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Biomedical subjects

Toru Kubota

Publications and source records attributed to Toru Kubota.

At least 37 records · Page 2Linked to original sources
PubMed2005

The role of splenomesenteric vein anastomosis after division of the splenic vein in pancreatoduodenectomy.

Division of the splenic vein was performed in 29 patients who underwent pancreatoduodenectomy to achieve lymph node dissection and neural resection around the superior mesenteric artery. The basic protocol for the splenic vein reconstruction to reduce congestion of the spleen and stomach is as follows. When the inferior mesenteric vein (IMV) drained into the splenic vein, the confluence was preserved without reconstruction of the splenic vein. When the IMV drained into the superior mesenteric vein (SMV) or the splenomesenteric angle, the division of the IMV and spleno-IMV anastomosis were performed. In postoperative venography, nine patients showed downward flow (from the splenic vein to the IMV) and three patients showed upward flow (from the IMV to the splenic vein). Postoperative computed tomography scans showed venous dilatation and splenomegaly in the upward flow group; there were no patients in the downward flow group. In selected patients, splenic vein reconstruction is necessary to reduce congestion of the spleen and stomach. When the flow is downward, spleno-IMV flow should be preserved. When the flow is upward, spleno-SMV anastomosis is necessary instead of spleno-IMV anastomosis.

Anastomosis, Surgical↗
PubMed2005

A good model of hepatic failure after excessive hepatectomy in mice.

AIMS: This study was intended to establish in mice: 1) a safety limit for the extent of hepatectomy and 2) the extent of hepatectomy invariably causing fatal hepatic failure, to facilitate gene expression analysis. MATERIALS AND METHODS: In 70%-hepatectomy, the left lateral and median lobes were removed, and in 90%-hepatectomy, all lobes except the caudate were resected. One-week survival rates, serum concentrations of aspartate aminotransferase, alanine aminotransferase and total bilirubin were measured. Histological examinations were performed using hematoxylin and eosin staining, and immunohistochemical tests were done with antibody against Ki-67 antigen. RESULTS: All of the 70%-hepatectomized mice were alive at 1 week, but the 90%-hepatectomized mice all died within 24 h after hepatectomy. Serum aminotransferase and total bilirubin levels were significantly higher in the 90%-hepatectomized mice than in the 70%-hepatectomized mice. Liver histology revealed more prominent vacuolar degeneration in the former. Ki67-positive hepatocytes appeared and proliferated immediately after 70%-hepatectomy, but few were observed in the 70%-hepatectomized mice. CONCLUSION: We established 90%-hepatectomy as the safety limit for murine hepatectomy and as a model for liver regeneration, and 90%-hepatectomy as a "fatal hepatic failure level."

Alanine Transaminase↗
PubMed2005

Usefulness of granular BCAA after hepatectomy for liver cancer complicated with liver cirrhosis.

OBJECTIVE: Nutritional disturbances such as ascites and hypoalbuminemia frequently arise after hepatectomy for liver cancer with liver cirrhosis. We examined the possibility of maintaining a favorable state of nutrition by outpatient administration of branched-chain amino acid (BCAA) granules. METHODS: Forty-three patients who had gross liver cirrhosis complicated by liver cancer and underwent surgery up to May 2002 were given BCAA granules (n = 21, BCAA group) or no granules (n = 22, control group). RESULTS: 1) Background details such as age, sex, surgical technique, blood loss, and duration of surgery showed no significant differences. 2) Among objective findings, improvement of ascites and edema tended to occur sooner in the BCAA group, but without a significant difference. 3) Although serum albumin recovered its preoperative value 9 mo after surgery in the control group, only 6 mo was required for recovery in the BCAA group. Total protein showed similar changes, but neither group showed any difference in changes of aspartate aminotransferase, alanine transferase, or platelets. 4) One year postoperatively, the change from the preoperative indocyanine green retention rate at 15 min after intravenous administration tended to be worse in the control group, but not significantly so. 5) In the BCAA group, hyaluronic acid and type IV collagen 7S improved significantly sooner than in the control group. CONCLUSIONS: BCAA supplementation after hepatectomy promotes rapid improvement in protein metabolism and inhibits progression to liver cirrhosis. Administration of BCAA after hepatectomy is considered beneficial to a patient's nutritional state.

Aged↗
PubMed2005

17 Beta-estradiol improves survival in male mice with cardiomyopathy induced by cardiac-specific tumor necrosis factor-alpha overexpression.

A transgenic mouse model of congestive heart failure (CHF) consequent to cardiac-specific overexpression of tumor necrosis factor-alpha (TNF-alpha) (TNF1.6) displays marked sex-related phenotypic differences. To clarify the potential contributions of estrogen to these sex-specific differences, male TNF1.6 mice were treated with 17beta- estradiol (E2). E2 treatment started at 25 +/- 1 days old (group A), but not at 36 +/- 2 days old (group B), significantly improved survival rate (p < 0.05). Furthermore, ventricular weight/body weight ratio was significantly decreased by E2 treatment in group A (p < 0.05). Echocardiography revealed that E2-treated hearts in group A exhibited less left ventricular dilatation (p < 0.05) relative to untreated male TNF1.6 mice (control). Moreover, in group A, E2 treatment partially reversed basal and isoproterenol-stimulated fractional shortening in TNF1.6 mice (p < 0.05). The cardiac content of TNF-alpha and interleukin-1beta (IL-1beta) was not changed by E2 treatment regardless of the timing of treatment. Thus, E2 exposure prior to puberty can limit the severity of cardiomyopathy in male TNF1.6 mice.

Animals↗
PubMed2005

Mumps virus V protein antagonizes interferon without the complete degradation of STAT1.

Mumps virus (MuV) has been shown to antagonize the antiviral effects of interferon (IFN) through proteasome-mediated complete degradation of STAT1 by using the viral V protein (T. Kubota et al., Biochem. Biophys. Res. Commun. 283:255-259, 2001). However, we found that MuV could inhibit IFN signaling and the generation of a subsequent antiviral state long before the complete degradation of cellular STAT1 in infected cells. In MuV-infected cells, nuclear translocation and phosphorylation of STAT1 and STAT2 tyrosine residue (Y) at 701 and 689, respectively, by IFN-beta were significantly inhibited but the phosphorylation of Jak1 and Tyk2 was not inhibited. The transiently expressed MuV V protein also inhibited IFN-beta-induced Y701-STAT1 and Y689-STAT2 phosphorylation, suggesting that the V protein could block IFN-beta-induced signal transduction without the aid of other viral components. Finally, a substitution of an alanine residue in place of a cysteine residue in the C-terminal V-unique region known to be required for STAT1 degradation and inhibition of anti-IFN signaling resulted in the loss of V protein function to inhibit the Y701-STAT1 and Y689-STAT2 phosphorylation.

Amino Acid Substitution↗
PubMed2005

Role of transforming growth factor-beta1 (TGF-beta1) in endotoxin-induced hepatic failure after extensive hepatectomy in rats.

Postoperative infections after hepatectomy sometimes lead to fatal hepatic failure, but the mechanism of the hepatic failure is unclear. Wistar rats underwent 90% hepatectomy, and were then divided into three groups: (i) the SAL group, injected with normal saline; (ii) the LPS group, injected with lipopolysaccharide (LPS) every day for 1 week; and (iii) the LPS plus TGF-Ab (LPS+TGF-Ab) group, injected with LPS with anti-transforming growth factor-beta1 (TGF-beta1) antibody. We investigated survival rates, TGF-beta1 expression in the liver, liver regeneration by proliferating cell nuclear antigen labeling index, hepatocyte apoptosis by single stranded DNA labeling index, and perisinusoidal fibrosis using Masson's trichrome staining. The LPS group (30.4%) had a significantly lower survival rate than the SAL group (84%) and tended to be lower than the LPS+TGF-Ab group (49.4%). Liver regeneration in the LPS group was significantly lower than in the other groups. In the LPS group, hepatocyte apoptosis and perisinusoidal fibrosis was significantly more remarkable, and TGF-beta1 expression was significantly higher than in the SAL group. TGF-beta1 enhanced by LPS plays an important role in the mechanism of hepatic failure by infections after hepatectomy, especially in inhibition of liver regeneration, and induction of hepatocyte apoptosis and perisinusoidal fibrosis.

Alanine Transaminase↗
PubMed2004

Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction.

OBJECTIVE: Transforming growth factor (TGF)-beta promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. METHODS: Anterior MI was produced in mice by ligating the left coronary artery. TGF-beta mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-beta signaling during the early phase of MI, an extracellular domain of TGF-beta type II receptor (TbetaIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. RESULTS: TbetaIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-beta signaling during the later phase, TbetaIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TbetaIIR. CONCLUSIONS: The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

Animals↗
PubMed2004

Degradation of nonylphenol polyethoxylates by ultraviolet B irradiation and effects of their products on mammalian cultured cells.

Nonylphenol polyethoxylates (NPEOs) are widely used as non-ionic surfactants and their biodegradation products such as 4-n-nonylphenol are stable and have been demonstrated to be cytotoxic. In the aquatic environment, these compounds are usually exposed to sunlight, and while the correlation between the biodegradation of NPEOs and changes in cytotoxicity has been reported, the relationship between the photodegradation of NPEOs and cytotoxicity has not. In this study, we investigated the degradation of NPEO by ultraviolet (UV) irradiation, especially UVB irradiation, and the effects on mammalian cell lines. NPEO with a smaller number of ethylene oxide (EO) units showed greater cytotoxicity. Although NPEO (10) completely inhibited the proliferation of the cells, NPEO (70) showed no toxicity. UVB irradiation significantly induced a shortening of the side chain, which was due to the production of ROS. The EO side chain of NPEO (10), was gradually degradated, but that of NPEO (70) was degradated near the benzene ring. Furthermore, the degradation of the benzene ring was more effective in NPEO (70) than NPEO (10). The toxicity of NPEO (10) in cultured cells decreased following UVB irradiation, whereas that of NPEO (70) was induced after UVB irradiation at 500 J/cm2 and disappeared at 1000 J/cm2. This might be due to the production of NPEO with a short side chain and 4-n-nonylphenol by the degradation of EO and due to the degradation of the benzene ring at higher doses of UVB irradiation. This study shows the significance of UV exposure to the degradation of alkylphenol polyethoxylates in the environment.

Animals↗
PubMed2004

Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice.

BACKGROUND: Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI). METHODS AND RESULTS: We created MI in 12- to 16-week-old, male GSHPx transgenic mice (TG+MI) and nontransgenic wild-type littermates (WT+MI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid-reactive substances measured in TG+MI at 4 weeks were significantly lower than those in WT+MI. The survival rate during 4 weeks of MI was significantly higher in TG+MI than in WT+MI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TG+MI. LV end-diastolic pressure was increased in WT+MI and reduced in TG+MI. Improvement of LV function in TG+MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WT+MI after 3 days but were attenuated in TG+MI. CONCLUSIONS: Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.

Animals↗
PubMed2004

Mechanism of liver regeneration after partial hepatectomy using mouse cDNA microarray.

BACKGROUND/AIMS: The liver has the capacity to regenerate after partial hepatectomy. In order to clarify the mechanism of liver regeneration, we observed the initial stage, especially the mechanism of gene expression during progress from G0 to S phase (0-24 h), and attempted to identify new genes controlling progress to the S phase. METHODS: We applied large-scale gene expression analysis with complementary DNA microarrays in mouse hepatectomy models to clarify the mechanism of liver regeneration after partial hepatectomy. RESULTS: As a result, 23 new immediate-early gene candidates such as interleukin-1 receptor associated kinase-1 and karyopherin alpha-1, which are involved in transportation within the nucleus, were discovered. Candidates for new genes concerned with the progress to the S phase were discovered: inhibitor of DNA binding 2 (ID2) and inhibitor of DNA binding 3 (ID3), both new liver regeneration factors that promoted progress to the S phase, and GADD45 gamma (growth arrest and DNA-damage-inducible protein) as a factor inhibiting that process. CONCLUSIONS: The above results not only suggest the importance of NFkappaB in the initial stage of liver regeneration but also points to the orderly maintenance of the proliferation of the cells in liver regeneration.

Animals↗
PubMed2004

Gene expression profiling during the transition to failure in TNF-alpha over-expressing mice demonstrates the development of autoimmune myocarditis.

Transgenic mice with cardiac-specific over-expression of tumor necrosis factor-alpha (TNF1.6) progress to dilated heart failure. A significant inflammatory response precedes functional deterioration, and may contribute to cardiac damage in this model. To evaluate the underlying molecular mechanisms, we assessed the gene expression in six groups of mouse hearts defined by age, gender, and phenotype (n = 3/group) using Affymetrix microarray analysis. Phenotype was defined as compensated (in young TNF1.6) or decompensated (in older TNF1.6) via echocardiogram. Of the >1000 transcripts altered in the compensated hearts (fold change > 2, P < 0.05 vs. wild-type (WT)), 102 were identified as immune response genes, 20 of which function in antigen presentation and processing. When comparing the compensated and decompensated hearts, >50 genes were differentially regulated, including seven immunoglobulin genes. Real-time reverse transcriptase-polymerase chain reaction and cDNA microarray confirmed the Affymetrix data. Mac3+ macrophages, CD4+ T and CD45/B220+ B-cells were identified in both compensated and decompensated hearts. However, a large amount of IgG was found deposited in areas devoid of B-lymphocytes in the myocardium of decompensated TNF1.6 mice; no such accumulation was seen in the compensated or age-matched controls. Furthermore, nuclei density analyses showed a two-fold increase in the myocardium of both compensated and decompensated TNF1.6 mice (vs. WT). This study suggests that TNF-alpha over-expression activates not only the inflammatory response, but also humoral immune responses within the transgenic hearts. The autoimmune response occurs concomitantly with cardiac decompensation and may participate in triggering the transition to failure in TNF1.6 mice.

Animals↗
PubMed2004

Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells.

Recent studies have demonstrated that upregulated Rho-kinase plays an important role in the pathogenesis of arteriosclerosis and vasospasm in both animals and humans. However, little is known about the molecular mechanism(s) involved in the Rho-kinase upregulation. Since inflammatory mechanisms have been implicated in the pathogenesis of arteriosclerosis and vasospasm, we examined whether inflammatory stimuli upregulate Rho-kinase in vitro and in vivo. In cultured human coronary vascular smooth muscle cells (hcVSMC), inflammatory stimuli, such as angiotensin II and interleukin-1beta, increased Rho-kinase expression (at both mRNA and protein levels) and function (as evaluated by the extent of the phosphorylation of the ERM (the ezrin/radixin/moesin) family, substrates of Rho-kinase) in a time- and concentration-dependent manner. The expression of Rho-kinase was inhibited by blockades of protein kinase C (PKC) (by either GF109253 or prolonged treatment with phorbol myristate acetate for 24 h) and an adenovirus-mediated gene transfer of dominant-active Ikappa-B, suggesting an involvement of PKC and NF-kappaB in the intracellular signal transduction pathway for the Rho-kinase expression. Furthermore, coronary vascular lesion formation (characterized by medial thickening and perivascular fibrosis) induced by a long-term administration of angiotensin II was markedly suppressed in NF-kappaB(-/-) mice with reduced expression and activity of Rho-kinase in vivo. These results indicate that the expression and function of Rho-kinase are upregulated by inflammatory stimuli (e.g. angiotensin II and IL-1beta) in hcVSMC with an involvement of PKC and NF-kappaB both in vitro and in vivo.

Angiotensin II↗
PubMed2004

Characterization of the amino acid residues of sendai virus C protein that are critically involved in its interferon antagonism and RNA synthesis down-regulation.

Sendai virus (SeV) encodes two accessory proteins, V and C, in the alternative reading frames in the P gene that are accessed transcriptionally (V) or translationally (C). The C protein is expressed as a nested set of four C-coterminal proteins, C', C, Y1, and Y2, that use different initiation codons. Using HeLa cell lines constitutively expressing the various C proteins, we previously found that the smallest (the 175-residue Y2) of the four C proteins was fully capable of counteracting the antiviral action of interferons (IFNs) and inhibiting viral RNA synthesis and that the C-terminal half of 106 residues was sufficient for both of these inhibitory functions (A. Kato et al., J. Virol. 75:3802-3810, 2001, and A. Kato et al., J. Virol. 76:7114-7124, 2002). Here, we further generated HeLa cell lines expressing the mutated C (Cm) proteins with charged amino acids substituted for alanine residues at either positions 77 and 80; 114 and 115; 139 and 142; 151, 153, and 154; 156; or 173, 175, and 176. We found that only the mutations at positions 151, 153, and 154 abolished IFN antagonism. All the Cm proteins lost the ability to bind with STAT1 under our assay conditions, regardless of their ability to inhibit IFN signaling. On the other hand, the Cm proteins that altered the tyrosine phosphorylation and dephosphorylation of STAT1 and STAT2 always retained IFN antagonism. Thus, the abnormality of phosphorylation or dephosphorylation appeared to be a cause of the IFN antagonism by SeV C. Regarding viral RNA synthesis inhibition, all mutants but the mutant with replacements at positions 114 and 115 greatly reduced the inhibitory activity, indicating that anti-RNA synthesis by the C protein is governed by amino acids scattered across its C-terminal half. Thus, amino acid sequence requirements differ greatly between IFN antagonism and RNA synthesis inhibition. In addition, we confirmed that another SeV accessory protein, V, does not antagonize IFN.

Amino Acid Substitution↗
PubMed2004

Contrast-enhanced sonography of autoimmune pancreatitis: comparison with pathologic findings.

OBJECTIVE: We evaluated the vascularity of autoimmune pancreatitis lesions on contrast-enhanced harmonic gray scale sonographic images in comparison with the pathologic findings. METHODS: Six patients with autoimmune pancreatitis were examined. All patients held their breath from 20 to 50 seconds after the injection of a contrast agent while the vascularity of the lesion was examined by contrast-enhanced harmonic gray scale sonography (early phase), and lesion enhancement was monitored at about 90 seconds after the injection while the patients held their breath for a few seconds (delayed phase). We then compared the vascularity on the contrast-enhanced harmonic gray scale sonographic images with the pathologic findings (fibrosis and inflammation) in all lesions. The vascularity of 3 of the 6 lesions was also evaluated by contrast-enhanced harmonic gray scale sonography before and after treatment with corticosteroids. RESULTS: The autoimmune pancreatitis lesions exhibited mild (n = 1), moderate (n = 3), or marked (n = 2) enhancement throughout almost the entire lesions in both the early and delayed phases. The grade of lesion vascularity on the contrast-enhanced harmonic gray scale sonographic images correlated with the pathologic grade of inflammation and inversely correlated with the grade of fibrosis associated with autoimmune pancreatitis. The vascularity of all 3 lesions had decreased on the contrast-enhanced harmonic gray scale sonographic images after steroid therapy. CONCLUSIONS: Contrast-enhanced harmonic gray scale sonography may be useful for evaluating the vascularity of autoimmune pancreatitis lesions and the therapeutic efficacy of steroid therapy.

Aged↗
PubMed2004

[Hepatic arterial infusion therapy for pancreatic cancer].

INTRODUCTION: One of the most difficult factors in curing pancreatic carcinoma is hepatic metastases. Many patients who undergo curative resection have hepatic recurrence, and unresected patients with hepatic metastases have terribly poor prognosis. AIM: In this study, we evaluated the efficacy of hepatic arterial infusion therapy for pancreatic carcinoma. PATIENTS AND METHOD: The subjects were 42 patients who underwent curative surgery, and 75 who were treated without resection over the past 10 years. A catheter was inserted from the femoral artery to the proper hepatic artery using the interventional technique. The main drug of this therapy was 5-fluorouracil. RESULT: The prophylactic therapy for curative resected cases was effective for pathologically mild venous permeation cases but not effective for severe venous permeation cases. Prophylactic hepatic arterial infusion therapy to prevent hepatic metastasis was not effective for unresected cases; however, for the patients with hepatic metastases this therapy was one of the factors for prolonging survival time.

Antimetabolites, Antineoplastic↗
PubMed2004

[Mechanism of liver failure after hepatectomy].

Liver failure after hepatectomy is caused by many factors such as excessive hepatectomy, ischemic-reperfusion injury, postoperative infection, etc. However, apoptosis of hepatocytes is the most important event in the molecular mechanism of liver failure. Liver failure after excessive hepatectomy is characterized by increased apoptosis of hepatocytes and diminished liver regeneration. The former is induced by hypercytokinemia and hyperendotoxemia, and the latter is caused by cell cycle arrest. In ischemic-reperfusion injury of the liver, the apoptosis of hepatocytes is caused by activation of the MMPT and calpain system that are induced by the intracellular accumulation of Ca. The possible mechanism of liver failure in cases with persistent infection is the inhibition of liver regeneration and the induction of apoptosis of hepatocytes due to transforming growth factor-beta 1. The knowledge of these mechanisms will lead to prompt and appropriate treatments for individual patients.

Animals↗