes were significantly weakened. In addition, BA treatment promoted the expression of proteins related to the JAK2/STAT3 signaling pathway. The results suggest that BA can ameliorate acute ATO-induced hepatic injury in mice, which is related to the inhibition of oxidative stress, thereby reducing inflammation and apoptosis. The mechanism of this protection is potentially related to the JAK2/STAT3 signaling pathway.

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Tibetan medicine Ershiwuwei Lvxue Pill attenuates collagen-induced arthritis via inhibition of JAK2/STAT3 signaling pathway

Cited by 29 publications

References 75 publications

Elucidating the material basis and potential mechanisms of Ershiwuwei Lvxue Pill acting on rheumatoid arthritis by UPLC-Q-TOF/MS and network pharmacology

Elucidating the material basis and potential mechanisms of Ershiwuwei Lvxue Pill acting on rheumatoid arthritis by UPLC-Q-TOF/MS and network pharmacology

Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

Protective effect of baicalin against arsenic trioxide-induced acute hepatic injury in mice through JAK2/STAT3 signaling pathway

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