AIM： To investigate the association of polymorphisms of nur-related receptor 1 （Nurrl） and development of alcohol dependence in Mexican Americans. METHODS： Peripheral blood samples were collected from 374 alcoholi...AIM： To investigate the association of polymorphisms of nur-related receptor 1 （Nurrl） and development of alcohol dependence in Mexican Americans. METHODS： Peripheral blood samples were collected from 374 alcoholic and 346 nonalcoholic Mexican Amer- icans; these two groups were sex- and age-matched. Sample DNA was extracted and genomic DNA was amplified by polymerase chain reaction. The -2922（C） 2-3 polymerase chain reaction products were digested with Sau96I, alleles of 1345（G/C）, and -1198（C/G） in the regulatory region as well as Ex＋132 （G/T/A/C） and Ex＋715（T/-） in exon 3 were studied by sequencing. RESULTS： The C2/C2, C2/C3, C3/C3 genotype distribu- tion of -2922（C） 2-3 was 34.4%, 38.2% and 27.5% in the nonalcoholic group compared to 23.3%, 51.2% and 25.4% in the alcoholic group （P = 0.001）. The C/C, C/G ,G/G genotype distribution of -1198（C/6） was 23.5%, 46.1% and 30.3% in the nonalcoholic group compared to 13.9%, 50.9% and 35.3% in the alcoholic group （P = 0.007）. However, the -1345 （G/C）, Ex3＋132（G/T/A/C） and Ex3＋715（T/-） alleles were not polymorphic in Mex- ican Americans, and all those studied had G/G, G/G and T/T genotype for these three alleles, respectively. The -2922（C） 2-3 did not show allele level difference be- tween alcoholic and nonalcoholic individuals, but -1198 （C/G） showed a significant allele frequency difference between alcoholic （39.3%） and nonalcoholic （46.6%） populations （P = 0.005）. Excluding obese individuals, significant differences were found at both genotypic and allelic levels for the -2922（C） 2-3 polymorphism （P = 0.000 and P = 0.049） and the -1198 （C/G） polymor- phism （P = 0.008 and P = 0.032） between nonobese alcoholics and nonobese controls. Excluding smokers, a significant difference was found only at the genotypic level for the -2922（C） 2-3 polymorphism （P = 0.037） between nonsmoking alcoholics and nonsmoking con- trols, but only at the allelic level for the -1198（C/G） polymorphism （P = 0.034）. CONCLUSION： Polymorphisms in the regulatory region of Nurrl are implicated in pathogenesis of alcohol de- pendence and the Nurrl/dopamine signaling pathway might be important for this dependence development in Mexican Americans.展开更多
Alcohol consumption causes significant liver damage,including hepatitis,fibrosis,cirrhosis,and even primary liver carcinoma.Metadoxine(MTDX)is considered to be a beneficial treatment for alcoholic liver disease(ALD)be...Alcohol consumption causes significant liver damage,including hepatitis,fibrosis,cirrhosis,and even primary liver carcinoma.Metadoxine(MTDX)is considered to be a beneficial treatment for alcoholic liver disease(ALD)because it accelerates the metabolism and elimination of ethanol.However,the underlying mechanism is not well understood.Here,the rat model of ALD was developed by feeding with 50%ethanol at the dose of 5 g/kg,and samples of serum and liver tissue were collected to test the levels of liver injury and inflammation and evaluate the hepatoprotective function of MTDX in alcohol-induced liver injury.Further investigation on the infiltration of immune cells was performed to understand the potential hepatoprotective mechanism of MTDX in the ALD model.The results showed that MTDX attenuated liver injury,evidenced by decreased levels of alanine transaminase(ALT),aspartate aminotransferase(AST),and alkaline phosphatase(ALP).Meanwhile,the liver proinflammatory environment was improved after MTDX treatment,evidenced by decreased levels of TNF-α,IL-6,and NLRP3 in the liver tissue.Furthermore,inhibited infiltrations of macrophages and neutrophils were observed in MTDX-treated ALD rats compared with the untreated ALD rats.Our results indicated that MTDX played an important role in preventing the progression of ALD,and the underlying mechanisms might be related to its function of attenuating liver inflammation by inhibiting immune cell infiltration.展开更多
基金Supported by NIH/NIAAA Grant RO1 AA 12081Centers of Biomedical Research Excellence Grant P20 RR021940
文摘AIM： To investigate the association of polymorphisms of nur-related receptor 1 （Nurrl） and development of alcohol dependence in Mexican Americans. METHODS： Peripheral blood samples were collected from 374 alcoholic and 346 nonalcoholic Mexican Amer- icans; these two groups were sex- and age-matched. Sample DNA was extracted and genomic DNA was amplified by polymerase chain reaction. The -2922（C） 2-3 polymerase chain reaction products were digested with Sau96I, alleles of 1345（G/C）, and -1198（C/G） in the regulatory region as well as Ex＋132 （G/T/A/C） and Ex＋715（T/-） in exon 3 were studied by sequencing. RESULTS： The C2/C2, C2/C3, C3/C3 genotype distribu- tion of -2922（C） 2-3 was 34.4%, 38.2% and 27.5% in the nonalcoholic group compared to 23.3%, 51.2% and 25.4% in the alcoholic group （P = 0.001）. The C/C, C/G ,G/G genotype distribution of -1198（C/6） was 23.5%, 46.1% and 30.3% in the nonalcoholic group compared to 13.9%, 50.9% and 35.3% in the alcoholic group （P = 0.007）. However, the -1345 （G/C）, Ex3＋132（G/T/A/C） and Ex3＋715（T/-） alleles were not polymorphic in Mex- ican Americans, and all those studied had G/G, G/G and T/T genotype for these three alleles, respectively. The -2922（C） 2-3 did not show allele level difference be- tween alcoholic and nonalcoholic individuals, but -1198 （C/G） showed a significant allele frequency difference between alcoholic （39.3%） and nonalcoholic （46.6%） populations （P = 0.005）. Excluding obese individuals, significant differences were found at both genotypic and allelic levels for the -2922（C） 2-3 polymorphism （P = 0.000 and P = 0.049） and the -1198 （C/G） polymor- phism （P = 0.008 and P = 0.032） between nonobese alcoholics and nonobese controls. Excluding smokers, a significant difference was found only at the genotypic level for the -2922（C） 2-3 polymorphism （P = 0.037） between nonsmoking alcoholics and nonsmoking con- trols, but only at the allelic level for the -1198（C/G） polymorphism （P = 0.034）. CONCLUSION： Polymorphisms in the regulatory region of Nurrl are implicated in pathogenesis of alcohol de- pendence and the Nurrl/dopamine signaling pathway might be important for this dependence development in Mexican Americans.
基金Jinan Technology Development Program(Grant No.201907035)。
文摘Alcohol consumption causes significant liver damage,including hepatitis,fibrosis,cirrhosis,and even primary liver carcinoma.Metadoxine(MTDX)is considered to be a beneficial treatment for alcoholic liver disease(ALD)because it accelerates the metabolism and elimination of ethanol.However,the underlying mechanism is not well understood.Here,the rat model of ALD was developed by feeding with 50%ethanol at the dose of 5 g/kg,and samples of serum and liver tissue were collected to test the levels of liver injury and inflammation and evaluate the hepatoprotective function of MTDX in alcohol-induced liver injury.Further investigation on the infiltration of immune cells was performed to understand the potential hepatoprotective mechanism of MTDX in the ALD model.The results showed that MTDX attenuated liver injury,evidenced by decreased levels of alanine transaminase(ALT),aspartate aminotransferase(AST),and alkaline phosphatase(ALP).Meanwhile,the liver proinflammatory environment was improved after MTDX treatment,evidenced by decreased levels of TNF-α,IL-6,and NLRP3 in the liver tissue.Furthermore,inhibited infiltrations of macrophages and neutrophils were observed in MTDX-treated ALD rats compared with the untreated ALD rats.Our results indicated that MTDX played an important role in preventing the progression of ALD,and the underlying mechanisms might be related to its function of attenuating liver inflammation by inhibiting immune cell infiltration.
