Inhibition of mouse hepatocyte apoptosis via anti-Fas ribozyme

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

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Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia

Journal of Clinical Medicine ◽

10.3390/jcm10122718 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2718

Author(s):

Omid Madadi-Sanjani ◽

Gunnar Bohlen ◽

Fabian Wehrmann ◽

Julia Andruszkow ◽

Karim Khelif ◽

...

Keyword(s):

Liver Injury ◽

Biliary Atresia ◽

Caspase 3 ◽

Serum Levels ◽

Healthy Individuals ◽

Serological Detection ◽

Caspase Activation ◽

Hepatocyte Apoptosis ◽

Non Invasive ◽

Cholestatic Diseases

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

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Lack of effect of furfural on unscheduled DNA synthesis in the in vivo rat and mouse hepatocyte DNA repair assays and in precision-cut human liver slices

Food and Chemical Toxicology ◽

10.1016/s0278-6915(01)00050-3 ◽

2001 ◽

Vol 39 (10) ◽

pp. 999-1011 ◽

Cited By ~ 7

Author(s):

B.G Lake ◽

A.J Edwards ◽

R.J Price ◽

B.J Phillips ◽

A.B Renwick ◽

...

Keyword(s):

Dna Repair ◽

Dna Synthesis ◽

Human Liver ◽

Unscheduled Dna Synthesis ◽

Mouse Hepatocyte ◽

Liver Slices ◽

Human Liver Slices

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Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00024.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. G45-G53 ◽

Cited By ~ 35

Author(s):

Bin Hu ◽

Lisa M. Colletti

Keyword(s):

Stem Cell ◽

Liver Injury ◽

Stem Cell Factor ◽

Cellular Proliferation ◽

Hepatocyte Proliferation ◽

Mrna Levels ◽

Wild Type ◽

Hepatocyte Apoptosis ◽

Large Reservoir ◽

A Cell

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.

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