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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 199 records · Page 11Linked to original sources
PubMed1996

Evaluation of the efficiency of targeting of antitumor drugs: simulation analysis based on pharmacokinetic/pharmacodynamic considerations.

Antitumor drugs can be classified into two groups; cell cycle phase nonspecific (type I) and specific (type II) drugs. The cytotoxic activity of type I drugs depends on the time-concentration product (AUC), whereas that of type II drugs is time-dependent. Therefore, not only the AUC in the target organ, but also the exposure time is an important factor for evaluating the efficiency of any delivery system for antitumor drugs. In the present study, we examined the factors governing the cytotoxicity of drugs in tumors based on a hybrid perfusion model. It is suggested that the increase in tumor tissue binding of drug results in an increased unbound drug mean residence time (MRTT,U), leading to the increased activity of type II drugs. In contrast, the cytotoxic activity of type I drugs is unaffected by the alteration in the tissue binding since the intracellular AUC defined for unbound drugs (AUCT,U) is unaffected by the extent of drug binding. We also found that the symmetrical increase in the permeability-surface area products (PS) for drug influx (PSinf) and efflux (PSeff) across the tumor plasma membrane results in the unaltered and reduced antitumor activity for the type I and type II drugs, respectively, due to the unaltered AUCT,U and to the reduced MRTT,U. The kinetic analysis suggests that the increase in PSinf/PSeff ratio results in the increased cytotoxic activity of both type I and type II drugs. Collectively, optimization of the antitumor activity can be attained by increasing the tissue binding for type II drugs and by increasing PSinf and/or by decreasing PSeff type I and type II drugs. The present simulation study was carried out by considering the pharmacodynamic features of antitumor drugs and was a method of predicting how the antitumor activity may change on altering each process (tissue binding and membrane permeability for the influx and efflux processes) which governs the characteristics of drug distribution to tumors.

Antineoplastic Agents↗
PubMed1996

[Repair of diaphragmatic hernia through the thoracoabdominal spiral incision].

Traumatic diaphragmatic hernia requires urgent surgical treatment. A 51-year-old female was injured in a speeding car. She had dyspnea, and resistance on the abdominal wall on physical examination. Intra-thoracic and abdominal visceral injury was suspected. A chest roentogenogram and CT scan revealed an obvious diaphragmatic herniation on the left which necessitated emergency operation. On the right semi-lateral position, left thoracoabdominal spiral incision was made through the 7th intercostal space. Good exposure of the chest and abdomen was easily obtained. Herniated organs and the abdominal cavity were thoroughly examined with ease. The diaphragm was repaired directly. She had an uneventful postoperative recovery, and was discharged in 17 days. Thoracoabdominal spiral incision offered an excellent operative exposure for the patient with a possible combined thoracic and abdominal visceral injury.

Female↗
PubMed1995

Long-term repopulation of hematolymphoid cells with only a few hemopoietic stem cells in mice.

A PCR-based assay has been devised for the detection and semiquantitation of cells originating from a few donor hematopoietic stem cells (HSCs) in a background of recipient cells. Upon sequencing a segment of murine Y chromosome contained in the plasmid pY2, oligonucleotide primers were designed for specific amplification of the Y chromosome-restricted segment. The HSCs were isolated from the bone marrow of mice on day 4 following a single i.v. injection of 5-fluorouracil and were readily distinguished from other bone marrow elements by the characteristics of low density, absence of lineage-specific surface markers, lack of expression of transferrin receptor, and a high expression of major histocompatibility complex class I antigen. Injection of as few as four such HSCs was shown to produce donor-derived cells (including lymphoid cells) for at least 8 months after transplantation into syngeneic female recipients. Retransplantation, employing 10(6) bone marrow cells from the initial recipients, also yielded clear evidence of repopulation with detectable levels of male donor cells. On statistical grounds, it is clear that long-term repopulation in vivo may result from even a single HSC having the characteristics defined herein.

Animals↗
PubMed1995

Regulation of the major histocompatibility complex class I mRNA expression by bile acids in cultured human hepatoma cells.

We investigated the effect of bile acids on major histocompatibility complex (MHC) class I gene expression in the cultured human hepatoma cell HepG2. Not only chenodeoxycholic acid, but its stereoisomer ursodeoxycholic acid as well, increased steady state level of MHC class I mRNA. When various bile acids were studied, inducibility of MHC class I mRNA was closely associated with the hydrophobicity of the corresponding bile acids. Pretreatment of the cells with a protein kinase C (PKC) inhibitor H7 suppressed induction of MHC class I mRNA by those bile acids. Furthermore, treatment of the cells with chenodeoxycholic acid significantly induced translocation of PKC from cytosol to membrane. In summary, our data strongly indicate up-regulatory effect of bile acids on MHC class I mRNA expression, most probably via activation of PKC-dependent pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Activation of thymic B cells by signals of CD40 molecules plus interleukin-10.

We have previously found that thymic B cells, particularly thymic CD5+ B cells, show low responsiveness to the usual B cell stimulants such as lipopolysaccharide or anti-IgM plus interleukin (IL)-4, although they proliferate and produce antibodies after direct interaction with major histocompatibility complex class II-restricted T blasts. These findings raise the possibility that a CD40-CD40 ligand (L) interaction is involved in the activation of thymic B cells. In the present study, we therefore examine this possibility using CD40L-transfected Chinese hamster ovary (CHO) cells or anti-CD40 monoclonal antibody (mAb). When B cells in the spleen and peritoneal cavity were stimulated, they proliferated and produced immunoglobulin (Ig) in the presence of CD40L-CHO cells or anti-CD40 mAb alone. However, another signal delivered by IL-10 in addition to CD40L-CHO cells or anti-CD40 mAb was found to be necessary for thymic B cells to proliferate and secrete Ig. Other interleukins acting on B cells, such as IL-4, IL-5, and IL-6, had no effect on the activation of thymic B cells, which thus have unique characteristics not found in peripheral B cells. This report discusses the physiological significance of IL-10- and CD40-driven signals in the activation of thymic B cells.

Animals↗
PubMed1995

Abnormalities of B cells and dendritic cells in SAMP1 mice.

The age-related changes in the function of antigen-presenting cells (APC) were examined using a substrain of senescence-accelerated mouse (SAMP1). In the primary mixed lymphocyte reaction (MLR), dendritic cells (DC) from aged SAMP1 mice showed less stimulatory activity than those of age-matched BALB/c or young SAMP1 mice. In the secondary MLR, the stimulatory activity of B cells was found to be lower in aged SAMP1 mice but not in age-matched BALB/c or young SAMP1 mice. In addition, these age-related decreases in the stimulatory activity of APC were found to be related to changes in the surface density of major histocompatibility complex class II and intercellular adhesion molecule-1 (ICAM-1) (but not B7-1 or B7-2 molecule) on APC (DC and B cells).

Aging↗
PubMed1995

Influence of high glucose on 1,25-dihydroxyvitamin D3-induced effect on human osteoblast-like MG-63 cells.

Impaired bone formation due to defective osteoblast function, as reflected in a decreased serum osteocalcin (OC) concentration in the patients with diabetes, has been implicated in the development of diabetic osteopenia. The role of hyperglycemia in this decrease in serum OC concentration was investigated. 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), an active form of vitamin D3, stimulated OC secretion from the human osteosarcoma cell line MG-63 in a dose-dependent manner. Exposure of the cells to high concentrations of glucose for 7 days significantly impaired 1,25(OH)2D3-induced OC secretion as compared with that observed with cells maintained under normal glucose (5.5 mM) or high mannitol conditions. The inhibitory effect of glucose was in a dose-dependent manner up to 55 mM. High glucose (55 mM) also attenuated the 1,25(OH)2D3-induced increase in OC mRNA abundance in MG-63 cells, suggesting that the inhibition of the 1,25(OH)2D3-induced increase in OC secretion by exposure to a high concentration of glucose was, at least in part, mediated at the transcriptional level. High glucose significantly decreased the number of 1,25(OH)2D3 receptors in MG-63 cells, without any change in the dissociation constant for 1,25(OH)2D3; this effect was not mimicked by high mannitol, indicating specificity for glucose. These observations suggest that a high glucose concentration significantly impairs the ability of osteoblastic cells to synthesize OC in response to 1,25(OH)2D3 by reducing 1,25(OH)2D3 receptor number, and that impaired cell function caused by sustained exposure to high glucose contributes to the defect in bone formation observed in the patients with diabetic osteopenia.

Amino Acid Sequence↗
PubMed1995

Effect of 1,25-dihydroxyvitamin D3 on induction of scavenger receptor and differentiation of 12-O-tetradecanoylphorbol-13-acetate-treated THP-1 human monocyte like cells.

We investigated the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of scavenger receptors in human monocytic cell line (THP-1 cells) treated for 24 h with 12-O-tetradecanoylphorbol-13-acetate (TPA) which induces their differentiation into macrophages. The capacity to degrade 125I-labeled acetyl low density lipoprotein (LDL) was developed in accordance with macrophage differentiation. The treatment with 10 nM 1,25(OH)2D3 for 72 h inhibited the degradation of acetyl LDL by THP-1 macrophages in a dose-dependent manner, suggesting that 1,25(OH)2D3 inhibits scavenging function in macrophages. In order to clarify the mechanism of its inhibitory effect on degradation of acetyl LDL, we performed the ligand binding assay using 125I-labeled acetyl LDL. Scatchard analysis revealed that 1,25(OH)2D3 decreased the number of scavenger receptors without changing the affinity for acetyl LDL. We next examined the effect of 1,25(OH)2D3 on the expression of scavenger receptor mRNA. The mRNA of type I scavenger receptor was first detected in THP-1 cells 4 days after the treatment with TPA, the mRNA level increased up to 6 days, and then decreased. The treatment with 1,25(OH)2D3 for 72 h dramatically decreased the mRNA levels after the acquisition of macrophage phenotypes as evidenced by nonspecific esterase staining. However, 1,25(OH)2D3 did not affect the activity of nonspecific esterase nor the induction of interleukin-1 beta mRNA by lipopolysaccharide in THP-1 macrophages. These findings suggest that 1,25(OH)2D3 exclusively decreases the expression of scavenger receptors in TPA-induced THP-1 macrophages without affecting the basic cellular functions as macrophages.

Base Sequence↗
PubMed1995

Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. I. Expression on dendritic cells and other subsets of mouse leukocytes.

Prior studies by a variety of groups demonstrated that the mAb NLDC-145 reacted primarily with dendritic cells (DCs) and the epithelial cells of the thymic cortex. We recently reported that this mAb recognizes DEC-205, a 205-kDa integral membrane glycoprotein with a unique amino-terminal sequence, and raised a rabbit polyclonal antibody to purified DEC-205 with higher affinity for the blotted antigen than the original mAb. Here we utilize both the polyclonal and NLDC-145 to reassess the expression and function of DEC-205 on leukocytes. By cytofluorography, DCs derived from the epidermis (Langerhans cells) and from proliferating bone marrow progenitors (BMDCs) expressed high levels (2-3 logs) of DEC-205, while freshly isolated spleen DCs comprised two subsets, most (80%) staining at low levels (< or = 1 log), the remainder moderately (1.5 logs). DEC-205 epitopes were sensitive to trypsin, but were regenerated in culture. Resident and inflammatory peritoneal macrophages did not express the antigen, except for small amounts on thioglycollate-elicited cells. B cells from spleen, lymph node, bone marrow, blood, and peritoneal fluid expressed levels of DEC-205 that were 10- to 50-fold lower than those on BMDCs. Marrow pro- and pre-B cells did not express DEC-205. Polyclonal anti-DEC-205 failed to inhibit either stimulation of a primary mixed leukocyte reaction by DCs in vitro, or a local graft vs host response in vivo, where parental T cells were injected into F1 mice. DEC-205 is therefore more broadly expressed on leukocytes than previously appreciated, but its function remains unclear.

Animals↗
PubMed1995

Expression of B7 costimulator molecules on mouse dendritic cells.

Dendritic cells express most known accessory molecules [ICAM's, LFA's, B7's, and CD40] for binding and stimulating T cells. B7 is the most abundant of these, and B7-2 very much predominates relative to B7-1. B7 expression is regulated, not by LPS, but by some signal [s] that parallels maturation. B7 contributes to the T cell stimulatory function of dendritic cells, as do the other accessory molecules. B7-2 is expressed on dendritic cells and macrophages at several sites in situ, especially dendritic cells in the T cell areas.

Animals↗
PubMed1995

Release of ciliary neurotrophic factor from cultured astrocytes and its modulation by cytokines.

CNTF rescues various types of lesioned neurons in vivo, and it needs to be released from astrocytes into the extracellular space to have the effect. However, direct evidence for CNTF release has not been unequivocally demonstrated. We hypothesized that the rapid sequestration by CNTF receptor present on cultured astrocytes might be the cause of the inability to detect CNTF released into astrocyte-conditioned medium (ACM). Therefore, we measured CNTF immunoreactivity in medium conditioned by astrocytes treated with phosphatidylinositol-specific phospholipase C (PI-PLC) which was used to prevent released CNTF from binding to the CNTF receptor, since PI-PLC cleaves glycosyl-phosphatidylinositol anchor of CNTFR alpha, the unique component involved in CNTF binding. CNTF was not detectable in untreated ACM, but was detectable in PI-PLC-treated ACM. These results together with the evidence that PI-PLC treatment did not have a toxic effect on astrocytes prove the fact that CNTF can be released from astrocytes without cell lysis. Subsequently, the effect of cytokines such as IL-1 beta, TNF-alpha, and EGF on CNTF release was examined. These cytokines increased CNTF protein levels in ACMs without increasing CNTF protein levels in astrocyte-extracts, indicating that they enhanced CNTF release from astrocytes.

Animals↗
PubMed1995

Natural course of diabetic peripheral neuropathy in spontaneous-onset diabetic Chinese hamsters.

We investigated metabolic and pathological changes in the peripheral nerve of the spontaneous-onset diabetic Chinese hamster. Electrophysiological examination revealed that the motor nerve conduction velocity was significantly decreased at 10 months and afterwards, however, the F-wave latency was significantly increased at 5 months and afterwards. Concerning sciatic nerve contents of sorbitol, myo- and scyllo-inositol, the content of sorbitol was not significantly increased at 5 months, but, myo- and scyllo-inositol were significantly decreased at 5 months and thereafter. At 10 and 15 months, however, sciatic nerve content of sorbitol was significantly increased. On morphological examination, loss of large myelinated fiber and reciprocal increase in degenerative fiber were also seen in sciatic nerve, but not in tibial nerve, at 5 months. At 15 months, these morphological changes were also found in the tibial as well as the sciatic nerve. Thus, we may hypothesize that F-wave latency is useful in the detection of initial diabetic neuropathy, and that the initial pathological changes in diabetic neuropathy of diabetic Chinese hamsters are predominantly found in the proximal site of peripheral nerves.

Aging↗
PubMed1995

Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats.

To clarify the contribution of P-glycoprotein to the biliary excretion of vincristine in rats, the effects of induction of hepatic P-glycoprotein by a phenothiazine treatment on the biliary excretion of [3H]vincristine were investigated. Immunoblot analysis using C219, a monoclonal antibody to P-glycoprotein, demonstrated that the phenothiazine treatment increased the P-glycoprotein level in isolated bile canalicular membrane vesicles approximately 6.5-fold. Transport of [3H]vincristine to canalicular membrane vesicles from the phenothiazine-treated and control rats revealed ATP-dependency, with an overshoot that results from the consumption of medium ATP. The maximum ATP-dependent uptake was increased in canalicular membrane vesicles from the phenothiazine-treated rats approximately 2-fold compared to the control. The biliary excretion of [3H]vincristine was further studied using an indicator dilution method in a single-pass perfused liver. The ratios of the cumulative amount of [3H]vincristine excreted into the bile ot the amount of [3H]vincristine taken up by the liver at 15, 30 and 90 min were significantly increased in the phenothiazine-treated rats by 60, 45 and 25%, respectively, compared to the control rats. Furthermore, the corrected mean residence time of [3H]vincristine in hepatocytes in the phenothiazine-treated rats was reduced to 21 min from that in the control rats (30 min), supporting the contention that the induction of hepatic P-glycoprotein on the bile canalicular membrane function sas a transporter not only in the isolated membrane but also in the more physiological perfused liver system. One must be cautious in the interpretation of the data, however, since phenothiazine can induce other proteins which might affect the behavior of [3H]vincristine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Suppressive effect of actarit on IgA production in mice: activation of CD4+ suppressor T-cells in Peyer's patches.

We examined the effects of actarit, a new antirheumatic drug, on antibody production after LPS stimulation in mice. Actarit did not affect the proliferative response of B-cells stimulated with LPS or anti-mouse mu-chain antibody plus rIL-4. Lymphocytes in the Peyer's patches (PP) of mice with oral administration of actarit suppressed the production of IgA (not IgM and IgG) by B-cells stimulated with LPS. Actarit affected neither the serum level of IgA nor IgA secretion from the gut of mice without LPS stimulation. Actarit did not change the percentage of Thy-1+ cells in the PP lymphocyte population or that of CD4+ or CD8+ cells in the Thy-1+ fraction of PP lymphocytes. The suppressive effect of PP lymphocytes from mice treated with actarit was abrogated by the elimination of CD4+ cells (not CD8+ cells) from PP lymphocytes. These results suggest that actarit activates CD4+ suppressor T-cells in the PP, resulting in a specific suppression of IgA production after LPS stimulation.

Animals↗
PubMed1995

Histochemical and functional characteristics of metachromatic cells in the nasal epithelium in allergic rhinitis: studies of nasal scrapings and their dispersed cells.

BACKGROUND: In allergic rhinitis, metachromatic cells in the nasal epithelium increase in number and are thought to play an important role in nasal allergic manifestation. METHODS: To determine immunohistochemical and functional characteristics of the metachromatic cells, nasal scrapings and their dispersed cells from patients with perennial allergic rhinitis were studied. RESULTS: Eighty-three percent of all metachromatic cells in dispersed cell preparations were tryptase-positive mast cells (MCT), 10% were tryptase-chymase-positive cells (MCTC), and 7% were negative (n = 10). The mean histamine chymase-positive cells (MCTC), and 7% were negative (n = 10). The mean histamine content per metachromatic cell was 1.9 +/- 2 pg. The histamine content and histamine release from nasal surface scrapings of patients sensitized with mite antigen were strongly correlated with the level of serum IgE antibody for mite antigen. The net histamine release from nasal scraping was antigen-dose-dependent (1:2 x 10(7) to 1:2 x 10(3) dilution), and the antigen stimulated release of up to 17% of cell-associated histamine within 5 to 7 minutes. Histamine release from nasal scrapings induced by calcium ionophore A23187 was up to 21% of cell-associated histamine within 2 to 4 minutes, but no histamine release was stimulated by compound 48/80, substance P, or poly-L-lysine. Histamine release from nasal scrapings was inhibited 46% (10(-5) mol/L) to 96% (10(-4) mol/L) by quercetin and 58% (10(-4) mol/L) to 72% (10(-3) mol/L) by sodium cromoglycate. CONCLUSIONS: These findings show the predominant characteristics of mast cells in the nasal epithelium in allergic rhinitis, and this information may be useful in relation to a therapeutic approach.

Adolescent↗