Biomedical subjects
Publications and source records attributed to K Onodera.
Male Wistar rats, maintained on a thiamine-deficient diet, showed a significant weight loss, decrease in heart frequency, disturbance of urinary excretion, and symptoms of polyneuritis. Once persistent erection ocurred in these rats, it continued throughout the study and subsided in most cases after the administration of thiamine HCl.
Although it is a gross measure, the pinna reflex test is easily administered and is, therefore, incorporated as a general screening tool in mutagenesis programs. Our recent application of this approach indicated that mutant mice lacking one of the small Maf proteins, in this case MafG, failed to exhibit a pinna reflex. In contrast, littermate controls, with the same mixed 129/CD1 background, and including both wild type and heterozygous mutant animals, passed the test. Because previous studies indicate that mafG is expressed in both cochlear and vestibular parts of the mouse inner ear, the source of this 'presumed deafness' was further assessed by making round window recordings to determine compound action potential thresholds. Auditory brainstem responses were also acquired to assess function along portions of the central auditory pathway. In all cases, responses in homozygous mutants (-/-) were comparable to those obtained from littermate controls, either wild type (+/+) or heterozygous mutants (+/-). Gross anatomy of the organ of Corti was also found to be similar in all three groups of mice. Hence, the lack of a pinna reflex must relate to nonauditory causes.
With the development of transplantation of hepatocytes into the spleen, interest has focused on the metabolic changes associated with hepatocyte proliferation. As these changes are important for drug metabolism in hepatocytes, we examined the expression and inducibility of the cytochrome P450 IIIA family within transplanted hepatocytes. Fetal hepatocytes were harvested at 20 days of gestation from spontaneously hypertensive rats (SHRs) and transplanted into recipient adult SHR spleens. Microscopic examination of the recipient spleens 4 and 10 wk after transplantation revealed masses of hepatocytes with cord-like structures in the red pulp. Proliferating hepatocytes were detected with a bromodeoxyuridine (BrdU) immunohistochemical stain. Immunochemical studies detected cytochromes (cytos) P450 p and P450 HLp in fetal hepatocytes before transplantation without prior induction. And although these cytos were not detected by 10 wk after transplantation, they were induced with dexamethasone. These results demonstrated that fetal hepatocytes can be transplanted successfully into recipient spleens and suggested that fetal hepatocytes grow in the spleen, similar to the adult hepatocyte response.
We examined the expression and enzymatic activity of cytochrome P450 LA omega within transplanted hepatocytes. Fetal hepatocytes were harvested at day 20 of gestation from spontaneously hypertensive rats (SHRs) and transplanted into recipient adult SHR spleens. Microscopic examination of the recipient spleens at 4 and 10 wk after transplantation revealed masses of hepatocytes with cord-like structures in the red pulp. Immunochemical studies detected cytochrome (cyto) P450 LA omega in the fetal hepatocytes before transplantation without prior induction. Although the cyto P450 LA omega was not detected by the second week after transplantation, by the 6th and 10th wk after transplantation, it was. Cyto P450-arachidonic acid omega/omega-1 hydroxylase activity (formation of 20- and 19-hydroxyeicosatetraenoic acid) was detected at 10 wk after transplantation, but not 2 or 6 wk after transplantation. These results demonstrated that fetal hepatocytes can be transplanted successfully into recipient spleens and then grow in the spleens, as in the case of the adult hepatocyte response.
Fourteen patients suffering from severe heart failure with 18 mmHg or higher diastolic pulmonary arterial pressure were given a transdermal therapeutic system of nitroglycerin (TTS-NTG). They were evaluated for changes in the hemodynamic responses over 24 hours. Diastolic pulmonary arterial pressure decreased from 27.1 +/- 2.3 mmHg (mean +/- SE) to 22.4 +/- 1.7 mmHg after 1 hour (p less than 0.01), which was maintained throughout the trial. Cardiac index increased from 2.42 +/- 0.13 l/min/m2 to 2.64 +/- 0.16 l/min/m2 after 1 hour (p less than 0.01). The analysis of cardiac and vascular function curves in individual patients suggested that the improvement of hemodynamics was induced mainly in six patients with an increase of contractility and in four patients with a reduction of afterload. No changes were observed in three patients in either contractility or afterload, and a decrease in contractility was seen in one patient. These results suggest that TTS-NTG can be transcutaneously absorbed well enough to produce improved hemodynamic responses in patients with severe heart failure by several mechanisms and maintain these effects over 24 hours.
In order to further elucidate the possible role of histamine in the seizure model, we determined the histamine levels in different brain regions of genetically epilepsy-prone Krushinski-Molodkina (KM) rats. Histamine levels in the striatum, hippocampus, amygdala, midbrain, thalamus and hypothalamus of KM rats were significantly lower than in the epilepsy-resistant Wistar rats. Previously, we have reported that the audiogenic seizures of KM rats were reduced by metoprine, which can markedly increase brain histamine. These findings are in agreement with the hypothesis that central histamine neuron system may be involved in the inhibitory mechanism of seizures.
The intracerebroventricular (icv) administration of histamine but not N-telemethylhistamine and 1-methyl-4-imidazole acetic acid induced catalepsy in mice. Histamine H1-receptor blockers such as cyproheptadine, mepyramine and diphenhydramine reduced histamine-induced catalepsy. However, astemizole which is known to be without central effects, did not reduce histamine-induced catalepsy. The icv pretreatment with histamine H2-receptor blockers, such as metiamide and cimetidine, also had no effect. Moreover, various antidepressants, both imipramine- and atypical-type drugs antagonized histamine-induced catalepsy to various degrees in this experiment. Thus, the induction of catalepsy by icv administration of histamine was mediated through histamine H1-receptors, and suggested that antidepressants reduced histamine-induced catalepsy via this mechanism. Histamine-induced catalepsy is a possible new animal model of depression which can also be used for evaluation of atypical antidepressants.
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The effects of betahistine, a histamine H1 agonist and H3 antagonist, were investigated in a light/dark test measuring anxiety in mice. Betahistine significantly decreased the locomotion and rearing in the light and dark zones, shuttle crossing and time spent in the light zone in the light/dark test. These phenomena suggest that betahistine has anxiogenic effects and/or locomotor suppressive effects. Pyrilamine (6 mg/kg) and ketotifen (6 mg/kg), H1-receptor antagonists, antagonized the effects of betahistine (100 mg/kg) on all parameters in the light/dark test but zolantidine (6 mg/kg), an H2-receptor antagonist, augmented its effects on some parameters decreased by betahistine. Especially, it potentiated the decreases by betahistine in the parameters showing anxiety in this test. The decreases in the light/dark test induced by zolantidine (6 mg/kg) plus betahistine (200 mg/kg) were antagonized by pyrilamine (12 mg/kg) but antagonism of the decrease in the time spent in the light zone as a parameter showing anxiety was not significant. These results suggest that the effects via H1 receptors are involved in anxiety in the light/dark test in mice but the other factor may be simultaneously needed for induction of behaviorally detectable anxiogenic effects in this test.
We sought to determine the functional significance of the c-kit receptor (Kit) in melanoma, breast carcinoma, and non-small cell lung cancer (NSCLC). To explore these issues, we first screened cell lines of each type for c-kit mRNA expression using a reverse-transcription polymerase chain reaction. We found that WM-39 melanoma cells, HTB-22 breast carcinoma cells, and A549 NSCLC cells all expressed c-kit mRNA. Of interest, all of these cells expressed the c-kit ligand, Steel factor (SF). We then assessed the functional significance of c-kit and SF expression by disrupting the gene's expression with antisense (AS) oligodeoxynucleotides (ODN) targeted to c-kit mRNA codons 1-6 and SF mRNA codons 2-7, respectively. Nonhybridizing sequences [sense (5) and scrambled (SCR)] were also employed as controls. WM-39, HTB-22, and A549 cells were exposed to ODN (approximately 25 microM) for 5-7 days. Downregulation of c-kit and SF mRNA, and c-kit protein was demonstrated in cells treated with AS ODN. Effects on viable cell growth were demonstrated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) or 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 -sulfophenyl)- 2H-tetrazolium (MTS) assay. In fact, c-kit antisense ODN inhibited the viable cell growth of A549 cells 66% and 79% compared to sense and untreated controls (P = .0003; P < .0001). Additionally, WM-39 cell growth was inhibited 48% and 21% (P < .0001, P < .03) and HTB-22 cell growth was inhibited 50% (P < .001) compared to sense and untreated controls. Viable cell growth was also significantly inhibited by SF AS ODN compared to S and SCR controls in all cell lines. These results demonstrate that WM-39, HTB-22, and A549 NSCLC cells all express the c-kit and SF protooncogenes and suggest that the encoded receptor and ligand are important for cell growth. By finding the presence, and functional importance, of both the receptor and ligand in these cells, this study suggests the existence of an autocrine loop growth mechanism worthy of further study.