Biomedical subjects
Y Mizoguchi
Publications and source records attributed to Y Mizoguchi.
Modulating effects of ellagic acid, vanillin and quercetin in a rat medium term multi-organ carcinogenesis model.
Effects of dietary supplementation with the antioxidants ellagic acid, quercetin and vanillin were examined using a medium term multi-organ carcinogenesis model in rats. Groups of 10-15 male F344 rats were given i.p. injections of diethylnitrosamine (DEN, 100 mg/kg body wt.) and N-methylnitrosourea (MNU, 20 mg/kg body wt), s.c. injections of 1,2-dimethylhydrazine (DMH, 40 mg/kg body wt.), together with 0.05% N-butyl-N-(4- hydroxybutyl)nitrosamine (BBN) and 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), both in the drinking water, for a total multiple initiation period of 4 weeks (DMBDD) treatment). Ellagic acid, quercetin or vanillin, each at a dose of 1% each in the diet were administered from 1 day before and throughout the carcinogen exposure period, or after completion of the initiation regimen. All surviving animals were sacrificed at the end of week 36, and major organs were examined histopathologically. In the small intestine, significant reductions in the incidence and number of tumors (adenomas and carcinomas) were observed in the groups administered ellagic acid during (8%, 0.08 +/- 0.29) or after (8%, 0.08 +/- 0.29) DMBDD treatment, and those receiving quercetin after DMBDD treatment (0%) compared to the control value (57%, 1.07 +/- 1.21). Although the incidences were not statistically significant, slightly decreased numbers of small intestinal tumors were found in the groups receiving vanillin during (0.33 +/- 0.72), or after (0.40 +/- 0.83) DMBDD treatment. The incidence of large intestinal carcinomas in the group treated with vanillin during DMBDD treatment was significantly higher (73%) than the control value (21%). These results indicated that while ellagic acid and quercetin exerted potent chemopreventive action in both the initiation and promotion stages in the present experimental system, their beneficial effects were restricted to the small intestine. Since small intestinal carcinomas are very infrequent in humans, the advantages of these phenolic compounds for human application as chemopreventors should not be overestimated.
Strong anti-mutagenic activity of the novel lipophilic antioxidant 1-O-hexyl-2,3,5-trimethylhydroquinone against heterocyclic amine-induced mutagenesis in the Ames assay and its effect on metabolic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d] imidazole (Glu-p-1).
Antimutagenic effects of a novel lipophilic antioxidant, 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), and other known antioxidants against heterocyclic amine- or other mutagen-induced mutagenesis were examined in the Ames assay using Salmonella strain TA 98 to access the chemo-preventive effects of antioxidants on heterocyclic amine-induced carcinogenesis. Further the mechanisms of inhibition by HTHQ were accessed. HTHQ was shown to potently inhibit mutagenesis induced by all of 8 different heterocyclic amines at rates between 100% and 63% in the presence of S9 mix. When the protection of HTHQ against 2-amino-6- methyldipyrido[1,2-alpha:3',2'-d]imidazole (Glu-P-1)-induced mutagenesis was compared with known antioxidants t-butylhydroquinone, propyl gallate, BHA, BHT and alpha-tocopherol, HTHQ showed the greatest effect. Among hexyl, butyl, ethyl and methyl derivatives of 1-O-alkyl-2,3,5-trimethylhydroquinone, HTHQ was the most effective in inhibiting Glu-P-1-, 3-amino-1-methyl-5-H-pyrido[4,3-b]indole (Trp-P-2)- or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced mutagenesis. On the other hand, HTHQ did not inhibit mutagenic activity induced by other mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) and benzo[a]pyrene. HTHQ weakly inhibited that due to direct mutagen 2-nitro derivative of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) only in the presence of S9 mix. No such influence on a 2-nitro derivative of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mutagenesis, was observed with or without the S9 mix. HTHQ slightly inhibited mutagenesis induced by activated Glu-P-1, a direct acting proximate metabolite of Glu-P-1, in the absence of the S9 mix. HPLC analysis revealed activated Glu-P-1 to be formed by incubating Glu-P-1 with the S9 mix, but this was considerably decreased by the addition of HTHQ. These results indicate that HTHQ is a powerful antimutagenic compound and specifically acts against heterocyclic amines. Its antimutagenic activity appeared to exert by both inhibiting metabolic activation of heterocyclic amines and action on activated N-hydroxy species.
Hepatocyte growth factor enhancement of preneoplastic hepatic foci development in rats treated with diethylnitrosamine and N-ethyl-N-hydroxyethylnitrosamine.
Effects of hepatocyte growth factor were investigated in a two-stage rat liver carcinogenesis protocol. Male F344 rats were first treated with diethylnitrosamine (200 mg/kg, i.p.) and then, starting two weeks later, with N-ethyl-N-hydroxyethylnitrosamine (EHEN) for 6 weeks at a dose of 0.01% in drinking water. Hepatocyte growth factor, which was injected i.v. at a dose of 200 micrograms/kg body weight one (at week 3) or two times (at weeks 3 and 4) during EHEN administration, significantly increased the development of preneoplastic glutathione S-transferase placental form-positive foci. Although the observed effects of hepatocyte growth factor were weaker than that of the two-thirds partial hepatectomy (PH) performed at week 3, the present results suggest that the enhancing effects of PH performed during the promotion stage may be largely mediated through induction of hepatocyte growth factor.
Hyalinizing trabecular adenoma of the thyroid: its unusual cytoplasmic immunopositivity for MIB1.
The monoclonal antibody Ki-67 reacts with a human nuclear cell proliferation-associated antigen that is expressed in all active parts of the cell cycle and is well established as a marker of cell proliferation. However, the Ki-67 method requires fresh frozen material. Recently, MIB1 has been reported to give an immunohistochemical staining pattern identical to Ki-67 on paraffin-embedded tissue sections, frozen sections and cytological samples. This proliferation-associated antigen is apparently localized in the nucleus. Recently, we performed immunohistochemical staining using the monoclonal MIB1 antibody upon a variety of tumors and non-neoplastic conditions of the thyroid. Tumor cells of hyalinizing trabecular adenoma revealed an intense cytoplasmic immunopositivity for MIB1. In contrast, cytoplasmic immunostaining for MIB1 was negative in all other thyroid tumors and non-neoplastic lesions. Because of this unusual staining pattern, we repeated the staining of all cases and found the results to be reproducible. Therefore, we believe that positive cytoplasmic immunostaining for MIB1 is a characteristic finding of hyalinizing trabecular adenoma and is useful in differentiating it from other thyroid tumors.
Intracerebral infiltration by monoclonal plasmacytoid cells in Waldenstrom's macroglobulinemia--case report.
A 68-year-old female presented with Waldenstrom's macroglobulinemia with infiltration into the cerebral parenchyma manifesting as increased confusion, memory loss, and disorientation. She had a past history of Waldenstrom's macroglobulinemia treated 3 years before. Magnetic resonance imaging showed a high intensity area on T2-weighted images in the left frontal lobe extending to the corpus callosum which was well enhanced by gadolinium-diethylenetriaminepenta-acetic acid. Direct infiltration of neoplastic cells was confirmed by biopsy. Immunohistochemical examination showed that mature plasmacytoid cells in the cerebral parenchyma were immunoglobulin M and lambda light chain antigen positive, but immature lymphocytes in Virchow-Robin space were negative. Monoclonal proliferation was confirmed by southern blot analysis. She became symptom free and the size of the lesion was dramatically reduced after 40 Gy irradiation. She showed no evidence of recurrence 3 years after irradiation. As no effective chemotherapy regimen for Bing-Neel syndrome has been established, irradiation is worth considering when neuroimaging suggests intracranial infiltration of neoplastic cells.
Characterization of arachidonate 12-lipoxygenase found in the liver of mongrel dog and its immunohistochemical localization in neutrophils.
The cytosol fraction of non-parenchymal cells isolated from the liver of adult mongrel dogs converted arachidonic acid to 12S-hydroxy-5,8,10,14-eicosatetraenoic acid. The arachidonate 12-lipoxygenase enzyme reacted with linoleic and alpha- and gamma-linolenic acids as well as arachidonic acid. The enzyme was immunoprecipitable with an antibody against the leukocyte 12-lipoxygenase, but not with an antibody against the platelet 12-lipoxygenase. By immunohistochemical observation with anti-leukocyte 12-lipoxygenase antiserum, hepatocytes, Kupffer cells and sinusoidal endothelial cells were not immunostained, but a large number of neutrophils located in sinusoidal cavities were positively stained. The 12-lipoxygenase activity thus detected may be attributed predominantly to the neutrophils appearing in sinusoidal cavities rather than the non-parenchymal cells in the liver of mongrel dog upon infection. In agreement with this finding there was essentially no neutrophil accumulation in the liver of Beagle dog which had no bacterial and parasitic infection.
Phenotypic alteration of hepatocellular foci in rats treated with clofibrate and phenobarbital.
In male F344 rats pretreated with diethylnitrosamine (DEN), subsequent administration of clofibrate increased the proportion of eosinophilic foci, to become the most abundant type, and reduced numbers of basophilic, clear and vacuolated foci, the total not being changed. A similar shift towards eosinophilia was also observed in phenobarbital-treated animals, but in this case clear increases in total number and area were apparent. Expression of the glutathione S-transferase placental form (GST-P) in foci was much lowered by clofibrate treatment, while the proportion of positive foci was very high in both phenobarbital and control groups. A marked contrast was found with eosinophilic foci, with 74% positive after phenobarbital as compared to only 15% for clofibrate. Thus, the decrease in GST-P positive foci by clofibrate was mainly due to increased negativity in the most abundant eosinophilic type foci. In a long-term feeding study without DEN initiation, similar negativity of foci was observed and, furthermore, only minimal effects of clofibrate on foci development was revealed in both young and old animals.
Characterization of plasma and intracellular membrane prolactin receptor in lactating mouse mammary cells.
Mammary cells were prepared from lactating mice by collagenase digestion in order to examine the reaction of prolactin (PRL) with its cellular receptors. Cells were treated with 10% acetic acid following PRL binding. Between 5 and 12.5% acetic acid, the dissociation of PRL remained constant. The ratio of dissociated PRL was comparable to that of tissue slices or disrupted cells with this treatment. In subcellular membranes, about 81% of PRL bound to plasma membrane receptors was dissociated by acid treatment while PRL dissociated from intracellular membrane receptors was about 21%. Based on the nature of their PRL dissociation, PRL receptors were classified as acid-sensitive or acid-insensitive. The reaction of PRL with either species was reversible and saturable, and was dependent on temperature and time. Both species showed high PRL-binding affinity. However, acid-insensitive receptor was unstable at 37 degrees C. The level of acid-sensitive receptor was close to that of acid-insensitive receptor in late pregnancy. During the first 3 days of lactation, the level of acid-sensitive receptor increased more slowly than that corresponding to acid-insensitive receptor. The above criteria suggest that the postpartum increase in PRL binding is characterized especially by an increase in the level of acid-insensitive PRL receptor located mainly on intracellular membrane.
[Effects of magnesium lithospermate B on cyclooxygenase activity in rat liver, adherent cells and enzyme's product].
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Network of cytokine and arachidonic acid cascade in acute hepatic failure.
When heat-killed Propionibacterium acnes (P. acnes) was intravenously injected into mice and 7 days later a small amount of lipopolysaccharide (LPS) endotoxin was administered, most of the mice died of massive liver necrosis. In this liver injury model, cytokines, immunomediators, and eicosanoids, inflammatory products, were produced by Kupffer cells and liver-infiltrated macrophages, which were thought to participate, directly or indirectly, in the induction of liver cell damage. Furthermore, these two networks seemed to regulate each other. Thus, this regulatory mechanism might play an important role in the induction of liver cell injury.
Varicella-zoster virus replication site in internal organs of an otherwise healthy child with varicella and sudden death.
Pathological findings of an otherwise healthy 17 month old boy who was exposed to Varicella-zoster virus (VZV) in his family and unexpectedly died 3 days after onset of varicella are reported. They showed a disseminated VZV infection with involvement of skin, lung, liver, spleen, gastrointestinal tract and other organs where VZV antigen was detected by the enzyme-immunoassay with monoclonal antibodies to VZV. Since the subject was the full-term product of an uncomplicated pregnancy, who grew and developed normally, and had no symptoms or laboratory findings suggestive of immunodeficiency until his death, these findings suggest that many organs are involved as major internal sites of viral replication before or during infection of skin with VZV in the immunocompetent host.
Importance of central nervous system involvement by neoplastic cells in a patient with Waldenström's macroglobulinemia developing neurologic abnormalities.
The clinicopathology of central nervous system (CNS) involvement with tumor formation in the brain of a patient with Waldenström's macroglobulinemia (WM) who developed neurologic abnormalities in the absence of blood hyperviscosity is reported. Extravascular infiltration by monoclonal lymphoplasmacytoid cells with considerable perivascular disruption of the brain and reactive gliosis was a conspicuous histopathologic picture. The tumor as well as the patient's neurologic symptoms were successfully controlled by local radiation to the brain. This case report illustrates the importance of CNS involvement by neoplastic cells in the differential diagnosis of a patient with WM developing neurologic abnormalities.
Phenotypic alteration of glioma cells during culture.
Tissue specimens and culture cells from three human gliomas (two astrocytomas and one glioblastoma) were immunohistochemically investigated, using GFAP, S-100P, vimentin, FN and TNF antibodies. Primary culture consisted of two cell types, flat cells and fibrous cells. Phenotypic alternation was observed during successive subculture. Differences between fibrous cells in astrocytoma and those in glioblastoma were remarkable, while flat cells in astrocytoma and glioblastoma examined in this study, were similar.
[Effects of magnesium lithospermate B on D-galactosamine induced rat liver injury].
To investigate the effective ingredients of Salvia miltiorrhizae on anti-liver injury, the water soluble component of the above drug, magnesium lithosperamate B, was used to conduct the experimental treatment of acute liver injury by D-galactosamine (10 mg/kg body weight, orally). The results showed that the component could obviously attenuate the necrosis of liver tissues, lower the activities of serum alanine amino transferase (ALT) and aspartate amino transferase (AST), P < 0.05. Compared with those of the normal rats, the levels of the products of cyclo-oxygenase (6-keto-prostaglandin F1 alpha, prostaglandin D2 and total prostaglandins) in the metabolism of arachidonic acid in non-parenchymal cells of acute liver-injured rats were markedly decreased (P < 0.05). These data revealed that magnesium lithosperamate B might be one of the main components of Salvia miltiorrhizae in anti-liver injury, while increasing the levels of total prostaglandins in liver non-parenchymal cells was perhaps one of the mechanisms of anti-liver injury.
[A case of prolonged liver injury caused by low dose of acetaminophen--the involvement of other multiple drugs such as Proheparum and Mazulene-S was considered in this drug-induced hepatitis].
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Drug-specific T cells derived from patients with drug-induced allergic hepatitis.
Drug-induced allergic hepatitis is a tissue-specific inflammatory disease caused by hypersensitivity to a particular drug. Although the frequency of drug-induced allergic hepatitis appears to increase in proportion to the medicine, the mechanism by which tissue specificity is determined is still to be elucidated. In this study, we established CD4+ T cell clones specific for particular drugs from patients with drug-induced allergic hepatitis accompanied with mild blood eosinophilia and analyzed the possible role of liver protein as a directing factor of liver-specific inflammatory reactions. All CD4+ T cell clones obtained from two patients with this disease proliferated in response to a combination of the particular drug plus liver specific protein (LSP), which consists of over 30 proteins. Some T cell clones were responsive to an antigenic conformation consisting of the 200-kDa glycoprotein (partly purified LSP), a component of LSP, plus the causal drug. In contrast, all CD4+ T cell clones from a patient with simple drug-induced eosinophilia responded to the causal drug in the absence of LSP and partly purified LSP. These data suggested that LSP or partly purified LSP of the appropriate Ag is the target that leads to liver-specific inflammation in drug-induced allergic hepatitis. Furthermore, T cell lines derived from patients with drug-induced allergic hepatitis and simple drug-induced eosinophilia produced large amounts of IL-5 after the appropriate antigenic stimulation, whereas CD4+ T cell clones from donors with a normal amount of peripheral blood eosinophils secreted a much less IL-5. Taken together, these results indicate that overproduction of IL-5 by the allergen-sensitized T cells may result in blood eosinophilia.
An analysis of proliferating cells in biopsy specimens from patients with small hepatocellular carcinoma.
The proliferation of neoplastic and nonneoplastic hepatocytes is caused by various humoral growth factors with autocrine and paracrine mechanisms, and the proliferative activity of both hepatocytes and nonhepatocytic cells contributes to neoplastic growth. The authors attempted to detect various kinds of proliferating cells immunohistochemically in small hepatocellular carcinoma (HCC) using a monoclonal antibody against DNA polymerase alpha. Most of the HCC cells that stained for this enzyme were small, had basophilic cytoplasm with poorly developed organelles, and aggregated to form clusters distributed randomly within cancer nests. Nonhepatocytic cells also were stained, including some endothelial cells, Kupffer's cells, macrophages, and lymphocytes. Fat-storing cells were not stained. The number of stained sinusoidal (capillary) cells decreased in this order: Kupffer's cells and macrophages, endothelial cells, and fat-storing cells. Nonhepatocytic cells, including lymphocytes, proliferated more actively in areas with actively growing HCC cells than in those with quiescent cancer cells. The relationship between stained HCC cells and stained sinusoidal cells was clearly defined; the correlation coefficient was 0.97. These findings suggest the possibility of a relationship between the proliferative activity of neoplastic hepatocytes and that of sinusoidal cells, including lymphocytes.