メタクリルアミドの肺腫瘍発生作用に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1058号, 学位授与年月日：平成1年6月21日,学位授与年：198

PrP in M2 macrophages and influenza

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection

Antibody-based immunotherapeutic attempts in experimental animal models of prion diseases.

BACKGROUND: There has been a dramatic decrease in the risk of transmission of bovine spongiform encephalopathy to humans. In contrast, the risk of human-to-human transmission of variant Creutzfeldt-Jakob disease (vCJD) via medical treatments became potentially high since 4 vCJD cases were reported to be possibly transmitted through blood transfusion in the UK. However, no treatments are yet available for curing prion diseases. OBJECTIVE: Conversion of the normal prion protein, PrP(C), to the amyloidogenic PrP, PrP(Sc), plays a pivotal role in the pathogenesis. Recently, certain anti-PrP or anti-37/67-kDa laminin receptor (LRP/LR) antibodies were shown to have the potential to cure chronically infected cells, clearing PrP(Sc) from the cells. This has raised the possibility of antibody based-immunotherapy for prion diseases. This article aims to introduce and discuss the recently published attempts of immunotherapy in prion diseases. METHODS: Bibliographic research was carried out using the PubMed database. Patent literature was searched using the UK Intellectual Property Office website. RESULTS/CONCLUSION: No satisfying consequences in animals could be detected with anti-PrP antibodies directly infused into the brains of animals by the intraventricular route or by anti-PrP or anti-LRP/LR single chain fragment antibodies directly delivered into the brain by virus vector-mediated gene transfer. This is probably because such delivery systems failed to deliver the antibodies to the neurons relevant for the treatments

陰膳方式食物収集による日本人の栄養調査 : 血清脂質と栄養摂取量

Nutrient intake was surveyed by total food duplicate method in combination with serum biochemistry among adult Japanese women. The survey was conducted twice in the same 19 sites all over Japan, once in the years around 1980 (the first survey on 199 women) and then in 1991-6 (the second survey on 379 women). The participants 19 sites were classified into four groups of those in Hokkaido, urban areas, rural areas and Okinawa by the location of residence, and relation of findings serum lipid analyses with nutrient intakes was examined. In the Hokkaido group, cholesterol and triglyceride in serum, and intake of animal fat and saturated fatty acids (SFAs) were lower in the second survey than in the first survey. In the urban group, serum cholesterol, and intakes of animal fats and SFAs were the highest among the four groups both in the first and second surveys. In contrast, serum cholesterol, and intakes of animal fats and SFAs in the rural group were lower than the levels in other groups in the first survey, but the three groups in the second survey. In Okinawa, serum cholesterol was lower than others in the second survey. Intake of fat-based energy was high, but intakes of monounsaturated fatty acids and n-6 polyunsaturated fatty acids were also high. When all subjects were combined, the serum cholesterol level was 193mg/100ml (as an arithmetic mean) in the first survey and it was 202 mg/100 ml in the second survey, and this increase was paralleled by the increase in the number of aged survey subjects. Serum triglyceride level was 111mg/100ml in the first survey, and 99 mg/dl in the second survey. The reduction may be attributable to the reduced nutrient intake among young people. Serum cholesterol correlated significantly with intake of animal fats and SFAs, but the correlation with total energy intake was significant only in the second survey. BMI correlated significantly with serum triglyceride levels in both surveys, but the correlation coefficient was smaller in the second survey than in the first survey. There was no correlation between BMI and serum cholesterol in both surveys

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout