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Biomedical subjects

Y Horiguchi

Publications and source records attributed to Y Horiguchi.

At least 19 recordsLinked to original sources
PubMed2001

A dual signaling cascade that regulates the ectodomain shedding of heparin-binding epidermal growth factor-like growth factor.

Ectodomain shedding is an important mechanism to regulate the biological activities of membrane proteins. We focus here on the signaling mechanism of the ectodomain shedding of heparin-binding epidermal growth factor (EGF)-like growth factor (pro HB-EGF). Lysophosphatidic acid (LPA), a ligand for seven-transmembrane G protein-coupled receptors, stimulates the shedding of pro HB-EGF, which constitutes a G protein-coupled receptor-mediated transactivation of the EGF receptor. Experiments using a series of inhibitors and overexpression of mutant forms of signaling molecules revealed that the Ras-Raf-MEK signal is essential for the LPA-induced shedding. In addition, the small GTPase Rac is involved in the LPA-induced shedding, possibly to promote MEK activation. 12-O-Tetradecanoylphorbol-13-acetate is another potent inducer of pro HB-EGF shedding. We also demonstrate that the LPA-induced pathway is distinct from the 12-O-tetradecanoylphorbol-13-acetate-induced pathway and that these pathways constitute a dual signaling cascade that regulates the shedding of pro HB-EGF.

Androstadienes↗
PubMed2001

Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases.

Escherichia coli cytotoxic necrotizing factors (CNFs) and Bordetella dermonecrotic toxin (DNT) have been recently found to comprise a novel family of dermonecrosis-inducing toxins which activate the small GTPases of the Rho family. They are single chain polypeptides consisting of an N-terminal domain responsible for binding to target cells and a C-terminal catalytic domain. CNFs (CNF1 and 2) and DNT share in the catalytic domain about 30% identical residues and a consensus sequence where the catalytically active center Cys resides. Both toxins deamidate Rho and other members of the Rho family, Rac and Cdc42, at Gln in the switch II region, which plays an important role in their GTPase activity. DNT, in addition, catalyzes a cross-link of the Gln of the GTPases with ubiquitous polyamines such as putrescine, spermidine, and spermine. The deamidation and the polyamination result in abrogation of the GTPase activity, and in addition, the polyamination endows Rho with the ability to interact with a downstream effector, ROCK, in a GTP-independent manner. These effects render the GTPases constitutively active, which underlies the toxicities of CNFs and DNT.

Animals↗
PubMed2001

Congestion of superior mesenteric veins and small bowel mucosal injury after endoscopic treatment of esophageal varices in patients with portal hypertension.

We investigated treatment-induced changes in venous return from the small bowel and small bowel intestinal mucosal injury induced by the treatment of esophageal varices in patients with portal hypertension. A total of 14 patients (age 59.8+/-9.5 years, five women and 9 men) who received prophylactic treatment of esophageal varices between December 1998 and March 1999 were investigated. Diamine oxidase (DAO) activity was measured before and after treatment. Changes in blood flow of the portal and superior mesenteric veins were investigated by Doppler ultrasonography in six patients. A significant decrease in DAO activity was observed three days after treatment (11.5+/-1.6 units/liter prior to treatment versus 8.6+/-1.6 units/liter three days after treatment; P < 0.001). Decreases in superior mesenteric and portal venous flow velocity were observed in four and three patients, respectively. In two patients with an increase in the cross-sectional area of the superior mesenteric vein with delayed venous return, a marked decrease in DAO activity was observed three days after treatment. In patients with portal hypertension, rapid reduction of pooling of portal flow caused by the treatment of esophageal varices can induce transient congestion of the mesenteric venous system which can produce some small bowel mucosal injury.

Amine Oxidase (Copper-Containing)↗
PubMed2001

Useful applications of DNA repair tests for differential diagnosis of atypical dyschromatosis symmetrica hereditaria from xeroderma pigmentosum.

Dyschromatosis symmetrica hereditaria (DSH) is a hereditary skin disease characterized by the presence of pigmented and hypopigmented macules on the extremities and freckles on the face. However, if clinical features are not fully developed in infantile patients, it is difficult to differentiate DSH from xeroderma pigmentosum by clinical features alone. A 2-year-old boy (patient 1), revealed atypical features of DSH with slight susceptibility to sunburn. However, his grandfather (patient 4) who was 67 years old, revealed typical features of DSH, which helped to make an exact diagnosis in patient 1. For patient 2, a 5-year-old boy, and patient 3, a 3-year-old girl, it was more difficult to make a diagnosis because there were no family members with DSH features. DNA repair ability was tested for all four cases by means of unscheduled DNA synthesis and colony formation of skin fibroblasts after ultraviolet light irradiation, which resulted in an accurate diagnosis of DSH. We propose that these tests be performed to make a diagnosis of DSH in the case of poor or atypical clinical symptoms.

Aged↗
PubMed2001

Intramolecular capture of pummerer reaction intermediates by an aromatic nucleophile: selective construction of 1,4-benzothiazine and indole ring systems.

The simple alkyl sulfoxide 6 carrying two aromatic nucleophiles, when treated with trifluoroacetic anhydride at room temperature (Pummerer reaction conditions), underwent an intramolecular aromatic sulfenylation of the 6-exo-tet process in an exclusive manner to yield two regioisomeric 1,4-benzothiazine derivatives, 8 and 9. On the other hand, a similar reaction of the alpha-acyl sulfoxide 7, possessing identical aromatic nucleophiles, caused an intramolecular aromatic alkylation of the 5-exo-trig process to produce the 3-oxo-indole derivative 14 in a quantitative yield. These results demonstrate that the construction of 1,4-benzothiazine and indole ring systems can be achieved in a selective manner by proper choice of the sulfoxide side chain.

Acetic Anhydrides↗
PubMed2001

A synthesis of 3-phenyl-1,2,3,4-tetrahydroisoquinoline and 2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-type cyclization: enhancing effect of boron trifluoride diethyl etherate on the cyclization.

A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).

Benzazepines↗
PubMed2001

Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide.

Recent investigations have demonstrated the efficacy of autologous dendritic cells (DCs) pulsed with tumor antigens to generate tumor-specific CTLs against cancer cells. Melanoma antigens (MAGE) are a family of tumor-specific antigens shown to be expressed in various tumors, including bladder cancers and melanoma, but not in normal tissues except for the testis. Because invasive bladder cancers are frequently reported to express MAGE, we explored the possibility of establishing a new immunotherapeutic modality against advanced bladder cancer using autologous DCs pulsed with one of the MAGE-3 epitope peptides (IMPKAGLLI), which is synthesized to bind specifically to HLA-A24. A MAGE-3-expressing bladder cancer cell line, FY, was newly established from a lymph node metastasis of bladder cancer in a HLA-A24+ patient. The FY cell-specific CTL response was significantly higher when CTL was induced by autologous DCs pulsed with IMPKAGLLI than by FY cells alone or by nonpulsed DCs in vitro. A total of four HLA-A24+ patients with advanced MAGE-3+ bladder cancers were treated with s.c. injections of autologous DCs pulsed with IMPKAGLLI every 2 weeks for a minimum of 6 and a maximum of 18 times. Three of four patients showed significant reductions in the size of lymph node metastases and/or liver metastasis. No significant untoward side effects were noted in these patients. This study indicated that, at sometime in the future, tumor-specific DC-based cancer immunotherapy may be useful as an additional treatment modality against advanced bladder cancer.

Aged↗
PubMed2000

Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein.

Claudins (claudin-1 to -18) with four transmembrane domains and two extracellular loops constitute tight junction strands. The peptide toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to claudin-3 and -4, but not to claudin-1 or -2. We constructed claudin-1/claudin-3 chimeric molecules and found that the second extracellular loop of claudin-3 conferred CPE sensitivity on L fibroblasts. Furthermore, overlay analyses revealed that the second extracellular loop of claudin-3 specifically bound to CPE at the K(a) value of 1.0x10(8) M(-1). We concluded that the second extracellular loop is the site through which claudin-3 interacts with CPE on the cell surface.

Animals↗
PubMed2000

Activation of rho through a cross-link with polyamines catalyzed by Bordetella dermonecrotizing toxin.

The small GTPase Rho, which regulates a variety of cell functions, also serves as a specific substrate for bacterial toxins. Here we demonstrate that Bordetella dermonecrotizing toxin (DNT) catalyzes cross-linking of Rho with ubiquitous polyamines such as putrescine, spermidine and spermine. Mass spectrometric analyses revealed that the cross-link occurred at Gln63, which had been reported to be deamidated by DNT in the absence of polyamines. Rac1 and Cdc42, other members of the Rho family GTPases, were also polyaminated by DNT. The polyamination, like the deamidation, markedly reduced the GTPase activity of Rho without affecting its GTP-binding activity, indicating that polyaminated Rho behaves as a constitutively active analog. Moreover, polyamine-linked Rho, even in the GDP-bound form, associated more effectively with its effector ROCK than deamidated Rho in the GTP-bound form and, when microinjected into cells, induced the anomalous formation of stress fibers indistinguishable from those seen in DNT-treated cells. The results imply that the polyamine-linked Rho, transducing signals to downstream ROCK in a novel GTP-independent manner, plays an important role in DNT cell toxicity.

3T3 Cells↗
PubMed2000

Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model.

Using a novel orthotopic MBT-2 murine bladder tumor model, we evaluated the feasibility of intravesical gene therapy utilizing a cationic liposome, DMRIE/DOPE. Superficial bladder tumors were consistently established by intravesical instillation of 5x10(5) MBT-2 cells in syngeneic C3H female mice. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/DMRIE/DOPE lipoplex. Beta-Galactosidase (beta-gal) gene expression was preferentially evident in bladder tumors and was present for at least 7 days after a single 30 min in situ transfection. Murine interleukin-2 (IL-2) gene was used for treatment of 3-day-old pre-established bladder tumors. Forty percent of animals treated with IL-2 gene were completely free of tumors by 60 days following the initial tumor implantation, while all control groups treated with beta-gal gene died. Those animals initially cured of pre-established tumors were completely resistant to a subsequent tumor re-challenge and their splenocyte-derived cytotoxic T lymphocytes were shown to be specific to MBT-2 cells, indicating that immunological memory against MBT-2 tumors was elicited by the treatment. These results demonstrate the possibility of an effective clinical application of this in situ intravesical IL-2 gene delivery system to high-risk superficial bladder tumors, obviating a need for tumor procurement and ex vivo gene transfer.

Administration, Intravesical↗
PubMed2000

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C.

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as 'sustained responders'. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life-threatening in patients who clear HCV. We analysed the long-term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1,277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999. We analysed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow-up 3 years after the end of IFN therapy, and the follow-up rate of sustained responders was significantly lower than that of non-sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN. Of the five patients who had regular medical follow-up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed-up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed-up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow-up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow-up protocol for sustained responders to IFN.

Adolescent↗
PubMed2000

Echocardiographic evaluation of the ductal morphology in patients with refractoriness to lipo-prostaglandin E1 therapy.

BACKGROUND: Lipo-prostaglandin (PG)E1 is effective at lower doses and has fewer side effects than PGE1-cyclodextrin (CD). Previous studies, however, have suggested that some patients show refractoriness to lipo-PGE1 in the course of treatment. The present paper examines: (i) whether such cases can be predicted by examining the ductal morphology before and 24 h after the start of lipo-PGE1 infusion; and (ii) whether PGE1-CD dilates the ductus arteriosus in patients with refractoriness to lipo-PGE1. METHODS: The ductal morphology was evaluated with two echo indices, such as minimal and minimal plus maximal intraluminal diameters of the ductus. Two-dimensional echocardiography was performed in 24 patients with ductus-dependent congenital heart disease. The two echo indices were measured before and 24 h after lipo-PGE1 infusion and also at least twice per week until surgery. RESULTS: In 19 of 24 patients, ductal patency was maintained until surgical treatment (group A). The remaining five patients (21%) showed ductal closure during the course of the lipo-PGE1 therapy (group B). There were no significant differences between the two groups, in either the maximal or minimal diameters, which were examined before and 24 h after treatment. In the five patients of group B, lipo-PGE1 was replaced with a relatively high dosage of PGE1-CD (50-100 ng/kg per min), resulting in good ductal patency until surgery. CONCLUSIONS: Patients with refractoriness to lipo-PGE1 therapy could not be predicted from initial intraluminal diameters of the ductus using echocardiography. Therefore, serial echocardiographic examinations are important to detect early findings of ductal closure. In addition, PGE1-CD is still useful as back-up therapy in such patients.

Alprostadil↗
PubMed2000

Eradication of hepatitis C virus 1b by interferon in a health care worker with acute hepatitis following needlestick transmission from a patient with chronic hepatitis C unresponsive to interferon.

Hepatitis C virus (HCV) was successfully eradicated by a short course of interferon (IFN) therapy in a nurse with acute HCV infection from a needlestick accident. The source patient had chronic hepatitis C and was a nonresponder to IFN therapy. The HCV genotype was 1b in patients, and a single point mutation (H-->R in amino acid 2218) was observed in the IFN sensitivity-determining region of the nonstructural 5A gene, in comparison with sequences of HCV-J, in HCV RNA from both the source patient (before and after IFN therapy) and the recipient (before IFN therapy). Though the strain transmitted was believed to be IFN-resistant in the patient with chronic hepatitis, the patient with acute hepatitis had a sustained response.

Acute Disease↗