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Biomedical subjects

M Mori

Publications and source records attributed to M Mori.

At least 397 records · Page 22Linked to original sources

Suppression of specific IgE antibody responses by liposome-conjugated ovalbumin in mice sensitized with ovalbumin via the respiratory tract.

BACKGROUND: Previously we have shown that intranasal administration of ovalbumin (OVA) together with cholera toxin (CT) abrogates nasal tolerance to OVA, resulting in the induction of specific IgE antibody (Ab) responses, and that intraperitoneal injection of OVA coupled with liposomes (OVA-liposomes) induces a selective suppression of IgE Ab responses to OVA. Whether OVA-liposomes suppress anti-OVA IgE Ab responses in mice sensitized with CT-combined OVA via the respiratory tract remains to be clarified. METHODS: In some experiments, mice were given OVA, liposomes or OVA-liposomes with or without CT intranasally three times, at 2-week intervals (weeks 0, 2 and 4). In other experiments, mice were given OVA-liposomes intranasally 2 days before or 1 and 3 weeks after CT-combined OVA (week 0), which was administered intranasally three times, at 2-week intervals (weeks 0, 2 and 4). Two weeks after the third administration of CT-combined OVA (week 0), nasal wash and serum IgA, IgG and IgE Ab responses were assayed. RESULTS: Pretreatment with OVA-liposomes suppressed IgE Ab responses to CT-combined OVA, with a significantly high production of both nasal IgA and serum IgG Abs. Moreover, treatment with OVA-liposomes 1 and 3 weeks after CT-combined OVA administration also suppressed IgE Ab responses. The suppression of anti-OVA IgE Ab production by OVA-liposomes was accompanied by a simultaneous enhancement of specific IgA and IgG (IgG1, and especially IgG2a) Ab production. CONCLUSIONS: Postimmunization treatment with OVA-liposomes, as well as preimmunization treatment, suppressed specific IgE Ab responses in mice sensitized intranasally with CT-combined OVA. Allergens conjugated to liposomes may be appropriate for preventing the development of allergies to inhaled or dietary antigens in humans.

Administration, Intranasal↗

Effects of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages.

BACKGROUND: N-acetylcysteine (NAC) and ambroxol (AMB) have recently been proposed as possible therapeutic agents in the treatment of pulmonary disorders. IL-12 plays an important role in host resistance to infection and the development of Th-1 cells. In contrast, IL-10 is involved in anti-inflammatory and immunoregulatory mechanisms. OBJECTIVE: We investigated the effects of NAC and AMB on secretions of IL-12 and IL-10 from human alveolar macrophages. METHODS: Alveolar macrophages were obtained from 7 healthy nonsmokers by bronchoalveolar lavage. The cells were first incubated with either NAC or AMB for 2 h and then cultured in lipopolysaccharide (LPS) solution for 24 h. IL-12 and IL-10 secretions were measured by ELISA. RESULT: Both NAC and AMB enhanced LPS-induced secretion of IL-12. NAC also enhanced LPS-induced IL-10 secretion, while AMB did not. The ratio IL-12/IL-10 secretion was increased by AMB, but NAC did not affect it. CONCLUSIONS: The results suggest that NAC enhances inflammatory and immune responses and prevents excessive responses reciprocally, through keeping local balance of IL-12 and IL-10 production in alveolar macrophages at inflammatory sites of bacterial pneumonia. AMB appears to strengthen inflammatory responses and cell-mediated immunity, facilitating the development of Th-1 cells, through shifting the local balance to IL-12 dominance.

Acetylcysteine↗

Identification of monoclonal insulin autoantibodies in insulin autoimmune syndrome associated with HLA-DRB1*0401.

We have characterized HLA and insulin autoantibodies in a Japanese female patient with insulin autoimmune syndrome. Serological HLA typing demonstrated the patient had HLA-DR4, and DNA typing showed she had HLA-DRB1*0401 which has not been reported in patients with insulin autoimmune syndrome in Japan. A single binding affinity of insulin autoantibodies was demonstrated by Scatchard analysis and immunoglobulin class of insulin autoantibodies was exclusively IgG-kappa. HLA-DRB1*0406 is strikingly associated with patients with insulin autoimmune syndrome who have polyclonal insulin autoantibodies. The present report demonstrated the first Japanese patient with insulin autoimmune syndrome carrying HLA-DRB1*0401 who was revealed to have monoclonal insulin autoantibodies. The present results indicate that HLA molecules are the major determinants of polyclonal insulin autoantibodies and monoclonal insulin autoantibodies in insulin autoimmune syndrome.

Aged↗

Expression of type II iodothyronine deiodinase in brain tumors.

Type II iodothyronine deiodinase (DII) messenger ribonucleic acid (mRNA) and its activity have been demonstrated in human normal brain. Although DII activity has been demonstrated in brain tumors, expression of DII mRNA has not been studied in these tumors. To investigate the mechanisms involved in the expression of DII activity in brain tumors, we studied DII mRNA and DII activity in astrocytoma (two cases), glioblastoma (three cases), and oligodendroglioma (one case). DII mRNA, the size of which was indistinguishable from that in control cerebral cortical tissue, was demonstrated in all of the brain tumors tested, although the intensity of the hybridization signal showed wide variation among the tumors. DII activity was also detected in all tumors. DII mRNA and DII activity were highest in the tissue from oligodendroglioma. A significantly positive correlation was observed between DII mRNA and DII activity in these tumors (r = 0.94; P < 0.01), suggesting that DII expression in brain tumors is regulated at the pretranslational level. The present results demonstrate, for the first time, that DII mRNA as well as DII activity are expressed in brain tumors, and that DII mRNA is significantly correlated with DII activity in those tissues.

Adult↗

Requirement of thyrotropin-releasing hormone for the postnatal functions of pituitary thyrotrophs: ontogeny study of congenital tertiary hypothyroidism in mice.

We recently reported that TRH-deficient mice showed characteristic tertiary hypothyroidism. In the present study, we investigated how this tertiary hypothyroidism occurred particularly in pre- and postnatal stages. Immunohistochemical analysis revealed a number of TSH-immunopositive cells in the TRH-/- pituitary on embryonic day 17.5 and at birth. The mutant pituitary at birth in pups born from TRH-deficient dams also showed no apparent morphological changes, indicating no requirement of either maternal or embryonic TRH for the development of pituitary thyrotrophs. In contrast, apparent decreases in number and level of staining of TSH-immunopositive cells were observed after postnatal day 10 in mutant pituitary. Similar decreases were observed in the 8-week-old mutant pituitary, while no apparent changes were observed in other pituitary hormone-producing cells, and prolonged TRH administration completely reversed this effect. Consistent with these morphological results, TRH-/- mice showed normal thyroid hormone levels at birth, but the subsequent postnatal increase was depressed, resulting in hypothyroidism. As expected, TSH content in the TRH-/- pituitary showed a marked reduction to only 40% of that in the wild type. Despite hypothyroidism in the mutant mice, both the pituitary TSHbeta and alpha mRNA levels were lower than those of the wild-type pituitary. These phenotypic changes were specific to the pituitary thyrotrophs. These findings indicated that 1) TRH is essential only for the postnatal maintenance of the normal function of pituitary thyrotrophs, including the normal feedback regulation of the TSH gene by thyroid hormone; 2) neither maternal nor embryonic TRH is required for normal development of the fetal pituitary thyrotroph; and 3) TRH-deficient mice do not exhibit hypothyroidism at birth. Moreover, reflecting its name, TRH has more critical effects on the pituitary thyrotrophs than on other pituitary hormone-producing cells.

Animals↗

Expression of receptors for glial cell line-derived neurotrophic factor (GDNF) and neurturin in the inner blood-retinal barrier of rats.

The retina is protected from somatic circulation by the blood-retinal barrrier (BRB) composed of tight junctions between retinal vascular endothelial cells (the inner BRB) and those between retinal pigment epithelial cells (the outer BRB). Our recent studies showed that glial cell line-derived neurotrophic factor (GDNF) secreted from astrocytes regulates the permeability of the BBB. In the present study, we immunohistochemically examined the expression of GDNF, neurturin (NTN) and their receptors, GFRalpha1 for GDNF and GFRalpha2 for NTN, because the capillaries of the inner BRB show specialization very similar to the blood-brain barrier (BBB). GDNF and NTN were detected in glial fibrillary acidic protein (GFAP)-positive cells, including Müller cells. GFRalpha1 and GFRalpha2 were localized in von Willebrand factor-positive cells. GDNF and NTN enhanced the barrier function of endothelial cells derived from porcine brain cortex. These results strongly suggest that the barrier function of the BRB is regulated by GDNF and NTN secreted from glial cells, like the BBB.

Animals↗

Pharmacokinetics of propranolol and its metabolites in horses after intravenous or oral administration.

The pharmacokinetics characteristics of propranolol (PPL) in horses was studied by administering the drug intravenously or orally to the animals. The predominant primary pathway was ring oxidation, and 4-hydroxypropranolol glucuronide (4-OHPG) was the major metabolite in both plasma and urine. Side-chain glucuronidation and oxidation were not significant. A two-compartment model was employed for PPL followed by a one-compartment model for 4-OHPG. After oral administration, one-step absorption and two-step first pass metabolism were employed. The fraction absorbed of PPL was approximately 70% after oral administration, and the bioavailability varied among individual horses from 1 to 79% depending on the first pass metabolism. The biologic half-life (T1/2) of PPL obeys the allometric equation in some animal species including rats and horses, except for human. T 1/2 of PPL in horses was approximately 2 h.

Administration, Oral↗

Drug targeting efficacy to underlying muscle following topical application. I. Evaluation based on a physiological pharmacokinetic model.

A physiological pharmacokinetic model describing the absorption and disposition of topically applied drugs was proposed, and the effect of various pharmacokinetic and physiological parameters on the drug delivery into the targeted muscle was simulated. The proposed model consists of vehicle, and stratum corneum, viable epidermis and muscle below the application and reference sites, and plasma, each joined with transfer clearance and plasma flow. Indomethacin concentrations in tissues and plasma after topical application to rats could be explained by the model. Most indomethacin delivered into the underlying muscle was via direct penetration. The model simulation showed that the increase in plasma clearance and clearance between viable skin and muscle, and the decrease in application area and plasma flow rate into viable skin and muscle would promote the targeting efficacy of topically applied drugs to the underlying muscle.

Administration, Topical↗

Development of ELISAs for irinotecan and its active metabolite SN-38.

Two highly sensitive and specific enzyme-linked immunosorbent assays (ELISAs) for the determination of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (irinotecan) and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, were developed, which are capable of measuring as low as 16 and 160 pg of each drug/ml, respectively. Anti-irinotecan antibody was obtained by immunizing rabbits with irinotecan conjugated with mercaptosuccinyl bovine serum albumin (MS.BSA) using N-(4-diazophenyl)maleimide (DPM) as a heterobifunctional coupling agent. An enzyme marker was similarly prepared by coupling irinotecan with horseradish peroxidase (HRP) via DPM. This ELISA for irinotecan was specific for irinotecan and showed almost no cross-reactivity with its active metabolite SN-38. Anti-SN-38 antibody was obtained by immunizing rabbits with SN-38 conjugated with BSA using the N-succinimidyl ester method. An enzyme marker was prepared by coupling SN-38 with HRP employing DPM. The ELISA for SN-38 was specific to SN-38 and showed a very slight cross-reactivity with irinotecan (0.08%). Using the 2 assays, we reconfirmed the rapid metabolite of irinotecan with rat serum. The 2 ELISAs may be a valuable tool for studies of the pharmacokinetics and pharmacodynamics of these drugs.

Antibody Specificity↗

A short-step synthesis of orally active carbapenem antibiotic CS-834.

An orally bioavailable carbapenem CS-834, which is a pivaloyloxymethyl (POM) ester-type prodrug and has (R)-5-oxopyrrolidin-3-ylthio moiety at the C-2 position of the 1 beta-methylcarbapenem skeleton, is currently under clinical trial. We accomplished a short-step synthesis of CS-834 by using phosphorus ylide from the intramolecular Wittig-type reaction in the key step for cyclization to the bicyclic carbapenem system. The POM ester group was found to be suitable for the cyclization conditions.

Carbapenems↗

Total synthesis of prostaglandin F2alpha using nickel-catalyzed stereoselective cyclization of 1,3-diene and tethered aldehyde via transmetalation of nickelacycle with diisobutylaluminum acetylacetonate.

Total synthesis of prostaglandin F2alpha utilizing a nickel(0)-catalyzed cyclization of 1,3-diene and tethered aldehyde was achieved. The cyclization proceeded via a transmetalation of nickelacycle with diisobutylaluminum acetylacetonate (iBu2-ALAC). Thus, the reaction of 19, having a side chain corresponding to the alpha-chain in PGF2alpha with Ni(cod)2 (10 mol %), PPh3 (20 mol %), and 1,3-cyclohexadiene (25 mol %) in the presence of iBu2-ALAC (1.5 eq) proceeded stereoselectively to give the cyclized product 26 in 54% yield. During the cyclization of 19, the Z-olefin at C-5 in the side chain completely retained its geometry, and the four contiguous chiral carbon centers in PGF2alpha were stereoselectively constructed. Transformation of the key intermediate 19 into PGF2alpha was successfully achieved.

Aldehydes↗

Stereocontrolled synthesis of piperidine-condensed tricyclic carbapenems (5-azatrinems) and their antibacterial activities.

Stereocontrolled synthesis of tricyclic carbapenem (5-azatrinem) derivatives 4, in which a piperidine ring is condensed to the carbapenem skeleton, was achieved. The pivotal tricyclic intermediate 2, allyl (8S,9R,10S)-5-(tert-butoxycarbonyl)-10-(R)-1-(tert-butyldimethylsilyl oxy)ethyl]-11-oxo-1,5-diazatricyclo[7.2.0.0(3,8)]undec-2- ene-2-carboxylate, was synthesized starting from an acetoxyazetidinone chiron 6 in a practical manner based on a C-C bond formation reaction between 6 and piperidinone-ester 5, palladium-catalyzed de(allyloxy)carbonylation of 7b and Wittig-type cyclization via an oxalimide 9. Selective deprotection of the N-Boc group of 2 was found to proceed smoothly by treatment with trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine to give the amino compound 3, whose functionalization on the nitrogen atom to derivatives 10 followed by deprotection led to various 5-azatrinem acids 4. These compounds showed potent in vitro activities against gram-positive and gram-negative bacteria.

Animals↗

Inhibition by dietary tea polyphenols of chemical mediator release from rat peritoneal exudate cells.

Male Wistar rats were given purified diets containing safflower (SAF), perilla (PER), or palm (PAL) oils with or without 1% tea polyphenols (TP) for 3 weeks, and chemical mediator releasing activity from rat peritoneal exudate cells (PEC) was measured. Histamine releasing activity was not influenced by TP, while histamine release and intracellular histamine content were significantly increased in the PAL-fed group. On the contrary, leukotriene B4 (LTB4) release was significantly lower in rats fed PER than in those fed SAF and PAL, and TP significantly decreased the release in all fat groups. TP also significantly inhibited the release of LTB5, which was generated only in rats fed PER. TP significantly decreased the proportion of arachidonic acid (AA) in PEC in the SAF-fed group and that of eicosapentaenoic acid (EPA), the precursor of LTB5 in the PER-fed group, but did not influence that of AA in the PAL- and PER-fed group. These results suggest that ingestion of TP improves type I allergic symptom through the inhibition of LT release though the inhibition by TP could not be totally explained by the reduction of substrate fatty acid.

Animals↗

Glycosidic fraction of flue-cured tobacco leaves: its separation and component analysis.

The fraction containing glycosidic components was separated from flue-cured tobacco (Nicotiana tabacum L.) leaves by a facile method. Some components of the fraction were isolated and elucidated to be syringin, coniferin, cichoriin, benzyl-beta-D-glucoside, Blumenol A-beta-D-glucoside, and 5,6-epoxy-5,6-dihydro-3-hydroxy-beta-ionyl-beta-D-glucoside. Syringin and coniferin were detected in the Nicotiana species for the first time.

Benzopyrans↗

Experimental reinfection with homologous porcine reproductive and respiratory syndrome virus in SPF pigs.

The present examination was conducted to determine if the pigs infected with one strain of porcine reproductive and respiratory syndrome virus (PRRSV) would be protected against a subsequent homologous virus challenge. Sixteen 4-week-old SPF pigs were assigned to 2 experimental groups A and B. The pigs in group A were inoculated with 10(6.5) TCID50 of PRRSV by intranasal route. On 77 days post-inoculation (PI), pigs in groups A and B were similarly inoculated with same virus. After the secondary inoculation, the pigs in group A didn't show any clinical sign including pyrexia and reduction of white blood cell (WBC) number. Viremia was detected only on 3 days PI with low virus titer and any virus was not recovered from serum and tissues at the time of necropsy on 14 or 28 days PI. In contrast, pigs in group B showed pyrexia for 14 days and reduction of WBC number on 3 days PI. Viremia was detected between 3 and 28 days PI, and virus was isolated from several tissues of all pigs. These results indicate that previous exposure to PRRSV can prevent development of clinical signs and reduce virus proliferation in pigs after subsequent infection with the homologous PRRSV.

Animals↗

Retrospective study of porcine circovirus 2 infection in Japan: seven cases in 1989.

Retrospectively, we demonstrated that seven pigs necropsied in 1989 had characteristic porcine circovirus 2 (PCV-2) lymphoid tissue lesions of severe lymphoid depletion, syncytial giant cell formation, and intracytoplasmic inclusion bodies in macrophages. Immunohistochemically, PCV-2 antigen was detected in these tissues and the distribution of positive staining corresponded to the distribution of inclusion bodies. Electron microscopy demonstrated viral particles compatible with porcine PCV-2. Therefore, the disease occurred in Japan as early as 1989.

Animals↗

Histological change after interferon therapy in chronic hepatitis C in view of iron deposition in the liver.

We examined the efficacy of interferon (IFN) therapy for chronic hepatitis C (CHC) in view of the change of liver histology and iron staining before and after IFN therapy. Enrolled in this study were 109 patients with CHC who completed IFN treatment and were followed for at least 1 yr after the end of IFN therapy. Serum iron, unsaturated-iron-binding capacity (UIBC), and total-iron-binding capacity (TIBC) were assessed before IFN therapy. Knodell's histological activity index (HAI) score and iron staining were examined in 55 patients in whom liver biopsy was performed at two points: before and. 1 yr after IFN therapy. Serum iron levels before IFN therapy did not correlate with the response to IFN. The HAI score significantly decreased after IFN therapy in complete responders (p < 0.01) and biochemical responders (p < 0.01). Three factors in the HAI, periportal necrosis, intralobular necrosis, and portal inflammation, but not fibrosis, were significantly decreased in complete responders (p < 0.01) and biochemical responders (p < 0.01). Of 55 patients, 23 (41.8%) were positive for iron staining before IFN therapy and 14 of 55 (25.5%) after IFN therapy. The positive rate for iron staining tended to decrease after IFN therapy, not correlating to the response to IFN, but the change was not statistically significant. In conclusion, the histological improvement by IFN therapy was mostly seen in necroinflammatory changes but not in fibrosis at least 1 yr after IFN, and iron staining tended to decrease after IFN therapy.

Adult↗

Preliminary study of combination therapy with interferon-alpha and zinc in chronic hepatitis C patients with genotype 1b.

We have evaluated the efficacy of interferon-alpha (IFN-alpha) plus zinc therapy in hepatitis C patients with genotype 1b, poor responders for IFN alone. Ten patients were injected with 10 MU of IFN-alpha every day for 4 wk, followed by three times a week for 20 wk (control group). Nine patients took 300 mg of zinc sulfate a day orally during IFN-alpha therapy (zinc sulfate group), and 15 patients took IFN-alpha and 150 mg of polaprezinc (polaprezinc group). On the d 8 of IFN therapy, circadian zinc levels in serum elevated significantly in the polaprezinc group compared to the zinc sulfate group or control group. Serum ALT levels normalized in 73.3% of the polaprezinc group, 55.6% of the zinc sulfate group, and 40.0% of the control group at 6 mo after the end of IFN therapy. Sustained eradication for the hepatitis C virus RNA judged at the end of the 6-mo follow-up period was higher in the polaprezinc group than in the zinc sulfate group (53.3% vs 11.1%, p < 0.05) or the control group (20.0%). No clinical side effects of zinc were observed at the dose used. The data suggest that polaprezinc is expected to increase the therapeutic response of IFN-alpha for chronic hepatitis C with genotype 1b.

Carnosine↗