1.
Xia P, Deng Q, Gao J, Yu X, Zhang Y, Li J, Guan W, Hu J, Tan Q, Zhou L, Han W, Yuan Y, Yu Y.
Eur J Pharmacol. 2016 Mar 9. pii: S0014-2999(16)30138-8. doi: 10.1016/j.ejphar.2016.03.017. [Epub ahead of print]
Abstract
Cholestasis leads to acute hepatic injury, fibrosis/cirrhosis,
inflammation, and duct proliferation.
We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model.
Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury.
Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1β expression levels in the liver by treatment with anti-RAGE.
Anti-RAGE also significantly reduced the mRNA levels of α1(1) collagen (Col1α1) and cholesterol 7α-hydroxylase, and the ratio of TIMP-1/MMPs, tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver.
In addition, anti-RAGE regulated the transcriptional level of Col1α1 and MMP-9 in transforming growth factor-β-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats.Copyright © 2016. Published by Elsevier B.V. KEYWORDS: Vitamin K1 (PubChem CID: 5284607); anti-RAGE; bile duct ligation; hepatic stellate cell; liver fibrosis; liver injury
We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model.
Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury.
Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1β expression levels in the liver by treatment with anti-RAGE.
Anti-RAGE also significantly reduced the mRNA levels of α1(1) collagen (Col1α1) and cholesterol 7α-hydroxylase, and the ratio of TIMP-1/MMPs, tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver.
In addition, anti-RAGE regulated the transcriptional level of Col1α1 and MMP-9 in transforming growth factor-β-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats.Copyright © 2016. Published by Elsevier B.V. KEYWORDS: Vitamin K1 (PubChem CID: 5284607); anti-RAGE; bile duct ligation; hepatic stellate cell; liver fibrosis; liver injury
- PMID:26970185 Similar articles
2.
Tai CJ, Choong CY, Shi YC, Lin YC, Wang CW, Lee BH, Tai CJ.
Molecules. 2016 Feb 25;21(3). pii: E269. doi: 10.3390/molecules21030269.
Abstract BACKGROUND: Advanced glycation end products (AGEs) signal through the receptor for AGE (RAGE), which can lead to hepatic fibrosis
in hyperglycemia and hyperlipidemia. We investigated the inhibitory
effect of aqueous extracts from Solanum nigrum (AESN) on AGEs-induced
RAGE signaling and activation of hepatic stellate cells (HSCs) and hyperglycemia induced by high-fat diet with ethanol. METHODS: An animal model was used to evaluate the anti-hepatic fibrosis
activity of AESN in rats fed a high-fat diet (HFD; 30%) with ethanol
(10%). Male Wistar rats (4 weeks of age) were randomly divided into four
groups (n = 6): (1) control (basal diet); (2) HFD (30%) + ethanol (10%)
(HFD/ethanol); (3) HFD/ethanol + AESN (100 mg/kg, oral administration);
and (4) HFD/ethanol + pioglitazone (10 mg/kg, oral administration) and
treated with HFD for 6 months in the presence or absence of 10% ethanol
in dietary water. RESULTS: We
found that AESN improved insulin resistance and hyperinsulinemia, and
downregulated lipogenesis via regulation of the peroxisome
proliferator-activated receptor α (PPARα), PPARγ co-activator (PGC-1α),
carbohydrate response element-binding protein (ChREBP), acetyl-CoA
carboxylase (ACC), and fatty acid synthase (FAS) mRNA levels in the liver of HFD/ethanol-treated rats. In turn, AESN may delay and inhibit the progression of hepatic fibrosis, including α-smooth muscle actin (α-SMA) inhibition and MMP-2 production. CONCLUSIONS: These results suggest that AESN may be further explored as a novel anti-fibrotic strategy for the prevention of liver disease.KEYWORDS: Solanum nigrum; advanced glycation end products (AGEs); hepatic fibrosis; hyperglycemia; hyperlipidemia
- PMID:26927042 Free Article Similar articles
3.
Go J, Kim JE, Koh EK, Song SH, Sung JE, Lee HA, Lee YH, Lim Y, Hong JT, Hwang DY.
Nutrients. 2016 Feb 23;8(3). pii: E107. doi: 10.3390/nu8030107. Abstract
To
investigate the toxicity, protective effects, and action mechanism of
gallotannin-enriched extracts isolated from Galla Rhois (GEGR) against
carbon tetrachloride (CCl₄)-induced hepatotoxicity in Institute for
Cancer Research (ICR) mice, alterations in serum biochemical indicators,
histopathological structure, antioxidative status, hepatic apoptosis-related proteins, and liver fibrosis
regulating factors were measured in mice pretreated with GEGR for five
days before CCl₄ injection. The GEGR/CCl₄ treated group showed decreased
levels of three serum marker enzymes (ALP, AST, and ALT) representing liver toxicity, although LDH levels remained constant. Necrotic area indicating hepatic
cell death significantly inhibited, while malondialdehyde (MDA)
concentration and superoxide dismutase (SOD) expression were
dramatically recovered in the GEGR preadministrated group. In mechanism
analyses of GEGR, the formation of active caspase-3 and enhancement of
Bax/Bcl-2 expression was effectively inhibited in the GEGR/CCl₄ treated
group. The level of pro-inflammatory cytokines, TNF-α and IL-6, as well
as the phosphorylation of p38 and JNK in the TNF-α downstream signaling
pathway was rapidly recovered in the GEGR/CCl₄ treated group, while
anti-inflammatory cytokine (IL-10) increased slightly in the same group.
Furthermore, the GEGR/CCl₄ treated group showed a significant decrease
in collagen accumulation results from alleviation of MMP-2
expression, TGF-β1 secretion and the phosphorylation of Smad2/3. Taken
together, these results suggest that GEGR may induce remarkable
protective effects against hepatic injury induced by CCl₄ treatment through upregulation of the anti-inflammatory and antioxidant system. KEYWORDS:Galla Rhois; hepatic fibrosis; hepatotoxicity; inflammation; oxidative stress PMID: 26907337 Free Article Similar articles
4.
Kang M, Zhao L, Ren M, Deng M, Li C.
Int J Clin Exp Med. 2015 Nov 15;8(11):20463-71. eCollection 2015. Abstract
This study is to investigate the effect and underlying mechanism of Zinc (Zn) on hepatic
stellate cell collagen synthesis. The proliferation and collagen
synthesis ability of LX-2 cells were detected after adding Zn. The
collagen synthesis related proteins of MMP-13
and TIMP1 along with TGF-β signaling pathway related proteins were
detected by Western blot. The role of TGF-β signaling pathway in
collagen synthesis inhibition was identified by TGF-β RI siRNA
silencing.
Compared with control group, LX-2 cell proliferation ability
was significantly inhibited at all Zn concentrations (50 μM, 100 μM and
200 μM). Zn at 50 μM did not affect the protein content of αSMA and type
I collagen while 100 μM and 200 μM Zn could significantly inhibit αSMA
expression. Compared with control group, gene expression and protein
content of MMP-13
in 200 μM Zn group was significantly increased while no difference in
gene expression and protein content of TIMP1 was found. TGF-β RI content
in 200 μM Zn group was significantly decreased and the protein content
of TGF-β RII was not affected. MMP-13
expression was significantly increased after TGF-β RI siRNA silencing.
Further results showed that in LX-2 cells those TGF-β RI expression was
inhibited, LX-2 cell proliferation ability and the expression of
synthesis collagen related proteins of αSMA and type I collagen were
greatly decreased. Zn could significantly inhibit the expression of αSMA
and type I collagen by inhibiting TGF-β RI expression and promoting MMP-13 expression. KEYWORDS: Collagen synthesis; Zn; hepatic fibrosis; hepatic stellate cells PMID: 26884962 [PubMed] PMCID: PMC4723807 Free PMC Article PMID: 26884962 Free PMC Article Similar articles
5.
Osawa Y, Oboki K, Imamura J, Kojika E, Hayashi Y, Hishima T, Saibara T, Shibasaki F, Kohara M, Kimura K.
EBioMedicine. 2015 Oct 8;2(11):1751-8. doi: 10.1016/j.ebiom.2015.10.010. eCollection 2015 Nov.Abstract
Wnt/β-catenin
is involved in every aspect of embryonic development and in the
pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of β-catenin-mediated signaling on liver fibrosis
remains unclear.
To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80(+) CD11b(+) and Ly6C(low) CD11b(+) macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis. KEYWORDS:
To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80(+) CD11b(+) and Ly6C(low) CD11b(+) macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis. KEYWORDS:
BDL,
bile duct ligation; Beta-catenin; CBP, CREB-binding protein; CCL, c–c
motif ligand; CCl4, carbon tetrachloride; CREB, cAMP-response
element-binding protein; CXCL, c–x–c motif ligand; Fibrosis; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCV, hepatitis C virus; HSC, hepatic stellate cell; Hepatic stellate cell; H–E, hematoxylin and eosin; Liver; MMP,
matrix metalloproteinase; Macrophage; PBDL, partial BDL; SPARC,
secreted protein acidic and rich in cysteine; TGF-β, transforming growth
factor; TIMP-1, tissue inhibitor of metalloproteinase; αSMA, α-smooth
muscle actin,
- PMID:26870800[PubMed - in process]PMCID: PMC 4740320 Free PMC Article PMID:26870800 Free PMC Article Similar articles
6.
Fujimoto
Y, Urashima T, Shimura D, Ito R, Kawachi S, Kajimura I, Akaike T,
Kusakari Y, Fujiwara M, Ogawa K, Goda N, Ida H, Minamisawa S.
PLoS One. 2016 Feb 10;11(2):e0148666. doi: 10.1371/journal.pone.0148666. eCollection 2016.
Abstract BACKGROUND: Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis
using a pulmonary artery banding (PAB)-induced right heart failure
model and investigated whether cardiac output (CO) is responsible for
the progression of hepatic fibrosis. METHODS AND RESULTS: Five-week-old
Sprague-Dawley rats divided into the PAB and sham-operated control
groups. After 4 weeks from operation, we measured CO by
echocardiography, and hepatic fibrosis
ratio by pathological examination using a color analyzer. In the PAB
group, CO was significantly lower by 48% than that in the control group
(78.2±27.6 and 150.1±31.2 ml/min, P<0 .01="" b="">Hepatic fibrosis ratio
7.
Tabet E, Genet V, Tiaho F, Lucas-Clerc C, Gelu-Simeon M, Piquet-Pellorce C, Samson M.
Toxicol Lett. 2016 Feb 4. pii: S0378-4274(16)30021-2. doi: 10.1016/j.toxlet.2016.02.005. [Epub ahead of print] Abstract
Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver
failure and death. Chlordecone is a chlorinated pesticide used in the
1990s. It is not itself hepatotoxic, but its metabolism in the liver
triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone
is now banned, but it persists in soil and water, resulting in an
ongoing public health problem in the Caribbean area.
We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.KEYWORDS:
We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.KEYWORDS:
CCl4; Chlordecone; Collagen; Fibrosis; Kepone; Liver
- PMID:
- 26853152
8.
Panchenko LF, Terebilina NN, Pyrozhkov SV, Naumova TA, Baronets VY, Balashova AA, Garmash IV.
Patol Fiziol Eksp Ter. 2015 Jul-Sep;(3):18-27. Russian.
Abstract
Abstract
In the serum of patients with alcoholism with varying degrees of severity of liver fibrosis were studied the content markers of fibrosis,
endothelial dysfunction and proinflammatory cytokines.
Concentration in blood indicators of fibrogenesis--collagen type 4, hyaluronic acid, TIMP-1, TIMP-2, YKL-40 and MMP-2 is considerably increased at the 4 degree of fibrosis and moderately increased at low and zero degrees of liver fibrosis. Similar results were obtained in respect of proinflammatory cytokines Il-6, IL-8, IL-12/p70 and IL-12/p40.
The magnitude of endothelial dysfunc tion, calculated based on its content in the blood markers--VEGF-A, MCP-1, s-VCAM, s-ICAM and endothelin, was maximal at 4 degrees of fibrosis and less pronounced at low degrees of fibrosis.
Correlations between of the average degree of fibrosis, endothelial dysfunction, and blood levels of proinflammatory cytokines were installed. Close relation between the immune cells releasing stimulators of inflammation and fibrogenesis, perisinusoidal fat cells producing collagen, and endothelium secreting vasoconstrictors in the pathogenesis of alcoholic liver fibrosis and cirrhosis was installed.
Concentration in blood indicators of fibrogenesis--collagen type 4, hyaluronic acid, TIMP-1, TIMP-2, YKL-40 and MMP-2 is considerably increased at the 4 degree of fibrosis and moderately increased at low and zero degrees of liver fibrosis. Similar results were obtained in respect of proinflammatory cytokines Il-6, IL-8, IL-12/p70 and IL-12/p40.
The magnitude of endothelial dysfunc tion, calculated based on its content in the blood markers--VEGF-A, MCP-1, s-VCAM, s-ICAM and endothelin, was maximal at 4 degrees of fibrosis and less pronounced at low degrees of fibrosis.
Correlations between of the average degree of fibrosis, endothelial dysfunction, and blood levels of proinflammatory cytokines were installed. Close relation between the immune cells releasing stimulators of inflammation and fibrogenesis, perisinusoidal fat cells producing collagen, and endothelium secreting vasoconstrictors in the pathogenesis of alcoholic liver fibrosis and cirrhosis was installed.
- PMID:
- 26852591
- [PubMed - indexed for MEDLINE]
- PMID:
- 26852591Similar articles
9.
Mohamed HE, Elswefy SE, Rashed LA, Younis NN, Shaheen MA, Ghanim AM.
Exp Biol Med (Maywood). 2016 Mar;241(6):581-91. doi: 10.1177/1535370215627219. Epub 2016 Jan 24.Abstract
Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver
in rats.
Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks.
Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
© 2016 by the Society for Experimental Biology and Medicine. KEYWORDS: Bone marrow-derived mesenchymal stem cells; bile duct ligation; cytokeratin-19; hepatic regeneration; hepatocyte growth factor; matrix mettaloproteinase-2
Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks.
Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
© 2016 by the Society for Experimental Biology and Medicine. KEYWORDS: Bone marrow-derived mesenchymal stem cells; bile duct ligation; cytokeratin-19; hepatic regeneration; hepatocyte growth factor; matrix mettaloproteinase-2
- PMID:
- 26811102
10.
Chu X, Wang H, Jiang YM, Zhang YY, Bao YF, Zhang X, Zhang JP, Guo H, Yang F, Luan YC, Dong YS.
J Pharmacol Sci. 2016 Jan;130(1):15-23. doi: 10.1016/j.jphs.2015.12.002. Epub 2015 Dec 15. Abstract We
investigated the ameliorative effects and potential mechanisms of tannic
acid (TA) in carbon tetrachloride (CCl4)-intoxicated mice and hepatic stellate cells (HSCs). Liver fibrosis
was observed in CCl4 (800 ml/kg)-induced mice, and high viability was
observed in CCl4 (10 mM)-intoxicated HSCs. Pre-treatment of mice with TA
(25 or 50 g/kg/day) significantly ameliorated hepatic
morphology and coefficient values and reduced the activities of
aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the
concentrations of malondialdehyde (MDA) and serum levels of
endothelin-1 (ET-1). In addition, TA increased the activities of
superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase
(GSH-Px), and endothelial nitric oxide synthase (eNOS) and the serum
level of NO. Moreover, TA reduced the expression of angiotensin II
receptor-1 (ATR-1), interleukin-1β (IL-1β), tumor necrosis factor-α
(TNF-α), transforming growth factor-β (TGF-β), caspase-3, c-fos, c-jun,
the ratio of Bax/bcl-2, tissue inhibitor of metalloproteinase-1 (TIMP-1)
and TA increased matrix metal proteinase-9 (MMP-9), matrix metalloproteinase-1 (MMP-1). Furthermore, TA (0.01 μM, 0.1 μM or 1 μM) decreased the TIMP-1/MMP-1 ratio and reduced the viability of HSCs. These results indicated that TA exerts significant liver-protective effects in mice with CCl4-induced liver fibrosis. The potential mechanism may rely on the inhibition of collagen accumulation, oxidative stress, inflammation and apoptosis.
Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.
KEYWORDS:
Anti-Apoptosis; Anti-Inflammation; Anti-fibrosis; Anti-oxidation; Tannic acid- PMID:
- 26810570
- [PubMed - in process]
- PMID:
- 26810570
11.
Malaguarnera M, Motta M, Vacante M, Malaguarnera G, Caraci F, Nunnari G, Gagliano C, Greco C, Chisari G, Drago F, Bertino G.
Am J Transl Res. 2015 Nov 15;7(11):2510-8. eCollection 2015.
Abstract
Chronic
hepatitis C is both a virologic and a fibrotic disease, with mortality
resulting mainly from the complications of cirrhosis and HCC. The aim
was to evaluate the impact on of supplementation with a new
pharmaceutical complex of silybinvitamin E-phospholipids in patients
with chronic hepatitis C treated with Pegylated-Interferon-α2b plus
Ribavirin. In this prospective, randomized, placebo controlled, double
blind clinical trial, 32 subjects with chronic hepatitis, received
Pegylated-Interferon-α2b (1.5 mg/kg per week) plus Ribavirin and
placebo, while 32 subjects received the same dosage of
Pegylated-Interferon-α2b plus Ribavirin plus association of Silybin 47
mg + vitamin E 15 mg + phospholipids 97 mg in two pill for 12 months.
Serum levels of the following markers of liver fibrosis were evaluated:
transforming growth factor beta, hyaluronic acid, metalloproteinase 2,
amino-terminal pro-peptide of type III procollagen, tissue inhibitor of
matrix metalloproteinase type I. The comparison between group A and
group B showed a significant difference in ALT (P<0 .001="" 12="" 6="" a="" activation="" after="" ameliorated="" ameliorative="" and="" antioxidants.="" at="" beta="" cells="" complex="" conclusion="" direct="" e-phosholipids="" effect="" fibrosis.="" follow="" hepatic="" in="" levels="" liver="" markers="" maybe="" mediated="" mmp-2="" months="" of="" on="" or="" p="" peg-ifn="" piiinp="" plus="" rbv="" reduced="" related="" response="" serum="" silybin-vitamin="" stellate="" supplementation="" tgf="" the="" timp-1="" to="" treatment="" up="" via="" viremia="" with="">
KEYWORDS:
Silybin; hepatitis C; interferons; liver fibrosis; ribavirin
12.
Ulitzky L, Lafer MM, KuKuruga MA, Silberstein E, Cehan N, Taylor DR.
PLoS One. 2016 Jan 5;11(1):e0145212. doi: 10.1371/journal.pone.0145212. eCollection 2016.
Abstract
Poor
outcome in response to hepatitis C virus, including higher viral load,
hepatocellular carcinoma and cirrhosis, is more associated with men and
postmenopausal women than with premenopausal women and women receiving
hormone replacement therapy, suggesting that β-estradiol plays an innate
role in preventing viral infection and liver disease. Consequently,
most research in the field has concluded that estrogen affects HCV
replication through viral interactions with estrogen receptor-α.
Previously, estrogen-like antagonists, including Tamoxifen, were shown
to reduce HCV RNA production and prevent viral entry, although the
authors did not identify host factors involved. Estrogen can act
alternatively through the membrane-bound G-protein-coupled estrogen
receptor, GPR30. Here, human hepatoma Huh7.5 cells were infected with
HCV J6/JFH-1 and treated with estrogen or Tamoxifen, resulting in a
marked decrease in detectable virus. The effect was mimicked by G1, a
GPR30-specific agonist, and was reversed by the GPR30-specific
antagonist, G15. While previous studies have demonstrated that estrogen
down-regulated occludin in cervical cancer cells, its action on liver
cells was unknown. Occludin is a tight junction protein and HCV receptor
and here we report that activation and cellular export of MMP-9 led to
the cleavage of occludin upon estrogen treatment of liver cells. This is
the first report of the cleavage of an HCV receptor in response to
estrogen. We also identify the occludin cleavage site in extracellular
Domain D; the motif required for HCV entry and spread. This pathway
gives new insight into a novel innate antiviral pathway and the
suboptimal environment that estrogen provides for the proliferation of
the virus. It may also explain the disparate host-virus responses to HCV
demonstrated by the two sexes. Moreover, these data suggest that
hormone replacement therapy may have beneficial antiviral enhancement
properties for HCV-infected postmenopausal women and show promise for
new antiviral treatments for both men and women.
13.
Mahmoud MF, Zakaria S, Fahmy A.
Adv Pharmacol Sci. 2015;2015:298792. doi: 10.1155/2015/298792. Epub 2015 Nov 25.
Abstract
The
aims of the present work were to study the effects of chronic NO
inhibition on liver cirrhosis and to analyze its relationship with liver
and kidney damage markers. Two inhibitors of NO synthesis (inducible NO
synthase (iNOS) inhibitor, aminoguanidine (AG), and nonselective NOS
inhibitor, L-nitroarginine methyl ester (L-NAME)) were administered for 6
weeks to bile duct ligated (BDL) rats 3 days after surgery. The present
study showed that BDL was associated with liver injury and renal
impairment. BDL increased liver NO content and myeloperoxidase (MPO)
activity. This was corroborated by increased oxidative stress, TNF-α,
TGF-1β, and MMP-13 genes overexpression. Although both drugs reduced NO
synthesis and TNF-α gene overexpression, only AG improved renal
dysfunction and liver damage and reduced liver oxidative stress.
However, L-NAME exacerbated liver and renal dysfunction. Both drugs
failed to modulate TGF-1β and MMP-13 genes overexpression. In
conclusion, inhibition of NO production by constitutive nitric oxide
synthase (cNOS) plays a crucial role in liver injury and renal
dysfunction while inhibition of iNOS by AG has beneficial effect. TNF-α
is not the main cytokine responsible for liver injury in BDL model.
Nitric oxide inhibition did not stop the progression of cholestatic
liver damage.
14.
Gopal K, Gowtham M, Sachin S, Ravishankar Ram M, Shankar EM, Kamarul T.
Sci Rep. 2015 Dec 16;5:18300. doi: 10.1038/srep18300.
Abstract
Angiotensin
II is one of the key regulatory peptides implicated in the pathogenesis
of liver disease. The mechanisms underlying the salubrious role of
α-tocopherol and β-carotene on liver pathology have not been
comprehensively assessed. Here, we investigated the mechanisms
underlying the role of Angiotensin II on hepatic damage and if
α-tocopherol and β-carotene supplementation attenuates hepatic damage.
Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin
II followed by oral administration with α-tocopherol and
β-carotene-enriched diet for 60 days. Investigations showed fibrosis,
kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell
apoptosis; sinusoidal dilatation along with haemorrhages; evidence of
fluid accumulation; increased ROS level and increased AST and ALT
activities. In addition, tPA and uPA were down-regulated due to 42-fold
up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were
down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol
and β-carotene treatment controlled ROS, fibrosis, hepatocyte
degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal
dilatation and fluid accumulation in the liver sinusoids, and liver
enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly
controlled by β-carotene treatment. Thus, Angiotensin II markedly
influenced hepatic damage possibly by restraining fibrinolytic system.
We concluded that α-tocopherol and β-carotene treatment has salubrious
role in repairing hepatic pathology.
15.
Arriola Benitez PC, Rey Serantes D, Herrmann CK, Pesce Viglietti AI, Vanzulli S, Giambartolomei GH, Comerci DJ, Delpino MV.
Infect Immun. 2015 Dec 14;84(2):598-606. doi: 10.1128/IAI.01227-15.
Abstract
The
liver is frequently affected in patients with active brucellosis. In the
present study, we identified a virulence factor involved in the
modulation of hepatic stellate cell function and consequent fibrosis
during Brucella abortus infection. This study assessed the role of
BPE005 protein from B. abortus in the fibrotic phenotype induced on
hepatic stellate cells during B. abortus infection in vitro and in vivo.
We demonstrated that the fibrotic phenotype induced by B. abortus on
hepatic stellate (LX-2) cells was dependent on BPE005, a protein
associated with the type IV secretion system (T4SS) VirB from B.
abortus. Our results indicated that B. abortus inhibits matrix
metalloproteinase 9 (MMP-9) secretion through the activity of the
BPE005-secreted protein and induces concomitant collagen deposition by
LX-2 cells. BPE005 is a small protein containing a cyclic nucleotide
monophosphate binding domain (cNMP) that modulates the LX-2 cell
phenotype through a mechanism that is dependent on the cyclic AMP
(cAMP)/protein kinase A (PKA) signaling pathway. Altogether, these
results indicate that B. abortus tilts LX-2 cells to a profibrogenic
phenotype employing a functional T4SS and the secreted BPE005 protein
through a mechanism that involves the cAMP and PKA signaling pathway.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
- PMID:
- 26667834
- [PubMed - in process]
- PMCID:
- PMC4730569
- [Available on 2016-07-25]
16.
Piao RL, Xiu M, Brigstock DR, Gao RP.
Hepatobiliary Pancreat Dis Int. 2015 Dec;14(6):651-9.
Abstract
BACKGROUND:
Pancreatic stellate cells (PSCs) play a critical role in the pathogenesis of pancreatic fibrosis and have emerging functions as progenitor cells, immune cells or intermediaries in pancreatic exocrine secretion. Increasing evidence has shown that desmin as an exclusive cytoskeleton marker of PSC is only expressed in part of these cells. This study was to establish a desmin-positive PSC cell line and evaluate its actions on pancreatic fibrosis, inflammation and immunity.METHODS:
The presence of cytoskeletal proteins, integrin alpha5beta1 or TLR4, was determined by immunocytochemistry while the production of desmin, collagen I, MMP-1, MMP-2, TIMP-2, or CD14 was evaluated by Western blotting. The levels of desmin, collagen I, IL-1 and IL-6 mRNA were determined by real-time quantitative PCR. The secretion of cytokines was detected by ELISA. Cell function was assessed using adhesion, migration, or proliferation assays.RESULTS:
A stable activated rat PSC cell line (designated as RP-2) was established by RSV promoter/enhancer-driven SV40 large T antigen expression. RP-2 cells retained typical PSC properties, exhibited a myofibroblast-like phenotype and persistently produced desmin. The cells produced collagen I protein, matrix metalloproteinases and inhibitors thereof. RP-2 cells demonstrated typical PSC functions, including proliferation, adherence, and migration, the latter two of which occurred in response to fibronectin and were mediated by integrin alpha5beta1. TLR4 and its response genes including proinflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemotactic cytokines (MCP-1, MIP-1alpha, Rantes) were produced by RP-2 cells and activated by LPS. LPS-induced IL-1 or IL-6 mRNA expression in this cell line was fully blocked with MyD88 inhibitor.CONCLUSION:
RP-2 cells provide a novel tool for analyzing the properties and functions of PSCs in the pathogenesis of fibrosis, inflammation and immunity in the pancreas.
17.
Sebode M, Schramm C.
Dig Dis. 2015;33 Suppl 2:83-7. doi: 10.1159/000440752. Epub 2015 Dec 7.
Abstract
BACKGROUND:
Oftentimes we are expected to make difficult decision when patients with autoimmune hepatitis (AIH) present themselves before us. Among these cases, advanced liver cirrhosis, fulminant AIH with hepatic failure or pregnancy with highly active AIH will pose challenges on their own. In patients where standard treatment has failed, the risk of disease progression including liver transplantation has to be weighed against the risk of drug-related side effects, including infectious complications.KEY MESSAGES:
Standard treatment of AIH includes the use of drugs like corticosteroids and usually azathioprine. However, up to 15% of patients will require second-line treatment. There are no prospective studies evaluating second- or third-line treatment regimens in AIH. In our opinion, it is essential to differentiate between those patients who are intolerant and those who do not respond sufficiently to standard treatment. For patients intolerant to prednisolone due to steroid-induced side effects, budesonide may be a feasible alternative, unless liver cirrhosis forbids its use. Our experience indicates that 6-mercaptopurine may be given as an alternative to azathioprine, especially in cases of gastrointestinal side effects, with good tolerance and response rates of up to 70%. As a more expensive alternative, mycophenolat mofetil (MMF) has been shown to effectively suppress disease activity in a majority of patients intolerant to azathioprine. Of note, MMF is contraindicated in pregnancy. In patients with insufficient response to azathioprine, the dose should be increased up to 2.5 mg/kg of body weight, and measurement of azathioprine metabolites (6TGN and MMP) may aid the optimal dosage. Several other immunosuppressive treatment strategies have been tested and published in small case series. These include the calcineurin inhibitors cyclosporine A and tacrolimus, mTOR inhibitors, anti-tumor necrosis factor α treatment with infliximab, rituximab as well as cyclophosphamide.CONCLUSIONS:
It is difficult to tell whether 1 strategy is superior to another in the case of difficult-to-treat AIH patients. Intolerance should be differentiated from insufficient response to standard treatment. The choice of second- and third-line treatment will depend on the comorbidities, patient's choice after informed consent and also local expertise.
19.
Kumagai
K, Tabu K, Sasaki F, Takami Y, Morinaga Y, Mawatari S, Hashimoto S,
Tanoue S, Kanmura S, Tamai T, Moriuchi A, Uto H, Tsubouchi H, Ido A.
PLoS One. 2015 Nov 23;10(11):e0143413. doi: 10.1371/journal.pone.0143413. eCollection 2015.
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