Biomedical subjects

Nobuyuki Terada

Publications and source records attributed to Nobuyuki Terada.

29 records · Page 2Linked to original sources

PubMed2003

Inflammatory liver steatosis caused by IL-12 and IL-18.

Acute fatty degeneration in the liver is caused by various agents, such as aspirin, valproic acid, and ibuprofen, that directly inhibit mitochondrial beta-oxidation of fatty acid and oxidative phosphorylation. Endogenous molecules, such as cytokines and hormones, are also known to mediate microvesicular steatosis in liver failure. In this study, we examined how interleukin-12 (IL-12) and IL-18 cause steatosis in the liver. Administration of these cytokines in combination caused marked hepatosteatosis and weight loss in mice. There were marked increases in levels of interferon-gamma (IFN-gamma), nitrite (NO(2)/NO(3)), and fibrinogen in the circulation in these mice. On the other hand, the ATP concentration and blood flow in the liver were significantly reduced. These changes, except the production of IFN-gamma and NO, were partially inhibited by Z-VAD-fmk, a synthetic tripeptide inhibitor for NO-induced caspases. These results indicate that IL-12 and IL-18 may mediate inflammatory hepatosteatosis through impairment of the microcirculation, which leads to mitochondrial dysfunction in hepatocytes.

Adenosine Triphosphate↗

PubMed2003

Effects of adrenaline and cortisone on the early activation of lymphocytes.

Using whole blood, we examined the effects of stress hormones on CD69 expression in Natural Killer (NK) cells. A series of diluted adrenaline or cortisone was added to 1 ml of whole blood. Propranolol was used to block the beta-adrenergic effect. The blood samples were activated with CD2/CD2R mitogenic antibody solution for four hours under 37 degrees C. Then CD69 antigen on NK cells was analyzed by flowcytometric assay. Adrenaline and cortisone doses dependently suppressed CD69 expression on NK cells. Propranolol blocked the suppressive effect of adrenaline. CD69 expression was significantly higher than the control when only propranolol was added. We concluded that blood constituents acting on mitogenic reaction and stress hormones affect the early stage on the way to proliferation and differentiation.

Adult↗

PubMed2002

Mouse uterine epithelial apoptosis is associated with expression of mitochondrial voltage-dependent anion channels, release of cytochrome C from mitochondria, and the ratio of Bax to Bcl-2 or Bcl-X.

The release of cytochrome c from mitochondria, which is regulated by Bcl-2 family members and is considered to take place through voltage-dependent anion channels (VDACs) on the outer membranes of mitochondria, results in activation of effector caspases, such as caspase-3, which induce apoptosis. We studied the involvement of the mitochondrial apoptosis pathway in uterine epithelial apoptosis. Estradiol-17beta pellets were implanted into ovariectomized mice and removed 4 days later (Day 0). The apoptotic index (percentage of apoptotic cells) of the luminal epithelium increased markedly, peaking on Day 2, whereas that of the glandular epithelium increased much less. Expression of VDAC1, 2, and 3 mRNAs increased in the luminal epithelium in correlation with the apoptotic index of the luminal epithelium. No increases in VDAC1, 2, and 3 mRNA levels were observed in the stroma or muscle, where no apoptosis occurs. VDAC1 protein levels in the uterus also correlated well with the apoptotic index of the luminal epithelium. In addition, the apoptotic index showed good correlation with the release of cytochrome c from mitochondria, activation of caspase-3, which was immunohistochemically detected only in the epithelium, and the mRNA and protein ratios of Bax:Bcl-2 and Bax:Bcl-X in the uterus. The present results suggest that the release of cytochrome c from mitochondria, which is regulated by Bcl-2 family members, plays a role in uterine epithelial apoptosis after estrogen deprivation. The increase in VDAC expression may facilitate the release of cytochrome c during apoptosis.

Animals↗

PubMed2002

Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model.

Osteolytic bone metastasis is a frequent problem in the treatment of cancer. Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used for the treatment of osteoporosis in some countries. Some other isoflavones also exhibit an antitumor effect in vitro and in vivo. Here, we studied the effects of ipriflavone on osteolytic bone metastasis of MDA-231 human breast cancer cells injected intracardially into athymic nude mice (ICR-nu/nu). Daily oral administration of ipriflavone at 12 mg/mouse significantly inhibited the development of new osteolytic bone metastases (p < 0.05) and the progression of established osteolytic lesions (p = 0.01), prolonging the life of tumor-bearing mice (p = 0.01 vs. control). In addition, ipriflavone reduced the number of osteoclasts at the bone-cancer interface with no severe adverse effects on the host. In vitro, ipriflavone inhibited the proliferation and DNA synthesis of MDA-231 cells and blocked the ligand-induced phosphorylation of Tyr(845) of the EGFR. Ipriflavone did not promote apoptosis of MDA-231 cells. Our results show that ipriflavone not only directly inhibits the growth of cancer cells but also reduces osteoclasts to prevent the soft tissue tumor burden and osteolytic bone metastases. These findings raise the possibility that ipriflavone may be of use as a therapeutic agent against osteolytic bone metastasis.

Analgesics↗

PubMed2002

Expression of diamine oxidase (histaminase) in guinea-pig tissues.

The expression of mRNA for diamine oxidase (histaminase) and the enzyme activity in guinea-pig tissues were investigated. Reverse transcription-polymerase chain reaction analysis revealed that the message corresponding to the long form present in humans and rats was expressed abundantly in the small intestine and liver. Small but detectable amounts of diamine oxidase mRNA were observed in the kidney, stomach, cerebellum, thalamus+hypothalamus, and cerebral cortex. Northern blot analysis showed that the message (2.8 kb in size) was observed abundantly in the liver and small intestine and was detectable in the kidney and stomach but not in the brain or lung. In situ hybridization showed that diamine oxidase mRNA was localized throughout the liver and epithelial cells of the small intestine. Diamine oxidase activity was detected at various levels in different tissues of the guinea-pig at the following relative abundance: liver>small intestine>lung, kidney>stomach. Histamine dose-dependently induced the contraction of sections of the guinea-pig small intestine, and the pretreatment of the tissue section with aminoguanidine (100 microM), a diamine oxidase inhibitor, but not with S-[4-(N,N-dimethylamino)butyl]isothiourea (100 microM), an inhibitor of histamine N-methyltransferase, shifted the dose-response curve of histamine-induced contraction to lower concentrations. These results suggest that diamine oxidase has a crucial role in the degradation of histamine in the guinea-pig small intestine and probably in the liver.

Amine Oxidase (Copper-Containing)↗

PubMed2002

Involvement of phosphorylation of Tyr-31 and Tyr-118 of paxillin in MM1 cancer cell migration.

We demonstrated previously that rat ascites hepatoma MM1 cells require both lysophosphatidic acid (LPA) and fibronectin (FN) for phagokinetic motility and transcellular migration and that these events are regulated through the RhoA-ROCK pathway. It remains to be elucidated, however, how the signals from both LPA and FN are integrated into cell migration. To examine this, total cellular lysates after stimulation with LPA or FN were subjected to time-course immunoblot analysis with anti-phosphotyrosine antibodies (Abs). Consequently, tyrosine-phosphorylation of paxillin was obviously persistent after stimulation with FN + LPA as compared to after stimulation with either alone. Tyrosine-phosphorylated paxillin comprised 2 components; slowly and fast migrating ones. Immunoblotting of anti-paxillin immunoprecipitates with phosphorylation site-specific Abs revealed the following: tyrosine-phosphorylation was enhanced preferentially on a slowly migrating component after stimulation with FN + LPA; this component contained phosphorylation at both tyrosine residue (Y) 31 and Y118; and phosphorylation of paxillin at Y181 was constitutive and not augmented by stimulation with either FN or LPA. Amiloride, an inhibitor of the Na+/H+ antiporter downstream of ROCK, suppressed cell motility and correspondingly paxillin tyrosine-phosphorylation at both Y31 and Y118. Paxillin phosphorylation weakly induced by FN alone, insufficient for cell migration, was not inhibited by amiloride. These results demonstrate that LPA collaborates with FN for persistent tyrosine phosphorylation of paxillin at both Y31 and Y118, regulated by the Na+/H+ antiporter downstream of ROCK and that this phosphorylated paxillin is essential for MM1 cancer cell migration.

Amiloride↗

PubMed2002

Primary carcinoid tumor of the urinary bladder.

A polyp of about 1.0 cm diameter was incidentally found at the center of the posterior wall of the urinary bladder in a 73-year-old man on cystoscopic examination. A polyp was resected through a transurethral route without recurrence for 22 months. A polyp consisted of a tumor covered with mucosa of the bladder. Tumor cells have round or oval nuclei with fine chromatin and one or two nucleoli per nucleus, and finely granular eosinophilic cytoplasm, being arranged in a trabecular or tubular pattern. Furthermore, they showed positive staining for chromogranin-A and with Grimelius stain, indicating that the tumor is a carcinoid tumor. Since there was no evidence of carcinoid tumors in organs other than the urinary bladder, the present case is a primary carcinoid tumor (well differentiated endocrine tumor) of the urinary bladder which is extremely rare.

Aged↗

PubMed2002

Plasma nitrotyrosine concentration relates to prognosis in human septic shock.

Interrelation of plasma nitrotyrosine (NT) concentrations in patients of septic shock and their prognosis was examined. Blood samples were obtained from 12 patients during the first episode of septic shock at hospitalization, and their plasma NT concentrations were measured. Five patients died within five days after hospitalization, but seven patients recovered. Plasma NT concentrations (means +/- SE) of the non-survivors and survivors were 0.68 +/- 0.13 nmol/mL (n = 7), and 0.21 +/- 0.05 nmol/mL (n = 5), respectively, the former being significantly higher than the latter. The present results suggest that plasma concentration of NT relates to prognosis in human septic shock, although further studies with a larger patient population are necessary for confirmation of the suggestion.

Adult↗

PubMed2002

Castration induces apoptosis in the mouse epididymis during postnatal development.

The effect of castration on apoptosis in the mouse epididymis during postnatal development was examined. The weight of the epididymis slowly increased from day 0 (day of birth) to day 20 after birth, followed by a rapid increase thereafter. Castration on days 0, 5, 10, 20, 30, 40 and 60 increased apoptotic indices (percentages of apoptotic cells) of epithelia of the caput (head), corpus (body), and cauda (tail) epididymis, their apoptotic indices reaching maximal levels on day 2 after castration with the exception of a maximal apoptotic index on day 4 in the tail after castration on day 60. The maximal levels of apoptotic indices of the head, body and tail after castration on days 0, 5, 10 and 20 were significantly lower than those after castration on days 40 and 60. DNAs extracted from the epididymides 2 days after castration on days 0, 5, 10 and 60 showed a ladder pattern on agarose gel electrophoresis, which is a characteristic of apoptosis. When testosterone propionate (10 microg/g body weight) was injected twice a day into mice which had been castrated on day 10, 30 or 60, the increases in apoptotic indices of the head, body and tail of the epididymis were completely inhibited. The weights of the paired epididymides 6 days after castration on days 0, 5, 10, 20, 30, 40 and 60 were significantly lower than those of sham-operated mice, indicating the secretion of androgen by the testes from birth to adulthood. The present results indicated that androgen deprivation caused by castration induces apoptosis in the epithelium of the epididymis of mice from birth to adulthood, and suggested that a proportion of epithelial cells, the survival of which is dependent on the testes, is smaller in the epididymides during a slow growth stage than in the epididymides after this stage.

Animals↗

PubMedDate not supplied

Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice.

Interleukin (IL)-18 exhibits antitumor as well as antiosteoclastogenic activities. These findings suggest that IL-18 is a potential tool for the treatment of cancers with associated osteolytic bone metastasis. We have previously shown that systemic daily administration of recombinant (r) IL-18 inhibits the development of osteolytic bone metastasis by human breast cancer cells. Here we demonstrate that systemic daily administration of rIL-18 (1 microg/mouse/d) for 21 days significantly inhibited the number and the total area of osteolytic bone metastasis by RWGT2 human lung cancer cells in nude mice. No severe adverse effects were observed. Natural killer (NK) cells did not increase in splenocytes from rIL-18-treated mice, and the in vitro NK activity of splenocytes against RWGT2 cells was only weakly enhanced in the presence of IL-18. The administration of rIL-18 made no difference in the growth of subcutaneous tumors, histologic indices (mitotic index, apoptotic index, and Ki-67-labeling index) of subcutaneous tumors or metastatic bone foci, or in the number of osteoclasts along the bone surface adjacent to tumors. Moreover, serum levels of cytokines including interferon-gamma, IL-1alpha, IL-6, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor, which regulate bone-resorbing activity of osteoclasts, were evaluated. Among them, IL-6 was remarkably downregulated in rIL-18-treated mice. These findings suggest that IL-18 inhibits osteolytic bone metastasis possibly through suppression of osteoclastic bone-resorption mediated in part by IL-6.

Animals↗

PubMedDate not supplied

Interleukin-18 inhibits lodging and subsequent growth of human multiple myeloma cells in the bone marrow.

An intravenous injection of ARH-77 cells (human multiple myeloma cell line) into mice with severe combined immunodeficiency disease (SCID mice) results in lodging of tumor cells in the bone marrow of thoracic and lumbar vertebrae, and in their subsequent growth, the cells destroying bone and invading the spinal cord and surrounding tissues, and the mice show hind leg paralysis. Using this model, we investigated the effects of interleukin (IL)-18 on the lodging and subsequent growth of multiple myeloma cells in the bone marrow. Mouse recombinant IL-18 (mIL-18) at 1 microg/mouse was daily injected according to protocols A and B. In protocol A, mIL-18 was injected from day 6 after tumor cell injection to examine the effect of mIL-18 on tumor growth, and in protocol B, it was injected from day 3 prior to tumor cell injection to day 3 after it to examine the effect of mIL-18 on lodging of tumor cells. The spread of a tumor was monitored as to the appearance of hind leg paralysis and the tumor area in a median longitudinal section of the vertebrae with the surrounding tissues. With protocol A, mIL-18 significantly and markedly decreased the cumulative rate of hind leg paralysis and the tumor area. This antitumor effect of mIL-18 was ascribed to its action on the activation of NK cells because mIL-18 exerted no significant effect when anti-asialo GM1 antiserum (a-ASGM1) was simultaneously injected to deplete the NK cell activity. With protocol B, mIL-18 also significantly and markedly decreased the cumulative rate of hind leg paralysis and the tumor area. However, most of this effect was not due to the action of mIL-18 on NK cells because mIL-18 showed a marked and significant effect with the administration of a-ASGM1. The present results indicate that mIL-18 inhibited the lodging and subsequent growth of multiple myeloma cells in the bone marrow, and suggest that IL-18 is worth investigating further as to its usefulness as a therapy for multiple myeloma.

Animals↗