24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis

Sombetzki, Martina; Fuchs, Claudia D.; Fickert, Peter; Österreicher, Christoph H.; Mueller, Maja; Claudel, Thierry; Loebermann, Micha; Engelmann, Robby; Langner, Cord; Sahin, Emine; Schwinge, Dorothee; Guenther, Nina; Schramm, Christoph; Mueller-Hilke, Brigitte; Reisinger, Emil C.; Trauner, Michael

doi:10.1016/j.jhep.2014.11.020

Cited by 55 publications

(37 citation statements)

References 35 publications

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“…Because immune cell-derived chemokines play a vital role in schistosome-induced pathology[25,26], one method to hamper disease progression could be by modulating chemokine production to limit hepatic eosinophil recruitment[27]. Importantly, although praziquantel therapy effectively kills adult Schistosoma , it has diminutive effects on liver fibrogenesis or portal hypertension[28,29]; thus, new strategies to treat schistosomiasis are urgently needed.…”

Section: Etiology and Pathological Characteristics Of Hepatic Fibrosismentioning

confidence: 99%

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Zhang¹,

Yuan²,

He³

et al. 2016

WJG

449

327

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Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

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Section: Etiology and Pathological Characteristics Of Hepatic Fibrosismentioning

confidence: 99%

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Zhang¹,

Yuan²,

He³

et al. 2016

WJG

449

327

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“…Nor-UDCA has, in addition to its potent choleretic and cholangiocyte healing actions, 109 notable antifibrotic actions in mouse models of liver disease, 110 whilst FXR agonists also seem to be potently antifibrotic. 111 However, the apparent functional absence of FXR in human (as opposed to mouse) myofibroblasts argues against this mechanism of action in humans.…”

Section: Targeting Fibrosismentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

113

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Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

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“…commun., Vienna, January 2012], indicating that targeting fibrosis may be of key importance. Notably, a recent study demonstrated more general antifibrotic and immunomodulatory actions of nor UDCA (but again not UDCA) on granuloma size and hepatic fibrosis in a mouse model of Schistosoma mansoni infection, a leading cause of hepatic fibrosis and portal hypertension [22]. The anti-inflammatory properties of nor UDCA were directed to MHC class II protein expression on dendritic cells and macrophages and nor UDCA reduced T-lymphocyte proliferation and serum levels of profibrogenic Th2 cytokines IL-13 and IL-4 [22].…”

Section: Nor Udca For Cholestatic Liver Diseasesmentioning

confidence: 99%

“…Notably, a recent study demonstrated more general antifibrotic and immunomodulatory actions of nor UDCA (but again not UDCA) on granuloma size and hepatic fibrosis in a mouse model of Schistosoma mansoni infection, a leading cause of hepatic fibrosis and portal hypertension [22]. The anti-inflammatory properties of nor UDCA were directed to MHC class II protein expression on dendritic cells and macrophages and nor UDCA reduced T-lymphocyte proliferation and serum levels of profibrogenic Th2 cytokines IL-13 and IL-4 [22]. Apart from the relevance of these findings for the treatment of hepatic schistosomiasis as one of the worldwide leading causes of portal hypertension, such properties may also contribute to anti-inflammatory and antifibrotic effects of nor UDCA in other noncholestatic and cholestatic conditions.…”

Section: Nor Udca For Cholestatic Liver Diseasesmentioning

confidence: 99%

Potential of <b><i>nor</i></b>-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders

Trauner

Halilbasic²,

Claudel³

et al. 2015

Dig Dis

Self Cite

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24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling ‘ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on ‘Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders.

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24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis

Abstract: Graphical abstract

Cited by 55 publications

References 35 publications

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Novel therapeutic targets in primary biliary cirrhosis

Potential of <b><i>nor</i></b>-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders

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