ENMD-1068 inhibits liver fibrosis through attenuation of TGF-β1/Smad2/3 signaling in mice

Sun, Quan; Wang, Yan; Zhang, Jie; Lü, Jing

doi:10.1038/s41598-017-05190-7

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…Growing evidence has linked inflammation to tissue damage and liver fibrosis in conditions such as drug-induced liver injury, alcoholic steatohepatitis, and nonalcoholic steatohepatitis [ 27 , 35 , 36 , 37 ]. We measured increased degeneration and necrosis of hepatocytes in Cav1 −/− and WT mice three and seven days post injury but the increase was more significant in the Cav1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Lü

Zhang

Wang

et al. 2018

IJMS

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Liver fibrosis is the common pathological process characterized by activation of hepatic stellate cells (HSCs) and overproduction of extracellular matrix (ECM). Caveolin-1 (Cav1), the principal component of caveolae, is regarded as an important inhibitor of multiple signaling molecules including transforming growth factor β1(TGF-β1) signaling. To evaluate the role of Cav1 in liver fibrosis, Cav1 deficient (Cav1−/−) and wild type (WT) mice were subjected to liver fibrosis induced by carbon tetrachloride (CCl4). Results indicated no significant difference between Cav1−/− and WT mice in inflammation or collagen content before CCl4 treatment. After CCl4 administration, Cav1−/− mice showed enhanced TGF-β1 signaling, as reflected by a significantly greater amount of phosphorylation of Smad2 and collagen deposition in livers over WT animals. Qualitative and quantitative analysis indicated that inflammatory injury to the liver was markedly aggravated, accompanied by increased degeneration and necrosis of hepatocytes, higher alanine aminotransferase (ALT)/aspartate aminotransferase (AST), TGF-α and IL-1β levels in Cav1−/− animals. The mRNA and protein levels of α-smooth muscle actin (α-SMA), Collagen α1(I), and Collagen α1(III) were further enhanced in Cav1−/− animals. We also observed a significant decrease in collagen content in Cav1−/− and WT animals administrated with Cav1 scaffolding domain peptides (CSD). In vitro study indicated that phosphorylation of Smad2 was inhibited after CSD treatment, accompanied by decreased protein levels of α-SMA, Collagen α1(I), and Collagen α1(III) in HSCs. We conclude that Cav1 is an important inhibitor of TGF-β1/Smad signaling in HSCs activation and collagen production, which might make it a promising target for therapy of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

“…The expression levels of proteins in livers and mouse HSCs were analyzed as previously described [ 35 ]. Primary antibodies were as follows: anti-mouse Cav1 (Cat.…”

Section: Methodsmentioning

confidence: 99%

Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Lü

Zhang

Wang

et al. 2018

IJMS

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“…α-SMA and type I collagen, which are induced by TGF-β1/Smad and ERK pathways 14,19,37,38 , are common makers for HSC activation. TGF-β1 is known as one of the most important key mediators of fibrosis in several organs such as the lung, kidney, and liver 14,17,[39][40][41] resulting from proliferation and differentiation of myofibroblasts through Smad and ERK signaling pathways 22,37 .…”

Section: Discussionmentioning

confidence: 99%

“…accepted that PAR2 is activated by trypsin-like enzymes and contributes to TGF-β1 production which is resulting in liver fibrosis 22 . Gingipain; a major virulence factor of P.g., is known to activate PAR2 13,23,24 .…”

Section: Pg-infection and Lps-pg (Pg-lps/lipoprotein) Stimulationmentioning

confidence: 99%

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Nagasaki

Sakamoto

Chea

et al. 2020

Sci Rep

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odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disease caused by obesity including simple steatosis and non-alcoholic steatohepatitis (NASH). The morbidity rate of NAFLD is high, up to 30% in Western countries, with increasing the number of NAFLD patients because of the increase of obesity 1-3 . Most NAFLD patients indicate simple steatosis, which is a reversible condition, but 10-20% of simple steatosis progresses to NASH, which is presented as inflammation with hepatocyte degeneration followed by hepatic fibrosis 3 . As some of the NASH cases eventually result in liver cirrhosis and cancer, it is a critical health problem requiring adequate prevention and early therapeutic intervention 2,4 . The mechanisms for the development and progression of NASH are extremely complicated. Recently, it was reported that fat deposition, inflammation and fibrosis in NASH are simultaneously caused by many factors such as up-regulation of free fatty acids (FFA), oxidation stress, cytokines and bacterial lipopolysaccharide (LPS) 5 .Porphyromonas gingivalis (P.g.) is a main periodontal pathogen. Periodontitis caused by P.g. is a well-recognized risk factor for many systemic diseases such as cardiovascular disease, preterm birth, diabetes mellitus, and rheumatoid arthritis 6-9 . P.g. can enter the blood circulation from periodontal disease sites and disseminate into the whole body and it can be detected in the distant organs including liver 6,7,10,11 . Furusho et al. reported that P.g.-odontogenic infect...

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“…The mechanism of TGF-β1 is as follows: the ligands combine with TGF-β receptors in cytomembrane, and type I receptors are activated; Type I receptors transmit signals to the intracellular media Smad-2/3; then those phosphorylated receptors of Smad-2/3 combine with Smad-4 and transduce TGF-β1 signals directly from the cytomembrane to the cell nucleus to control the expression of downstream target genes. Smad-2/3, the specific key factors in the TGF-β signal transduction pathway 33 , play a significant role in formation, remodeling, and maintenance of bone [34][35][36] . In this study, the expressions of TGF-β1, Smad-2/3 in group B were significantly increased compared with group A, suggesting that the mechanism of PMOP was related to the abnormal expression of transduction factors in the TGF-β1 and Smad signaling pathway.…”

Section: Effect On Bone Metabolism Markers and Tgf-β1/smad-2/3 Signalmentioning

confidence: 99%

Effects of Acupoint Application Therapy with TianGui Powder on Osteoporosis in Ovariectomized Rats through TGF‐β1 and Smad2/3 Signaling Pathway

Lin

Wang

Zhang

et al. 2019

Orthopaedic Surgery

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Objectives To explore the effects of acupoint application therapy (AAT) with TianGui Powder (TGP) on the expressions of the transforming growth factor β1 (TGF‐β1) and Smad‐2/3 signaling pathway in ovariectomized osteoporosis rats. Methods Sixty rats were randomly divided into four groups: normal group (group A), model group (group B), TGP group (group C), and Western medicine group (group D). Group A had only the corresponding amount of adipose tissue around the ovary removed; rats in the other groups had bilateral ovariectomies. After 1 week, groups A and B were given 1 mL/100 mg normal saline solution by gavage, group C was treated with AAT with TGP on ShenQue acupoint (0.2 piece/rat, 6 h/time, 1 time/d) and group D was given calcium carbonate vitamin D3 (36 mg/kg/d) and alfacalcidol (0.05 μg/kg/d) tablet suspension. In this study, the bone mineral density (BMD) , the levels of BALP, TRAP‐5b, and BGP in serum and the changes in bone histomorphology was detected. For acquiring lumbar experimental data, the expression of TGF‐β1, Smad‐2/3 proteins and mRNA of TGF‐β1and Smad‐2/3 were assessed. After 12 weeks, the data were collected for analysis. Results Compared with group A, the bone trabecula was thinner and significantly reduced in other groups. The result of BMD improved significantly in both groups C and D compared to group B after intervention ( P < 0.05). In contrast, compared to group B, the levels of BALP, TRAP‐5b, and BGP significantly declined in both groups C and D. In group C, the results of protein expressions in TGF‐β1, Smad‐2/3 were 2.870 ± 0.270, 1.552 ± 0.111, and 1.420 ± 0.079, respectively. In groups C and D, those indications significantly declined compared to group B ( P < 0.01). In group C, the level of mRNA expressions of TGF‐β1, Smad‐2/3 were 1.872 ± 0.177, 1.672 ± 0.086, and 1.790 ± 0.136, respectively. Compared with group B, those indications had significant difference in groups C and D ( P < 0.05). Conclusion Acupoint application therapy with TGP could significantly improve the BMD. The TGF‐β1 and Smad‐2/3 signaling pathway could be a therapeutic target of TGP in postmenopausal osteoporosis rats.

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ENMD-1068 inhibits liver fibrosis through attenuation of TGF-β1/Smad2/3 signaling in mice

Cited by 24 publications

References 28 publications

Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation

Effects of Acupoint Application Therapy with TianGui Powder on Osteoporosis in Ovariectomized Rats through TGF‐β1 and Smad2/3 Signaling Pathway

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