Search PubMed⌕ Search

Biomedical subjects

M Fukushima

Publications and source records attributed to M Fukushima.

At least 127 records · Page 7Linked to original sources
PubMed2000

Hepatic LDL receptor mRNA in rats is increased by dietary mushroom (Agaricus bisporus) fiber and sugar beet fiber.

Plasma cholesterol concentration is reduced by feeding some dietary fibers and mushroom fruit body, but the mechanism is not fully understood. We examined the effects of mushroom (Agaricus bisporus) fiber and sugar beet fiber on serum cholesterol and hepatic LDL receptor mRNA in rats. Rats were fed a cholesterol-free diet with 50 g/kg cellulose powder (CP), 50 g/kg mushroom (Agaricus bisporus) fiber (MSF) or 50 g/kg sugar beet fiber (BF) for 4 wk. There were no significant differences in the body weight, food intake and cecum weight among the groups. The relative liver weight in the CP group was significantly greater than that in the MSF and BF groups. The cecal pH in the CP and MSF groups was significantly higher than that in the BF group. Cecal acetic acid, butyric acid and total short-chain fatty acid (SCFA) concentrations in the BF group were significantly higher than those in the other groups. The serum total cholesterol, VLDL + intermediate density lipoprotein (IDL) + LDL cholesterol concentrations in the CP group were significantly greater than those in the MSF and BF groups. The HDL cholesterol concentration in the MSF group was significantly lower than that in the CP group. The hepatic LDL receptor mRNA level in the MSF and BF groups was significantly higher than that in the CP group. The results of this study demonstrate that mushroom fiber and sugar beet fiber lowered the serum total cholesterol level by enhancement of the hepatic LDL receptor mRNA.

Agaricales↗
PubMed2000

Cytotoxic mechanisms of inhibitor of RNA synthesis, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106).

We investigated the molecular mechanisms of cell death induced by 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106: Figure 1), a potent inhibitor of RNA synthesis, using mouse mammary tumor FM3A cells and human fibrosarcoma HT1080 cells. ECyd induced the characteristics of apoptosis on these cells, such as morphological changes, DNA fragmentations and caspase-3-like protease activation. General caspases inhibitor (Z-Asp-CH2-DCB) inhibited cell death. Interestingly, we also found that ECyd induced rRNA fragmentation with the size of 3.2, 2.8 and 1.5 kb, and which might be caused by inhibition of RNA synthesis. rRNA fragmentation was mainly occurred in D8 domain of 28 S rRNA, and the end of 5'-terminal sequence of 1.5 kb fragment was C3220pC3221p or C3221pG3222p, that was identical to the recognition sequence of RNase L. Furthermore, the fragmentation patterns of rRNA digested with RNase L resembled that of ECyd treated cells in shape. These results indicate that antitumor mechanisms of ECyd are involved in activation of RNase L. rRNA fragmentation may be one of the death events as a result of inhibition of RNA synthesis and play an important role in the antitumor activity of ECyd.

Animals↗
PubMed2000

Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil.

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), with co-amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. 5-FU sensitivity of resected tumor specimens was measured by the tetrazolium-based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5-FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5-FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5-FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5-FU in patients with gastric cancer.

Antimetabolites, Antineoplastic↗
PubMed2000

Teaching of posterior composite restorations in Japanese dental schools.

AIM: This study was conducted to assess the teaching programmes for Class I and II composite restorations in Japanese dental schools to obtain an overview of what is being taught, the relative teaching volume, the criteria for the provision of posterior composite restorations and the placement techniques taught. DESIGN: Questionnaire forms mailed to the operative dentistry teaching departments in all 29 Japanese dental schools. RESULTS: The response rate was 93 per cent, with replies from 27 of the 29 dental schools. Twenty-five (93 per cent) responding schools taught the use of Class I and two schools stated that they did not teach the use of posterior composite restorations. One of the two schools had no plan to teach posterior composites within the next five years. The other school did not answer this question. Most schools anticipated that the proportion of teaching time devoted to posterior composite restorations would increase within the next five years. Diversities and similarities between teaching programmes were noted between Japanese, North American and European dental schools, the Japanese programmes being closer to those in Europe than those in North America. CONCLUSION: The diversities in the teaching of posterior composite restorations in Japanese dental schools are as great as in other parts of the world. Such diversities must affect the overall quality of restorations in general practice.

Bicuspid↗
PubMed2000

Polymorphism in the interleukin-4 promoter affects acquisition of human immunodeficiency virus type 1 syncytium-inducing phenotype.

The emergence of syncytium-inducing (SI) variants of human immunodeficiency virus type 1 (HIV-1) in infected individuals is an indicator of poor prognosis and is often correlated with faster CD4(+) cell depletion and rapid disease progression. Interleukin-4 (IL-4) is a pleiotropic cytokine with various immune-modulating functions including induction of immunoglobulin E (IgE) production in B cells, down-regulation of CCR5 (a coreceptor for HIV-1 non-SI [NSI] strains), and up-regulation of CXCR4 (a coreceptor for HIV-1 SI variants). Here we show that homozygosity of a polymorphism in the IL-4 promoter region, IL-4 -589T, is correlated with increased rates of SI variant acquisition in HIV-1-infected individuals in Japan. This mutation was also shown to be associated with elevated serum IgE levels in HIV-1-infected individuals, especially in those at advanced stages of disease. In contrast, neither a triallele polymorphism in IL-10, another Th2 cytokine, nor a biallele polymorphism in the RANTES promoter affected acquisition of the SI phenotype. This finding suggested that IL-4-589T increases IL-4 production in the human body and thus accelerates the phenotypic switch of HIV-1 from NSI to SI and possibly disease progression of AIDS.

Alleles↗
PubMed2000

A case of penetrating aortic atherosclerotic ulcer with hemoptysis.

A 69-year old Japanese woman with hypertension was admitted because of continuous back pain and recurrent hemoptysis. Radiographic findings showed an enhanced irregular mass, at the aortic arch fed by the tracheal artery, which implied both a penetrating aortic atherosclerotic ulcer and lung cancer. Diagnostic surgery revealed no evidence of cancer but did reveal a rupture of the intima at the distal part of the aortic arch. It is assumed that the transmural oozing occurred after development of the penetrating aortic ulcer, which formed an extra-aortic hematoma and caused surrounding inflammation, and led to tracheal artery feeding. The intramural hematoma might have weakened vascular wall tension from the aorta, and formed an oozing extra-aortic hematoma instead of an acute rupture.

Aged↗
PubMed2000

The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents.

The role of oral chemotherapy has been getting expanded because of the potential advantage in patients' convenience and better quality of life as well as in cost-effectiveness as compared with intravenous chemotherapy. In this article, the history, mechanism of anti-tumor activity, and clinical use of oral chemotherapy using 5-fluorouracil (5-FU) derivative chemotherapeutic agents are reviewed. Pharmacological analysis has revealed that 5-FU, a basic chemotherapeutic agent widely used against a variety of malignant tumors, shows a time dependent anti-tumor activity, and that continuous maintenance of 5-FU concentration in blood is the optimal method in 5-FU administration. UFT, a combination drug of ftorafur (tetrahydrofuranyl-5-fluorouracil, tegafur, FT) and uracil, has been developed to have potent anti-tumor activity by maintaining higher 5-FU concentration in blood and tumor tissues for a long time. FT is a pro-drug that releases 5-FU continuously, and uracil is added to inhibit degradation of the released 5-FU. Clinically, oral administration of UFT has proved to be effective as an adjuvant therapy after surgery for some malignant tumors such as non-small cell lung cancer. Moreover, UFT has proved to be effective for inoperable advanced malignancies such as colorectal cancer, especially in combination with leucovorin or cisplatin. Recently, S-1, a more active oral 5-FU derivative chemotherapeutic agent has been developed in Japan. Several factors to affect anti-tumor effects and/or toxicities of 5-FU and the derivatives, such as thymidylate synthase activity, dehydropyrimidine dehydrogenase activity and p53 status, are also discussed in the article. In conclusion, oral administration of 5-FU derivatives such as UFT may have several clinical advantages over intravenous 5-FU administration.

Animals↗
PubMed2000

Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

OBJECTIVE: The aim of the study was to investigate the relationships between remnant-like particle (RLP) cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 86 nonobese Japanese type 2 diabetic patients (72 men and 14 women, aged 40-83 years, BMI 20.1-26.6 kg/m2) were studied. BMI, HbA1c levels, and fasting concentrations of plasma glucose, serum lipids (RLP cholesterol, total cholesterol, HDL cholesterol, and triglycerides), and serum insulin were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The subjects were divided into two groups according to the value of HOMA-IR. Values >2.5 were indicative of the insulin-resistant state, and values <2.5 were indicative of the insulin-sensitive state. RESULTS: The insulin-resistant group had significantly higher RLP cholesterol and triglyceride levels and lower HDL cholesterol levels compared with the insulin-sensitive group. Univariate regression analysis showed that insulin resistance was positively correlated with BMI (r = 0.254, P = 0.019), HbA1c levels (r = 0.278, P = 0.011), RLP cholesterol levels (r = 0.315, P = 0.004), and triglyceride levels (r = 0.332, P = 0.002) and was negatively correlated with HDL cholesterol levels (r = -0.301, P = 0.006) in our diabetic patients. Multiple regression analysis showed that insulin resistance was independently associated with serum triglyceride levels, which explained 13.5% of the variability of insulin resistance in our nonobese Japanese type 2 diabetic patients. CONCLUSIONS: These results indicate that 1) nonobese Japanese type 2 diabetic patients with insulin resistance are characterized by high RLP cholesterol and triglyceride levels, and low HDL cholesterol levels; and 2) the level of serum triglycerides is an independent predictor of insulin resistance in these patients.

Apolipoproteins↗
PubMed2000

Epitope analysis and utility of monoclonal antibodies to native and recombinant human thymidylate synthase.

The expression of thymidylate synthase (TS) in human cancer tissues has been suggested to be a prognostic factor for patients receiving 5-fluorouracil-based chemotherapy. We generated monoclonal antibodies to both recombinant and native TS and analyzed the epitopes on the TS molecule. Two monoclonal antibodies were obtained from recombinant human TS proteins (RTSMA1 and RTSMA2) and two monoclonal antibodies raised to native TS in human cancers (NTSMA1 and NTSMA2) were obtained, and were found to have a high affinity and specificity for TS proteins. To identify the human TS epitope that these monoclonal antibodies recognized, we constructed plasmids to produce full-length and two partially deleted TS proteins fused to glutathion-S-transferase (GST). Western blot analysis showed that RTSMA1 and 2 only reacted with full-length TS and NTSMA1 and 2 reacted with all three recombinant TS proteins, suggesting that the epitopes of the former were located at C-terminal sites (D186-V313), and those of the latter were at N-terminal sites (M1-M61). The RTSMA 1 and 2 epitopes were more accurately mapped using 8 oligopeptides to the region of I267 to L282 which was situated at the surface of the TS protein. Highly sensitive detection of human TS was also possible by sandwich ELISA using a combination of different types of antibody rather than a single type. In conclusion, different type monoclonal antibodies to human TS protein may contribute to the detection of TS in cancer patients.

Amino Acid Sequence↗
PubMed2000

Experimental postoperative adjuvant chemotherapy by UFT using primary tumor amputation model.

We evaluated the postoperative adjuvant chemotherapy by UFT using the primary tumor amputation-pulmonary metastasis model. When Lewis lung carcinoma (LLC) primary tumors on the hind foot pad grew palpable, they were amputated on two different days. In experiment (A) (earlier amputation model), micrometastases were detected on the day of amputation only by the histopathological examination. In the experiment (B) (later amputation model), nodules could be determined even by necropsy. Long-term (60-day) consecutive administration of UFT (22 mg/kg/day), which produced no body weight loss, markedly prolonged the survival period in experiment (A) (ILS: over 118%), 1 of the 15 mice being cured. UFT had a relatively weak but significant effect (67% of ILS) in schedule (B). Using the same model, we examined the inhibitory effect of UFT (2-week administration) on the number of metastatic nodules. A significant decrease of metastatic nodules was observed by UFT with both amputation schedules, but its effect was superior with schedule (A). In the same model using Colon 26 PMF-15, UFT markedly prolonged the survival period of mice (150% of ILS) and significantly decreased the metastatic nodules (86% inhibition). The dose of UFT used was relatively low, and did not significantly inhibit the growth of large tumors. However, the sensitivity to the micrometastases was high. These findings suggest that the postoperative adjuvant chemotherapy by the long-term consecutive administration of UFT would be effective for clinical cancer especially in curatively resected cases.

Amputation, Surgical↗
PubMed2000

Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.

5-Fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FdUrd) and 5-trifluorothymidine (F3(d)Thd) are antimetabolites which are metabolized to their corresponding active forms which inhibit DNA synthesis via inhibition of thymidylate synthase (TS). To investigate ways of overcoming 5-FU-resistance, we established acquired-resistant colorectal cancer cell lines against these three drugs by continuous and step-wise escalation of drugs, and analyzed the cytotoxicity and the mechanism of resistance to the drugs. When cells were incubated with the 3 drugs for 72 h, the resistance ratio to parental DLD-1 human colorectal tumor cells was 65.2 for DLD-1/5-FU, 9.7 for DLD-1/FdUrd and 448.6 for DLD-1/F3(d)Thd cells. DLD-1/5-FU cells did not show any cross-resistance against FdUrd and F(3)dThd. However, DLD-1/FdUrd cells showed 3- and 9-fold increased resistance to 5-FU and F3(d)Thd, respectively, and DLD-1/F3(d)Thd cells also showed about 90-fold resistance to FdUrd. Analysis of enzyme activities and gene expression associated with pyrimidine metabolism indicated that a significant decrease in orotate phosphoribosyltransferase activity in DLD-1/5-FU cells, a 7-fold increase of TS mRNA in DLD-1/FdUrd cells, and a 37-fold decrease in thymidine kinase activity of DLD-1/F3(d)Thd cells were the major mechanisms of drug resistance. These findings were closely associated with the cytotoxicity of 5-FU, FdUrd and F3(d)Thd against the established 5-FU-, FdUrd- or F3(d)Thd-resistant cells. When DLD-1/FdUrd cells expressing increased TS mRNA were treated with FdUrd and F3(d)Thd for only 4 h, the resistance ratios of DLD-1/FdUrd cells to parental DLD-1 cells were markedly different for FdUrd and F3(d)Thd, suggesting that the cytotoxicity with short-time exposure to F3(d)Thd is due to a mechanism other than TS inhibition, although the cytotoxicity of F3(d)Thd in the short-time is low compared to that of long-time exposure. In conclusion, F3(d)Thd, an antimetabolite that inhibits TS activity, may be effective against 5-FU and/or FdUrd-resistance in colorectal cancer cells caused by amplification of TS and/or deletion of orotate phosphoribosyltransferase.

Antimetabolites, Antineoplastic↗