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1.
Carcinogenesis ; 31(3): 504-11, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20015863

ABSTRACT

To identify key genes involved in the complex multistep process of hepatotumorigenesis, we reduced multivariate clinicopathological variables by using the Long-Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissues from rats of a naive status (4 weeks old), through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). Of 31 099 probe sets used for microarray analysis, 87 were identified as being upregulated in a stepwise manner during disease progression and tumor development. Quantitative real-time reverse transcription-polymerase chain reaction and statistical analyses verified that IQGAP1 and vimentin mRNA expression levels increased significantly throughout hepatotumorigenesis. A hierarchical clustering algorithm showed both genes clustered together and in the same cluster group. Immunohistochemical and western blot analyses showed similar increases in protein levels of IAGAP1 and vimentin. Finally, pathway analyses using text-mining technology with more comprehensive and recent gene-gene interaction data identified IQGAP1 and vimentin as important nodes in underlying gene regulatory networks. These findings enhance our understanding of the multistep hepatotumorigenesis and identification of target molecules for novel treatments.


Subject(s)
Gene Regulatory Networks/genetics , Liver Neoplasms, Experimental/genetics , Oxidative Stress , Vimentin/physiology , ras GTPase-Activating Proteins/physiology , Animals , Copper/metabolism , Disease Models, Animal , Disease Progression , Gene Expression Profiling , Genetic Association Studies , Hepatolenticular Degeneration , Humans , Liver/metabolism , Liver Neoplasms, Experimental/etiology , Liver Neoplasms, Experimental/metabolism , Male , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Inbred LEC , Rats, Long-Evans , Reverse Transcriptase Polymerase Chain Reaction , Vimentin/biosynthesis , Vimentin/genetics , ras GTPase-Activating Proteins/biosynthesis , ras GTPase-Activating Proteins/genetics
2.
Hum Cell ; 22(2): 43-8, 2009 May.
Article in English | MEDLINE | ID: mdl-19379463

ABSTRACT

Under organ culture, female fetal gonads in mice cannot develop beyond the preantral follicle stage unless the follicles are individually isolated and cultured again. In this study, we investigated the effect of in vitro culture of female fetal gonads before transplantation on subsequent in vivo development. The gonads derived from female fetuses 12.5 days postcoitum were organ-cultured for 0, 7 and 14 days, and then were grafted underneath the kidney capsules of severe combined immunodeficient mice and recovered at 21, 14 and 7 days post-transplantation, respectively. The histological analysis of the grafts showed that the in vitro culture of the fetal gonads restricted follicular development to the antral follicle stage post-transplantation. In the grafts cultured for 14 days, particularly, no antral follicle was observed. However, the oocytes in these follicles had grown to around 65 microm in diameter and had competence to resume meiosis in vitro. When the fetal gonads were grafted after culture for 7 and 14 days, 13.0% and 6.8% of the oocytes progressed to the metaphase II stage, respectively. These data showed significant differences (P < 0.05) in comparison with the control group (25.3%). Our results indicate that the in vitro culture of female fetal gonads before transplantation affects the subsequent in vivo development of both follicular cells and oocytes, and in vitro oocyte maturation. However, this effect seems to be more severe in terms of follicular development when compared with oocyte growth and maturation.


Subject(s)
Oocytes/growth & development , Ovary/embryology , Animals , Female , Kidney , Male , Meiosis , Metaphase , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Organ Culture Techniques , Ovarian Follicle/growth & development , Ovary/growth & development , Ovary/transplantation , Severe Combined Immunodeficiency
3.
J Hepatol ; 48(3): 486-93, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18191270

ABSTRACT

BACKGROUND/AIMS: To assess the effect of lactoferrin on oxidative liver damage and its mechanism, we used Long-Evans Cinnamon (LEC) rats that spontaneously develop fulminant-like hepatitis and lethal hepatic failure. METHODS: Four-week-old female LEC rats were divided into the untreated and treated groups. The latter was fed bovine lactoferrin at 2% mixed with conventional diet. RESULTS: The cumulative survival rates were 75.0% vs. 100% at 14 weeks, 37.5% vs. 91.7% at 15 weeks, and 12.5% vs. 91.7% at 16 weeks, respectively, for untreated and treated rats (P=0.0008). The 8-OHdG levels in liver mitochondrial DNA and malondialdehyde in plasma and liver tissues were significantly lower in treated than untreated rats (P<0.001, =0.017 and 0.034, respectively). Mitochondrial DNA mutations were more common in untreated rats. OGG1 mRNA and protein expression levels were significantly lower in untreated than treated rats (P=0.003 and 0.007, respectively). Hypermethylation of the second CpG island located upstream of OGG1 gene was observed in untreated rats. CONCLUSIONS: Our findings indicated that lactoferrin inhibits oxidative liver damage in LEC rats. Lactoferrin could be potentially useful for the treatment of oxidative stress-induced liver diseases.


Subject(s)
DNA Glycosylases/metabolism , Deoxyguanosine/analogs & derivatives , Lactoferrin/pharmacology , Liver/enzymology , Mitochondria, Liver/enzymology , 8-Hydroxy-2'-Deoxyguanosine , Animals , Caspase 3/metabolism , Cattle , CpG Islands/physiology , DNA Damage/physiology , DNA Glycosylases/genetics , DNA Methylation/drug effects , DNA Repair/physiology , DNA, Mitochondrial/metabolism , Deoxyguanosine/metabolism , Disease Models, Animal , Down-Regulation , Female , Hepatitis/metabolism , Hepatitis/pathology , Liver/drug effects , Liver/pathology , Liver Failure, Acute/metabolism , Liver Failure, Acute/pathology , Malondialdehyde/metabolism , Mitochondria, Liver/drug effects , Rats , Rats, Inbred LEC
4.
Lasers Surg Med ; 39(1): 76-82, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17096413

ABSTRACT

BACKGROUND AND OBJECTIVE: We developed a new imaging system to detect sentinel nodes (SNs) using a novel fluorescent tracer, ATX-S10Na(II), and investigated its usefulness in an animal model. STUDY DESIGN/MATERIALS AND METHODS: Human gastric carcinoma cells were implanted orthotopically into nude rats. ATX-S10Na(II) was injected subserosally into the primary tumor lesion, and visualized by a fluorescence spectro-laparoscope. Presence of tumor cells in lymph nodes (LNs) was determined by RT-PCR specific for human beta-actin. RESULTS: Injection of ATX-S10Na(II) was successful in 27 tumor-bearing rats. A red fluorescence was incorporated into the left gastric and hepatic LNs in 25 and 2 rats, respectively. Of note, human beta-actin was detected in most of these LNs. Fluorescence was not detected in LNs that did not contain cancer. CONCLUSION: ATX-S10Na(II) is useful for the detection of cancer-containing SNs in an animal model of gastric carcinoma, and may serve as a novel tracer in SN navigation surgery.


Subject(s)
Fluorescent Dyes , Lymphatic Metastasis/diagnosis , Porphyrins , Spectrometry, Fluorescence , Stomach Neoplasms/pathology , Actins/metabolism , Animals , CA-19-9 Antigen/blood , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Neoplasm Staging , Neoplasm Transplantation , Rats , Rats, Inbred F344 , Rats, Nude , Reverse Transcriptase Polymerase Chain Reaction , Sentinel Lymph Node Biopsy
5.
Exp Anim ; 54(1): 97-9, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15725686

ABSTRACT

The optimum dose for establishing superovulation in mice of Fertirelin Acetate (FA), an LH-RH analogue, was examined. Mice were subcutaneously injected with 5 IU of hCG at 17:00 (Day 0), and with various doses of FA (0.001 to 1.0 microg) five times at 4 h intervals on and after 22:00 on Day 0. To induce ovulation, 5 IU of hCG was again injected subcutaneously at 17:00 on Day 2. In the groups administered with doses ranging from 0.01 to 0.5 microg of FA, the number of ovulated eggs was significantly (p<0.05) larger than in the control group (12.9 +/- 5.9). The greatest number of ovulated eggs (22.6 +/- 7.3) was obtained in the group administered with 0.025 microg of FA. The results indicate that the effective dose of LH-RH analogue, FA, is between 0.1 and 0.5 microg for superovulation induction in mice.


Subject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/administration & dosage , Ovulation Induction/methods , Superovulation , Animals , Dose-Response Relationship, Drug , Female , Gonadotropin-Releasing Hormone/pharmacology , Mice , Mice, Inbred Strains , Superovulation/drug effects
6.
Int Immunopharmacol ; 4(3): 367-75, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15037214

ABSTRACT

BACKGROUND: The effects of the non-impairing, H(1)-receptor antagonist fexofenadine were investigated in in vivo mouse models of eosinophilia and systemic anaphylaxis. METHODS: Eosinophilia was investigated in C57BL/6 mice (n=5 per group) infected with Trichinella spiralis, with and without administration of fexofenadine HCl (5, 10 and 20 mg/kg/day). Eosinophilia was also studied, with and without fexofenadine administration, in mice with a congenital mast-cell deficiency (W/W(v)) and controls (+/+). The effect of fexofenadine HCl (20 mg/kg/day) on IL-5 and eotaxin blood levels was also investigated in C57BL/6 mice. In a separate model, systemic anaphylaxis was induced in C57BL/6 mice using T. spiralis antigen. Fexofenadine HCl (5, 10 and 20 mg/kg) or vehicle was administered 20 min before antigen challenge (n=5 per group). The effect of fexofenadine on systemic anaphylaxis caused by IgE and anti-IgE was also examined in CBF1 mice injected with serum from NC/Nga mice with high IgE levels. Rectal temperature was measured as an indicator of anaphylaxis. RESULTS: In C57BL/6 mice, repetitive oral administration of fexofenadine HCl (5, 10 and 20 mg/kg/day) resulted in dose-dependent suppression of eosinophilia (p<0.05-0.0001). No suppression was observed in mast-cell deficient W/W(v) mice. In addition, single oral administration of fexofenadine HCl (10 and 20 mg/kg) significantly suppressed the decrease in rectal temperature (p<0.01), a marker for systemic anaphylaxis, in C57BL/6 mice. In CBF1 mice injected with serum from NC/Nga mice with high IgE levels, the decrease in rectal temperature was suppressed by single administration of fexofenadine HCl (10 and 20 mg/kg; p<0.01 and p<0.001, respectively). Fexofenadine had no effect on peripheral IL-5 and eotaxin levels. CONCLUSION: These results indicate that fexofenadine suppresses both eosinophilia and systemic anaphylaxis, both of which are fundamental reactions in allergic diseases.


Subject(s)
Anaphylaxis/drug therapy , Eosinophilia/drug therapy , Histamine H1 Antagonists/therapeutic use , Terfenadine/analogs & derivatives , Terfenadine/therapeutic use , Trichinellosis/drug therapy , Anaphylaxis/etiology , Animals , Antigens, Helminth/chemistry , Chemokine CCL11 , Chemokines, CC/blood , Dose-Response Relationship, Drug , Endotoxins/analysis , Eosinophilia/etiology , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/pharmacology , Interleukin-5/blood , Intestine, Small/drug effects , Intestine, Small/pathology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Species Specificity , Terfenadine/administration & dosage , Terfenadine/pharmacology , Trichinella spiralis , Trichinellosis/complications , Trichinellosis/immunology
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