Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Bcl-2 family of proteins regulates apoptosis chiefly by controlling mitochondrial membrane permeability. It has previously been shown that the BH4 domain of Bcl-2/Bcl-xL is essential for the prevention of apoptotic mitochondrial changes, including the release of cytochrome c and apoptotic cell death. We have previously reported that BH4 peptide fused to the protein transduction domain of HIV-1 TAT protein (TAT-BH4) significantly inhibits etoposide-induced apoptosis in a cell line. This time, we investigated whether TAT-BH4 peptide was cytoprotective in ex vivo and in vivo rodent models. Intraperitoneal injection of TAT-BH4 peptide greatly inhibited X-ray-induced apoptosis in the small intestine of mice and partially suppressed Fas-induced fulminant hepatitis. In addition, this peptide markedly suppressed heart failure after ischemia-reperfusion injury in isolated rat heart, probably by preventing mitochondrial dysfunction. These findings demonstrate that TAT-BH4 peptide exerts anti-apoptotic activity both in vivo and ex vivo, and imply that it may be a useful therapeutic agent for diseases involving mitochondrial dysfunction and apoptosis.
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PMID:BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo. 1462 84

DNA fragmentation is a key feature of the degradation phase of apoptosis. In this work we have developed an assay, based on radioimager (beta-IMAGER and micro-IMAGER) quantification of radioactive nick end labelling (RANEL), which is quantitative, rapid and sensitive to study in vitro and in vivo induced apoptosis. To establish the technique, in vitro apoptosis of T cell lines was induced by stimulation of the Fas receptor; cells were labelled using TdT-mediated [alpha-33P] dCTP nick end labelling, after which then radioactivity was quantified using a beta-IMAGER. We have also shown that the RANEL method can be applied to the quantification and visualisation, by micro-IMAGER analysis, of liver tissue sections from mouse Fas-induced fulminant hepatitis or from Dengue-1 virus infected individuals. Finally, this system has also been used to detect apoptosis induced by rabies virus in Jurkat T cells. These data have established a large field of application for the RANEL assay.
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PMID:Combined use of radioimagers and radioactive 3'OH DNA nick end labelling to quantify apoptosis in cell lines and tissue sections: applications to virus-induced apoptosis. 1463 79

Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2's importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1 microg/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P<0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-alpha. The enhanced sensitivity to anti-Fas or TNF-alpha stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels.
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PMID:Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. 1468 86

Recently, liver natural killer T (NKT) cells, which are specifically stimulated by alpha-galactosylceramide (alpha-GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell-dependent liver injury induced by alpha-GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on alpha-GalCer-induced hepatitis. Pre-exposure of 12 hours of foot shock stress before alpha-GalCer administration significantly enhanced alpha-GalCer-triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive hepatocytes, thus indicating that the liver NKT cell-dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU-486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress-induced enhancement of the alpha-GalCer-triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a micro-opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not beta-endorphin, as responsible for such stress-induced aggravation in mouse hepatitis models. In conclusion, foot shock stress-induced elevation of endogenous GCs exacerbates alpha-GalCer-initiated hepatic apoptosis through the expansion of liver NKT cells and the up-regulation of hepatocyte Fas antigen.
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PMID:Electric foot shock stress-induced exacerbation of alpha-galactosylceramide-triggered apoptosis in mouse liver. 1505 17

Fas ligand- (FasL) mediated apoptosis is an important element of tissue-specific organ damage. We have developed biologically active small exocyclic peptide mimetics that disable apoptotic functions of Fas. The most effective mimetic binds to both its receptor and FasL with comparable affinity. In vitro, the most effective antagonist blocked FasL-induced cytotoxicity completely and specifically. In vivo, the antagonistic mimetic also prevented Concanavilin A (Con A) induced hepatitis, a CD4(+) T cell-mediated animal model of liver injury. Although current approaches prevent Fas receptor signaling by excluding FasL binding to Fas, the small molecule mimetics reported here disable Fas by promoting a defective Fas-FasL receptor complex. This event desensitizes FasL-mediated apoptosis by inhibiting extracellular signal regulated kinase activity and up-regulating NF-kappaB.
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PMID:Fas-disabling small exocyclic peptide mimetics limit apoptosis by an unexpected mechanism. 1508 39

Bupleuri Radix (Chai-hu in Chinese and Saiko in Japanese) is one of the most important traditional Chinese crude drugs for treating hepatitis malaria and intermittent fever. B. kaoi is one of the Bupleurum spp. families locally found in Taiwan. The effects of saponin-enriched fraction (SEF) from Bupleurum Kaoi in human non-small cell lung cancer A549 cells were investigated in this study. An enhancement in Fas and its two forms of ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), was responsible for the apoptotic effect induced by SEF. Taken together, our study suggests that the activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of SEF in A549 cells.
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PMID:The antiproliferative activity of saponin-enriched fraction from Bupleurum Kaoi is through Fas-dependent apoptotic pathway in human non-small cell lung cancer A549 cells. 1525 50

Fas (CD95)-induced hepatocyte apoptosis and cytotoxic activity of neutrophils infiltrating the injured liver are two major events leading to hepatitis. Because it has been reported that opioids, via a direct interaction, sensitize splenocytes to Fas-mediated apoptosis by upregulating Fas messenger RNA (mRNA) and modulated neutrophil activity, we assumed that opioids may participate in the pathophysiology of hepatitis. Using the hepatitis model induced by agonistic anti-Fas antibody in mice, we showed that opioid receptor blockade reduced liver damage and consequently increased the survival rate of animals when the antagonist naltrexone was injected simultaneously or prior to antibody administration. Treatment of mice with morphine enhanced mortality. Naloxone methiodide-a selective peripheral opioid antagonist-had a protective effect, but the absence of opioid receptors in the liver, together with lack of morphine effect in Fas-induced apoptosis of primary cultured hepatocytes, ruled out a direct effect of opioids on hepatocytes. In addition, the neutralization of opioid activity by naltrexone did not modify Fas mRNA expression in the liver as assessed with real-time quantitative polymerase chain reaction. Injured livers were infiltrated by neutrophils, but granulocyte-depleted mice were not protected against the enhancing apoptotic effect of morphine. In conclusion, opioid receptor blockade improves the resistance of mice to Fas-induced hepatitis via a peripheral mechanism that does not involve a down-modulation of Fas mRNA in hepatocytes nor a decrease in proinflammatory activity of neutrophils.
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PMID:Opioid receptor blockade reduces Fas-induced hepatitis in mice. 1538 66

Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.
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PMID:Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. 1564 37

1. Minocycline has anti-inflammatory and antiapoptotic effects on cartilage, neurons and periodontal tissues, and both properties are central to the pharmaceutical treatment of liver diseases. We investigated the effects of minocycline on fulminant hepatitis in C57BL/6J mice induced by lethal challenge of the activating anti-Fas antibody, Jo2. 2. Intraperitoneal injection of Jo2 (0.6 microg g(-1)) to mice resulted in fulminant hepatitis, as evidenced by increase of serum alanine/aspartate transaminase activities and histopathological alterations in liver sections, as well as animal death. Nevertheless, mice pretreated with three doses of minocycline (5 mg kg(-1)) resisted this lethal effect significantly. Minocycline treatment improved the survival kinetics, although to a lesser extent, when mice were challenged simultaneously with Jo2 or even treated 30 min after the lethal challenge. 3. Jo2-induced activation of caspase-3 or -9 in liver tissues was inhibited by minocycline pretreatment, and yet the direct addition of minocycline to liver extracts from Jo2-challenged mice failed to block caspase activation in vitro. Moreover, minocycline efficiently suppressed the release of cytochrome c from mitochondria of the liver tissues from Jo2-challenged mice. In contrast, caspase-8 activation and Bid truncation triggered by Jo2 were not diminished by minocycline pretreatment in mouse livers. 4. Our results suggest that easing of Fas-triggered fulminant hepatitis by minocycline may involve a mitochondrial apoptotic pathway, probably through preventing cytochrome c release and thereby blocking downstream caspase activation.
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PMID:Effects of minocycline on Fas-mediated fulminant hepatitis in mice. 1566 64

The normalization of plasma alanine aminotransferase (ALT) has been proved to be a strategy for preventing the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infection. Glycyrrhizin, a plant medicine, normalizes plasma ALT and prevents HCC. However, glycyrrhizin is administered intravenously and thereby chemical which is effective on oral administration is required. Coumarin compounds are active components of herbs used for the treatment of various diseases. The ability of coumarin compounds to lower plasma ALT were examined using mice concanavalin A-induced hepatitis and mice anti-Fas antibody-induced hepatitis. Furanocoumarins pd-Ia, pd-II and pd-III lower plasma ALT, but they are large molecules that are hardly absorbed on oral administration. Furocoumarin effectively lowers plasma ALT, but the safety range between the effective and toxic dosages is narrow. In contrast, osthole, a simple coumarin, causes strong reduction of plasma ALT and also inhibits caspase-3 activation. Furthermore, this chemical is quite safe upon large dose administration. In the structure of osthole, the methoxy group at position-7 and the 3-methyl-2-butenyl group at position-8 were elucidated to be essential for the beneficial effect of this chemical. We conclude that osthole will become a leading chemical for synthesizing a compound which prevents HCC on oral administration.
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PMID:Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. 1572 Feb 60


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