Tanshinone IIA protects against acetaminophen-induced hepatotoxicity via activating the Nrf2 pathway

Wang, Wenwen; Guan, Cuiwen; Sun, Xiaozhe; Zhao, Zhongxiang; Li, Jia; Fu, Xinlu; Qiu, Yudong; Huang, Min; Jin, Jing; Huang, Zhiying

doi:10.1016/j.phymed.2016.02.022

Cited by 70 publications

(45 citation statements)

References 32 publications

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“…Consequently, these results indicated that FMF alleviated APAP-induced hepatic apoptosis partially through inactivation of JNK/ERK MAPK pathway. Nrf2, which is a key sensor of oxidative stress, plays a protective role against APAP-induced hepatotoxicity by regulating the expression of intracellular detoxifying and antioxidant genes responsible for cytoprotective progress [12]. To examine whether FMF affects Nrf2 signaling, Nrf2 protein expression and nuclear accumulation were measured.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous studies have demonstrated the active involvement of Nrf2 in oxidative stress-mediated hepatotoxicity induced by APAP treatment [12–17]. To explore the possible mechanism of hepatoprotection, the present work investigated inductive effects of FMF on the activation of Nrf2 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator kelch-like ECH-associated protein 1 (Keap1) serve as an important reaction axis for cells to combat oxidative stress [12]. Nrf2 belongs to the basic leucine zipper family of transcription factors and is implicated as a major regulator of antioxidant response element- (ARE-) mediated detoxification and antioxidant gene expression [13].…”

Section: Introductionmentioning

confidence: 99%

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Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Wu¹,

Zhang²,

Huang³

et al. 2017

Oxidative Medicine and Cellular Longevity

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Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1–6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-β-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP-induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Wu¹,

Zhang²,

Huang³

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…In a similar study, an induction hepatic mMrp2 following Nrf2 activation was demonstrated in mice, clearly suggesting the presence of an adaptive mechanism to the APAP-triggered injury [ , 9]. In line with these observations, therapeutic activation of Nrf2 has been proposed as a possible strategy to ameliorate APAP-associated hepatotoxicity [50][51][52]. Nrf2 bears a special toxicological relevance due to its activation by pro-oxidant compounds and reactive metabolites usually associated with situations of drug overdose or exposure to environmental toxicants.…”

Section: Transcriptional Regulationmentioning

confidence: 82%

Hepatic and Intestinal Multidrug Resistance-Associated Protein 2: Transcriptional and Post-transcriptional Regulation by Xenobiotics

Arana¹,

Tocchetti²,

Rigalli³

et al. 2016

Toxicology - New Aspects to This Scientific Conundrum

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We are daily exposed to a large number of pharmacological drugs, environmental pollutants, and natural toxins, which represent a potential toxic insult. The organism possesses a sophisticated system of detoxiication particularly expressed in the liver, intestine, and kidney. This system consists of intracellular biotransformation enzymes that convert the toxins into more hydrophilic derivatives followed by their elimination through membrane transporters. Multidrug resistance-associated protein 2 MRP2, ABCC2 is an important member of the ATP-binding cassete ABC superfamily of transporters localized at the apical membrane of polarized cells, such as hepatocytes, enterocytes, and renal tubular cells. MRP2 is proposed as a major actor in the elimination of endo-and xenobiotics, mainly conjugated with glucuronic acid, glutathione, and sulfate. The small intestine and the liver constitute relevant detoxiication organs expressing MRP2 and therefore preventing absorption and promoting the hepatobiliary clearance of xenobiotics. MRP2 expression and/or function can be modulated by therapeutic drugs, herbal products, dietary compounds, and environmental pollutants. Consequently, MRP2 modulation could cause changes in tissue exposure, with potential toxicological and pharmacological consequences. This chapter reviews the information available on the role of hepatic and intestinal MRP2 in detoxiication processes, and their regulation by xenobiotics, considering in particular its toxicological relevance.

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“…Guan et al. (2016) identified that TSN IIA could prevent acetaminophen‐induced hepatotoxicity by increasing expression of Nrf2 target genes [39]. Bai et al .…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of tanshinone IIA against neuropathic pain in diabetic rats through the Nrf2/ARE and NF‐κB signaling pathways

Feng

Qiu

2018

The Kaohsiung J of Med Scie

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The study aims to investigate whether tanshinone (TSN) IIA affects diabetic neuropathic pain (DNP) via the Nrf2/AR and NF-κB signaling pathways. Rats were randomly assigned into DNP group, TSN group (injected with TSN IIA), TSN + DRB group (injected with TSN IIA and 15 mg/kg Nrf2/ARE inhibitors), TSN + PDTC group (injected with TSN IIA and 60 mg/kg NF-κB inhibitors) or control group. The first four groups were successfully established as DNP models after injection of streptozotocin. The blood glucose level, mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), nerve conduction velocity (NCV) and antioxidase level were detected. Transmission electron microscopy and toluidine blue staining were utilized to observe the sciatic nerve. RT-qPCR and western blot were used to measure expression levels of Nrf2/ARE and NF-κB signaling pathway-related genes. Blood glucose, malondialdehyde (MDA) and erythrocyte glutathione peroxidase (GSH-Px) levels as well as expression of Keap1 and NF-κB were increased in the TSN, TSN + DRB and TSN + PDTC groups compared to control group. Furthermore, the MWT, TWL, NVC, and superoxide dismutase (SOD) levels and expression of Nrf2, heme oxygenase 1 (HO-1) and inhibitory kappa B (IκB) decreased in the treatment groups. The TSN + DRB and TSN + PDTC groups showed similar trend when compared with the TSN group, while the opposite trend was observed in the TSN group when compared with the DNP group. Our study demonstrates that TSN IIA alleviates neuropathic pain by activating the Nrf2/ARE signaling pathway and inhibiting the NF-κB signaling pathway in diabetic rats.

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Tanshinone IIA protects against acetaminophen-induced hepatotoxicity via activating the Nrf2 pathway

Cited by 70 publications

References 32 publications

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Hepatic and Intestinal Multidrug Resistance-Associated Protein 2: Transcriptional and Post-transcriptional Regulation by Xenobiotics

Neuroprotective effect of tanshinone IIA against neuropathic pain in diabetic rats through the Nrf2/ARE and NF‐κB signaling pathways

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