N‐methyl‐4‐isoleucine cyclosporine attenuates CCl<sub>4</sub>‐induced liver fibrosis in rats by interacting with cyclophilin B and D

Wang, Hui; Zhang, Yuguo; Wang, Tailing; You, Hong; Jia, Jidong

doi:10.1111/j.1440-1746.2010.06406.x

Cited by 29 publications

(26 citation statements)

References 41 publications

(54 reference statements)

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“…Liver fibrosis was induced in mice by intraperitoneal injection of CCl 4 (40% CCl 4 in olive oil, 0.2 ml/100 g body weight, twice weekly) for 6 weeks as previously reported (21). A total of four groups were studied: Group 1, normal control mice; group 2, CCl 4 alone; group 3, CCl 4 + vatalanib (50 mg/kg/d by gavage for 6 weeks, vatalanib was administered simultaneously with a CCl 4 injection for 6 weeks); and group 4, CCl 4 + vatalanib (50 mg/kg/d by gavage for 4 weeks, CCl 4 alone was administered to mice for 2 weeks, following which vatalanib was administered to mice simultaneously with CCl 4 injection for another 4 weeks).…”

Section: Methodsmentioning

confidence: 99%

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Kong

et al. 2017

Molecular Medicine Reports

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Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α-smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α-SMA, transforming growth factor (TGF)-β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen-1, VEGFR1, and VEGFR2. Levels of α-SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.

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Section: Methodsmentioning

confidence: 99%

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Kong

et al. 2017

Molecular Medicine Reports

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“…Under oxidative stress, glycolysis and gluconeogenesis are inhibited. Isoleucine is a branched-chain amino acid, which is involved in the synthesis of glucose into triglycerides (TCA) in mammals by acetyl-coenzyme A (acetyl CoA) (37). If gluconeogenesis is restrained, it may lead to an increase of isoleucine in hepatic cells (38).…”

Section: Discussionmentioning

confidence: 99%

Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

Gao

Qin

Jiang

et al. 2017

Experimental and Therapeutic Medicine

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Liver fibrosis is caused by liver injury induced by a number of chronic liver diseases, including schistosome infection, hepatitis infection, metabolic disease, alcoholism and cholestasis. The tissue damage occurring after injury or inflammation of the liver is a reversible lesion; however, liver fibrosis has become a worldwide problem and poses a threat to human health. The development of an effective drug for the prevention and treatment of liver fibrosis is ongoing and uses information from different occurrences of liver fibrosis. In the present study, carbon tetrachloride (CCl4)-induced metabonomic changes in serum and urine at 12 weeks were analyzed using gas chromatography-mass spectrometry (GC/MS) to investigate potential biomarkers. Liver fibrosis was induced in rats by subcutaneous injections of CCl4 twice a week for 12 consecutive weeks. Histopathological changes were used to assess the successful production of a CCl4-induced liver fibrosis model. Serum and urine samples from the two groups were collected at 12 weeks. The metabolic profile changes were analyzed by GC/MS alongside principal component analysis and orthogonal projections to latent structures. Metabolic profile studies indicated that the clustering of the two groups could be separated and seven metabolites in serum and five metabolites in urine were identified. In serum, the metabolites identified included isoleucine, L-malic acid, α-copper, carnitine, hippuric acid, glutaric acid and glucose. In urine 2-hydroxy butyric acid, isoleucine, N-acetyl-β-alanine, cytidine and corticoid were identified. The present study demonstrated that the pathogenesis of liver fibrosis may be associated with the dysfunction of a number of metabolic pathways, including glucose, amino acid, P450, fatty acid, nucleic acid, water-electrolyte and glutathione biosynthesis. Assessing potential biomarkers may therefore provide novel targets and theories for the innovation of novel drugs to prevent and cure liver fibrosis.

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“…This effect is accompanied by diminished SMAD2 and 3 phosphorylation (TGFβ signaling pathway) and lower collagen RNA levels [229][230][231][232]. In rodent studies CsA and NIM811 decreased carbon tetrachloride (CCl 4 )-induced liver fibrosis, and NIM811 additionally decreased serum ALT, AST, liver inflammation, TIMP-1 and TGFβ mRNA [233,234]. CRV431 decreased liver fibrosis both in the murine CCl 4 model and in the streptozotocin-plus-HFD (STAM) mouse model of NASH.…”

Section: Cyclophilin Involvement In Fibrosismentioning

confidence: 99%

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

Ure¹,

Trepanier²,

Mayo³

et al. 2019

Expert Opinion on Investigational Drugs

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N‐methyl‐4‐isoleucine cyclosporine attenuates CCl₄‐induced liver fibrosis in rats by interacting with cyclophilin B and D

Abstract: NIM811 attenuates liver fibrosis in a CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.

Cited by 29 publications

References 41 publications

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

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N‐methyl‐4‐isoleucine cyclosporine attenuates CCl4‐induced liver fibrosis in rats by interacting with cyclophilin B and D

Abstract: NIM811 attenuates liver fibrosis in a CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.

Cited by 29 publications

References 41 publications

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

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N‐methyl‐4‐isoleucine cyclosporine attenuates CCl₄‐induced liver fibrosis in rats by interacting with cyclophilin B and D