PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice

Ye, Nanhui; Wang, Hang; Hong, Jing; Zhang, Tao; Lin, Chaotong; Meng, Chun

doi:10.4062/biomolther.2015.077

Cited by 21 publications

(17 citation statements)

References 26 publications

(32 reference statements)

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“…Our results indicate that GA could potently restrain macrophage-mediated inflammation stimulated by LPS. Taken together with recent reports showing that GA reduced inflammatory responses in CCl 4 -induced liver [ 13 ] and high-glucose-stimulated human umbilical vein endothelial cells [ 12 ], all of these findings corroborate the global anti-inflammatory potential of GA targeting versatile phlogogenous factors.…”

Section: Discussionsupporting

confidence: 85%

“…Although other types of ginkgolides have shown anti-inflammatory activity, which of GA has not been widely reported. Only two studies recently showed that GA could mediate protection against liver inflammation in CCl 4 -induced mice [ 12 ] and reduce inflammatory responses in high-glucose-stimulated human umbilical vein endothelial cells [ 13 ]. However, the exact anti-inflammatory activity of GA and the underlying mechanisms have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo

Yao

et al. 2017

IJMS

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Ginkgolide A (GA) is a natural compound isolated from Ginkgo biloba and has been used to treat cardiovascular diseases and diabetic vascular complications. However, only a few studies have been conducted on the anti-inflammatory effects of GA. In particular, no related reports have been published in a common inflammation model of lipopolysaccharide (LPS)-stimulated macrophages, and the anti-inflammatory mechanisms of GA have not been fully elucidated. In the present study, we extensively investigated the anti-inflammatory potential of GA in vitro and in vivo. We showed that GA could suppress the expression of pro-inflammatory mediators (cyclooxygenase-2 (COX-2) and nitric oxide (NO) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β) in LPS-treated mouse peritoneal macrophages, mouse macrophage RAW264.7 cells, and differentiated human monocytes (dTHP-1) in vitro. These effects were partially carried out via downregulating Nuclear factor kappa-B (NF-κB), Mitogen-activated protein kinases (MAPKs) (p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK), and activating the AMP-activated protein kinase (AMPK) signaling pathway also seems to be important. Consistently, GA was also shown to inhibit the LPS-stimulated release of TNF-α and IL-6 in mice. Taken together, these findings suggest that GA can serve as an effective inflammatory inhibitor in vitro and in vivo.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo

Yao

et al. 2017

IJMS

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“…We found that AKG supplementation decreased the expression of phosphorylated NF-κBp65, IκB, and IKKα proteins in the jejunum and ileum, while increasing the expression of NF-κBp65 and IL-10 proteins, suggesting that AKG administration plays an important role in the suppression of NF-κB pathway. Actually, this regulation is intrinsically associated with intestinal metabolism, specifically metabolism of AKG and its metabolites [ 9 , 24 , 25 ]. Of note, intracellular AKG would likely be almost completely absorbed by intestinal mucosal surfaces thus precluding efficient luminal delivery, then it was utilized in the TCA cycle and generate large amounts of energy in the gut [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway

Huang

et al. 2017

Oncotarget

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Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-κB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-κB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF-κB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates.

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“…Even though many studies have established the mutual inhibition between PXR and NF-κB, the exact mechanism by which PXR represses NF-κB is not well understood. Indeed, Ye et al[ 64 ] showed that PXR activation by a natural PXR ligand Ginkgolide-A (GA) repressed NF-κB indirectly by enhancing the expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (Iκ-Bα), an inhibitory protein of NF-κB activity. When siRNA was used for silencing of PXR, GA did not increase the expression of Iκ-Bα, showing that the induction happens in a PXR dependent manner[ 64 ] (Figure 2B ).…”

Section: Pxr and Its Role In Counteracting Inflammationmentioning

confidence: 99%

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

Mohandas

Vairappan

2017

WJH

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Bacterial translocation (BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases (CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gut-liver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. PubMed was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.

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PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice

Cited by 21 publications

References 26 publications

Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo

Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo

Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

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