Biomedical subjects

H Yoshiji

Publications and source records attributed to H Yoshiji.

At least 55 records · Page 3Linked to original sources

PubMed1997

Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells.

In this study, we used a self-contained tetracycline-regulated retroviral vector system to elucidate the role of vascular endothelial growth factor (VEGF) in controlling s.c. growth of human T-47D breast carcinoma cells. VEGF expression was tightly regulated by this system, both in vitro and in nude mouse xenografts. A 2.4-fold increase in tumor volume was associated with VEGF overexpression. Tumor growth was almost completely inhibited when VEGF was suppressed from the time of T-47D cell inoculation, and a 6-fold reduction in tumor volume was observed when VEGF suppression was started in 175-mm3 tumors. However, no growth inhibition was observed when VEGF suppression was started in 820-mm3 tumors. In these tumors, basic fibroblast growth factor and transforming growth factor alpha RNA expression was detected after VEGF was switched off. These findings demonstrate that VEGF is critical for the initial s.c. growth of T-47D breast carcinoma cells, whereas other angiogenic factors can compensate for the loss of VEGF after the tumors have reached a certain size.

Animals↗

PubMed1997

Inhibition by N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid of exogenous and endogenous development of putative preneoplastic, glutathione S-transferase placental form-positive lesions in the livers of rats.

The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid (tRA) on the exogenous and endogenous models of rat liver carcinogenesis respectively using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the exogenous study, male Fischer 344 rats, 6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at week 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and killed at the end of week 8. For the endogenous study, rats were fed the CDAA diet containing 4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR decreased the numbers and sizes of the glutathione S-transferase placental form-positive foci, assayed as putative preneoplastic lesions, the levels of 8-hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the DEN-initiated case and, more prominently, in the CDAA diet-associated case. In contrast, while tRA failed to exert inhibitory effects apparently on foci development, 8-OHG formation or BrdU labeling in the DEN-initiated case, it reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by all three doses in the CDAA diet-associated case. Furthermore, both 4-HPR and tRA inhibited the CDAA diet-associated induction of hepatocyte necrosis and connective tissue increase but not intrahepatocellular fat accumulation. These results indicate that 4-HPR exerts chemopreventive effects against the exogenous and endogenous rat liver carcinogenesis, while tRA can inhibit only the latter.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1997

Tissue inhibitors of metalloproteinases: structure, regulation and biological functions.

Four members of the tissue inhibitor of metalloproteinases (TIMP) family have been characterized so far, designated as TIMP-1, TIMP-2, TIMP-3, and TIMP-4. TIMP-1 and TIMP-2 are capable of inhibiting the activities of all known matrix metalloproteinases (MMPs) and as such play a key role in maintaining the balance between extracellular matrix (ECM) deposition and degradation in different physiological processes. Accelerated breakdown of ECM occurs in various pathological processes, including inflammation, chronic degenerative diseases and tumor invasion. TIMP-1 and TIMP-2 can inhibit tumor growth, invasion, and metastasis in experimental models which has been associated with their MMP inhibitory activity. Recent developments in TIMP research suggest that TIMP-1 and TIMP-2 are multifunctional proteins with diverse actions. Both inhibitors exhibit growth factor-like activity and can inhibit angiogenesis. Structure-function studies have separated the MMP inhibitory activity of TIMP-1 from its growth promoting effect. TIMP-1 has also been implicated in gonadal steroidogenesis and as a cellular elongation factor. TIMP-3 is the only member of the TIMP family which is found exclusively in the extracellular matrix (ECM). It is regulated in a cell cycle-dependent fashion in certain cell types and may serve as a marker for terminal differentiation. The most recently discovered TIMP, TIMP-4, may function in a tissue-specific fashion in extracellular matrix hemostasis. The main aim of this article is to review recent literature on TIMPs with special emphasis on their biological activities and the possibility that they may have paradoxical roles in tumor progression.

Amino Acid Sequence↗

PubMed1996

Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer.

Angiogenesis is essential for the growth and metastasis of solid tumors. In this study, we examined gene expression of vascular endothelial growth factor (VEGF); its receptor, flt-1; basic fibroblast growth factor; and transforming growth factors (TGFs) alpha and beta in 18 paired cases of human breast carcinomas and the adjacent nonneoplastic tissues. In all of the paired cases, VEGF expression was markedly increased in the carcinomas. In contrast, an insignificant difference was observed in the expression of flt-1, basic fibroblast growth factor, TGF-alpha, and TGF-beta between the malignant breast tissue and the nonneoplastic counterpart. Immunostaining showed variable VEGF positivity of the malignant cells, whereas the nonneoplastic breast epithelial cells were negative. The findings of this study suggest that VEGF is an important angiogenic factor in human breast cancer.

Angiogenesis Inducing Agents↗

PubMed1996

Enhanced RNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human breast cancer.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is known to have at least 2 distinct types of activity, i.e., as a regulator of collagenolytic activity, and erythroid potentiating activity (EPA). In this study, we examined the expression of TIMP-1 in human mammary carcinomas, non-malignant breast tissues and benign breast tumors. A total of 53 samples were subjected to Northern-blot analysis, including 23 of primary breast cancer, 26 of non-malignant breast tissues, and 4 benign tumors. Of the 53 samples, 10 were paired malignant and non-malignant breast-tissue samples from the same patient. TIMP-1 RNA expression was significantly higher in the malignant tumor tissues than in the non-malignant counterpart. Similar differences were observed in the level of TIMP-1 protein expression in the paired breast samples examined. Moreover, breast-cancer cell lines secreted larger amounts of TIMP-1 in vitro than non-neoplastic breast epithelial lines. The up-regulation of TIMP-1 expression in breast cancer may suggest that TIMP-1 has an additional role to that of metalloproteinase inhibitor.

Adult↗

PubMed1995

Ulex europaeus I lectin induces activation of matrix-metalloproteinase-2 in endothelial cells.

In this report, we show that the lectin Ulex europaeus agglutinin I (UEA I), which binds to alpha-linked fucose residues on the surface of endothelial cells, mediates activation of the 72-kDa matrix metalloproteinase-2 (MMP-2). A dose-dependent increase in the active 62-kDa form of MMP-2 was observed in conditioned medium from monkey aortic endothelial cells (MAEC) following incubation with concentrations of UEA I ranging from 2 to 100 micrograms/ml. The increase in the 62-kDa MMP-2 gelatinolytic activity was not reflected by a rise in MMP-2 gene expression. The UEA I-mediated activation of MMP-2 was blocked by L-fucose, which competes with UEA I for binding to alpha-fucose. These findings may suggest that a similar in vivo mechanism exists, whereby adhesive interactions between tumor cell lectins and endothelial cells can mediate MMP-2 activation.

Animals↗

PubMed1995

Interferon treatment of chronic hepatitis C in patients with hemophilia or von Willebrand's disease in Japan.

Seven patients with chronic hepatitis C, six hemophiliacs and a patient with von Willebrand's disease, were treated with interferon-alpha (IFN-alpha). Either 9 MU of recombinant IFN-alpha 2a or 3 MU of lymphoblastoid alpha-IFN was administered daily for 2 weeks and then three times a week for 22 weeks. Liver histology, hepatitis C virus (HCV) genotypes, and HCV-RNA levels in sera were investigated in all of the patients before IFN therapy was instituted. Liver histology was classified by the European classification. HCV genotyping conformed to the so-called Okamoto's classification. HCV-RNA levels in sera were quantitated by competitive polymerase chain reaction, using mutant RNA. Liver histology, HCV genotype, and serum HCV-RNA level (copies/ml) in each patient were: patient 1, chronic persistent hepatitis, type II, 3 x 10(3) respectively; patient 2, chronic active hepatitis (CAH) 2a, type III, 6 x 10(4); patient 3, CAH2a, type IV, 2 x 10(5); patient 4, CAH2b, type I, 2 x 10(7); patient 5, CAH2b, type II, 8 x 10(4); patient 6, CAH2b, type III, 7 x 10(6); and patient 7, CAH2b, type IV, 1 x 10(7). Sustained elimination of HCV was achieved in patient 3 and temporary elimination was achieved in patients 1 and 2. The other patients showed persistent HCV-RNA positivity in sera both during and after IFN treatment. Poor responsiveness to IFN was observed in patients with relatively progressive liver histology and high levels of HCV viremia.

Adult↗

PubMed1995

A case of early gastric malignant lymphoma diagnosed and completely resected by strip biopsy.

A case of early gastric malignant lymphoma definitively diagnosed by strip biopsy is reported. The subsequent operation revealed that the strip biopsy had resulted in radical resection. A 55-year-old woman visited our hospital for detailed examination of a small gastric lesion. Histologic findings of the specimens obtained by conventional forceps biopsy indicated reactive lymphoid hyperplasia, although the possibility of malignant lymphoma was not completely ruled out. Strip biopsy was, therefore, performed to establish a definitive diagnosis. Histopathological examinations of the strip biopsy specimen revealed definitive findings of malignant lymphoma, which was B-cell phenotype immunocytochemically. The margin of the resected specimen was free of invasion by malignant lymphoma and no lymph node involvement was suggested by endoscopic ultrasonography, computed tomography, and gallium scintigram. Subtotal gastrectomy was subsequently performed to rule out the possibility of remaining malignant lymphoma cells. It was proven that the strip biopsy removed the lesion completely and no perigastric lymph nodes were involved. While is still controversial as to whether strip biopsy should be adopted for the radical resection of early gastric lymphoma, this procedure can definitely provide excellent specimens for the accurate diagnosis of gastric malignant lymphoma and probably for group III lesions in the stomach.

Biopsy↗

PubMed1994

Spontaneous passage of a colon cast in the absence of abdominal aneurysm.

The spontaneous passage of colon cast from a 76-year-old Japanese female patient is reported. Macroscopically, the colon case was shaped like the airbladder of a fish. Histopathologically, the cast consisted of degenerated colonal mucosa, including glands. No inflammatory reaction was apparent. The patient lacked any evidence of abdominal aneurysm. Since there have been only five reported cases of colon cast in the literature, and since in all of those association with abdominal aneurysms was always described, the present study represents the first report demonstrating the formation of a colon cast in the absence of associated abdominal aneurysm. However, the patient was found to exhibit several risk factors for ischemic colitis, such as arteriosclerosis on the wall of the abdominal aorta, chronic constipation, and colonic stenosis. Her colonal mucosal surface, indeed, suggested ischemic colitis. This case report, therefore, indicates that ischemic colitis, due to various causes, may be responsible for the formation of colon casts, and that the presence of an abdominal aneurysm is not necessarily a prerequisite for colon cast formation. This report may contribute to a better understanding of the pathogenesis of colon casts.

Aged↗

PubMed1994

Inhibitory effects of 2-O-octadecylascorbic acid and other vitamin C and E derivatives on the induction of enzyme-altered putative preneoplastic lesions in the livers of rats fed a choline-deficient, L-amino acid-defined diet.

Effects of a lipophilic derivative of vitamin C, 2-O-octadecylascorbic acid (CV-3611), as well as its parent L-ascorbic acid (AscA), DL-alpha-tocopherol (alpha-T) and its hydrophilic derivative, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), on the number and size of gamma-glutamyltransferase (GGT)-positive putative preneoplastic lesions were examined and compared with their influences on 8-hydroxyguanine formation in DNA and 2-thiobarbituric acid-reacting substance generation in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet for 12 weeks. A total of 90 male Fischer 344 rats, 6 weeks old, were divided into 18 groups each consisting of five rats. Group 1 received the CDAA diet alone; Groups 2, 3 and 4 received the CDAA diet containing respectively 0.01, 0.05 and 0.10% CV-3611; Groups 5-7, 8-10 and 11-13 similarly received the CDAA diet containing AscA, alpha-T and Trolox, respectively, at these same low, middle and high concentrations; Group 14 received a choline-supplemented, L-amino acid-defined (CSAA) diet alone; Groups 15-18 were given the CSAA diet containing CV-3611, AscA, alpha-T and Trolox, respectively, all at the 0.10% level. While all four vitamin derivatives exerted inhibitory effects on all four parameters, in each case dose-dependently, CV-3611 demonstrated the most pronounced effects. The present results indicated that lipophilic vitamin C derivatives may be particularly effective chemopreventive agents against CDAA diet-associated, oxidative stress-related hepatocarcinogenesis via its superior antioxidative properties.

Amino Acids↗

PubMed1994

Different roles of 8-hydroxyguanine formation and 2-thiobarbituric acid-reacting substance generation in the early phase of liver carcinogenesis induced by a choline-deficient, L-amino acid-defined diet in rats.

The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline-deficient, L-amino acid-defined (CDAA) diet by examining the effects of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8-hydroxy-guanine (8-OHGua) for DNA and that of 2-thiobarbituric acid-reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S-transferase (EC 2.5.1.18) placental form (GSTP)- and/or gamma-glutamyltransferase (GGT, EC 2.3.2.2)-positive lesions and levels of 8-OHGua and TBARS were determined. The GSTP-positive lesions of 0.08 mm2 or larger were all stained positively for GGT as well in cross-sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP-positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8-OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8-OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.

Animals↗

PubMed1993

Autoimmunity during alpha-interferon therapy for chronic hepatitis C.

One hundred twenty-five patients with chronic hepatitis C were treated with natural IFN alpha or recombinant IFN alpha-2a, daily doses of 3 MU or 9 MU, respectively. IFNs were given 6 times a week for the first 2 weeks followed by thrice weekly administration for 12 weeks or more. ANA, TMA, AMA and anti-DNA antibody newly developed in 8, 1, 2 and 1 patient, respectively. Furthermore, we encountered some cases in which underlying autoimmune disorders were thought to be exacerbated by IFNs. It is important to pay sufficient attention to the development of autoimmune diseases in IFN therapy for chronic hepatitis C.

Adult↗

PubMed1992

High incidence of hepatocellular carcinomas induced by a choline deficient L-amino acid defined diet in rats.

The carcinogenicities of a choline deficient L-amino acid defined (CDAA) diet and a semipurified choline deficient diet were comparatively examined. A total of 60 male Fischer 344 rats, 6 weeks old, were divided into 5 experimental groups each consisting of 12 rats. Group 1 received the CDAA diet chronically to the end of the 52-week experiment while Group 2 was given the same diet for the first 24 weeks and then a basal diet for the following 28 weeks. Groups 3, 4, and 5 received a choline supplemented L-amino acid defined diet, the semipurified choline deficient diet, and a semipurified choline supplemented diet, respectively, throughout the experimental period. All surviving rats were subjected to complete macroscopic examination at Week 52. Histopathologically diagnosed hepatocellular carcinomas were induced in Group 1 at an incidence of 100%; multiple metastatic nodules were seen in the lungs of one of the animals. Hepatocellular carcinomas were also induced in Group 4 rats at a significantly lower incidence of 20%. No hepatocellular carcinomas were observed in rats in Groups 2, 3, and 4. The results indicate that the CDAA diet exerts more potent carcinogenicity for the livers of rats than does the semipurified choline deficient diet. However, limited exposure for 24 weeks may have not been sufficient for hepatocellular carcinoma induction by the CDAA diet at Week 52 although a high incidence of hyperplastic nodules and slight cirrhosis were evidence of persistent lesions.

Amino Acids↗

PubMed1992

Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet.

Effects of dietary iron deficiency on inductions of putative preneoplastic lesions and oxidative alterations in the livers of rats by a choline-deficient L-amino acid defined (CDAA) diet were examined. Male Fischer 344 rats, 4 weeks old, were used with a total experimental period of 16 weeks, consisting of 4-week pretreatment and 12-week treatment periods (periods A and B respectively). During period A, a choline-supplemented L-amino acid defined (CSAA) or an iron-deficient CSAA diet was administered, and the CDAA or an iron-deficient CDAA diet was fed in period B. Formation of 8-hydroxydeoxyguanosine (8OHdG), a DNA adduct generated by activated oxygen species, in DNA and lipid peroxidation in liver cell membranes were sequentially determined after the beginning of period B. At the end of the experiment, development of gamma-glutamyltransferase (GGT) and glutathione S-transferase placental form (GSTP) positive liver lesions were quantitatively analysed. In the animals fed the CDAA diet, formation of 8OHdG and lipid peroxidation increased with time, and GGT and GSTP positive liver lesions developed. Formation of 8OHdG, lipid peroxidation and the numbers of induced enzyme-altered liver lesions were all reduced in rats fed the iron-deficient CSAA diet in period A and/or the iron-deficient CDAA diet in period B. The present results indicate that iron plays an important role in induction of preneoplastic liver lesions in rats caused by exposure to the CDAA diet possibly in connection with its known catalytic role in generation of highly reactive activated oxygen species.

Amino Acids↗

PubMed1992

Possible enhancing effect of the immunosuppressive agent, 6-mercaptopurine(6-MP) on focal lesion development in cirrhotic liver induced by carbon tetrachloride but not furfural in F344 rats.

The modifying effects of an immunosuppressive agent, 6-mercaptopurine (6-MP), on development of focal lesions in liver cirrhosis models induced by carbon tetrachloride (CCl4) or furfural were studied in male F344 rats. Feeding of 6-MP at 50 p.p.m. for 20 weeks to animals with pre-existing liver cirrhosis caused immunosuppression, and significantly enhanced the induction of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the CCl4 but not furfural case. Glutathione S-transferase P (GST-P)-positive preneoplastic lesions were not affected. Moreover, phenobarbital (PB) also enhanced the induction of GGT-positive hepatocellular lesions only in the CCl4-induced liver cirrhosis model, no promotion influence being exerted after treatment with the non-carcinogenic furfural. This study, therefore, suggests that 6-MP can enhance the induction of one type of preneoplastic foci and nodules and that essential differences exist between focal lesions arising in cirrhotic livers caused by CCl4 as opposed to furfural.

Alkaline Phosphatase↗

PubMed1991

Inhibitory effect of dietary iron deficiency on the induction of putative preneoplastic foci in rat liver initiated with diethylnitrosamine and promoted by phenobarbital.

The effects of dietary iron deficiency on induction of putative preneoplastic, gamma-glutamyltransferase (GGT)-positive hepatocyte focal lesions in the liver of rats treated with diethylnitrosamine (DEN) followed by phenobarbital (PB) were investigated. Male Fischer 344 rats of 4 weeks old were placed on an iron deficient (ID) diet containing less than 5 p.p.m. of iron or an iron supplemented (IS) diet containing 180 p.p.m. of iron throughout experimental period of 12 weeks. Both groups of rats were administered 200 mg kg-1 body weight of DEN by a single intraperitoneal injection at Week 4 followed by PB mixed into each diet at a concentration of 0.05% from Week 6 to the final sacrifice at Week 12 when induction of GGT-positive foci was quantitatively analysed. On the ID and IS diets, respective numbers of GGT-positive foci were 6.3 and 14.2 cm-2. The sizes of foci were not altered by the iron content of the diet. The present results indicate that iron plays a role in the development of preneoplastic foci in the livers of rats initiated with DEN and promoted by PB especially in the initiation phase.

Anemia, Hypochromic↗

PubMed1990

Endocytosis-independent uptake of liposome-encapsulated superoxide dismutase prevents the killing of cultured hepatocytes by tert-butyl hydroperoxide.

Liposome-encapsulated (LSOD) or free (FSOD), human recombinant Cu-Zn superoxide dismutase prevented the killing of cultured rat hepatocytes by tert-butyl hydroperoxide (TBHP). A dose of 32 U/ml of LSOD reduced the cell killing by 50%. By contrast, it required 288 U/ml of FSOD to similarly reduce the toxicity of TBHP by 50%. Both LSOD and FSOD increased the cell-associated superoxide dismutase activity of the cultured hepatocytes. Whereas 64 U/ml of LSOD increased cell-associated superoxide dismutase activity fourfold, it required 500 U/ml of FSOD to achieve a similar increase. Furthermore, methylamine, benzyl alcohol, cytochalasin B, oligomycin, and monensin, all inhibitors of endocytosis, prevented the increase in cell-associated superoxide dismutase produced by 500 U/ml of FSOD. These same inhibitors had no effect on the increase in cell-associated superoxide dismutase activity produced by a much lower concentration of LSOD. Thus, liposome-encapsulated superoxide dismutase prevented the cell killing by TBHP more efficiently than free superoxide dismutase because it more efficiently entered the hepatocytes by a mechanism that was independent of the endocytosis responsible for the uptake of FSOD. These data further define the conditions of the toxicity of TBHP. The target hepatocyte must contribute superoxide anions, in addition to the previously shown ferric iron. It is hypothesized that superoxide anions reduce ferric to ferrous iron; the latter then reacts with the hydroperoxide to form tert-butyl alkoxyl radicals. Such radicals are potent oxidizing agents that can initiate the peroxidation of cellular lipids previously shown to lethally injure the hepatocytes.

Animals↗

PubMed1990

Production of both 8-hydroxydeoxyguanosine in liver DNA and gamma-glutamyltransferase-positive hepatocellular lesions in rats given a choline-deficient, L-amino acid-defined diet.

The comparative carcinogenic activities of a choline-deficient, L-amino acid-defined diet (CDAADD) and a purified choline-deficient diet (CDD) for rat liver were studied in terms of both 8-hydroxydeoxyguanosine induction, a marker of DNA damage induced by oxidative stress, and development of gamma-glutamyltransferase (GGT)-positive putative preneoplastic lesions, including foci and hyperplastic nodules. Twelve weeks after the beginning of treatment, DNA damage could be detected in the liver DNA of rats receiving either CDAADD or CDD, the degree being significantly greater in the former case. Similarly, while GGT-positive liver lesions were induced by both CDAADD and CDD, the numbers were higher and the areas of lesions were larger in rats receiving CDAADD than in those given CDD. Histologically, hyperplastic nodules were induced in the livers of animals administered CDAADD whereas only foci were seen in the CDD case. The results thus indicate that oxidative stress might be directly involved in rat liver carcinogenesis by CDD and, to a greater degree, with CDAADD.

8-Hydroxy-2'-Deoxyguanosine↗