Advances of natural activators for Nrf2 signaling pathway on cholestatic liver injury protection: a review

The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2−Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate–cysteine ligase catalytic (GCLC) subunit, glutamate–cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2−Keap1 signaling pathway.

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Guavinoside B from Psidium guajava alleviates acetaminophen-induced liver injury via regulating the Nrf2 and JNK signaling pathways

Food & Function ◽

10.1039/d0fo01338b ◽

2020 ◽

Vol 11 (9) ◽

pp. 8297-8308

Author(s):

Yuanyuan Li ◽

Jialin Xu ◽

Dongli Li ◽

Hang Ma ◽

Yu Mu ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathways ◽

Signaling Pathway ◽

Phenolic Compound ◽

Psidium Guajava ◽

Jnk Signaling ◽

Nrf2 Signaling Pathway ◽

Jnk Signaling Pathway

GUB, a main phenolic compound present in guava fruits, could alleviate APAP-induced liver injury in vitro and in vivo by activating the Nrf2 signaling pathway and inhibiting the JNK signaling pathway.

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Quantitative Proteomics Reveals the Protective Effects of Huangqi Decoction Against Acute Cholestatic Liver Injury by Inhibiting the NF-κB/IL-6/STAT3 Signaling Pathway

Journal of Proteome Research ◽

10.1021/acs.jproteome.9b00563 ◽

2019 ◽

Vol 19 (2) ◽

pp. 677-687 ◽

Cited By ~ 2

Author(s):

Jia-Sheng Wu ◽

Qian Liu ◽

Shan-Hua Fang ◽

Xing Liu ◽

Min Zheng ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Quantitative Proteomics ◽

Protective Effects ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Cholestatic Liver Injury

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[48] RETENTION OF TOXIC BILE ACIDS ACTIVATE THE MTOR, P70S6K/RPS6 SIGNALING PATHWAY IN MOUSE MODELS OF CHOLESTATIC LIVER INJURY

Journal of Hepatology ◽

10.1016/s0168-8278(07)61646-8 ◽

2007 ◽

Vol 46 ◽

pp. S23

Author(s):

T. Moustafa ◽

P. Fickert ◽

P. Vesely ◽

D. Silbert ◽

J. Gumhold ◽

...

Keyword(s):

Liver Injury ◽

Bile Acids ◽

Signaling Pathway ◽

Mouse Models ◽

Cholestatic Liver Injury

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Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

10.21203/rs.3.rs-1116597/v1 ◽

2021 ◽

Author(s):

Yangping Zhu ◽

Changling Wang ◽

Jingyi Yu ◽

Yingying Miao ◽

Yuanyuan Chai ◽

...

Keyword(s):

Bile Acid ◽

Liver Injury ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Lithocholic Acid ◽

Farnesoid X Receptor ◽

Multi Drug Resistance ◽

Caspase 8 ◽

Obeticholic Acid ◽

Cholestatic Liver Injury

Abstract Background: Lithocholic acid (LCA) is one kind of endogenous bile acids which is a typical index in primary biliary cholangitis (PBC). It could cause severe cholestatic liver injury in rodents. Obeticholic acid (OCA) is a major treatment for PBC. However, its effect and mechanism in LCA-induced liver injury was still unclear beside of bile acid regulation. This study aims to evaluate the hepatoprotective effect and mechanism of OCA against LCA-induced cholestatic liver injury. Results: LCA-induced upregulations of ALT, AST, ALP and TBA were reduced and the bile acid profiles in serum, liver and bile were improved significantly by OCA. This bile acid regulating effect of OCA was mainly based on increasing the expression of bile acid efflux transporters bile salt export pump (BSEP), multidrug resistant associated protein 2 (MRP2), MRP3 and multi-drug resistance 3 (MDR3) instead of bile acid synthesis inhibition. Furthermore, it was found that OCA reduced the activation and expression of Caspase 8/3 signaling pathway without the change of p-MLKL and BAX in LCA-induced cholestatic model. And the inhibition of Caspase 8/3 signaling pathway depended on the activation of Farnesoid X receptor (FXR) to inhibit Caspase 8 cleavage to form a active complex.Conclusions: This study found OCA improved LCA-induced cholestatic liver injury via FXR-induced exogenous cell apoptosis, which provided a new evidence for the application of OCA to ameliorate PBC in clinical.

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Luteolin Alleviates AflatoxinB1-Induced Apoptosis and Oxidative Stress in the Liver of Mice through Activation of Nrf2 Signaling Pathway

Antioxidants ◽

10.3390/antiox10081268 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1268

Author(s):

Shahid Ali Rajput ◽

Aftab Shaukat ◽

Kuntan Wu ◽

Imran Rashid Rajput ◽

Dost Muhammad Baloch ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Signaling Pathway ◽

Aflatoxin B1 ◽

Physiological Saline ◽

Protective Effects ◽

Biochemical Alterations ◽

Protein Levels ◽

Nrf2 Signaling Pathway ◽

Induced Apoptosis

Aflatoxin B1 (AFB1), a threatening mycotoxin, usually provokes oxidative stress and causes hepatotoxicity in animals and humans. Luteolin (LUTN), well-known as an active phytochemical agent, acts as a strong antioxidant. This research was designed to investigate whether LUTN exerts protective effects against AFB1-induced hepatotoxicity and explore the possible molecular mechanism in mice. A total of forty-eight mice were randomly allocated following four treatment groups (n = 12): Group 1, physiological saline (CON). Group 2, treated with 0.75 mg/kg BW aflatoxin B1 (AFB1). Group 3, treated with 50 mg/kg BW luteolin (LUTN), and Group 4, treated with 0.75 mg/kg BW aflatoxin B1 + 50 mg/kg BW luteolin (AFB1 + LUTN). Our findings revealed that LUTN treatment significantly alleviated growth retardation and rescued liver injury by relieving the pathological and serum biochemical alterations (ALT, AST, ALP, and GGT) under AFB1 exposure. LUTN ameliorated AFB1-induced oxidative stress by scavenging ROS and MDA accumulation and boosting the capacity of the antioxidant enzyme (CAT, T-SOD, GSH-Px and T-AOC). Moreover, LUTN treatment considerably attenuates the AFB1-induced apoptosis in mouse liver, as demonstrated by declined apoptotic cells percentage, decreased Bax, Cyt-c, caspase-3 and caspase-9 transcription and protein with increased Bcl-2 expression. Notably, administration of LUTN up-regulated the Nrf2 and its associated downstream molecules (HO-1, NQO1, GCLC, SOD1) at mRNA and protein levels under AFB1 exposure. Our results indicated that LUTN effectively alleviated AFB1-induced liver injury, and the underlying mechanisms were associated with the activation of the Nrf2 signaling pathway. Taken together, LUTN may serve as a potential mitigator against AFB1-induced liver injury and could be helpful for the development of novel treatment to combat liver diseases in humans and/or animals.

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Aronia melanocarpa Prevents Alcohol-Induced Chronic Liver Injury via Regulation of Nrf2 Signaling in C57BL/6 Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4054520 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Zhuqian Wang ◽

Yange Liu ◽

Xuyu Zhao ◽

Shuyan Liu ◽

Yang Liu ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Antioxidant Activities ◽

Organ Damage ◽

Chronic Liver ◽

Related Factor ◽

Chronic Liver Injury ◽

Aronia Melanocarpa ◽

Nrf2 Signaling Pathway ◽

Cytokine Levels

Aronia melanocarpa (AM), which is rich in anthocyanins and procyanidins, has been reported to exert antioxidative and anti-inflammatory effects. This study aimed to systematically analyze the components of AM and explore its effects on alcohol-induced chronic liver injury in mice. A component analysis of AM revealed 17 types of fatty acids, 17 types of amino acids, 8 types of minerals, and 3 types of nucleotides. Chronic alcohol-induced liver injury was established in mice via gradient alcohol feeding over a period of 6 months, with test groups orally receiving AM in the last 6 weeks. AM administration yielded potential hepatoprotective effects by alleviating weight gain and changes in organ indexes, decreasing the ratio of alanine aminotransferase/aspartate aminotransferase, reducing lipid peroxidation, enhancing antioxidant activities, decreasing oxidation-related factor levels, and regulating inflammatory cytokine levels. Histological analyses suggest that AM treatment markedly prevented organ damage in alcohol-exposed mice. Furthermore, AM activated nuclear factor erythroid 2-like 2 (Nrf2) by downregulating the expression of Kelch-like ECH-associated protein 1, resulting in elevated downstream antioxidative enzyme levels. AM activated Nrf2 via modulation of the phosphatidylinositol-3-hydroxykinase/protein kinase B signaling pathway. Altogether, AM prevented alcohol-induced liver injury, potentially by suppressing oxidative stress via the Nrf2 signaling pathway.

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Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

Frontiers in Pharmacology ◽

10.3389/fphar.2021.785403 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chuanrui Ma ◽

Jiaqing Xiang ◽

Guixiao Huang ◽

Yaxi Zhao ◽

Xinyu Wang ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Cholestatic Liver Disease ◽

P53 Signaling ◽

Promising Target ◽

Underlying Mechanisms ◽

Cholestatic Liver Injury ◽

P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

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