The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Xu, Dongwei; Xu, Min; Jeong, Seogsong; Qian, Yongxiang; Wu, Hailong; Xia, Qiang; Kong, Xiaoni

doi:10.3389/fphar.2018.01428

Cited by 185 publications

(148 citation statements)

References 90 publications

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“…Oxidative stress and inflammation are considered as a common pathological mechanism to be involved in the initiation and progression of liver injury [7,8]. Both enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT) and non-enzymatic antioxidants such reduced glutathione (GSH) are important for cellular response and are used as indexes to evaluates the level of oxidative stress [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress

Munakarmi

Chand

Shin

et al. 2020

IJMS

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3,3′-Diindolylmethane (DIM), a metabolic product of indole-3-carbinol extracted from cruciferous vegetables exhibits anti-inflammatory and anti-cancer properties. Earlier, the product has been demonstrated to possess anti-fibrotic properties; however, its protective effects on liver injury have not been clearly elucidated. In this study, we postulated the effects and molecular mechanisms of action of DIM on carbon tetrachloride (CCl4)-induced liver injury in mice. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 ml/kg) into mice. DIM was injected via subcutaneous route for three days at various doses (2.5, 5 and 10 mg/kg) before CCl4 injection. Mice were sacrificed and serum was collected for quantification of serum transaminases. The liver was collected and weighed. Treatment with DIM significantly reduced serum transaminases levels (AST and ALT), tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by DIM treatment by the reduction in the levels of cleaved caspase-3 and Bcl2 associated X protein (Bax). DIM treated mice significantly restored Cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in CCl4 treated mice. In addition, DIM downregulated overexpression of hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4 mediated apoptosis. Our results suggest that the protective effects of DIM against CCl4- induced liver injury are due to the inhibition of ROS, reduction of pro-inflammatory mediators and apoptosis.

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Section: Introductionmentioning

confidence: 99%

Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress

Munakarmi

Chand

Shin

et al. 2020

IJMS

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“…Nrf2 activation also inhibits the transcription of IL-6 and IL-1β [ 40 ] and reduces hepatic glucose production in humans [ 32 ]. Osteocalcin, scutellarin, apigenin, and berberine were found to improve MAFLD by activating the Keap1/Nrf2 antioxidant system [ 4 , 42 ].…”

Section: Nrf2 Connection With Liver Diseasesmentioning

confidence: 99%

“…Nrf2 is a pivotal player in the preservation of cellular homeostasis. In liver, Nrf2 has an important protective role during inflammation, fibrogenesis, and carcinogenesis [ 4 ]. In normal conditions, Nrf2 is present in cytoplasm, interacting with the actin-binding protein Kelch-like ECH-associated protein 1 (Keap1).…”

Section: Introductionmentioning

confidence: 99%

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

et al. 2020

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Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.

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“…When activated by ROS, Nrf2 can translocate to the nucleus and bind to the antioxidant response element (ARE) to regulate gene expressions involved in anti-oxidation. Pre-activation of Nrf2 has been shown to reduce the liver damage caused by ischemia/reperfusion in mice [37]. Several studies have shown that gRb1 can protect neurons through activation of the Nrf2/ARE pathway in human SK-N-SH dopaminergic cells, SH-SY5Y cells, and neural progenitor cells [38][39][40].…”

Section: Effects Of Rg On Brain Ischemiamentioning

confidence: 99%

Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

Zhu¹,

Sakanaka²

2019

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Red ginseng, as an effective herbal medicine, has been traditionally and empirically used for the treatment of neuronal diseases. Many studies suggest that red ginseng and its ingredients protect the brain and spinal cord from neural injuries such as ischemia, trauma, and neurodegeneration. This review focuses on the molecular mechanisms underlying the neuroprotective effects of red ginseng and its ingredients. Ginsenoside Rb1 and other ginsenosides are regarded as the active ingredients of red ginseng; the anti-apoptotic, anti-inflammatory, and anti-oxidative actions of ginsenosides, together with a series of bioactive molecules relevant to the above actions, appear to account for the neuroprotective effects in vivo and/or in vitro. Moreover, in this review, the possibility is raised that more effective or stable neuroprotective derivatives based on the chemical structures of ginsenosides could be developed. Although further studies, including clinical trials, are necessary to confirm the pharmacological properties of red ginseng and its ingredients, red ginseng and its ingredients could be promising candidate drugs for the treatment of neural injuries.

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The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Cited by 185 publications

References 90 publications

Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress

Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

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