Recent advances in alcoholic liver disease. IV. Dysregulated cytokine metabolism in alcoholic liver disease

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States for which there is no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of TNF-alpha and TNF-alpha-inducible cytokines/chemokines, such as IL-6, -8, and -18, have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. Cytokines, such as transforming growth factor-beta, play a critical role in the fibrosis of ALD. Multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.     

Severity of alcohol dependence in patients with alcoholic liver disease.

To determine the severity of dependence on alcohol in patients with alcoholic liver disease the severity of alcohol dependence questionnaire was administered to 193 patients with various types of alcoholic liver disease established histologically, in whom a detailed history of lifetime alcohol consumption was also obtained. Only 34 patients (18%) were classified as being severely dependent compared with 56% of patients without overt liver disease who were attending a neighbouring alcohol treatment unit. There was a significant correlation between the severity of dependence and mean daily alcohol consumption (r = 0.45 and 0.39 for men and women, respectively) but not duration of drinking. Dependence scores tended to be lower in patients with cirrhosis than in those with precirrhotic liver disease, but this difference reached significance only in women. These findings confirm that patients who develop chronic alcoholic liver disease are usually only mildly dependent on alcohol and support the hypothesis that patients who escape florid symptoms of alcohol dependence are at greater risk of developing liver damage because they are able to sustain a continual consumption of alcohol over many years.     

Genetic susceptibility to Alzheimer disease

Alzheimer disease (AD) is the leading cause of dementia in the elderly. Less than a decade ago, it was questioned as to whether or not genes were even involved in anything but rare early onset AD. Since that time, using a variety of genetic epidemiological and molecular biological techniques, four loci have been identified that play a role in the genetic susceptibility of AD, AD presents as a prototype of the power of genetic techniques in defining the etiology of a complex disease.     

Genetic susceptibility to infectious disease

Our understanding of the variation in individual clinical responses to pathogens has become increasingly relevant, particularly in the face of new emerging epidemics as well as the increasing number of multi-drug-resistant organisms. An effective immune response to infection has contributed to the development of host genetic diversity through selective pressure, with an increasing number of studies characterizing the role that host genetics plays in disease susceptibility. Knowledge of the role host mechanisms play in the pathogenesis of infectious disease can contribute to the design of new therapeutic strategies. Rapid advances in the field of human genomics offer great opportunities for adopting this approach to find new insights into pathogenesis.     

Genetic polymorphism of MMP family and coronary disease susceptibility: a meta-analysis

The issue that genetic polymorphism of matrix metalloproteinase (MMP) family is in association with coronary disease is controversial. So we did a meta-analysis to clarify it clearly. We made a literature search of PubMed, the Web of Science, and Cochrane Collaboration's database to identify eligible reports. The methodological quality of each included studies was assessed. We calculated the pooled ORs with their 95%CI for each genetic polymorphism in STATA 11 software. Separate analysis was performed to address the consistency of results across the subgroup with different continents. A total of 39 studies were included, with a sample of 42269 individuals. This meta-analysis provided evidence that genetic polymorphism of MMP1-1607 1G/2G, MMP3-Gly45lys, MMP3-376 G/C, MMP3-1171 5A/6A, MMP9-1562 C/T and MMP9-R279Q have a small to medium effect on incidence of coronary disease. There was no evidence that MMP1-519 A/G, MMP1-340 T/C and MMP2-1306 C/T polymorphism could increase risk of coronary disease. Results from subgroup analysis supported a relation between MMP3-1711 5A allele, MMP9-1562 C allele and coronary disease especially in Asian population. The results provide moderate association between the six common genetic polymorphism of matrix metalloproteinase family and coronary disease. However, the challenge for researcher is identifying separate effect on different races.     

Genetic polymorphism of matrix metalloproteinase 9 and susceptibility to chronic obstructive pulmonary disease: A meta-analysis

BackgroundTo systematically analyze the influence of genetic polymorphisms of matrix metalloproteinase 9 (MMP9) on susceptibility to chronic obstructive pulmonary disease (COPD).MethodsRelevant literatures reporting MMP9 and susceptibility to COPD in PubMed, Web of Science, VIP, Wanfang and CNKI databases were searched using the key words "matrix metalloproteinases 9/MMP9, COPD/chronic obstructive pulmonary disease". Data of eligible literatures were extracted and analyzed for the odds ratio (OR) and corresponding 95% CI.ResultsA total of 16 independent studies reporting MMP9-1562C/T and COPD patients were enrolled and analyzed. None of the genetic models revealed the relationship between MMP9-1562C/T and susceptibility to COPD. Subgroup analyses identified lower risk of COPD in Chinese population carrying the TT genotype for theMMP9 rs3918242 relative to those carrying CT and CC genotypes (P=0.03, OR=0.67, 95% CI=0.46-0.97).ConclusionsChinese population carrying the TT genotype for the MMP-9 rs3918242 present lower susceptibility to COPD relative to those carrying CT and CC genotypes.     

Genetic susceptibility to chronic periodontal disease

Evidence suggests that there is a significant genetic component to susceptibility and resistance to chronic periodontal disease. Data from both clinical studies and studies using animal models are reviewed here. Also outlined are the genomic methods that are now available for identifying susceptibility and resistance loci.     

酒精依赖相关基因的遗传多态性

酒精依赖综合征受到复杂的生理、心理、个体遗传及环境等诸多因素的影响。有关研究已经证实了某些候选基因和酒精依赖密切相关。文章主要对与酒精依赖相关的酒精代谢关键酶(乙醇脱氢酶和乙醛脱氢酶以及细胞色素P450 2E1)基因以及调节神经递质作用的酶和受体(儿茶酚氧位甲基转移酶, 多巴胺受体D2、D4, μ阿片受体)基因遗传多态性研究作一综述。     

Genetic susceptibility to mycobacterial disease in humans

Mycobacterial disease remains a serious global health problem. Tuberculosis causes more than 2 million deaths a year, and leprosy is still a cause of severe disability in many parts of the world. As a result of the study of individuals with marked susceptibility to usually nonpathogenic mycobacteria, as well as case-control studies with candidate genes and genome-wide screens of affected populations, there is substantial evidence for the role of genetic factors in the susceptibility to mycobacterial disease. These studies have defined immunological processes essential for the control of mycobacteria infections in humans.     

Genetic markers in alcoholic liver cirrhosis.

11 genetic markers were typed in 157 individuals suffering from alcoholic cirrhosis, and compared with a random sample of healthy individuals. No significant differences were found for transferrin, specific group component, orosomucoid, esterase D, phosphogluconate dehydrogenase and adenylate kinase. Strong associations between alcoholic cirrhosis and alpha-1-antitrypsin PI*Z allele, haptoglobin HP*1 allele and acid phosphatase ACP AC phenotype were observed. The biological significance of these associations and their relationships with the development of alcoholic cirrhosis are also discussed.     

Genetic polymorphism of erythrocytic enzymes in Yakut populations

Polymorphism of the erythrocytic enzymes PGM1, ACP1, ESD, and GLO1 was found in Yakut populations. The allelic frequencies of the polymorphic systems studied varied within the following ranges: PGM1*1+, 0.5833-0.7791; PGM1*1-, 0.0345-0.1176; PGM1*2+, 0.1250-0.2813; ACP1*A, 0.1429-0.3382; ACP1*B, 0.6548-0.8571; ESD*2, 0.1250-0.4643; and GLO1*1, 0.0116-0.2845.     

Plasma membrane proteome analysis of the early effect of alcohol on liver: implications for alcoholic liver disease

In humans, the over-consumption of alcohol can lead to serious liver disease. To examine the early effects of alcohol on liver disease, rats were given sufficient ethanol to develop liver cirrhosis. Rats before the onset of fibrosis were studied in this work. Plasma membranes (PM) of liver were extracted by twice sucrose density gradient centrifugation. The proteome profiles of PM from ethanol-treated rats and the controls were analyzed using two-dimensional gel electrophoresis (2-DE) and isobaric tag for relative and absolute quantitation (iTRAQ) technology. Ethanol treatment altered the amount of 15 different liver proteins: 10 of them were detected by 2-DE and 5 by iTRAQ. Keratin 8 was detected by both methods. Gene ontology analysis of these differentially detected proteins indicated that most of them were involved in important cell functions such as binding activity (including ion, DNA, ATP binding, etc.), cell structure, or enzyme activity. Among these, annexin A2, keratin 8, and keratin 18 were further verified using western blot analysis and annexin A2 was verified by immunohistochemistry. Our results suggested that alcohol has the potential to affect cell structure, adhesion and enzyme activity by altering expression levels of several relevant proteins in the PM. To the best of our knowledge, this is the first time to study the effect of alcohol on the liver PM proteome and it might be helpful for understanding the possible mechanisms of alcohol-induced liver disease.     

Genetic polymorphism of rat liver gangliosides

Liver ganglioside patterns of eight rat strains were classified according to two phenotypes: SHR type, characterized by predominance of b-series gangliosides (GD1b, GT1b, GQ1b), and DA type, characterized by predominance of a-series gangliosides (GM1, GD1a). Comparison of ganglioside pattern expressed in the liver of F1 hybrids and backcross F2 hybrids indicated that SHR type is controlled by a single autosomal-dominant gene which probably determines the expression of sialytransferase 2 activity for synthesis of GD3 from GM3.     

Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: Implications for ethanol metabolism and cytotoxicity

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung β-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation,K _m values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The β₂ allele, coding for β₂ polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH₂ 2-2 (exhibiting β₂β₂) and ADH₂ 1-1 (exhibiting β₁β₁) and the heterozygous phenotype ADH₂ 2-1 (exhibiting β₂β₂, β₂β₁, and β₁β₁) were determined to be 999±77, 48±17, and 494±61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30±3 and 17±1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both theADH ₂ and theALDH ₂ loci. The results suggest that individuals with highV _max β₂-ADH and deficient in low-K _m mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. This work was supported by Grants NSC 77-0412-B016-58 and NSC 80-0412-B016-21 from the National Science Council, Republic of China.     

Genetic diversity and disease susceptibility.

The range of genetic diversity within human populations is enormous. Genetic susceptibility to common chronic disease is a significant part of this genetic diversity, which also includes a variety of rare clear-cut inherited diseases. Modern DNA-based genomic analysis can now routinely lead to the identification of genes involved in disease susceptibility, provides the basis for genetic counselling in affected families, and more widely for a genetically targeted approach to disease prevention. This naturally raises problems concerning the use of information on an individual''s decisions, but for employment, and health and life insurance.     

Zinc prevention and treatment of alcoholic liver disease

Alcoholic liver disease (ALD) is associated with decreases in zinc (Zn) and its major binding protein, metallothionein (MT), in the liver. Studies using animal models have shown that Zn supplementation prevents alcohol-induced liver injury under both acute and chronic alcohol exposure conditions. There are hepatic and extrahepatic actions of Zn in the prevention of alcoholic liver injury. Zn supplementation attenuates ethanol-induced hepatic Zn depletion and suppresses ethanol-elevated cytochrome P450 2E1 (CYP2E1) activity, but increases the activity of alcohol dehydrogenase in the liver; an action that is likely responsible for Zn suppression of alcohol-induced oxidative stress. Zn also enhances glutathione-related antioxidant capacity in the liver. At the cellular level, Zn inhibits alcohol-induced hepatic apoptosis partially through suppression of the Fas/FasL-mediated pathway. Zn supplementation preserves intestinal integrity and prevents endotoxemia, leading to inhibition of endotoxin-induced tumor necrosis factor-alpha (TNF-alpha) production in the liver. Zn also directly inhibits the signaling pathway involved in endotoxin-induced TNF-alpha production. These hepatic and extrahepatic effects of Zn are independent of MT. However, low levels of MT in the liver sensitize the organ to alcohol-induced injury, and elevation of MT enhances the endogenous Zn reservoir and makes Zn available when oxidative stress is imposed. Zn has a high potential to be developed as an effective agent in the prevention and treatment of ALD.