HRAS1 Variable Number of Tandem Repeats Polymorphism in Japanese Patients with Colorectal Adenoma and Cancer

The highly polymorphic HRAS1 variable number of tandem repeats (VNTR) has been described as an inherited predisposing factor in various human cancers. The aim of the present study was to evaluate the association between the presence of rare HRAS1 VNTR alleles and colorectal adenoma and cancer. A total of 165 Japanese patients underwent total colonoscopy with informed consent, and were divided into 2 groups: colorectal neoplastic and non-neoplastic patients. Two hundred and sixteen HRAS1 VNTR alleles from 108 colorectal neoplastic patients (67 adenomas and 41 cancers) and 114 alleles from 57 non-neoplastic patients were genotyped using PCR-based long-agarose gel electrophoresis assay of peripheral blood leukocyte DNA. Rare alleles were differentiated from 4 types of common allele (a1, a2, a3 and a4) by shifts in electrophoretic mobility. The prevalence of rare HRAS1 VNTR alleles was higher in colorectal neoplastic patients than in non-neoplastic patients (25.4% and 34.1% versus 8.8%). The adjusted odds ratio with at least one rare allele was 8.65 (95% confidence interval = 2.93 ? 25.53, P < 0.0001) in colorectal neoplastic patients. The presence of rare HRAS1 VNTR alleles could be a genetic predisposing factor for risk of colorectal neoplasm in Japanese people

Functional Polymorphisms in the Promoter Regions of Matrix Metalloproteinase-2, -3, -7, -9 and TNF-alpha Genes, and the Risk of Colorectal Neoplasm in Japanese

Colorectal carcinogenesis involves environmental factors and genetic predispositions. Recent studies have suggested the associations between colorectal neoplasm and functional polymorphism of matrix metalloproteinases (MMPs) and cytokine genes. In this study, we analyzed polymorphisms of MMPs and tumor necrosis factor (TNF)-alpha genes, focusing on the susceptibility to colorectal neoplasm and the tumor progression. The subjects were 186 patients (95 men and 91 women) who underwent total colonoscopy, and were classified into cancer, adenoma and non-neoplasm (control) groups of 47, 72 and 67 patients, respectively. The polymorphisms at the MMP-2 ?1306C/T, MMP-3 ?1171 5A/6A, MMP-7 ?181A/G, MMP-9 ?1562C/T and TNF-alpha ?308G/A loci were analyzed. Regarding background factors, significant differences were found in the age, sex ratio and alcohol-drinking and cigarette-smoking histories in the adenoma and cancer groups, compared to those in the control group. On these factors-adjusted logistic regression analysis of polymorphisms and disease susceptibility, no significant difference was noted in the frequency of any polymorphism in the adenoma and cancer groups, compared to those in the control group. The analysis of the involvement of polymorphisms in tumor progression in the adenoma and cancer groups revealed that the odds ratio for the MMP-3 5A allele was significantly higher in the cancer group (2.74; 95% confidence interval = 1.11?6.74, P = 0.02). The polymorphisms of MMP genes and TNF-alpha genes were not associated with the susceptibility to colorectal neoplasm, but the involvement of the MMP-3 5A allele in the progression of adenoma to cancer was suggested

Vitamin K2 Has No Preventive Effect on Recurrence of Hepatocellular Carcinoma after Effective Treatment

Hepatocellular carcinoma (HCC) has a poor prognosis because of its high recurrence rate. Recently, vitamin K2 has been reported to inhibit the growth of HCC cell lines. To clarify the preventive effect of vitamin K2 on HCC recurrence, we studied 72 HCC patients who had been treated with surgical resection, local ablation or transarterial embolization: their etiologies were hepatitis B virus (n = 21), hepatitis C virus (n = 47), both B and C viruses (n = 2) and non-B or non-C virus (n = 2). We divided them into 2 groups: in one group, patients were treated with 45-mg/day vitamin K2 [K2-treated group (n = 23)], and in another, patients were not given vitamin K2 or a placebo [non-treated control group (n = 49)]. The obtained results between the 2 groups were compared. HCC recurred in 12 (52.2%) of the 23 K2-treated patients, and 22 (44.9%) of the 49 control patients. The differences in cumulative recurrence-free rate and cumulative survival rate between both groups were not significant (P = 0.92 and P = 0.08, respectively). As observed, chemopreventive effects of vitamin K2 at a clinically relevant dose on HCC recurrence were ineffective after effective treatment for HCC. Different regimens such as higher doses of vitamin K2 or combination therapy with other drugs may be worth testing to further explore the preventive effect on HCC recurrence

Combination Therapy with Olmesartan and Temocapril Ameliorates Renal Damage and Upregulates the klotho Gene in 5/6 Nephrectomized Spontaneously Hypertensive Rats

Recent studies suggest that chronic kidney disease may induce cardiovascular disease through oxidative stress, and that the aging suppressor gene klotho reduces oxidative stress in the kidney. In this study, we examined the changes in klotho gene expression, and the renoprotective effects of olmesartan (OLM), angiotensin II receptor blocker (ARB) alone or in combination with temocapril (TEM), angiotensin-converting enzyme inhibitor (ACEI) in 5/6-nephrectomized (5/6-Nx) spontaneously hypertensive rats. Male 5/6-Nx spontaneously hypertensive rats were randomly assigned to 5 groups as follows: control group; 5/6-Nx group, 5/6-Nx rats; low OLM group, 5/6-Nx rats administered low-dose OLM (3 mg/kg/day); high OLM group, 5/6-Nx rats administered high-dose OLM (10 mg/kg/day); OLM+TEM group, 5/6-Nx rats administered high-dose OLM and TEM (10 mg/kg/day each). These drugs were administered for 12 weeks. Systolic blood pressure, glomerular sclerosis and transforming growth factor beta 1 mRNA in high OLM and OLM+TEM groups were significantly lower than that in the 5/6-Nx group. Only the OLM+TEM group showed improvement of serum creatinine and urinary 8-hydroxy-2'-deoxyguanosine. Ex-pression of klotho mRNA, which was downregulated in the 5/6-Nx group, was upregulated in the high OLM and OLM+TEM groups. OLM dose-dependently prevented klotho mRNA downregulation in 5/6-Nx rats, thus confirming a renoprotective effect. In addition, combination therapy of OLM and TEM was more effective than OLM alone. In conclusion, the combination of OLM and TEM inhibits the progression of renal damage in 5/6-Nx rats through the upregulation of klotho gene

The Effects of Olmesartan and Alfacalcidol on Renoprotection and klotho Gene Expression in 5/6 Nephrectomized Spontaneously Hypertensive Rats

Recently, an angiotensin inhibitor has been shown to upregulate the klotho mRNA level in chronic renal failure. In addition, the administration of vitamin D has been reported to improve the mortality of patients with chronic renal failure. In this study, we examined the effects of an angiotensin inhibitor and/or vitamin D on the progression of chronic renal failure by using male 5/6 nephrectomized (5/6Nx) spontaneously hypertensive rats. Male 5/6Nx spontaneously hypertensive rats were assigned to 4 groups as follows: 5/6Nx group, 5/6Nx rats; Alf group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day); Olm group, 5/6Nx rats administered olmesartan (15 mg/kg/day); Alf + Olm group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day) and olmesartan (15 mg/kg/day). These drugs were administered for 12 weeks. Systolic blood pressure in the Alf, Olm and Alf + Olm groups were significantly decreased relative to that in the 5/6Nx group during the 12-week experimental period. As a result, all treated groups showed renoprotection based on improvement of the systolic blood pressure, urinary protein excretion and histological renal fibrosis. Combination therapy of alfacalcidol and olmesartan was more effective than either alfacalcidol or olmesartan alone. Expression of klotho mRNA was significantly upregulated in the Alf + Olm group in comparison with in the 5/6Nx group. Serum levels of fibroblast growth factor 23 in the Alf group and the Alf + Olm group were significantly higher than those in the 5/6Nx group and the Olm group. In conclusion, the combination of Olm and Alf inhibited the progression of renal damage in the 5/6Nx group through the strong antihypertensive effect as well as the upregulation of the klotho gene

α-Fetoprotein Messenger RNA in the Blood Predicts Poor Prognosis of the Patients with Hepatocellular Carcinoma

α-Fetoprotein (AFP) messenger RNA (mRNA) in the peripheral blood of patients with hepatocellular carcinoma (HCC) may indicate hematogenous spread of HCC. This study examined the presence of AFP mRNA in the blood of 148 patients, in terms of clinical parameters, tumor metastasis and survival rate. For the prospective study, 109 patients with HCC were followed in the period between March 1996 and March 1999. AFP mRNA in the blood was examined by means of nested reverse transcription polymerase chain reaction. AFP mRNA was detected in the blood in 23 (15.5%) of 148 patients with HCC. AFP mRNA in the blood was significantly correlated with protein induced by vitamin K absence or antagonist II level, higher AFP level (200 IU/mL or more) and extrahepatic metastases, but not with tumor size, number of tumor nodules or tumor-nodule-metastasis stage. This prospective study confirmed that intra- and extra-hepatic metastases developed more frequently in the 22 AFP mRNA-positive patients than in the 87 AFP mRNA-negative patients (P < 0.01). The cumulative survival rate was significantly lower in the former than in the latter (P < 0.01). In conclusion, AFP mRNA in the blood is closely related to hematogenous spread and might be a good predictor of metastasis and poorer survival rate in HCC patients

Protection by Exogenously Added Coenzyme Q9 against Free Radical-Induced Injuries in Human Liver Cells

Reduced coenzyme Q10 (CoQ10H2) is known as a potent antioxidant in biological systems. However, it is not yet known whether CoQ9H2 could act as an antioxidant in human cells. The aim of this study is to assess whether exogenously added CoQ9 can protect human liver cells against injuries induced by a water-soluble radical initiator, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and a lipid-soluble radical initiator, 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). CoQ9-enriched cells were obtained by treatment of HepG2 cells with 10 µM CoQ9 liposomes for 24 h. CoQ9-enriched cells were exposed to 10 mM AAPH and 500 µM AMVN over 4 h and 24 h, respectively. The loss of viability after treatment with AAPH or AMVN was much less in CoQ9-enriched cells than in naive HepG2 cells. The decrease in glutathione and the increase in thiobarbituric acid-reactive substance after treatment with AAPH or AMVN were also suppressed in CoQ9-enriched cells. The incubation of CoQ9-enriched cells with AAPH or AMVN led to a decrease in cellular CoQ9H2 and reciprocal increase in cellular CoQ9 resulting from its antioxidant function. Taken together, it was demonstrated for the first time that exogenously added CoQ9 could prevent oxidative stress-mediated damage to human cells by virtue of its antioxidant activity