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Biomedical subjects

F Sekiguchi

Publications and source records attributed to F Sekiguchi.

At least 55 records · Page 3Linked to original sources

[Diabetic peculiarity of the ALS-Ay and ALR-Ay strains].

ALS and ALR mice were developed as mouse models of alloxan-induced diabetes. These strains do not show spontaneous onset of diabetes. When an obesity gene (Ay) was introduced to these two strains, severe diabetic conditions occurred spontaneously in the produced ALS-Ay and ALR-Ay strains. These strains were examined body weight gain, food consumption, water consumption, urinary sugar content, ketone body level and blood sugar level, and subjected to glucose tolerance test. As a result, in comparison with ALS mice, male ALS-Ay mice showed no obesity and very low tolerance to the glucose tolerance test performed 24 weeks after birth. The level of insulin secretion was 5.0 microU/ml or less, showing hardly any secretory reaction. On the other hand, female ALS-Ay mice were obese and showed no marked decrease in glucose tolerance. The level of insulin secretion was high, and the secretory reaction was strong. In ALR-Ay strain, both male and female mice were obese and showed diabetic conditions similar to those of ALS-Ay mice, though the severity tended to be lower. The characteristic features of diabetic conditions in these mice suggest that these strains, particularly ALS-Ay, may serve as useful new-type models of diabetes.

Alloxan↗

[Comparative studies on the antitumor activity of fluorinated pyrimidine derivatives against human bladder, cervical and ovarian cancer xenografts in nude mice].

Fluorinated pyrimidines given orally were examined for their antitumor activity with 11 human cancer xenograft models (4 bladder, 4 cervical and 3 ovarian cancers). The drugs were evaluated to be effective when they inhibited tumor growth over 58%. UFT was not effective against all of 11 cancer xenografts tested. 5-Fluorouracil (5-FU) was effective against only one bladder cancer xenograft among 6 cancer xenografts tested. On the other hand, 5'-deoxy-5-fluorouridine (5'-DFUR) was effective against one bladder, 3 cervical and one ovarian cancer xenografts. The Antitumor activity of 5'-DFUR was correlated with the enzyme activity of pyrimidine nucleoside phosphorylase, which is an essential enzyme for phosphorolysis of 5'-DFUR to 5-FU.

Administration, Oral↗

Complementary DNA encoding the human T-cell FK506-binding protein, a peptidylprolyl cis-trans isomerase distinct from cyclophilin.

The recently discovered macrolide FK506 has been demonstrated to have potent immunosuppressive activity at concentrations 100-fold lower than cyclosporin A, a cyclic undecapeptide that is used to prevent rejection after transplantation of bone marrow and organs, such as kidney, heart, and liver. After the recent discovery that the cyclosporin A-binding protein cyclophilin is identical to peptidylprolyl cis-trans isomerase, a cellular binding protein for FK506 was found to be distinct from cyclophilin but to have the same enzymatic activity. In this study, we isolated a cDNA coding for FK506-binding protein (FKBP) from human peripheral blood T cells by using mixed 20-mer oligonucleotide probes synthesized on the basis of the sequence, Glu-Asp-Gly-Lys-Lys-Phe-Asp, reported for bovine FKBP. The DNA isolated contained an open reading frame encoding 108 amino acid residues. The first 40 residues of the deduced amino acid sequence were identical to those of the reported amino-terminal sequence of bovine FKBP, indicating that the DNA sequence isolated represents the gene coding for FKBP. Computer-assisted analysis of the deduced amino acid sequence indicates that FKBP exhibits no internal homology and does not have significant sequence similarity to any other amino acid sequences of known proteins, including cyclophilin. This result suggests that two catalytically similar proteins, cyclophilin and FKBP, evolved independently. In Northern blot analysis, mRNA species of approximately 1.8 kilobases that hybridized with human FKBP cDNA were detected in poly(A)+ RNAs from brain, lung, liver, and placental cells and leukocytes. Induction of Jurkat leukemic T cells with phorbol 12-myristate 13-acetate and ionomycin did not affect the level of FKBP mRNA. Southern blot analysis of human genomic DNA digested with different restriction enzymes suggests the existence of only a few copies of the DNA sequence encoding FKBP. This is in contrast to the result that as many as 20 copies of the cyclophilin gene and possible pseudogenes may be present in the mammalian genome.

Amino Acid Isomerases↗

Genetic profile of alloxan-induced diabetes-susceptible mice (ALS) and-resistant mice (ALR).

Two inbred strains from a foundation stock derived from Crj: CD-1 (ICR) mice were established after more than 20 generations of full-sib mating, and by simultaneous selective breeding for developing and not developing diabetes after alloxan administration (45 mg/kg in males, 47 mg/kg in females). To elucidate the genetic background of the two inbred strains, i. e., alloxan-induced diabetes-susceptible (ALS) strain and alloxan-induced diabetes-resistant (ALR) strain, their biochemical genetic markers and immunogenetic markers were examined. 1) For both strains, investigation of biochemical genetic markers at 19 loci and immunogenetic markers at 11 loci revealed no variation in any gene within the same strain, showing to be homogeneous, thus indicating establishment of the inbred strains. 2) The two strains differed from each other at 2 loci of biochemical genetic markers and at 5 loci of immunogenetic markers. 3) The ALS and ALR strains can be regarded as new inbred strains derived from ICR mice. 4) The results show that the marker genes of the two strains are different at 7 loci, but it remains unclear whether or not these genes are involved in the difference between the two strains in susceptibility to alloxan.

Alloxan↗

Amelogenesis imperfecta, a new dental mutation in rats.

We discovered a new dental mutation causing morphological abnormalities of the teeth in the SHR-SP strain of rats, maintained in the Research institute, Daiichi Seiyaku, Co., Ltd. The incisors of rats with this mutation are white in color, lacked hardness and were easily worn. The incisors broke or became bent with extended growth. Histological examination of the abnormal rats revealed amelogenesis imperfecta due to underdevelopment of tooth ameloblasts. The results of mating tests showed that this characteristic was inherited as an autosomal single recessive trait. We named this gene amelogenesis imperfecta (ami). The rats will prove to be a valuable models for studies on enamel formation.

Ameloblasts↗

[The effect of an antihypertensive drug budralazine on cerebrovascular lesions in salt-loaded SHR].

Budralazine was evaluated for its protective effect on the onset of cerebrovascular lesions in SHR given 1.5% NaCl as drinking water. The salt-loading for 67 days rapidly accelerated the development of hypertension in SHR (from 180 to over 250 mmHg, 40 days after the loading). The acceleration of hypertension was accompanied by an increase in the incidence of brain softening, cerebral infarct, angionecrosis and hemorrhage by 30-60% following the thrombosis and necrosis of cerebral arterioles. Renal angionecrosis associated with the interstitial nephrosis was also observed by 90% in the animals. Throughout the salt-loading period, oral administration of budralazine (1, 4 and 15 mg/kg/day) resulted in a dose-dependent inhibition of the accelerated hypertension. At larger doses (4 and 15 mg/kg/day), budralazine almost completely ameliorated the cerebral and renal lesions and significantly attenuated the rise of weight in the brain and heart observed in the salt-loaded control rats. Changes in the serum biochemical findings were also inhibited by this drug. In some of the parameters measured, budralazine appeared to be more efficacious than hydralazine (1, 4 and 15 mg/kg/day, p.o.). These results suggest that budralazine attenuates the serious development of hypertension and reduces the incidence and severity of stroke in salt-loaded SHR.

Animals↗

Creeping: a new mutant rat with neurological disease.

We describe a new mutant rat, named creeping, that exhibits severe ataxia characterized by a creeping posture due to the inability to stand up. Affected animals can be recognized at 14.8 +/- 1.6 (mean +/- SD) days of age and die within 35 days after birth. There are no sex differences in phenotype. The breeding data suggest that the abnormal locomotion is caused by an autosomal recessive gene. We have tentatively named the gene creeping (cre). The cerebellum of affected rats is much smaller than that of normal littermates. The cerebellar lobes of the mutant are barely formed. The notable histopathological changes are disarrangement of neuronal cells in the cerebellum and cerebral cortices, although the several cell types that are present in the cortices of normal rats are also found in the cortex of the creeping rats. The same type of change is also present in the hippocampus and fascia dentata.

Animals↗

[Childhood liposarcoma of the eyelid--a case report].

An 11-year-old girl noted a small mass on the left upper eyelid. The tumor was excised and diagnosed as round cell-type liposarcoma. In spite of intensive multimodal therapy, the tumor tended to recur, metastasizing to the central nervous system and soft tissues. The patient died of progressive disease three years after diagnosis. Features unique to this case include the ophthalmological primary site, the age at onset, the histological subtype and the mode of metastasis.

Brain Neoplasms↗

[Experimental cerebral ischemia after bilateral common carotid artery ligation in SHRSP, SHRSR and Wistar rats: correlation between blood pressure and degree of ischemia].

Three different pressure groups of rats, stroke-prone spontaneously hypertensive rats (SHRSP, 200-270 mmHg), stroke-resistant SHR (SHRSR, 160-240 mmHg), and Wistar rats (WR, 120-160 mmHg) were used to investigate the effect of prior existing hypertension on the severity of brain damage induced by ischemia. The cerebral ischemia was induced by bilateral common carotid artery ligation (BLCL) and the survival rate, cerebral blood flow, cerebral energy metabolites (ATP, lactate c-AMP) and water content were measured. Colloidal carbon perfusion was also performed. Sixteen-week-old male rats were used. The survival rate was observed until 24 hours after BLCL. Cerebral blood flow was measured in parietal cortex by hydrogen clearance method. ATP was measured by luciferin-luciferase method, and lactate by enzymatic method using LDH. c-AMP was measured by radioimmunoassay. Brain water content was measured by freeze-dry method. These measurements were done for animals surviving 6 hours of BLCL. Colloidal carbon perfusion was done according to Ames' Method. The survival rate was lower in the hypertension group. The survival of SHRSP and SHRSR were 20% compared to 71% in WR after 24 hours of BLCL. The cerebral circulation of SHRSP fell abruptly and was near to zero after one hour of BLCL. In SHRSR this fall of cerebral blood flow was prominent in the rats of higher blood pressure. On the other hand there was no apparent fall of cerebral blood flow in WR after BLCL. The cerebral energy metabolites. ATP and c-AMP showed the lowest level in SHRSP which had the negative correlation to blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

[An experimental study on the stability of the knee joint. Special reference to the mechanisms of rotatory stability of the knee joint].

In order to evaluate the stabilizing mechanisms of the ligaments, menisci and the conformity of the condylar surface, six human knee joints and five dog's knee joints were tested by the rotatory stability testing machine devised by myself. The torque-rotation curve and the amount of the up hill movement were measured under various compressive loads. Internal and external rotation were applied to the knee joint with range of 0.2 radian respectively. During rotatory movement, various compressive loads (0 kgf, 20 kgf, 40 kgf, 60 kgf, 80 kgf) were applied on the tibio-femoral joint. The following results were obtained in this study. Within a range of 0.2 radian in internal and external rotation respectively, rotatory stability was almost unaffected by sectioning of the cruciate ligaments. Rotatory stability was affected significantly by sectioning the medial collateral ligament. Almost the same results were obtained by removal of the medial meniscus. The intrinsic factors, especially the medial collateral ligament and the medial meniscus, provided the stability of external rotation for the knee joint. The amount of the up hill movements were measured 0.5 mm in internal rotation, and 0.1-0.2 mm in external rotation respectively. Only after removal of the medial meniscus, the amount of the up hill movement were decreased obviously. This decreases of the up hill movement were observed in external rotation. So, it was concluded that medial meniscus has the stabilizing mechanism of external rotation by the up hill movement. The conformity of the condylar surface was an important factor in the stability of the knee joint under compressive load. Especially, it restricts internal rotation.

Adult↗

Effects of human fibroblast interferon on human gliomas transplanted into nude mice.

Daily intratumor injection of human fibroblast interferon (HuIFN-beta) resulted in significant growth inhibition of human gliomas transplanted into nude mice. Light and electron microscope examinations were conducted to estimate the efficacy of HuIFN-beta. A 29-day daily treatment with HuIFN-beta induced complete regression of oligodendroglioma KG-1--a slowly growing tumor line positive for S-100 protein and negative for glial fibrillary acidic protein (GFAP)--in 9 out of 10 mice receiving 6 X 10(5) IU and 6 out of 9 given 1 X 10(5) IU. In mice with glioblastoma multiforme TMIMS-583, which showed more rapid growth and was positive for GFAP, dose-dependent growth inhibition was observed during 23 days of HuIFN-beta administration. Pathological changes of TMIMS-583 induced by HuIFN-beta were characterized by a decrease of the metaphase tumor cells, by enhanced degeneration of tumor cells with stromal reaction and round cell infiltrates, and by prominence of multinuclear giant cells containing glial filaments. Tumor weights were well correlated with the number of tumor cells in the metaphase (r = 0.89).

Adult↗

Effects of human fibroblast interferon on human tumors transplanted into nude mice: sensitivity of malignant melanoma.

The antitumor effects of human fibroblast interferon (HuIFN-beta) on three lines of human malignant melanoma (AM-1, SK-14, SK-2) were studied using a nude mouse-human tumor xenograft system. The sensitivity of melanoma to interferon in relation to melanin productivity was investigated. Intratumoral administration of 6 X 10(5) IU of HuIFN-beta significantly inhibited proliferation of AM-1 and SK-14, but did not inhibit that of SK-2. The sensitivity to HuIFN-beta was in the order of SK-14, AM-1 and SK-2, and was well correlated with the susceptibility of cell division observed histologically. Although these tumors differ in production of melanin, difference in sensitivity to HuIFN-beta due to melanin productivity was not clear. The relationship between the antitumor effect and the administration method was studied with SK-14, which was the most sensitive to HuIFN-beta. Antitumoral activities depending on the routes of administration were in the order of intratumoral, peritumoral-subcutaneous and intraperitoneal. Intratumoral and subcutaneous administrations of high doses brought about complete disappearance of the tumor cells or decrease in size of the tumor mass.

Animals↗

Effects of human fibroblast interferon on human tumors transplanted into nude mice: sensitivity of human tumors to interferon.

The antitumor effect of human fibroblast interferon (HuIFN-beta) was examined using a nude mouse-human tumor xenograft group. Eight subcutaneously transplanted tumors--one line each of ovarian carcinoma, laryngeal carcinoma, carcinoma of the nasopharynx and hepatoma, and two lines each of lung carcinoma and melanoma--were used. HuIFN-beta at 1 X 10(5) IU/mouse was injected subcutaneously around the tumor or into the tumor itself. In the former case, statistically significant growth-suppressive effects were observed in one lung carcinoma (PC-12) and both melanomas (AM-1 and SK-14), but no effect was seen on the other five tumors. Further studies were made to ascertain the effects of intratumoral injections. Increased growth inhibition was observed in both melanomas (AM-1 and SK-14), but not in lung cancer (PC-12). Complete regression was seen in 3 of 8 mice carrying SK-14. The sensitivity of tumors to HuIFN-beta was correlated to the inhibitory effect of HuIFN-beta on cell division detected by histological observation.

Animals↗