Imatinib Mesylate Improves Liver Regeneration and Attenuates Liver Fibrogenesis in CCL4-Treated Mice

Kuo, Wen-Ling; Yu, Ming–Chin; Lee, Ju-Fang; Tsai, Chia-Lung; Chen, Tse–Ching; Chen, Miin‐Fu

doi:10.1007/s11605-011-1764-7

Cited by 23 publications

(13 citation statements)

References 35 publications

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“…108 Similarly, imatinib, a small molecule tyrosine kinase antagonist used in chronic myeloid leukaemia (CML) and GI stromal tumours, is antifibrotic. 109110 Nilotinib is another novel small molecule tyrosine kinase inhibitor of Bcr-Abl that reduces liver injury and fibrosis through multiple mechanisms. 111 …”

Section: Antifibrotic Therapiesmentioning

confidence: 99%

Pathobiology of liver fibrosis: a translational success story

Lee

Wallace

Friedman

2015

Gut

794

695

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Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.

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Section: Antifibrotic Therapiesmentioning

confidence: 99%

Pathobiology of liver fibrosis: a translational success story

Lee

Wallace

Friedman

2015

Gut

794

695

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“…Sorafenib has been shown to be anti-fibrotic in experimental liver cirrhosis (42). Other examples for drugs targeting the same mechanism include imatinib (43) and nilotinib (44). Downstream intracelluar targets include ROCK, a kinase involved in the shape and movement of the cytoskeleton.…”

Section: Promising Therapeutic Strategies From Other Organs Than the Gutmentioning

confidence: 99%

Intestinal fibrosis

Latella

Rieder

2017

Current Opinion in Gastroenterology

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Purpose of the review Intestinal fibrosis is a common complication of several enteropathies with inflammatory bowel disease being the major cause. Intestinal fibrosis affects both ulcerative colitis and Crohn’s disease, and no specific anti-fibrotic therapy exists. This review highlights recent developments in this area. Recent findings The pathophysiology of intestinal stricture formation includes inflammation dependent and independent mechanisms. A better understanding of the mechanisms of intestinal fibrogenesis and the availability of compounds for other, non intestinal fibrotic diseases bring clincial trials in stricturing Crohn’s disease within reach. Summary Improved understanding of its mechanisms and ongoing development of clincial trial endpoints for intestinal fibrosis will allow the testing of novel anti-fibrotic compounds in inflammatory bowel disease.

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“…PDGF-β overexpression causes liver fibrosis via TGF-β1 independent mechanism. Small molecules imatinib and nilotinib block the tyrosine kinase activity of PDGF receptors (51,52). These molecules also bind to the ATP-binding pocket of Abelson kinase (c-Abl) which is an important downstream signaling molecule of TGF-β signaling thus blocks two major profibrotic pathways.…”

Section: Small Drug Moleculesmentioning

confidence: 99%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

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Imatinib Mesylate Improves Liver Regeneration and Attenuates Liver Fibrogenesis in CCL4-Treated Mice

Abstract: STI-571 treatment effectively attenuated liver fibrogenesis and improved in liver regeneration in vivo and induced apoptosis in HSCs both in vitro and in vivo.

Cited by 23 publications

References 35 publications

Pathobiology of liver fibrosis: a translational success story

Pathobiology of liver fibrosis: a translational success story

Intestinal fibrosis

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

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