Astilbin promotes the induction of regulatory NK1.1− CD4+ NKG2D+ T cells through the PI3K, STAT3, and MAPK signaling pathways

Han, Sen; Lin, Zhijie; Wen, Jianqiang; Wu, Keyan; Xu, Yemin; Lu, Guotao; Xiao, Weiming; Ding, Yanbing; Jia, Xiao‐Bin; Deng, Bin; Gong, Weijuan

doi:10.1016/j.intimp.2019.106143

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…CCR9 expression of lymphocytes indicates the gut-homing activity. Consistent with the effect of astilbin on NK1.1 - CD4 + NKG2D + regulatory T cells ( Han et al, 2020 ), the expression of CCR9 on CD4 + T cells was also enhanced with astilbin treatment in a dose-dependent manner. Unexpectedly, no changes in the expression of IL-10 and CCR6 in astilbin-treated CD4 + T cells were observed ( Supplementary Figures S1B,C ).…”

Section: Resultssupporting

confidence: 71%

“…Several studies have found that astilbin treatment increases the expression of SOCS3 ( Wang et al, 2016 ; Han et al, 2020 ; Sharma et al, 2020 ). Variations of SOCS3 were first measured in freshly isolated, IL-12-activated, or α-CD3/α-CD28-activated CD4 + T cells treated by astilbin.…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms of astilbin-mediated anti-inflammation and immunosuppression are involved with downregulating the activities of macrophages, dendritic cells ( Ding et al, 2014 ), and effector T cells and inducing regulatory B cells ( Xu et al, 2020 ) and T cells ( Han et al, 2020 ). Astilbin suppresses the function of inflammatory cells by inhibiting the PI3K/AKT, TLR4/MyD88/NF-κB ( Li et al, 2019 ), and MAPK signaling pathways and promoting the expression of SOCS3 and activating AMPK, leading to less production of IL-1β, IL-6, TNF-α, IFN-γ, and MMPs ( Sharma et al, 2020 ; Yang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Astilbin Activates the Reactive Oxidative Species/PPARγ Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1

Ding

Wang

et al. 2022

Front. Pharmacol.

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Astilbin, as a compound of flavonoids, exerts anti-inflammation, antioxidation, and immune-suppression activities. Decreased activation of NF-κB and p38 MAPK and increased activation of SOCS3 and AMPK have been found in astilbin-treated cells. However, what molecules are docked by astilbin to initiate signaling cascades and result in functional changes remains unknown. In the study, we found that astilbin efficiently suppressed TNF-α production and increased CCR9 and CD36 expression of CD4+ T cells. In vivo administration of astilbin repressed the occurrence of type 1 diabetes mellitus in non-obese diabetic mice. The PPARγ/SOCS3, PPARγ/PTEN, and PPARγ/AMPK signaling pathways were substantially activated and played key roles in astilbin-induced downregulation of CD4+ T cell functions. Transcriptome sequencing results confirmed the changes of signaling molecules involved in the immune system, inflammatory responses, and indicated variations of multiple enzymes with oxidant or antioxidant activities. Astilbin directly induced cytoplasmic ROS production of CD4+ T cells ex vivo, but had no effects on mitochondrial ROS and mitochondrial weight. When cellular ROS was depleted, astilbin-treated CD4+ T cells remarkably reversed the expression of TNF-α, IFN-γ, CCR9, CD36, and signaling molecules (PPARγ, PTEN, p-AMPK, and SOCS3). Based on bioinformatics, two P450 enzymes (CYP1B1 and CYP19A1) were selected as candidate receptors for astilbin. CYP1B1 was identified as a real docking protein of astilbin in ROS production by AutoDock Vina software analysis and surface plasmon resonance assay. Collectively, astilbin downregulates effector CD4+ T cell activities via the CYP1B1/ROS/PPARγ pathway, which firmly supports its potential use in the treatment of inflammation.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astilbin Activates the Reactive Oxidative Species/PPARγ Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1

Ding

Wang

et al. 2022

Front. Pharmacol.

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“…Especially up-regulating activated MAPK protein expression, including extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 are closely related to intestinal inflammation ( Xie et al, 2019 ). As reported earlier ( Zanello et al, 2011 ), the inflammatory response of swine intestine caused by E. coli infection is closely related to the MAPK signaling pathway, and the Astilbin improves inflammatory bowel disease through PI3K, STAT3, and MAPK signaling pathways ( Han et al, 2020 ). Published work suggests that regulation of gut microbial composition, reduces the phosphorylation of MAPK and AKT proteins ( Serreli et al, 2020 ; Zhang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 66%

Cichorium pumilum Jacq Extract Inhibits LPS-Induced Inflammation via MAPK Signaling Pathway and Protects Rats From Hepatic Fibrosis Caused by Abnormalities in the Gut-Liver Axis

et al. 2021

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The development of liver fibrosis is closely related to the gut microbiota, and the “gut-liver axis” is the most important connection between the two. ethyl acetate extract of Cichorium pumilum Jacq (CGEA) is an herbal extract consisting mainly of sesquiterpenoids. The anti-inflammatory and hepatoprotective effects of CGEA have been reported, but the anti-fibrotic effects of CGEA via intestinal microbes and the “gut-liver axis” cycle have rarely been reported. In this study, we observed that CGEA not only directly attenuated inflammatory factor levels in inflamed mice, but also attenuated liver inflammation as well as liver fibrosis degeneration in rats with liver fibrosis caused by colitis. We observed in vitro that CGEA significantly promoted the growth of Bifidobacterium adolescentis. Similarly, fecal 16S rDNA sequencing of liver fibrosis rats showed that CGEA intervention significantly altered the composition of the intestinal microbiota of liver fibrosis rats. CGEA increased the abundance of intestinal microbiota, specifically, CGEA increased the ratio of Firmicutes to Bacteroidetes, CGEA could significantly increase the levels of Ruminococcus. In addition, CGEA intervention significantly protected intestinal mucosal tissues and improved intestinal barrier function in rats. Lactucin is the main sesquiterpenoid in CGEA, and HPLC results showed its content in CGEA was up to 6%. Lactucin has been reported to have significant anti-inflammatory activity, and in this study, we found that Lactucin decreased p38 kinases (p38), phosphorylation of the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) protein phosphorylation in lipopolysaccharide (LPS)-activated RAW264.7 cells, thereby reducing mRNA expression and protein expression of pro-inflammatory factors inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and inhibiting the release of inflammatory factors interleukin (IL)-6 and nitric oxide (NO), exerting anti-inflammatory effects. In summary, the prevention of liver fibrosis caused by intestinal inflammation by CGEA may be achieved by regulating the intestinal microbiota and restoring the intestinal barrier thereby improving the “gut-liver axis” circulation, reducing liver inflammation, and ultimately alleviating liver fibrosis. Notably, the direct anti-inflammatory effect of CGEA may be due to its content of Lactucin, which can exert anti-inflammatory effects by inhibiting the phosphorylation of Mitogen-activated protein kinase (MAPK) and Akt signaling pathways.

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“…Baicalin has been studied in osteoporosis (Zhao et al, 2020), cancer (Wu et al, 2020), and obesity and hyperlipidemia (Wang et al, 2020). Astilbin (Xu et al, 2020;Xin et al, 2020;Han et al, 2020) has been primarily investigated for its role in cellular oxidative stress (Xu et al, 2020;Xin et al, 2020;Han et al, 2020).…”

Section: Findings From This Studymentioning

confidence: 99%

Covid-19 and Flavonoids: In silico Molecular Dynamics Docking to the Active Catalytic Site of SARS-CoV and SARS-CoV-2 Main Protease

Peterson¹

2022

AFJPS

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Inhibition of the main protease 3CLpro of SARS-CoV and SARS-CoV-2 is being targeted in the search for antivirals to shorten patient recovery times from Covid-19 disease. We investigated 72 flavonoids for their potential to bind with the active catalytic site of 3CLpro for SARS-CoV and SARS-CoV-2. In silico molecular dynamics docking was performed using energy-minimized states of the flavonoids. Three variants of the active catalytic site of the protease 3CLpro were used: one based on x-ray crystallography for SARS-CoV, the second based on x-ray crystallography for SARS-CoV-2, and the third based on a 3D-modeled form of an amino acid sequence alignment of SARS-CoV-2 3CLpro from 8 humans. Docking involved characterization of the best putative pose in the "pocket" of the active site based on altering rotatable bonds in each molecule. The binding energy (kcal/mol) and number of hydrogen bonds were assessed during each pose. Mean binding energy across the 3 variants of 3CLpro was sorted in ascending order to rank each flavonoid, since more negative values indicate stronger binding. The top 10 flavonoids identified were amentoflavone, gallocatechin gallate, diosmin, epigallocatechin gallate, hidrosmin, catechin gallate, elsamitrucin, pectolinaren, quercetin, and isoquercetin. Other flavonoids investigated with significant binding energies were hesperidin, rutin, rhoifolin, and peurarin. In vivo animal research is now needed for evaluating whether these flavonoids can minimize early infection and alleviate symptoms and shorten recovery times for late-stage Covid-19 disease. Human prevention trials for minimizing early infection and combination therapy trials with antivirals for shortening recovery times in late-stage Covid-19 disease could also be pursued.

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Astilbin promotes the induction of regulatory NK1.1− CD4+ NKG2D+ T cells through the PI3K, STAT3, and MAPK signaling pathways

Cited by 11 publications

References 29 publications

Astilbin Activates the Reactive Oxidative Species/PPARγ Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1

Astilbin Activates the Reactive Oxidative Species/PPARγ Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1

Cichorium pumilum Jacq Extract Inhibits LPS-Induced Inflammation via MAPK Signaling Pathway and Protects Rats From Hepatic Fibrosis Caused by Abnormalities in the Gut-Liver Axis

Covid-19 and Flavonoids: In silico Molecular Dynamics Docking to the Active Catalytic Site of SARS-CoV and SARS-CoV-2 Main Protease

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