Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling

Oh, Chang Joo; Kim, Joon‐Young; Min, Ae Kyung; Park, Keun Gyu; Harris, R. Adron; Kim, Han Jong; Lee, In Kyu

doi:10.1016/j.freeradbiomed.2011.11.012

Cited by 136 publications

(115 citation statements)

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“…47 The antioxidant sulforaphane suppresses TGF-benhanced expression and TGF-b-stimulated phosphorylation of Smad2 and Smad3 in human immortalized HSCs through an effect that is significantly abolished by Nrf2 knockdown. 48 Because Nrf2 expression in significantly stimulated by melatonin, data obtained in the present research suggest the possibility that suppression of fibrogenic gene expression by melatonin could be mediated, at least in part, through Nrf2-dependent inhibition of the canonical TGF-b/Smad signaling. A direct antifibrogenic effect of melatonin on HSC cannot be ruled out, given the fact that the expression of a-SMA is significantly reduced by the indol.…”

Section: Discussionmentioning

confidence: 57%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl 4 ). Mice in treatment groups received CCl 4 5 mL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl 4 administration. Treatment with CCl 4 resulted in fibrosis evidenced by the staining of Van Gieson and a-smooth muscle actin (a-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl 4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-b, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of a-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-b, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl 4 -induced liver fibrosis. (Translational Research 2015;165:346-357) Abbreviations: a-SMA ¼ a-smooth muscle actin; CCl 4 ¼ carbon tetrachloride; CTGF ¼ connective tissue growth factor; HSC ¼ hepatic stellate cell; MMP-9 ¼ matrix metalloproteinase 9; Nrf2 ¼ nuclear factor erythroid 2-related factor 2; PDGF ¼ platelet-derived growth factor; TGF-b ¼ transforming growth factor b; TIMP-1 ¼ tissue inhibitor of metalloproteinase 1 H epatic fibrosis is a reversible wound-healing response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by an excessive deposition of extracellular matrix (ECM) resulting in liver dysfunction and irreversible cirrhosis. During liver fibrogenesis, hepatic stellate cells (HSCs) undergo activation to a a-smooth muscle actin (SMA)-positive myofibroblastic phenotype and synthesize excess ECM components, particularly collagen. 1 Among the numerous From the

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Section: Discussionmentioning

confidence: 57%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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“…Masson's trichrome staining was performed on the paraffin-embedded, formalin-fixed liver tissue to assess fibrosis and other histopathological features of cholestasis [18]. Images of the stained samples from 5 non-overlapping fields were acquired with the help of an optical microscope (Motic, Spain) and were examined semi-quantitatively.…”

Section: Histopathological Evaluationmentioning

confidence: 99%

Effects of folic acid on dyslipidemia and serum homocysteine in a rat model of cholestasis and hepatic fibrosis

Mohammadian¹,

Eidi²,

Mortazavi³

et al. 2015

pjp

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The liver is the major site for storage and metabolism of folate. Folate deficiency is common in many liver diseases and causes severe effects on cellular metabolism and increases oxidative stress and the homocysteine (Hcy) level. The objective of this research was to investigate the effects of folic acid on dyslipidemia and serum Hcy concentrations in an experimental rat model of cholestasis. Eighty-one male Wistar rats were divided into nine groups: control, sham-operated, folic acid control, bile duct-ligated (BDL), and BDL+ folic acid groups. In folic acid treated groups, folic acid (1, 5, and 10 mg/kg body weight) was given orally for 28 days. After taking blood and liver samples, plasma lipid profiles and Hcy and hepatic reduced and oxidized glutathione concentrations were measured. Histopathological features of cholestasis were assessed by Masson's trichrome staining. Treatment of folic acid in BDL rats significantly prevented the progression of hepatic fibrosis and improved the serum and liver biochemical changes. These results suggest that folic acid protects the liver against cholestasis by reducing serum Hcy and by its antioxidant properties. Folic acid can be an important therapeutic intervention in dyslipidemia caused by cholestasis.

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“…On examination of the molecular mechanism underlying antifibrotic properties of Nrf2 activators on HSC activation, a further contrasting point is that another prototypical Nrf2 activator, sulforaphane, has recently been reported to suppress the TGF-b signaling pathway by inhibiting phosphorylation and transcriptional activation of SMAD3, leading to a reduction in TGF-b-induced expression of fibrogenic genes (Oh et al, 2012). Although the contributions made by their antifibrotic effects remain unclear, OPZ and NK-252 may also have the same effect.…”

Section: Nrf2 Activators Attenuate Fibrosis Progression In Nash Modelmentioning

confidence: 99%

Nrf2 Activators Attenuate the Progression of Nonalcoholic Steatohepatitis–Related Fibrosis in a Dietary Rat Model

et al. 2013

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Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we used two chemically distinct types of Nrf2 activator. One is the thiolreactive agent oltipraz (OPZ), a typical Nrf2 activator, and the other is a novel biaryl urea compound, termed NK-252 (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea). NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we used rats on a choline-deficient L-amino acid-defined (CDAA) diet, which demonstrate pathologic findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histologic abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2 activators with independent mechanisms of action, we show that, in a rat model of NASH, the activation of Nrf2 is responsible for the antifibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.

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Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling

Cited by 136 publications

References 38 publications

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Effects of folic acid on dyslipidemia and serum homocysteine in a rat model of cholestasis and hepatic fibrosis

Nrf2 Activators Attenuate the Progression of Nonalcoholic Steatohepatitis–Related Fibrosis in a Dietary Rat Model

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