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T Ogihara

Publications and source records attributed to T Ogihara.

At least 235 records · Page 13Linked to original sources
PubMed1999

[Genetic analysis of candidate gene polymorphisms in elderly hypertension].

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.

Aged↗
PubMed1999

[An analysis of questionnaires about geriatric medicine/medical education sent to members of the Japanese Society of General Medicine].

Geriatric medical care can be viewed as general medical care for the elderly. We conducted a survey of members of the Japanese Society of General Medicine who belong to a university hospital, on their views of geriatric medicine/medical education. The questionnaires consisted of six categories of items about: (1) the physician's career; (2) whether the physician performs geriatric research in his/her laboratory; (3) whether the physician has an interest in geriatric medicine or medical education; (4) the physician's views on geriatric medicine or medical education; (5) of what pre- and post-graduate medical education on geriatric medicine should consist, from the physician's point of view: and (6) the physician's ideas about geriatric medicine/medical education in view of general medicine. Out of the 181 questionnaires sent, 96 (53%) people replied, of whom 51 (53.1%) were members of a Department of General Medicine, 57 (60%) were teaching staff, 46 (48.4%) had experience in home medical care such as home visits, and 17 (18.1%) belonged to the Japanese Society of Geriatric Medicine. Seventy-six respondents (85.4%) had an interest in geriatric medicine/medical education. Of the respondents, 96.8% recognized the need for pre- and post-graduate medical education concerning geriatrics. Some members of the Japanese Society of General Medicine who answered the questionnaire see geriatric medicine as entirely general medicine, and also that geriatric medicine is important, necessary and special. In addition, they see that the field of geriatric medicine is not yet developed in regard to geriatric medical care and education. Most respondents could not specify which section in a medical university is responsible for teaching the fields of basic and social medicine. This result shows that it may be difficult to incorporate pre-graduate geriatric medical education into the curriculum. As part of the pre-graduate curriculum of medical education on geriatrics, a practical exercise such as inspection of a geriatric hospital and geriatric home was considered most desirable by the respondents. Out of nine items, the top three most important aspects of post-graduate medical education on geriatrics for clinical and social medicine, were (1) studying the medical care and welfare of the elderly, (2) assessing the impaired life function of the elderly, and (3) studying pharmaco- therapy. Out of 6 items, the top three most important aspects of a practical exercise in post-graduate medical education in geriatrics were (1) providing general care to the elderly, (2) giving rehabilitation guidance and (3) providing psychological support for the elderly. Furthermore, 20 of the respondents (22.5%) have performed geriatric medical research on either the activities of daily life of the elderly or living wills, both of which seem to reflect the health and life of elderly people.

Attitude of Health Personnel↗
PubMed1999

[Diabetes mellitus in the elderly].

The prevalence of diabetes mellitus and glucose intolerance increases with advancing age. Age-related changes in glucose intolerance in non-diabetic subjects are primarily observed in postprandial blood glucose levels with only small changes in fasting levels. Age-related adjustment in the goals of treatment is much more important than that in diagnostic criteria. A careful assessment of the current medical status and consideration of remaining life expectancy are important in elderly patients with diabetes mellitus. Elderly patients with diabetes mellitus can be divided into two subgroups: elderly age-at-onset and younger age-at-onset groups. Diabetes in the former category is usually mild whereas patients in the latter category often suffer from chronic diabetic complications. It is important to assess the current status of patients relative to these categories and adjust the treatment of diabetes mellitus relative to current medical status of patients.

Adult↗
PubMed1999

[Gene loci and polymorphisms of angiotensin II receptor].

The gene encoding angiotensin II type 1 receptor (AT1) is mapped on 3q21-q25 region, and a polymorphism, A1166C, is located at 3'untranslated region (UTR). A1166C is associated with increased risk for hypertension, aortic stiffness, left ventricular hypertrophy and diabetic nephropathy, and synergistically increases the risk for ischemic heart disease with DD polymorphism of angiotensin converting enzyme gene. However, these results were still in controversy. On the other hand, the gene encoding angiotensin II type 2 receptor (AT2) gene is mapped on Xq22-q23 region, and a polymorphism, C3123A, is identified at 3'UTR of AT2 gene. However, any significant association with C3123A has not been obtained in case control studies yet.

Cardiomegaly↗
PubMed1999

[The usefulness of a new class antihypertensive drug, angiotensin II receptor antagonist, for essential hypertension].

Nonpeptide angiotensin II type 1-receptor antagonists, AT1 receptor antagonists, are newly developed and useful drugs for essential hypertension. In Japan, the efficacy and safty of losartan and candesartan cilexetil in patients with essential hypertension have been evaluated by the double-blind, parallel group-comparison study using enelaprol maleate as control drug. Both trials revealed that these drugs showed a hypotensive effect comparable to that of enalapril with a high safety since the adverse drug reaction of cough was recognized in very few patients. Since the blood pressure normalizes only in the patient of about 50%, it is often required to add low-dose hydrochlorothiazide or calcium antagonist. Combination therapies further decreased blood pressure without any increases in side effects of the drugs. AT1 receptor antagonists in both mono-therapy and combination therapy with diuretics/Ca antagonists are very useful and safe in the hypertension treatment.

Angiotensin Receptor Antagonists↗
PubMed1999

[A new medical treatment for thrombosis by genetic engineering].

There has been established a new medical treatment that is due to the progress of genetic engineering and the development of gene delivery techniques. As well as other fields, cardiologists investigate a protocol for gene therapy, including thrombosis and its related diseases. They make steady progress in the application of clinical trials. Specially, they have focused on gene therapy for the restenosis after percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG), and there are many successful reports. As one of the strategy for an inhibition of thrombosis formation, they try to deliver the genes of cyclooxygenase-1, tissue plasminogen activator (tPA) and endothelial nitric oxide synthetase (eNOS). Also, we target for the introduction of anti-sense oligonucleotide; proliferating cell nuclear antigen (PCNA), cell division cycle (cdc)-2 kinase, or p21 (sdi-1) gene in order to inhibit the progression of cell cycle in which vascular smooth muscle cells (VSMCs). Others and we pay attention to the function of vessel protection and find a protocol for the gene delivery of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which selectively induce the growth of endothelial cell. Since, particularly, VEGF and HGF induce angiogenesis, Others and we try to cure arteriosclerosis obliterans (ASO) with delivering these genes to the affected part. In addition, we develop new techniques such as the delivery of NF kappa B gene toward myocardial infarction and the transplantation of genetically modified myocardium that is treated with gene therapy. We place our hopes on these new technical applications to the clinical trial.

Genetic Therapy↗
PubMed1999

[Motilin].

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Adolescent↗
PubMed1999

[Allantoin].

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Adolescent↗
PubMed1998

Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2.

Adipocytes contain three major substrate proteins of the insulin receptor, termed IRS-1, IRS-2, and IRS-3. We demonstrated that IRS-1 and IRS-2 are located mainly in the low density microsome (LDM) fraction and are tyrosine phosphorylated in response to insulin stimulation, leading to phosphatidylinositol (PI) 3-kinase activation. In contrast, IRS-3 is located mainly in the plasma membrane (PM) fraction and contributes to PI 3-kinase activation in the PM fraction. The different cellular localizations of IRS proteins may account for the mechanism of insulin resistance induced by a high fat diet, considering that PI 3-kinase activation in the LDM fraction is reportedly essential for the translocation of GLUT4 in adipocytes. High fat feeding in rats increased both protein and mRNA levels of IRS-3 but decreased those of IRS-1 and IRS-2 in epididymal adipocytes. As a result, selective impairment of insulin-induced PI 3-kinase activation was observed in the LDM fraction, whereas PI 3-kinase activation was conserved in the PM fraction. This is the first report showing that different IRS proteins function in different subcellular compartments, which may contribute to determining the insulin sensitivity in adipocytes.

Adipocytes↗
PubMed1998

Novel therapeutic strategy for atherosclerosis: ribozyme oligonucleotides against apolipoprotein(a) selectively inhibit apolipoprotein(a) but not plasminogen gene expression.

BACKGROUND: Because mechanisms of atherosclerosis by lipoprotein(a) [Lp(a)] have been postulated in the decrease in active transforming growth factor-beta conversion by decreased plasmin, selective decrease in apolipoprotein(a) [apo(a)] independent of plasminogen may have therapeutic values. Although antisense can decrease apo(a), its application may be difficult because of very high homology of apo(a) gene to plasminogen. Thus we used ribozyme strategy that actively cleaves targeted genes to selectively inhibit apo(a) expression. METHODS AND RESULTS: We constructed ribozyme oligonucleotides containing phosphorothioate DNA- and RNA-targeted kringle 4 of the apo(a) gene that showed 80% homology to plasminogen. Transfection of human apo(a) gene produced Lp(a) in medium of HepG2 cells, whereas Lp(a) could not be detected in control cells. Cotransfection of ribozyme and apo(a) gene resulted in the decrease in mRNA of apo(a) but not plasminogen. Moreover, marked decrease in Lp(a) was also observed in the medium transfected with ribozyme and apo(a) gene compared with apo(a) gene alone (P<0.01), whereas there was no significant change in plasminogen level between ribozyme-transfected and control cells. Incubation of human vascular smooth muscle cells (VSMC) with conditioned medium from apo(a)-transfected HepG2 cells resulted in a significant increase in VSMC number, whereas addition of conditioned medium from cells cotransfected with ribozyme oligonucleotides and apo(a) gene resulted in no VSMC growth (P<0.01). DNA-based control oligonucleotides and mismatched ribozyme oligonucleotides did not have an inhibitory effect on Lp(a) production. CONCLUSIONS: Overall, our data revealed that transfection of ribozyme against the apo(a) gene resulted in the selective inhibition of the apo(a) but not the plasminogen gene, providing novel therapeutic strategy for treatment of high Lp(a), a risk factor for atherosclerosis.

Aorta↗
PubMed1998

Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes.

The cytotoxicity of reactive oxygen intermediates (ROIs) has been implicated in the destruction of pancreatic beta cells in insulin-dependent diabetes mellitus (IDDM). Thioredoxin (TRX), a redox (reduction/oxidation)-active protein, has recently been shown to protect cells from oxidative stress and apoptosis. To elucidate the roles of oxidative stress in the development of autoimmune diabetes in vivo, we produced nonobese diabetic transgenic mice that overexpress TRX in their pancreatic beta cells. In these transgenic mice, the incidence of diabetes was markedly reduced, whereas the development of insulitis was not prevented. Moreover, induction of diabetes by streptozotocin, an ROI-generating agent, was also attenuated by TRX overexpression in beta cells. This is the first direct demonstration that an antioxidative and antiapoptotic protein protects beta cells in vivo against both autoimmune and drug-induced diabetes. Our results strongly suggest that oxidative stress plays an essential role in the destruction of beta cells by infiltrating inflammatory cells in IDDM.

Animals↗
PubMed1998

Stimulatory effect of lipoprotein (a) on proliferation of human mesangial cells: role of lipoprotein (a) in renal disease.

As lipoprotein (a) [Lp(a)] abnormalities would accelerate glomerular injury, we studied the effect of Lp (a) on proliferation of cultured human mesangial cells (MC). Transfection of human apo (a) gene into human hepatoma cells, HepG2 cells, producing human apo B, resulted in the formation of Lp (a), while no Lp (a) was detected in control cells. In contrast, free apo (a) was detected in the medium of apo (a)-transfected MC. Incubation of cultured medium of HepG2 cells transfected with apo (a) gene with MC resulted in a significant increase in cell number compared to control (P<0.01). In contrast, little effect of transfection of apo (a) gene directly into MC on growth of MC was observed. Of importance, addition of LDL into the medium of MC transfected with apo (a) vector resulted in a significant increase in number of MC compared to control, whereas LDL did not show any effects on MC growth. As active TGF-beta was not detected in the medium of MC, and addition of neutralizing anti-TGF-beta antibody did not alter growth of MC, Lp (a) stimulated growth of MC via the independent mechanisms from the inhibition of TGF-beta activation.

Apolipoproteins A↗
PubMed1998

Application of transcription factor "decoy" strategy as means of gene therapy and study of gene expression in cardiovascular disease.

Recent progress in molecular biology has provided new techniques for inhibiting target gene expression. In particular, the application of DNA technology, such as antisense strategy to regulate the transcription of disease-related genes in vivo, has important therapeutic potential. Recently, transfection of cis-element double-stranded oligodeoxynucleotides (ODNs), referred to as "decoy" ODNs, has been reported to be a powerful tool in a new class of anti-gene strategies for gene therapy and in the study of transcriptional regulation. Transfection of double-stranded ODNs corresponding to the cis sequence will result in the attenuation of authentic cis-trans interaction, leading to the removal of trans factors from the endogenous cis elements with subsequent modulation of gene expression. This "decoy" strategy is not only a novel strategy for gene therapy as an anti-gene strategy but also a powerful tool for the study of endogenous gene regulation in vivo as well as in vitro. In this article, we reviewed (1) the mechanisms and (2) the potential applications of decoy strategy.

Animals↗
PubMed1998

Hydrogen peroxide induces up-regulation of Fas in human endothelial cells.

Hydrogen peroxide (H2O2), an oxidant generated by inflammatory cells, is an important mediator of injury of endothelial cells (ECs). Here we show that H2O2 induces up-regulation of the expression of Fas, a death signal, in human ECs in culture. Flow cytometric analysis with a mAb against human Fas showed that incubation for 24 h with H2O2 induced a dose-dependent increase in the level of Fas in ECs. Coincubation with catalase, which rapidly degrades H2O2, inhibited H2O2-induced up-regulation of Fas. H2O2 also induced a dose-dependent increase in Fas mRNA level. A significant increase in Fas mRNA levels was observed from 6 h after stimulation with H2O2. Vanadate, a protein phosphatase inhibitor, significantly enhanced Fas mRNA and protein levels in H2O2-treated ECs. On the other hand, genistein, a tyrosine kinase inhibitor, inhibited H2O2-induced Fas mRNA expression. Furthermore, a flow cytometric method with propidium iodide staining and electron microscopic analysis showed that incubation with an agonistic Ab against Fas (anti-Fas IgM) induced apoptosis in H2O2-treated cells. These findings suggest that H2O2 induces up-regulation of Fas in ECs and that activation of protein tyrosine kinase may be involved in the mechanism of H2O2-induced Fas expression. Therefore, Fas-mediated apoptosis may have a pathologic role in H2O2-induced EC injury and thereby provide a new therapeutic target.

Apoptosis↗
PubMed1998

Role of AP-1 complex in angiotensin II-mediated transforming growth factor-beta expression and growth of smooth muscle cells: using decoy approach against AP-1 binding site.

The cis element double-stranded oligodeoxynucleotides (ODN) ("decoy") approach has enabled us to clarify the responsible elements. Using this approach, we transfected AP-1 decoy ODN into VSMC cultured from WKY rats (WKY Adu) which produce latent TGF-beta, but not active TGF-beta, and Sprague-Dawley rats (CNC) which produce active and latent TGF-beta under Ang II-stimulation. AP-1, but not mismatched, decoy ODN abolished Ang II-stimulated TGF-beta gene expression and production in both Adu and CNC. However, AP-1 decoy did not alter DNA, RNA, and protein synthesis in Adu. In contrast, cell number was increased under Ang II stimulation by AP-1 decoy ODN in CNC without significant change in RNA and protein synthesis. These results showed that Ang II stimulated TGF-beta production through the AP-1 complex. In VSMC that produce active TGF-beta (CNC), the AP-1 complex stimulated by Ang II may inhibit cell growth through active TGF-beta production. Overall, this study demonstrates the utility of the decoy approach to study the specific function of cis elements in endogenous gene regulation such as Ang II-induced TGF-beta expression.

Angiotensin II↗
PubMed1998

A novel vascular modulator, hepatocyte growth factor (HGF), as a potential index of the severity of hypertension.

HGF (hepatocyte growth factor), a member of endothelium-specific growth factors, might contribute to protection and/or repair of vascular endothelial cells injured by high blood pressure (BP). If so, serum HGF level might be elevated in response to endothelial cell damage. To test this hypothesis, we measured serum levels of HGF in hypertensive and normotensive patients. Serum HGF concentration in hypertensive patients without any complication was significantly higher than normal subjects (p < 0.001). Serum HGF concentration showed a significant positive correlation with BP (p < 0.01). Interestingly, serum HGF concentration in hypertensive patients with complications was significantly higher than that in hypertensive patients without complication and normotensive subjects (p < 0.01). Of importance, hypertensive patients treated with antihypertensive drugs showed the same level of serum HGF concentration as normotensive subjects (p < 0.001). The present study demonstrated that serum concentration of HGF is significantly elevated dependent on the severity of hypertension, suggesting that HGF may be a new index of the severity of hypertension.

Antihypertensive Agents↗