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Biomedical subjects

Tomohiro Asai

Publications and source records attributed to Tomohiro Asai.

At least 19 recordsLinked to original sources
PubMed2006

The role of Staphylococcus aureus adhesins in the pathogenesis of ventricular assist device-related infections.

Ventricular assist devices (VADs) are an important form of therapy for end-stage congestive heart failure. However, infection of the VAD, which is often caused by Staphylococcus aureus, poses a major threat to survival. Using a novel in vitro binding assay with VAD membranes and a heterologous lactococcal system of expression, we identify 3 S. aureus proteins--clumping factor A (ClfA) and fibronectin binding proteins A and B (FnBPA and FnBPB) as the main factors involved in adherence to VAD polyurethane membranes. Adherence is greatly diminished by long implantation times, reflecting a change in topological features of the VAD membrane, and is primarily mediated by the FnBPA domains in the staphylococcal proteins. We also compare the adherence of S. aureus mutant strains and show that other staphylococcal components appear to be involved in adherence to VAD membranes. Finally, we demonstrate that ClfA, FnBPA, and FnBPB mediate bacterial infection of implanted murine intra-aortic polyurethane patches.

Adhesins, Bacterial↗
PubMed2006

Mitral-aortic intervalvular pseudoaneurysm with ventricular septal defect.

A 35-year-old woman was found on echocardiography to have a pseudoaneurysm of the mitral-aortic intervalvular fibrosa, residual ventricular septal defect, and aortic regurgitation. She had undergone surgical closure of a ventricular septal defect at age 7 and was found to have residual shunt several years later. She had been followed nonsurgically and had symptoms of cardiac failure during her 2 pregnancies. The pseudoaneurysm and the septal defect were successfully repaired.

Aneurysm, False↗
PubMed2005

Antiangiogenic photodynamic therapy (PDT) by using long-circulating liposomes modified with peptide specific to angiogenic vessels.

For the improvement of therapeutic efficacy in photodynamic therapy (PDT) by using a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), we previously prepared polyethylene glycol (PEG)-modified liposomes encapsulating BPD-MA (PEG-Lip BPD-MA). PEGylation of liposomes enhanced the accumulation of BPD-MA in tumor tissue at 3 h after injection of it into Meth-A-sarcoma-bearing mice, but, unexpectedly, decreased the suitability of the drug for PDT when laser irradiation was performed at 3 h after the injection of the liposomal photosensitizer. To improve the bioavailability of PEG-Lip BPD-MA, we endowed the liposomes with active-targeting characteristics by using Ala-Pro-Arg-Pro-Gly (APRPG) pentapeptide, which had earlier been isolated as a peptide specific to angiogenic endothelial cells. APRPG-PEG-modified liposomal BPD-MA (APRPG-PEG-Lip BPD-MA) accumulated in tumor tissue similarly as PEG-Lip BPD-MA and to an approx. 4-fold higher degree than BPD-MA delivered with non-modified liposomes at 3 h after the injection of the drugs into tumor-bearing mice. On the contrary, unlike the treatment with PEG-Lip BPD-MA, APRPG-PEG-Lip BPD-MA treatment strongly suppressed tumor growth after laser irradiation at 3 h after injection. Finally, we observed vasculature damage in the dorsal air sac angiogenesis model by APRPG-PEG-Lip BPD-MA-mediated PDT. The present results suggest that antiangiogenic PDT is an efficient modality for tumor treatment and that tumor neovessel-targeted, long-circulating liposomes are a useful carrier for delivering photosensitizer to angiogenic endothelial cells.

Angiogenesis Inhibitors↗
PubMed2005

Enhanced antitumor activity of xanthohumol, a diacylglycerol acyltransferase inhibitor, under hypoxia.

Cancer chemotherapy for hypoxic tumor cells is thought to be an important issue, since hypoxia is related to tumor growth, apoptosis, angiogenesis and metastasis. Here, the bioactivities of xanthohumol (XN), a diacylglycerol acyltransferase inhibitor, against hypoxic cells were investigated. At first, the inhibitory effects of XN on the formation of lipid droplets in the cytoplasm were evaluated in hypoxia. Hypoxia upregulated the synthesis of triglyceride and promoted the formation of lipid droplets in the cytoplasm, however, the treatment of XN downregulated the triglyceride synthesis and completely canceled the appearance of lipid droplets. Second, the effects of XN on the proliferation and the motility of HT-1080 human fibrosarcoma were investigated. The proliferation of HT-1080 was significantly suppressed in the presence of XN only in hypoxic condition but not in normoxic condition. XN also suppressed the motility of HT-1080 that was enhanced by hypoxia. Since, most cells in solid tumor were thought to be in hypoxic condition and acquired malignancy in response to hypoxia, these data suggest that XN may have potent and specific activities against cancerous cells. Furthermore, these data suggested that lipid metabolism may play an important role for hypoxic tumor cells and proposed a new therapeutic target for cancer chemotherapy.

Acyltransferases↗
PubMed2005

Time-dependent regional myocardial denervation as a nonspecific response to transmyocardial laser revascularization.

BACKGROUND: It is known that denervation occurs in the regions of myocardium treated by laser transmyocardial revascularization (TMR). The purpose of this study was to determine when regional denervation occurs in the early postoperative period and whether or not it is specific to laser TMR when compared with TMR using ultrasonically activated energy. METHODS: Dogs with normal myocardium underwent either holmium:yttrium-aluminum-garnet laser TMR, TMR using an ultrasonic activated surgical blade, or a thoracotomy as sham operation. The responses of mean arterial pressure to topical application of bradykinin were examined at 3 time points: before, 1 hour after, and 2 weeks after surgery. The hearts were excised for Western blot and immunohistochemical analysis. RESULTS: The response of mean arterial pressure to bradykinin was similarly attenuated in both TMR groups 1 hour after treatment and decreased to almost none after 2 weeks compared with pretreatment values. By comparison, the sham group showed persistent responses at both time points. Tissue tyrosine hydroxylase content of the treated area decreased significantly compared with the non-treated area in both TMR groups. Immunohistochemistry using anti-Protein Gene Product 9.5 and anti-synaptophysin antibodies showed a significant decrease in the number of positive nerve fibers in both TMR treatment groups compared with the sham group. CONCLUSIONS: Transmyocardial revascularization caused partial alteration in myocardial innervation immediately after TMR. Tissue responses may continue to occur for the first 2 weeks after treatment. Tissue responses may also contribute to the development of denervation regardless of the energy source in non-ischemic canine myocardium.

Animals↗
PubMed2005

Influence of ischemic injury on vein graft remodeling: role of cyclic adenosine monophosphate second messenger pathway in enhanced vein graft preservation.

OBJECTIVE: Endothelial injury during the harvest of saphenous vein grafts might play an important role in the development of vein graft disease after coronary artery bypass grafting. Using a murine autologous arterialized vein patch model, we tested whether the initial ischemic insult of vein grafts was linked to the later development of graft neointimal hyperplasia and whether the restoration of the cyclic adenosine monophosphate second messenger pathway would attenuate the development of neointimal hyperplasia. METHODS: A segment of the external jugular vein of a mouse was grafted onto its abdominal aorta. Three weeks after the operation, the degree of neointimal hyperplasia of the implanted graft was compared among (1) grafts without preservation, (2) grafts with 2 hours of preservation (25 degrees C) in heparinized saline, and (3) grafts with 2 hours of preservation in heparinized saline in the presence of a cyclic adenosine monophosphate analog. In addition, cyclic adenosine monophosphate contents of vein grafts and leukocyte adherence to the graft endothelium were assessed. RESULTS: Cyclic adenosine monophosphate contents were significantly decreased after 2 hours of preservation (212 +/- 8 vs 156 +/- 5 pmol/L, P < .01). The grafts preserved for 2 hours showed greater neointimal hyperplasia compared with the grafts without preservation (neointimal expansion, 68.7% +/- 9.6% vs 46.1% +/- 4.8%; P < .01). The addition of a cyclic adenosine monophosphate analog to the preservation solution significantly suppressed neointimal hyperplasia of grafts preserved for 2 hours (44.3% +/- 5.0%). Inhibiting the cyclic adenosine monophosphate-dependent protein kinase by adding Rp-cAMPS abrogated the beneficial effects. Furthermore, grafts preserved for 2 hours had significantly more leukocytes adhering to the graft endothelium 24 hours after the operation compared with nonpreserved grafts, which was significantly reduced by the cyclic adenosine monophosphate treatment. CONCLUSIONS: Ischemic insult during vein graft harvest and preservation is a key factor in the development of vein graft neointimal hyperplasia at least in part caused by the depletion of cyclic adenosine monophosphate. We conclude that stimulation of the cyclic adenosine monophosphate second messenger pathway might be a potential strategy for the prevention of vein graft disease.

Adenosine Monophosphate↗
PubMed2005

Liposomalized oligopeptides in cancer therapy.

Organ-specific delivery of biofunctional agents is thought to enhance their activity and to reduce their side effects. Liposomes have been used as drug carriers in cancer chemotherapy, since they accumulate passively in tumor tissues due to an enhanced permeability and retention (EPR) effect. In addition, modification of liposomes with specific ligands enables active targeting. A small peptide having a high affinity for a certain antigen is suitable for modification of liposomes, since it is biocompatible, biodegradable, and less antigenic compared with antibody and other modifiers. Oligopeptide-modified liposomes are prepared by using lipophilic derivatives of the peptide, which are synthesized easily and incorporated readily into the liposomal bilayer. We describe two examples of the use of liposomal oligopeptides: one for antimetastatic therapy and the other for antineovascular therapy. Arg-Gly-Asp (RGD)-related peptides are known to contribute various cellular functions such as adhesion and invasion and to inhibit tumor metastasis. However, peptide drugs are generally rapidly hydrolyzed and eliminated from the bloodstream. Liposomal RGD enables the half-lives and affinity to be improved, resulting in enhancement of antimetastatic activity. We then describe the usefulness of liposomal Ala-Pro-Arg-Pro-Gly (APRPG) for tumor treatment, which is specific for tumor angiogenic vessels. APRPG is originally isolated by use of a phage-displayed peptide library. Adriamycin encapsulated in APRPG-modified liposomes accumulated specifically in and damage tumor neovessels, resulting in notable antitumor efficacy.

Animals↗
PubMed2005

Digital radiographic quantification of myocardial blood flow around a transmyocardial laser channel in rabbit hearts.

BACKGROUND: A mechanism underlying the benefits of transmyocardial laser revascularization (TMLR) has been presumed to be improvement in perfusion. We evaluated myocardial blood flow around a laser channel using digital radiography combined with a 3H-labeled desmethylimipramine ([3H]DMI) deposition. METHODS AND RESULTS: A laser channel was created in the left ventricular wall using a YAG-laser in 6 non-ischemic rabbit hearts. After 8 weeks, [3H]DMI(1.11 MBq) was injected into the left atrium and the TMLR-treated myocardium was sectioned. Another 6 hearts were examined as controls. We measured [3H]DMI density in arbitrary units with digital radiography in the channel remnant, the surrounding area and a remote area. Flow distribution was quantified by the coefficient of variation of flows (CV). The surrounding area had the highest density (p < 0.001) and the lowest CV (p < 0.001), and had higher density (p < 0.001) and lower CV (p < 0.001) than the controls. There was no transmural difference in the density in all domains. The CV increased with depth in the remote area, as well as in controls (p < 0.001), but there was no transmural difference in the surrounding area. CONCLUSIONS: The TMLR increases myocardial blood flow and decreases flow heterogeneity in the surrounding area. The disappearance of transmural difference in flow heterogeneity might indicate the remodeling of microcirculation to improve regional oxygen delivery.

Animals↗
PubMed2005

Antineovascular therapy, a novel antiangiogenic approach.

Angiogenesis is a crucial event in tumour growth, since the growth of tumour cells depends on the supply of essentials such as oxygen and nutrients. Therefore, suppression of angiogenesis is expected to show potent therapeutic effects on various cancers. Additionally, this 'antiangiogenic therapy' is thought not only to eradicate primary tumour cells, but also suppress tumour metastases through disruption of haematogenous metastatic pathways. Tumour dormancy therapy does not aim to disrupt newly formed angiogenic vessels but aims to inhibit further formation of neovessels through inhibiting certain processes of angiogenesis. This raises a question of whether or not these antiangiogenic agents bring complete cure of tumours as complete cut-off of oxygen and nutrients is not expected by the treatment with these agents. This paper will review a novel antiangiogenic therapy, antineovascular therapy (ANET). ANET is categorised in antiangiogenic therapy but is different from tumour dormancy therapy using conventional angiogenic inhibitors: ANET aims to disrupt neovessels rather than to inhibit neovessel formation. ANET is based on the fact that angiogenic endothelial cells are growing cells and would be effectively damaged by cytotoxic agents when the agents are effectively delivered to the neovessels. The complete eradication of angiogenic endothelial cells may cause complete cut-off of essential supplies to the tumour cells and lead to indirect but strong cytotoxicity instead of cytostasis caused by the inhibition of angiogenesis. For the purpose of ANET, an angiogenic vasculature-targeting probe has been developed, by which cytotoxic anticancer agents are actively delivered to the angiogenic endothelial cells by using drug delivery system (DDS) technology. Another way to damage newly formed vessels by cytotoxic agents is achieved by metronomic-dosing chemotherapy. This chemotherapy shifts the target of chemotherapeutic agents from tumour cells to angiogenic endothelial cells by selective dosing schedule. Similarly, the shift of target from tumour cells to angiogenic endothelial cells enhanced therapeutic efficacy of cancer photo-dynamic therapy (PDT): in this antiangiogenic PDT, photosensitizers are delivered more to neovessel endothelial cells than to tumour cells. These therapeutic strategies would be clinically applied in the future.

Angiogenesis Inhibitors↗
PubMed2004

Regional cerebral blood volume reduction in transgenic mutant APP (V717F, K670N/M671L) mice.

Recent advance in nuclear magnetic resonance (NMR) microimaging has enabled in vivo cerebral blood volume (CBV) mapping with high spatial resolution. Using an intravascular susceptibility contrast agent and T(2)-weighted magnetic resonance imaging (MRI) on a 9.4T NMR microimager, the regional CBV was measured in mice as the transverse relaxation increase induced by the contrast agent. CBV maps in an Alzheimer's disease mouse model at resting state were obtained and examined. Four-month-old male transgenic mutant APP (V717F, K670N/M671L) mice (N = 10) and littermate wild-type controls (N = 12) were used. Regional analysis of the multi-slice CBV maps revealed statistically significant CBV reductions among the APP mice in cerebral cortex (-9.29%, P = 0.0002), hippocampus (-4.22%, P = 0.02), and thalamus (-5.21%, P = 0.03), indicating an early change of microvasculature in these selected regions. No significant difference was found in olfactory bulb, pons, midbrain, superior colliculus, medulla, and cerebellum.

Animals↗
PubMed2004

(-)-Epigallocatechin gallate inhibits membrane-type 1 matrix metalloproteinase, MT1-MMP, and tumor angiogenesis.

Membrane-type 1 matrix metalloproteinase (MT1-MMP), which hydrolyzes type I collagen and activates MMP-2, are deeply involved in angiogenesis as well as in tumor cell invasion and metastasis. We previously screened a number of natural and synthetic compounds to obtain a specific inhibitor of MT1-MMP and observed that (-)-epigallocatechin gallate (EGCG) has a potent and distinct inhibitory activity against MT1-MMP. In the present study, we investigated the effect of EGCG on tumor angiogenesis. EGCG significantly inhibited the invasion of human umbilical vein endothelial cells (HUVECs) at the concentration of 10 microM. This effect was not due to the toxicity of EGCG since this concentration of EGCG did not affect the HUVEC growth. Furthermore, morphological change of HUVEC at this concentration of EGCG was not observed under confocal laser scanning microscopy. EGCG suppressed tube formation by HUVECs in vitro and angiogenesis in vivo by using dorsal air sac model. Finally, we observed that both colon 26 NL17 carcinoma and Meth A sarcoma growth was suppressed in these tumor-bearing mice by EGCG administration, at least partly though the inhibition of angiogenesis.

Angiogenesis Inhibitors↗
PubMed2004

Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase.

Because membrane type-1 matrix metalloproteinase (MT1-MMP) is expressed specifically on the angiogenic endothelium as well as tumor cells, an agent possessing the ability to bind to this molecule might be useful as a tool for active targeting of tumor angiogenic vessels. Based on the sequences of peptide substrates of MT1-MMP, which had been determined by using a phage-displayed peptide library, we examined the binding ability of peptide-modified liposomes for endothelial cells and targeting ability for tumor tissues by positron emission tomography (PET). Liposomes modified with stearoyl-Gly-Pro-Leu-Pro-Leu-Arg (GPLPLR-Lip) showed high binding ability to human umbilical vein endothelial cells and accumulated in the tumor about 4-fold more than did the unmodified liposomes. Because we reported previously that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, strongly suppressed tumor growth when delivered in liposomes modified with another angiogenic homing peptide, we examined the antitumor activity of DPP-CNDAC entrapped in GPLPLR-Lip. DPP-CNDAC/GPLPLR-Lip showed significant tumor growth suppression compared to DPP-CNDAC/unmodified liposomes. These results suggest that DPP-CNDAC-liposomes modified with MT1-MMP-targeted peptide are useful for cancer anti-neovascular therapy (ANET), namely, tumor growth suppression by damage to angiogenic endothelial cells.

Angiogenesis Inhibitors↗
PubMed2004

PKCbeta regulates ischemia/reperfusion injury in the lung.

Activation of PKCbetaII is associated with the response to ischemia/reperfusion (I/R), though its role, either pathogenic or protective, has not been determined. In a murine model of single-lung I/R, evidence linking PKCbeta to maladaptive responses is shown in the following studies. Homozygous PKCbeta-null mice and WT mice fed the PKCbeta inhibitor ruboxistaurin subjected to I/R displayed increased survival compared with controls. In PKCbeta-null mice, phosphorylation of extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38 MAPK was suppressed in I/R. Expression of the immediate early gene, early growth response-1 (Egr-1), and its downstream target genes was significantly increased in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this expression was attenuated in PKCbeta-null mice or WT mice fed ruboxistaurin. In vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by inhibition of PKCbeta, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These findings elucidate key roles for PKCbetaII activation in I/R by coordinated activation of MAPKs (ERK1/2, JNK) and Egr-1.

Animals↗
PubMed2003

Right ventricle-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome.

OBJECTIVE: Pulmonary overcirculation through a systemic-pulmonary shunt has been one of the major causes of early death after the Norwood procedure. To avoid this lethal complication, we constructed a right ventricle-pulmonary shunt in first-stage palliation of hypoplastic left heart syndrome. METHODS: Between February 1998 and February 2002, 19 consecutive infants, aged 6 to 57 days (median, 9 days) and weighing 1.6 to 3.9 kg (median, 3.0 kg), underwent a modified Norwood operation with the right ventricle-pulmonary artery shunt. The procedure included aortic reconstruction by direct anastomosis of the proximal main pulmonary artery and a nonvalved polytetrafluoroethylene shunt between a small right ventriculotomy and a distal stump of the main pulmonary artery. The size of the shunt used was 4 mm in 5 patients and 5 mm in 14. RESULTS: All patients were managed without any particular manipulation to control pulmonary vascular resistance. There were 17 survivors (89%), including 3 patients weighing less than 2 kg. Two late deaths occurred due to obstruction of the right ventricle-pulmonary artery shunt. Thirteen patients underwent a stage II Glenn procedure after a mean interval of 6 months, with 2 hospital deaths. To date, a stage III Fontan procedure has been completed in 4 patients. Overall survival was 62% (13/19). Right ventricular fractional shortening at the last follow-up (3-48 months after stage I) ranged from 26% to 43% (n = 13, mean, 33%). CONCLUSION: Without delicate postoperative management to control pulmonary vascular resistance, the modified Norwood procedure using the right ventricle-pulmonary shunt provides a stable systemic circulation as well as adequate pulmonary blood flow. This novel operation may be particularly beneficial to low-birth-weight infants with hypoplastic left heart syndrome.

Blood Pressure↗
PubMed2003

Inhibitory effect of green tea polyphenols on membrane-type 1 matrix metalloproteinase, MT1-MMP.

Matrix metalloproteinases (MMPs), especially membrane-type 1 matrix metalloproteinase (MT1-MMP), which generates an active form of MMP-2 from proMMP-2, are deeply involved in angiogenesis as well as in tumor cell migration and metastasis. To obtain a specific inhibitor for MT1-MMP, we screened a number of natural and synthetic compounds using recombinant human MMP-2, MMP-7, and soluble MT1-MMP in a fluorogenic peptide cleavage assay. (-)-Epigallocatechin 3-O-gallate (EGCG) followed by (-)-epigallocatechin 3,5-di-O-gallate and epitheaflagallin 3-O-gallate, was found to have potent and distinct inhibitory activity against MT1-MMP. Therefore, we investigated the effect of EGCG on the suppression of MMP-2 activation as determined by gelatin zymography, and observed that the active form of MMP-2 in the conditioned medium of human umbilical vein endothelial cells was decreased in the presence of EGCG. The results suggest the possibility that tea polyphenols suppress tumor growth through the suppression of angiogenesis.

Angiogenesis Inhibitors↗
PubMed2002

Anti-neovascular therapy by liposomal DPP-CNDAC targeted to angiogenic vessels.

We previously reported that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity. Three doses of APRPG-modified DPP-CNDAC-liposomes (15 mg/kg as CNDAC) strongly inhibited tumor growth compared with the same number of doses of unmodified DPP-CNDAC-liposomes. The life span was increased 31.8%, with one completely cured mouse out of the six mice treated. Since the accumulation of liposomes in the tumor tissue was not so much different between APRPG-liposomes and non-modified liposomes, the enhanced therapeutic efficacy may be explained as the alteration of targets, i.e. APRPG-modified DPP-CNDAC-liposomes caused tumor growth suppression through damage of angiogenic endothelial cells. Anti-neovascular therapy promises no drug resistance, and should be effective against essentially any kind of solid tumor; and thus the present results demonstrate another benefit of the therapy, namely, high efficacy of cancer treatment.

Amino Acid Sequence↗
PubMed2002

Anti-neovascular therapy using novel peptides homing to angiogenic vessels.

Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.

Amino Acid Sequence↗