Tanshinone IIA prevents rifampicin‐induced liver injury by regulating BSEP/NTCP expression via epigenetic activation of NRF2

Yang, Yujie; Liu, Lei; Zhang, Xiqian; Jiang, Xuehua; Wang, L

doi:10.1111/liv.14262

Cited by 30 publications

(25 citation statements)

References 42 publications

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“…Tan IIA administration is associated with improvement in silicamediated pulmonary inflammatory response, structural damage and fibrosis via Nrf2/ARE activation [121]. Furthermore, Tan IIA prevents liver injury via epigenetic activation of Nrf2 and reinforcing antioxidant defense system [122]. Hence, Tan IIA stimulates Nrf2 signaling as a way of recovering redox homeostasis and inhibiting pulmonary fibrosis [123].…”

Section: Natural Compounds In Ameliorating Doxorubicin-mediated Toxicitymentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

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Section: Natural Compounds In Ameliorating Doxorubicin-mediated Toxicitymentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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“…Tanshinone IIA is a lipid-soluble natural compound isolated from the medicinal herb Salvia miltiorrhiza Burge and associated with cardiovascular and cerebrovascular protective effects. The involvement of epigenetic mechanisms in the induction of Nfe2l2 by Tanshinone IIA has been demonstrated in TPA-induced neoplastic transformation of JB6 P+ cells [ 95 ] and in in vitro and in vivo models of rifampicin-induced liver injury [ 96 ]. Hypomethylation of the N fe2l2 promoter was mechanistically linked to potent induction of Nfe2l2 mRNA and Nrf2 protein levels by Tanshinone IIA.…”

Section: Phytochemicals and The Epigenetic Regulation Of Nrf2 Signmentioning

confidence: 99%

“…Hypomethylation of the N fe2l2 promoter was mechanistically linked to potent induction of Nfe2l2 mRNA and Nrf2 protein levels by Tanshinone IIA. While one study reported decreased expression of Dnmts and Hdac1, Hdac3, and Hdac8 by Tanshinone IIA in JB6 P+ cells [ 95 ], another found no significant changes in DNMTs, but elevated expression of DNA demethylases, especially ten-eleven translocation 2 (TET2), in human hepatocyte L02 and Hepa RG cells [ 96 ]. The latter investigation showed that Tanshinone IIA could prevent rifampicin-induced liver injury by inducing the expression of bile salt efflux pump (BSEP) and Na+/taurocholate cotransporter (NTCP), which were directly regulated by NRF2 [ 96 ].…”

Section: Phytochemicals and The Epigenetic Regulation Of Nrf2 Signmentioning

confidence: 99%

Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals

Bhattacharjee

Dashwood

2020

Antioxidants

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Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases.

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“…9 Classical nuclear factor, farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor 2 (NRF2) play an important role in regulating bile acids efflux and uptake. 10,11 Our previous studies have shown that TAN IIA could induce the expression of NTCP by regulating NRF2. 11 However, the changes in NTCP functional activity after treatment of RFP or TAN IIA were not examined, and the relationship between NTCP expression and activity under this state is still unknown.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Our previous studies have shown that TAN IIA could induce the expression of NTCP by regulating NRF2. 11 However, the changes in NTCP functional activity after treatment of RFP or TAN IIA were not examined, and the relationship between NTCP expression and activity under this state is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone ⅡA may alleviate rifampin-induced cholestasis by regulating the expression and function of NTCP

Yang

Liu

et al. 2020

Hum Exp Toxicol

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The Na+-taurocholate cotransporting polypeptide (NTCP) acts as the major hepatic basolateral uptake system, and plays a key role in balancing bile flow. The anti-tuberculosis drugs rifampin (RFP) can affect bile flow causing liver injury, while tanshinone IIA (TAN IIA) has the effect of protecting liver. This study aimed to investigate the effects of RFP and TAN IIA on the NTCP expression and activity, and explore the potential connections. Herein, we established sandwich-cultured primary rat hepatocytes, and quantified mRNA and protein levels of NRF2 and NTCP after treatment with RFP (10, 25, or 50 μM) or co-treatment with TAN IIA (5, 10, or 20 μM) for 12, 24, 48 h (n = 3). NTCP activity was assessed by measuring the initial uptake rates of known substrates taurocholate (TCA) (n = 3) after treatment with different concentrations of RFP, TAN ⅡA for 12, 24 and 48 h. We found that RFP had inhibition effects on NRF2, NTCP mRNA and protein expression, and co-administration of TAN IIA could reverse RFP inhibition. TCA cellular accumulation was significantly decreased by RFP (39.1%), and TAN IIA could significantly induce TCA uptake of NTCP (2.9-fold at 48 h). The TCA uptake activity was correlated with the NTCP mRNA expression, confirming the role of RFP or TAN IIA on NTCP expression and activity is synchronous, and we can predict NTCP activity by detecting its mRNA expression. In conclusion, our work will enrich the significance of NTCP in the liver protection, and provide theoretical basis for TAN IIA to prevent RFP induced cholestatic liver injury.

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Tanshinone IIA prevents rifampicin‐induced liver injury by regulating BSEP/NTCP expression via epigenetic activation of NRF2

Cited by 30 publications

References 42 publications

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals

Tanshinone ⅡA may alleviate rifampin-induced cholestasis by regulating the expression and function of NTCP

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