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Biomedical subjects

Hirohito Tsubouchi

Publications and source records attributed to Hirohito Tsubouchi.

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

Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease.

The repair of intestinal mucosal injuries is a tightly regulated process involving epithelial restitution, cell proliferation and maturation, and the dedifferentiation of epithelial cells. Deeper injuries also require additional repair mechanisms, including inflammatory processes, angiogenesis, and extracellular-matrix deposition. Once intestinal mucosal injury occurs, numerous growth factors and cytokines, including hepatocyte growth factor (HGF), keratinocyte growth factor, endothelial growth factor, epidermal growth factor, transforming growth factor-beta1, intestinal trefoil factor, interleukin (IL)-1, and IL-2, are induced in both the intestinal lumen and submucosa, and these factors cooperatively stimulate epithelial mucosal repair. HGF, a major agent promoting hepatocyte proliferation, also modulates intestinal epithelial cell proliferation and migration, leading to the acceleration of intestinal mucosal repair. Additionally, the proteolytic activation of HGF, which is mediated by HGF activator, is essential for the regeneration of injured intestinal mucosa. Recently, several studies have shown that the administration of recombinant human HGF or HGF gene therapy abrogates disease severity in several animal models of inflammatory bowel disease (IBD). Recombinant human HGF will soon be available for administration to patients with fulminant hepatic failure. Although additional preclinical biological studies are required, HGF has the potential to be an important new treatment modality promoting intestinal mucosal repair in patients with IBD.

Animals↗
PubMed2005

Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia.

For the oncogenesis of many malignancies, it is crucial to prevent the shortening of the telomeres by the action of telomerase. In this study, clinical data and disease outcomes were analyzed in conjunction with the telomerase activity (TA) and telomere length (TL) of peripheral blood mononuclear cells. The study was carried out in 22 patients with adult T-cell leukemia (ATL) (7 chronic and 15 acute types) and in 13 asymptomatic human T-lymphotropic virus type 1 (HTLV-1) carriers. The mean values of TA in acute and chronic type patients were 13.8 and 1.6 total product generated (TPG) units, respectively, as determined by telomeric repeat amplification assays. The mean TA values in HTLV-1 carriers and healthy volunteers were 1.8 and 0.7 TPG, respectively. The mean TA value in acute type patients was significantly higher than in the three other subject groups. The mean TL values in patients with acute and chronic types were 5.39 and 4.38 Kb, respectively, while the mean TL values in HTLV-1 carriers and healthy volunteers were 7.69 and 7.06 Kb, respectively. The mean TL values in all ATL patients and in non-ATL subjects were 5.2 and 7.3 Kb, respectively. The former value is significantly shorter than the latter (p < 0.01). Neither TA nor TL of ATL cells showed any significant association with the number of ATL cells, serum soluble interleukin-2 receptor, or serum lactate dehydrogenase in the peripheral blood of acute type patients. This suggests that the levels of TA and TL did not reflect the ATL tumor load. The median survival period of acute ATL patients with high TA and shortened TL was 0.47 years, however, which was significantly shorter than that of acute ATL patients with low TA and normal TL (4.21 years) (p < 0.002). These data suggest that high TA and shortened TL were associated with poorer prognosis, and that TA and TL may be novel markers for the prognosis of ATL patients.

Adult↗
PubMed2005

Hepatocyte growth factor facilitates the repair of large colonic ulcers in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in rats.

BACKGROUND: Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration, serving as a critical regulator of intestinal wound healing. The aim of this study was to clarify the effects of administration of recombinant human HGF on colonic mucosal damage in vivo. METHODS: Rats were given 7.5 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS) per rectum on day 0. On day 5, the degree of TNBS-induced colitis was evaluated endoscopically, and rats suffering from large ulcers (occupying more than two thirds of the luminal circumference) were treated with intravenous bolus injections of recombinant human HGF (1.0 mg/kg per day) or phosphate-buffered saline (PBS) for 5 days. RESULTS: Rats with TNBS-induced colitis given human HGF showed a significant reduction in colonic ulcer coverage and large intestinal shortening compared with those treated with PBS. Administration of recombinant human HGF also stimulated the proliferation of epithelial cells and reduced the inflammatory cell infiltrate. Finally, HGF treatment decreased the myeloperoxidase activity and tumor necrosis factor alpha levels in the TNBS-inflamed colon tissues. CONCLUSIONS: These results indicate that intravenous injection of HGF accelerates colonic mucosal repair and reduces infiltration of inflammatory cells in rats with TNBS-induced colitis and suggest that HGF has the potential to be a new therapeutic modality to promote intestinal mucosal repair in patients with inflammatory bowel disease.

Animals↗
PubMed2005

Hepatocyte growth factor accelerates the proliferation of hepatic oval cells and possibly promotes the differentiation in a 2-acetylaminofluorene/partial hepatectomy model in rats.

BACKGROUND: Hepatocyte growth factor (HGF) is the primary agent promoting the proliferation of mature hepatocytes. The purpose of the present paper was to clarify the effects of HGF on the proliferation and differentiation of hepatic oval cells using a 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in rats. METHODS: Recombinant human HGF (0.2 mg/day) was administered to 2-AAF/PH rats for 7 days using osmotic pumps intraperitoneally implanted in conjunction with hepatectomy (day zero). RESULTS: Periportal basophilic areas consisting of oval cells were significantly enlarged by treatment with HGF on day 8. In control animals, expression of alpha-fetoprotein (AFP) in the liver was gradually upregulated, leading a marked increase on day 12. In HGF-treated rats, AFP expression was stimulated at an earlier date and decreased to an undetectable level on day 12. Conversely, expression of albumin transcripts, which was stimulated by HGF-treatment at a later date, continued to increase even after HGF administration ceased, leading to an extremely high level on day 12. Moreover, treatment with HGF also stimulated the expression of hepatocyte nuclear factor-1alpha and -4alpha at an early date. CONCLUSIONS: These results indicate that, besides the proliferation of hepatic oval cells, HGF possibly promotes the differentiation to hepatocytes in vivo, suggesting that recombinant human HGF accelerates the regeneration of severely damaged livers, a situation in which the proliferation of mature hepatocytes is impaired.

2-Acetylaminofluorene↗
PubMed2005

Inhibition of hepatocyte growth factor production in human fibroblasts by ursodeoxycholic acid.

Hepatocyte growth factor (HGF) stimulates the proliferation of hepatocytes and biliary epithelial cells and protects hepatocytes from apoptosis induced by various stimuli. In view of HGF induction by interferons, substances used for the treatment of chronic hepatitis C, this study was conducted to determine whether ursodeoxycholic acid (UDCA), which is widely used for the treatment of cholestatic liver diseases, modulates HGF production. UDCA did not induce HGF production in human dermal fibroblasts, but it potently inhibited phorbol-12-myristate-13-acetate (PMA)- and cholera-toxin-induced HGF production without affecting cell viability. The inhibitory effects of UDCA were as potent as those of transforming growth factor-beta1 and dexamethasone. Up-regulations of HGF gene expression induced by PMA and cholera toxin were also inhibited by UDCA. Moreover, UDCA dose-dependently inhibited high constitutive HGF production by MRC-5 cells without decreasing cell viability. Deoxycholate, chenodeoxycholate, taurochenodeoxycholate and glycochenodeoxycholate also inhibited cholera-toxin-induced HGF production at non-cytotoxic doses. UDCA, however, had no apparent effect on PMA-induced phosphorylation of mitogen-activated protein kinase, which is crucial for HGF induction by PMA. These results indicate that non-cytotoxic doses of UDCA inhibited constitutive and induced HGF production and suggest that UDCA supplemented with HGF or HGF inducers could have a more potential therapeutic effect.

Cell Line↗
PubMed2005

Possible involvement of neutrophils in a serum level increase of hepatocyte growth factor in non-Hodgkin's lymphoma.

Serum levels of hepatocyte growth factor (HGF), a potent angiogenic factor, increase during various haematological malignancies. In this study, we examined serum HGF in 59 patients with non-Hodgkin's lymphoma (NHL). Serum HGF levels in NHL patients were increased, as were levels in patients with multiple myeloma, chronic myeloproliferative disorders, and myelodysplastic syndrome. Some 29 patients with T-cell lymphoma, including 20 with adult T-cell leukemia/lymphoma, exhibited a significant increase in serum HGF, as did 23 with B-cell lymphoma. The levels of serum HGF correlated with increased neutrophil counts (r=0.487, p<0.0001), and also paralleled a neutrophil increase in NHL patients who received granulocyte-colony stimulating factor (G-CSF) at the nadir of neutrophil count following chemotherapy. Additionally, in in vitro experiments, HGF secretion from polymorphonuclear neutrophils and its expression in bone marrow myeloid cells were stimulated by G-CSF. Although HGF has been thought to be involved in the pathogenesis of NHL through its angiogenic activities, these results suggest that HGF production by neutrophils and myeloid lineage cells may also contribute to an increase in serum HGF in NHL patients.

Hematologic Neoplasms↗
PubMed2004

Inhibition of hepatocyte growth factor induction in human dermal fibroblasts by interleukin-1 and its prevention by interferon-gamma.

Hepatocyte growth factor (HGF) is one of the vital factors for liver regeneration. HGF production is induced by the activation of protein kinase A and protein kinase C-mediated pathways, interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and epidermal growth factor (EGF) in mesenchymal cells. We here report that IL-1 and TNF-alpha, hitherto regarded as HGF inducers, potently inhibited HGF production stimulated by other HGF inducers. IL-1alpha, IL-1beta, and TNF-alpha alone had minimal stimulating effects on HGF production in human dermal fibroblasts, but they strongly inhibited production of HGF induced by cholera toxin, 8-bromo-cAMP, EGF, and phorbol 12-myristate 13-acetate (PMA). Moreover, although the high level of HGF production in MRC-5 cells was enhanced by PMA and less markedly by IL-1beta, HGF production in MRC-5 cells treated with PMA plus IL-1beta was less than that in the cells treated with PMA alone. In the presence of interferon (IFN)-gamma, however, cholera toxin- and 8-bromo-cAMP-induced HGF production was not inhibited by IL-1beta. Pretreatment of cells with IL-1beta suppressed the phosphorylation of cAMP-responsive element-binding protein induced by cholera toxin but not that induced by 8-bromo-cAMP. Taken together, our results indicate that IL-1 inhibited HGF production stimulated by various inducers, including protein kinase A-activating agents, and that IFN-gamma overcame this inhibition of induction of HGF production.

Cells, Cultured↗
PubMed2004

Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia.

Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) infection, occurs in 2% to 4% of the HTLV-1 carriers with a long latent period, suggesting that additional alterations participate in the development of ATL. To characterize and identify novel markers of ATL, we examined the expression profiles of more than 12 000 genes in 8 cases of acute-type ATL using microarray. One hundred ninety-two genes containing interleukin 2 (IL-2) receptor alpha were up-regulated more than 2-fold compared with CD4(+) and CD4(+)CD45RO(+) T cells, and tumor suppressor in lung cancer 1 (TSLC1), caveolin 1, and prostaglandin D2 synthase showed increased expression of more than 30-fold. TSLC1 is a cell adhesion molecule originally identified as a tumor suppressor in the lung but lacks its expression in normal or activated T cells. We confirmed ectopic expression of the TSLC1 in all acute-type ATL cells and in 7 of 10 ATL- or HTLV-1-infected T-cell lines. Introduction of TSLC1 into a human ATL cell line ED enhanced both self-aggregation and adhesion ability to vascular endothelial cells. These results suggested that the ectopic expression of TSLC1 could provide a novel marker for acute-type ATL and may participate in tissue invasion, a characteristic feature of the malignant ATL cells.

Adult↗
PubMed2004

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy.

BACKGROUND: The objective of the current study was to determine the characteristic features of sustained responders who develop hepatocellular carcinoma after treatment with interferon for chronic hepatitis C. METHODS: This study included 3626 patients with chronic hepatitis C who had received interferon monotherapy. Cox proportional hazards analysis was used to compare sustained responders who did and did not develop hepatocellular carcinoma, and nonsustained responders who developed hepatocellular carcinoma in a multicenter, retrospective cohort study. RESULTS: Among 1197 sustained responders, 27 patients developed hepatocellular carcinoma (2.3%). Compared with sustained responders who did not develop hepatocellular carcinoma, patients who developed disease more often were male (P = 0.0212), were older (P = 0.0068), and had advanced-stage histologic disease before interferon therapy (P = 0.0345). Conversely, compared with patients with hepatocellular carcinoma who were not sustained responders, patients who were sustained responders tended to be older at the time of the initiation of interferon therapy (P = 0.0552) and at the time hepatocellular carcinoma was detected (P = 0.0593), and they also were predominantly male (P = 0.0507). The histologic staging and serum aminotransferase levels at the initiation of interferon therapy, the interval to the detection of tumor, and the tumor size showed no significant differences between the two groups. CONCLUSIONS: Sustained responders in the group at high risk for developing hepatocellular carcinoma after interferon therapy were older, more often were male, and had more advanced histologic disease stage. Such patients should be followed carefully periodically for > 10 years after they complete interferon therapy.

Age Factors↗
PubMed2004

Hypermethylation of the wild-type ferrochelatase allele is closely associated with severe liver complication in a family with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by cellular decreases in ferrochelatase (FECH) activity. Clinical expression of this disorder usually requires coinheritance of a mutant FECH allele and a normal FECH allele expressed at a low level. In this study, we investigated the methylation status of a normal, but poorly expressed, FECH gene in a single Japanese family with EPP. In this family, the proband died from liver failure, whereas the mother and sister exhibited overt EPP with mild liver dysfunction. A splicing mutation (IVS9+1g-->a) in the FECH gene, which produces a mutant FECH transcript lacking exon 9, was detected in the maternal allele of the proband and his sister. All subjects, including the father, who did not exhibit EPP, possessed the IVS3-48c/c genotype. This allele increases the proportion of aberrantly spliced mRNA, resulting in reduced FECH activity. Normal FECH transcripts were, however, detected in the mother and sister, but not in the proband. The CpG sites in the region from bases -78 to -31 were partially methylated in the proband and his father, but not in his mother or sister. Additionally, CpG methylation within this region reduced transcription of the FECH gene. These results suggest that whereas the combination of a maternal IVS9+1a allele and a paternal IVS3-48c allele results in overt EPP, CpG methylation of the FECH gene promoter, likely inherited from the father, increases the severity of EPP, leading to fatal liver failure, as seen in the proband.

Adult↗
PubMed2004

Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injury.

BACKGROUND: Hepatocyte growth factor (HGF) is involved in the proliferation and migration of various types of epithelial cells. HGF is produced as a single-chain precursor (pro-HGF) and functions after activation by HGF activator (HGFA). In this study, we aimed to examine the activation of pro-HGF to mature HGF and the expressions of HGF-related molecules, such as HGFA and HGFA inhibitor type 1 (HAI-1), in a monkey model of gastric mucosal injury. METHODS: Gastric mucosal injury was induced in Japanese monkeys by administration of HCl using nasal-gastric tubes. HGF activation was evaluated by Western blotting and enzyme-linked immunosorbent assay (ELISA), and the expression of HGF, HGFA, HAI-1, and c-Met were examined by Northern blotting and immunohistochemistry. RESULTS: Pro-HGF, but not mature HGF, was detected in normal gastric mucosa. When gastric mucosal injuries were induced, the expression of HGF significantly increased, and immunostaining of HGF was detected in fibroblasts in the gastric mucosa. In addition, conversion to mature HGF was observed in the injured gastric tissues, and mature HGF continued to increase for 48 h. HGFA was stably expressed in monkey livers, regardless of HCl administration. HAI-1 expression was detected in normal gastric mucosa, and its levels decreased after the induction of gastric mucosal injury. CONCLUSIONS: These results indicate that pro-HGF is stored in normal gastric tissues, and suggest that its conversion to mature HGF, associated with HGFA and HAI-1, is important for the repair of gastric mucosal injury.

Animals↗
PubMed2004

Interferon therapy for aged patients with chronic hepatitis C: improved survival in patients exhibiting a biochemical response.

BACKGROUND: In Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60. METHODS: Seven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients. RESULTS: Mean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76-2.45) and 0.73 (95% CI, 0.52-0.98) for overall death, and 10.70 (95% CI, 4.29-22.05) and 5.05 (95% CI, 3.38-7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01-2.97 and SMR, 3.25; 95% CI, 0.87-8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01-3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01-0.95] and 0.50 [95% CI, 0.11-2.21], respectively). CONCLUSIONS: These results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

Aged↗
PubMed2004

Orally administered Kampo medicine, Juzen-taiho-to, ameliorates anemia during interferon plus ribavirin therapy in patients with chronic hepatitis C.

BACKGROUND: Interferon plus ribavirin (IFN/Rib) therapy is currently standard treatment for chronic hepatitis C. Hemolytic anemia, however, is a serious side effect of this treatment, requiring reductions in or complete withdrawal of ribavirin. METHODS: We retrospectively investigated the effect of the Kampo medicine Juzen-taiho-to (TJ-48), which contains bone marrow-stimulating compounds, on anemia in 67 patients with chronic hepatitis C, who received IFN/Rib therapy. RESULTS: The reduction in hemoglobin levels was significantly ameliorated in TJ-48-treated patients (P<0.05). Consequently, only 13% (4/32) of TJ-48-treated patients received altered doses of ribavirin, while the ribavirin dose had to be reduced or withdrawn in 43% (15/35) of patients in the absence of TJ-48 administration (P<0.001). CONCLUSIONS: These results indicate the possibility that oral administration of TJ-48 supports IFN/Rib therapy without necessitating ribavirin reduction or withdrawal.

Administration, Oral↗
PubMed2004

Transforming growth factor-beta-induced stimulation of formation of collagen fiber network and anti-fibrotic effect of taurine in an in vitro model of hepatic fibrosis.

The cell strain M, which was established from normal rat liver cells, is characterized by the active formation of a collagen fiber network. In this study, we investigated the characterization of M cells and evaluated the anti-fibrogenic effects of taurine using this culture system. M cells expressed cytokeratin (CK)8, CK18, vimentin, and alpha-smooth muscle actin, whereas expression of CK-19 or desmin was not detected. Also, M cells expressed transforming growth factor (TGF)-beta1, -beta2, and TGF-beta type I and II receptors, and treatment with TGF-beta1 (1ng/ml) for 6 days markedly stimulated the formation of a collagen fiber network and expression of procollagen alpha1(I) mRNA. When M cells were treated with various concentrations of taurine (10-50mM), network formation and procollagen alpha1(I) expression were significantly suppressed in a dose dependent manner. Additionally, even in the presence of TGF-beta1, taurine treatment effectively reduced the formation of a collagen fiber network. These results suggest that M cells exhibit features of not only hepatocytes but also myofibroblasts, and TGF-beta1 plays an important role in the formation of collagen fiber networks in this culture system. Additionally, this M cell culture system is appropriate for use as an in vitro model of hepatic fibrosis in the evaluation of the anti-fibrogenic effects of various agents.

Journal Article↗
PubMed2004

Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein.

Hepatocyte growth factor (HGF) stimulates liver regeneration and has the potential to be a therapeutic agent for fatal liver diseases, including fulminant hepatic failure and liver cirrhosis. In this study, we investigated the pharmacokinetics of recombinant human HGF, which will be soon available for clinical applications. When recombinant human HGF (0.1mg/kg) was administered intravenously to normal rats, serum levels of human HGF increased to 89.7+/-20.6ng/ml 5min after the bolus injection, followed by a decrease with a half-life of 2.4min. Recombinant HGF administered intravenously was distributed primarily to the liver and induced c-Met tyrosine phosphorylation in liver tissues. In comparison, rats given recombinant human HGF via the portal vein exhibited lower serum HGF and an increase in hepatic distribution. Additionally, when compared with normal rats, those with 70% partial hepatectomy or liver cirrhosis showed an increase in serum levels of human HGF with a prolonged half-life. These results suggest that, despite a short half-life, bolus injection of recombinant human HGF may induce therapeutic effect in patients with fatal live disease, and that the dose of this recombinant protein should be modulated according to the degree of liver injury.

Journal Article↗