Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats

Yao, Qunyan; Xu, Beili; Wang, Jiyao; Liu, Hongchun; Zhang, Shuncai; Tu, Caixia

doi:10.1186/1472-6882-12-156

Cited by 102 publications

(74 citation statements)

References 45 publications

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“…31 Our data demonstrate that the upregulation of TGF-b was associated with increased phosphorylation of Smad3, effects which were partially abrogated by melatonin. These results similar to those previously reported in rats treated with CCl 4 for asiatic acid, a natural product from Centella asiatica, 32 and curcumin 30 suggest that restoring the balance of TGF-b/Smad signaling may be a central mechanism by which melatonin inhibits liver fibrosis.…”

Section: Discussionsupporting

confidence: 90%

“…36 It has been reported that in rats treated with CCl 4 silymarin decreases CTGF to improve liver fibrosis 37 and curcumin significantly attenuates the severity of liver damage through inhibition of CTGF expression. 30 Our findings confirmed that chronic CCl 4 administration markedly enhanced the intrahepatic expression of CTGF mRNA and protein, and that melatonin significantly reduced these CCl 4 -induced increases.…”

Section: Discussionsupporting

confidence: 83%

“…9 The role of profibrogenic cytokines is central for the development of fibrosis, with progression greatly dependent on the production of TGF-b, which is the master cytokine in liver fibrogenesis and one of the primary targets in the development of antifibrotic agents. 29 TGF-b is downregulated in animal models of fibrosis by treatment with curcumin, 30 epigallocatechin-3-gallate, 6 or polyprenols. 7 Present data confirm that melatonin also decreases TGF-b expression in CCl 4 -treated mice, a fact that undoubtedly contributes to the interference of the indol with the activation of HSCs.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…17 Twenty rats were randomly divided into two groups. Rats in Group 1 (n = 10) received twiceweekly injections of olive oil (vehicle control) while those in Group 2 (n = 10) received twice-weekly injections of CCl 4 plus oral PBS (CCl 4 -treated rats).…”

Section: Liver Injury Modelmentioning

confidence: 99%

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

Guo

Chen

et al. 2015

Laboratory Investigation

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A considerable amount of research has focused on the roles of microRNAs (miRNA) in the pathophysiology of liver fibrosis in view of their regulatory effects on hepatic stellate cell (HSC) functions, including proliferation, differentiation, and apoptosis. Recently, miR-17-5p was shown to promote cell proliferation and migration in liver. Transforming growth factor-β1 (TGF-β1) has been characterized as the master fibrogenic cytokine that stimulates HSC activation and promotes progression of liver fibrosis. The issue of whether miR-17-5p plays a role in TGF-β1-induced hepatic fibrogenesis remains to be established. In this study, we demonstrated a dose-/time-dependent increase in miR-17-5p expression in TGF-β1-treated HSCs. Enhanced miR-17-5p expression was additionally observed in CCl 4 -induced rat liver fibrosis. Inhibition of miR-17-5p led to suppression of HSC proliferation induced by TGF-β1 without affecting cellular apoptosis. Notably, miR-17-5p was significantly associated with TGF-β1-induced expression of type I collagen and α-SMA in HSC. Furthermore, Smad7, a negative regulator of the TGF-β/Smad pathway, was confirmed as a direct target of miR-17-5p. Serum miR-17-5p levels were significantly higher in patients with cirrhosis, compared to healthy controls. Our results collectively indicate that miR-17-5p promotes HSC proliferation and activation, at least in part, via reduction of Smad7, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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“…4 Multiple studies in both animals and human indicated that curcumin possesses a variety of potent properties, including antioxidant, antiÀinflammation, radicalÀscavenging, anticancer, and so on. 5,6 Several studies indicated that curcumin can suppress the proliferation of leukemia and induce cell death. [7][8][9] Besides, it shows no significant side effects compared with other chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

Curcumin induces apoptosis in human leukemic cell lines through an IFIT2-dependent pathway

Zhang

Kong

Liu

et al. 2017

Cancer Biology & Therapy

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Curcumin, the primary bioactive component isolated from turmeric, has been shown to possess variety of biologic functions including anti-cancer activity. However, molecular mechanisms in different cancer cells are various. In the present study, we demonstrated that curcumin induced G2/M cell cycle arrest and apoptosis by increasing the expression levels of cleaved caspase-3, cleaved PARP and decreasing the expression of BCL ¡ 2 in U937 human leukemic cells but not in K562 cells. We found some interferon induced genes, especially interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were significantly upregulated when treated with curcumin in U937 cells by gene expression chip array, and further confirmed that the expression of IFIT2 was obviously higher in U937 than that in K562 cells by Western blot assay. In addition, inhibiting the expression of IFIT2 by shRNA in U937 rescued curcumininduced apoptosis and exogenous overexpression of IFIT2 by lentiviral transduction or treating with IFNg in K562 cells enhanced anti-cancer activity of curcumin. These results indicated for the first time that curcumin induced leukemic cell apoptosis via an IFIT2-dependent signaling pathways. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for curcumin combined with interferon in the cancer therapeutics.

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Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats

Cited by 102 publications

References 45 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

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

Curcumin induces apoptosis in human leukemic cell lines through an IFIT2-dependent pathway

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