Biomedical subjects

Yoshiharu Motoo

Publications and source records attributed to Yoshiharu Motoo.

At least 19 recordsLinked to original sources

PubMed2007

Pancreatitis-associated protein: from a lectin to an anti-inflammatory cytokine.

Pancreatitis-associated protein (PAP) was discovered in the pancreatic juice of rats with acute pancreatitis. PAP is a 16 kDa secretory protein structurally related to the C-type lectins although classical lectin-related function has not been reported yet. Then, it was demonstrated that PAP expression may be activated in some tissues in a constitutive or injury- and inflammation-induced manner. More recently, it has been found that PAP acts as an anti-inflammatory factor in vitro and in vivo. PAP expression can be induced by several pro- and anti-inflammatory cytokines and by itself through a JAK/STAT3-dependent pathway. PAP is able to activate the expression of the anti-inflammatory factor SOCS3 through the JAK/STAT3-dependent pathway. The JAK/STAT3/SOCS3 pathway seems to be a common point between PAP and several cytokines. Therefore, it is reasonable to propose that PAP is a new anti-inflammatory cytokine.

Animals↗

PubMed2006

Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells.

AIM: To investigate the expression of genes involved in the gemcitabine-induced cytotoxicity in human pancreatic cancer cells. METHODS: A human pancreatic cancer cell line, PANC-1, was cultured. 1x10(4) PANC-1 cells were plated in 96-well microtiter plates. After being incubated for 24 h, gemcitabine was added to the medium at concentrations ranging 2.5-1000 mg/L. The AlamarBlue dye method was used for cell growth analysis. DNA fragmentation was quantitatively assayed using a DNA fragmentation enzyme-linked immunosorbent assay (ELISA) kit. PAP and TP53INP1 mRNA expression was determined using the reverse transcription-polymerase chain reaction with semi-quantitative analysis. The expression of GSK-3beta and phospho-GSK-3beta proteins was examined with Western blot analysis. RESULTS: The IC50 for the drug after a 48-h exposure to gemcitabine was 16 mg/L. The growth of PANC-1 cells was inhibited by gemcitabine in a concentration-dependent manner (P<0.0001) and the cell growth was also inhibited throughout the time course (P<0.0001). The DNA fragmentation rate in the gemcitabine-treated group at 48 h was 44.7%, whereas it was 25.3% in the untreated group. The PAP mRNA expression was decreased after being treated with gemcitabine, whereas the TP53INP1 mRNA was increased by the gemcitabine treatment. Western blot analysis showed that phospho- GSK-3beta (ser9) was induced by the gemcitabine treatment. CONCLUSION: Gemcitabine suppresses PANC-1 cell proliferation and induces apoptosis. Apoptosis is considered to be associated with the inhibition of PAP and GSK-3beta, and the activation of TP53INP1 and pospho-GSK-3beta (ser9).

Antigens, Neoplasm↗

PubMed2006

Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer.

AIM: Overexpression of tumor protein p53-induced nuclear protein 1 (TP53INP1) induces G1 cell cycle arrest and increases p53-mediated apoptosis. To clarify the clinical importance of TP53INP1, we analyzed TP53INP1 and p53 expression in gastric cancer. METHODS: TP53INP1 and p53 expression were examined using immunohistochemistry in 142 cases of gastric cancer. The apoptosis of gastric cancer cells was analyzed using the TUNEL method. The relationship between the expression of TP53INP1 and clinicopathological factors was statistically analyzed. RESULTS: TP53INP1 was expressed in 98% (139/142 cases) of non-cancerous gastric tissues and was down-expressed in 64% (91/142 cases) of gastric cancer lesions from the same patients. TP53INP1 expression was significantly decreased (43.9%) in poorly differentiated adenocarcinoma compared with well or moderately differentiated adenocarcinoma (81.6%). Cancers invading the submucosa or deeper showed lower positively (59.1%) compared with mucosal cancers (85.2%). Decrease or loss of TP53INP1 expression was significantly correlated with lymphatic invasion (54.3% vs 82.0% without lymphatic invasion) and node-positive patients (31.3% vs 68.3% in node-negative patients). P53 was expressed in 68 (47.9%) patients of gastric cancer, whereas it was absent in normal gastric tissues. A significant association was also observed between TP53INP1 status and the level of apoptosis in tumor cells: the apoptotic index in TP53INP1-positive tissues was significantly higher than that in TP53INP1-negative portions. Finally, when survival data were analyzed, loss of TP53INP1 expression had a significant effect in predicting a poor prognosis (P=0.0006). CONCLUSION: TP53INP1-positive rate decreases with the progression of gastric cancer. TP53INP1 protein negativity is significantly associated with aggressive pathological phenotypes of gastric cancer. TP53INP1 is related to the apoptosis of gastric cancer cells. The decreased expression of the TP53INP1 protein may reflect the malignant grade of gastric cancer and is regarded as an adverse prognostic factor.

Adenocarcinoma↗

PubMed2006

Successful cystic fenestration for a macrocystic serous cystadenoma of the pancreas causing obstructive jaundice: report of a case.

A 72-year-old man was admitted to our hospital for investigation of jaundice. We made a preoperative diagnosis of macrocystic serous cystadenoma (SCA) of the pancreas, but did not perform palliative choledochojejunostomy because aspiration of the pancreatic cystic fluid caused the cysts to shrink and relieved the compressive stenosis of the common bile duct (CBD) during the operation. Frozen sections of the cyst wall taken by incision biopsy showed no signs of malignancy. Therefore, we performed fenestration of the cystic wall after fixing the inner epithelium of the cyst with 100% ethanol and aspirating the cystic fluid. Cholangiography after the cystic fenestration showed resolution of the CBD stenosis and abdominal computed tomography (CT) confirmed the disappearance of the pancreatic cysts. No recurrence of cystic swelling or obstructive jaundice has been detected by abdominal CT or laboratory data for more than 2 years since the cystic fenestration. Thus, cystic fenestration may be a better palliative option for treating benign compressive tumors such as macrocystic SCA of the pancreas causing obstructive jaundice.

Aged↗

PubMed2006

[Effects of Chinese herbal medicines on spontaneous chronic pancreatitis in rats and the pathological relationships between formulas and syndromes].

OBJECTIVE: To investigate the effects of Guizhi Decoction, Chaihu Guizhi Decoction, Xiaochaihu Decoction and camostat on rat spontaneous chronic pancreatitis and the pathological relationships between formulas and syndromes. METHODS: Fifty-seven male WBN/Kob rats at age of 4 weeks were divided into five groups: untreated group (n=18), Guizhi Decoction-treated group (n=9), Chaihu Guizhi Decoction-treated group (n=9), Xiaochaihu Decoction-treated group (n=9) and camostat-treated group (n=12). The rats in each group were fed with corresponding drugs for 12 weeks. The pancreatic wet weight and histopathological changes of pancreatic tissue were observed every four weeks. Meanwhile, the expression level of pancreatitis-associated protein (PAP) in pancreas was detected by RT-PCR technique and immunohistochemical method. RESULTS: In the untreated group, the histopathological changes in pancreas were observed in rats at 12-week age, while such changes were absent in the Guizhi Decoction-treated group. The histopathological changes in pancreas were quite remarkable in rats at 16-week age in both the Xiaochaihu Decoction-treated and the camostat-treated groups. The expression level of PAP mRNA was lower in the Guizhi Decoction-treated group than those in the other groups. The PAP expressions were absent in rats at 12-week age in the Guizhi Decoction-treated and the Chaihu Guizhi Decocion-treated groups. CONCLUSION: Guizhi Decoction, Chaihu Guizhi Decoction, Xiaochaihu Decoction and camostat are all beneficial to prevention and cure of chronic pancreatitis, and Guizhi Decoction is the most effective one. It is speculated that Taiyang exterior syndrome may be the pathogenesis of basic syndrome may be the pathogenesis of basic syndrome of spontaneous chronic pancreatitis, and the expression of PAP may be its pathological basis.

Animals↗

PubMed2005

Herbal medicine Ninjinyoeito ameliorates ribavirin-induced anemia in chronic hepatitis C: a randomized controlled trial.

AIM: Ribavirin (RBV) shows a strong antiviral effect on hepatitis C virus when used in combination with interferon. However, RBV-induced anemia is a major problem in this therapy. It would be of great clinical importance to ameliorate the anemia without reducing the RBV dose. We report here that, Ninjinyoeito (NYT), a herbal medicine can reduce the RBV-induced anemia. METHODS: Twenty-three patients with chronic hepatitis C were treated with interferon alpha 2b plus RBV with (NYT group) or without (control group) NYT by a randomized selection. Eighteen patients completed the treatment schedule, and hemato-biochemical and virological effects were evaluated. RESULTS: There was no significant difference in biochemical and virological responses between the two groups. However, anemia was significantly reduced in the NYT group compared with the control group. The maximal decrease of Hb in the NYT group (2.59+/-1.10 g/dL) was significantly (P = 0.026) smaller than that in the control group (3.71+/-0.97 g/dL). There was no significant difference in serum glutathione peroxidase activity, serum RBV concentration, and Th1/Th2 balance between the two groups. There was no specific adverse effect in NYT administration. CONCLUSION: These results suggest that NYT could be used as a supportive remedy to reduce the RBV-induced anemia in the treatment of chronic hepatitis C.

Anemia↗

PubMed2005

Duct-narrowing chronic pancreatitis without immunoserologic abnormality: comparison with duct-narrowing chronic pancreatitis with positive serological evidence and its clinical management.

We reviewed the clinical features and clinical course of patients with duct-narrowing chronic pancreatitis who were negative for immunoserologic test results (n = 16) in comparison with the findings for serological test-positive patients (n = 20) in order to determine an adequate treatment for those who had typical morphology of autoimmune pancreatitis in the absence of immunoserologic abnormality. No significant differences were found between the two groups of patients in clinical profiles including associated autoimmune-related diseases, pancreatic histology, and response to steroid therapy. Of the seronegative patients, eight who showed an improvement in narrowing of the main pancreatic duct with steroid therapy and three who did no show an improvement or who relapsed after surgical resection without this therapy had stenosis of the common bile duct with increased levels of serum hepatobiliary enzymes, except for two patients with affected sites limited to the body or tail of the gland. For the remaining five patients, who showed an improvement in pancreatic duct changes or long-term remission after surgery without steroid administration, normal biochemistry test results for liver functions were obtained, with no abnormal cholangiographic findings in the three patients examined. Duct-narrowing chronic pancreatitis without immunoserologic abnormality overlaps in clinical features with that fulfilling the immunoserologic criteria for a diagnosis of autoimmune pancreatitis. In particular, the disease with bile duct involvement should be treated clinically as autoimmune pancreatitis, for which steroid therapy is recommended, even if an autoimmune mechanism is not demonstrated serologically.

Adult↗

PubMed2005

Expression of mesothelin mRNA in pure pancreatic juice from patients with pancreatic carcinoma, intraductal papillary mucinous neoplasm of the pancreas, and chronic pancreatitis.

OBJECTIVES: In the gene expression analysis of pancreatic carcinoma (PCa) using serial analysis of gene expression (SAGE) according to Ryu et al, the tag for the mesothelin mRNA transcript was present in 7 of 8 SAGE libraries derived from PCa but not in the 2 SAGE libraries derived from normal pancreatic duct epithelial cells. Mesothelin mRNA expression was confirmed with in situ hybridization in all 4 resected primary PCa tumors and with RT-PCR in 18 of 20 PCa cell lines, whereas mesothelin protein expression was confirmed with immunohistochemistry in all 60 resected primary PCa tissues by Argani et al. We evaluated mesothelin mRNA expression in pure pancreatic juice (PPJ) obtained from patients with PCa, chronic pancreatitis (CP), and intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS: We evaluated mesothelin mRNA expression in the PPJ obtained from 21 patients with PCa, 22 with CP, and 11 with IPMN with reverse transcriptase PCR (RT-PCR). The PCR products were analyzed with agarose gel electrophoresis. DNase I treatment before RT-PCR and direct sequencing of the RT-PCR bands were performed for the analysis of the RT-PCR bands. RESULTS: Two products, of 308 and 226 bp, were obtained with RT-PCR, and the 308-bp RT-PCR product was confirmed as being that derived from the genomic DNA by direct DNA sequencing. Mesothelin mRNA expression was discovered using RT-PCR in 11 (52%) of 21 patients with PCa, 5 (45%) of 11 with IPMN, and 3 (14%) of 22 with CP. Fisher's exact test revealed significant differences between PCa and CP for mesothelin mRNA (P < 0.01). Moreover, the RT-PCR product (226 bp) of mesothelin mRNA in the PPJ samples with PCa was generally stronger than that in the PPJ samples with IPMN. CONCLUSION: Expression of mesothelin mRNA in PPJ was not strictly specific to PCa and was apt to be stronger in PCa than in IPMN. Quantitative detection of mesothelin mRNA in PPJ may have potential diagnostic implications for pancreatic tumors.

Adenocarcinoma, Mucinous↗

PubMed2005

Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment.

OBJECTIVES: The purpose of this study was to assess the long-term prognosis in patients with duct-narrowing chronic pancreatitis (DNCP) and determine the indications for steroid therapy. METHODS: We evaluated clinical and imaging outcomes in patients with DNCP classified into 3 groups (A, B, and C) according to the treatment given. Group A included 6 patients who underwent surgical resection. Groups B and C included 21 and 10 patients treated medically with and without steroid therapy, respectively. RESULTS: In group A, 2 patients relapsed in the remnant pancreas. In group B, pancreatic swelling was resolved in all the patients, and moreover, both the irregular narrowing of the main pancreatic duct (MPD) and the strictures of the common bile duct (CBD) improved after initiation of corticosteroid therapy in all but 1 of the patients, including 5 without immunoserologic abnormality. However, clinical recurrences occurred in 4 patients (19%) during or after the maintenance therapy. In group C, all the patients showed an improvement in swelling of the gland, while only 5 showed improvement of pancreatic duct involvement. Four of these 5 patients did not show any serologic data suggesting autoimmune abnormality or CBD involvement. In all the other 5 patients in whom MPD irregularities did not improve, bile duct strictures or positive immunoserologic test results were noted. CONCLUSIONS: Steroid therapy is effective for improving pancreatic duct and bile duct lesions in patients with DNCP and is indicated particularly in those with CBD strictures or immunoserologic abnormality, although some patients have recurrences.

Adrenal Cortex Hormones↗

PubMed2005

[DU-PAN-2, SPan-1].

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Antigens, Neoplasm↗

PubMed2004

Detection of p53 gene mutations in the supernatant of pancreatic juice and plasma from patients with pancreatic carcinomas.

AIM: The sensitivity of pure pancreatic juice (PPJ) cytology for the diagnosis of pancreatic carcinoma (PCa) is still low. The usefulness of genetic analyses of PPJ seems to be limited because of insufficient sensitivity or false positivity. To improve the molecular diagnosis of PCa, we analyzed mutations of p53 together with K-ras in DNA extracted not only from the sediment but also from the supernatant of PPJ samples. METHOD: Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were used for analyses of p53 mutations in exons 5-8. K-ras mutations at codon 12 were examined by mutant allele-specific amplification. RESULTS: In PPJ supernatant from patients with PCa, p53 and K-ras mutations were detected in 42.9% (9 of 21) and 81.0% (17 of 21) of cases, respectively. The incidence of p53 and K-ras mutations in the sediment was 28.6% and 71.4%, respectively. By a combination assay with supernatant and sediment, p53 mutations were detected in 52.4% (11 of 21) of PCa cases. Moreover, p53 mutations were detected in 7 of 15 (46.7%) cases of PCa in which the cytologic diagnosis was negative. Among 25 patients with chronic pancreatitis (CP), none harbored mutant p53, although K-ras mutations were detected at an incidence of 28% (7 of 25) in the supernatant and 20% (5 of 25) in the sediment. In addition, mutant bands of p53 in plasma were detected in 2 of 11 patients with PCa in whom p53 mutations were detectable in PPJ. CONCLUSION: These results suggest that the sensitivity of detection for p53 mutations with high cancer specificity could be improved by using the Sup in PPJ samples of PCa. Genetic analysis of p53 could complement PPJ cytology. p53 mutations were detectable in PCa from plasma samples.

Adult↗

PubMed2004

Serum tumor markers and molecular biological diagnosis in pancreatic cancer.

Recent studies on genetic abnormalities in pancreatic ductal cancer have led to the investigation of tumor markers and genetic markers in both serum and pancreatic juice (PJ). Serum type 1 chain carbohydrate antigens such as CA19-9 are positive in nearly 80% of patients with pancreatic cancer (PCa), of which most are in advanced stage, whereas false-positive rates are relatively high at 20%-30% in benign hepatobiliary and pancreatic diseases. Although the prevalence of type 2 chain carbohydrate antigens, such as SLX, is relatively low, cancer specificity of these antigens is high. However, serum tumor markers have limited diagnostic value for early detection of PCa. In PJ collected endoscopically from patients with PCa, K-ras mutations (KRM) are detectable in > 80%, whereas KRM are observed in 20%-30% of PJ from patients with chronic pancreatitis (CP), reflecting benign mucous cell hyperplasia harboring KRM. Thus, a qualitative analysis of KRM in PJ is unsuitable for diagnosis of PCa. On the other hand, using an hybridization protection assay that can quantitatively determine KRM, KRM were positive in 66% of PCa but only in 40% of CP cases, indicating that qualitative analysis of KRM in PJ may be useful for differentiating PCa from CP. p53 Mutations are found in 4%-50% in PJ from patients with PCa but are not detectable in PJ from CP, suggesting that the specificity of p53 mutations is very high for PCa. Furthermore, p53 mutations were detected in 7 of 15 (47%) patients with PCa in which the PJ cytologic diagnosis was negative. Telomerase (TE) activity or its catalytic subunit, h-TERT, was reportedly positive >80% in PJ from PCa but was detected in <20% of PJ from CP. TE activity in PJ from CP originates from lymphocytes. The development and application of these new genetic and epigenetic markers with high specificity and sensitivity for PCa in serum and PJ will significantly improve our diagnostic accuracy.

Adult↗

PubMed2004

Expression of vacuole membrane protein 1 (VMP1) in spontaneous chronic pancreatitis in the WBN/Kob rat.

OBJECTIVES: VMP1 is a stress-induced gene that is overexpressed in acute pancreatitis. Its overexpression promotes the formation of intracellular vacuoles and cell death. We investigated the expression of VMP1 mRNA and its relation to apoptosis in spontaneous chronic pancreatitis in the WBN/Kob rat. METHODS: Four-week-old male WBN/Kob rats were fed a special breeding diet, MB-3, for 20 weeks. Rats were killed every 4 weeks, and the pancreas was examined. VMP1 mRNA expression was determined by reverse transcriptase polymerase chain reaction with a semiquantitative analysis, direct sequencing, and in situ hybridization. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) were used to detect cell proliferation and apoptosis, respectively. RESULTS: Vacuolar formation was most prominent at 12 weeks, when chronic pancreatitis occurred. VMP1 mRNA was also strongly expressed at 12 weeks. In situ hybridization revealed VMP1 mRNA was expressed in acinar cells. Apoptosis was increased at 12 and 20 weeks, and PCNA expression was strongest at 16 weeks in the course of chronic pancreatitis. CONCLUSIONS: VMP1 mRNA expression paralleled the formation of vacuoles and apoptosis in acinar cells in the course of chronic pancreatitis in WBN/Kob rats.

Animals↗

PubMed2004

Expression of interleukin-8 in human obstructive pancreatitis.

CONTEXT: Obstructive pancreatitis is a specific form of pancreatitis, which is caused by the obstruction of the main pancreatic duct due to tumors or some other causes. Interleukin-8 is induced in acute pancreatitis, but its expression in obstructive pancreatitis has not been clarified. OBJECTIVE: We attempted to provide some insight into the significance of interleukin -8 in the pathogenesis of pancreatic fibrosis. PATIENTS: Fifteen cases of pancreatic cancer, 7 cases of mucinous cystadenoma, 3 cases of Vater's papilla cancer and 9 normal pancreases were included in this study. MAIN OUTCOME MEASURES: The obstructive pancreatitis portions of the above pathologies were evaluated for interleukin-8 expression by means of immunohistochemistry and in situ hybridization. RESULTS: Interleukin-8 was positive in 72% of cases of obstructive pancreatitis. The positive rate was not significantly related to the etiology of the obstruction (P=0.972). Interleukin-8 was expressed in infiltrating cells, proliferating ductular cells and acinar cells. In contrast, normal pancreases and tumor cells lacked interleukin-8 expression (P<0.001 vs. obstructive pancreatitis). Both immunohistochemistry and in situ hybridization demonstrated that interleukin-8 was expressed mostly in acinar cells in mild pancreatic fibrosis, whereas it was expressed in stromal and ductular cells in moderate and severe pancreatic fibrosis. CONCLUSIONS: These results suggest that interleukin-8 expression is related to the fibrotic process in obstructive pancreatitis.

Aged↗

PubMed2004

Tumor protein p53-induced nuclear protein 1 (TP53INP1) in spontaneous chronic pancreatitis in the WBN/Kob rat: drug effects on its expression in the pancreas.

CONTEXT: The tumor protein p53-induced nuclear protein 1 (TP53INP1) gene was found using DNA microarray technology as an overexpressed gene in acute pancreatitis. However, expression of TP53INP1 in chronic pancreatitis has not been previously reported. OBJECTIVE: This study investigated TP53INP1 gene expression and its relationship with p53 and apoptosis in spontaneous chronic pancreatitis in the Wistar-Bonn/Kobori rat. METHODS: Ninety four-week-old male Wistar-Bonn/Kobori rats were fed a special breeding diet until sacrifice. Camostat mesilate (n=30) or a herbal medicine (Saiko-keishi-to; n=30) were mixed with the diet, while the other 30 rats were untreated. The rats were sacrificed every 4 weeks for 20 weeks, and the pancreas was examined. In addition, 6 four-week-old male Wistar-Bonn/Kobori rats were sacrificed and studied as starting reference. Finally, Wistar rats (n=36) were studied as controls. MAIN OUTCOME MEASURE: TP53INP1 mRNA expression was determined by reverse transcription-polymerase chain reaction using semi-quantitative analysis, direct sequencing and in situ hybridization. RESULTS: TP53INP1 mRNA was strongly expressed at 12 weeks when chronic pancreatitis developed, with a second peak at 20 weeks. The expression kinetics of TP53INP1 mRNA paralleled acinar cell apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The p53 mRNA expression showed a single peak at 12 weeks. In situ hybridization revealed that TP53INP1 mRNA was expressed mainly in acinar cells. Therapeutic drugs such as camostat mesilate and a herbal medicine Saiko-keishi-to suppressed the TP53INP1 mRNA expression. TP53INP1 mRNA induction in acinar cells was confirmed with in vitro experiments using an arginine-induced rat pancreatic acinar AR4-2J cell injury model. CONCLUSIONS: TP53INP1 expression may reflect the acute-phase response and apoptosis of acinar cells in the course of chronic pancreatitis.

Animals↗

PubMed2004

[Amylase].

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Amylases↗

PubMed2004

[Macroamylase].

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Amylases↗

PubMed2004

[Trypsin].

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Humans↗