Biomedical subjects

H Kasai

Publications and source records attributed to H Kasai.

At least 127 records · Page 7Linked to original sources

PubMed1998

[Augmented antitumor activity in combination chemotherapy of nedaplatin with etoposide].

Augmented antitumor activity in combination chemotherapy of Nedaplatin (NDP) or Cisplatin (CDDP) with Etoposide (ETP) against murine and human lung cancer cells was demonstrated. NDP and CDDP were administered once and ETP daily for five days via tail vein. In the mice bearing Lewis lung carcinoma, a combination of NDP and ETP resulted in synergistically enhanced inhibition of tumor growth, and prolonged survival in comparison with either NDP or ETP alone. NDP showed a more potent combination effect with ETP than CDDP did. These effects were also demonstrated in human lung cancer cell lines. Although body weight loss was enhanced by the combination of NDP or CDDP with ETP, it was tolerable, and no significant difference between NDP plus ETP and CDDP plus ETP was observed. Thrombocytopenia was not enhanced in the combined treatment of NDP with ETP. These results suggest the usefulness of the combination of NDP with ETP as a clinical therapy for lung cancer.

Animals↗

PubMed1998

[Corneal endothelial cell damage associated with pars plana vitrectomy].

We performed a prospective study of corneal endothelial damage associated with pars plana vitrectomy in 51 eyes of 46 patients. The corneal endothelium was examined with a specular microscope preoperatively and three months postoperatively. The mean endothelial cell loss for 51 eyes was 11.54%. The 51 eyes were divided into three groups, and the mean cell loss was 25.85% in the pars plana lensectomy (including anterior capsule removal) combined group, 7.53% in the phacoemulsification combined group, and 1.91% in the phakic group. The corneal epithelium removal did not affected the cell loss. The cell loss for the phacoemulsification combined group did not differ significantly from that for the control group (6 eyes received only phacoemulsification). In the pars plana lensectomy combined group the cell loss was related significantly with gas tamponade duration. This study suggests that we must note the endothelial cell damage in vitrectomy-pars plana lensectomy combined with gas tamponade.

Adolescent↗

PubMed1998

Effects of loxiglumide on pancreatic exocrine secretion stimulated by cholecystokinin-8 in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by exogenously administered CCK-8 were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion in dogs was significantly increased by intravenous infusion of CCK-8 at a dose of 0.06 microgram/kg/h. Loxiglumide inhibited CCK-8-augmented outputs of pancreatic protein, trypsin and amylase at intravenous doses of 1, 3, 10 mg/kg/h (p < 0.05 or 0.01), and inhibited pancreatic juice volume at a dose of 10 mg/kg/h (p < 0.05). These results demonstrated that the selective CCK-A antagonist loxiglumide inhibited the increase of pancreatic exocrine secretion stimulated by CCK-8 based on selective blockade of receptor binding of CCK in dogs.

Amylases↗

PubMed1998

Effects of loxiglumide on pancreatic exocrine secretion stimulated by meal in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by meal were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion was stimulated by intraduodenal infusion of a liquid test meal and postprandial plasma CCK levels were apparently elevated. Loxiglumide inhibited the meal-stimulated outputs of pancreatic protein, amylase and bicarbonate at an intravenous dose of 10 mg/kg/h (p < 0.05). However, loxiglumide did not show apparent inhibition of pancreatic juice volume and trypsin output. These results show that the selective CCK-A antagonist loxiglumide may inhibit the increase of pancreatic exocrine secretion based on selective blockade of receptor binding of CCK endogenously induced by meal in dogs.

Amylases↗

PubMed1998

Biochemical and pharmacological profiles of loxiglumide, a novel cholecystokinin-A receptor antagonist.

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR1505) is a new derivative of glutaramic acid. Radioligand displacement assay was performed to characterize the selectivity of loxiglumide to CCK-A (cholecystokinin-A) receptor (rat pancreas and bovine gallbladder) and CCK-B/gastrin receptors (guinea pig cerebral cortex and guinea pig gastric parietal cell). And tissue bioassay was performed to investigate the effect of the compound on contractions of the guinea pig gallbladder and ileum. Loxiglumide inhibited 125I-CCK-8 binding to rat pancreatic and bovine gallbladder membranes with IC50 values of 195 and 77.1 nmol/l, respectively. Loxiglumide also inhibited 125I-CCK-8 binding to guinea pig cerebral cortex membranes and parietal cells with IC50 values of 12363 and 15455 nmol/l, respectively. In addition, loxiglumide inhibited 125I-gastrin binding to guinea pig parietal cells with IC50 values of 6134 nmol/l. These results indicate that the affinity of loxiglumide to CCK-A receptor is at least 63 times greater than that to CCK-B/gastrin receptors. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig gallbladder and ileum further demonstrate that loxiglumide acts as a competitive CCK antagonist with a high affinity to these tissues (gallbladder, pA2:6.71).

Animals↗

PubMed1998

Effects of loxiglumide on experimental acute pancreatitis in comparison with gabexate mesilate.

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR 1505) is a cholecystokinin-A (CCK-A) receptor antagonist. In this report, the effects of loxiglumide and gabexate mesilate were studied on three experimental acute pancreatitis models induced by caerulein, sodium taurocholate + caerulein and closed duodenal loop. The intravenous injection of loxiglumide at 3 and 10 mg/kg (6 times at hourly intervals) significantly inhibited an increase in serum amylase activity induced by the intraperitoneal injection of caerulein (50 micrograms/kg i.p., 6 times at hourly intervals) in mice. But gabexate mesilate at 10, 30 and 60 mg/kg did not. The intravenous infusion of loxiglumide at 18 and 60 mg/kg/h showed a life prolonging effect in the lethal necrotizing pancreatitis, induced by the subcutaneous injection of caerulein (50 micrograms/kg s.c., 4 times at 2 h intervals) after the injection of sodium taurocholate (10%, 0.1 ml/body) into the common bile duct, cumulative survival rates being 86 and 90%, respectively. Gabexate mesilate at 180 mg/kg/h showed the prolonging effect (cumulative survival rates 75%). The intravenous injection of loxiglumide at 6, 18 and 60 mg/kg/h significantly inhibited an increase in total ascitic lipase activity, and plasma amylase and lipase activity of rats with closed duodenal loop. These results suggest that CCK plays an important role in the progression of acute pancreatitis, and that loxiglumide may have a therapeutic potential for pancreatitis.

Acute Disease↗

PubMed1998

[Surgical outcomes of vitrectomy for retinal detachment due to macular hole with proliferative vitreoretinopathy].

We retrospectively studied surgical outcomes in 13 patients (13 eyes) who underwent vitrectomy for proliferative vitreoretinopathy (PVR) due to macular hole. While the success rate of the initial surgery was only 46% (6 eyes), retinal reattachment was ultimately obtained in 92% (12 eyes) with additional surgery. Reattachment rate in the initial was poor in eyes with posterior staphyloma. It was better in eyes treated with macular buckling and/or scleral encircling, and in eyes without iatrogenic retinal tears. These results indicate that appropriate treatment for the macular hole as well as extensive removal of vitreous gel and vitreoretinal traction are necessary in order to obtain the successful results in vitrectomy for PVR due to macular hole.

Aged↗

PubMed1998

[Ultrasound biomicroscopic findings of anterior hyaloidal fibrovascular proliferation].

We performed ultrasound biomicroscopy (UBM) on 5 eyes with anterior hyaloidal fibrovascular proliferation (AHFVP), which had developed after vitrectomy for proliferative diabetic retinopathy. AHFVP was observed as a thick membrane or a mass image which extended from the vitreous base to the pars plicata, and was apparently differentiated from the anterior vitreous membrane and cilliary body. UBM showed proliferative stalks extending from sclerotomy sites toward the anterior vitreous membrane. These UBM images indicated that AHFVP originated from sclerotomy sites. UBM also enabled us to detect traction detachment of the peripheral retina associated with AHFVP, which could not be observed by conventional B-mode echography. Thus UBM is useful in establishing a diagnosis of AHFVP, and this technique is valuable to determine the indication and the timing of surgical treatment for AHFVP.

Adult↗

PubMed1998

[Augmented antitumor efficacy of combination chemotherapy of nedaplatin with 5-fluorouracil in in vivo murine and human tumor model].

Augmented antitumor activity was demonstrated in combination chemotherapy of Nedaplatin (NDP) or Cisplatin (CDDP) with 5-fluorouracil (5-FU) against murine lung carcinoma and human squamous carcinoma from head and neck. Either NDP or CDDP (1/4 to 1 maximum tolerated dose; MTD) was injected once and 5-FU (1/16 MTD) was injected daily for five days via tail vein to tumor-implanted mice. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) showed severe body weight loss followed by the toxic death of tumor-bearing mice at the MTD of NDP or CDDP. In contrast, the reverse sequence of the treatment, that is, 5-FU prior to NDP or CDDP (FN or FC therapy), resulted in the synergistically enhanced inhibition of tumor growth and the prolonged survival in comparison with NDP, CDDP or 5-FU monotherapy. The antitumor activities of the combinations of CDDP with 5-FU was less than those of the combination of NDP with 5-FU. Especially, at the MTD of NDP in FN therapy, long-term tumor-free survival was frequently observed. Thus, FN therapy was thought to be the most efficient regimen in combination of NDP with 5-FU as a clinical therapy.

Animals↗

PubMed1997

Hrs is associated with STAM, a signal-transducing adaptor molecule. Its suppressive effect on cytokine-induced cell growth.

We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Construction of mutants of Salmonella typhimurium deficient in 8-hydroxyguanine DNA glycosylase and their sensitivities to oxidative mutagens and nitro compounds.

8-Hydroxyguanine (8-OH-G) DNA glycosylase is an enzyme involved in repair of oxidative DNA damage, e.g., 8-OH-G in DNA. In order to assess the roles of 8-OH-G in spontaneous and chemically-induced mutagenesis, the mutMST gene encoding 8-OH-G DNA glycosylase of Salmonella typhimurium was disrupted in several Ames tester strains, i.e., S. typhimurium TA1535 (hisG46, uvrB-, rfa), TA1975 (hisG46, uvr+, rfa) and TA102 (hisG428, uvr+, rfa). The spontaneous mutation frequencies were increased 2.4 and 1.6 times, respectively, by the mutMST deletions in strains TA1535 and TA1975, which are spontaneously reverted to His+ by mutations mainly at G:C base pairs. The resulting strains YG3001 (TA1535 delta mutMST) and YG3002 (TA1975 delta mutMST) were 2 to 8 times more sensitive to the mutagenicities of methylene blue plus visible light, neutral red plus visible light and 2-nitrofluorene than the parent strains. The strain YG3002 but not YG3001 was about 30 times more sensitive to the mutagenicity of 4-nitroquinoline N-oxide than the parent strain TA1975. Neither hydrogen peroxide nor phenazine methosulfate was mutagenic in the mutMST-deletion strains as well as in the parent strains. In contrast, the mutMST deletion did not affect the spontaneous mutation frequency of strain TA102, which has an A:T base pair at the critical site for reversion. The sensitivities of strain TA102 to the chemicals were not enhanced by the mutMST deletion except for hydrogen peroxide. These results suggest that 8-OH-G in DNA plays important roles in spontaneous mutagenesis occurring at G:C base pairs in S. typhimurium, and some nitro aromatics such as 4-nitroquinoline N-oxide or 2-nitrofluorene as well as the photosensitizers plus visible light can produce 8-OH-G in DNA, thereby inducing mutations. In the case of 4-nitroquinoline N-oxide, 8-OH-G rather than DNA adducts seems to play major roles in mutagenesis in uvr+ background. The new strains could be useful for the evaluation of the roles of 8-OH-G in mutagenesis in S. typhimurium and permit the efficient detection of some oxidative mutagens in the environment.

4-Nitroquinoline-1-oxide↗

PubMed1997

Mutations induced by 2-hydroxyadenine on a shuttle vector during leading and lagging strand syntheses in mammalian cells.

An oxidatively damaged base, 2-hydroxyadenine (2-OH-Ade), was incorporated into a predetermined site of one of the strands {(+)- or (-)-strand} of the double-stranded shuttle vector, pSVK3, and the modified DNAs were transfected into simian COS-7 cells. The nucleotide sequences in which the modified base was incorporated were 5'-GTCGA*C and 5'-CTTA*AG (A* represents 2-OH-Ade). The former is the recognition site for the restriction enzyme SalI, and the latter is that for AflII. The DNAs replicated in the cells were recovered and were transfected again into Escherichia coli. The DNAs recovered from the COS-7 cells transfected with a plasmid containing 2-OH-Ade at either site of the (+)-strand (a template strand for lagging strand synthesis) formed colonies about 50%-70% as frequently as the unmodified DNA. This indicated that the base weakly blocked DNA replication during lagging strand synthesis. On the other hand, the base in the (-)-strand did not appear to affect the efficiency of leading strand synthesis in COS-7 cells. The mutation frequencies of 2-OH-Ade in COS-7 cells were 0.6%-0.1%, depending on the sequence and the strand location. Although the mutation spectra of 2-OH-Ade also differed with sequences and strands, the base elicited substitution and deletion mutations in mammalian cells, as in E. coli. These results indicate that 2-OH-Ade is mutagenic in eukaryotic cells as well as in prokaryotic cells.

Animals↗

PubMed1997

Effect of sodium tauroursodeoxycholate (UR-906) on liver dysfunction in bile duct-ligated rats.

We investigated the effect of sodium tauroursodeoxycholate (UR-906) on cholestasis in common bile duct-ligated rats in comparison with the effect of dehydrocholic acid. UR-906 (30-180 mumol/kg) and dehydrocholic acid (180 mumol/kg) were intravenously given once daily for consecutive 20 days in rats and the common bile duct was ligated for the last 10 days. On the next day after the last test drug administration, serum biochemical and plasma hemostatic variables were determined. UR-906 significantly ameliorated the elevation of serum cholesterol, phospholipid, bilirubin and bile acid concentrations in bile duct-ligated rats. UR-906 significantly suppressed the prolongation of plasma prothrombin time and activated partial thromboplastin time. Furthermore, UR-906 significantly suppressed the decreases in plasma coagulation factor II and X activities. However, dehydrocholic acid did not cause significant changes in any of the variables examined in this model. These results suggest that UR-906 has a beneficial effect against cholestasis induced by bile duct ligation in rats and that this drug may be useful in the treatment of clinical cholestatic disorders.

Animals↗

PubMed1997

Multiple exocytotic pathways in pancreatic beta cells.

Ca2+-dependent exocytotic pathways in mouse pancreatic beta cells were investigated using both capacitance measurement and amperometric detection of vesicular contents. Serotonin was preloaded into large dense-core vesicles for the amperometry. Exocytosis was induced by rapid elevation of cytosolic Ca2+ concentrations using caged-Ca2+ compounds. Capacitance measurement revealed two major components of exocytosis, and only the slow component was accompanied by amperometric events reflecting quantal serotonin secretion. Moreover, the fast and slow exocytoses induced the two forms of endocytosis that were reported to follow the exocytoses of small-clear and large dense-core vesicles, respectively. Interestingly, we recorded two types of responses of quantal events: in the type-1 response, most quantal events occurred with a delay of 0.2 s and were rapidly exhausted with a time constant of 1.7 s, while, in the type-2 response, quantal events occurred with a delay of 2.5 s and were sustained. This suggests the existence of two pathways or modes of the exocytosis involving large dense-core vesicles. Thus, we have revealed three exocytotic pathways with divergent fusion kinetics in beta cells, which provide a new basis for the understanding of the physiology and pathology of beta cells.

Animals↗

PubMed1997

Mutational specificity of glyoxal, a product of DNA oxidation, in the lacI gene of wild-type Escherichia coli W3110.

To determine the mutation spectrum of glyoxal, which is produced from DNA by oxygen free-radicals, we analyzed the chromosomal lacI gene of mutants induced by treatment of a wild-type Escherichia coli strain with glyoxal. The cell death and the mutation frequency increased according to the concentration of glyoxal added to the culture medium. The majority of the spontaneous mutations (82%) and that of the glyoxal-induced mutations (50%) were the addition or deletion of a 5'-TGGC-3' sequence at positions 623-634, which was reported to be a mutational hot spot in the lacI gene. In the glyoxal-induced mutants, however, the ratio of base-pair substitutions was increased (35%). Although all types of base-pair substitutions were detected, 78% of the base-pair substitutions occurred at G:C sites. Among them, G:C-->A:T transitions were predominant, followed by G:C-->T:A transversions. These mutations appeared to be distributed randomly within the lacI gene. These results suggest that glyoxal-induced mutations may correlate to mutations induced by oxygen free-radicals.

Bacterial Proteins↗

PubMed1997

Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney.

We have developed an experimental model of iron-induced oxidative nephrotoxicity and renal cancer. Using this model, the effect of vitamin E, a known antioxidant, was investigated. Three-week-old male Wistar rats were fed with vitamin E-sufficient (control) and vitamin E-supplemented diets throughout the experiment. After 1 month of feeding, iron-induced tissue lipid peroxidation, apoptosis, and formation of 8-hydroxydeoxyguanosine, a known DNA oxidative modification, were observed by cold Schiff staining, in situ labeling method (staining by terminal deoxynucleotidyl transferase-mediated nick end labeling), and high-performance liquid chromatography with electrochemical detection system, respectively, in the groups of rats treated with ferric nitrilotriacetate (Fe-NTA; Fe, 10 mg/kg body weight). For the vitamin E intervention study on Fe-NTA-induced renal carcinogenesis, two groups of rats fed vitamin E-sufficient and vitamin E-supplemented diets (30 and 20 rats, respectively) were treated with Fe-NTA (Fe, 7.5 mg/kg body weight once or twice a week) i.p. for 3 months and observed for 9 additional months. Five of the vitamin E-sufficient rats died during the first 3-month period. The results showed that vitamin E could inhibit tissue lipid peroxidation, apoptosis, 8-hydroxydeoxyguanosine formation, and the development of cancer [11 of 25 rats (44%) for vitamin E-sufficient versus 1 of 20 rats (5%) for vitamin E-supplemented rats, respectively]. These studies strongly suggest that in Fe-NTA-induced renal cancer, as with certain other types of cancer, oxidative stress plays an important role in carcinogenesis, and an antioxidant is an effective chemopreventive measure.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1997

Types of mutations induced by glyoxal, a major oxidative DNA-damage product, in Salmonella typhimurium.

We have analyzed the types of mutations induced by glyoxal, a major oxidative DNA-damage product, in Salmonella typhimurium. A set of six strains, TA7001 to TA7006, was used to detect base-pair substitutions, and the TA98 strain was employed to detect frameshift mutations. Glyoxal did not induce mutations at A:T base pairs. The majority of the mutations induced by glyoxal were base-pair substitutions at G:C base pairs, and a small level of frameshift mutations was detected in the TA98 strain.

Base Composition↗

PubMed1997

Glyoxal, a major product of DNA oxidation, induces mutations at G:C sites on a shuttle vector plasmid replicated in mammalian cells.

Glyoxal is a major product of DNA oxidation in which Fenton-type oxygen free radical-forming systems are involved. To determine the mutation spectrum of glyoxal in mammalian cells and to compare the spectrum with those observed in other experimental systems, we analyzed mutations in a bacterial suppressor tRNA gene (supF) in the shuttle vector plasmid pMY189. We treated pMY189 with glyoxal and immediately transfected it into simian COS-7 cells. The cytotoxicity and mutation frequency increased according to the dose of glyoxal. The majority of glyoxal-induced mutations (48%) were single-base substitutions. Eighty three percent of the single-base substitutions occurred at G:C base pairs. Among them, G:C-->T:A transversions were predominant, followed by G:C-->C:G transversions and G:C-->A:T transitions. A:T-->T:A transversions were also observed. Mutational hotspots within the supF gene were detected. These results suggest that glyoxal may play an important role in mutagenesis induced by oxygen free radicals.

Animals↗