Search PubMed⌕ Search

Biomedical subjects

H Esumi

Publications and source records attributed to H Esumi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development.

Our own recent studies have demonstrated that inducible nitric oxide synthase (iNOS) is predominantly localized in granulosa cells of healthy immature follicles in the rat ovary, whereas granulosa cells of either healthy mature follicles or follicles destined to be atretic are devoid of iNOS. These findings suggest that iNOS is pivotal for immature follicles to remain dormant. To test this hypothesis, we examined the effects of a GnRH agonist (buserelin), a proapoptotic substance, and epidermal growth factor (EGF), a mitogenic and, consequently, antiapoptotic factor, on the amount of iNOS mRNA in rat granulosa cells. Administration of buserelin in immature female rats transiently diminished iNOS mRNA levels in the ovaries as determined by Northern blot analysis. In cultured rat granulosa cells, buserelin and EGF increased the incidence of apoptosis and DNA synthesis, respectively, whereas both reduced iNOS mRNA levels as determined by reverse transcription-coupled polymerase chain reaction. The concomitant addition of S-nitroso-N-acetyl-DL-penicillamine, an NO donor, together with buserelin or EGF eliminated the observed effects of these substances (i.e., induction of apoptosis and stimulation of DNA synthesis, respectively). These results suggest that the changes in developmental status of immature follicles either into development or atresia are associated with reduced iNOS levels in granulosa cells, thus reinforcing the notion of NO as a cytostatic factor in ovarian follicles.

Animals↗
PubMed2000

Association of aldehyde dehydrogenase 2 gene polymorphism with multiple oesophageal dysplasia in head and neck cancer patients.

BACKGROUND: Multiple occurrences of oesophageal dysplasia are frequently observed in head and neck cancer patients, and closely associated with alcohol consumption. Acetaldehyde, the first metabolite of ethanol, is thought to play an important role in the carcinogenesis of the upper aerodigestive tract. AIM: To investigate if genetic polymorphism in alcohol metabolising enzymes (ADH3, alcohol dehydrogenase 3; ALDH2, aldehyde dehydrogenase 2) is associated with oesophageal multiple dysplasia in head and neck cancer patients. METHODS: Thirty one consecutive patients with head and neck cancer were included in the study. Multiple oesophageal dysplasia was detected endoscopically as multiple Lugol voiding lesions (multiple LVL) using the Lugol dye staining method. The ADH3 and ALDH2 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Among the 31 patients with head and neck cancer, 17 had multiple LVL. Multiple LVL were closely associated with a second primary oesophageal carcinoma in head and neck cancer patients (odds ratio 60.7, 95% CI 5.6-659). Furthermore, the mutant ALDH2 allele was significantly more prevalent in patients with multiple LVL (65% v 29%; p<0.05) whereas no difference was observed in ADH3 polymorphism. CONCLUSIONS: The mutant ALDH2 allele appears to be a risk indicator for multiple LVL in head and neck cancer patients. Accumulation of acetaldehyde due to low ALDH2 activity may play a critical role in cancerous changes throughout the mucosa in the upper aerodigestive tract.

Aged↗
PubMed1999

Mutagenic activation of environmental carcinogens by microsomes of gastric mucosa with intestinal metaplasia.

Coexpression of cytochrome P450 monooxygenases (CYPs) and reductase was found in human gastric mucosa with intestinal metaplasia. Immunohistochemistry showed reactivity to P450 reductase in metaplastic epithelial cells and in pyloric gland cells in glands showing intestinal metaplasia. These cells exhibit NADPH-diaphorase activity. Reverse transcription-PCR analysis and Western blotting showed that CYP1A1 and CYP1A2 were expressed in specimens with intestinal metaplasia. Tissue distribution of CYP1A1 coincided with that of P450 reductase. However, immunoreactivity to CYP1A2 protein was localized only in the pyloric gland cells near the intestinal metaplastic gland. Salmonella typhimurium mutagen assay definitively revealed that microsomes prepared from gastric mucosa with intestinal metaplasia, in particular in the pyloric gland, functionally activated benzo(a)pyrene and 2-amino-3-methylimidazo [4,5-f]quinoline. These results indicate that carcinogen activation by CYP enzymes expressed in the gastric mucosa may contribute to carcinogenesis of the stomach.

Carcinogens, Environmental↗
PubMed1999

Characterization of mouse nNOS2, a natural variant of neuronal nitric-oxide synthase produced in the central nervous system by selective alternative splicing.

Mouse neuronal nitric-oxide synthase 2 (nNOS2) is a unique natural variant of constitutive neuronal nitric-oxide synthase (nNOS) specifically expressed in the central nervous system having a 105-amino acid deletion in the heme-binding domain as a result of in-frame mutation by specific alternative splicing. The mouse nNOS2 cDNA gene was heterologously expressed in Escherichia coli, and the resultant product was characterized spectroscopically in detail. Purified recombinant nNOS2 contained heme but showed no L-arginine- and NADPH-dependent citrulline-forming activity in the presence of Ca2+-promoted calmodulin, elicited a sharp electron paramagnetic resonance (EPR) signal at g = 6.0 indicating the presence of a high spin ferriheme as isolated and showed a peak at around 420 nm in the CO difference spectrum, instead of a 443-nm peak detected with the recombinant wild-type nNOS1 enzyme. Thus, although the heme domain of nNOS2 is capable of binding heme, the heme coordination geometry is highly abnormal in that it probably has a proximal non-cysteine thiolate ligand both in the ferric and ferrous states. Moreover, negligible spectral perturbation of the nNOS2 ferriheme was detected upon addition of either L-arginine or imidazole. These provide a possible rational explanation for the inability of nNOS2 to catalyze the cytochrome P450-type monooxygenase reaction.

Alternative Splicing↗
PubMed1999

Expression of the cyclin D1 gene in rat colorectal aberrant crypt foci and tumors induced by azoxymethane.

Cyclin D1 is a cell cycle regulator which is overexpressed in a variety of human cancers. We examined overexpression of cyclin D1 in several stages of rat colorectal carcinogenesis induced by azoxymethane (AOM) treatment. The level of cyclin D1 in 13 aberrant crypt foci (ACF) (atypical hyperplasias), 22 colorectal tumors (14 non-invasive adenocarcinomas and eight invasive adenocarcinomas) was assessed by immunostaining using a polyclonal antibody. Cell proliferation of these samples was investigated by measurement of 5-bromo-2'-deoxyuridine-labeling index. Indices of cyclin D1-positive cells in adenocarcinomas and atypical hyperplasias were significantly higher than that in normal crypts (P < 0.05). Moreover, cyclin D1-positive rates in the two types of adenocarcinomas were significantly higher than that in atypical hyperplasias (P < 0.05). Staining of nuclear cyclin D1 was very strong in almost all adenocarcinomas and four ACF. Comparisons of BrdU-positive indices in colorectal lesions showed similar results to the cyclin D1-positive indices. These results suggested that overexpession of cyclin D1 occurs early in the multistep carcinogenesis, and plays an important role in rat colorectal carcinogenesis.

Adenocarcinoma↗
PubMed1999

Ketoconazole inhibits lipopolysaccharide-induced activation of the nitric oxide synthase gene in the murine macrophage cell line J774.

The aim of this study was to determine whether ketoconazole can affect the expression of the nitric oxide (NO) synthase gene in the murine macrophage cell line J774. The inducible enzyme (i-NOS) is activated in murine macrophages by LPS and cytokines. Exposure of the J774 cell line to ketoconazole for 24 h did not induce any NO release. Cells preincubated with ketoconazole and treated with LPS showed a significant decrease in nitrite levels in the culture medium, compared with controls (cells treated with LPS alone). The addition of 1 mM N-monomethyl-L-arginine (L-NMMA), a structural analogue of arginine, reduced nitrite levels by about 88+/-9.2% in cells treated with LPS alone, whereas in those treated with ketoconazole + LPS, the levels were comparable to the baseline values detected in control cells. Northern blotting, used to assess i-NOS mRNA expression in the J774 cells, showed that ketoconazole reduced the LPS-induced increase in i-NOS mRNA activation by about 50%. These results support another mechanism for the antiinflammatory effect of ketoconazole (i.e. reduction in i-NOS gene expression and consequently inhibition of reactive radical NO production), that may explain the antierythema and antiedema action of this compound, besides its antimycotic effects.

Animals↗
PubMed1998

Lineage and clonal development of gastric glands.

Individual gastric glands of the stomach are composed of cells of different phenotypes. These are derived from multipotent progenitor stem cells located at the isthmus region of the gland. Previous cell lineage analyses suggest that gastric glands, as in the colon and small intestine, are invariably monoclonal by adult stages. However, little is known about the ontogenetic progression of glandular clonality in the stomach. To examine this issue, we employed an in situ cell lineage marker in female mice heterozygous for an X-linked transgene. We found that stomach glands commence development as polyclonal units, but by adulthood (6 weeks), the majority progressed to monoclonal units. Our analysis suggests that at least three progenitor cells are required to initiate the development of individual gastric glands if they are analyzed just after birth. Hence, unlike the colon and small intestine, stomachs showed a significant fraction (10-25%) of polyclonal glands at adult stages. We suggest that these glands persist from polyclonal glands present in the embryonic stomach and hypothesize that they represent a subpopulation of glands with larger numbers of self-renewing stem cells.

Animals↗
PubMed1998

Suppression of the 5' splice site mutation in the Nagase analbuminemic rat with mutated U1snRNA.

Nagase analbuminemic rats (NAR) are deficient in serum albumin due to skipping of the albumin exon H caused by a mutation in the intron HI. This mutation deletes nucleotides from +5 to +11 in the 5' splice site region, where it interacts with U1snRNA. To determine whether the mutation can be suppressed by the compensatory base substitution in U1snRNA, we constructed mutated U1snRNA genes with various degrees of complementarity to the mutated 5' splice site. Several mutated U1snRNA genes activated the mutated 5' splice site of the intron HI, when cotransfected with the albumin minigene derived from NAR. In vivo activity of these mutated U1snRNAs correlated well with the predicted thermodynamic stability. Since mutation in the 5' splice site is one of common causes of genetic defects in human (5), these data indicate that NAR is a good model system to examine the possibility of gene therapy using a mutated U1snRNA.

Animals↗
PubMed1998

Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue.

BACKGROUND: The authors examined somatic mutations of the adenomatous polyposis coli (APC) gene in 84 human aberrant crypt foci (ACF) to determine whether APC gene mutations were involved in the histologic progression of ACF. METHODS: Mutation cluster regions of the APC gene were subjected to polymerase chain reaction single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Four kinds of deletion were detected in the mutation cluster regions of APC gene in five ACF. APC mutation was detected in 1 of 18 ACF with Stage I abnormalities (6%). Four of 10 adenomatous ACF (40%) harbored the mutation. There were no mutations in 56 hyperplastic ACF. CONCLUSIONS: These results suggest that APC mutations may be involved initially in only a limited number of adenomas in ACF.

Adenomatous Polyposis Coli↗
PubMed1998

Loss of heterozygosity in the tuberous sclerosis gene associated regions in adenocarcinoma of the lung accompanied by multiple atypical adenomatous hyperplasia.

To investigate the potential allelic loss of tumor suppressor gene loci in the tuberous sclerosis complex (TSC)-associated regions located on the long arm of chromosome 9 (9q) and on the short arm of chromosome 16 (16p) in human lung carcinoma, we analyzed 21 paired normal and tumor DNAs with 11 polymorphic markers on the chromosomes. All tumors were adenocarcinoma of the lung, which included 9 adenocarcinomas with associated multiple atypical adenomatous hyperplasia (AAH). A precise microdissection technique followed by polymerase chain reaction (PCR) amplification to prevent under-evaluation of loss of heterozygosity (LOH) was used. Twelve of the 21 (57%) adenocarcinomas displayed LOH on 9q. Five of the 21 adenocarcinomas (24%) showed LOH at all informative loci on 9q, whereas 7 (33%) demonstrated partial LOH on 9q34. Among these 21, 5 (24%) showed partial LOH between D9S149 and D9S150, where TSC1 is located. The incidence of associated AAH was significantly higher in adenocarcinoma harboring a partial LOH in the TSC1-associated region (p = 0.0048). Twelve of the 21 (57%) adenocarcinomas displayed LOH on 16p. No significant differences in the clinico-pathological characteristics could be discerned between adenocarcinomas with and without LOH on 16p. When combining these data, a partial LOH at TSC1- and/or TSC2-associated loci was observed more frequently in cases with well-differentiated adenocarcinoma (p = 0.086) and associated AAH (p = 0.081). In conclusion, our results suggest that the TSC-associated regions are new candidate loci for tumor suppressor genes in lung adenocarcinoma, especially when it is accompanied by multiple AAH.

Adenocarcinoma↗
PubMed1998

Induction of hepatic poly(ADP-ribose) polymerase by peroxisome proliferators, non-genotoxic hepatocarcinogens.

Two peroxisome proliferators, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) or di(2-ethylhexyl) phthalate (DEHP), were given orally to male F-344 rats for up to 78 or 97 weeks. At 1 week, the activity of poly(ADP-ribose) polymerase (pADPRP) was increased 2- and 1.8-fold in the liver of rats treated with Wy-14,643 and DEHP, respectively. The induction of the activity was maintained at 2.5- or 2-fold for up to 52 weeks. The immunoblot and Northern blot analyses revealed that the induction of pADPRP activity would be responsible for the increase in the amount of mRNA. In addition, in the liver tumor induced by Wy-14,643 and DEHP, the pADPRP mRNA level increased 3.6- or 3.7-fold. The magnitude of the increase in the mRNA level was higher than that in the non-tumor portion. These findings suggest that the induction of pADPRP may play an important role in the hepatocarcinogenesis induced by peroxisome proliferators.

Administration, Oral↗
PubMed1998

Modification by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) of 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced rat pancreatic and intestinal tumorigenesis.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has been shown to induce marked atrophic changes of exocrine pancreas of rats when given at 400 ppm in diet. On the other hand, 3,2'-dimethyl-4-aminobiphenyl (DMAB) causes pancreatic acinar tumors. Both chemicals also induce intestinal tumors. In the present experiment, the possible promotional effects of PhIP on DMAB-induced carcinogenesis in the rat were investigated with particular attention given to the pancreas and intestine. After initiation with subcutaneous injections of DMAB (150 mg/kg b.w.) once a week for 3 weeks, PhIP was administered in the diet at doses of 200, 100, 25 and 0 ppm from weeks 5 to 40. In a dose-dependent manner, PhIP clearly increased the numbers of basophilic acinar foci and nodules while decreasing development of acidophilic lesions. The incidences of adenocarcinomas of the small intestine but not the colon demonstrated a tendency for an increase with the higher doses of PhIP. The results thus indicated that PhIP administration after DMAB treatment exerts two different effects on pancreatic acinar cell lesions, enhancing the growth of basophilic foci and suppressing that of their acidophilic counterparts. Any influence on alimentary canal tumorigenesis was limited to the small intestine.

Adenocarcinoma↗
PubMed1998

Prostaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D2 (PGD2) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD2 modulates NO metabolism in rat VSMCs. PGD2 at a concentration of 10(-7) mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1beta (IL-1beta). In a dose-response analysis of IL-1beta and nitrite accumulation, PGD2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD2 at cytokine receptors. Northern analysis showed that PGD2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1beta-stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A2 (TXA2) analogue, U46619 (10(-5) mol/L), produced less inhibition of NO generation than did PGD2. Neither the PGI2 analog carbaprostacyclin nor PGE1 showed any inhibition. PGD2 dose-dependently inhibited NO generation despite the addition of the TXA2 antagonist SQ29548. PGJ2, delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2, all metabolites of PGD2, were as potent as or slightly stronger than PGD2 in the inhibition of NO generation. These data suggest that PGD2 suppresses NO generation in VSMCs by inhibiting iNOS mRNA expression, most likely through the cascade of the PGJ2 series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD2 regulates NO metabolism in vascular lesions.

Animals↗
PubMed1998

Expression and localization of inducible nitric oxide synthase in the rat ovary: a possible involvement of nitric oxide in the follicular development.

In the present study, using Northern blot analysis, we demonstrated that the level of iNOS mRNA in the ovary of immature rats decreased after 6 h of pregnant mare serum gonadotropin administration and recovered gradually up to the untreated level 48 h after the administration. Both in situ hybridization and immunohistochemistry revealed that iNOS mRNA and protein was predominantly localized in granulosa cells in most of immature follicles, but not in mature follicles with an antrum, which was a consistent finding regardless of gonadotropin treatment. Furthermore, we found that cultured granulosa cells had the ability to express iNOS mRNA in the presence of cytokines such as tumor necrosis factor-alpha, interleukin-1 beta and interferon-gamma, which are inherently detectable in the ovary. These results raise the possibility that locally produced NO synthesized by iNOS may be involved in the developmental status of ovarian follicles in concert with gonadotropin.

Animals↗
PubMed1998

Increased nitric oxide production in the liver in the perioperative period of partial hepatectomy with Pringle's maneuver.

BACKGROUND/AIMS: There is no evidence that nitric oxide is produced in the liver during ischemia/reperfusion injury. This study examined the production of nitric oxide and inducible nitric oxide synthase in patients undergoing partial hepatectomy. METHODS: Twenty patients undergoing partial hepatectomy with only Pringle's maneuver were included. Peripheral blood was taken 1 day before the operation, during the operation (just after laparotomy and the first and last Pringle's maneuver) and 1 and 3 days after the operation, for measurement of plasma nitrate/nitrite, endotoxin and cytokine levels. Blood was also sampled from hepatic veins after Pringle's maneuver. Two liver specimens were taken from each patient, one before ischemia and one after partial hepatectomy, for the detection of inducible nitric oxide synthase. RESULTS: Average nitrate reached a maximum (33.5+/-3.4 micromol/l) after the final clamp (hepatic venous level). The increase in nitrate level during the operation correlated with the total duration of clamping. Endotoxin and interleukin-6 levels increased in a similar manner to nitrate levels, but tumor necrosis factor-alpha and interleukin-1 beta levels did not. In liver specimens taken after partial hepatectomy from patients, inducible nitric oxide synthase mRNA and protein were detected. CONCLUSIONS: Nitric oxide was produced in livers during ischemia/reperfusion injury and inducible nitric oxide synthase was involved in nitric oxide production.

Adult↗
PubMed1998

Protective effect of prostaglandin E1 against ischemia/reperfusion-induced liver injury: results of a prospective, randomized study in cirrhotic patients undergoing subsegmentectomy.

BACKGROUND/AIMS: The cytoprotective effects of prostaglandin E1 on livers suffering from ischemia/reperfusion injury in the clinical setting are unproved. These effects were examined, focusing on inflammatory cytokine and nitric oxide metabolism. METHODS: Twenty-four cirrhotic patients with hepatocellular carcinoma undergoing subsegmentectomy under ischemia induced only by Pringle's maneuver were divided into two groups (patients given prostaglandin E1 by injection and untreated controls) and postoperative results were compared. Peripheral blood was taken perioperatively and the plasma aminotransferase, cytokines and nitrate/nitrite levels of the two groups were compared. Two liver specimens were taken from each patient, one before ischemia and the other after hepatectomy, and the levels of inducible nitric oxide synthase and cytokine mRNAs and proteins were analyzed. RESULTS: Although no apparent differences were recognized in postoperative complications or duration of postoperative hospital stay between the groups, the perioperative plasma aminotransferase level was significantly lower in the prostaglandin E1 group. Significant differences were also seen in interleukin-6 and nitrate plasma levels during the observation period and the interleukin-6 protein levels in the liver supernatants after hepatectomy in the two groups. In contrast, no significant differences were apparent between the interleukin-1 beta and tumor necrosis factor-alpha plasma levels of the two groups. The corrected fluorescence activities of interleukin-6 and inducible nitric oxide synthase mRNAs in the liver after hepatectomy correlated significantly. No interleukin-1 beta or tumor necrosis factor-alpha mRNAs or proteins were detected. CONCLUSIONS: Prostaglandin E1 exerted hepatoprotective effects on livers suffering from ischemia/reperfusion injury, and interleukin-6 might play an important role in these effects.

Aged↗
PubMed1998

Microsatellite instability in female non-small-cell lung cancer patients with familial clustering of malignancy.

There is accumulating evidence of an increased risk of familial clustering of cancer in the first-degree relatives of lung cancer probands. However, no explanation has been proposed for these epidemiological data. We reviewed 379 female non-small-cell lung cancer (NSCLC) patients to obtain their family histories of malignancy. Among them, nine female NSCLC patients with three or more relatives diagnosed with malignancy and 28 control patients without a family history of malignancy were selected to be analysed for instability at six different microsatellite loci. We observed microsatellite instability (MSI) more frequently in the patients with three or more family histories of malignancy (six out of nine, 67%) than the control patients (5 out of 28, 18%). The incidence of MSI in the former was significantly higher than that in the control (P=0.011: Fisher's exact test). We detected no significant difference in clinicopathological characteristics between the cases with MSI and those without MSI, except for their family histories of cancer. Our results show that a significantly higher rate of MSI is associated with familial clustering of malignancy. MSI could be one of the underlying mechanisms for familial clustering of malignancy in female NSCLC patients.

Adenocarcinoma↗