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Biomedical subjects

H Onodera

Publications and source records attributed to H Onodera.

At least 55 records · Page 3Linked to original sources
PubMed2000

Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome.

Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8(+) cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury, and attempted to evaluate apoptosis-related factors in bronchoalveolar lavage fluid (BALF) from ARDS patients. Quantitative polymerase chain reaction (PCR) analysis revealed that the messenger ribonucleic acids (mRNAs) for several apoptosis molecules, such as perforin, granzyme A, granzyme B, FasL, and Fas were highly upregulated in the acute phase of ARDS following sepsis. In contrast, low or negligible mRNA expression of these molecules was detected in patients with normal lung function, in septic patients without lung injury (septic non-ARDS), and in patients in the late phase of septic ARDS (late ARDS). While the genes of the classic proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8, and inducible nitric oxide synthase (iNOS) were upregulated in septic non-ARDS or late ARDS patients, expressions of these genes in the acute phase of septic ARDS were most distinct. The immunofluorescence flow cytometry showed that only the lymphocyte population in BALF from acute phase of septic ARDS patients expressed perforin and granzyme. The level of soluble FasL in the BALF increased only in the acute ARDS patients. These results thus suggested that the dual apoptosis pathway, perforin/granzyme and FasL/Fas system, is likely to be another participant for the pathogenesis of acute lung injury.

Adult↗
PubMed2000

Toxicity and blood concentrations of xylazine and its metabolite, 2,6-dimethylaniline, in rats after single or continuous oral administrations.

To cast light on whether the carcinogenic risk of 2,6-dimethylaniline (DMA), a metabolite of xylazine, may increase by ingestion of edible tissues from domestic animals treated with xylazine, the following studies of xylazine and DMA were performed. In Experiment I, male F344 rats received a single oral administration of 150 mg/kg of xylazine hydrochloride. Rats showed symptoms suggesting loss of sensation and pain immediately after the treatment. These signs had disappeared after 3 hr, but the animals died of hydrothorax and pulmonary edema by 9 hr. The plasma concentration of xylazine was 2.88 +/- 0.95 micrograms/ml at 15 min, and then decreased to 0.10 +/- 0.01 microgram/ml at 6 hr. The plasma level of DMA remained at 0.03 to 0.04 microgram/ml during the measurement period. In Experiment II, male F344 rats were fed a diet containing 1000 ppm of xylazine hydrochloride, regarded as the maximum tolerated dose, for 4 weeks. No clear clinical signs were evident and the plasma levels of xylazine and DMA were at the detection limit (0.02 microgram/ml) or less, although follicular cell hypertrophy of the thyroid was observed in all the treated animals. In Experiment III, male F344 rats were fed a diet containing 3000 ppm or 300 ppm of DMA for 4 weeks. Histological changes, such as atrophy of Bowman's gland and irregular arrangement of olfactory epithelial cells, were only observed in the olfactory epithelium of the 3000 ppm group. The plasma levels of DMA were 0.20 to 0.36 microgram/ml in the 3000 ppm group, but under the detection limit in the 300 ppm group. These results suggest that the probability of nasal carcinogenic effects of DNA on consumers via ingestion of edible tissues from food-producing animals treated with xylazine is extremely low, since DMA levels in the blood of rats subjected to continuous administration of high doses of xylazine remained under the detection limit.

Administration, Oral↗
PubMed2000

Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG level in DNA.

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively modified lesions in DNA. Our previous study (Kondo et al, Free Radic. Biol. Med., 27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively stressed based on 8-OHdG determination. To elucidate 8-OHdG metabolism and its clinical significance in colorectal carcinoma, we studied the 8-OHdG repair system in DNA by measuring specific lyase activity and hOGG1 expression using quantitative-competitive reverse transcription-PCR. In addition, we searched for the presence of mutations and single nucleotide polymorphisms of the hOGG1 gene by single-strand conformational polymorphism and sequencing analyses. It was found that 8-OHdG-specific lyase activity and hOGG1 expression were significantly up-regulated in carcinoma, and a proportional association between 8-OHdG levels and either 8-OHdG lyase activity (r = 0.641, P < 0.05) or hOGG1 expression (r = 0.702, P < 0.05) was present. Whereas no difference was detected in the 8-OHdG level between early- and advanced-stage cancer, lyase activity (1.2-fold) and hOG1 expression (1.6-fold) were significantly increased in advanced-stage cancer. No mutation was found in the 25 tumors examined. Three kinds of single nucleotide polymor. phism were observed, including that of codon 326 (Ser/Cys) in exon 7. However, there was no correlation between any of the three polymorphic patterns and either 8-OHdG level or lyase activity. These results suggest that increased 8-OHdG levels in colorectal carcinoma are attributed to increased formation and are maintained by induced 8-OHdG repair activity at appropriate high levels. Our results may offer a unique approach in the development of preventive and therapeutic interventions as well as new insights into the pathogenesis of colorectal carcinoma.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Two consecutive fasciculation potentials having different motor unit origins are an electromyographically pathognomonic finding of ALS.

To electrophysiologically diagnose amyotrophic lateral sclerosis (ALS), fasciculation potentials (FPs) were evaluated in each wasted muscle in 12 ALS and 14 other neurogenic disorders (non-ALS patients). Various types of FPs were observed in ALS. The number of discharged FPs and firing rate of FPs were significantly increased in ALS compared to those in non-ALS. These findings indicate that more motor units take part in discharging FPs in ALS than in non-ALS, and that injured lower motor neurons exhibit hyperexcitability. Although nine of 12 ALS patients showed two consecutive FPs having different motor unit origins, non-ALS patients did not show such FPs. Since the two consecutive FPs having different motor unit origins reflect an involvement of both upper and lower motor neurons, these potentials are an electrophysiologically pathognomonic finding to ALS.

Action Potentials↗
PubMed2000

[A 90-day repeated dose oral toxicity study of magnesium chloride in F344 rats].

In order to examine the toxicity of magnesium chloride hexahydrate, four groups of 10 male and 10 female F344 rats received the compound by dietary supplementation at 2.5, 0.5, 0.1 or 0% for 90 days. No treatment-related death was observed during the study. Transient soft stool and sustained increase in water consumption were observed both in males and females of the 2.5% group and slight reduction in body weight gain was noted in the high-dose males. There were no toxic changes in food consumption, organ weights, hematology and biochemistry, and histopathological examinations in any treated-groups. Based on these results, the no-observed-adverse-effect-level was estimated to be 0.5%, and 2.5% is considered to be appropriate as highest dose for a 2-year carcinogenicity study.

Administration, Oral↗
PubMed1999

Prolactin secretion in response to prolactin-releasing peptide and the expression of the prolactin-releasing peptide gene in the medulla oblongata are estrogen dependent in rats.

Prolactin-releasing peptide (PrRP), recently isolated from bovine hypothalamus as an endogenous ligand to a seven transmembrane-domain orphan receptor, is a candidate specific prolactin-releasing factor. The prolactin-releasing activity of the peptide and the expression of the PrRP gene were examined in vivo in relation to estrogen status. Plasma prolactin levels increased significantly with a peak at 5 min after the administration of 50 microg/kg PrRP in female rats in estrus under urethane anesthesia as compared with those in vehicle-treated control rats, but not in female rats in diestrus or proestrus or in male rats. In ovariectomized rats treated with supraphysiological concentration of estrogen, a dose-dependent increase of prolactin secretion in response to 2-50 microg/kg PrRP was observed. However, the peak values induced by 50 microg/kg PrRP were much less than those induced by 2 microg/kg thyrotropin-releasing hormone (TRH). PrRP mRNA levels in the medulla oblongata were decreased by ovariectomy and increased by estrogen treatment. The data indicate that estrogen is prerequisite to the stimulatory effect of PrRP on the secretion of prolactin and to the increase of PrRP mRNA levels in the medulla oblongata. The weak in vivo potency of PrRP on prolactin secretion relative to TRH suggests that PrRP differs from the classical hypophysiotropic hypothalamic releasing hormones.

Animals↗
PubMed1999

Tumor-promoting activity of 2,6-dimethylaniline in a two-stage nasal carcinogenesis model in N-bis(2-hydroxypropyl)nitrosamine-treated rats.

The potential promotion activity on nasal carcinogenesis of 2,6-dimethylaniline (DMA), an alpha2-adrenergic agonist metabolite of xylazine which is used for food-producing animals as a sedative agent, was examined. Male F344 rats received diet containing 0 or 3000 ppm DMA for 52 weeks after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Histopathological assessment showed the incidence of carcinomas in the DHPN+DMA group (33%) to be significantly elevated as compared with that for the DHPN-alone group (5%). Incidences and/or multiplicity of epithelial hyperplasias and dysplastic foci were also increased in the DHPN+DMA group. These lesions were exclusively observed in the olfactory mucosa. The lowest plasma levels of DMA in tumor- and dysplastic foci-bearing rats were 0.05 and 0.20 microg/ml, respectively. These results indicate that DHPN acts as an appropriate initiator for nasal carcinogenesis and that DMA exerts a tumor-promoting effect on the olfactory mucosa in the rat nasal cavity.

Adenoma↗
PubMed1999

Cellular localization of prolactin-releasing peptide messenger RNA in the rat brain.

Prolactin-releasing peptide (PrRP), a novel peptide identified as the endogenous ligand for an orphan receptor isolated from the pituitary, is a potent stimulator of prolactin release. To get a clue of the functional roles of the peptide, we performed in situ hybridization histochemistry for PrRP mRNA to define the cellular localization of PrRP-producing cells in the brain of the cycling adult female rat during diestrus. The PrRP mRNA-containing cells were located in the caudal part of the dorsomedial nucleus of the hypothalamus. In the brainstem, the cells were found in the caudal part of the solitary tract nucleus and in the caudal ventrolateral medulla (ventrolateral intermediate reticular field). Specific signals for PrRP mRNA were not detected in other brain regions. Although PrRP is a candidate for being a hypophysiotropic specific releasing factor, the discrete distribution of PrRP in the extrahypothalamic area suggests that the peptide has other physiological functions in the central nervous system.

Animals↗
PubMed1999

Possible paracrine mechanism of insulin-like growth factor-2 in the development of liver metastases from colorectal carcinoma.

BACKGROUND: Insulin-like growth factor-2 (IGF-2) is considered one of the autocrine growth factors in colorectal carcinoma. In addition, it is well known that IGF-2 is produced in the liver. However, the role of IGF-2 in liver metastasis is not yet understood clearly. METHODS: Immunohistochemical staining of IGF-2 and IGF-1 receptor (IGF-1R) was performed on tissue samples of liver metastases from 30 colorectal carcinoma patients. In situ hybridization of IGF-2 also was conducted on the same tissue samples. Furthermore, proliferating cell nuclear antigen (PCNA) was immunohistochemically stained for use as an indicator of the proliferative activity of cancer cells. RESULTS: Invasive margins of liver metastases were stained highly by both IGF-2 (70%) and IGF-1R (83%). Overexpression of IGF-2 protein and mRNA was observed in the normal liver adjacent to the tumor. The PCNA labeling indices (LIs) of the IGF-2 positive groups were significantly higher than those of the IGF-2 negative group (P < 0.0001). In addition, the PCNA LIs for the IGF-1R positive groups also were significantly higher than those for the IGF-1R negative group (P=0.0002). CONCLUSIONS: These findings suggest that hepatocyte-derived IGF-2 stimulates tumor cell proliferation by a paracrine mechanism and plays an important role in tumor progression in colorectal carcinoma patients with liver metastases.

Aged↗
PubMed1999

The relationship between decrease in Cx32 and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis in the rat.

To examine the relationship between the decrease in connexin 32 (Cx32) and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis, a total of 20 male F344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or given the saline vehicle alone and starting 2 weeks later given diet containing 0.18, 0.09, and 0% clofibrate for 6 weeks. All animals were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Absolute and relative (ratios to body weight) liver weights were significantly increased in the DEN + clofibrate groups compared with the DEN-alone group. Diffuse hepatocellular hypertrophy with granular cytoplasmic eosinophilia characterized by a marked increase in peroxisomes and smooth endoplasmic reticulum, was observed in the clofibrate treated rats. Induction of cytochrome P450 (CYP) 4A1 and 2B1/2 was noted in the DEN + clofibrate groups, this being most marked in the CYP 2B1 case. Immunohistochemically, positive immunostaining for anti-CYP 4A1 and CYP 2B1 were observed diffusely and centrilobularly, respectively. The numbers and areas of Cx32-positive spots per hepatocyte in the centrilobular areas in the treated rats were significantly decreased in an essentially dose-dependent manner, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form (GST-P) were decreased in a dose dependent manner in the clofibrate treated groups. These results suggest that the CYP 2B1/2 induction and Cx32 decrease in centrilobular hepatocytes, similarly to those thought to be involved in the hepatic promotion mechanism of phenobarbital, may also play important roles in clofibrate actions in the liver, in addition to its causation of oxidative DNA injury.

Animals↗
PubMed1999

Clinical application of a blood pressure autoregulation system during hypotensive anesthesia.

A blood pressure autoregulation system based on the state-predictive control method was developed to minimize intraoperative blood loss and hence avoid blood transfusion. In this report, the system is further improved by incorporating fuzzy logic with a fail-safe function and an individual parameter-identifying function. The safety and stability of this system had been confirmed by preclinical experiments with dogs. Thereafter clinical application with 17 patients was conducted to maintain their mean arterial pressure at around 60 mmHg during major surgery. The use of this system resulted in decreased blood loss and more speedy and accurate surgery due to a clearer surgical field. Unwanted effects of hypotension were not observed clinically or in laboratory tests. This system is therefore safe, stable, and effective in reducing the blood loss during major surgery that otherwise might cause substantial blood loss.

Anesthesia↗
PubMed1999

Differential expression of c-fos mRNA in the rat neocortex by in situ hybridization.

The c-fos mRNA expression pattern in rat neocortex, was determined in the rat kept in a 12:12 light/dark cycle, in constant dark, or in constant light by in situ hybridization. At the beginning of the light period, c-fos mRNA was induced both in the neocortex and suprachiasmatic nucleus (SCN). Transiently increased c-fos mRNA expression was detected from 0830 to 0900 and soon declined to basal levels. Immediately prior to the beginning of the dark period, c-fos mRNA expression also increased and remained elevated in the neocortex following the dark period. In the constant dark group, c-fos mRNA expression showed no transient elevation at the beginning of the light period. On the other hand, c-fos mRNA expression in the constant light group increased during their subjective dark period as well as normal light/dark cycle. These results demonstrate a circadian pattern of c-fos mRNA expression in the neocortex which is similar to that observed previously in the inner and outer nuclear layers of the retina.

Animals↗
PubMed1999

The first evidence of paralytic shellfish toxins in the fresh water cyanobacterium Cylindrospermopsis raciborskii, isolated from Brazil.

The blooms of toxic cyanobacteria (blue-green algae) are causing problems in many countries. During a screening of toxic freshwater cyanobacteria in Brazil, three strains isolated from the State of Sao Paulo were found toxic by the mouse bioassay. They all were identified as Cylindrospermopsis raciborskii by a close morphological examination. Extracts of cultured cells caused acute death to mice when injected intraperitoneally after developing neurotoxic symptoms which resembled to those caused by paralytic shellfish toxins. The analysis of the sample by HPLC-FLD postcolumn derivatization method for paralytic shellfish toxins resulted in the detection of several saxitoxin analogs. To avoid being misled by false peaks, the sample was reanalyzed after purification and also under the different postcolumn derivatizing conditions. Finally, the newly developed LC-MS method for paralytic shellfish toxins was applied to unambiguously identify the toxins. One isolate produced neosaxitoxin predominantly with saxitoxin as a minor component. The other two showed identical toxin profiles containing saxitoxin and gonyautoxins 2/3 isomers in the ratio of 1:9. This is the first evidence of paralytic shellfish toxins in this species and also the occurrence of the toxin producing cyanobacterium in South American countries.

Animals↗
PubMed1999

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma.

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3-nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Expression of a src-type protein tyrosine kinase gene, AcSrc1, in the sea urchin embryo.

By screening a cDNA library and 3'-rapid amplification of cDNA ends, the cDNA for a non-receptor type protein tyrosine kinase from the sea urchin Anthocidaris crassispina was analyzed. The deduced protein (AcSrc1) with the highest identity of about 60% to mammalian Src family kinases shows the characteristic features of the Src family. AcSrc1 mRNA is maternally expressed in unfertilized eggs, while zygotic expression is first detected in blastulae and continues through the pluteus stage. Zygotic mRNA expression, visualized by in situ hybridization, is detected specifically in archenteron at the gastrula stage, while it is restricted in plutei to the midgut and hindgut, suggesting specific roles for AcSrcl in the formation and/or functions of the digestive tract. Meanwhile, western blot analysis has shown that the AcSrc1 protein is constantly expressed throughout embryogenesis. By immunostaining, it was found that the protein (distributed evenly in the cytoplasm of unfertilized eggs) is translocated to the membrane after fertilization. All through the following development, AcSrcl was localized to the peripheries of different embryonic cells, although at a relatively low level of localization at the boundaries between adjacent cells.

Amino Acid Sequence↗
PubMed1999

Promoting effects of kojic acid due to serum TSH elevation resulting from reduced serum thyroid hormone levels on development of thyroid proliferative lesions in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

In order to examine whether kojic acid (KA) exerts a promoting effect on thyroid carcinogenesis, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (BHP; 2800 mg/kg body wt, single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 2 or 0% KA for 12 weeks. Untreated control rats were given basal diet for 13 weeks. As an additional experiment, two groups without BHP initiation received basal diet or diet containing 2% KA for 20 weeks. The serum triiodothyronine (T3) and thyroxine (T4) levels were significantly decreased (half to one-third of values of the BHP alone group) and serum thyroid-stimulating hormone (TSH) was markedly increased (13-19 times higher than the values of the BHP-alone group) in the BHP + KA group at weeks 4 and 12. Similar changes in serum thyroid-related hormones were observed in the group with 2% KA alone at week 4, but not at week 20. Thyroid weights were significantly increased in the BHP + KA and KA-alone groups. Focal thyroid follicular hyperplasias and adenomas were observed in 4/5 and 3/ 5 rats in the BHP + KA group at week 4, respectively. At weeks 12, these lesions were observed in all rats in the BHP + KA group. Animals of the KA alone group showed marked diffuse hypertrophy of follicular epithelial cells at weeks 4 and 20. No changes in thyroid-related hormone levels or thyroid histopathological lesions were observed in either the BHP alone or the untreated control groups. Measurement of liver T4-uridine diphosphate glucuronosyltransferase (UDP-GT) activity at week 4 revealed no significant intergroup differences. These results suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanism independent of T4-UDP-GT activity.

Adenoma↗
PubMed1999

Changes in thyroid function during development of thyroid hyperplasia induced by kojic acid in F344 rats.

To clarify the mechanism of tumorigenesis by kojic acid (KA), dose and time dependence of iodine uptake in the thyroid gland and serum thyroid stimulating hormone (TSH) and thyroid hormone levels were investigated in F344 rats fed a diet containing 2% KA. After 4 weeks, thyroid hyperplasia was apparent in males, associated with a decrease in (125)I uptake into the thyroid gland to only 3% of that in controls. The serum triiodothyronine (T(3)) and thyroxine (T(4)) levels dropped to 0.36 ng/ml, 1.7 micrograms/dl from the initial values of 0.61 ng/ml, 4.0 micrograms/dl and TSH increased seven times to 15 ng/ml. In females, the effects on thyroid weight and (125)I uptake were less prominent, although the changes in serum T(3), T(4) and TSH levels were similar to those in males. Time-dependent changes in serum T(3), T(4) and TSH levels correlated with the inhibition of iodine uptake in the thyroid. Inhibition of organic iodine formation was only observed after 3 weeks treatment. On return to the control diet, normal serum T(3), T(4) and TSH levels became evident within 48 h in both sexes. These data suggest that KA interrupts thyroid function, primarily by inhibiting iodine intake, consequently causing a decrease in serum T(3) and T(4). Increased TSH from the pituitary gland in turn stimulates thyroid hyperplasia, which is reversible on withdrawal of KA.

Animals↗