Chronic ingestion of ethanol increases acetaldehyde and leads to the production of acetaldehyde-derived advanced glycation end-products (AA-AGE). We evaluated the toxicity of AA-AGE on hepatocytes ...and studied the role of AA-AGE in the pathogenesis of alcoholic liver disease (ALD).
Rat hepatocyte cultures were treated with N-ethyllysine (NEL) or AA-AGE and the cell viability was evaluated using MTT assay. Male Wistar rats were fed with liquid diet containing 5% ethanol for 8 weeks following normal diet for another 12 weeks. A group of animals was sacrificed at 4th, 6th, and 8th week and the remaining animals at 12th, 14th, 16th, 18th, and 20th week. The liver sections were stained for AA-AGE and 4-hydroxy-2-nonenal (4-HNE). Liver biopsy obtained from ALD patients was also stained for AA-AGE and 4-HNE.
Hepatocyte viability was significantly reduced in cultures treated with AA-AGE compared to NEL treated or control cultures. Severe fatty degeneration was observed during chronic administration of ethanol increasing from 4-8 weeks. The staining of AA-AGE and 4-HNE was correlated with the degree of ALD in both rat and human. In rats, hepatic fatty degeneration was completely disappeared and the staining for both AA-AGE and 4-HNE returned to normal at 12th week of abstinence. Staining for AA-AGE and 4-HNE was completely absent in normal human liver.
The data demonstrated that AA-AGE is toxic to hepatocytes, but not NEL. Chronic ethanol ingestion produces AA-AGE and reactive oxygen species that contribute to the pathogenesis of ALD. Abstinence of alcohol results in complete disappearance of both AA-AGE and 4-HNE along with fatty degeneration suggesting that AA-AGE plays a significant role in the pathogenesis of ALD.
Abstract We report an association between gastric cancer (GC) and polymorphisms in IL17A , rs2275913 (−197 G > A), rs3748067 (∗ 1249 C > T), and pri-miR-938, rs2505901 (T > C). We employed the ...multiplex PCR-SSCP method to detect gene polymorphisms in 337 GC cases and 587 controls. The minor allele frequency of rs2275913 was significantly higher, and those of rs3748067 and rs2505901 significantly lower, in GC cases than controls. The rs2275913 AA homozygote was associated with an increased risk (OR, 2.38; 95%CI, 1.63–3.46; p < 0.0001) for the development of both intestinal and diffuse types of GC. The rs3748067 T polymorphism was associated with a decreased risk for intestinal GC (OR, 0.511; 95%CI, 0.272–0.962; p = 0.037), whereas rs2505901 C locus carried a decreased risk overall for GC (OR, 0.733; 95%CI, 0.545–0.985; p = 0.039). In addition, rs3748067 T allele was inversely correlated with lymph node metastasis. Our results suggest that polymorphisms in both IL17A and pri-miR-938 contribute to cancer risk susceptibility and therefore can affect the development of gastric cancer.
Background
Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS ...(sensory-neuron specific), encoded by
SCN10A
, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and
SCN10A
non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C).
Methods
The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms.
Results
The 3218 CC homozygotes had a reduced risk for the development of FD odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402–0.864;
p
= 0.0067. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD (
p
= 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448–0.853;
p
= 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS (
p
= 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in
Helicobacter pylori
-negative subjects (OR 0.463; 95 % CI 0279–0.9768;
p
= 0.0029).
Conclusion
We conclude that genetic polymorphisms of
SCN10A
are closely associated with FD (both EPS and PDS), especially in
H. pylori
-negative subjects, in Japanese.
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are representative types of fatty liver disease (FLD) and have similar histologic features. In this study, we aimed to compare ...the associations of the two FLD types with hypertension (HT), diabetes mellitus (DM), and dyslipidemia (DL). A nationwide survey investigating FLD status included 753 Japanese subjects (median age 55 years; male 440, female 313) with biopsy-proven ASH (n=172) or NASH (n=581). We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. Older age and a higher body mass index were significant factors associated with HT. Older age, female sex, a higher body mass index, advanced liver fibrosis, and the NASH type of FLD (odds ratio 2.77; 95% confidence interval 1.78–4.31; P<0.0001) were significant factors associated with DM. Finally, the NASH type of FLD (odds ratio 4.05; 95% confidence interval 2.63–6.24; P<0.0001) was the only significant factor associated with DL. Thus, the associations of NASH with DM and DL were stronger than those of ASH with DM and DL. In the management of FLD subjects, controlling DM and DL is particularly important for NASH subjects.
AIM To assess how serum gamma-glutamyltransferase(GGT) fractions vary in patients with alcoholic liver disease(ALD) and non-alcoholic fatty liver disease(NAFLD). METHODS Serum samples were obtained ...from 14 patients with biopsy-proven alcoholic liver diseases and 9 patients with biopsy proven non-alcoholic fatty liver disease. In addition to these biopsy-proven cases, 16 obese(body mass index > 25) patients without any history of alcohol consumption but with a fatty liver on ultrasound examination and with elevated GGT were included for an additional analysis. Serum GGT fractionation was conducted by high-performance gel filtration liquid chromatography and was separated into the four fractions, big-GGT, medium-GGT, small-GGT(s-GGT), and free-GGT(f-GGT).RESULTS The results were expressed as a ratio of each fraction including the total GGT(t-GGT). The s-GGT/t-GGT ratioswere lowest for the control group and highest for the ALD group. The differences between the control and NAFLD groups and also between the NAFLD and ALD groups were statistically significant. In contrast, the f-GGT/t-GGT ratios were highest in the control group and lowest in the ALD group, with the differences being statistically significant. As a result, the s-GGT/f-GGT ratios were markedly increased in the NAFLD group as compared with the control group. The increase of the s-GGT/t-GGT ratios, the decrease of the f-GGT/t-GGT ratios, and the increase of s-GGT/F-GGT ratios as compared with the control group subjects were also found in obese patients with clinically diagnosed fatty change of the liver.CONCLUSION Serum GGT fractionation by high-performance gel filtration liquid chromatography is potentially useful for the differential diagnosis of ALD and NAFLD.
Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. The -1018 G>A (rs2067474) in an enhancer element of the promoter and non-synonymous ...rs79385261 (Asn46Thr) were identified in HRH2. We attempted to clarify the associations of these polymorphisms with gastric carcinogenesis. The study was performed in 321 patients with gastric cancer and 599 subjects with no evidence of gastric malignancies on upper gastroduodenal endoscopy. The genotypes were determined using a one-tube multiplex PCR-SSCP method. The degree of gastritis was assessed in 496 subjects and serum pepsinogen (PG) I/II levels were measured in 124 subjects without gastric cancer. The minor allele of Asn46Thr could not be detected. The frequencies of the -1018 A allele in the non-GC and GC groups were 13.5% and 8.26%, respectively (p=0.00077). Overall, -1018 GG homozygotes had an increased risk for developing gastric cancer (OR 1.68; 95% CI 1.17-2.42; p=0.0052), especially intestinal type cancer (OR 1.94; 95% CI 1.23-3.08; p=0.0047). In subjects aged >60 years, the adjusted risk for gastric cancer among individuals who were -1018 GG homozygotes was 1.87 (range 1.19-2.93; p=0.0065) compared with A carriers. In the gastric cancer cases located in the antrum and at comparative advanced stage, -1018 GG homozygosity was a significantly increased risk factor. In subjects >60 years, the metaplasia score was significantly higher in -1018 GG homozygotes than A carriers. Both atrophy and metaplasia scores were significantly increased with age only in -1018 GG homozygotes. The PG I/II ratio was significantly decreased in H. pylori positive GG homozygotes than negative GG homozygotes and positive A carriers. Our results suggest that -1018 GG homozygosity of HRH2 may be associated with the severity of gastric mucosal atrophy. This genotype has an increased risk for the subsequent development of gastric cancer, especially intestinal type, at advanced age.
We compared the relationships of alcoholic fatty liver and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia. Using a nationwide Japanese survey, we collected data on ...subjects with biopsy-proven alcoholic fatty liver or nonalcoholic fatty liver. Multiple logistic regression analysis was performed to determine whether alcoholic fatty liver and nonalcoholic fatty liver are associated factors for these diseases. Data on 191 subjects (65, alcoholic fatty liver; 126, nonalcoholic fatty liver) were analyzed. Alcoholic fatty liver (odds ratio, 2.54; 95% confidence interval, 1.06–6.32; p = 0.040), age ≥55 years, and body mass index ≥25 kg/m2 were correlated with hypertension, whereas nonalcoholic fatty liver (odds ratio, 2.32; 95% confidence interval, 1.08–5.20; p = 0.035) and serum γ-glutamyl transpeptidase levels ≥75 IU/l were correlated with dyslipidemia. Furthermore, we found that there were biological interactions between alcoholic fatty liver and body mass index ≥25 kg/m2 in ≥55-year-old subjects (attributable proportion due to interaction, 0.68; 95% confidence interval, 0.19–1.17), as well as between alcoholic fatty liver and age ≥55 years in subjects with body mass index ≥25 kg/m2 (attributable proportion due to interaction, 0.71; 95% confidence interval, 0.24–1.18). Alcoholic fatty liver was more strongly associated with hypertension than nonalcoholic fatty liver and nonalcoholic fatty liver was more strongly associated with dyslipidemia than alcoholic fatty liver. Moreover, alcoholic fatty liver, obesity, and older age may interact to influence hypertension status.
AIM：To clarify the association between a polymorphism-449 C〉G（rs72696119） in 5＇-UTR of NFKB1 with ulcerative colitis（UC）.METHODS：The studied population comprised 639 subjects,including patients with ...UC（UC cases,n = 174） and subjects without UC（controls,n = 465）.We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism.RESULTS：The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%,respectively（P = 0.10）.Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls（P = 0.017）,and the GG homozygote was significantly associated with susceptibility to UC odds ratio（OR）,1.88;95%CI,1.13-3.14.In male subjects,the GG homozygote was associated with an increased risk for UC（OR,3.10;95%CI,1.47-6.54;P = 0.0053）,whereas this association was not found in female subjects.In addition,the GG homozygote was significantly associated with the risk of non-continuous disease（OR,2.06;95%CI,1.12-3.79;P = 0.029）,not having total colitis（OR,2.40;95%CI,1.09-3.80,P = 0.040）,disease which developed before 20 years of age（OR,2.80;95%CI,1.07-7.32,P = 0.041）,no hospitalization（OR,2.28;95%CI,1.29-4.05;P = 0.0090） and with a maximum of 8 or less on the UCDAI score（OR,2.45;95%CI,1.23-4.93;P = 0.022）.CONCLUSION：Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC.This polymorphism influences the susceptibility to and pathophysiological features of UC.
: Background: Since no clinical or biochemical parameters allow an accurate diagnosis of non‐alcoholic steatohepatitis (NASH), the diagnosis by exclusion of alcoholic hepatitis is necessary. However, ...it is difficult to get the accurate amount of alcohol consumed from the patients, especially from females. To differentiate between NASH and alcoholic hepatitis, we investigated whether serum biochemical markers of chronic alcohol abuse are useful or not.
Methods: Sera were obtained from 13 patients with NASH and 26 patients with alcoholic hepatitis. Diagnoses in these patients were confirmed histologically by needle biopsy of the liver. All patients with alcoholic hepatitis consumed more than 80 g of ethanol/day for more than 10 years. As markers of chronic alcohol abuse, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma‐glutamyl transpeptidase (GGT), hyaluronate, mean corpuscular volume of red blood cells (MCV) and carbohydrate‐deficient transferrin (CDT) were measured.
Results: Among alcohol markers, serum values of AST, AST/ALT ratio, GGT, CDT and MCV in patients with alcoholic hepatitis were significantly higher than those in patients with NASH, respectively. However, serum values of these markers, except for CDT, were overlapped in many cases of NASH and alcoholic hepatitis. Serum CDT values of all patients with NASH were lower than the cutoff value, 2.66%, and those of all patients with alcoholic hepatitis were higher than the cutoff value.
Conclusion: The results of the present study suggest that serum CDT level could be used to differentiate between NASH and alcoholic hepatitis.
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