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Biomedical subjects

M Honda

Publications and source records attributed to M Honda.

At least 127 records · Page 7Linked to original sources
PubMed2000

Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited birth disorder caused by a defect in 7-dehydrocholesterol (3beta-hydroxysteroid) delta7-reductase, the final enzyme in cholesterol biosynthesis. To investigate in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we measured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG-CoA synthase, HMG-CoA reductase, squalene synthase and 7-dehydrocholesterol delta7-reductase in liver specimens from a patient with SLOS and 11 controls. Hepatic microsomal 7-dehydrocholesterol delta7-reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly increased 7- and 8-dehydrocholesterol concentrations were observed in the patient's microsomes. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG-CoA reductase activity in SLOS was supported by measuring plasma levels of mevalonic acid, the immediate product of HMG-CoA reductase. The levels in SLOS patients (n = 9) were significantly low compared with age-matched controls (n = 8) (12+/-2 vs 28 + 6nmol/L, p < 0.05). These results suggest that in most SLOS patients in vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations.

Case-Control Studies↗
PubMed2000

Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines.

Lactacystin (LC) is a specific inhibitor of the proteasome, and has recently been shown to induce apoptosis in certain cell lines. In the present study, we established Fas-resistant adult T-cell leukemia (ATL) cell subclones RSO4 and RST1 from their parental Fas-sensitive cell lines SO4 and ST1, and examined whether LC can overcome Fas resistance. LC completely inhibited proteasome function as determined by a peptidyl-MCA substrate (LLVY-MCA and LLE-MCA), and induced apoptosis in these cell lines irrespective of Fas sensitivity at low concentrations (approximately 10 microM). LC induced the activation of caspase 3 (CPP32/Yama) and caspase 6 proteases in an identical manner to Fas-mediated apoptosis. Moreover, LC induced the activation of caspase 8 (FLICE) protease, which is the initiator of the Fas-mediated apoptotic cascade. Synthesized proteasome inhibitory peptide MG-115 (ZLLnV-CHO) also induced apoptosis in these cell lines. These results indicated that proteasome inhibitors overcome Fas-resistance by bypassing the proximal part of the Fas signal. Inhibition of the proteasome function may be a new strategy for the treatment of ATL.

Acetylcysteine↗
PubMed2000

Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration.

Accumulating evidence has shown the importance of vascular endothelial growth factor (VEGF) in chorioretinal angiogenesis. However, whether or not VEGF is indeed critical for the pathogenesis of subretinal neovascularization (SRN) in adulthood, which is a serious complication of age-related macular degeneration, has to be further investigated. We constructed an adenovirus expressing an entire ectodomain of the human VEGF receptor/flt-1 fused to Fc portion of human IgG (Adflt-ExR): this soluble receptor is secreted from Adflt-ExR-transfected cells. We studied the effect of Adflt-ExR on the formation of experimental SRN. Experimental SRN was induced by intense photocoagulation on the retina in pigmented rats and Adflt-ExR was injected into the femoral muscle. The formation of SRN assessed by fluorescein angiography was more significantly inhibited for 7 days in the Adflt-ExR-treated rats than in the control rats who received either an adenovirus vector encoding LacZ gene or balanced salt solution (BSS). The serum concentration of this soluble receptor increased for 7 days and thereafter gradually decreased. An immunohistochemical study disclosed the fibroblast cell proliferation and inflammatory cell infiltration to be reduced in the photocoagulation spot of Adflt-ExR-treated rats. VEGF plays a crucial role in the formation of SRN and VEGF soluble receptor gene transfection can inhibit SRN. This method will contribute to future gene therapy for age-related macular degeneration.

Adenoviridae↗
PubMed2000

Distinctive distribution of human papillomavirus type 16 and type 20 DNA in the tonsillar and the skin carcinomas of a patient with epidermodysplasia verruciformis.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare skin disease characterized by disseminated pityriasis versicolor-like or flat wart-like lesions and by the development of skin carcinomas. It is well established that specific cutaneous human papillomaviruses (EV-HPVs) are associated with both benign and malignant skin lesions in EV patients. However, little is known of the relationship between HPV and the mucosal lesions of EV patients. OBJECTIVES: To detect and identify HPV types associated with skin and mucosal lesions of an EV patient. PATIENT/METHODS: We investigated the skin carcinoma and the coexisting tonsillar carcinoma of a 41-year-old man with EV. Histopathologically, both lesions were squamous cell carcinomas. We analysed these two lesions by immunohistochemistry, in situ hybridization, and by molecular virology. RESULTS: Neither skin nor tonsillar lesions exhibited positivity for HPV capsid antigen by immunohistochemistry. By Southern blot hybridization, however, the skin carcinoma harboured 'EV-specific' HPV20 DNA, while the tonsillar carcinoma harboured 'genital' HPV16 DNA. In addition, in situ hybridization localized the respective viral DNA in the corresponding lesion. CONCLUSIONS: The results indicate that EV-HPV could be responsible for the development of the skin carcinoma, but not the mucosal carcinoma in this patient.

Adult↗
PubMed2000

Induction of CD95 ligand expression on T lymphocytes and B lymphocytes and its contribution to apoptosis of CD95-up-regulated CD4+ T lymphocytes in macaques by infection with a pathogenic simian/human immunodeficiency virus.

Using an established SIV/HIV-C2/1-infected cynomolgus monkey model displaying stable CD4+ T cell depletion, the kinetics of apoptosis and the levels of expression of CD95 membrane-associated CD95L on lymphocytes were investigated to test the involvement of the CD95/CD95L system in CD4+ T lymphocyte loss in vivo. Rapid depletion of CD4+ T cells occurred up to 2 weeks after infection, with chronic CD4+ T lymphopenia thereafter. During the initial CD4+ T cell loss, which was accompanied by viraemia, about 90% of the peripheral CD4+ T cell subset underwent spontaneous apoptotic cell death during 24 h of culture. Increased expression of CD95 was observed on both CD4+ and CD8+ T cell subsets, with CD95 expression on CD8+ cells declining rapidly, but high CD95 expression being maintained on CD4+ cells. Since CD95L was expressed on CD8+ T cells, B cells and to a lesser extent on CD4+ T cells, this suggests that CD95-mediated apoptosis might be controlled in an autocrine/paracrine fashion.

Animals↗
PubMed2000

Sarcomatoid renal cell carcinoma with scant carcinomatous components.

A 30-year-old male underwent radical nephrectomy for a right renal tumor 15 cm in diameter. On microscopic examination of initial 17 sections, the tumor consisted of pleomorphic giant cells and spindle neoplastic cells. There was no carcinomatous component. Immunohistochemically, the neoplastic cells were negative for keratin and epithelial membrane antigen but positive for vimentin. The giant cells were also scatteringly, weakly positive for myoglobin. At that time a diagnosis of rhabdomyosarcoma of the kidney was made. However, further microscopic examination of another eight sections revealed small areas of clear cell-type renal cell carcinoma (RCC) which transited to sarcomatous components and led to a diagnosis of sarcomatoid RCC. The patient underwent three cycles of adjuvant chemotherapy. He has been free of the disease for 14 months after nephrectomy.

Adult↗
PubMed2000

Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells.

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma. Several lines of evidence suggest that the core protein of HCV may play a role in the development of this cancer. The authors examined regulation of the cell cycle in stable cell lines derived from Chinese hamster ovary (CHO-K1) cells that constitutively expressed one or more of the structural proteins of HCV. In media containing low concentrations of serum (serum starvation), cell lines expressing the core protein showed a significantly lower population of viable cells than noncore-expressing cells. The low viability of the core-expressing cells was a result of the increased population of cells undergoing apoptosis. Interestingly, the cell cycle analysis revealed that the arresting function at G(0) was impaired, and the cell cycle was accelerated in core-expressing cell lines even under serum starvation. Thus, the HCV core protein sensitizes the apoptosis to serum starvation, although it promotes the cell cycle in CHO-K1 cells. To explain these findings, the authors examined the expression of revival apoptosis and cell-cycle-related genes. Expression of the c-myc genes was significantly induced in core-expressing cells in response to serum starvation. Other apoptosis-inducing genes downstream of c-myc, p53, p21WAF1/CIP1 and Bax were significantly highly induced, although there was no induction of Bcl-2, which prevents apoptosis in core-expressing cells. Thus, the HCV core protein induced apoptosis and impaired the regulation of the cell cycle by activating c-myc expression, whereas the p53 and Bax pathways play a role in the induction of apoptosis.

Animals↗
PubMed2000

Cartilage formation by cultured chondrocytes in a new scaffold made of poly(L-lactide-epsilon-caprolactone) sponge.

PURPOSE: This study investigated the ability of chondrocytes grown in culture and inoculated into a newly developed biodegradable sponge to form ectopic cartilage tissue. MATERIALS AND METHODS: Chondrocytes obtained from costochondral cartilage dissected from Lewis rats were cultured to allow proliferation and then were inoculated into a sponge consisting of a biodegradable polymer, poly (L-lactide-epsilon-caprolactone). The composites of chondrocytes and sponge were transplanted subcutaneously into Nude mice and removed after 4 weeks for histologic and Northern blot analysis. RESULTS: Staining with hematoxylin and eosin showed the formation of a cartilage-like structure in the sponge. Northern blot analysis of the total RNA in the composites showed the presence of aggrecan transcripts of about 9 kb. CONCLUSION: The poly (L-lactide-epsilon-caprolactone) sponge system, is suitable as a matrix for tissue-engineered cartilage.

Absorbable Implants↗
PubMed2000

3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts.

Sitosterolemia is an inherited recessive disease characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients hyperabsorb sitosterol. In addition, hepatic, ileal, and mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway, is markedly suppressed in this disease. It is still controversial whether the down-regulation is due to accumulated sitosterol, but the effect of sitosterol on HMG-CoA reductase activity has not been studied in sitosterolemic tissues. To investigate whether sitosterol inhibits HMG-CoA reductase activity in sitosterolemia, we measured the enzyme activities in liver and cultured skin flbroblasts from patients. Hepatic HMG-CoA reductase activities in patients were decreased 76% (P < .05) as compared with results in control subjects. In contrast, HMG-CoA reductase activities in sitosterolemic fibroblasts were not decreased as compared with results in control fibroblasts, and the activities in all cells were up-regulated similarly when they were exposed to delipidated medium. Because the cultured sitosterolemic fibroblasts contained only trace amounts of plant sterols, we added 20 microg/mL sitosterol directly to the cell medium. Raising the intracellular sitosterol concentration to 7% of cellular cholesterol level increased HMG-CoA reductase activity 23% (P < .05), while the addition of the same amount of cholesterol to the cells reduced the activity 46% (P < .05). Thus, when sitosterolemic skin fibroblasts were used, it was possible to distinguish between the effects of cholesterol and those of sitosterol on the activity of HMG-CoA reductase. These results suggest that reduced HMG-CoA reductase activity in this disease is caused by secondary effects of unknown regulator(s) other than sitosterol.

Adolescent↗
PubMed2000

Essential role of the right superior parietal cortex in Japanese kana mirror reading: An fMRI study.

Functional magnetic resonance imaging (fMRI) was used to investigate the neural substrates responsible for Japanese kana mirror reading. Japanese kana words, arranged vertically from top to bottom, were used in the mirror reading task in 10 normal right-handed Japanese adults. Since both mirror-reversed and normally oriented kana items are read in the same (top to bottom) direction, it was possible to minimize the oculomotor effects which often occur in the process of mirror reading of alphabetical language. By using the SPM96 random effect analysis method, a significant increase in the blood oxygen level-dependent signal during mirror reading relative to normal reading was detected in multiple brain regions, including the bilateral superior occipital gyri, bilateral middle occipital gyri corresponding to Brodmann area (BA) 18/19, bilateral lingual gyri (BA 19), left inferior occipital gyrus (BA 18), left inferior temporal cortex (BA 37), bilateral fusiform gyri (BA 19), right superior parietal cortex (SPC) (BA 7), left inferior frontal gyrus (BA 44/45) and an inferior part of the left BA 6. In addition to these cortical regions, the right caudate nucleus and right cerebellum were also activated. The activation found in the right SPC and the left inferior temporal region is consistent with the hypothesis that mirror reading involves both the dorsal visuospatial and ventral object recognition pathways. In particular, a significant correlation was found between the fMRI signal change in the right SPC and the behavioural performance (error index) in the task. This may reflect increased demand on the right SPC for the spatial transformation which is required for the accurate recognition of mirror-reversed kana items. This relationship between the haemodynamic response in a specific brain area and the behavioural data provides new evidence for the essential role of the right SPC in Japanese kana mirror reading.

Adult↗
PubMed2000

Participation of the left posterior inferior temporal cortex in writing and mental recall of kanji orthography: A functional MRI study.

To examine the neuropsychological mechanisms involved in writing kanji (morphograms), we used functional MRI (fMRI) in 10 normal volunteers, all right-handed, native Japanese speakers. The experimental paradigms consisted of kana-to-kanji transcription, mental recall of kanji orthography and oral reading and semantic judgement of kana words. The first two tasks require manual and mental transcription of visually presented kana words into kanji, respectively, whereas the last two tasks involve language processing of the same set of stimulus words without recall of kanji. The transcription and mental recall tasks yielded lateralized activation of the left posterior inferior temporal cortex (PITC). By contrast, neither oral reading nor semantic judgement produced similar activation of the area. These results, in good accordance with lesion data, provide converging evidence that the left PITC plays an important role in writing kanji through retrieval of their visual graphic images, and suggest language-specific cerebral organization of writing. The set of fMRI experiments also provides new neuroimaging data on the cortical localization of basic language functions in people using a non-alphabetical language.

Adult↗
PubMed2000

Distinct action of aranidipine and its active metabolite on renal arterioles, with special reference to renal protection.

Aranidipine, a newly developed calcium antagonist, possesses unique pharmacologic characteristics in that its metabolite (M-1) still has antihypertensive action. We examined the effects of both agents on renal microcirculation using the isolated perfused hydronephrotic rat kidney. During norepinephrine-induced constriction, the addition of aranidipine dilated both afferent and efferent arterioles in a dose-dependent manner; at 10(-6) M, 83 +/- 6% and 90 +/- 6% reversal, respectively. In contrast, its active metabolite exerted dilator action predominantly on the afferent arteriole (79 +/- 4% vs. 44 +/- 17% at 10(-6) M for afferent and efferent arterioles, respectively). We further examined the long-term (8 weeks) effect of these agents on the development of renal injury in salt-loaded subtotally nephrectomized spontaneously hypertensive rats. Both aranidipine and M-1 reduced blood pressure by a similar magnitude. The decreases in proteinuria were observed in the aranidipine-treated group at weeks 6, 8, and 10, whereas in the M-1 group, significant reduction was attained only at week 6. Histopathologic examination revealed that both treatments improved glomerular and arteriolar sclerosis. Glomerular sclerosis, however, was less pronounced in the aranidipine-treated group than in the M-1 group. In conclusion, aranidipine has dilator action on both arterioles, whereas M-1 caused predominant dilation of afferent arterioles. Such metabolic changes may constitute a determinant of efferent arteriolar action of the calcium antagonist.

Animals↗
PubMed2000

Protective immune responses induced by a non-pathogenic simian/human immunodeficiency virus (SHIV) against a challenge of a pathogenic SHIV in monkeys.

A simian/human immunodeficiency virus (SHIV)-NM3n containing the human nef, but not the monkey nef, and vpr genes of SIV was inoculated into two cynomolgus monkeys, resulting in systemic infection with a minimum level of transient virus load. In order to study the nature of immune responses associated with the prevention of a pathogenic SHIV, the SHIV-NM3n-inoculated monkeys and three naive monkeys were intravenously challenged with a pathogenic SHIV containing the envelope gene of HIV-1 89.6. After the heterologous virus challenge, all of the SHIV-NM3n-inoculated animals completely avoided the loss of CD4+ T lymphocytes in PBMC as well as lymphoid tissues compared to pathogenic SHIV-injected control animals. The inhibition of CD4+ cell depletion was associated with maintaining the proliferative response of helper T-cells against SIV p27 in the previously nonpathogenic virus-inoculated animals following the pathogenic virus challenge. Furthermore, the decline of CD28+ cells, the increase in CD95+ cells, and the enhancement of in vitro apoptosis in PBMC were inhibited in the non-pathogenic virus-inoculated animals. These results suggest that nonpathogenic SHIV-NM3n infection induces the protection of monkeys from heterologous pathogenic viruses that may be associated with blocking the change in immune responses and the cell loss induced by a pathogenic virus.

AIDS Vaccines↗
PubMed2000

Decline in the HIV-1 isolation rate in Japan: a 12-year observation.

Since 1988, we have isolated HIV-1 from 614 HIV-1-infected persons (total sample=2,785) in Japan. During the past 12 years, we have found a decline in the HIV-1 isolation rate in Japan, with two identifiable turning points, 1991-1992 and 1996-1997. The two turning points correspond to shifts in anti-HIV-1 therapy. These findings suggest that HIV-1 in Japan is currently biologically well controlled, probably due to anti-HIV-1 therapy. On the other hand, this decline is inconsistent with the recent increase of genetic drug-resistant HIV-1 in Japan. Further studies are needed to clarify mechanisms that might explain the discrepancy.

Adolescent↗
PubMed2000

Negative p53/positive p21 immunostaining is a predictor of favorable response to chemotherapy in patients with locally advanced bladder cancer.

The relationship between clinical response to DNA-damaging drugs and p53 and p21 status in patients with locally advanced transitional cell carcinoma (TCC) of the bladder was assessed. The response to intraarterial chemotherapy (IAC) comprising 100 mg / m(2) of cisplatin (CDDP) and 40 mg / m(2) of pirarubicin (THP) and the prognosis were assessed in 23 patients (the mean follow-up period was 19 months). The p53 gene status of tumors was analyzed at exons 5 - 8 using polymerase chain reaction-single strand conformation polymorphism analysis in 19 patients, and paraffin-embedded tumor sections were immunostained for p53 and p21 in 23 patients. The overall objective response rate (incidence of good responders) was 70%. The negative p53 group (n = 17) showed a significantly higher objective response rate than the positive p53 group (n = 6) (82% vs. 33%; P = 0.045). The p53 gene status or p21 staining status was not significantly associated with responsiveness. When the p53 and p21 immunostaining results were combined, good responders were more accurately predicted than by p53 staining status alone; the negative p53 / positive p21 group (n = 12) showed an objective response rate of 92%, which was significantly higher than that of the positive p53 and / or negative p21 group (45%, n = 11) (P = 0.027). Cause-specific survival of the negative p53 group was significantly superior to that of the positive p53 group (P = 0.015). Negative p53 / positive p21 immunostaining is a possible predictor of favorable chemotherapeutic response in patients with TCC of the bladder.

Adult↗
PubMed2000

Expression of functional chemokine receptors of human placental cells.

PROBLEM: Chemokine receptors of placental trophoblasts possibly act as co-receptors or alternative receptors of maternal fetal infection by HIV. To clarify their possible expression and the physiological roles of chemokines on human placentae, we studied chemokine chemokine receptor expression and the effects of exogenous chemokines on choriocarcinoma cell lines. MATERIALS AND METHODS: Placental samples were obtained from 13 placentae of various gestational ages. Villous tissue was mechanically dissected from samples. Trophoblasts were enriched by anti-human chorionic gonadotropin (hCG)-coated magnetic beads. Human choriocarcinoma cell lines (JAR, BeWo, JEG-3) were maintained in RPMI 1640 media supplemented with 10% FCS. Expression of chemokine receptors was studied by RT-PCR. The effects of MIP-1alpha, RANTES, MCP-1 on hCG production were estimated by EIA. Effects of chemokines on proliferation of choriocarcinoma cell lines were examined by MTT assay. RESULTS: We observed mRNA expression of CCR-1, 2, 3, 4, 5 and CXCR-1, 2, 4 in 1st trimester placental villi, CCR-I, 2, 4 and CXCR-1, 2. 4 in 2nd trimester placental villi, CCR-1, 2, 4 and CXCR-4 in 3rd trimester placental villi. Using MACS enriched trophoblasts, we observed identical results. A choriocarcinoma cell line BeWo expressed CCR-1, 3, 4 and CXCR-1, 2, 4 while JEG-3 and JAR expressed CCR-1, 3, 4, 5 and CXCR-1, 2, 4. Expression of the CCR-5 and CXCR-4 protein in choriocarcinoma cell lines and MACS-enriched trophoblats were confirmed by flow cytometry. Chemokine MCP-3, MIP-1alpha, RANTES mRNA were expressed by the 1st, 2nd and 3rd trimester placental samples and the three choriocarcinoma cell lines examined. MCP-1 was expressed by 1st and 2nd trimester placental villi. Administration of chemokines up-regulated proliferation (10(-1) - 10 ng/mL) and hCG production (10(-1) - 10(-2)ng/ mL) of the three choriocarcinoma cell lines examined. CONCLUSIONS: Our results suggest possible roles of chemokines/chemokine receptors on placental physiology and their involvement in HIV transmission as alternative receptors.

Chemokines↗