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Biomedical subjects

Toshikazu Yoshikawa

Publications and source records attributed to Toshikazu Yoshikawa.

At least 19 recordsLinked to original sources
PubMed2003

Cancer chemopreventive effects of oral feeding alpha-tocopherol on ultraviolet light B induced photocarcinogenesis of hairless mouse.

Ultraviolet light is the most common cause of skin cancers in humans and several effects of ultraviolet light B (UVB: 290-320 nm) are thought to contribute to skin photocarcinogenesis. The generation of free radicals and related oxidants produced by UVB exposure, result in photocarcinogenesis by directly damaging DNA. On the other side, activating of transcription factor, activator protein 1 (AP-1) induced by UVB exposure causes tumor promotion. alpha-tocopherol has two principal physiological activities and one is an antioxidant activity through which alpha-tocopherol protects unsaturated fatty acids, protein and DNA from oxidation. The other activity is to stabilize the structure of the biomembrane. In addition to these two activities, it has been recently established that alpha-tocopherol plays important roles in cell signal transduction. In course of these studies, we examined such effects of alpha-tocopherol on UVB induced skin photocarcinogenesis in hairless mice. These results indicate that oral feeding of alpha-tocopherol including diet exhibited a marked inhibitory effects on both tumor incidence and multiplicity in UVB induced mouse skin photocarcinogenesis.

Administration, Oral↗
PubMed2003

The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.

Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CML), but remissions induced in advanced-phase CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Blocking of NF-kappaB activation enhances the tumor necrosis factor alpha-induced apoptosis of a human gastric cancer cell line.

The transcription factor NF-kappaB is constitutively activated in many human cancers and induces the expression of multiple genes, including those of anti-apoptotic proteins. This study investigated the mechanism by which human gastric cancer cells (MKN45) are resistant to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). Confluent monolayers of MKN45 cells were either pretreated or not for 60 min with PSI, a peptide aldehyde known to specifically inhibit the chymotrypsin-like activity of 26S proteasome. Cells were subsequently stimulated with recombinant human TNF-alpha, and cell viabilities were determined by the WST-1 assay. Apoptosis was confirmed by fluorescence microscopy after staining with Hoechst 33342, and DNA fragmentation was determined by a DNA fragmentation detection kit. A 24-h incubation with either TNF-alpha or PSI alone did not affect cell viabilities; however, pretreatment with PSI significantly enhanced the level of apoptosis induced by TNF-alpha. Therefore, this study suggests the possibility that blocking of NF-kappaB activity renders gastric cancer cells susceptible to the apoptosis induced by TNF-alpha.

Apoptosis↗
PubMed2003

Rosmarinic acid inhibits lung injury induced by diesel exhaust particles.

Epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) may be involved in recent increases in lung diseases. DEP has been shown to generate reactive oxygen species. Intratracheal instillation of DEP induces lung inflammation and edema in mice. Rosmarinic acid is a naturally occurring polyphenol with antioxidative and anti-inflammatory activities. We investigated the effects of rosmarinic acid on lung injury induced by intratracheal administration of DEP (500 microg/body) in mice. Oral supplementation with administration of rosmarinic acid (2 mg/body for 3 d) inhibited DEP-induced lung injury, which was characterized by neutrophil sequestration and interstitial edema. DEP enhanced the lung expression of keratinocyte chemoattractant (KC), interleukin-1beta, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha, which was inhibited by treatment with rosmarinic acid. DEP enhanced expression of iNOS mRNA and formation of nitrotyrosine and 8-OHdG in the lung, which was also inhibited by rosmarinic acid. These results suggest that rosmarinic acid inhibits DEP-induced lung injury by the reduction of proinflammatory molecule expression. Antioxidative activities of rosmarinic acid may also contribute to its protective effects.

Administration, Oral↗
PubMed2003

Tumor initiating activity of Helicobacter pylori water extract on mouse skin carcinogenesis.

Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis, but responsible and detail mechanisms are insufficient by the absence of adequate data. To obtain direct evidence regarding the carcinogenicity of H. pylori, we investigated the initiating and promoting activity of H. pylori water extract (HPE) in two-stage mouse skin carcinogenesis model. HPE treatment, as an initiation, significantly enhanced tumor formation compared with control group. Moreover, HPE treatment increased production of 8-hydroxydeoxyguanosine in epidermal cells and HPE-initiated/TPA-promoted papillomas demonstrated a point mutation of the Ha-ras gene. These results suggest an initiating activity of HPE on two-stage mouse skin carcinogenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Late preconditioning by ethanol is initiated via an oxidant-dependent signaling pathway.

Ingestion of alcoholic beverages at low to moderate levels 24 h prior to ischemia and reperfusion (I/R) prevents postischemic leukocyte/endothelial cell adhesive interactions, a phenomenon referred to as late ethanol preconditioning (EtOH-PC). The aim of this study was to determine whether oxidants act as initiators of late EtOH-PC. Ethanol was instilled into the stomachs of C57BL/6 mice as a bolus by gavage at a dose that produced a peak plasma concentration of 45 mg/dl 30 min after administration and returned to control levels 60 min after ingestion. Twenty four hours later, the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion. The numbers of rolling and firmly adherent leukocytes were quantified in postcapillary venules of the small intestine in sham animals (no EtOH-PC, no I/R), in mice subjected to I/R alone or EtOH-PC + I/R, and in animals treated with Mn-TBAP (a cell-permeant superoxide dismutase mimetic), oxypurinol (a XO inhibitor), the NAD(P)H oxidase inhibitors PR-39 or apocynin, or oxypurinol plus PR39 during the period of EtOH-PC on Day 1 followed by I/R on Day 2. In separate groups of mice, oxypurinol or apocynin were also administered 1 h after ethanol ingestion on Day 1, with induction of I/R 24 h later. I/R induced marked increases in leukocyte rolling and adherence, effects that were completely prevented by EtOH-PC. Coincident treatment with Mn-TBAP, oxypurinol, PR-39, apocynin, or oxypurinol plus PR-39 with ethanol attenuated these anti-inflammatory actions of EtOH-PC. However, administration of oxypurinol or apocynin 1 h after ethanol ingestion failed to prevent these protective effects of EtOH-PC. Our results indicate that reactive oxygen species formed during the period of ethanol exposure on Day 1 trigger the development of an anti-inflammatory phenotype that renders the small bowel resistant to the proadhesive effects of I/R 24 h later.

Animals↗
PubMed2003

Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma.

We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3(+)CD4(-)CD8(+) T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.

Adult↗
PubMed2003

Augmentation of central arterial pressure as a marker of atherosclerosis in patients with type 2 diabetes.

Macrovascular disease is the most common cause of morbidity and mortality in diabetic patients. With the increasing numbers of patients with type 2 diabetes, a simple, noninvasive method is needed to detect atherosclerosis. Augmentation represents the difference between the second and first peaks of the central arterial pressure waveform in systole and is a measure of systemic arterial stiffness, which causes the pressure wave to rebound. We investigated whether augmentation could serve as a marker of atherosclerosis in patients with type 2 diabetes. Central arterial pressure and degree of its augmentation by pulse wave rebound were measured sphygmographically in 208 consecutive patients with type 2 diabetes and 117 healthy control subjects. The relationship between augmentation and carotid atherosclerosis detected by carotid ultrasonography was investigated in a subgroup of 81 diabetic patients. Augmentation was greater in diabetic patients than control subjects (13.2+/-6.9 vs. 9.4+/-5.7 mm Hg, P<0.0001). The positive correlation between augmentation and intima-media thickness (r=0.309, P=0.0051) and between augmentation and plaque score (r=0.304, P=0.0059) were found in patients with type 2 diabetes. Augmentation was greater in diabetic patients with cardiovascular disease (n=47) than without (n=161; 15.1+/-8.4 vs. 12.6+/-6.3 mm Hg, P=0.031). Augmentation of central arterial pressure is a reliable marker for atherosclerosis in patients with type 2 diabetes. This simple, noninvasive determination would permit large-scale, early screening for atherosclerosis in patients with type 2 diabetes, who are at increased risk for cardiovascular disease.

Aged↗
PubMed2003

Increased concentration of pentosidine, an advanced glycation end product, and interleukin-6 in the vitreous of patients with proliferative diabetic retinopathy.

To investigate the relationship between advanced glycation end products (AGEs) and interleukin-6 (IL-6) in the development of diabetic retinopathy, we determined the concentrations of pentosidine, a well-characterized AGE, and IL-6 in the vitreous of 62 patients with proliferative diabetic retinopathy (PDR) and 50 non-diabetic control subjects. We also investigated the effect of AGEs on the production of IL-6 by human retinal Müller cells. The levels of pentosidine and IL-6 in the vitreous of patients with PDR were significantly higher compared with controls. In patients with PDR with vitreous hemorrhage (VH), the mean vitreous concentration of IL-6 was significantly higher than that in PDR patients without VH. There was a strong positive correlation between the vitreous levels of pentosidine and IL-6. Levels of IL-6 were strikingly higher in the vitreous compared with the serum and there was no correlation between IL-6 concentrations in the two fluids. Treatment of Müller cells with AGEs for 48 h resulted in a dose-dependent increase of IL-6 in the culture medium. These results suggest that increased formation of AGEs in the vitreous may be involved in the development of diabetic retinopathy by inducing the production of IL-6 from retinal Müller cells.

Adult↗
PubMed2003

A novel vitamin E derivative (TMG) protects against gastric mucosal damage induced by ischemia and reperfusion in rats.

The aim of the present study was to investigate the antioxidative effects of water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), on ischemia-reperfusion (I/R) -induced gastric mucosal injury in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery and reoxygenation was produced by removal of the clamp. The area of gastric mucosal erosion, the concentration of thiobarbituric acid-reactive substances, and the myeloperoxidase activity in gastric mucosa significantly increased in I/R groups compared with those of sham-operated groups. These increases were significantly inhibited by pretreatment with TMG. The contents of both mucosal TNF-alpha and CINC-2beta in I/R groups were also increased compared with the levels of those in sham-operated groups. These increases of the inflammatory cytokines were significantly inhibited by the treatment with TMG. It is concluded that TMG inhibited lipid peroxidation and reduced development of the gastric mucosal inflammation induced by I/R in rats.

Animals↗
PubMed2003

Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice.

It has recently been reported that not only endogenous nitric oxide (NO) but also carbon monoxide (CO) produced by heme oxygenase (HO) have many physiological functions. The objective of the present study was to determine whether endogenous NO or CO is involved in the experimental pulmonary or liver metastasis of colon cancer in mice. Intravenous or intrasplenic injection of colon 26 cells from a mouse colon adenocarcinoma cell line resulted in multiple pulmonary or liver metastases. NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase (NOS), or zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG), a competitive inhibitor of HO, was administered to the mice only on the day of tumor inoculation. We assessed the number of tumor cells 24 h later and the outcome of metastases of the target organ. In the pulmonary metastasis model, L-NAME increased both the number of tumor cells 24 h later and outcome of metastases 18 days later, but did not have a significant effect on liver metastasis. On the other hand, metastasis to the liver, but not that to the lung, increased following administration of ZnDPBG. These results suggest that the activities of NOS and HO could influence experimental metastasis in an organ-specific manner.

Animals↗
PubMed2003

Different remodelling against left ventricular overload between diabetic and non-diabetic haemodialysis patients.

1. Diabetes mellitus is significantly associated with the occurrence of congestive heart failure in end-stage renal disease patients undergoing maintenance haemodialysis. In the present study, we asked whether the left ventricular remodelling against sustained pressure and/or volume overload to the left ventricle may be different between diabetic and non-diabetic haemodialysis patients. 2. Left ventricular parameters, including left ventricular mass index (LVMI), interventricular septal wall thickness (IVST) and relative left ventricular wall thickness (rLVWT), were assessed in 486 patients receiving maintenance haemodialysis (145 diabetic and 341 non-diabetic patients) using transthoracic echocardiography. Plasma concentrations of B-type natriuretic peptide (BNP), measured with an immunoradiometric assay, were used as a humoral parameter indicating left ventricular wall stress. 3. In non-diabetic patients, the plasma BNP concentration correlated with LVMI (r = 0.245; P = 0.0001), IVST (r = 0.250; P = 0.0001) and rLVWT (r = 0.149; P = 0.006). Furthermore, LVMI was correlated with mean blood pressure and pulse pressure and IVST and rLVWT were correlated with pulse pressure. 4. In contrast, none of the measured factors was correlated with LVMI and IVST in diabetic patients. Plasma BNP concentrations were positively correlated with end-systolic and end-diastolic left intraventricular dimensions and were inversely correlated with rLVWT and left ventricular fractional shortening in diabetic patients, but not in non-diabetic patients. 5. In conclusion, a sustained increase in left ventricular wall stress is likely to elicit eccentric left ventricular remodelling in diabetic haemodialysis patients, whereas it causes concentric left ventricular remodelling in non-diabetic haemodialysis patients. This difference in left ventricular remodelling against left ventricular overload may be associated with the high incidence of congestive heart failure in diabetic haemodialysis patients.

Aged↗
PubMed2003

Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice.

BACKGROUND AND AIMS: Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of inflammatory bowel disease. To further define the role of TNF-alpha in intestinal inflammation, we studied the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of TNF-alpha gene. METHODS: Acute colitis was induced in female TNF-alpha-/- and TNF-alpha+/+ mice by administering 4.5% DSS orally in drinking water for seven days. The colonic mucosal injury and inflammation was evaluated based on body weight changes, total colon length, luminal hemoglobin, and histological findings. Colonic mRNA expression for inducible nitric oxide synthase (iNOS), TNF-alpha, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by reverse transcription polymerase chain reaction (RT-PCR), and nuclear factor kappaB (NF-kappaB) activation was evaluated by electrophoretic mobility shift assay. RESULTS: In each assessment, colonic injury was significantly aggravated in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. The survival rate of TNF-alpha-/- mice on day seven was 40%; in contrast, all TNF-alpha+/+ mice were alive. Histological study also showed an enhanced infiltration of inflammatory cells, especially neutrophils, and mucosal cell disruption in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. On day seven, mRNA levels of IFN-gamma and IL-4 in the colons of TNF-alpha-/- mice were faint or not detected; in contrast, those of TNF-alpha+/+ mice were detected. Although the expression of iNOS mRNA and luminal nitrite levels were similarly increased in both mice on day seven, this induction was delayed in TNF-alpha-/- mice during the early phase. The degree of NF-kappaB binding activity seemed to be similar between the two types of mice on day seven. CONCLUSION: DSS-induced inflammation is significantly enhanced in TNF-alpha-/- mice compared to TNF-alpha+/+ mice. These data suggest that persistent and marked blockage of TNF-alpha bioactivity may provide a detrimental effect on acute intestinal inflammation.

Acute Disease↗
PubMed2003

A case of lupus peritonitis and cystitis after ovulation induction therapy.

We report a patient in whom lupus peritonitis and cystitis developed after ovulation induction therapy with human menopausal and chorionic gonadotropins followed by in vitro fertilization and embryo transfer. The lupus peritonitis and cystitis presented clinically as an acute abdomen. This disease should not be misdiagnosed as a nonspecific or infectious pelvic peritonitis, especially after oocyte retrieval.

Adult↗
PubMed2003

Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice.

Dietary antioxidants may attenuate oxidative damage from strenuous exercise in various tissues. Beneficial effects of the antioxidant astaxanthin have been demonstrated in vitro, but not yet in vivo. We investigated the effect of dietary supplementation with astaxanthin on oxidative damage induced by strenuous exercise in mouse gastrocnemius and heart. C57BL/6 mice (7 weeks old) were divided into groups: rested control, intense exercise, and exercise with astaxanthin supplementation. After 3 weeks of exercise acclimation, both exercise groups ran on a treadmill at 28 m/min until exhaustion. Exercise-increased 4-hydroxy-2-nonenal-modified protein and 8-hydroxy-2'-deoxyguanosine in gastrocnemius and heart were blunted in the astaxanthin group. Increases in plasma creatine kinase activity, and in myeloperoxidase activity in gastrocnemius and heart, also were lessened by astaxanthin. Astaxanthin showed accumulation in gastrocnemius and heart from the 3 week supplementation. Astaxanthin can attenuate exercise-induced damage in mouse skeletal muscle and heart, including an associated neutrophil infiltration that induces further damage.

8-Hydroxy-2'-Deoxyguanosine↗