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Biomedical subjects

H Inoue

Publications and source records attributed to H Inoue.

At least 613 records · Page 34Linked to original sources
PubMed1998

Putrescine-stimulated intracellular Ca2+ release for invasiveness of rat ascites hepatoma cells.

Our previous study showed that treatment of highly invasive rat ascites hepatoma (LC-AH) cells with alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, decreased both their intracellular level of putrescine and their in vitro invasion of a monolayer of calf pulmonary arterial endothelial (CPAE) cells, and that both these decreases were completely reversed by exogenous putrescine, but not spermidine or spermine. Here we show that all adhering control (DFMO-untreated) cells migrated beneath CPAE monolayer with morphological change from round to cauliflower-shaped cells (migratory cells). DFMO treatment increased the number of cells that remained round without migration (nonmigratory cells). Exogenous putrescine, but not spermidine or spermine, induced transformation of all nonmigratory cells to migratory cells with a concomitant increase in their intracellular Ca2+ level, [Ca2+]i. The putrescine-induced increase in their [Ca2+]i preceded their transformation and these effects of putrescine were not affected by antagonists of the voltage-gated Ca2+ channel, but were completely suppressed by ryanodine, which also suppressed the invasiveness of the control cells. The DFMO-induced decreases in both [Ca2+]i and the invasiveness of the cells were restored by thapsigargin, which elevated [Ca2+]i by inhibiting endoplasmic Ca2+-ATPase, indicating that thapsigargin mimics the effects of putrescine. These results support the idea that putrescine is a cofactor for Ca2+ release through the Ca2+ channel in the endoplasmic reticulum that is inhibited by ryanodine, this release being initiated by cell adhesion and being a prerequisite for tumor cell invasion.

Animals↗
PubMed1998

Increased expression of sucrase and intestinal-type alkaline phosphatase in human gastric carcinomas with progression.

The activities of sucrase, total alkaline phosphatase (total ALP) and intestinal-type alkaline phosphatase (I-ALP) were assayed in gastric carcinomas and in their surrounding mucosae from 57 patients with advanced cancers, and the localization of sucrase in 203 carcinomas, including 86 early cancers, was examined immunohistochemically using polyclonal anti-sucrase antibody. All three enzymes were active in the 57 carcinomas as well as in their surrounding mucosae, but the levels were fairly low as compared to those in normal jejunum mucosa. A considerable part of the total ALP activity in tumor specimens was assumed to be due to I-ALP itself. Increased sucrase and I-ALP were found with greater depth of invasion by undifferentiated-type carcinomas. The pattern of immunohistochemical localization of sucrase in the 203 carcinomas also clearly indicated increased expression with greater depth of invasion even in differentiated-type carcinomas.

Adenocarcinoma↗
PubMed1998

Azathioprine-induced megaloblastic anemia with pancytopenia 22 years after living-related renal transplantation.

Macrocytosis and megaloblastic changes in the bone marrow are frequently seen in renal transplant recipients treated with azathioprine (Az). However, severe anemia is a rare side effect of Az. We recently observed a case of severe megaloblastic anemia with pancytopenia in a renal transplant recipient who had been receiving Az therapy for 22 years. The patient was a 46-year-old woman who had been administered Az and prednisolone at a dose of approximately 1.7 mg/kg and 0.17 mg/kg daily, respectively. A bone marrow aspiration revealed megaloblastic anemia with the depletion of myeloid cells and megakaryocytes. She did not have vitamin B12 or folate deficiency. Therefore, FK506 (tacrolimus), a macrolide produced by Streptomyces tsukubaensis, which acts directly on T cells and is known to have less myelosuppression than Az, was substituted for Az. Although the leukopenia improved, the anemia and thrombocytopenia did not improve in the short term. She developed dyspnea and severe subcutaneous bleeding of the right lower extremity due to knee contusions. Hemodialysis was started to treat her uremic state. Although it was impossible to evaluate the long-term effects of FK506 therapy for the pancytopenia in our case, the conversion from Az to a less myelosuppressive drug, such as FK506, should be considered in renal transplant recipients with severe myelosuppression caused by long-term Az treatment.

Anemia, Megaloblastic↗
PubMed1998

Cathepsin D expression in skin metastasis of breast cancer.

Cathepsin D, an aspartic proteinase, correlates with invasion and metastasis in breast cancer and with poor prognosis. In the present study, we examined the immunohistological expression of cathepsin D in both primary (5 cases) and skin-metastatic breast cancers (13 cases) and compared it to those in gastric (2 cases) and lung (4 cases), and primary eccrine cancers (3 cases). All breast and gastric cancers were adenocarcinomas. The 2 gastric cancers were poorly differentiated, while the 4 lung cancers consisted of 2 poorly differentiated adenocarcinomas, 1 poorly differentiated large cell carcinoma, and 1 moderately to poorly differentiated squamous cell carcinoma. We also surveyed the immunohistological distribution of cathepsin B, carcinoembryonic antigen, gross cystic disease fluid protein-15, c-erbB-2, and estrogen receptor. In almost all breast cancer samples, the cancer cells demonstrated strong expression of cathepsin D in the cytoplasm, but weak staining patterns with other antibodies. Gastric and lung cancer cells did not respond with cathepsin D (except one metastatic lung cancer) or the other immunohistological markers. Since cathepsin D is strongly expressed in primary and metastatic lesions of breast cancer, cathepsin D could be useful as an adjunct to a panel of immunohistochemical stains in determining the primary site of origin of metastatic cancer in the skin.

Adenocarcinoma↗
PubMed1998

Suppression of v-src transformation by the drs gene.

Previously, we isolated a novel gene, drs, which was downregulated by retroviral oncogenes such as v-src and v-K-ras, from a cDNA library of primary rat embryo fibroblasts. Experiments using a temperature-sensitive mutant of the v-src gene indicated that downregulation of drs mRNA was dependent on functional expression of v-Src. In addition, expression of drs mRNA was also reduced by serum stimulation of G0-arrested normal rat fibroblast cells. To clarify the function of the drs gene in cell transformation and proliferation, we introduced drs linked to a potent promoter into a normal rat cell line, F2408, and examined the effect of ectopic expression of exogenous drs on the transformation by the v-src gene and growth properties. Cells expressing exogenous drs gene showed significantly decreased efficiency of transformation by v-src irrespective of functional expression of v-Src kinase, while the growth rate and G1/S progression of the cells were not suppressed by expression of exogenous drs gene, indicating that drs has the ability to suppress v-src transformation without disturbing cell proliferation.

Animals↗
PubMed1998

Localization of cyclooxygenase-2 and regulation of its mRNA expression in gastric ulcers in rats.

It has been reported that cyclooxygenase-2 (COX-2) may play a crucial role in gastric ulcer healing. We examined the localization of COX-2 and the regulation of COX-2 mRNA expression in acetic acid ulcers in rats. PGE2 production was elevated in ulcerated tissue but not in intact tissue. COX-2 mRNA expression was induced in only the ulcerated tissue, and COX-2 protein was found in fibroblasts, monocytes/macrophages, and granulocytes. A selective COX-2 inhibitor inhibited increased PGE2 production by the ulcerated tissue. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) mRNAs were also expressed only in the ulcerated tissue. In a culture of isolated ulcer base, blockade of IL-1beta and TNF-alpha reduced COX-2 mRNA expression and PGE2 production. In contrast, COX-2 mRNA expression and PGE2 production were promoted by prevention of TGF-beta1 action. These results indicate that COX-2 protein is highly localized in the base of gastric ulcers in rats and that COX-2 mRNA expression might be regulated positively by IL-1beta and TNF-alpha and negatively by TGF-beta1.

Acetic Acid↗
PubMed1998

Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure.

To elucidate the time course of sympathovagal balance and its relationship to left ventricular function in heart failure, we serially evaluated left ventricular contractility and relaxation and autonomic tone in 11 conscious dogs with tachycardia-induced heart failure. We determined a dynamic map of sympathetic and parasympathetic modulation by power spectral analysis of heart rate variability. The left ventricular peak +dP/dt substantially fell from 3,364 +/- 338 to 1,959 +/- 318 mmHg/s (P < 0.05) on the third day and declined gradually to 1,783 +/- 312 mmHg/s at 2 wk of rapid ventricular pacing. In contrast, the time constant of left ventricular pressure decay and end-diastolic pressure increased gradually from 25 +/- 4 to 47 +/- 5 ms (P < 0.05) and from 10 +/- 2 to 21 +/- 3 mmHg (P < 0.05), respectively, at 2 wk of pacing. The high-frequency component (0.15-1.0 Hz), a marker of parasympathetic modulation, decreased from 1,928 +/- 1,914 to 62 +/- 68 x 10(3) ms2 (P < 0.05) on the third day and further to 9 +/- 12 x 10(3) ms2 (P < 0.05) at 2 wk. Similar to the time course of left ventricular diastolic dysfunction, plasma norepinephrine levels and the ratio of low (0.05- to 0.15-Hz)- to high-frequency component increased progressively from 135 +/- 50 to 532 +/- 186 pg/ml (P < 0.05) and from 0.06 +/- 0.06 to 1.12 +/- 1.01 (P < 0.05), respectively, at 2 wk of pacing. These cardiac and autonomic dysfunctions recovered gradually toward the normal values at 2 wk after cessation of pacing. Thus a parallel decline in left ventricular contractility with parasympathetic influence and a parallel progression in left ventricular diastolic dysfunction with sympathoexcitation suggest a close relationship between cardiac dysfunction and autonomic dysregulation during development of heart failure.

Animals↗
PubMed1998

Pituitary adenylate cyclase activating peptide regulates neurally mediated airway responses.

To clarify the protective effects of pituitary adenylate cyclase activating peptide (PACAP) on airway narrowing, we examined the effects of PACAP on smooth muscle contraction and plasma extravasation in guinea-pig airways. Smooth muscle contraction evoked by electrical field stimulation (EFS) or exogenously applied acetylcholine (ACh) or substance P (SP) was measured before and after PACAP in vitro. The effect of PACAP on airway plasma extravasation was also measured in vivo. In trachea, PACAP (10(-9) - 10(-7) M) significantly suppressed smooth muscle contraction evoked by EFS without affecting ACh sensitivity, suggesting that PACAP inhibits cholinergic neuroeffector transmission. In the main bronchi, PACAP (10(-9) - 10(-8) M) significantly suppressed the contraction evoked by EFS without affecting SP sensitivity in the presence of atropine, suggesting that PACAP inhibits SP release from excitatory nonadrenergic noncholinergic (eNANC) nerves. In animals treated with atropine and propranolol, PACAP attenuated the increase in plasma extravasation induced by electrical vagus stimulation or by SP. These results suggest that pituitary adenylate cyclase activating peptide may play a role in modulation of airway responses through inhibition of cholinergic and noncholinergic mechanisms.

Acetylcholine↗
PubMed1998

Eosinophilic airway inflammation induced by repeated exposure to cigarette smoke.

Acute exposure to cigarette smoke causes airway hyperresponsiveness (AHR) in guinea-pigs, which resolves within a few hours. Repeated exposure may have a different effect on the airways. To address this question, guinea-pigs were repeatedly exposed to cigarette smoke (six cigarettes for 1 h x day(-1)) for 14 consecutive days. Airway responsiveness to inhaled histamine and differential cell counts in bronchoalveolar lavage fluid (BALF) were evaluated 1 day after the last exposure. Significant neutrophilia in BALF was observed after 3 days of smoke exposure. Significant eosinophilia in BALF and AHR were observed after 14 days of smoke exposure, but not after 3 or 7 days of smoke exposure. These changes persisted until 3 days after the last exposure and resolved 7 days afterwards. Histologically, the recruited eosinophils were observed predominantly in the airways, but not in the alveoli. Treatment with E-6123, a specific platelet-activating factor receptor antagonist (1 mg x kg(-1) x day(-1) p.o. during smoke exposure) significantly inhibited the eosinophil influx and AHR. Repeated exposure to cigarette smoke may induce prolonged airway inflammation and airway hyperresponsiveness in guinea-pigs. Platelet-activating factor or platelet-activating factor-like lipids may play a key role in airway hyperresponsiveness, presumably by the induction of eosinophilic airway inflammation.

Animals↗
PubMed1998

pH-dependent growth retardation of Escherichia coli caused by overproduction of Na+/H+ antiporter.

The overproduction of Na+/H+ antiporter NhaA in Escherichia coli caused growth retardation. Quantities and the activity of the antiporter were studied for their causative roles in terms of this retardation. We constructed a series of nhaA-expression plasmids differing in their transcriptional and translational efficiencies. Low-level nhaA expression complemented the defect of an nhaA mutant and allowed the mutant to survive on a high-NaCl or high-LiCl medium. However, when the production of NhaA was strongly induced by the combination of a stronger promoter, an efficient translational initiation signal and a high copy number plasmid, the growth of the cells carrying the plasmid was severely retarded. This growth retardation correlated well with the amount of NhaA protein produced from the plasmids. Surprisingly, the growth retardation caused by overproduction of NhaA was enhanced more extensively at an alkaline pH than at a neutral pH, in which the antiporter activity was stimulated. However, these retardations were also observed for mutant NhaA antiporters without the activity. These results indicated that the growth retardation was due to an overproduction of the antiporter rather than its increased antiporter activity, and also affected by a pH-dependent change in NhaA, possibly its structural change.

Cell Division↗
PubMed1998

Cardiovascular effects of 1,5-benzothiazepine derivatives having a l-cis and d-cis configuration in anesthetized dogs.

TA-993, a new 1,5-benzothiazepine derivative having a l-cis configuration, has a selective increasing action on limb blood flow, in addition to an antiplatelet aggregating action. The cardiovascular action of TA-993 is quite different from diltiazem, which is a well-known 1,5-benzothiazepine derivative having a d-cis configuration. Therefore, we compared the cardiovascular actions of d-cis and l-cis isomers of TA-993 with those of diltiazem. l-cis-Diltiazem, as well as TA-993, progressively increased femoral, brachial and common carotid blood flow with little change in arterial pressure or vertebral blood flow. However, the peak response to l-cis-diltiazem (20 min after the administration) was observed earlier than that to TA-993 (60 min after the administration). On the other hand, d-cis-TA-993, as well as diltiazem, caused transient hypotension, tachycardia and increases in vertebral, brachial, femoral and common carotid blood flow. Furthermore, their peak effects were observed immediately after the administration. Potency ratios of the vasorelaxing effects of TA-993, l-cis-diltiazem and d-cis-TA-993 to diltiazem in the isolated and K+-contracted canine femoral artery were 0.096, 0.032 and 1.209, respectively. pA2 values for TA-993 and diltiazem against Ca2+-induced contractions in the isolated and K+-depolarized canine saphenous artery were 5.50+/-0.11 and 7.12+/-0.18, respectively. These results indicate that TA-993 shares a common profile with l-cis-diltiazem, and suggest that 1,5-benzothiazepine derivatives of a l-cis configuration are a different class of drug from that of the d-cis configuration.

Anesthesia↗
PubMed1998

Familial evidence of vasospastic angina and possible involvement of HLA-DR2 in susceptibility to coronary spasm.

An association between genetic factors and susceptibility to coronary spasm has not been proven. Because we encountered 7 patients with familial occurrence of vasospastic angina (VSA) in 3 families, the association of a genetic factor with coronary spasm was assumed. HLA typing as one of the genetic markers was performed in the 3 families, and the affected members in each family were found to share a HLA haplotype, carrying both HLA-DR52 and DQ6. This raised the possibility that one of the susceptibility genes for coronary spasm is located in the HLA region. To assess this possibility, HLA typing was performed and compared in 110 patients with VSA but without a family history of VSA (VSA group) and 55 patients with chest pain syndrome (CPS group) as control subjects. All patients underwent a provocation test for coronary spasm, and spasm was angiographically documented in the VSA group but not in the CPS group. Of all HLA antigens, the frequency of only HLA-DR2 was significantly higher in the VSA group than in the CPS group (39.1% vs 18.2%, p<0.01). The result implied that HLA-DR2 is in linkage disequilibrium with a susceptibility gene of VSA and thus is possibly involved in susceptibility to coronary spasm in some patients with VSA.

Adult↗
PubMed1998

Head-up tilt test combined with isoproterenol infusion provokes coronary vasospastic angina.

The association of the autonomic nervous system with coronary vasospasm has been controversial. The aim of the present study was to examine the involvement of the autonomic nervous system in coronary vasospasm by applying the head-up tilt (HUT) test to patients with coronary vasospastic angina. Fifteen consecutive patients with coronary vasospastic angina and without significant organic coronary stenoses underwent the HUT test. Prior to the test, coronary spasm was documented angiographically by using an intracoronary injection of acetylcholine or ergonovine. The HUT test was performed in the early morning and repeated in the afternoon if the test was positive in provoking angina pectoris and syncope or presyncope. If the test was negative, it was repeated under intravenous infusion of isoproterenol at a rate of 1-2 microg/min. The HUT test under isoproterenol infusion in the morning provoked vasospastic angina with syncope or presyncope in 9 of the 15 patients. In the test-positive group, heart rate was significantly reduced (104+/-17 beats/min to 84+/-25 beats/min, p<0.05), which preceded a reduction in systolic blood pressure (158+/-25 mmHg to 125+/-17 mmHg, p<0.001), angina attack and syncope. The HUT test without isoproterenol infusion in the morning and the HUT test in the afternoon with or without isoproterenol infusion failed to provoke angina. The heart rate reduction preceding reduced systemic blood pressure and anginal attack suggested that parasympathetic nerve excitation plays an important role in coronary vasospasm. The results also implied that the HUT test combined with isoproterenol infusion is useful for the provocation of coronary spasm.

Acetylcholine↗
PubMed1998

Vulnerability of synaptic plasticity in the striatum of methamphetamine-sensitized rats.

We examined the influence of ischemia on methamphetamine (MAP)-induced behavioral sensitization and enhancement of dopamine (DA) release. After the recovery period of the ischemia operation, rats were treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days. Re-administration of MAP (0.5 mg/kg, i.p.) potentiated the increase of locomotor activity after a 3-day withdrawal and the enhancement of DA release from striatal slices after a 6-day withdrawal. The MAP-induced sensitization was impaired by 5 min ischemia. On the other hand, the increase of locomotor activity induced by single MAP (1 mg/kg, i.p.) administration was impaired by 20 min of ischemia. Moreover, in saline-treated rats the increase of DA release from striatal slices induced by MAP (10 microM) application was also impaired by 20 min of ischemia. These results indicate that the neuronal plastic change may be very vulnerable to ischemia in MAP-induced sensitization.

Animals↗
PubMed1998

Oxidation of trichloroethylene and dimethyl sulfide by a marine Methylomicrobium strain containing soluble methane monooxygenase.

Sixteen marine methanotrophic bacteria were isolated and 14 marine methanotrophic mixed cultures were obtained. They were assayed for soluble methane monooxygenase (sMMO) by naphthalene oxidation and only one isolate (strain NI) was positive. Strain NI degraded trichloroehylene (TCE) more efficiently than other methanotrophic isolates containing no sMMO only under copper limiting conditions. Dimethyl sulfide (DMS), one of the radiatively important trace gases released from the sea, was transformed to dimethyl sulfoxide (DMSO) by methanotrophs and the efficiency for the transformation of DMS to DMSO was not as much affected by the presence of sMMO as that of TCE. The taxonomical properties of strain NI and phylogenetic analysis based on 16S rDNA genes indicated that strain NI was a type I methanotroph belonging to the genus Methylomicrobium, and closely related to Methylomicrobium pelagicum. The partial mmoX gene of strain NI was amplified by the primers common to three other mmoX genes and its 270 bp were sequenced. 77 residues out of the 89 amino acids derived from the sequences were common among the four mmoX genes.

Air Pollutants↗
PubMed1998

Relationship between electrocardiographic voltage and geometric patterns of left ventricular hypertrophy in patients with essential hypertension.

To assess whether we could predict left ventricular (LV) geometric patterns on echocardiography from voltages in standard electrocardiograms (ECG) in patients with essential hypertension, standard 12-lead ECG and echocardiograms were recorded in 106 consecutive, untreated patients (50+/-11 yr old) with essential hypertension. Subjects were assigned to the following four groups based on relative wall thickness (RWT) and LV mass index (LVMI) as determined by echocardiography: a normal geometry group (n = 44), a concentric remodeling group (increased RWT and normal LVMI, n = 10), an eccentric hypertrophy group (increased LVMI and normal RWT, n = 23), and a concentric hypertrophy group (increased RWT and LVMI, n = 29). The following ECG variables were determined: Sokolow-Lyon voltage (SV1 = RV5: SL), Cornell voltage (RaVL + SV3: CN), sum of 12-lead QRS voltage (12-lead sum), and RV6/RV5 ratio (RV6/V5). LVMI correlated with SL, CN, and 12-lead sum, but not with RV6/V5 in the study group as a whole. The concentric hypertrophy group showed increased voltages for all ECG variables except RV6/V5. The concentric remodeling group showed increased voltages for SL and 12-lead sum, but a decreased RV6/V5 ratio. In contrast, the eccentric hypertrophy group had increased voltage only for the 12-lead sum. The combination of SL, RV6/V5, and CN showed modest sensitivity and specificity in the diagnosis of concentric remodeling, concentric hypertrophy, and normal geometry, but not in the diagnosis of eccentric hypertrophy. Conventional ECG criteria can predict LVMI, but not LV geometry in the patients with essential hypertension. The combination of SL, CN, and RV6/V5 is useful in differentiating the four LV geometric patterns seen in essential hypertension.

Adult↗