Biomedical subjects

Koji Miyagawa

Publications and source records attributed to Koji Miyagawa.

13 recordsLinked to original sources

PubMed2006

Long-term survival of a case with multiple liver metastases from duodenal gastrointestinal stromal tumor drastically reduced by the treatment with imatinib and hepatectomy.

Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors (GISTs). But there is little information on whether combination of imatinib mesylate (IM) and surgical treatment can prolong survival in the cases with unresectable multiple liver metastases. We report a case of postoperative recurrence of GIST treated by the tyrosine kinase inhibitor IM and surgical treatment. The initial complete response (CR) to treatment continued for 18 mo, but single liver metastasis showed regrowth in the left hepatic lobe during IM treatment. After partial resection of the recurrent tumor, postoperative course was uneventful and the patient has survived without recurrence for 24 mo. Currently, imatinib is the first-line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. Even if tolerance to imatinib occurs, a combination of imatinib and surgical treatment can prolong survival in some cases as reported here. However, further studies on a large number of cases of recurrent GIST are necessary to evaluate the effectiveness of IM treatment combined with surgery.

Adult↗

PubMed2005

Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-alpha accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical. METHODS AND RESULTS: Diverse iron transporters, including iron import proteins (transferrin receptor [TfR] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]) coexist in human umbilical endothelial cells (HUVECs). TNF-alpha caused upregulation of TfR and DMT1 and downregulation of FP1, which were demonstrated in mRNA as well as protein levels. These changes in iron transporters were accompanied by accumulation of iron that was both transferrin-dependent and transferrin-independent. Modifications of these mRNAs were regulated post-transcriptionally, and were coordinated with activation of binding activity of iron regulatory protein 1 to the iron responsive element on transporter mRNAs. Using a salicylate trap method, we observed that only simultaneous exposure of endothelial cells to iron and TNF-alpha accelerated hydroxyl radical production. CONCLUSIONS: TNF-alpha could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease.

Aconitate Hydratase↗

PubMed2005

Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers.

PURPOSE: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray. EXPERIMENTAL DESIGN AND RESULTS: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-beta (TGF-beta)-induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of approximately 21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified approximately 28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-beta signaling pathway. CONCLUSION: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

Animals↗

PubMed2005

Comparison of cytotoxicity of cysteine and homocysteine for renal epithelial cells.

BACKGROUND: Although the cytotoxic effects of cysteine (Cys) on renal cells have been established, the effects of homocysteine (Hcy), which causes endothelial cell dysfunction, have not been well tested. We compared the direct toxicity of Hcy on renal tubular cells to that of Cys and examined the mechanism of cell toxicity. METHODS: LLC-PK1 cells were incubated with test media containing 500 microM Cys or Hcy in the presence or absence of 100 microM copper. Lactate dehydrogenase release and thiobarbituric acid reactive substance were measured for estimating cytolysis and lipid peroxidation, respectively. The generation of hydrogen peroxide and hydroxyl radical, and the cell redox state were analyzed using the scopoletin method, salicylate-trap method, and glutathione (GSH) content, respectively. Superoxide dismutase, catalase, and vitamin E also were used for clarifying the mechanism of toxicity. RESULTS: In the presence of copper (+ Cu), cytolysis at 16 h was more prominent in cells exposed to Cys than Hcy. In accordance with cytotoxicity, lipid peroxidation at 4 h of incubation, as well as hydrogen peroxide and hydroxyl radical formation in a shorter incubation, were remarkably greater in Cys + Cu than Hcy + Cu. The addition of Hcy, but not Cys, decreased GSH content significantly. CONCLUSION: In the presence of copper, Cys was extraordinarily more cytotoxic to renal cells than Hcy. Cytotoxicity from Hcy may be dependent upon depletion of cellular GSH, while Cys cytotoxicity is primarily dependent upon the generation of reactive oxygen species and lipid peroxidation.

Animals↗

PubMed2005

Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer.

Our previous studies suggest that lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer, but potential roles of other members of the RUNX family genes have not yet been reported. We examined the expression of 3 Runt-related (RUNX) genes, RUNX1, RUNX2 and CBFB, in gastric cancer cell lines and primary gastric cancer specimens and compared them to those of RUNX3 reported earlier in conjunction with clinicopathologic factors. Expression of RUNX family genes in 9 gastric cancer cell lines, 56 primary gastric cancer specimens and surrounding normal gastric mucosa were estimated by Northern blot analysis, quantitative RT-PCR and in situ hybridization. Northern blot analysis in gastric cancer cell lines showed downregulation of RUNX1 and RUNX3 in 67% and 78% of the cell lines tested, respectively. The ratio of the average RUNX mRNA/beta-actin mRNA ratio (x10(3)) for RUNX1 was 48.0 +/- 21.1 vs. 21.4 +/- 8.1; RUNX2, 1.1 +/- 0.3 vs. 1.0 +/- 0.2; RUNX3, 9.2 +/- 6.3 vs. 3.1 +/- 1.3 and CBFB, 42.0 +/- 19.4 vs. 21.0 +/- 8.4 (normal vs. tumor, respectively, average +/-SD). The basal RUNX2 expression was very weak, and there was no significant change in gastric cancers. Both RUNX1 and RUNX3 showed remarkable downregulation in 62% and 69%, respectively, of surgically resected specimens compared to surrounding mucosa analyzed by quantitative RT-PCR (p < 0.01). Furthermore, CBFB, the gene encoding the cofactor of RUNX1, -2, -3, was also downregulated in significant fraction (32%, p < 0.05). The percentage of downregulation of RUNX1, RUNX3 and CBFB increased as the cancer stage progressed. Tricostatin A and 5'-azacitidin reactivate RUNX3 expression, but they could not reactivate expression of RUNX1 and CBFBeta in gastric cancer cells, suggesting that the downregulation was due to mechanisms other than methylation of the promoter region. These findings suggest that RUNX1 and CBFBeta in addition to RUNX3 play some roles in gastric cancers and that roles of RUNX gene family in gastric cancer are more widespread and complex than previously realized.

Aged↗

PubMed2005

[A long-term survival case with multiple liver metastases from duodenal gastrointestinal stromal tumor that was drastically reduced by the treatment with imatinib].

Constitutive activation of c-kit receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether a combination of IM and surgical treatment can prolong survival in a case of unresectable multiple liver metastases. We report a case of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor IM and surgical treatment. Therefore, we discuss some important implications. This 37-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003. The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400 mg of IM once daily with only weak liver dysfunction as a side effect. The initial response to treatment of CR continued for 18 months. Currently, IM is the first-line therapy for non-resectable GISTs. As the mechanisms of recurrence and resistance to imatinib in GIST remain unclear, they should be intensively performed in the sight of both clinical and molecular biological viewpoints. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.

Adult↗

PubMed2004

Accumulation of cyanide and thiocyanate in haemodialysis patients.

BACKGROUND: Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. METHODS: We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. RESULTS: Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. CONCLUSIONS: The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.

Adult↗

PubMed2004

[Pericarditis].

Explore the source record for details and available documents.

Anti-Inflammatory Agents↗

PubMed2003

Free cysteine is increased in plasma from hemodialysis patients.

BACKGROUND: Although only the total thiol concentration, which includes bound and free forms, has been determined in most previous clinical studies, the free form may be a better predictor of cardiovascular risk. METHODS: We measured the apparent concentration of free homocysteine (Hcy) and cysteine (Cys) in filtered and acid-soluble fractions of plasma in healthy control subjects and in patients with chronic renal failure just before and after a hemodialysis session. RESULTS: In control, filtered Hcy and acid-soluble Hcy were similar, while filtered Cys was much smaller than in acid-soluble Cys. In prehemodialysis samples, filtered Cys was more than 60 times as abundant (259.2 +/- 26.2 micromol/L) as in control samples (4.1 +/- 0.7 micromol/L ). Free-to-total ratios for filtered Cys were 1.6 +/- 0.3% in controls, but 40.9 +/- 2.7% in prehemodialysis patients. CONCLUSIONS: The filtered fraction of thiols can be used to estimate solute transport across the dialysis membrane. In addition, the possible involvement of cysteine in the pathogenesis of atherosclerosis in hemodialysis patients should be reexamined.

Acids↗

PubMed2003

A nitric oxide-generating beta-blocking agent prevents renal injury in the rat remnant kidney model. Comparative study of two beta-blocking drugs, nipradilol and propranolol.

BACKGROUND: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether beta-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. METHODS: Nipradilol, a beta-blocker with an ONO(2) group (5, 10 or 15 mg/kg/day) and propranolol, a beta-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U(NOx)) and cyclic GMP (U(cGMP)). RESULTS: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U(NOx) in comparison with the sham-operated rats. Nipradilol increased U(NOx) and U(cGMP) significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U(NOx). The addition of nipradilol increased U(NOx) and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. CONCLUSION: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The beta-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.

Adrenergic beta-Antagonists↗

PubMed2003

[A case of sarcoidosis overlapping with rheumatoid arthritis].

We report the case of a 54-year-old woman who presented on May 28, 2001 with sarcoidosis overlapping with rheumatoid arthritis. She had experienced morning stiffness 2 years previously and was diagnosed as having rheumatoid arthritis. She had been treated with bucillamine and loxoprofen for 3 months. In October 2000, she developed proteinurea. The patient discontinued treatment with bucillamine and loxoprofen. Proteinurea persisted, and the patient's renal function declined. On admission, subcutaneous nodules were palpable in the patient's legs. The patient's serum creatinine and calcium levels were 2.49 mg/dl and 11.6 mg/dl, respectively. Intact-PTH was suppressed, and PTHrP was not elevated. Despite the presence of hypercalcemia, the patient's serum 1 alpha 25(OH)2D3 was not suppressed. Serum ACE and lysozyme levels were elevated beyond the normal ranges. A renal biopsy was performed, and non-caseous epithelioid granuloma was found in the renal interstitium. Based on the histological findings, the patient was diagnosed as having sarcoidosis. Following treatment with prednisolone, the patient's serum calcium levels returned to normal and her renal function improved.

Anti-Inflammatory Agents↗

PubMed2003

[Possible involvement of inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers].

Our previous study using a cDNA microarray demonstrated that positive identification of differently expressed genes among gastric cancer cells involved in peritoneal dissemination could be accomplished. One of these genes with overexpression is inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3). IP3R3 is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family. But the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancers is still unclear. In this study, IP3R3 is overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in gastric cancer cell lines established from primary tumor as well as in normal gastric epithelial cells. IP3R1 and 2 are expressed only weakly or not at all in these cells. The antagonist of IP3R, 2-APB, inhibited cell proliferation and induced apoptosis of gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose dependent manner. Conversely, 2-APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia cell HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells that express IP3R3 mRNA (i.e., pancreatic aciner cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2-APB, may thus be useful for the treatment of gastric cancer, especially for peritoneal dissemination.

Apoptosis↗

PubMed2002

Association of hyperhomocysteinemia with plasma sulfate and urine sulfate excretion in patients with progressive renal disease.

BACKGROUND: Plasma total homocysteine (tHcy) level is increased in patients with renal disease, parallel to serum creatinine concentration. In renal failure, the final product of sulfated amino acid metabolism, sulfate, also accumulates as renal function declines. We hypothesized that the elevation in sulfate level could cause hyperhomocysteinemia and tested the relation between tHcy level and both urinary excretion and plasma levels of sulfate. METHODS: Forty patients with renal disease were divided into three groups: patients without renal failure (nRF; creatinine clearance [CCr] > or = 80 mL/min/1.73 m2 [> or =1.33 mL/s/1.73 m2]), patients with mild renal failure (mRF; 80 > CCr > or = 25 mL/min/1.73 m2 [1.33 > CCr >/ or 0.42 mL/s/1.73 m2]), and patients with severe renal failure (sRF; CCr < 25 mL/min/1.73 m2 [<0.42 mL/s/1.73 m2]). Daily urinary excretion and plasma levels of tHcy, total cysteine (tCys), and sulfate were measured. A healthy control (HC) group also was tested. Serum methionine, taurine, vitamin B12, and folate levels also were determined in patients with renal disease. RESULTS: Plasma tHcy and sulfate concentrations in the groups with mRF and sRF were greater than in the HC group. Plasma tCys concentrations in the mRF and sRF groups were greater than in the nRF group. Daily urinary Hcy and Cys excretion did not differ among the four groups. Daily urine sulfate and urea nitrogen excretion in the sRF group were significantly less than in the HC and nRF groups. Multiple regression analyses showed that plasma creatinine (beta = 0.40) and sulfate (beta = 0.43) levels were independently associated with plasma Hcy level; among urine parameters, only daily urine sulfate excretion (beta = -0.52) was independently associated with plasma Hcy level. CONCLUSION: The elevated plasma sulfate level, in accordance with renal function, is associated with plasma tHcy level. Decreased sulfate excretion, which might parallel the intake of sulfated amino acid or protein, may increase tHcy levels.

Analysis of Variance↗