Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia

Barash, Hila; Gross, Eitan; Edrei, Yifat; Pappo, Orit; Spira, Gad; Vlodavsky, Israël; Galun, Eithan; Matot, Idit; Abramovitch, Rinat

doi:10.1002/hep.22394

Cited by 26 publications

(35 citation statements)

References 42 publications

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“…Mdr2 −/− mice offer a model that recapitulates key features of the human disease, including inflammatory environment, genomic instability, and fibrosis (9,23,24,26). Using this model, we explored the interaction between inflammation, regeneration, and HCC and propose a molecular explanation for the enhanced liver tumorigenesis following PHx.…”

Section: Discussionmentioning

confidence: 99%

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Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

Barash

Gross²,

Edrei³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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106

115

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence. hepatocellular carcinoma | MRI | MDR2 -/-mice | genomic instability

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Section: Discussionmentioning

confidence: 99%

“…In previous studies, we followed the development of liver fibrosis and determined the role of inflammation in the development of HCC in these mice (9,(24)(25)(26). In this study, we aimed to assess the impact of regenerative stress during chronic liver inflammation on carcinogenesis.…”

mentioning

confidence: 99%

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

Barash

Gross²,

Edrei³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

115

View full text Add to dashboard Cite

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“…Animals were randomly divided into five groups with six individuals in each group. Four groups of rats were injected with TAA (200 mg/kg i.p., 3% in physiological saline) twice a week for 8 consecutive weeks to induce hepatic fibrosis (Barash et al, 2008). Another group of rats serving as a normal control was treated with normal saline.…”

Section: Methodsmentioning

confidence: 99%

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hao¹,

Zhang²,

Jiang³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5-to 2.5-fold and 2.5-to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.

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“…Increase in liver perfusion was attenuated according to degree of fibrosis in rats. 99 This approach, if validated in patients with liver disease, may offer an additional noninvasive diagnostic tool for evaluation and follow-up of liver diseases.…”

Section: Noninvasive Means To Assess Liver Fibrosis and Fibrogenesismentioning

confidence: 99%

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

2009

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We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (HEPATOLOGY 2009;50:1294-1306

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Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia

Cited by 26 publications

References 42 publications

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

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