Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0023890 (cirrhosis)
42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These present studies have identified some important differences between male and female subjects in ethanol pharmacokinetics. The development of alcohol misuse in female subjects clearly altered the rate of ethanol elimination as well as increasing the circulating levels of blood acetaldehyde. The identification of an increased level of acetaldehyde in subjects homogenous for ADH(3)(2) genotype, may in part contribute to the higher incidence of alcohol-related damage, i.e. liver cirrhosis, associated with this ADH(3) genotype. The enhanced presystemic alcohol metabolism identified in female Caucasian controls, but not female alcohol misusers, may be an important factor in removing a significant quantity of ethanol during its first pass through the liver and thereby reduce circulating acetaldehyde concentrations.
...
PMID:Women and alcohol susceptibility: could differences in alcohol metabolism predispose women to alcohol-related diseases? 1462 74

Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABAA receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-d-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor beta subunit mRNA expression, and GABB2 and DRD2B genotypes with beta subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence.
...
PMID:Genes and gene expression in the brain of the alcoholic. 1534 66

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance. This fact, as well as the discovery of the proliferation of the smooth endoplasmic reticulum (SER) after chronic alcohol consumption, suggested the existence of an additional pathway which was then described by Lieber and DeCarli, namely the microsomal ethanol oxidizing system (MEOS), involving cytochrome P450. The existence of this system was initially challenged but the effect of ethanol on liver microsomes was confirmed by Remmer and his group. After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1, most conclusively shown in alcohol dehydrogenase negative deer mice. There is also cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, the conversion of hepatotoxic agents to toxic metabolites increases, which explains the enhanced susceptibility of alcoholics to the adverse effects of various xenobiotics, including industrial solvents. CYP2E1 also activates some commonly used drugs (such as acetaminophen) to their toxic metabolites, and promotes carcinogenesis. In addition, catabolism of retinol is accelerated resulting in its depletion. Contrasting with the stimulating effects of chronic consumption, acute ethanol intake inhibits the metabolism of other drugs. Moreover, metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione (GSH) and other defense systems against oxidative stress which plays a major pathogenic role in alcoholic liver disease. CYP1A2 and CYP3A4, two other perivenular P450s, also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. CYP2E1 has also a physiologic role which comprises gluconeogenesis from ketones, oxidation of fatty acids, and detoxification of xenobiotics other than ethanol. Excess of these physiological substrates (such as seen in obesity and diabetes) also leads to CYP2E1 induction and nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), with pathological lesions similar to those observed in alcoholic steatohepatitis. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP2E1 up-regulation was also demonstrated in obese patients as well as in rat models of obesity and NASH. Furthermore, NASH is increasingly recognized as a precursor to more severe liver disease, sometimes evolving into "cryptogenic" cirrhosis. The prevalence of NAFLD averages 20% and that of NASH 2% to 3% in the general population, making these conditions the most common liver diseases in the United States. Considering the pathogenic role that up-regulation of CYP2E1 also plays in alcoholic liver disease (vide supra), it is apparent that a major therapeutic challenge is now to find a way to control this toxic process. CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds are too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated phosphatidylcholines extracted from soybeans (and its active component dilinoleoylphosphatidylcholine), were discovered to decrease CYP2E1 activity. PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically.
...
PMID:The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. 1555 33

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.
...
PMID:Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. 1567 Jun 60

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.
...
PMID:Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease. 1569 22

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.
...
PMID:Alcohol and liver cancer. 1605 81

An 85-year-old woman with Parkinson's disease was admitted to our hospital to conduct a further work-up for progressive gait disturbance. She had been on medications for the disease for more than a decade prior to admission. In order to improve her condition, she was newly administered pramipexole, a dopamine agonist, from day 3 in addition to the preceding anti-Parkinson's therapy. However, on day 10, her consciousness level was rapidly deteriorated into delirium(JCS II-10), which was not accompanied by neurological signs and symptoms. Laboratory tests showed severe hyponatoremia with relatively increased urinary sodium excretion, and severe low serum osmolarity with an increased urinary osmolarity. Brain CT and brain MRI showed no specific abnormalities except for those related to aging. Blood concentration of ADH measured at the onset was substantially higher(39.5 pg/ml) than normal (0.3-3.5 pg/ml under normal osmolarity). Diseases causing hyponatremia, such as liver cirrhosis, congestive heart failure, hypotonic dehydration, and malignancy-associated inappropriate ADH secretion (SIADH), were all excluded. Under the suspicion of SIADH due to pramipexole, the drug was discontinued and as a result, her consciousness level improved rapidly together with a prompt reduction in ADH level (9.2 pg/ml). To the best of our knowledge, the present case is the first that demonstrates pramipexole-induced SIADH. Since pramipexole is classified as a dopaminergic receptor agonist, this case may provide new insight into a link between ADH and the dopaminergic receptor in the central nervous system.
...
PMID:[Syndrome of inappropriate ADH secretion (SIADH) induced by pramipexole in a patient with Parkinson's disease]. 1613 Apr 8

Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in a total of 818 patients with alcohol-associated esophageal (n=123), head and neck (n=84) and hepatocellular cancer (n=86) as well as in patients with alcoholic pancreatitis (n=117), alcoholic liver cirrhosis (n=217), combined liver cirrhosis and pancreatitis (n=17) and in alcoholics without gastrointestinal organ damage (n=174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p<0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (CI, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.
...
PMID:Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers. 1628 84

Alcohol abuse reduces response rates to IFN therapy in patients with chronic hepatitis C. To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes. High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines. Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway. In contrast, when combined with exogenously applied IFN-alpha, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation. These effects of alcohol occurred independently of i) alcohol metabolism via ADH and CYP2E1, and ii) cytotoxic or cytostatic effects of ethanol. In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication. Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink 12.Recombinant interferon alpha (IFN-alpha) therapy produces sustained responses (ie clearance of viremia) in 8-12% of patients with chronic hepatitis C 3. Significant improvements in response rates can be achieved with IFN plus ribavirin combination 456 and pegylated IFN plus ribavirin 78 therapies. However, over 50% of chronically infected patients still do not clear viremia. Moreover, HCV-infected patients who abuse alcohol have extremely low response rates to IFN therapy 9, but the mechanisms involved have not been clarified.MAPKs play essential roles in regulation of differentiation, cell growth, and responses to cytokines, chemokines and stress. The core element in MAPK signaling consists of a module of 3 kinases, named MKKK, MKK, and MAPK, which sequentially phosphorylate each other 10. Currently, four MAPK modules have been characterized in mammalian cells: Extracellular Regulated Kinases (ERK1 and 2), Stress activated/c-Jun N terminal kinase (SAPK/JNK), p38 MAP kinases, and ERK5 11. Interestingly, ethanol modulates MAPKs 12. However, information on how ethanol affects MAPKs in the context of innate antiviral pathways such as the Jak-Stat pathway in human cells is extremely limited. When IFN-alpha binds its receptor, two receptor associated tyrosine kinases, Tyk2 and Jak1 become activated by phosphorylation, and phosphorylate Stat1 and Stat2 on conserved tyrosine residues 13. Stat1 and Stat2 combine with the IRF-9 protein to form the transcription factor interferon stimulated gene factor 3 (ISGF-3), which binds to the interferon stimulated response element (ISRE), and induces transcription of IFN-alpha-induced genes (ISG). The ISGs mediate the antiviral effects of IFN. The transcriptional activities of Stats 1, 3, 4, 5a, and 5b are also regulated by serine phosphorylation 14. Phosphorylation of Stat1 on a conserved serine amino acid at position 727 (S727), results in maximal transcriptional activity of the ISGF-3 transcription factor complex 15. Although cross-talk between p38 MAPK and the Jak-Stat pathway is essential for IFN-induced ISRE transcription, p38 does not participate in IFN induction of Stat1 serine phosphorylation 1416171819. However, cellular stress responses induced by stimuli such as ultraviolet light do induce p38 MAPK mediated Stat1 S727 phosphorylation 18. In the current report, we postulated that alcohol and HCV proteins modulate MAPK and Jak-Stat pathways in human liver cells. To begin to address these issues, we characterized the interaction of acute ethanol on Jak-Stat and MAPK pathways in Huh7 cells, HCV replicon cells lines, and primary human hepatocytes.
...
PMID:Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells. 1632 17

Diuretic therapy is a drug therapy that increases urine volume, but not glomerular filtration rate (GFR). The diuretics act predominantly on tubular sites; the drugs that increase GRF are the aminophyllines, the positive inotropy or vasoactive substances that increase afferent arteriolar flux or intraglomerular pressure. We can divide the diuretics into six categories: 1) carbonic anhydrase inhibitors: acetazolamide, dichlorphenamide, methazolamide; 2) osmotic diuretics: glycerol, mannitol, urea; 3) loop diuretics: furosemide, bumetanide, ethacrynic acid, piretanide, torsemide; 4) thiazide and thiazide-like diuretics: chlorothiazide, trichlormethiazide, indapamide, chlorthalidone, metolazone; 5) potassium-sparers: a) kidney epithelial sodium channel inhibitors: amiloride and triamterene; b) aldosterone receptor antagonists: spironolactone, canrenoate potassium, eplerenone; 6) ADH antagonists: lithium salts, demeclocycline and ethanol. Diuretic therapy is useful in treating acute and chronic renal insufficiency, congestive heart failure, cirrhosis, overhydration and hypertension. Diuretic therapy increases urine volume, ion loss (except Na+, K+), and modifies diffusion (dilute urine) and convection mechanisms (reduced tubular absorption). Therefore, diuretics are very useful non-dangerous drugs.
...
PMID:[Diuretic therapy in heart failure]. 1663 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---