Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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1. The acid-base state of arterial blood and cerebrospinal fluid, and the ventilatory response to CO2, were measured in twelve patients with liver disease. The CO2 response was also measured in eight goats before and after the experimental production of liver failure. Arterial PCO2 and pH, cerebral blood flow and the cerebral metabolic rate for oxygen were also measured in four of the goats while they breathed air and various CO2-enriched gas mixtures. 2. Liver failure was accompanied by a respiratory alkalosis in both the patients and in the goats. Decreased PCO2 and increased pH occurred in the cerebrospinal fluid and in the arterial blood of the patients. 3. The slope of the ventilatory response to CO2 was reduced when liver failure was severe, in patients and goats alike. In addition there was a reduction in the extrapolated PCO2 at zero ventilation, even when liver failure was mild. 4. Cerebral blood flow and metabolic rate were consistently reduced in the goats during liver failure. There was also less cerebral vasodilatation and a greater reduction in cerebral metabolism during experimental hypercapnia when these animals were in liver failure. 5. The decreases in the ventilatory and cerebral circulatory responsiveness to CO2 indicate that the brain is less well defended against hypercapnia in liver failure, and these changes are especially unfavourable as cerebral function deteriorates when the PCO2 is increased.
Clin Sci Mol Med 1975 Aug
PMID:Effect of liver failure on the response of ventilation and cerebral criculation to carbon dioxide in man and in the goat. 23 83

1. The properties of ferritin in serum have been compared with those of ferritin from a number of tissues including blood cells. On anion-exchange chromatography with DEAE-Sephadex, the behaviour of human heart ferritin is different from that of liver, kidney or spleen ferritin. Reticulocyte ferritin appears to have similar characteristics to heart ferritin. 2. Serum ferritin from normal subjects and patients with various degrees of iron load, leukaemia or liver disease all have a much lower affinity for the anion-exchange column that any tissue ferritin, suggesting a difference in isoelectric point. The elution point of serum ferritin from patients with acute myeloblastic leukaemia is significantly different from normal. 3. Density gradient centrifugation in sucrose showed that ferritin in leucocyte extracts and partially purified ferritin from the serum of two patients with iron overload behaved as apoferritin rather than the iron-rich protein. 4. The results suggest that ferritin is modified during its entry into the plasma and that even in cases of iron overload the iron content of serum ferritin may be low. The findings are of importance in considering the origin of plasma ferritin, the clearance of ferritin from plasma and its role in iron metabolism.
Clin Sci Mol Med 1975 May
PMID:The characteristics of ferritin from human tissues, serum and blood cells. 116 59

1. Hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content was measured in thirty-five patients with liver disease and in ten control subjects with duodenal ulcer. The patients with liver disease were divided into three groups consisting of non-drinkers, moderate drinkers and alcoholic/heavy drinkers. 2. There was no significant difference in hepatic alcohol dehydrogenase activity between the groups with liver disease, but all patients had less than half the hepatic alcohol dehydrogenase activity of the control subjects (P less than 0-001). 3. The ascorbic acid in leucocytes was significantly lower in the alcoholic/heavy drinker group than that in the control subjects (P less than 0-02) when the Student's t-test was applied, but no significant difference was found when the Mann-Whitney U-test was used. 4. A correlation coefficient of r = 0-77 (P less than 0-001) was observed among the thirty-five patients with liver disease when hepatic alcohol dehydrogenase activity was compared with leucocyte ascorbic acid content. An insignificant correlation (r = 0-332) was found in the control subjects with no liver disease. 5. This comparison was also significant among non-drinkers with liver disease (r = 0-873; P less than 0-001), moderate drinkers (r = 0-739; P less than 0-02) and alcoholic/heavy drinkers (r = 0-702; P less than 0-005). 6. The addition of ascorbic acid in vitro (0-5-10 mmol/1) had no effect on the activity of alcohol dehydrogenase. 7. The relation between hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content is probably a consequence of liver disease, as opposed to any specific effect of ascorbic acid deficiency of alcohol consumption on alcohol dehydrogenase activity.
Clin Sci Mol Med 1975 Dec
PMID:Relation between hepatic alcohol dehydrogenase activity and the ascorbic acid in leucocytes of patients with liver disease. 120 90

The nuclear lamina of mammalian cells consists of three major proteins, lamins A, B and C, which form a fibrous meshwork interposed between the inner nuclear membrane and the chromatin. Sera from certain patients with systemic lupus erythematosus (SLE) and autoimmune liver disease contain high titers of autoantibodies against lamin B. We have shown previously that anti-lamin B autoantibodies in SLE recognize epitopes highly specific for lamin B, even though lamin B and lamins A/C are highly homologous proteins. To further characterize the specificities of these autoantibodies, fusion proteins carrying fragments of lamins B and C were tested for reactivity with SLE sera by immunoblotting. Five distinct epitopes of lamin B were identified, at least four of which were located in the highly conserved coiled-coil rod domain. Epitopes located on amino acids (AA) 80-193 and 245-303 were recognized by 4/10 and 8/10 anti-lamin B positive sera, respectively. Affinity purified anti-lamin B autoantibodies reacted preferentially with lamin B, indicating that they recognized mainly portions of lamin B that differ from lamins A and C. On the contrary, most of the affinity-purified anti-lamin C autoantibodies from SLE sera cross-reacted with lamin B, suggesting that the anti-nuclear lamina immune response in these patients is directed primarily against lamin B. The preferential reactivity of these sera with multiple epitopes specific to lamin B, and the finding that the autoantibodies to lamins A and C present in some of these sera cross-react with lamin B suggest that autoantibodies to lamin B are generated in response to the authentic lamin B protein rather than a cross-reactive foreign protein.
Mol Immunol 1992 Sep
PMID:Recognition of multiple epitopes in the coiled-coil domain of lamin B by human autoantibodies. 137 77

Different liver diseases are associated with modifications in hepatocyte cytoskeletal organization and formation of Mallory bodies (MBs). Since the structure of a protein is critical for its function, we studied the changes in the molecular structure of the cytoskeletal protein in the liver from mice fed griseofulvin (GF), which is a good animal model for studying liver disease. Using pressure-tuning infrared spectroscopy we compared the infrared spectra of the cytoskeletal proteins from control liver and griseofulvin treated liver. The results show that the overall structure of the cytoskeletal protein was modified by the griseofulvin treatment. A relative increase in the amount of alpha-helices to beta-sheets was observed in the liver cytoskeleton from the GF-treated mice. Moreover, the random coil and the turn segments were dramatically decreased compared to controls. Pressure-induced modifications including denaturation were irreversible in the control samples whereas they were reversible in the griseofulvin-treated samples. These changes reflect important fundamental modifications in the molecular structure of the cytoskeletal proteins in the griseofulvin-treated hepatocytes. We suggest that these changes are related to the modification of the organization of intermediate filaments and the formation of MBs that occur in the GF-treated liver.
Exp Mol Pathol 1991 Oct
PMID:Alteration in molecular structure of cytoskeleton proteins in griseofulvin-treated mouse liver: a pressure tuning infrared spectroscopy study. 193 12

Cytochrome P450IIE1 (IIE1) is a microsomal xenobiotic-activating enzyme that is inducible not only by various chemical agents but also by fasting and diabetes. Using a rat model that mimics human obesity, we have found that hepatic IIE1 levels are also increased by this common clinical disorder. Liver microsomes from rats made obese by feeding with an energy-dense diet displayed elevated aggregate P450 content (+28%) and enhanced catalytic activities associated with IIE1, including low-Km N-nitrosodimethylamine demethylation (+66%), aniline hydroxylation (+52%), p-nitrophenol hydroxylation (+170%), and acetaminophen-cysteine conjugate formation (+28%). In contrast, obesity had no significant effect on cytochrome b5 content, P450 reductase activity, benzphetamine demethylation, or erythromycin demethylation, with the latter two reactions being linked with rat IIC11 and IIIA1, respectively. The enhancement of IIE1-dependent drug-metabolizing activities noted in liver microsomes from obese rats was paralleled by a similar increase (111%) in hepatic IIE1 protein content in these animals, as assessed on immunoblots developed with anti-hamster IIE1 IgG. Anti-IIE1-inhibitable rates of microsomal p-nitrophenol metabolism, a reaction highly correlated with IIE1 content (r = 0.88, p less than 0.01), were over 3-fold higher in obese rats than in nonobese controls, providing additional evidence for the obesity-related increase of hepatic IIE1. The induction of IIE1 by the pathophysiological condition of obesity may provide a biochemical basis for the increased incidence of occult liver disease and certain cancers noted in obese individuals.
Mol Pharmacol 1991 Mar
PMID:Induction of cytochrome P450IIE1 in the obese overfed rat. 200 76

Homozygosity for alpha 1-antitrypsin deficiency, usually of the genotype PIZZ, is one of the more common single gene defects in infants of European origin, occurring in about 1 in 2000 to 1 in 7000 of the newborn population. About 17% of such infants present with neonatal hepatitis and a small number with intracranial haemorrhage thought to be caused by vitamin K deficiency associated with cholestasis. At least 3% of PIZZ infants will die of cirrhosis in later childhood unless successfully treated by liver transplant. The pathogenesis of the liver disease is not understood and this is unsatisfactory both for treatment and for genetic counselling. The locus coding for alpha 1-antitrypsin (alpha 1AT) is designated PI for proteinase inhibitor. Careful study of the genotypes at this locus in neonatal disease shows that the only certain association is with the homozygous PIZZ genotype. The mutation results in a normal rate of synthesis of a polypeptide that becomes entrapped in the endoplasmic reticulum of the hepatocyte. Some other factor (or factors), as yet unidentified, determines whether severe liver damage results. The low level of alpha 1AT in the plasma seems unlikely to be the primary cause of damage but may play a secondary role. There is some evidence that the other factor(s) may be familial since in one study, though not in all, a high correlation for severity of liver disease was found between PIZZ siblings. The heterogeneity of the clinical course does not result from heterogeneity of PIZ alleles and there is no evidence that it is determined by variation in other related genes on chromosome 14. Only two possible clues have emerged so far. There is some evidence of a protective effect of breast-feeding, and a recent study has found the HLA class II DR3 antigen to be more common than expected in children with alpha 1-antitrypsin deficiency and liver disease. Accumulation of alpha 1AT protein in the hepatocytes may predispose them to some unidentified alteration of the immune response. It is possible that lack of antiprotease activity in the plasma might exacerbate the original damage, so the possibility of useful therapy with alpha 1AT cannot be ruled out entirely. At present, there is no valid way of predicting the severity of disease in a PIZZ child; hence, it is common for parents of a severely affected child to wish to terminate any future PIZZ pregnancy. The most direct method to diagnose the PIZZ genotype of a chorion villus sample is by allele-specific hybridization or sequencing of amplified DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Biol Med 1990 Apr
PMID:Genetics of alpha 1-antitrypsin deficiency in relation to neonatal liver disease. 218 61

Biochemical considerations suggest that bioflavonoids may be effective antihepatotoxic and hepatoprotective agents. We, therefore, designed a morphometric study to examine the effect of (+)-cyanidanol-3 on ethanol-induced hepatocellular alterations. Using a stereologic point and intersection counting method we determined the volume fraction of cytoplasmic components, the surface area of cytoplasmic membranes, some parameters of mitochondria, and numerical densities of some organelles, after chronic ethanol intoxication and hepato-protective treatment of rats. Consistent with previous qualitative and quantitative descriptions, chronic ethanol feeding caused increases in parameters of mitochondria, microsome, and Golgi complex. The hepatoprotective (+)-cyanidanol-3 treatment restored most of the morphologic distortion caused by ethanol ingestion. The (+)-cyanidanol-3 treatment alone caused an elevation of the surface area of smooth endoplasmic reticulum and nonsignificant changes in mitochondrial parameters, possibly due to its inducing effect on microsomes and activating effect on mitochondrial enzymes. These data indicate that bioflavonoids could be of potential benefit in hepatotoxic or alcohol-related liver disease.
Exp Mol Pathol 1990 Apr
PMID:Quantitative ultrastructural analysis of hepatoprotective effects of (+)-cyanidanol-3 on alcoholic liver damage. 233 41

We have developed a transgenic mouse strain, Z#2, which represents a model for alpha 1-protease inhibitor (alpha 1-antitrypsin: alpha 1-Pi)-associated liver disease (Dycaico et al., 1988). Fifteen percent of human infants with alpha 1-Pi disease develop non-viral hepatitis which is sometimes associated with growth retardation. Such hepatitis and growth retardation tend to occur in a subset of families with other alpha 1-Pi affected members who have had non-viral hepatitis. The Z#2 mouse strain exhibits non-viral hepatitis and growth retardation. This phenotype is more pronounced in transgenic offspring of crosses between Z#2 mice and DBA/2J inbred mice, and less pronounced in transgenic offspring of crosses between Z#2 and CBA/J inbred mice. Such phenotypic differences resemble the phenotypic differences seen in human families with alpha 1-Pi-associated liver disease.
Mol Biol Med 1989 Apr
PMID:Neonatal growth delay in alpha-1-antitrypsin disease. Influence of genetic background. 261 43

Homozygous inheritance of the Z mutation (exon V, Glu342GAG----Lys342AAG), the most common cause of alpha-1-antitrypsin (alpha 1AT) deficiency, is associated with a high risk for emphysema and liver disease. This study presents a rapid and accurate approach to definitive genotypic diagnosis of the Z homozygous state using a combination of polymerase chain reaction amplification of exon V of the alpha 1AT gene and ribonuclease cleavage of an exon V-specific antisense RNA probe. Taking advantage of the concept that ribonuclease A will cleave at points of mismatch of RNA-DNA hybrids, a 0.79 kb antisense RNA probe was designed with complementarity to the sense strand of exon V of the alpha 1AT gene (the site of the Z mutation) along with small regions of the 5' and 3' flanking sequences. After amplification of exon V of the alpha 1AT gene from genomic DNA by the polymerase chain reaction, the amplified DNA was analyzed by hybridization to a 32P-labeled exon V antisense RNA probe followed by digestion with RNase A. Any substitution mutations resulting in DNA-RNA mismatch were detected by evaluation with polyacrylamide gel electrophoresis under denaturing conditions followed by autoradiography (expected fragment lengths: 0.33 kb when the exon V probe hybridized to the normal amplified genomic DNA, 0.25 and 0.08 kb fragments when the exon V probe hybridized to the amplified genomic DNA with the Z mutation). Double-blinded evaluation of genomic DNA of 36 individuals (phenotypes MM n = 14, MZ n = 5, ZZ n = 16, ZNull n = 1; included among the "M" alleles were representatives of all the major normal M alleles) demonstrated definitive diagnosis of the Z mutation with absolute specificity for all 36 specimens, i.e., ZZ homozygotes, MZ heterozygotes, and normals were all detected accurately. This approach should be useful not only for screening for the Z mutation of the alpha 1AT gene, but by this type of analysis, mutational alterations of the alpha 1AT gene can be screened for without prior knowledge of the sequence changes and without complex cloning and sequencing methods.
Am J Respir Cell Mol Biol 1989 Oct
PMID:Ribonuclease A cleavage combined with the polymerase chain reaction for detection of the Z mutation of the alpha-1-antitrypsin gene. 262 66


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