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Biomedical subjects

Y Kaneda

Publications and source records attributed to Y Kaneda.

At least 163 records · Page 9Linked to original sources
PubMed2000

Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo.

Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10 expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ) was intraperitoneally injected into mice on day -3. This was followed by intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase activity of bronchoalveolar lavage fluid and tumor necrosis factor-alpha mRNA expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline content of the whole lung on day 21 were inhibited significantly by hIL10-HVJ treatment. However, Cont-HVJ treatment could not suppress any of these parameters. We also examined the in vitro effects of IL-10 on the human lung fibroblast cell line WI-38. IL-10 significantly reduced constitutive and transforming growth factor-beta-stimulated type I collagen mRNA expression. However, IL-10 did not affect the proliferation of WI-38 cells induced by platelet-derived growth factor. These data suggested that exogenous IL-10 may be useful in the treatment of pulmonary fibrosis.

Animals↗
PubMed2000

In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy.

Cardiac angiotensin-converting enzyme (ACE) may play an important role in regulating cardiac hypertrophy. Angiotensin II (Ang II) stimulates cardiac hypertrophy as well as the production of extracellular matrix. However, it is still unclear whether Ang II exerts a direct effect on cardiac hypertrophy independent of its effect on blood pressure or the circulating renin-angiotensin system. Although ACE inhibitors and/or Ang II receptor antagonists have regressed cardiac hypertrophy, classic pharmacological experiments cannot exclude the contribution of hemodynamics and the circulating renin-angiotensin system. In vivo gene transfer provides the opportunity of assessing the effects of increased cardiac angiotensin in the intact animal without circulating angiotensin or blood pressure. Therefore, we used a "gain of function" approach to obtain local overexpression of cardiac ACE. Transfection of the human ACE vector into rat myocardium resulted in a significant increase in cardiac ACE activity (P<0.01). More interestingly, morphometry at 2 weeks after transfection revealed a significant increase in the thickness and areas of cardiac myocytes in hearts transfected with the ACE vector (P<0.01). In addition, transfection of the ACE vector also resulted in a significant increase in collagen content (P<0.01). This increase in cardiac hypertrophy was abolished by the administration of perindopril. Local transfection of the ACE vector into the heart did not result in systemic effects such as increased blood pressure, heart rate, or serum ACE activity. In summary, we have demonstrated that increased autocrine/paracrine angiotensin can directly cause cardiac hypertrophy independent of systemic factors and hemodynamic effects. This approach has important potentials for defining the role of autocrine/paracrine substances in cardiovascular disease.

Animals↗
PubMed2000

Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting enzyme expression attenuates neointimal formation: evidence for tissue angiotensin-converting enzyme function.

It has been proposed that vascular angiotensin-converting enzyme (ACE) plays an important role in regulating vascular growth. Indeed, ACE inhibitors have been reported to prevent neointimal formation after vascular injury in a rat carotid artery model. However, classic pharmacological experiments cannot exclude the potential contributions of hemodynamics and the circulating renin-angiotensin system (RAS). In this study, we used antisense oligodeoxynucleotide (ODN) to obtain local blockade of vascular ACE expression without effects on systemic hemodynamics and circulating RAS. To increase the effectiveness of antisense action, we modified the hemagglutinating virus of Japan-liposome ODN delivery method by cotransfection with nuclear protein (high mobility group 1 [HMG-1]) and RNase H. In vitro experiments showed the enhanced efficacy of antisense ODN by cotransfection of HMG-1 and RNase H compared with ODN alone. In vivo transfection of antisense ACE ODNs into intact uninjured rat carotid artery resulted in a significant reduction of vascular ACE activity, and cotransfection of HMG-1 and RNase H showed further reduction. We examined the effects of local blockade of vascular ACE expression on neointimal formation after vascular injury. Transfection of antisense ACE ODNs resulted in the attenuation of neointimal formation, whereas sense and scrambled ODNs did not. Blood pressure, heart rate, and serum ACE activity were not affected by antisense treatment. The magnitude of vascular ACE inhibition correlated with the suppression of the neointimal size. Overall, this study demonstrates that local antisense ODN inhibition of vascular ACE expression attenuates neointimal formation independent of hemodynamics and circulating RAS. The results support the existence of a functional tissue angiotensin system in the rat vessel wall.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Catheter-delivered in vivo gene transfer into rat myocardium using the fusigenic liposomal mediated method.

We compared the efficacy of four different in vivo hemagglutinating virus of Japan (HVJ)-liposome gene transfer methods, i.e., direct myocardial injection (i.m.), injection into the left ventricular cavity (LV), infusion at the level of the coronary cusps (CI), or injection into the left ventricular cavity with a balloon catheter blocking aortic flow (LV+B) to transfer beta-galactosidase, FlTC-labeled oligodeoxynucleotide (ODN), and/or luciferase genes into the rat heart. I.m. caused highly efficient gene transfer in the limited area around the injection site, which suggests that i.m. may be a suitable method for targeted treatment of focal lesion. In the LV+B group, all rats had myocardial beta-galactosidase staining and fluorescence of FITC-labeled ODN in the nuclei of cardiac myocytes around the coronary arteries and the vasa vasorum, and some transfected myocytes were observed in the middle of the myocardium without any evidence of injury. In contrast, in the CI group, only half of the animals had myocardial expression of beta-galactosidase. In contrast, fluorescence or luciferase activity was present throughout the left ventricle in the LV+B group. However, the percentage of myocytes that exhibited fluorescence was less than 1% of the total ventricular myocyte population and luciferase activity in the LV+B group was 1.6% of that in the i.m. group. No evidence of luciferase expression was observed in brain, lung, liver, kidney, or testis in either the i.m. or LV+B group. These results suggest that HVJ-liposome gene transfer into the myocardium through the coronary arteries using a balloon-catheter technique is safe and has the potential for causing widespread transgene expression with organ-specificity, although the efficiency of gene transfer should be improved.

Animals↗
PubMed2000

Oligonucleotide-based gene therapy for cardiovascular disease: are oligonucleotide therapeutics novel cardiovascular drugs?

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, for which no known effective therapy exists. One strategy for combating disease processes has been to target to the transcriptional process. Two approaches have been used to accomplish this. One is the use of antisense that is complimentary to the mRNA of interest. The second approach is the use of ribozymes, a unique class of RNA molecules that not only store information but also process catalytic activity. Ribozymes are known to catalytically cleave specific target RNA leading to degradation, whereas antisense inhibit translation by binding to mRNA sequences on a stoicheometric basis. Theoretically, ribozymes are more effective to inhibit target gene expression. Especially, the application of DNA technology such as antisense strategy to regulate the transcription of disease-related genes in vivo has important therapeutic potential. More recently, transfection of cis-element double stranded (ds) oligodeoxynucleotides (ODN) (= decoy) as a powerful tool in a new class of anti-gene strategies for gene therapy has been reported. Transfection of ds ODN corresponding to 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 review, we have focused on the future potential of oligonucleotide (antisense, decoy & ribozyme)-based gene therapy for the treatment of cardiovascular disease.

Cardiovascular Diseases↗
PubMed2000

Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes.

In this study, we examined the feasibility of introducing macromolecules into cultured mouse brain capillary endothelial cells (MBEC4 cells) by utilizing the hemagglutating virus of Japan (HVJ)-liposomes with fusogenic activity. We used fluorescein isothiocyanate dextran (FITC-Dextran) and FITC-labeled oligodeoxynucleotide (FITC-ODN) as models of a macromolecule and an ODN, respectively. Intracellular fluorescence appeared rapidly after the exposure of MBEC4 cells to FITC-Dextran-containing HVJ-liposomes, and remained detectable for at least 3 days. Only a control level of intracellular fluorescence was seen after treatment with FITC-Dextran alone, FITC-Dextran with empty HVJ-liposomes or FITC-Dextran-containing liposomes without fusogenic activity. In the early phase after administration (0-30 min), the introduction of FITC-Dextran into MBEC4 cells by the HVJ-liposome method resulted in a rapid and time-dependent increase of intracellular fluorescence intensity. Moreover, FITC-ODN was also introduced into MBEC4 cells by the HVJ-liposome method, although FITC-ODN alone was not introduced. These results indicate that the HVJ-liposome method is useful for the efficient introduction of macromolecules, including ODN, into brain capillary endothelial cells.

Animals↗
PubMed2000

Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases.

Recent progress in molecular biology has led to the development of gene therapy as a new strategy to treat a variety of cardiovascular diseases. Targeted diseases range from single gene deficiency diseases to more complex diseases in adults such as restenosis after angioplasty. One obvious major target in the field of gene therapy is ischemic diseases such as myocardial infarction, angina and peripheral arterial diseases (i.e. ASO (arteriosclerosis obliterans)). In a large proportion of such patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for severe ischemic hearts and critical ischemic limbs. Therefore, novel therapies are required to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. The endothelial cell specificity of VEGF has been considered to be an important advantage for therapeutic angiogenesis, as endothelial cells represent the critical cellular element responsible for new vessel formation. Indeed, human gene therapy for ASO and angina has already begun in the USA, with surprising and beneficial effects. We have focused on hepatocyte growth factor (HGF), which is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis in various types of cells. Recently, HGF is also considered to be a powertul growth tactor for endothelial cells. In this review, we described the potential gene therapy for ischemic diseases using HGF.

Animals↗
PubMed2000

[The Japanese version of the Calgary Depression Scale for Schizophrenics (JCDSS)].

Depressive features are clearly recognized within the context of schizophrenia, and clarification of the comorbidity has important clinical implications particularly when choosing the best neuroleptics for treatment. However, in some cases, it is difficult to clearly distinguish between depressive symptoms, negative symptoms and extrapyramidal side-effects. Conventionally, the Zung's Self-Rating Depression Scale or Hamilton's Depression Rating Scale has been used as an evaluation scale of depressive symptoms. However, as these scales are designed for assessment of depression in non-psychotic populations, they do not necessarily distinguish depressed from non-depressed psychotic subjects. Recently, Addington et al. developed a new depression scale, the Calgary Depression Scale for Schizophrenics(CDSS), which was designed for the assessment of depression in schizophrenia. CDSS is a nine item structured interview scale, in which each item has a four point measure, each point anchored by descriptors. It has been tested, and it has been shown that there is no overlap with negative or extrapyramidal symptoms. Therefore, for its clinical application, we prepared the Japanese-language version(JCDSS).

Depression↗
PubMed2000

The relation between anxiety and depressive symptoms in normal subjects and patients with anxiety and/or mood disorders.

OBJECTIVE: We investigated the associations between anxiety and depressive symptoms in normal subjects and patients with mood and/or anxiety disorders, using the Japaneses version of Spielberger's STAI and the Zung SDS. METHODS: The subjects for the present study were 60 normal subjects, 15 patients with anxiety disorders and, 12 patients with mood disorders meeting the DSM-IV diagnostic criteria. Informed consent was obtained from all subjects. RESULTS: 1) Both the mean total state-anxiety (S-anxiety) and trait-anxiety (T-anxiety) scores were significantly higher in patients with anxiety disorders and mood disorders than in normal subjects. 2) The mean total SDS score was significantly higher in patients with anxiety disorders and mood disorders than in normal subjects. 3) In normal subjects, there were significant positive correlations between the total T- and S-anxiety scores and total SDS scores. 4) In patients with anxiety disorders, there were significant positive correlations between the total T- and S-anxiety scores and total SDS scores. 5) In patients with mood disorders, there were nonsignificant positive correlations between the total T- and S-anxiety scores and total SDS scores. CONCLUSION: Our results might provide support for the existence of common underlying mechanisms to anxiety and depression.

Adult↗
PubMed2000

[The Japanese version of the serotonin syndrome scale (JSSS)].

The serotonin(5-HT) syndrome(SS) is a condition of both the central and peripheral 5-HTergic hyperstimulation, characterized by a constellation of 5-HT-related side effects(confusion, agitation, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering or tremor in the setting of the recent addition of 5-HTergic agents. The SS is produced most often by the concurrent use of monoamine oxidase inhibitors and other 5-HTergic agents. However, more recent reports suggest that the tricyclic antidepressant or selective serotonin reuptake inhibitor(SSRI) monotherapy induces the SS. Recently, for the operationalized assessment of both the presence and the severity of the core symptoms of the SS, Hegerl et al. developed the Serotonin Syndrome Scale(SSS) as a modification of the diagnostic criteria of the SS proposed by Sternbach. Since, in Japan, some novel 5-HTergic agents have been, and will be in use, recognition of the SS is quite important. Therefore, for clinical application of SSS, we prepared the Japanese-language version (JSSS).

Diagnostic Techniques, Neurological↗
PubMed2000

Serologic response to Blastocystis hominis infection in asymptomatic individuals.

The pathogenic potential of Blastocystis hominis in the human intestine is subject to controversy because the organism has been found in both symptomatic and asymptomatic individuals. To help clarify this issue, we monitored the serologic response to the organism in B. hominis-infected individuals free of gastroenterologic disorders. 1) Serum antibodies to B. hominis were detected in 70% of infected asymptomatic individuals by an indirect immunofluorescence (IFA) test. 2) IFA and immunoelectron microscopy revealed that the antibody response was directed against a surface antigen(s) of the organism. 3) Analysis by immunoblotting implicated a 12 kDa protein of B. hominis. 4) The strongest positive reaction was obtained in an individual chronically infected for more than 2 years. It may be that long exposure to the parasite is necessary for a serologic response.

Animals↗
PubMed2000

Improvement of contralateral pulmonary function after unilateral lung volume reduction surgery (LVRS).

We evaluated contralateral pulmonary function after unilateral lung volume reduction surgery using pulmonary washout with Xe 133 gas before and 3 months after the operation. Eight patients underwent unilateral lung volume reduction surgery by video-assisted thoracoscopy. Dynamic single photon emission tomography was performed and the real half-time (T1/2) of each lung, defined as the time required to reach 50% of the equilibrium count during washout, was assessed on transaxial images. The preoperative total lung T1/2 was 126+/-12 sec, and this decreased significantly to 97+/-14 sec after surgery (p<0.01). The T1/2 of the operated lung decreased from 124+/-12 sec to 101+/-16 sec, but it increased postoperatively in two patients. The T1/2 of the contralateral lung also decreased significantly from 129+/-14 sec to 88+/-10 sec after surgery, including these two patients (p<0.01). Three patients (including these two) subsequently underwent contralateral volume reduction surgery 3 to 5 months after the first operation. The total lung T1/2 increased in one patient, although it improved slightly in the other two patients after the second operation. Unilateral volume reduction surgery does appear to have some benefit for contralateral pulmonary function. Even when the T1/2 of the operated lung increased postoperatively, the contralateral washout time was improved resulting in improvement of the total lung T1/2. In patients who did not benefit from unilateral volume reduction surgery, subsequent contralateral surgery may fail to improve pulmonary function.

Aged↗
PubMed2000

Gene therapy as a potential treatment for restenosis and myocardial infarction.

Cardiovascular disease is the leading cause of mortality and morbidity in developed countries. Most conventional therapy is inefficient and tends to treat the symptoms rather than the underlying causes of the disorder. Gene therapy offers a novel approach for the prevention and treatment of cardiovascular diseases. Gene transfer into somatic cells to interfere with the pathogenetic processes contributing to cardiovascular disease may provide such a novel approach for better prevention and treatment of cardiovascular disorders. The major development of gene transfer has importantly contributed to intense investigation of the potential of gene therapy in cardiovascular medicine. The amazing advances in molecular biology have provided a dramatic improvement in the technology that is necessary to transfer target genes into somatic cells. Recently, transfection of cis element double-stranded oligonucleotides (ODN), referred to as decoy ODN, has been reported to be a powerful tool in a new class of antigene strategies for gene therapy. In this article, we review the successful treatment of restenosis and myocardial infarction using the decoy strategy combined with an efficient gene transfer method.

Journal Article↗
PubMed1999

In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis.

A number of investigators have reported augmented expression of PDGF in lungs with idiopathic pulmonary fibrosis (IPF) or with other types of pulmonary fibrosis. To accomplish such a regulation of PDGF activity, we constructed an expression plasmid of the extracellular domain of PDGF receptor beta chain (XR), which lacks intracellular tyrosine kinase domain and transmembrane portions, and estimated the therapeutic effects of XR gene transfer through the trachea on bleomycin-induced lung fibrosis of C57BL/6 mice using the hemagglutinating virus of Japan(HVJ)-liposome method. The XR gene transfer ameliorated the increases in the wet weight and hydroxyproline content and the histopathologic changes of the lung induced by bleomycin. These findings suggest that PDGF plays a crucial role in the pathogenesis of pulmonary fibrosis, and that XR gene transfer using the HVJ-liposome method may limit the progression of pulmonary fibrosis.

Animals↗
PubMed1999

Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis.

The human 15-lipoxygenase (15-LO) gene was transfected into rat kidneys in vivo via intra-renal arterial injection. Three days later, acute (passive) or accelerated forms of antiglomerular basement membrane antibody-mediated glomerulonephritis were induced in transfected and nontransfected or sham-transfected controls. Studies of glomerular functions (filtration and protein excretion) and ex vivo glomerular leukotriene B(4) biosynthesis at 3 hr, and up to 4 days, after induction of nephritis revealed preservation or normalization of these parameters in transfected kidneys that expressed human 15-LO mRNA and mature protein, but not in contralateral control kidneys or sham-transfected animals. The results provide in vivo-derived data supporting a direct anti-inflammatory role for 15-LO during immune-mediated tissue injury.

Animals↗
PubMed1999

RNA melanoma vaccine: induction of antitumor immunity by human glycoprotein 100 mRNA immunization.

An RNA melanoma vaccine was investigated to induce protective immunity in a mouse-melanoma model. LacZ mRNA was synthesized in vitro by pSFV3 expression vector and introduced into the spleen of mice, using HVJ-liposomes. A high level of beta-galactosidase activity was detected for 10 days in mouse spleen. The human melanoma-associated antigen gp100 mRNA was synthesized in vitro by pSFV3 vector and encapsulated in HVJ-liposomes. Immunization by direct injection of the gp100 mRNA HVJ-liposomes into mouse spleen induced both anti-gp100 Ab and CTL responses against B16 melanoma. Immunization by administration of gp100 mRNA into the spleen delayed tumor growth and significantly prolonged survival compared with control treated mice. These preclinical studies demonstrate that an RNA tumor antigen vaccine strategy has potential application for human cancer treatment and prevention.

Animals↗
PubMed1999

Angiotensinogen gene-activating elements regulate blood pressure in the brain.

Although the angiotensinogen gene is a possible candidate as a determinant of hypertension, the molecular mechanisms of tissue angiotensinogen gene regulation have yet to be clarified. We identified essential transcription regulators of angiotensinogen production in the central nervous system using synthetic double-stranded oligodeoxynucleotides (ODNs) as "decoy" cis elements to block the binding of nuclear factors to promoter regions of the targeted gene. Using a gel mobility shift assay, angiotensinogen gene-activating element (AGE) 2 binding protein was detected in the brain nuclear extracts of both spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs). Importantly, the binding activity of AGE 2 and angiotensinogen mRNA level were significantly higher in the brain of SHRs than in that of WKYs. Using the decoy approach, we demonstrated a significant decrease in the blood pressure of SHRs by transfection of AGE 2 decoy, but not mismatched, ODNs into the lateral cerebroventricle, accompanied by a significant decrease in brain angiotensinogen concentration and mRNA, and angiotensin II level. That these effects, demonstrated herein, are due to central effects is confirmed by the fact that no changes in circulating levels of angiotensinogen or angiotensin II concentrations were observed. Notably, AGE 2 decoy ODNs did not decrease the blood pressure of WKYs. We conclude that the abnormal expression of AGE 2 binding protein in the central nervous system plays a crucial role in high blood pressure of a genetically hypertensive rat model.

Angiotensinogen↗