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Biomedical subjects

K Ohishi

Publications and source records attributed to K Ohishi.

At least 19 recordsLinked to original sources
PubMed1998

Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships.

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

Acrylonitrile↗
PubMed1998

A homologue of Saccharomyces cerevisiae Dpm1p is not sufficient for synthesis of dolichol-phosphate-mannose in mammalian cells.

Dolichol-phosphate-mannose (Dol-P-Man) serves as a donor of mannosyl residues in major eukaryotic glycoconjugates. It donates four mannosyl residues in the N-linked oligosaccharide precursor and all three mannosyl residues in the core of the glycosylphosphatidylinositol anchor. In yeasts it also donates one mannose to the O-linked oligosaccharide. The yeast DPM1 gene encodes a Dol-P-Man synthase that is a transmembrane protein expressed in the endoplasmic reticulum. We cloned human and mouse homologues of DPM1, termed hDPM1 and mDPM1, respectively, both of which encode proteins of 260 amino acids, having 30% amino acid identity with yeast Dpm1 protein but lacking a hydrophobic transmembrane domain, which exists in the yeast synthase. Human and mouse DPM1 cDNA restored Dol-P-Man synthesis in mouse Thy-1-deficient mutant class E cells. Mouse class E mutant cells had an inactivating mutation in the mDPM1 gene, indicating that mDPM1 is the gene for class E mutant. In contrast, hDPM1 and mDPM1 cDNA did not complement another Dol-P-Man synthesis mutant, hamster Lec15 cells, whereas yeast DPM1 restored both mutants. Therefore, in contrast to yeast, mammalian cells require hDPM1/mDPM1 protein and a product of another gene that is defective in Lec15 mutant cells for synthesis of Dol-P-Man.

Amino Acid Sequence↗
PubMed1998

Suppression of interleukin-11-mediated bone resorption by cyclooxygenases inhibitors.

We previously found that human melanoma (A375M) and human breast cancer (MDA-MB-231) cells formed osteolytic bone metastasis in vivo. These cancer cells produced interleukin-11 (IL-11) by themselves and stimulated its production from osteoblasts. Interleukin-11 could increase the number of osteoclasts and raise the calcium concentration in the medium of neonatal murine calvaria organ culture, indicating bone resorption in vitro. Therefore, IL-11 could play an important role in the promotion of osteolysis at the site of bone metastasis. In the present study, we used the calvaria culture system to try to clarify the mechanisms of IL-11-mediated bone resorption. The murine calvaria expressed both the specificity-determining alpha subunit and the signal-transducing beta subunit (gp130) of the IL-11 receptor. When IL-11 was added to the calvaria culture, the concentrations of prostaglandin E2 (PGE2) was elevated. Pretreatment of calvaria with cyclooxygenases inhibitors (e.g., indomethacin, NS-398, and dexamethasone) suppressed the production of PGE2 and the bone resorption induced by IL-11. Addition of exogenous PGE2 overcame the inhibitory effect of cyclooxygenases inhibitors and promoted bone resorption. These results indicate that IL-11 promotes bone resorption through a PGE2 synthesis-dependent mechanism and that cyclooxygenases inhibitors could be interesting drugs to suppress IL-11-mediated osteolytic bone metastasis of cancer cells.

Animals↗
PubMed1998

Functional competence of T cells in the absence of glycosylphosphatidylinositol-anchored proteins caused by T cell-specific disruption of the Pig-a gene.

T lymphocytes express various glycosylphosphatidylinositol (GPI)-anchored surface proteins, such as Thy-1 and Ly-6A. However, functional contribution of GPI-anchored proteins in T cell activation is as yet poorly understood. Here we report the generation of mutant mice deficient in the expression of GPI-anchored molecules exclusively in their T cells. We established mice carrying three identically oriented lox-P sites within the Pig-a gene, which encodes a component essential for the initial step of GPI anchor biosynthesis. These mice were crossed with mice carrying the Cre recombinase gene driven by the T cell-specific p56lck proximal promoter. Offspring carrying both the lox-P-containing Pig-a gene and the Cre transgene exhibited almost complete loss of the surface expression of GPI-anchored molecules on peripheral T cells. Interestingly, those T cells deficient in GPI-anchored molecules were capable of responding to T cell receptor stimulation in vitro and in vivo. These results indicate that T cells lacking the expression of GPI-anchored molecules are functionally competent in exerting TCR-mediated immune responses.

Alleles↗
PubMed1998

The role of oxygen free radicals in cisplatin-induced acute renal failure in rats.

We examined the role of oxygen free radicals in cisplatin-induced acute renal failure (ARF). The intravenous injection of cisplatin (5 mg/kg body weight) induced an increase in serum creatinine and tubular damage in the outer stripe of the outer medulla in rats. The renal content of malondialdehyde (MDA) transiently increased. Treatment with the free radical scavengers dimethylthiourea (DMTU) or lecithinized superoxide dismutase (L-SOD) attenuated the increase in serum creatinine. The beneficial effect of DMTU, a hydroxyl radical scavenger, was associated with less accumulation of MDA, less tubular damage, and enhanced expression of proliferating cell nuclear antigen (PCNA) in the damaged tubular cells, but not with improvement of reduced renal blood flow (RBF). On the other hand, the beneficial effect of L-SOD, a superoxide anion scavenger, was associated with preservation of RBF and increased urinary guanosine 3',5'-cyclic monophosphate excretion but not with modification of tubular damage or PCNA expression. These results suggest that (1) cisplatin-induced nephrotoxicity was associated with lipid peroxidation, (2) the hydroxyl radical scavenger prevented ARF through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells, and (3) the superoxide anion scavenger did the same through preservation of RBF. It follows that oxygen free radicals may play an important role in cisplatin-induced ARF by reducing RBF and inducing tubular damage.

Acetylglucosaminidase↗
PubMed1998

Immunizing effect of vaccinia virus expressing the nucleoprotein of rinderpest virus on systemic rinderpest virus infection in rabbits.

A recombinant vaccinia virus (RVV) expressing the nucleoprotein (NP) of rinderpest virus (RPV) was examined in rabbits for the involvement of the NP protein in protection from the RPV infection. Despite their production of anti-NP antibody, the RVV-immunized rabbits succumbed to the RPV challenge, although there was a slight delay in the onset of disease after the low-dose challenge. On the other hand, the animals immunized with RVV expressing the hemagglutinin (H) protein of the RPV were completely protected. These results indicate that the NP protein might be not so effective as the H protein for the protection against viremic and systemic infection with RPV.

Animals↗
PubMed1998

Pharmacokinetic study of an oral cephalosporin, cefdinir, in hemodialysis patients.

The pharmacokinetics of cefdinir were investigated in six hemodialysis patients. For the present study, two tests were carried out, one with 4 h of hemodialysis and the other without hemodialysis. Cefdinir was given orally to each patient in a dose of 100 mg, and blood was collected serially for 48 h after dosing in the test without dialysis and for 72 h in the test with dialysis. In the test without dialysis, the maximum plasma concentration (Cmax) was 2.36 +/- 0.53 micrograms/ml (mean +/- standard deviation) and the time to Cmax was 9.00 +/- 2.45 h. The terminal elimination half-life (t1/2) and area under the concentration-time curve (AUC) were 16.95 +/- 1.20 h and 69.05 +/- 14.84 micrograms.h/ml, respectively. In the test with dialysis, t1/2 during hemodialysis decreased approximately to one-sixth of that obtained in the test without dialysis, although t1/2 in the latter elimination phase did not differ from that in the nondialysis test. AUC was reduced to 43% of that in the test without dialysis. The fractional removal of cefdinir by hemodialysis was 61%. These findings indicate that clearance of cefdinir is prolonged in patients with renal failure, and cefdinir is well removed by introduction of hemodialysis, although t1/2 (during hemodialysis) and AUC were two and eight times higher than the data previously reported for healthy volunteers, respectively. The pharmacokinetic data suggest that 100 mg of oral cefdinir once a day would result in a sufficient concentration in plasma in hemodialysis patients, but this remains to be confirmed by multiple-dose studies.

Administration, Oral↗
PubMed1998

Impaired water excretion in a hyponatremic patient following thyroidectomy: causal role of glucocorticoid deficiency.

We evaluated the causal role of glucocorticoid deficiency in the hyponatremia that developed in a 57-year-old Japanese man with hypothyroidism following the performance of a total thyroidectomy for laryngeal cancer. The plasma concentration of vasopressin (1.78 pg/ml) was not suppressed in the presence of hyponatremia (125 mEq/l). The urinary excretion of sodium was increased, and the plasma renin activity and plasma aldosterone concentration were suppressed. The infusion of hypertonic saline increased the plasma osmolality, but not the plasma concentration of vasopressin. An oral water load (20 ml/kg of body weight) did not suppress the plasma vasopressin level or induce diuresis. Pretreatment with hydrocortisone normalized the response of plasma vasopressin to the water load was well as the diuretic response during the hypothyroid state. The urinary excretion of 17-hydroxycorticosteroids was below normal in the hypothyroid state in the face of normal serum cortisol concentration. The correction of the hypothyroidism returned these abnormalities to normal. A disturbed metabolism of glucocorticoid may have been responsible for the hyponatremia and disturbance in plasma vasopressin regulation observed in this hypothyroid patient.

Diuresis↗
PubMed1997

Inhibition of osteoblastic cell differentiation by conditioned medium derived from the human prostatic cancer cell line PC-3 in vitro.

Human prostatic carcinoma frequently metastasizes to bone tissue and activates bone metabolism, especially bone formation, at the site of metastasis. It has been reported that an extract of prostatic carcinoma and conditioned medium (CM) of a human prostatic carcinoma cell line, PC-3, established from a bone metastastic lesion, stimulate osteoblastic cell proliferation. However, there is little information about the effect of PC-3 CM on the differentiation of osteoblastic cells. In this study, we investigated the effect of PC-3 CM on the differentiation of two types of osteoblastic cells, primary fetal rat calvaria (RC) cells containing many undifferentiated osteoprogenitor cells, and ROS 17/2.8, a well-differentiated rat osteosarcoma cell line. PC-3 CM inhibited bone nodule formation and the activity of alkaline phosphatase (ALPase), an osteoblastic marker enzyme, on days 7, 14, and 21 (RC cells) or 3, 6, and 9 (ROS 17/2.8 cells) in a dose-dependent manner (5-30% CM). However, the CM did not affect cell proliferation or cell viability. PC-3 CM was found to markedly block the gene expression of ALPase and osteocalcin (OCN) mRNAs but had no effect on the mRNA expression of osteopontin (OPN), the latter two being noncollagenous proteins related to bone matrix mineralization. These findings suggest that PC-3 CM contains a factor that inhibits osteoblastic cell differentiation and that this factor may be involved in the process of bone metastasis from prostatic carcinoma.

Alkaline Phosphatase↗
PubMed1997

Structures and chromosomal localizations of the glycosylphosphatidylinositol synthesis gene PIGC and its pseudogene PIGCP1.

More than 10 genes are involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors many mammalian cell surface proteins to the membrane. Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a somatic mutation in a GPI biosynthesis gene within the hematopoietic stem cell. The X-linked gene PIGA has been found to be mutated in all patients with PNH. This is probably because all other GPI synthesis genes are autosomal; hence two somatic mutations must occur to cause PNH, whereas one somatic mutation is sufficient to inactivate PIGA. Consistent with this notion, three other genes, PIGB, PIGF, and PIGH, are autosomal. Here we isolated a genomic clone of another GPI-synthesis gene, PIGC, and mapped it to chromosome 1q23-q25, further supporting this notion. PIGC is an intronless gene. We found an intronless pseudogene of PIGC, PIGCP1, and mapped it to chromosome 11p12-p13. The presence of a processed pseudogene is a common feature of PIGA, PIGF, and PIGC.

Amino Acid Sequence↗
PubMed1997

Stimulation of interleukin-11 production from osteoblast-like cells by transforming growth factor-beta and tumor cell factors.

Bone is one of the most common sites of metastasis in melanoma and breast cancer cells. Human melanoma (A375M) and human breast cancer (MDA-MB-231) cells form osteolytic bone metastasis in vivo when these tumor cells are injected into the left ventricles of BALB/c nude mice. These tumor cells promote bone resorption in the in vitro neonatal murine calvaria organ culture system by indirectly stimulating the production of a bone resorption-inducing factor (or factors) from human osteoblast-like cells. This secreted factor was identified as interleukin-11 (IL-11). Although many cytokines and hormones were associated with IL-11 production from osteoblasts, transforming growth factor-beta (TGF-beta) was found to be involved in the promotion of IL-11 production from osteoblasts, because the addition of a neutralizing anti-TGF-beta antibody decreased the production of IL-11. However, these tumor cells did not produce TGF-beta by themselves. We found that they enhanced IL-11 production by activating latent TGF-beta produced from osteoblast-like cells. Our results indicate that metastatic tumor cells induce osteolysis by activating TGF-beta, which leads IL-11 production from osteoblasts to promote bone resorption.

Animals↗
PubMed1997

GPI-anchor synthesis in mammalian cells: genes, their products, and a deficiency.

Protein GPI anchors are ubiquitous in eukaryotic cells. More than 50 mammalian proteins are anchored to the membrane via GPI. GPI anchoring is a posttranslational modification occurring in the endoplasmic reticulum where preassembled GPI anchor precursors are transferred to proteins bearing a C-terminal GPI signal sequence. The GPI anchor precursors are synthesized in the endoplasmic reticulum by sequential addition of sugar and other components to phosphatidylinositol. More than ten genes participate in this biosynthetic pathway, eleven of the mammalian genes having been cloned by means of complementation of mutant cells that are defective in this pathway or based on sequence homology to previously cloned yeast counterparts. A somatic mutation in one of those genes, PIG-A, involved in the first reaction step, is responsible for the hemolytic disease, paroxysmal nocturnal hemoglobinuria.

Animals↗
PubMed1997

[A case of pseudomembranous enterocolitis which diagnosis was delayed in the outpatient clinic].

A 71-year-old male visited our hospital because of diarrhea. At first we suspected infectious colitis and levofloxacin (300 mg/day) was administered for four days. But the diarrhea continued, so performed a barium enema after about 3 weeks from onset. Round polyposis from the rectum to the sigmoid colon were found. Colonoscopy was suggested to the patient, but was rejected. However diarrhea continued and fever appeared. Ceftriaxone (1 g/day) and sparfloxacin (200 mg/day) were administered, but the symptoms increased. He was admitted about 6 weeks from onset, and the colonoscopy showed multiple round yellow-white pseudomembranes. Pseudomembranous enterocolitis diagnosed because Clostridium difficile and its toxin were positive in the feces. After oral administration of vancomycin (1.5 g/day) was started, the symptoms alleviated rapidly and disappearance of pseudomembrane was confirmed by colonoscopy.

Aged↗
PubMed1997

Role for C-MPL and its ligand thrombopoietin in early hematopoiesis.

Proto-oncogene c-mpl is structurally homologous with the hematopoietic growth factor receptor superfamily. The ligand for c-mpl was purified and its gene cloned. Extensive functional studies revealed that the ligand for c-mpl plays a crucial role in megakaryocytopoiesis and platelet production, hence, this ligand proved to be the long-sought hematopoietin, thrombopoietin (TPO). We briefly review here the role for TPO in early hematopoiesis, based on our in vitro data obtained using a serum-free culture system. TPO in combination with the ligand for c-kit (SF) or interleukin-3 (IL-3) but not TPO alone supported the growth of murine primitive hematopoietic progenitors. Studies on lineage expression indicated that the progenitors supported by TPO plus SF or TPO plus IL-3 are multipotential. Delayed addition experiments demonstrated that TPO has the potential to effectively support the survival of primitive hematopoietic progenitors. TPO also hastened IL-3-dependent growth of progenitors by shortening the time required for cell-cycling. While size of the colonies did not differ between colonies supported by IL-3 alone and those supported by IL-3 plus TPO, the incidence of megakaryocyte-containing colonies in cultures supported by IL-3 plus TPO was higher than that in cultures supported by IL-3 alone. Taken together, TPO as a single factor can support the survival of hematopoietic progenitors and TPO synergizes with SF or IL-3 to be active on early multipotential hematopoietic progenitors. These findings suggest that the function of TPO initially thought to be restricted to the megakaryocytic lineage proved to be greater in hematopoiesis. Reports from other laboratories regarding the involvement of TPO in early hematopoiesis are also discussed.

Animals↗
PubMed1997

Peptide-based bovine leukemia virus (BLV) vaccine that induces BLV-Env specific Th-1 type immunity.

In controlling retrovirus infection and replication, cell-mediated immunity (CMI) is considered to be effective. To develop a synthetic peptide vaccine capable of inducing CMI, mannan-coated liposome encapsulating 20-mer synthetic peptide, spanning the 98-117 amino acids of bovine leukemia virus (BLV) envelope glycoprotein (Env) gp51 was constructed and inoculated to BALB/c mice. The liposome induced specific delayed-type hypersensitivity, lymphocyte proliferative responses, and a weak cytotoxic lymphocyte response. The spleen cells from the immunized mice produced a large amount of IFN-gamma and IL-2, whereas they released neither IL-4 or IL-10. Mannan-coated liposome containing two kinds of peptides (the 121-140 and 142-161 regions of BLV Env gp51) also induced peptide-specific lymphocyte proliferative response and IFN-g production in C57BL/6 mice. Thus, the synthetic T-cell epitope peptide-liposome system augmented a strong Th-1 type immunity in mice.

Amino Acid Sequence↗
PubMed1997

Stage-specific cell-cycling of hematopoietic progenitor cells.

We studied the growth of hematopoietic progenitors at different progressive stages of differentiation and focused especially on changes in cell-cycling. Hematopoietic progenitors from 5-fluorouracil (5-FU)-treated mice were separated into three groups on the basis of differentiation, Stages I, II, and III, and have studied their cell-cycling. Primary marrow cells collected from 5-FU-treated mice were categorized as Stage I progenitors. Stages II and III progenitors are early and late progenies of Stage I progenitors, respectively. The rate of growth of hematopoietic progenitors supported by interleukin-3 (IL-3) and steel factor (SF) was estimated by sequential analysis of colony formation and studying replating efficiency of individual colonies. The time required for hematopoietic progenitors to go through the cell-cycle shortened as their stage of differentiation progressed. Similar results were obtained with other growth factor combinations. The analysis of DNA content of cells suggests that shortening of cell-cycling is mainly due to a decrease in the time of G1 phase of the cell-cycle. Our results demonstrate that in early hematopoiesis, the cell-cycling of hematopoietic progenitors accelerates as they differentiate.

Animals↗