Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1

Jiang, Haiyan; Bao, Yanni; Lin, Fengmei; Jin, Yong

doi:10.1177/09603271211056330

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…CYP2E1 overexpression promotes the sensitivity of Kupffer cells ( Ye et al, 2013 ). At the same time, CYP2E1 inducer (pyrazole) can activate the NF-κB signaling pathway, promote oxidative stress and inflammation, and aggravate liver injury, while the effect of an enzyme inhibitor (clomethiazole) is just the opposite ( Jiang et al, 2021 ). Our results show that ROF can downregulate abnormal CYP2E1 and inhibit the activity of the NF-κB signaling pathway, but whether ROF plays a therapeutic effect by affecting the interaction between CYP2E1 and NF-κB signaling pathway needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway

et al. 2022

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Background: Alcoholic liver disease (ALD) is a common chronic liver disorder worldwide, which is detrimental to human health. A preliminary study showed that the total flavonoids within Citrus grandis “Tomentosa” exerted a remarkable effect on the treatment of experimental ALD. However, the active substances of Citrus grandis “Tomentosa” were not elucidated. Rhoifolin (ROF) is a flavonoid component present in high levels. Therefore, this research aimed to evaluate the hepatoprotective effects of ROF and its possible mechanisms.Methods: Molecular docking was performed to analyze the binding energy of ROF to the main target proteins related to ALD. Subsequently, mice were fed ethanol (ETH) for 49 days to establish the chronic alcoholic liver injury models. The liver pathological injury, serum aminotransferase levels, and oxidative stress levels in the liver tissue were measured. Human normal hepatocytes (LO2 cells) were incubated with ETH to construct the alcoholic liver cell model. The inflammatory markers and apoptosis factors were evaluated using real-time PCR and flow cytometry. Finally, the effects of ROF on the CYP2E1 and NF-κB signaling pathways were tested in vitro and in vivo.Results: Molecular docking results demonstrated that ROF was able to successfully dock with the target proteins associated with ALD. In animal studies, ROF attenuated ETH-induced liver damage in mice by decreasing the serum concentrations of AST and ALT, reducing the expression of inflammatory cytokines, and maintaining antioxidant balance in the liver tissue. The in vitro experiments demonstrated that ROF suppressed ETH-induced apoptosis in LO2 cells by promoting Bcl-2 mRNA and inhibiting Bax mRNA and caspase 3 protein expression. ROF decreased the level of LDH, ALT, AST, ROS, and MDA in the supernatant; induced the activity of GSH and SOD; and inhibited TNF-α, IL-6, and IL-1β expression levels. Mechanistically, ROF could significantly downregulate the expression levels of CYP2E1, TLR4, and NF-κB phosphorylation.Conclusion: This study indicates that ROF is the active component within the total flavonoids, which may alleviate ETH-induced liver injury by inhibiting NF-κB phosphorylation. Therefore, ROF may serve as a promising compound for treating ALD.

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Section: Discussionmentioning

confidence: 99%

Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway

et al. 2022

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“…A metabolomic study showed that TP treatment induced metabolic disorders, such as changes in carnitine, lysophosphatidylcholine (LPC), and a series of amino acids in female mice, and regulating the activity of CYP3A4 can modulate LPC levels, amino acid levels, the glutathione (GSH)/Glutathione disulfide (GSSG) ratio, and oxidative stress, thereby altering TP-induced hepatotoxicity ( Xiao et al, 2020 ). Moreover, the TP-induced increase in CYP2E1 expression induces hepatic oxidative stress ( Jiang et al, 2021 ). In C57 mice and IHHA-1 cell models, CYP2E1 expression was upregulated after TP exposure, which not only directly increased ROS levels, but also increased the expression of nuclear factor kappa B (NF-κB) (p65) to mediate oxidative stress and inflammatory responses ( Jiang et al, 2021 ).…”

Section: The Mechanisms Of Tp-induced Hepatotoxicitymentioning

confidence: 99%

“…Moreover, the TP-induced increase in CYP2E1 expression induces hepatic oxidative stress ( Jiang et al, 2021 ). In C57 mice and IHHA-1 cell models, CYP2E1 expression was upregulated after TP exposure, which not only directly increased ROS levels, but also increased the expression of nuclear factor kappa B (NF-κB) (p65) to mediate oxidative stress and inflammatory responses ( Jiang et al, 2021 ).…”

Section: The Mechanisms Of Tp-induced Hepatotoxicitymentioning

confidence: 99%

“…OS causes lipid and DNA damage, leading to organelle dysfunction and damage ( Pole et al, 2016 ; Campbell and Colgan, 2019 ). Numerous in vivo and in vitro studies have found that administration of TP causes an increase in ROS and malondialdehyde (MDA), and a decrease in superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST) and GSH ( Li et al, 2014 ; Jiang et al, 2021 ). Thus, TP-induced hepatotoxicity is associated with oxidative stress.…”

Section: The Mechanisms Of Tp-induced Hepatotoxicitymentioning

confidence: 99%

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The molecular pathogenesis of triptolide-induced hepatotoxicity

Wang

et al. 2022

Front. Pharmacol.

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Triptolide (TP) is the major pharmacologically active ingredient and toxic component of Tripterygium wilfordii Hook. f. However, its clinical potential is limited by a narrow therapeutic window and multiple organ toxicity, especially hepatotoxicity. Furthermore, TP-induced hepatotoxicity shows significant inter-individual variability. Over the past few decades, research has been devoted to the study of TP-induced hepatotoxicity and its mechanism. In this review, we summarized the mechanism of TP-induced hepatotoxicity. Studies have demonstrated that TP-induced hepatotoxicity is associated with CYP450s, P-glycoprotein (P-gp), oxidative stress, excessive autophagy, apoptosis, metabolic disorders, immunity, and the gut microbiota. These new findings provide a comprehensive understanding of TP-induced hepatotoxicity and detoxification.

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“…Triptolide (TP) is the main active component isolated from Tripterygium wilfordii Hook F. Tripterygium wilfordii has excellent immunosuppressive and anti-inflammatory effects (Law et al, 2011;Ziaei and Halaby, 2016;Cheng et al, 2021;Cao et al, 2022), and it can be used for the treatment of SLE (Tao and Lipsky, 2000). TP has been reported to play a role in various diseases by inhibiting the NF-κB signaling pathway (Jiang et al, 2021;Liu et al, 2022). Moreover, it can inhibit the differentiation of B cells into CD138 + CD27 + plasma cells and inhibit the secretion of IgA, IgG, and IgM by plasma cells (Zhao et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Triptolide in the treatment of systemic lupus erythematosus - regulatory effects on miR-146a in B cell TLR7 signaling pathway in mice

Zhang

Zhang²,

Gao³

et al. 2022

Front. Pharmacol.

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Objective: To clarify the mechanism of triptolide (TP) in alleviating the conditions underlying SLE.Methods: Eight-week-old MRL/lpr mice were randomly divided into a model group (n = 5), low-dose TP (TP-L) group (n = 5), and high-dose TP (TP-H) group (n = 5). Mice in these groups were gavaged with normal saline, low-dose TP solution, and high-dose TP solution for 8 weeks, respectively. The expression levels of anti-dsDNA, IgG, IgM, IgA, C3, C4, and CREA, BUN, ALT, AST, ALB, and ALP indexes in the serum of mice were detected. The proportion of CD19+CD138+B220− cells in the spleen and the pathological changes of kidney tissue in the mice were also evaluated. The possible signaling pathways and microRNA (miRNA) targets of TP in the treatment of SLE were analyzed using network pharmacology. The expressions of TLR7 mRNA and miR-146a in Raji cells (a B lymphocyte line) were detected using qPCR before and after intervention with a miR-146a inhibitor. The protein expression levels of TLR7, MyD88, p-IRAK1, and p-NF-κBp65 were detected using western blot analysis.Results: TP could significantly decrease the levels of ds-DNA and IgG, alleviate pathological injury in renal tissue, and upregulate miR-146a expression in the B cells of MRL/lpr mice without obvious liver and kidney toxicity. Network pharmacology analysis showed that TP could mainly regulate the Toll-like receptor signaling pathway, and NF-κB signaling pathway, among others. miRNA target prediction suggested that TP could regulate miRNAs such as miR-146a. In vitro cell experiments further confirmed that TP could significantly upregulate miR-146a expression and downregulate the expression of TLR7 mRNA and protein levels TLR7, MyD88, p-IRAK1, and p-NF-κBp65. After intervention with a miR-146a inhibitor, TP had no obvious inhibitory effects on TLR7, MyD88, p-IRAK1, and p-NF-κBp65 expression.Conclusion: TP may exert therapeutic effects on SLE by regulating miR-146a expression, inhibiting the TLR7/NF-κB signaling pathway, and affecting B cell activation.

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Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1

Cited by 10 publications

References 38 publications

Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway

Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway

The molecular pathogenesis of triptolide-induced hepatotoxicity

Triptolide in the treatment of systemic lupus erythematosus - regulatory effects on miR-146a in B cell TLR7 signaling pathway in mice

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