Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Oxid Med Cell Longev
2018 Apr 19;2018:5045734. doi: 10.1155/2018/5045734.
Show Gene links
Show Anatomy links
Antifibrotic Effect of Marine Ovothiol in an In Vivo Model of Liver Fibrosis.
Brancaccio M
,
D'Argenio G
,
Lembo V
,
Palumbo A
,
Castellano I
.
???displayArticle.abstract???
Liver fibrosis is a complex process caused by chronic hepatic injury, which leads to an excessive increase in extracellular matrix protein accumulation and fibrogenesis. Several natural products, including sulfur-containing compounds, have been investigated for their antifibrotic effects; however, the molecular mechanisms underpinning their action are partially still obscure. In this study, we have investigated for the first time the effect of ovothiol A, π-methyl-5-thiohistidine, isolated from sea urchin eggs on an in vivo murine model of liver fibrosis. Mice were intraperitoneally injected with carbon tetrachloride (CCl4) to induce liver fibrosis and treated with ovothiol A at the dose of 50 mg/kg 3 times a week for 2 months. Treatment with ovothiol A caused a significant reduction of collagen fibers as observed by histopathological changes and serum parameters compared to mice treated with control solution. This antifibrotic effect was associated to the decrease of fibrogenic markers involved in liver fibrosis progression, such as the transforming growth factor (TGF-β), the α-smooth muscle actin (α-SMA), and the tissue metalloproteinases inhibitor (TIMP-1). Finally, we provided evidence that the attenuation of liver fibrosis by ovothiol A treatment can be regulated by the expression and activity of the membrane-bound γ-glutamyl-transpeptidase (GGT), which is a key player in maintaining intracellular redox homoeostasis. Overall, these findings indicate that ovothiol A has significant antifibrotic properties and can be considered as a new marine drug or dietary supplement in potential therapeutic strategies for the treatment of liver fibrosis.
Figure 3. Protein expression of liver fibrosis markers. (a) A representative experiment of Western blot analysis of cytosolic extracts obtained from hepatic tissues of mice treated with ovothiol A or vehicle, after induction of liver fibrosis, compared to samples of healthy mice (NT), using antibodies specific for TGF-β, α-SMA, and TIMP1. Histograms of the densitometry analysis of protein bands obtained by Western blot for liver markers: (b) TGF-β; (c) α-SMA; and (d) TIMP1. Data were normalized for GAPDH. Data are expressed as mean ± SD, n = 7. The significance was determined by ANOVA test. (#p < 0.05) and (##p < 0.01) represent significance compared to NT; (∗∗p < 0.01) represents significance compared to the treated with vehicle + CCl4.
Figure 5. GGT activity and glutathione content. (a) The enzymatic activity of GGT was evaluated on liver tissue microsomal extracts containing membrane-bound GGT. The activity of GGT was normalized compared to the mature protein band (50 kDa) detected by Western blot. (b) The levels of glutathione were determined in hepatic tissue of mice treated with ovothiol A or vehicle, after induction of hepatic fibrosis, compared to samples of healthy tissue mice (NT). Data are expressed as mean ± SD, n = 6. The bars indicated the mean of 7 measures +/− SD (standard deviation). The significance was determined by the ANOVA and post hoc analysis: (#p < 0.05) represents significance compared to healthy control; (∗∗p < 0.01) represents significance compared to mice treated with vehicle + CCl4.
Figure 6. Proposed mechanism of action for ovothiol. During the development of liver fibrosis, membrane-bound GGT activity increases, leading to ROS overproduction. ROS can activate TGF-β, which in turn upregulates α-SMA and TIMP1, favoring ECM deposition. Ovothiol acts as a GGT inhibitor and in turn reduces TGF-β activation, thus inducing a cascade of events leading to downregulation of profibrogenic molecules and induction of fibrolytic enzymes.
Altmann,
Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.
2017, Pubmed
Altmann,
Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.
2017,
Pubmed
Blunt,
Marine natural products.
2018,
Pubmed
Castellano,
Shedding light on ovothiol biosynthesis in marine metazoans.
2016,
Pubmed
,
Echinobase
Castellano,
On ovothiol biosynthesis and biological roles: from life in the ocean to therapeutic potential.
2018,
Pubmed
Castellano,
Anti-Inflammatory Activity of Marine Ovothiol A in an In Vitro Model of Endothelial Dysfunction Induced by Hyperglycemia.
2018,
Pubmed
,
Echinobase
Castellano,
γ-Glutamyltranspeptidases: sequence, structure, biochemical properties, and biotechnological applications.
2012,
Pubmed
D'Argenio,
Garlic extract prevents CCl(4)-induced liver fibrosis in rats: The role of tissue transglutaminase.
2010,
Pubmed
D'Argenio,
Garlic extract attenuating rat liver fibrosis by inhibiting TGF-β1.
2013,
Pubmed
Daunay,
Short protecting-group-free synthesis of 5-acetylsulfanyl-histidines in water: novel precursors of 5-sulfanyl-histidine and its analogues.
2016,
Pubmed
Dominici,
Prooxidant reactions promoted by soluble and cell-bound gamma-glutamyltransferase activity.
2005,
Pubmed
Dominici,
Redox modulation of NF-kappaB nuclear translocation and DNA binding in metastatic melanoma. The role of endogenous and gamma-glutamyl transferase-dependent oxidative stress.
2003,
Pubmed
Halliwell,
Ergothioneine - a diet-derived antioxidant with therapeutic potential.
2018,
Pubmed
Hemmann,
Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies.
2007,
Pubmed
Issa,
Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration.
2003,
Pubmed
Jacob,
A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms.
2006,
Pubmed
King,
A novel, species-specific class of uncompetitive inhibitors of gamma-glutamyl transpeptidase.
2009,
Pubmed
Li,
Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis.
2015,
Pubmed
Novo,
Hepatic myofibroblasts and fibrogenic progression of chronic liver diseases.
2015,
Pubmed
Oh,
Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.
2012,
Pubmed
O'Neill,
The transcriptome of Euglena gracilis reveals unexpected metabolic capabilities for carbohydrate and natural product biochemistry.
2015,
Pubmed
Parsons,
Molecular mechanisms of hepatic fibrogenesis.
2007,
Pubmed
Puche,
Hepatic stellate cells and liver fibrosis.
2013,
Pubmed
Russo,
Ovothiol isolated from sea urchin oocytes induces autophagy in the Hep-G2 cell line.
2014,
Pubmed
,
Echinobase
Schuppan,
Evolving therapies for liver fibrosis.
2013,
Pubmed
Shapiro,
The control of oxidant stress at fertilization.
1991,
Pubmed
,
Echinobase
Shin,
Effect of dietary supplementation of grape skin and seeds on liver fibrosis induced by dimethylnitrosamine in rats.
2010,
Pubmed
Shinkawa,
S-allylcysteine is effective as a chemopreventive agent against porcine serum-induced hepatic fibrosis in rats.
2009,
Pubmed
Tang,
Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis.
2016,
Pubmed
Turner,
Ovothiols, a family of redox-active mercaptohistidine compounds from marine invertebrate eggs.
1987,
Pubmed
,
Echinobase
Turner,
Ovothiol replaces glutathione peroxidase as a hydrogen peroxide scavenger in sea urchin eggs.
1988,
Pubmed
,
Echinobase
Vamecq,
Potent mammalian cerebroprotection and neuronal cell death inhibition are afforded by a synthetic antioxidant analogue of marine invertebrate cell protectant ovothiols.
2003,
Pubmed
Vitaglione,
Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins.
2010,
Pubmed
Weng,
The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis.
2009,
Pubmed
Yu,
Elevated serum gamma-glutamyltransferase predicts advanced histological liver damage in chronic hepatitis B.
2016,
Pubmed
