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Biomedical subjects

K Goto

Publications and source records attributed to K Goto.

At least 91 records · Page 5Linked to original sources
PubMed2001

Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells.

Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that saturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsaturated FFA, arachidonic acid, had no effect on the cell survival, even at supraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder formation and annexin V-EGFP/propidium iodide staining of the cells. The apoptotic effects of palmitic acid and stearic acid were unrelated to the increase of ceramide generation or nitric oxide production and were also completely blocked by Triacsin C, an inhibitor of acylcoenzyme A synthetase. In addition, acylcoenzyme A, pamitoylcoenzyme A, and stearylcoenzyme A markedly suppressed granulosa cell survival, whereas arachidonoylcoenzyme A had no such effect, and this finding was consistent with the effect of the respective FFA form. Surprisingly, arachidonic acid instead showed a protective effect on palmitic acid- and stearic acid-induced cell apoptosis. A Western blot analysis showed the apoptosis of the granulosa cells induced by palmitic acid to be accompanied by the down-regulation of an apoptosis inhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa cells caused by the metabolism of the respective acylcoenzyme A form, and the actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on granulosa cell survival may be a possible mechanism for reproductive abnormalities, such as amenorrhea, which is frequently observed in obese women.

Acyl Coenzyme A↗
PubMed2001

Antinociceptive effect of U-50488H, a kappa-opioid agonist, in streptozotocin-induced diabetic mice.

We compared the antinociceptive activity of a kappa-opioid agonist, U-50488H, in streptozotocin-induced diabetic mice with that in non-diabetic mice. Subcutaneously administered U-50488H (3 and 10 mg kg(-1)) showed a more potent antinociceptive effect, as evaluated by the tail-pressure method, in diabetic mice than in non-diabetic mice. Increased antinociceptive activity of U-50488H observed in diabetic mice was also observed in mice given U-50488H intrathecally (3 and 10 microg). However, there were no differences observed between diabetic and non-diabetic mice given U-50488H intracerebroventricularly (3 and 10 microg). Although the antinociceptive effect of U-50488H (3 mg kg(-1), s.c.) in non-diabetic mice was increased by treatment with PD135158 (100 ng, i.c.v.), a cholecystokininB (CCKB) antagonist, the antinociceptive activity of U-50488H which was enhanced in diabetic mice was not influenced by PD135158. Moreover, the increased antinociceptive activity of U-50488H (3 mg kg(-1), s.c.) in diabetic mice diminished when desulfated octapeptide of cholecystokinin (3-100 ng, i.c.v.), a CCKB agonist, was administered. These results suggested that diabetic mice were selectively hyper-responsive to spinal kappa-opioid receptor-mediated antinociception. The function of the analgesia inhibitory system in which cholecystokinin is used as a transmitter might be diminished in diabetic mice.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2001

Basic and therapeutic relevance of endothelin-mediated regulation.

Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.

Animals↗
PubMed2001

Immunohistochemical characterization of hepatoblastomas in B6C3F1 mice treated with diethylnitrosamine and sodium phenobarbital.

Hepatoblastomas (HBs) were induced in B6C3F1 male mice by diethylnitrosamine (DEN) and sodium phenobarbital (PB). Six-week-old mice received a single intraperitoneal dose of DEN followed by a continuous treatment with PB in diet at a concentration of 0 (group 1) or 500 (group 2) ppm for 50 weeks. HBs were observed in 13 of 21 (62%) group 2 mice, with typical histologic features as reported previously, while no such tumors were observed in group 1. Seven of 13 (54%) HBs were found in and/or adjacent to hepatocellular adenomas (HCAs) or hepatocellular carcinomas (HCCs). Immunohistochemically, all HBs were positive for S-100 protein but negative for keratin, alpha-fetoprotein (AFP), albumin (ALB) and vimentin, while HCC cells occasionally reacted positively for AFP with a mosaic pattern. HCC and HCA cells were occasionally positive for ALB. Non-neoplastic hepatocytes and normal bile ducts were positively stained for ALB and keratin/S-100 protein, respectively. S-100 protein is known to be expressed in many mesenchymal tissues and neoplasms including neuroectodermal elements but negative in cells of the hepatic lineage. Thus, the present immunohistochemical results suggested that mesenchymal differentiation occurs in mouse HB cells as observed in human HBs, one of the most frequent infant liver tumors in humans. Although the susceptibility of mouse HBs to PB-promotion suggests a hepatocytic histogenesis, the present immunohistochemical results support the hypothesis that the mouse HB is derived from pluripotent endodermal stem-like cells.

Albumins↗
PubMed2001

Novel findings regarding photoinduced commitments of G1-, S- and G2-phase cells to cell-cycle transitions in darkness and dark-induced G1-, S- and G2-phase arrests in Euglena.

Effects of light and darkness on cell-cycle progression were studied in the log-linear photoautotrophic growth mode of Euglena gracilis. We found that there are light-dependent restriction points in the post-G1 phases, quite in contrast to Chlamydomonas, where a light-dependent restriction is known to exist only in the G1 phase. Thus, in E. gracilis, there are photoinduced commitments of G1-, S- and G2-phase cells that allow them to progress to the G1, S and G2 phases in darkness, and there are dark-induced G1-, S- and G2-phase arrests. In darkness, only committed cells were able to progress to the committed phases (G1, S or G2), whereas uncommitted cells were unable to undergo a cell-cycle transition. Whether or not cells were induced to commit by irradiation, they were eventually arrested somewhere in the G1, S or G2 (but not M) phase within 14 h of being transferred to darkness. We also describe the dependence of photoinduced commitment on light intensity and discuss the results as they relate to cell-cycle progression in continuous light.

Animals↗
PubMed2001

Change of hypervariable region proteins of hepatitis C virus E2 in two infants.

Two infants vertically infected with hepatitis C virus (HCV) were followed-up from 3 or 4 months to 2.5 years of age. We analyzed five complementary DNA (cDNA) clones from each patient and compared the genetic drift of the HCV E2 gene hypervariable region (HVR) between the two infants and between the infants and their mothers within the two families. The HCV strains initially detected in infant 1 were identical to those found in her mother, while the HCV strains initially detected in infant 2 were very different from those of her mother. The mutation rate of HVR-1 proteins was higher in mother 1 than in mother 2, but was 1.6 to 2-fold higher in infant 2 than in infant 1 during the follow-up period. Serum ALT levels or serum HCV-core protein activity did not correlate with the mutation rates of HVR-1 proteins in either infant. However, the mutation rate of HVR-1 proteins significantly increased from 6 months of age in both infants, with concomitantly increased serum HCV antibody (anti-HCV) levels.

Adult↗
PubMed2001

Concurrent versus sequential radiotherapy for small cell lung cancer.

Two meta-analyses have shown that thoracic radiotherapy plus chemotherapy is superior to chemotherapy alone in the treatment of limited-stage small cell lung cancer. To minimize the likelihood of emergence of chemotherapy resistance, the optimal schedule for integration of the two modalities might be to introduce radiotherapy early in the course of treatment. The Cancer and Leukemia Group B trial performed from 1981 to 1984 failed to show an advantage for early concurrent chemoradiation. However, three recent controlled trials of thoracic irradiation timing (the National Cancer Institute of Canada trial, the Yugoslavian trial, and the Japan Clinical Oncology Group trial) showed that early radiotherapy is superior to delayed radiotherapy. These three trials used the combination of cisplatin/etoposide and showed that a long-term survival rate greater than 20% is achievable using early integrated chemoradiation. For the present, early concurrent administration of thoracic radiotherapy with a cisplatin/etoposide-based regimen should be standard therapy. Semin Oncol 28 (suppl 4):23-26.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

[Aortitis syndrome associated with ulcerative colitis, preceded by pulmonary infarction involvement].

A 21-year-old woman with a 6-year history of ulcerative colitis admitted to our hospital with chest pain, cough and fever of unknown origin in August 1998. On admission, laboratory data showed positive inflammatory signs. A chest radiograph and chest computed tomogram (CT) revealed nodular shadows in the right upper lung field. Fifty days after admission, hypertension developed and a bruit was audible in the neck and the upper abdomen. Digital subtraction angiography showed stenosis in carotid, renal and right upper pulmonary arteries. On the basis of these results, a diagnosis of aortitis syndrome was made. Moreover, these findings indicated pulmonary infarction in the right upper lobe due to aortitis syndrome. Aortitis syndrome preceded by pulmonary infarction involvement is very rare. Autoimmune disorders may have been involved in this case because of the association with ulcerative colitis.

Adult↗
PubMed2001

[Anesthetic management of a patient with Cockayne's syndrome].

Cockayne's syndrome is a disease of childhood characterized by mental retardation and premature aging. An 11-year-old girl with Cockayne's syndrome underwent general anesthesia for acute appendicitis. Although we had expected the difficulty of intubation because of her small jaw with limited movement, we could visualize her vocal cord, and intubate easily. High peak airway pressure was needed to ventilate her lung after intubation suggesting decreased lung compliance for this syndrome. We have to consider anesthetic problems resulting not only from pediatric but also from geriatric anesthesia for the management of this syndrome.

Acute Disease↗
PubMed2001

[A quadriplegic patient with chronic inflammatory demyelinating polyneuropathy (CIDP) who responded well to corticosteroids and intravenous immunoglobulin therapy].

We report an elderly patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presenting with complete quadriplegia who responded well to the treatment. A 74-year-old woman was transferred to our hospital from a hospital for the elderly patients. The patient had a history of progressive limb weakness over three years, and has been quadriplegic for the last six months. The patient was unable to move her extremities, but neither respiratory nor bulbar dysfunction was observed. Deep tendon reflexes were absent. Glove and stocking type sensory disturbance was noted. Nerve conduction studies showed slowed motor and sensory conduction velocities with diminished compound muscle action potentials (CMAP). Abnormal temporal dispersion and conduction blocks were also demonstrated. Cerebrospinal fluid examination revealed an elevated protein level of 78 mg/dl with normal cell counts. The patient was diagnosed as having CIDP. She was treated with methylprednisolone pulse therapy and oral prednisolone, followed by high dose intravenous immunoglobulin treatment. Significant recovery occurred during the first week, and she became able to walk four months later. Motor nerve conduction velocity (MCV) and CMAP were also improved. It is suggested that CIDP must be considered in patients with quadriplegia of unknown etiology: such patients may be seen in hospitals for elderly patients.

Aged↗
PubMed2000

A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells.

Estrogen is the most important endocrine hormone that stimulates the growth of hormone-dependent breast cancer. The biosynthesis of estrogens in breast tissue is catalyzed by cytochrome P450 aromatase (P450arom). The expression of P450arom is controlled by the tissue- or cell-specific promoters of CYP 19 gene. The roles of nuclear receptor systems for the aromatase activity in breast cancer cells have not yet been fully investigated. In the present study, we investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line, using each selective ligand for retinoic acid receptor (RAR) (TTNPB), RXR (LG100268), PPARgamma (troglitazone), and vitamin D(3) receptor (vitamin D(3)). The treatment of the cells with TTNPB or LG100268 alone for 2 days increased slightly the aromatase activity, but the increases were not statistically significant in comparison to the control. However, the combined treatment with TTNPB (10(-7) M) and LG100268 (10(-7) M) caused a dramatic stimulation of the aromatase activity. The treatment with other ligands had little or no effect on the aromatase activity. The stimulation of the aromatase activity by TTNPB plus LG100268 was dose-dependent, and a maximum stimulation was observed at 10(-7) M in both compounds. In addition, the increase in the aromatase activity was accompanied by an increase in the P450arom mRNA levels determined by RT-PCR in MCF-7 cells. The increase in the P450arom transcript was also found to be related to the specific usage of promoter 1a of the CYP 19 gene based on the analysis using RT-PCR. This is the first demonstration that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells.

Aromatase↗
PubMed2000

Functional analysis of five endothelin-B receptor mutations found in human Hirschsprung disease patients.

Several missense mutations of the endothelin-B receptor (EDNRB) associated with Hirschsprung disease have recently been identified. Five mutated EDNRB (A183G, W276C, R319W, M374I and P383L) cDNAs were transiently expressed in several cell lines to examine the effects of these mutations. Ligand-receptor binding experiments demonstrated that all mutants examined here accept endothelins with a high affinity. Especially, the affinity of endothelins to P383L was increased. However, the number of binding sites of A183G, W276C and P383L was markedly decreased. The subcellular localization of these mutant receptors was the same as that of wild-type EDNRB, whereas the amount of protein of each mutant receptor was decreased. All mutant receptors were impaired in intracellular Ca(2+) mobilization. These findings indicate that these missense mutations result in loss of function of EDNRB, and may provide the molecular pathological basis of Hirschsprung disease in some individuals.

Animals↗
PubMed2000

Subtype-specific translocation of diacylglycerol kinase alpha and gamma and its correlation with protein kinase C.

We examined the translocation of diacylglycerol kinase (DGK) alpha and gamma fused with green fluorescent protein in living Chinese hamster ovary K1 cells (CHO-K1) and investigated temporal and spatial correlations between DGK and protein kinase C (PKC) when both kinases are overexpressed. DGKalpha and gamma were present throughout the cytoplasm of CHO-K1 cells. Tetradecanoylphorbol 13-acetate (TPA) induced irreversible translocation of DGKgamma, but not DGKalpha, from the cytoplasm to the plasma membrane. The (TPA)-induced translocation of DGKgamma was inhibited by the mutation of C1A but not C1B domain of DGKgamma and was not inhibited by staurosporine. Arachidonic acid induced reversible translocation of DGKgamma from the cytoplasm to the plasma membrane, whereas DGKalpha showed irreversible translocation to the plasma membrane and the Golgi network. Purinergic stimulation induced reversible translocation of both DGKgamma and alpha to the plasma membrane. The timing of the ATP-induced translocation of DGKgamma roughly coincided with that of PKCgamma re-translocation from the membrane to the cytoplasm. Furthermore, re-translocation of PKCgamma was obviously hastened by co-expression with DGKgamma and was blocked by an inhibitor of DGK (R59022). These results indicate that DGK shows subtype-specific translocation depending on extracellular signals and suggest that PKC and DGK are orchestrated temporally and spatially in the signal transduction.

Animals↗
PubMed2000

Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system.

We demonstrated involvement of the ventral tegmental area (VTA) dopaminergic system in orexin-induced hyperlocomotion and stereotypy in rats. In double-label immunohistochemical study of rat brain, we found that tyrosine hydroxylase (TH)-immunoreactive cells in the VTA received innervation from orexin immunoreactive-fibers. Orexin-A induced an increase in [Ca(2+)](i) in isolated A10 dopamine neurons in a dose-dependent manner. In behavioral studies, we found that orexin-A induced hyperlocomotion, stereotypy and grooming behavior when administered centrally in rats, and these effects were abolished by dopamine D(2) (haloperidol and sulpiride) or D(1) (SCH23390) antagonists. These results suggest that the orexin-induced hyperlocomotion, stereotypy and grooming behavior are mediated by the dopaminergic system and this pathway might be involved in orexin-induced emotional responses.

Animals↗
PubMed2000

Orexins suppress catecholamine synthesis and secretion in cultured PC12 cells.

New orexigenic peptides called orexin-A and -B have recently been described in neurons of the lateral hypothalamus and perifornical area. No orexins have been found in adipose tissues or visceral organs, including the adrenal gland. However, expression of the orexin-receptor 2 (OX2R) in the rat adrenal gland has been reported. To test the effects of orexins on peripheral organs, we investigated their effects on catecholamine synthesis and secretion in the rat pheochromocytoma cell line PC12. Orexin-A and -B (100 nM) significantly reduced basal and PACAP-induced tyrosine hydroxylase (TH) (the rate-limiting enzyme in the biosynthesis of catecholamines) mRNA levels. Orexin-A and -B (100 nM) also significantly inhibited the PACAP-induced increase in the cAMP level, suggesting that the suppressive effect on TH mRNA is mediated, at least in part, by the cAMP/protein kinase A pathway. Furthermore, orexin-A and -B (100 nM) significantly suppressed basal and PACAP-induced dopamine secretion from PC12 cells. Next, we examined whether orexin receptors (OX1R, OX2R) were present in the rat adrenal gland and PC12 cells. In the adrenal glands, OX2R was as strongly expressed as in the hypothalamus, but OX1R was not detected. On the other hand, neither OX1R nor OX2R was expressed in PC12 cells. However, binding assays showed equal binding of orexin-A and -B to PC12 cells, suggesting the existence in these cells of some receptors for orexins. These results indicate that orexins suppress catecholamine release and synthesis, and that the inhibitory effect is mediated by the cAMP/protein kinase A pathway.

Adrenal Gland Neoplasms↗