Activation of Nrf2/AREs-mediated antioxidant signalling, and suppression of profibrotic TGF-β1/Smad3 pathway: a promising therapeutic strategy for hepatic fibrosis — A review

Gong, Yongfang; Yang, Yan

doi:10.1016/j.lfs.2020.117909

Cited by 57 publications

(25 citation statements)

References 133 publications

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“…Furthermore, the ROS increase mediated by TGF-β1 represses Nrf2 signaling [ 86 ], and it could be hypothesized that the Keap1–NRF2 system participates in the inhibition of TGF-β1 signaling [ 86 , 87 ]. It is therefore noteworthy that Nrf2 and NF-κB cross-talk among them, where the absence of the first can exacerbate cytokine production, whereas NF-κB can modulate Nrf2 transcription and activity [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Rodríguez

Sabaj

Tolosa

et al. 2021

Cells

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Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1β were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-β and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.

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Section: Discussionmentioning

confidence: 99%

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Rodríguez

Sabaj

Tolosa

et al. 2021

Cells

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“…HSCs are lipid-storing cells in the space between hepatocytes and LSECs on the hepatic lobule and contain 50–80% of all vitamin A in the body [ 26 ]. By stimulating signaling molecules such as transforming growth factor (TGF)-β1, mainly released from KCs, HSCs produce collagen fibers and extracellular matrix constituents and are directly involved in liver fibrosis [ 27 ]. Activated HSCs produce leptin, which enhances liver fibrosis through the upregulation of TGF-β expression and the mechanism of autocrine activation in HSCs [ 28 ].…”

Section: The Constituent Cells and The Immune Microenvironment In The Livermentioning

confidence: 99%

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Oura

Morishita

Tani

et al. 2021

IJMS

270

180

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Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

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“…Interestingly, the antioxidant effects of Nrf2 have been suggested to specifically counteract the effects of Nox4 in mediating the myofibroblast phenotype and corresponding lung fibrosis [ 89 ]. Indeed, there is increasing evidence of a contribution of oxidative stress to tissue fibrosis, and links between Nrf2, TGF-β signaling and fibrosis have been the subject of several additional studies [ 88 , 96 , 97 ].…”

Section: Nrf2-mediated Regulation Of Ecmmentioning

confidence: 99%

The Nrf2 transcription factor: A multifaceted regulator of the extracellular matrix

Hiebert

2021

Matrix Biology Plus

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The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is widely recognized as a master regulator of the cellular stress response by facilitating the transcription of cytoprotective genes. As such, the Nrf2 pathway is critical in guarding the cell from the harmful effects of excessive reactive oxygen species/reactive nitrogen species (ROS/RNS) and in maintaining cellular redox balance. While excessive ROS/RNS are harmful to the cell, physiological levels of ROS/RNS play important roles in regulating numerous signaling pathways important for normal cellular function, including the synthesis of extracellular matrix (ECM). Recent advances have underscored the importance of ROS/RNS, and by extension, factors that influence redox-balance such as Nrf2, in regulating ECM production and deposition. In addition to reducing the oxidative burden in the cell, the discovery that Nrf2 can also directly target genes that regulate and form the ECM has cemented it as a multifaceted player in the regulation of ECM proteins, and provides new insight into its potential usefulness as a target for treating ECM-related pathologies.

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Activation of Nrf2/AREs-mediated antioxidant signalling, and suppression of profibrotic TGF-β1/Smad3 pathway: a promising therapeutic strategy for hepatic fibrosis — A review

Cited by 57 publications

References 133 publications

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

The Nrf2 transcription factor: A multifaceted regulator of the extracellular matrix

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