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1.
Physiol Res ; 72(3): 371-382, 2023 07 14.
Article in English | MEDLINE | ID: mdl-37449749

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by viruses or alcohol. Fibrotic hepatitis, cirrhosis, and hepatocellular carcinoma can develop. The recent increase in NAFLD incidence worldwide has stimulated drug development efforts. However, there is still no approved treatment. This may be due in part to the fact that non-alcoholic steatohepatitis (NASH) pathogenesis is very complex, and its mechanisms are not well understood. Studies with animals are very important for understanding the pathogenesis. Due to the close association between the establishment of human NASH pathology and metabolic syndrome, several animal models have been reported, especially in the context of overnutrition. In this study, we investigated the induction of NASH-like pathology by enhancing cholesterol absorption through treatment with hydroxypropyl-beta-cyclodextrin (CDX). Female Sprague-Dawley rats were fed a normal diet with normal water (control group); a high-fat (60 kcal%), cholesterol (1.25 %), and cholic acid (0.5 %) diet with normal water (HFCC group); or HFCC diet with 2 % CDX water (HFCC+CDX group) for 16 weeks. Compared to the control group, the HFCC and HFCC+CDX groups showed increased blood levels of total cholesterol, aspartate aminotransferase, and alanine aminotransferase. At autopsy, parameters related to hepatic lipid synthesis, oxidative stress, inflammation, and fibrosis were elevated, suggesting the development of NAFLD/NASH. Elevated levels of endoplasmic reticulum stress-related genes were evident in the HFCC+CDX group. In the novel rat model, excessive cholesterol intake and accelerated absorption contributed to NAFLD/NASH pathogenesis.


Subject(s)
Hypercholesterolemia , Hyperlipidemias , Non-alcoholic Fatty Liver Disease , Humans , Rats , Female , Animals , Non-alcoholic Fatty Liver Disease/chemically induced , 2-Hydroxypropyl-beta-cyclodextrin/metabolism , 2-Hydroxypropyl-beta-cyclodextrin/therapeutic use , Rats, Sprague-Dawley , Diet, High-Fat/adverse effects , Liver/metabolism , Cholesterol , Hypercholesterolemia/metabolism , Disease Models, Animal
2.
Physiol Res ; 66(5): 791-799, 2017 11 24.
Article in English | MEDLINE | ID: mdl-28730823

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes.


Subject(s)
Disease Progression , Liver/pathology , Liver/physiopathology , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/physiopathology , Animals , Blood Glucose/metabolism , Body Weight/physiology , Diet, High-Fat/adverse effects , Female , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/blood , Organ Size/physiology , Pregnancy
3.
Curr Cancer Drug Targets ; 12(7): 847-56, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22515525

ABSTRACT

Castrate resistant prostate cancer (CRPC) is a disease that is resistant to both hormone therapy and chemotherapy. At present, no curative therapy for CRPC has been established. Therefore, it is necessary to determine a novel molecular target for the development of therapeutic agents. We previously reported that AlkB homolog 3 (ALKBH3) is highly expressed in prostate cancer but not in benign prostatic hyperplasia or in normal prostate epithelium and that the expression levels of ALKBH3 protein are significantly correlated with the hormone-independent state of prostate cancer. Moreover, ALKBH3 regulates the invasion of prostate cancer cells via the regulation of matrix metalloproteinase 9. Here, we show that ALKBH3 gene silencing markedly induces apoptosis in hormone-independent prostate cancer cell line DU145 but not in the normal prostate epithelial cell line PNT2. Moreover, the in vivo tumorigenicity of DU145 cells was significantly inhibited by the administration of ALKBH3 siRNA. Furthermore, the anchorage-independent growth of DU145 cells was inhibited by ALKBH3 knockdown and promoted by ALKBH3 overexpression, significantly. ALKBH3 shRNA-expressing prostate cancer cells formed significantly smaller tumors than those of control shRNA transfectants in an in vivo xenograft model. These findings suggest that ALKBH3 is a promising target molecule for the development of CRPC therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , DNA Repair Enzymes/antagonists & inhibitors , DNA Repair Enzymes/genetics , Dioxygenases/antagonists & inhibitors , Dioxygenases/genetics , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/genetics , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , DNA Repair Enzymes/metabolism , Dioxygenases/metabolism , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Gene Silencing/drug effects , Humans , Male , Molecular Targeted Therapy/methods , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology
4.
Dentomaxillofac Radiol ; 35(1): 24-9, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16421260

ABSTRACT

OBJECTIVES: The purpose of this study was to investigate the usefulness of a new scanning agent of technetium-99m-hexakis-2-methoxy-isobutyl-isonitrile (Tc-99m-MIBI) for the diagnosis of malignant tumours of the head and neck. METHODS: Scintigraphy with Tc-99m-MIBI was performed in 19 patients with malignant tumours of the head and neck. Factors of the early and delayed static scans (hot, warm or cold uptake), the early and delayed retention indexes, the blood flow index and the tumour retention index were obtained from Tc-99m-MIBI scintigraphy. Tumour retention indexes were classified into three grades; slightly (>0.9), moderately (0.9-0.8) and severely (0.8>) decreased. Grade of tissue differentiation of tumour (well, moderately or poorly differentiated) and tumour size (T1 approximately T4) were examined using the excised tumour. Scintigraphic indexes and tumour characteristics were compared. RESULTS: The early static scan and tumour size showed a correlation with the blood flow index. However, the delayed static scan did not show any relationship with blood flow index and tumour size. The tumour retention index had a tendency to decrease in malignant tumours, and showed a significant correlation with the grade of tissue differentiation of the tumour. CONCLUSIONS: The tendency of the tumour retention index to decrease in Tc-99m-MIBI scintigraphy showed the malignancy of tumour and would be useful for the diagnosis of malignant tumours of the head and neck.


Subject(s)
Carcinoma, Squamous Cell/diagnostic imaging , Mouth Neoplasms/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Sestamibi , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/blood supply , Cell Differentiation , Female , Humans , Male , Middle Aged , Mouth Neoplasms/blood supply , Radionuclide Imaging , Regional Blood Flow
5.
Dentomaxillofac Radiol ; 34(5): 274-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16120876

ABSTRACT

OBJECTIVES: The purpose of this study is to estimate the role of permeability-glycoprotein (P-gp) in the technetium-99m-hexakis-2-methoxy-isobutyl-isonitrile (99Tc(m)-MIBI) scintigraphy. METHODS: 71 patients with squamous cell carcinoma (39 patients with well differentiated, 19 with moderately differentiated and 13 with poorly differentiated tumour) were examined. Eighteen of these patients underwent 99Tc(m)-MIBI scintigraphy (early and delayed scans). The tumour retention index, obtained from the ratio of the accumulation of the delayed scan to that of the early scan, was divided into three groups. The immunohistochemical evaluation of P-gp expression was performed in all 71 patients. Levels of the P-gp expression were classified into three grades (score 0, 1 and 2). Correlations among the tumour retention index, the P-gp expression and the tumour tissue differentiation were evaluated. RESULTS: 17 of 18 patients showed a decreasing of the tumour retention index ranging from 0.70 to 0.93 (mean+/-SD=0.850+/-0.071). The tumour retention index showed a statistical correlation with the P-gp expression and the tumour tissue differentiation (chi-squared=7.802>7.779, P=0.10 and 16.835>14.860, P=0.005, respectively). Moreover, there was a statistical correlation between the P-gp expression and the tumour tissue differentiation (chi-squared=14.863>14.860, P=0.005). CONCLUSION: There is a possibility that the P-gp expression is high in the high-grade malignant tumours and P-gp causes the decrease of tumour retention index.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , Carcinoma, Squamous Cell/diagnostic imaging , Head and Neck Neoplasms/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Sestamibi , Aged , Carcinoma, Squamous Cell/pathology , Cell Differentiation , Female , Head and Neck Neoplasms/pathology , Humans , Immunohistochemistry , Male , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Technetium Tc 99m Sestamibi/pharmacokinetics , Time Factors
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