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Biomedical subjects

I Takeyoshi

Publications and source records attributed to I Takeyoshi.

At least 19 recordsLinked to original sources
PubMed2004

An angiogenesis inhibitor TNP-470 (AGM-1470) suppresses vascular smooth muscle cell proliferation in experimental rat aortotomy models.

AIM: Vascular intimal hyperplasia is an important clinical concern in vascular diseases, such as anastomotic stricture as a possible complication of cardiovascular surgery. We recently suggested that a rat aortotomy model could be substituted for a vascular anastomotic stricture around a suture line. TNP-470 is known as an angiogenesis inhibitor and has demonstrated abilities to inhibit DNA synthesis of smooth muscle cells (SMCs) and SMCs proliferation. The aim of this study was to investigate the effect of TNP-470 on SMC proliferation using rat aortotomy models. METHODS: Longitudinal aortotomy was performed in the abdominal aorta of rats. Rats received a subcutaneous injection of materials (TNP-470, 20 mg/kg) or vehicle 3 times a week (n=10 in each group). The aorta was harvested 2 weeks after aortotomy. Serial sections from tissues were stained with hematoxylin and eosin, and the ratio of intimal to medial cross-sectional areas (I/M ratio) was determined. Values are expressed as the mean +/- the standard deviation. Results. Thickening of the intimal layer 2 weeks following aortotomy was observed in the control group however, intimal thickening was inhibited in the TNP-treated group. The I/M ratio was significantly (p = 0.0376) lower in the TNP-treated group than in the control group (8.3 +/- 4.8 vs 15.6 +/- 9.6%). Conclusion. TNP-470 significantly suppressed intimal thickening in experimental rat aortotomy models. TNP-470 might inhibit the development of anastomotic stricture after cardiovascular surgery.

Angiogenesis Inhibitors↗
PubMed2003

Mutations in the ST7/RAY1/HELG locus rarely occur in primary colorectal, gastric, and hepatocellular carcinomas.

Human cancers frequently show a loss of heterozygosity on chromosome 7q31, which indicates the existence of broad-range tumour-suppressor gene(s) at this locus. Truncating mutations in the ST7 gene at this locus are seen frequently in primary colon cancer and breast cancer cell lines. Therefore, the ST7 gene represents a novel candidate gene for the tumour suppressor at this locus. However, more recent studies have reported that ST7 mutations are infrequent or absent in primary cancer and cell lines. To ascertain the frequency of mutations of the ST7 gene in cancer cells, we examined mutations in the ST7 coding sequence in 48 colorectal, 48 gastric, and 48 hepatocellular carcinomas using polymerase chain reaction-single-strand conformational polymorphism and direct sequencing. We detected somatic mutations, which were located near the exon-intron junction in intron 8, in only three out of 144 cases. We conclude that mutations in the ST7 gene are rare in primary colorectal, gastric, and hepatocellular carcinomas.

Bacterial Proteins↗
PubMed2001

Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to university of wisconsin solution on reperfusion injury in liver transplantation.

BACKGROUND: Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury in nonhepatic organs, such as the heart. However, the role of p38 MAPK activation in the liver is unclear. We examined the effects of FR167653, a novel p38 MAPK inhibitor, as an additive to University of Wisconsin (UW) solution in rat liver transplantation. METHODS: Rat orthotopic liver transplantation was performed after 30 hr of cold storage using UW solution with or without FR167653. Ten-day survival rates, serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels, liver tissue blood flow, histological findings, and activities of p38 MAPK and p46/p54 c-Jun N-terminal kinase (JNK) in liver grafts were evaluated. RESULTS: The addition of FR167653 significantly increased animal survival rates. FR167653 significantly suppressed serum ALT and LDH levels and improved liver tissue blood flow after transplantation. FR167653 also ameliorated histological damage to the liver graft. Neither p38 MAPK nor p46/p54 JNKs was activated during cold storage, whereas both were markedly activated within 30 min of reperfusion and remained activated until 60 min after reperfusion. FR167653 inhibited the activation of p38 MAPK both 30 and 60 min after reperfusion, but it did not affect the activation of p46/p54 JNKs. CONCLUSIONS: The addition of FR167653 to UW solution improved liver graft viability and animal survival rates associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting the activation of p38 MAPK may attenuate ischemia/reperfusion injury in liver transplantation.

Adenosine↗
PubMed2001

Mucosal damage and recovery of the intestine after prolonged preservation and transplantation in dogs.

BACKGROUND: Although much is known about the mucosal damage that occurs after intestinal warm ischemia and reperfusion and its recovery, little is known about the effect of cold preservation and transplantation on the mucosa. We studied the electrophysiological, biochemical, and histological changes of the intestinal mucosa after preservation for 24 hr and subsequent transplantation. METHODS: The small intestines from adult mongrel dogs were harvested. The intestines were orthotopically autotransplanted immediately (control group) or after preservation for 24 hr (preservation group). Jejunal and ileal tissues were taken before harvesting, at the end of preservation, 1 hr after reperfusion, and on postoperative days 3, 7, 14, and 28. The Ussing chamber method was used to study the electrophysiologic changes. Tissue maltase, diamine oxidase, and ornithine decarboxylase were measured. A histological analysis was also performed. RESULTS: Control group grafts showed no evident deterioration in electrophysiology, biochemistry, or morphology. In contrast, preservation group grafts exhibited electrophysiological and biochemical degradation, complete denudation of the villi, and crypt injury (especially in the ileum) after reperfusion. Electrophysiologic function and the mucosa biochemical marker recovered within 3 days in the jejunum and within 7-14 days in the ileum; however, histological recovery of mucosal injury required 28 days in the jejunum and more than 28 days in the ileum. CONCLUSIONS: Our study showed that despite severe destruction of mucosal integrity by prolonged preservation and transplantation, the intestinal mucosa has an enormous regenerative capacity. Our study also showed that regeneration was more pronounced in the jejunum than in the ileum.

Animals↗
PubMed2001

Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor.

BACKGROUND: Type II citrullinemia (CTLN2) characterized by a liver-specific argininosuccinate synthetase deficiency is an adult onset genetical disorder caused by the mutation of SLC25A13 gene, which results in fulminant hyperammonemia often with poor prognosis. METHODS: A 16-year-old Japanese boy presented fulminant hyperammonemia and encephalopathy and recovered after aggressive medical treatment. The patient was diagnosed as CTLN2 by plasma amino acid pattern and detection of the mutated SLC25A13 gene. We performed living-related liver transplantation (LRLT) using a graft from the genetically proven heterozygote father. RESULTS: Serum amino acid concentration was normalized within a day after transplantation without protein restriction and medication. The patient's postoperative course was natural. The patient is back in school 6 months after surgery. CONCLUSIONS: Living-related liver transplantation using a graft from genetically proven heterozygote donors might be a permissible treatment modality for CTLN2. Long-term observation may be necessary to make a definite conclusion possible.

Adolescent↗
PubMed2001

Effects of FK3311 on pulmonary ischemia-reperfusion injury in a canine model.

BACKGROUND: This study investigated the effects of a selective COX-2 inhibitor, FK3311, on warm ischemia-reperfusion (I/R) injury in the canine lung. MATERIALS AND METHODS: Sixteen adult mongrel dogs were used in this study. In the FK group (n = 8), FK (1 mg/kg) was administered intravenously 15 min before ischemia and 15 min before reperfusion. In the control group (n = 8), a vehicle was injected in the same manner. Warm ischemia was induced for 3 h by clamping the left pulmonary artery, veins, and bronchus. Five-minute clamping tests of the right pulmonary artery were performed before ischemia and 30 min after reperfusion. During the test, left pulmonary vascular resistance (L-PVR), cardiac output (CO), and arterial oxygen pressure (PaO(2)) were measured. The lung specimens were simultaneously harvested for wet-to-dry weight ratio (WDR) measurements, histopathological studies, and polymorphonuclear neutrophil (PMN) counts. Serum thromboxane (Tx) B(2) and 6-keto-prostaglandin (PG) F(1alpha) (stable metabolites of TxA(2) and PGI(2), respectively) were also measured 30 min after reperfusion. RESULTS: L-PVR, CO, PaO(2), and WDR were significantly (P < 0.05) better in the FK group than in the control group. Histological tissue edema was mild, and PMN infiltration was significantly (P < 0.05) reduced in the FK group compared to the control group. The serum TxB(2) levels were significantly (P < 0.05) lower in the FK group than in the control group, while 6-keto-PGF(1alpha) levels were not significantly (P < 0.05) reduced. Two-day survival rate was significantly (P < 0.05) better in the FK group than in the control group. CONCLUSIONS: FK has protective effects on pulmonary I/R injury stemming from marked inhibition of TxA(2).

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Cardiac transplantation following a 24-h preservation using a perfusion apparatus.

BACKGROUND: We developed a new apparatus for heart preservation and have already reported successful transplantation following 12 h of preservation using this apparatus. The efficacy of coronary perfusion with an oxygenated Celsior solution was investigated through transplantation following 24 h of preservation using the apparatus. MATERIALS AND METHODS: After being harvested, grafts were preserved with a combination of immersion in a 4 degrees C Celsior solution and perfusion with an oxygenated Celsior solution using the apparatus in the coronary perfusion (CP) group and simply immersed in a 4 degrees C Celsior solution in the simple immersion(SI) group. beta-Adenosine triphosphate (beta-ATP), phosphocreatine (Pcr), and inorganic phosphate (P(i)) levels and myocardial pH (pH(i)) were measured immediately after the heart was excised and at 12 and 24 h after preservation. Following preservation, orthotopic transplantation was performed. Cardiac function was measured 2 h after weaning from cardiopulmonary bypass (CPB). RESULTS: beta-ATP/P(i), Pcr/P(i), and pH(i) levels were significantly higher in the CP group than in the SI group at 12 and 24 h after preservation. Four of six animals in the CP group and two of six in the SI group were successfully weaned from CPB. The recovery rates of cardiac function were better in the CP group than in the SI group. CONCLUSION: Twenty-four hours of heart preservation may be possible with a combination of immersion in a 4 degrees C Celsior solution and perfusion with an oxygenated Celsior solution using the perfusion apparatus.

Animals↗
PubMed2001

The effect of a selective cyclooxygenase-2 inhibitor in extended liver resection with ischemia in dogs.

BACKGROUND: Pringle's procedure is commonly used during liver surgery, and it sometimes causes liver failure. Metabolites of arachidonic acid, which are converted by cyclooxygenase (Cox), are involved in ischemia-reperfusion injury. This study evaluated the effects of FK 3311, which selectively inhibits Cox-2, on ischemia-reperfusion injury during liver resection in dogs. MATERIALS AND METHODS: The animals were divided into four groups and subjected to 60 min of warm ischemia by partial inflow occlusion. The FK-treated groups (FK0.2: 0.2 mg/kg, FK1: 1 mg/kg, FK3: 3mg/kg) received FK3311, and the control group received vehicle. Following reperfusion, the nonischemic lobes were resected and remnant liver function was evaluated. RESULTS: Tissue blood flow and serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase were significantly better in the FK1 and FK3 groups, especially FK1, than in the control group. Thromboxane B(2) was significantly lower in the FK1 and FK3 groups than in the control group. The level of 6-keto-prostaglandin F(1alpha) was significantly lower in the FK3 group and relatively unchanged in the FK1 group. Histological damage was milder in the FK1 group. There were significantly fewer polymorphonuclear neutrophils in the FK1 group than in the control group. CONCLUSIONS: FK3311 ameliorates the ischemia-reperfusion injury caused by Pringle's procedure during extensive liver resection. This agent may be clinically useful in extended liver surgery involving vascular isolation.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Effect of a cyclooxygenase-2 inhibitor, FK3311, in a canine lung transplantation model.

BACKGROUND: In the process of ischemia-reperfusion, inflammatory cytokines and arachidonic acid metabolites are released and followed by tissue damage. FK3311 (FK) is a selective cyclooxygenase-2 inhibitor that inhibits conversion of arachidonic acid into thromboxane A2 or prostaglandin I2. We investigated the effects of FK in canine lung transplantation. METHODS: FK3311 was administered in the FK group, and vehicle was injected in the control group. The left lung was orthotopically transplanted after 12-hour preservation in Euro-Collins solution. After reperfusion, the right pulmonary artery and bronchus were ligated, and the animals were observed. Pulmonary gas exchange and hemodynamics were measured, histopathologic damages were investigated, and technetium-99m-labeled albumin scintigraphy was performed. The serum prostanoid levels were also measured. RESULTS: In the FK group, pulmonary gas exchange and hemodynamics were significantly (p < 0.05) better, histologic damage and neutrophil infiltration was reduced, and technetium-99m-albumin accumulation was considerably suppressed. Also, thromboxane B2 was significantly (p < 0.05) lower, but 6-keto-prostaglandin F1alpha was not significantly reduced. CONCLUSIONS: FK3311 generates protective effects on lung transplantation by a marked inhibition of thromboxane A2.

Anilides↗
PubMed2001

FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase.

BACKGROUND: FR167653 is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1) production, and was shown to attenuate ischemia and reperfusion (I/R) organ injury in our previous experiment. Because p38 mitogen-activated protein (MAP) kinase has been reported to regulate the production of TNF-alpha and IL-1, we examined the effects of FR167653 in the rat lung I/R model and determined the expression and activation of p38 MAP kinase. METHODS: Experiment 1: After 1 hour of ischemia, p38 MAP kinase, phosphorylated p38 MAP kinase (active form), histologic changes of the lung, and serum levels of TNF-alpha and IL-1beta were examined. Experiment 2: After 2 hours of reperfusion, arterial oxygen content (PaO(2)) and saturation (SaO(2)), serum TNF-alpha and IL-1beta levels, and histologic changes in the lung were examined. Rats were divided into three groups in Experiment 1. In the control group, a saline solution was administered and, in the FR group, 0.1 mg/kg per hour of FR167653 was administered, intravenously throughout the experiment, beginning 30 minutes before ischemia. In the non-ischemic group, samples were taken soon after thoracotomy. The rats were divided into control and FR groups in Experiment 2. RESULTS: Experiment 1: One hour of ischemia induced almost no changes in the lung or serum cytokine levels. Meanwhile, FR167653 markedly attenuated the expression of phosphorylated p38 MAP kinase. Experiment 2: SaO(2) and PaO(2) were improved, serum cytokines were lower, and lung damage was less extensive in the FR group than in the control group. CONCLUSION: FR167653 attenuates I/R injury of the lung and this attenuation is associated with suppression of p38 MAP kinase activation.

Animals↗
PubMed2001

The effect of cyclooxygenase-2 inhibitor FK3311 on ischemia-reperfusion injury in a canine total hepatic vascular exclusion model.

BACKGROUND: Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model. STUDY DESIGN: Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted. RESULTS: Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower. CONCLUSIONS: FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs.

BACKGROUND: Nitric oxide attenuates ischemia-reperfusion injury by maintaining organ circulation through its actions as a vasoregulator, an inhibitor of platelet aggregation, and an attenuator of leukocyte adhesion. Otherwise, the harmful effects of enhanced nitric oxide production induced by inducible nitric oxide synthase mediate ischemia-reperfusion injury. FK409 has been characterized as a spontaneous nitric oxide donor. The aim of this study was to evaluate the effects of FK409 on extended liver resection with ischemia using a canine model. STUDY DESIGN: Adult mongrel dogs were subjected to 60 minutes of warm ischemia by partial inflow occlusion. After reperfusion the nonischemic lobes were resected and the remnant liver function was evaluated. The dogs were divided into two groups: the control group (n = 7) and the FK409 group (n = 6), which was given FK409 through the portal vein. RESULTS: The hepatic tissue blood flow, serum liver enzymes levels, and serum endothelin-1 level after reperfusion were significantly better in the FK409 group than in the control group. Electron microscopy demonstrated that endothelial cells and Ito cells were well-preserved in the FK409 group. The 3-day survival rate was statistically better in the FK409 group (67%) than in the control group (14%). CONCLUSIONS: FK409 appears to have protective effects during extended liver resection with ischemia.

Animals↗
PubMed2001

A spontaneous nitric oxide donor ameliorates small bowel ischemia-reperfusion injury in dogs.

Nitric oxide (NO) appears to play an important role in tissue injury during reperfusion. FK409 is the first spontaneous NO donor that increases plasma guanosine 3',5'-cyclic monophosphate. We investigated the effects of the NO donor FK409 (FK) on ischemia-reperfusion injury in a canine warm ischemia model. Fourteen adult mongrel dogs were divided into two groups: the control group and the FK group, which received FK. The superior mesenteric artery and vein were both clamped for 2 h and then reperfused for 12 h. Arterial and intramucosal pH were well maintained in the FK group in comparison with the control group. Histologically, ischemia-reperfusion injury was significantly more severe in the control group than in the FK group. The serum NO levels were significantly higher in the FK group than in the control group during FK administration. FK409 has protective effects on ischemia-reperfusion injury of the small intestine due to NO release.

Animals↗
PubMed2001

Effects of endothelin receptor antagonist TAK-044 on small bowel autograft from a controlled non-heart-beating donor model.

BACKGROUND: This study investigated the possibility of pharmacologic protection using an endothelin (ET) receptor antagonist, TAK-044 (TAK), for small bowel autograft in a canine controlled non-heart-beating donor (NHBD) model. METHODS: Sixteen adult mongrel dogs were allocated into 2 groups. TAK (3 mg/kg) (n = 8) was administered intravenously 30 minutes before ischemia and 30 minutes before graft reperfusion. Vehicle was administered in the control (n = 8). The superior mesenteric artery and vein were clamped for 90 minutes to induce warm ischemia as a controlled NHBD model. The entire small bowel then was harvested and stored in 4 degrees C University of Wisconsin solution for 4 hours. The autograft was transplanted orthotopically. Mucosal tissue blood flow, intramucosal pH (pHi), and serum ET-1 levels were measured. Specimens were evaluated histopathologically and ET-1 immunohistochemically. RESULTS: TAK provided significantly higher tissue blood flow and pHi at 3 and 6 hours after graft reperfusion and significantly higher serum ET-1 levels at 1 hour after graft reperfusion as compared with the control group. TAK had histopathologic tissue damage graded as superficial, did not reach to grade 5 on Park's grading as in controls, and provided less intense immunoreactivity for ET-1 immunohistochemical staining. CONCLUSIONS: TAK may have clinical application in small bowel transplantation from controlled NHBD or conditions related to ischemia-reperfusion (I/R) injury.

Animals↗
PubMed2001

Effects of a dual inhibitor of tumor necrosis factor-alpha and interleukin-1 on lipopolysaccharide-induced lung injury in rats: involvement of the p38 mitogen-activated protein kinase pathway.

OBJECTIVE: Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653. DESIGN: Prospective, randomized study. SETTING: Animal research facility in a university. SUBJECTS: Male Sprague-Dawley rats weighing 200-270 g. INTERVENTIONS: All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs. MEASUREMENTS AND MAIN RESULTS: LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues. CONCLUSIONS: FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.

Animals↗
PubMed2001

The effect of Celsior solution on 12-hour cardiac preservation in comparison with University of Wisconsin solution.

BACKGROUND: Celsior is a new extracellular-type preservation solution which has been developed to act not only as a storage medium but also as a perfusion fluid during initial donor heart arrest, poststorage graft reimplantation and early reperfusion. We designed this experimental study to evaluate the effect of the Celsior solution in comparison with the University of Wisconsin solution from the viewpoint of energy depletion. METHODS: Adult mongrel dogs weighing 9 to 13 kg were divided into two groups. In the UW group (n=7), a 4 degrees C University of Wisconsin solution was used for coronary vascular washout and storage following cardiac arrest using a glucose-insulin-potassium solution. In the Celsior group (n=7), the Celsior solution was used to obtain cardiac arrest, coronary vascular washout and storage. High energy phosphate levels and myocardial pH were measured using (31)P-nuclear magnetic resonance spectroscopy immediately after preservation and at 3, 6 and 12 hours after preservation. After 12-hour cold storage, left ventricular free wall tissues were harvested for histological examination. RESULTS: High energy phosphate levels and myocardial pH were significantly better preserved in the Celsior group than in the UW group. In the histological findings, glycogen granules were preserved well in the Celsior group. CONCLUSIONS: We conclude from our study that the Celsior solution is comparable to the University of Wisconsin solution for use in 12-hour heart preservation in canine models.

Adenosine↗