ABSTRACT
G protein- coupled receptors (GPCRs), also known as seven- transmembrane domain receptors, constitute the largest superfamily of cell surface receptors. By coupling to heterotrimeric G proteins, arrestins and other signaling molecules, GPCRs modulate diverse signal transduction pathways under physiological and pathological conditions. Recent studies have revealed crucial roles of GPCRs in tumorigenesis and development of cancer metastasis. This review summarizes roles of GPCRs, particularly the roles of those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine and angiotensin in proliferation, invasion, metastasis and angiogenesis of hepatoma cells and development of hepatocellular carcinoma. The potential of GPCRs- based therapeutics being used for hepatocellular carcinoma is also highlighted.
ABSTRACT
Transforming growth factor β(TGF-β)superfamily ligands play an important role in regulating cellular homeostasis including proliferation,differentiation,apoptosis,immune sur-veillance and angiogenesis.Type Ⅲ TGF-βreceptor (TβRⅢ) is considered to be the coreceptor of TGF-βsuperfamily.TβRⅢnot only has an effect on classical Smad signaling pathway,but also on non-Smad signaling pathway.TβRⅢplays a crucial role in fibrosis,tumor,cardiovascular diseases via mediating kinds of signaling pathways.This paper reviews TβRⅢ mediated sig-naling pathway and its role in fibrotic diseases.
ABSTRACT
β-arrestins, a kind of important adaptor protein and signal transduction protein found in the purification process ofβ-adrenergic receptor kinase (β-ARK) ,were first identified as pro-teins that have the ability to desensitize G protein-coupled recep-tors ( GPCR) . Fibrosis is defined by the overgrowth, hardening, and scarring of various tissues and is attributed to excess deposi-tion of extracellular matrix ( ECM ) components including colla-gen . A large number of studies have shown thatβ-arrestins play an important role in the process of fibrotic diseases, involved in inflammatory response and excess deposition of ECM. This re-view discusses the research status and development prospects ofβ-arrestins-mediated fibrotic diseases.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of Shaoqiduogan (SQDG) on the expression of matrix metalloproteinase 13 (MMP-13) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in carbon tetrachloride (CCl4) induced hepatic fibrosis rats and transforming growth factor beta1 (TGF-beta1) irritated hepatic stellate cells (HSC), and to explore its possible mechanisms.</p><p><b>METHOD</b>The model of chemical hepatic fibrosis induced by CCl4 was prepared. The rats were randomly divided into 5 groups, including normal control group, liver fibrosis model group and SQDG (42. 5, 85, 170 mg x kg(-1)) treated groups. The level of collagen type 1 (C-1) in serum was determined by radioimmunoassay. Masson stain was used to examine the histopathological change. MMP-13 and TIMP-1 ex-pression in liver tissues were assayed by immunohistochemistry. In vitro, effects of SQDG on the expression of MMP-13, TIMP-1 and C-1 in HSC-T6 stimulated by TGF-beta were measured by Western-blot.</p><p><b>RESULT</b>The results showed that SQDG significantly decreased the elevated level of C-1 in serum of hepatic fibrosis rats induced by CCl4. Pathological examination showed that SQDG could remarkably alleviate the degree of liver fibrogenesis and formation of pseudolobulus. The results of immunohistochemistry demonstrated that SQDG significantly increased MMP-13 expression and decreased TIMP-1 expression in liver tissues. Furthermore, SQDG (20-160 mg x L(-1)) could facilitate MMP-13 expression, inhibit TIMP-1 expression and significantly inhibit the C-I production of HSC stimulated with TGF-beta1 in vitro.</p><p><b>CONCLUSION</b>The anti-fibrotic effects of SQDG may be associated with its action of promoting collagen degradation via controlling the levels of MMP-13 and TIMP-1 in liver.</p>
Subject(s)
Animals , Humans , Male , Rats , Disease Models, Animal , Drugs, Chinese Herbal , Gene Expression , Hepatic Stellate Cells , Metabolism , Liver Cirrhosis , Drug Therapy , Genetics , Metabolism , Matrix Metalloproteinase 13 , Genetics , Metabolism , Rats, Sprague-Dawley , Tissue Inhibitor of Metalloproteinase-1 , Genetics , MetabolismABSTRACT
Aim To investigate the effects of Shaoqiduogan(SQDG)on immunological hepatic fibrosis induced by human albumin in rats as well as its possible mechanisms.Methods The model of immunological hepatic fibrosis induced by human albumin was prepared.The rats were randomly divided into 6 groups,namely normal control group,liver fibrosis model group,SQDG(42.5,85,170 mg·kg~(-1))treated groups and colchicine(0.1 mg·kg~(-1)) treated group.HE staining was used to examine the histopathological change.The activities of transaminase in serum,malondiadehyde(MDA)content,superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)activities,hydroxyproline(Hyp)content in liver homogenate were assayed byspectrophotometry.The levels of hyaluronic acid(HA)and procollagen Ⅲ (PCⅢ)in serum were determined by radioimmunoassay.In vitro,the collagen production of hepatic stellate cell(HSC)-T6 stimulated with transforming growth factor beta1(TGF-β1)was measured with 3H-Proline uptake.Results SQDG had obvious protective effects on human albumin induced hepatic fibrosis in rats.The results showed that the serum ALT and AST decreased by SQDG treatment,but had no significant difference compared with model group.Pathological examination showed that SQDG could remarkably alleviate the hepatic fibrosis.SQDG not only decreased the Hyp content in liver homogenates,but also the elevated level of HA,PCⅢ in serum.SQDG also ameliorated the oxidative stress state of hepatic fibrosis rats,decreased the production of MDA and enhanced the activities of antioxidative enzyme including SOD and GSH-Px.Furthermore,SQDG(20～160 mg·L~(-1))inhibited the collagen production of HSC stimulated with TGF-β1 in vitro.Conclusion sSQDG has protective effect on liver fibrosis rats induced by human albumin.The mechanisms of its anti-fibrotic effects may be associated with its action of ameliorating the oxidative stress in liver,and inhibiting the production of collagen in HSC.
ABSTRACT
Liver fibrosis can be classified as a wound-healing response to a variety of chronic stimuli,and is characterized by an excessive deposition of extracellular matrix(ECM)proteins.Hepatic stellate cells(HSCs)are presently regarded as one of the key cell types involved in the progression of liver fibrosis.Following a fibrogenic stimulus,HSC changes from a quiescent to an activated,collagen-producing cell.Each cellular response to extracelluar stimuli must be framed in a scenario.Along these lines,the identification and characterization of intracellular signaling pathways activated by different stimuli in HSCs represent a mandatory step.Drug targets which aim at the extra-cellular signals or intra-cellular cascades are required for ameliorating liver fibrosis.
ABSTRACT
Hepatic fibrosis is a pathological process in which excessive deposition of extracellular matrix components, occurs due to an imbalance between the production and degradation of matrix. Fibrosis is the hallmark of most chronic liver diseases. It is also the major factor of the development of chronic hepatitis and cirrhosis. Therefore, in light of the regulative factors on different levels and mechanism of fiber synthesis and degradation, antifibrotic medicine can inhibit the synthesis of matrix or increase its degradation on different links. The present situation concerning the study of the therapeutic effect of traditional Chinese medicine and natural medicine on hepatic fibrosis is reviewed.