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

The 77C-->G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C-->G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C-->G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C-->G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.
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PMID:The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis. 1639 78

We synthesized and evaluated a series of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides to identify potent inhibitors of calcium-release-activated calcium (CRAC) channels with greater selectivity than voltage-operated calcium (VOC) channels. These efforts resulted in identification of compounds 22 and 24. The former exhibits highly potent and selective CRAC channel inhibitory activity, and the latter inhibited phytohemagglutinin-induced interleukin-2 production by Jurkat T lymphocytes and concanavalin A-induced hepatitis in mice.
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PMID:Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 1: synthesis and inhibitory activity of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides. 1658 Feb 12

Like other nonsteroidal anti-inflammatory drugs, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide) triggers hepatitis in a few recipients. Although nimesulide has been shown to uncouple mitochondrial respiration and cause hepatocyte necrosis in the absence of albumin, mechanisms for cell death are incompletely understood, and comparisons with human concentrations are difficult because 99% of nimesulide is albumin-bound. We studied the effects of nimesulide, with or without a physiological concentration of albumin, in isolated rat liver mitochondria or microsomes and in human hepatoma cells. Nimesulide did not undergo monoelectronic nitro reduction in microsomes. In mitochondria incubated without albumin, nimesulide (50 microM) decreased the mitochondrial membrane potential (DeltaPsim), increased basal respiration, and potentiated the mitochondrial permeability transition (MPT) triggered by calcium preloading. In HUH-7 cells incubated for 24 h without albumin, nimesulide (1 mM) decreased the DeltaPsim and cell NADPH and increased the glutathione disulfide/reduced glutathione ratio and cell peroxides; nimesulide triggered MPT, ATP depletion, high cell calcium, and caused mostly necrosis, with rare apoptotic cells. Coincubation with either cyclosporin A (an MPT inhibitor) or the combination of fructose-1,6-diphosphate (a glycolysis substrate) and oligomycin (an ATPase inhibitor) prevented the decrease in DeltaPsim, ATP depletion, and cell death. A physiological concentration of albumin abolished the effects of nimesulide on isolated mitochondria or HUH-7 cells. In conclusion, the weak acid, nimesulide, uncouples mitochondria and triggers MPT and ATP depletion in isolated mitochondria or hepatoma cells incubated without albumin. However, in the presence of albumin, only a fraction of the drug enters cells or organelles, and uncoupling and toxicity are not observed.
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PMID:The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. 1661 66

Acute pancreatitis develops immediately after the causative impulse, while chronic pancreatitis develops after the long-term action of the noxious agent. A typical representative of acute pancreatitis is biliary pancreatitis, chronic pancreatitis develops in alcoholism and has a long latency. As alcoholic pancreatitis is manifested at first as a rule by a potent attack, it is classified in this stage as acute pancreatitis. The most frequent etiological factors in our civilization are thus cholelithiasis and alcoholism (both account for 20-50% in different studies). The assumed pathogenetic principles in acute biliary pancreatitis are the common canal of both efferent ducts above the obturated papilla, duodenopancreatic reflux and intrapancreatic hypertension. A detailed interpretation is however lacking. The pathogenesis of alcoholic pancreatitis is more complicated. Among others some part is played by changes in the calcium concentration and fusion of cellular membranes. Idiopathic pancreatitis occurs in up to 10%, part of the are due to undiagnosed alcoholism and cholelithiasis. Other etiologies are exceptional. Similarly as in cholelithiasis pancreatitis develops also during other pathological processes in the area of the papilla of Vater such as dysfunction of the sphincter of Oddi, ampulloma and juxtapapillary diverticulum, it is however usually mild. The incidence of postoperative pancreatitis is declining. Its lethality is 30% and the diagnosis is difficult. In the pathogenesis changes of the ion concentration are involved, hypoxia and mechanical disorders of the integrity of the gland. Pancreatitis develops in association with other infections--frequently in mumps, rarely in hepatitis, tuberculosis, typhoid and mycoses. Viral pancreatitis is usually mild. In parasitoses pancreatitis develops due to a block of the papilla Vateri. In hyperparathyroidism chronic pancreatitis is more likely to develop, recent data are lacking. As to dyslipoproteinaemias, pancreatitis develops in the Ist, IVth and Vth type of Frederikson's classification, in rare recessive disorders and other conditions such as hypothyroidism, renal insufficiency, oestrogen substitution and others. In pancreas divisum chronic pancreatitis is more likely to develop. In exotic countries tropical pancreatitis is most frequent. It is however similarly as alcoholic pancreatitis primarily chronic. A very serious course is usual in traumatic pancreatitis. Risk factors of pancreatitis after ERCP are in particular undilated biliary pathways, dysfunction of the sphincter of Oddi and the use of a needle knife (bistoury). Medicamentous prevention is not substantiated. Drug induced pancreatic damage is much rarer than hepatotoxicity. Pancreatitis is caused most frequently by immunosuppressives, methyldopa, corticoids and oestrogens. The question remains to what extent the course of pancreatitis is influenced by its etiology. Biliary, alcoholic, traumatic and postoperative pancreatitis is usually severe, pancreatitis associated with viroses and induced by drugs is usually mild.
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PMID:[Etiological factors of acute pancreatitis]. 1673 20

Parameters of hepatic free radical oxidation and catalytic properties of NADP-isocitrate dehydrogenase (EC 1.1.1.42; NADP-IDH) have been investigated in normal rats and under conditions of toxic hepatitis. Development of hepatitis was accompanied by the increase of conjugated dienes, malondialdehyde and some chemiluminescence parameters. Toxic hepatitis was also accompanied by the increase of liver NADP-IDH. Homogenous preparations of liver NADP-IDH from normal and toxic rats exhibited different sensitivity to effectors studied (Fe2+, Ca2+, H2O2, reduced glutatione).
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PMID:[The intensity of free radical oxidation and catalytic properties of the rat liver NADP-isocitrate dehydrogenase in the norm and in toxic hepatitis]. 1680 86

Rat liver oxidative stress caused by toxic hepatitis is accompanied by increased activity of glucose-6-phospate dehydrogenase (EC 1.1.1.4.9; G6PDG). Electrophoretically homogenous G6PDG preparations purified from livers control rats and animals with hepatitis had specific activity of 4.13 and 6.54 EU, respectively. Fe2+ and Cu2+ ions showed non-competetive type inhibition of G6PDG at normal and under pathological condition, whereas Ca2+ activated G6PDG. Hydrogen peroxide exhibited mixed type inhibition of G6PD (K(i) 0.36 mM and 0.95 mM at norm and experimental toxic hepatitis, respectively). The participation of oxidised and reduced glutathione in G6PDG activity regulation has been shown.
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PMID:[Regulatory properties of glucose-6-phosphate dehydrogenase from rat liver under conditions of the intensification of free-radical oxidation stimulated by toxic hepatitis]. 1689 86

1. The aim of the present study was to assess the protective effect of Sargassum polycystum (sulphated polysaccharide) extract against paracetamol-induced DNA strand breaks and modulation of membrane-bound phosphatases, protein thiols and inorganic cations during toxic hepatitis. 2. Seaweed extract (200 mg/kg per day for 21 days) was administered to male Wistar rats against paracetamol challenge. Serum and liver tissues were used to assess levels of ATPase, protein thiols and inorganic cations using atomic absorption spectroscopy. The fragmentation of DNA was assessed by agarose gel electrophoresis. 3. Paracetamol induced intracellular stress, accompanied by changes in the structural and functional characteristics of liver cell membranes, which affected DNA integrity, membrane-bound ATPase and inorganic cations homeostasis. Rats intoxicated with paracetamol (800 mg/kg, i.p.) showed significant impairment in activities of total ATPase, Mg2+-ATPase, Ca+-ATPase and Na+/K+-ATPase, with concomitant changes in the levels of tissue protein thiols and inorganic cations, such as Na+, K+ and Ca2+. These changes were prevented in animals pretreated with S. polycystum extract, which indicates that S. polycystum supplementation could exert some protective effect against paracetamol-induced toxic hepatitis in rats. 4. The protective effect of the seaweed extract may be due to the presence of sulphated compounds that have free radical-scavenging activity.
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PMID:Efficacy of Sargassum polycystum (Phaeophyceae) sulphated polysaccharide against paracetamol-induced DNA fragmentation and modulation of membrane-bound phosphatases during toxic hepatitis. 1725 Jun 30

Aims of treatment for primary sclerosing cholangitis are as follows: prevention of progression of hepatobiliary disease, reduction of symptoms and consequences of cholestasis (pruritus, osteoporosis), and prevention of complications (colorectal cancer, hepatobiliary cancer). Ursodeoxycholic acid (UDCA) improves biliary secretion and laboratory parameters of cholestasis, but its effects on liver histology and survival are not clear. It reduces the incidence of dysplasias and carcinomas of the colon in patients with colitis and possibly has a beneficial effect on the incidence of bile duct carcinomas. At present, UDCA represents the most promising therapeutic option. Immunosuppressive treatment has not been proven to be effective; it appears to be indicated in the overlap syndrome with autoimmune hepatitis but may be harmful in bacterial cholangitis. Bacterial cholangitis is common in patients with dominant stenoses and requires antibiotic treatment. Endoscopic treatment of dominant stenoses improves cholestasis and prolongs survival in comparison to predicted survival. Pruritus represents a problem in some patients, and cholestyramine represents the first-line treatment. If ineffective, opioid antagonists, rifampin, or ondansetron may be tried. For treatment of osteoporosis and osteopenia, calcium and vitamin D supplementation are recommended, and in selected cases, bisphosphonates may be indicated. In patients with severe cholestasis and coagulation defects, parenteral supplementation of vitamin K may be indicated. During treatment, all patients should be regularly screened for colonic and bile duct carcinomas. Patients with cirrhosis of the liver and its complications are treated accordingly, and in end-stage disease, liver transplantation is indicated.
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PMID:Treatment of primary sclerosing cholangitis. 1739 26

The two ribozymes of hepatitis delta virus (HDV) cleave faster in divalent metal ions than in monovalent cations, and a variety of divalent metal ions can act as catalysts in supporting these higher rates. Although the ribozymes are closely related in sequence and structure, they display a different metal ion preference; the genomic form cleaves moderately faster in Mg2+ than in Ca2+ while the reverse is true for the antigenomic ribozyme. This difference raises questions about understanding the catalytic role of the metal ion in the reaction. We found that the metal ion reactivity preference correlated with the identity of a single nucleotide 5' of the cleavage site (-1 position). It is a U in the genomic sequence and a C in the antigenomic sequence. With both ribozymes, the reactivity preference for Mg2+ and Ca2+ could be reversed with a change at this position (C to U or U to C). Moreover, with an A at position -1, there was a relative increase in cleavage rates in low concentrations of Mn2+ for both ribozymes. Metal ion reactivity preference was also linked to changes in pH, and the pH-rate profiles could be shifted with nucleotide changes at position -1. Together, the data provide biochemical evidence in support of an organized active site, as seen in the crystal structures, where at least one metal ion, an ionizable group, and the conformation of the phosphate backbone at the cleavage site interact in concert to promote cleavage.
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PMID:A single nucleotide linked to a switch in metal ion reactivity preference in the HDV ribozymes. 1741 76

The endoplasmic reticulum (ER) is a dominant metabolic compartment in the maintenance of intracellular homeostasis and plays a decisive role in adaptation to changes of the extra- and intracellular environment. Various stressors (e.g. disturbances of intracellular calcium balance, hypoglycaemia, hypoxia, altered redox homeostasis, virus infection) affect the protein folding in the ER lumen, resulting in an accumulation of unfolded proteins. They cause the activation of ER specific signaling pathways called unfolded protein response (UPR). Activated UPR pathways have been demonstrated in various diseases the etiology of which is totally different (diabetes, neurodegenerative diseases, hepatitis etc), therefore, UPR represents a common pathomechanism. Understanding of ER stress related events can open new perspectives to improve the current therapy.
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PMID:[Endoplasmic reticulum stress--common pathomechanism of different diseases?]. 1787 32


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