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Cytopathology 08/2011; · 1.59 Impact Factor
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ABSTRACT: Several studies have reported green tea catechin to have both antifibrotic and anti-oxidative effects. The goal of this study was to evaluate the effect of green tea cathechin therapy in hepatic tissue injury using cholestatic rats with bile duct ligation.
We performed bile duct ligation on cholestatic seven-week-old male Wistar rats and classified them into three groups according to the method of treatment. The groups comprised the SHAM group, the NT-group (no-treatment-group), and the T-group (treatment-group). The rats were orally administered green tea catechin at a dose of 50mg/kg/day and were sacrificed on the 17th postoperative day. We subsequently investigated the levels of fibrosis and antioxidant activity associated with various clinical markers. We evaluated the serum AST and ALT levels and performed immunohistochemical analyses for 4-hydroxynonenal (4-HNE), 8-oxo-2'deoxyguanosine (8-OHdG) and transforming growth factor-beta1 (TGF-beta1). We also evaluated the levels of activator protein-1 m-RNA (AP-1 m-RNA) and tissue inhibitor metalloproteinase-1 m-RNA (TIMP-1 m-RNA) by Real Time PCR. Finally, we performed Azan staining and immunohistochemical staining of alpha-smooth muscle actin (alpha-SMA) to evaluate the degree of fibrosis.
The values of serum AST, serum ALT, AP-1 m-RNA, alpha-SMA, TGF-beta1, 4-HNE, and 8-OHdG in the T-Group were significantly lower than those in NT-Group. Therefore, the administration of green tea catechin might have suppressed the oxidative stress, controlled the stellate cell activation and consequently reduced the fibrosis.
Green tea catechin may reduce hepatic fibrosis by suppressing oxidative stress and controlling the transcription factor expression involved in stellate cell activation.
Phytomedicine: international journal of phytotherapy and phytopharmacology 03/2010; 17(3-4):197-202. · 2.17 Impact Factor
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S Takemoto,
K Ushijima,
K Kawano,
T Yamaguchi,
A Terada,
N Fujiyoshi,
S Nishio,
N Tsuda,
M Ijichi,
T Kakuma, M Kage,
D Hori,
T Kamura
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ABSTRACT: Stat3 is a member of the Janus-activated kinase/STAT signalling pathway. It normally resides in the cytoplasm and can be activated through phosphorylation. Activated Stat3 (p-Stat3) translocates to the nucleus to activate the transcription of several molecules involved in cell survival and proliferation. The constitutive activation of Stat3 has been shown in various types of malignancies, and its expression has been reported to indicate a poor prognosis. However, the correlation between the constitutive activation of Stat3 and the prognosis of cervical cancer patients has not been reported.
The immunohistochemical analysis of p-Stat3 expression was performed on tissues from 125 cervical squamous-cell carcinoma patients who underwent extended hysterectomy and pelvic lymphadenectomy, and the association of p-Stat3 expression with several clinicopathological factors and survival was investigated.
Positive p-Stat3 expression was observed in 71 of 125 (56.8%) cases and was significantly correlated with lymph node metastasis, lymph vascular space invasion, and large tumour diameter (>4 cm) by Fisher's exact test. Kaplan-Meier survival analysis showed that p-Stat3 expression was statistically indicative of a poor prognosis for overall survival (P=0.006) and disease-free survival (P=0.010) by log-rank test.
These data showed that p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis.
British Journal of Cancer 07/2009; 101(6):967-72. · 5.04 Impact Factor
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Cytopathology 09/2008; 20(6):406-8. · 1.59 Impact Factor
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M Kage,
T Fujisawa,
K Shiraki,
T Tanaka,
A Kimura,
K Shimamatsu,
E Nakashima,
M Kojiro,
M Koike,
Y Tazawa, [......],
A Matsui,
T Hayashi,
T Etou,
S Terasawa,
K Sugiyama,
H Tajiri,
A Yoden,
Y Kajiwara,
M Sata,
Y Uchimura
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ABSTRACT: Limited information is available regarding the histology of hepatitis C virus infection in children. The aim of this study was to determine the histological pattern of chronic hepatitis C (CHC) in children, and liver biopsy specimens from 109 pediatric patients with CHC were examined. Each biopsy specimen was evaluated based on a numerical scoring system for the stage of fibrosis (1-4), the grade of portal/periportal necroinflammation (0-4), the grade of lobular necroinflammation (0-4), and their sum (final grade). The histological lesions considered to be characteristic of chronic hepatitis were also evaluated. None of the children had liver cirrhosis, and 105 cases (97%) were stage 1 or 2. Only 4 children were stage 3. Two of these 4 cases showed hemosiderosis. A significant correlation was observed between the staging score and the final grade in the pediatric patients (r = .59; P < .0001). The histological characteristics of adult CHC, such as lymphoid aggregate, bile duct injury, and fatty changes, were also observed in the children. In conclusion, the majority of children with CHC presented with mild fibrosis, but a few showed CHC with lobular distortion and hemosiderosis. Frequent blood transfusion may aggravate hepatic lesions in pediatric CHC.
Hepatology 12/2003; 26(3):771 - 775. · 11.66 Impact Factor
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M. Sata,
O. Hashimoto,
S. Noguchi,
Y. Uchimura,
F. Akiyoshi,
N. Matsukuma,
H. Fukushima,
H. Suzuki, M. Kage,
M. Kojiro,
K. Tanikawa
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ABSTRACT: Between March 1994 and March 1996 we studied transmission routes and clinical courses in eight patients with sporadic acute hepatitis C (two men, six women). Of the eight patients, three were treated for another illness 1–2 months before the onset of hepatitis, one was a parenteral drug abuser, one had an accidental needlestick injury and two had sexual contact with a partner with chronic hepatitis C virus (HCV) infection. Clinical courses included four women whose HCV RNA and alanine aminotransferase (ALT) became persistently negative without treatment, and four men and two women with the same results following interferon (IFN) treatment. It is thought that IFN therapy may prevent the progression to chronic liver disease. Results from this study might be useful in the future management of patients with sporadic acute hepatitis C.
Journal of Viral Hepatitis 11/2003; 4(4):273 - 278. · 4.09 Impact Factor
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ABSTRACT: Lichen planus (LP), common mucocutaneous disorder, involves not only oral mucosa and skin but genitalia membrane. LP is frequently seen in patients with HCV infection. This study evaluated patients with HCV-associated oral lichen planus (OLP) for vulvar and vaginal LP involvement, and the possible intraspousal transmission of HCV. We examined a total of 24 female Japanese patients with OLP for genitalia LP: 14 OLP-HCV positive and 10 OLP-HCV negative. All subjects were evaluated for genital LP by a gynecologist. All 24 subjects and 10 of the husbands were tested for anti-HCV and serum HCV RNA. Vulvar LP was observed in 10 (41.7%) of 24 patients with OLP. Vulvar LP in 14 (OLP-HCV positive) and 10 patients (OLP-HCV negative) were observed in 42.9 and 40%, respectively. There were no significant differences (age, sites of OLP, blood transfusion, HCV infection, and degree of liver diseases) between the vulvar LP and non-vulvar LP patients. Two spouses of 10 married couples were shown to be infected with HCV. In one couple with HCV infection, the wife and husband had also erosive OLP, the wife had erosive vulvar LP. In conclusion, the majority of OLP patients suffered from genitalia LP in Japan. Clinicians should follow the OLP patients with sufficient attention to the presence of extraoral manifestations. These data may suggest the occurrence of intraspousal transmission of HCV through erosive vulvar LP.
International Journal of Molecular Medicine 12/2002; 10(5):569-73. · 1.98 Impact Factor
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M Kage
Nippon rinsho. Japanese journal of clinical medicine 11/2001; 59 Suppl 6:478-81.
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ABSTRACT: The roles of interleukin (IL)-4 and interferon (IFN)-gamma in Schistosoma japonicum egg granuloma formation were investigated in cercariae-infected (infection model) or after implantation of laid parasite eggs (egg implantation model) in cytokine deficient mice. Two weeks after hepatic egg-implantation, a markedly decreased mononuclear cell infiltration and lack of multinuclear cell formation were characteristic features in IL-4 deficient mice. By 4 weeks (late stage), the cellular reactions around the eggs were negligible in the deficient mice. Compared to the controls, there was a drastic reduction in the production of the Th2 cytokines, IL-4, IL-5 and IL-13. MCP-1 levels were also significantly lowered. In mice experimentally infected with cercariae, granuloma cellularity in both the wild-type and IL-4 deficient mice at 45 days and 10 weeks postinfection was analogous to the egg implantation model at 2 and 4 weeks. Overall, the effects of IFN-gamma deficiency on granuloma induction differed markedly from the IL-4 results. Two weeks after egg implantation, IFN-gamma deficient mice showed suppressed neutrophil response and hepatic necrosis with confluent mononuclear cell infiltration along the outer layer of granulomas. By 4 weeks, there was a decrease in cell infiltration, fibrosis and MCP-1 production while IL-10 production increased. While these early characteristic features for IFN-gamma deficiency were common to both the egg implantation (at 2 and 4 weeks) and cercariae infection model (at 45 days), there was a surprising difference, i.e. marked fibrosis was found in the late stages (at 10 weeks postinfection) of cercariae-infected mice, but not in parasite egg implanted mice. Furthermore, while IL-13 levels were unchanged, both MCP-1 and IL-4 production were significantly lower at 10 weeks in comparison with wild-type. The present study clearly demonstrates the importance of both Th1 and Th2 cytokine responses in S. japonicum egg-induced granuloma formation.
Parasite Immunology 07/2001; 23(6):271-80. · 2.60 Impact Factor
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ABSTRACT: Nitric oxide (NO) plays diverse roles in a variety of pathological processes. We investigated the role of NO in Schistosoma japonicum egg-induced granuloma formation in a mouse hepatic model. Immunohistological analysis revealed that there is the most intense and extensive inducible nitric oxide (iNOS) expression 2 weeks after egg implantation, and thereafter it decreased considerably with time. Treatment with nitric oxide synthase inhibitors, NIL (L-N6- (iminoethyl)-lysine) or N(omega)-nitro-L-arginine methyl ester (L-NAME), resulted in two different types of unusual granulomas at 2 weeks. One type showed suppressed fibrosis, while another showed foreign body-type multinuclear cell formation which frequently appeared particularly when 50 microg/ml NIL was given. At 3 weeks following treatment, fibrotic granulomas with scanty peripheral cellularity was obvious. However, there were no apparent changes after this period (at 4 weeks). Cytokine analysis in NIL-treated mice showed a significant increase of IL-4 and IL-13 production at 2 weeks. These findings indicated that nitric oxide contributes to granuloma development during the early stages, probably through the regulation of Th2 cytokine production.
Parasite Immunology 07/2001; 23(6):281-9. · 2.60 Impact Factor
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ABSTRACT: To characterize the clinical and histologic features of chronic hepatitis C virus (HCV) infection after blood transfusion in Japanese children.
We studied 231 children with a history of blood product transfusion. Patients were divided into two groups: 116 patients with a history of malignant disease (group 1), 115 patients who had undergone open heart surgery (group 2). We examined changes in serum alanine aminotransferase (ALT) activity and HCV markers, and patients' clinical course. Moreover, in 38 patients in whom the time of HCV infection could be defined, we examined liver histology.
The proportions of patients in each group who were anti-HCV-positive were 35 out of 116 (30%) and 20 out of 115 (17%), respectively. Of the anti-HCV-positive patients, the proportions of HCV RNA-positive patients in each group were 30 out of 35 (86%) and 12 out of 20 (60%), respectively. Levels of ALT activity in patients with HCV infection varied widely for several years after blood transfusion; thereafter ALT activity fell to <100 IU/L in 2 groups. Serum ALT activity in patients who were HCV RNA-negative became normal. With regard to liver histology, there were no differences in the grade of necroinflammation or stage of fibrosis in patients with different durations of infection or when patients were analyzed according to the presence or absence of malignant disease. Patients mostly had grade 2-4 inflammation and stage 1-2 fibrosis. Thus, chronic hepatitis C was a morphologically mild disease in most children in this study.
Sixty percent to 80% of children with HCV infection in this study developed chronic hepatitis C. However, examination of liver histology findings in children with chronic hepatitis C showed only mild changes.
Pediatrics 01/2000; 105(1 Pt 1):62-5. · 5.44 Impact Factor
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T Kato,
M Mizokami,
M Mukaide,
E Orito,
T Ohno,
T Nakano,
Y Tanaka,
H Kato,
F Sugauchi,
R Ueda,
N Hirashima,
K Shimamatsu, M Kage,
M Kojiro
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ABSTRACT: Although TT virus (TTV) was isolated from a cryptogenic posttransfusion hepatitis patient, its pathogenic role remains unclear. It has been reported that the majority of the healthy population is infected with TTV. To elucidate the differences between TTV infection in patients with liver diseases and TTV infection in the healthy population, a quantification system was developed. TTV DNA was quantified by a real-time detection PCR (RTD-PCR) assay on an ABI Prism 7700 sequence detector. With this system, TTV DNA was quantified in 78 hepatitis C virus (HCV)-infected patients (63 with elevated serum alanine aminotransferase [ALT] levels and 15 with normal ALT levels) and in 70 voluntary blood donors (BDs). The quantification range was 2.08 to 7.35 log copies/ml. The intra-assay and interassay coefficients of variation were 0.37 to 6.33% and 0.60 to 7.07%, respectively. The mean serum TTV DNA levels in the HCV-infected patients with both elevated and normal ALT levels and BDs were 3.69 +/- 0.89, 3.45 +/- 0.76, and 3.45 +/- 0.67 log copies/ml, respectively. Comparison of the serum TTV DNA levels among the HCV-infected patients revealed that they were not related to the serum ALT and HCV core protein levels or to the histopathological score on liver biopsy. This study showed that (i) the RTD-PCR assay for the detection of TTV was accurate and had a high degree of sensitivity, (ii) the mean serum TTV DNA level was similar among HCV-infected patients, irrespective of their ALT level, and also among BDs, and (iii) a high serum TTV DNA level does not affect the serum ALT and HCV levels or liver damage in HCV-infected patients.
Journal of Clinical Microbiology 01/2000; 38(1):94-8. · 4.15 Impact Factor
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T Kato,
M Mizokami,
E Orito,
T Nakano,
Y Tanaka,
R Ueda,
N Hirashima,
Y Iijima,
F Sugauchi,
M Mukaide,
K Shimamatsu, M Kage,
M Kojiro
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ABSTRACT: Although a novel DNA virus, TT virus (TTV), has been isolated from a patient with cryptogenic post-transfusion hepatitis, its pathogenic role remains unclear. To elucidate its prevalence and clinical impact in patients with liver diseases, the presence of TTV DNA was assessed in patients with liver diseases and blood donors (BDs) in Japan using two primer sets, one conventional and the other new and highly sensitive.
We studied 261 samples, 72 with chronic hepatitis associated hepatitis C virus (HCV-CH), 57 with hepatocellular carcinoma associated HCV (HCV-HCC), 12 with HCC without either HCV or hepatitis B virus (NBNC-HCC), and 120 of BDs.
Using two primer sets, TTV DNA was detected in 68 (94.4%), 53 (93.0%), 12 (100%), and 98 (81.7%) HCV-CH, HCV-HCC, NBNC-HCC, and BDs, respectively. The prevalence was not significantly different between HCV-CH and HCV-HCC, or between HCV-HCC and NBNC-HCC. Comparison between patients with and without TTV revealed no significant differences in backgrounds or biochemical findings. Histopathological findings in patients with HCV-CH, and number, maximum diameter, and histological differentiation of HCC also did not demonstrate any relation to TTV infection. TTV strains can be divided into five groups using phylogenetic analysis, but no disease-specific group appears to exist.
Our data suggest that: 1) TTV is very prevalent among patients with liver diseases and even among BDs in Japan, 2) TTV infection does not impact on liver damage with HCV infection, and 3) TTV infection also does not affect the development or progression of HCC.
Journal of Hepatology 09/1999; 31(2):221-7. · 9.26 Impact Factor
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ABSTRACT: We report a patient with gastric enterochromaffin-like-cell tumor with liver and splenic metastases. He was 68 years old and presented with major complaints of epigastric pain and weight loss. Under the diagnosis of gastric carcinoma with liver metastasis, total gastrectomy with splenectomy and lateral segmentectomy of the liver was performed. Intraoperative findings resulted in a diagnosis of adenocarcinoma T3N2P0H1, in stage IVa. Histological examination of the resected specimens showed a well differentiated neuroendocrine carcinoma (enterochromaffin-like-cell tumor) with liver and splenic metastasis which demonstrated high-grade lymphatic and vascular invasion. There was no lymph node metastasis. The tumor cells in the stomach, liver and spleen were immunoreactive for chromogranin A and Grimelius--positive. We review the literature, as well as presenting this case report.
Journal of Gastroenterology 07/1999; 34(3):383-6. · 4.16 Impact Factor
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ABSTRACT: Budd-Chiari syndrome (BCS) was initially defined as a symptomatic occlusion of the hepatic veins, but subsequent reports on various obliterative changes that occur in the hepatic portion of the inferior vena cava (IVC) and hepatic vein orifices have resulted in a broadened and ambiguous definition. Membranous obstruction of the inferior vena cava has been regarded by many as a congenital vascular malformation, but its relation to the classical BCS has remained obscure. With modern imaging and recent histological study of new cases, membranous obstruction of the IVC is now considered to be a sequela to thrombosis. How to classify various forms of occlusion and stenosis of the IVC and hepatic vein ostia is a major challenge. In this review, we emphasize that primary hepatic vein thrombosis (classical Budd-Chiari) and an obliterative disease predominantly affecting the hepatic portion of the IVC, both of which account for most patients with venous outflow block, are clinically quite different. In the West, the former is more common than the latter, which constitutes the vast majority of cases of outflow block in developing countries such as Nepal, South Africa, China, and India. The latter is frequently complicated by hepatocellular carcinoma (HCC), and primary hepatic vein thrombosis is not. The major cause of thrombosis is a hypercoagulable state in hepatic vein thrombosis, but more of the latter cases are idiopathic. The clinical presentation of the latter is milder, and onset is frequently inapparent, whereas the former is more severe, sometimes causing acute hepatic failure. Markedly enlarged subcutaneous veins over the body trunk characterize the latter. We propose that these two disorders be clinically distinguished with a suggested term "obliterative hepato-cavopathy" for the latter against classical BCS.
Hepatology 12/1998; 28(5):1191-8. · 11.66 Impact Factor
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ABSTRACT: We sought to clarify important unresolved points regarding angioarchitecture and blood circulation in focal nodular hyperplasia.
Twenty-nine surgically resected focal nodular hyperplasia lesions were examined histologically, immunohistochemically, and radiologically. In three autopsy cases, red- and blue-colored gelatin was injected into the hepatic artery and the portal vein, respectively, to demonstrate the vasculature in focal nodular hyperplasia.
Histologically, no orientation with respect to portal tracts and central veins was evident in any lesion. Within lesions, vessels were classified as: (i) anomalous arteries in the fibrous septa, (ii) capillaries in the fibrous septa, or (iii) venous vessels located mainly in the parenchyma. Vessels and sinusoids adjacent to fibrous septa were stained for CD 34 and von Willebrand factor. The anomalous arteries were connected to the capillaries. Capillaries in the fibrous septa were connected to sinusoids adjacent to fibrous septa. Venous vessels were connected to central or hepatic veins surrounding the lesions. Intranodular sinusoids were connected to the sinusoids in the surrounding normal liver. Red-colored gelatin, injected at autopsy into the hepatic artery, appeared not only in the anomalous arteries but also in capillaries and in sinusoids adjacent to the fibrous septa of the lesion. Angiography clearly depicted hepatic veins located near the lesions in nine cases. Computed tomography during arterial portography disclosed no portal blood flow in the lesions.
In focal nodular hyperplasia, arterial blood flows from the anomalous arteries via the capillaries into sinusoids adjacent to fibrous septa. The blood in the sinusoids drained to the hepatic vein either directly or via perinodular sinusoids.
Journal of Hepatology 10/1998; 29(3):470-5. · 9.26 Impact Factor
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ABSTRACT: Pedunculated hepatocellular carcinoma (HCC) or extrahepatic growth of HC C is an uncommon but not rare pathological form, but its genesis is unknown. Right-sided adrenal metastases of HCC that were abutting on or about to fuse with the right hepatic lobe were resected in three patients. The masses seemed to have originated in the para-adrenal tissue, leaving the adrenal gland intact. They were partially supplied by the hepatic artery as well as by the suprarenal artery. Four cases of autopsied pedunculated HCC of the right lobe were also studied. The mass was protruding caudad from the noncancerous parenchyma of the right lobe. Postmortem angiography carried out on one liver showed that only a small portion of the mass toward the liver was supplied from the hepatic artery. These observations suggest that some, perhaps most, of the right-sided pedunculated HCCs represent fusion of the right lobe and para-adrenal or adrenal metastatic HCC. This phenomenon may be explained by possible transport of cancer cells toward the right adrenal gland through the so-called adrenohepatic fusion, a relatively common anatomical change in advanced age.
Hepatology 02/1998; 27(1):81-5. · 11.66 Impact Factor
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ABSTRACT: Schistosoma japonicum produces an enormous quantity of eggs during infection. This study was conducted to examine the effect of egg-derived antigens on the development of granuloma formation around S. japonicum eggs in the livers of mice. When soluble egg antigen (SEA) (75 micrograms/mouse/day) was injected 3-4 times via a vein into mice implanted with laid eggs, the magnitude of tissue lesion was drastically inhibited when assessed at maximal occurrence (14 days after implantation of eggs), whereas adult worm antigen (AWA), rabbit hyperimmune serum against SEA, or bovine serum albumin (BSA) did not show any effect on either the cellularity or the magnitude. In contrast to intravenous injection, there was no effect from subcutaneous injections of SEA. When serum taken from heavily infected mice or rabbit was transferred, there was a considerable extent of inhibition. In addition, an immune complex fraction of infected rabbit serum was found to have a stronger inhibitory effect than the supernatant fraction. This study indicates that the amount of egg-derived circulating antigens has a crucial effect on the development of schistosome granuloma formation.
Journal of Parasitology 11/1997; 83(5):842-7. · 1.40 Impact Factor
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ABSTRACT: Schistosomiasis japonica (SCJ) patients frequently develop hepatocellular carcinoma (HCC). This study investigated relationship between SCJ infection, hepatitis virus infection, and incidence of HCC, in 25 patients with chronic SCJ infection and HCC (SCJ with HCC group), 51 patients with chronic SCJ infection without HCC (SCJ group) and 65 HCC patients without SCJ (HCC group). Number of patients who were positive to HBsAg or hepatitis B virus DNA were 4 (16.0%) in the SCJ with HCC group, none (0%) in the SCJ group, and 5 (7.9%) in the HCC group; while number of patients who were positive to anti-hepatitis C virus antibody were 21 (87.5%) in the SCJ with HCC group, 3 (5.9%) in the SCJ group, and 58 (84.6%) in the HCC group. Biopsy was performed for all patients, and background histological features of each specimen were evaluated based on the histological activity index scoring system. Mean scores of inflammatory changes in both the portal area and parenchyma in the SCJ with HCC group were significantly higher than those in the SCJ group. Nodular formation which is common in post-viral hepatitis was frequently observed in the SCJ with HCC group, and histological changes in non-cancerous area of the SCJ with HCC group showed the characteristics of chronic viral hepatitis. We conclude that infection of hepatitis virus, particularly hepatitis C virus, affects synergistically on the hepatocarcinogenesis in patients having SCJ infection.
International Journal of Oncology 11/1997; 11(5):1103-7. · 2.40 Impact Factor
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T Takahata,
Y Sasaki,
K Hirano,
Y Ishiguro,
T Takahashi,
K Suto,
T Suto,
A Munakata,
H Yodono,
M Tanaka,
H Kudo, M Kage
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 10/1997; 94(9):615-21.
