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1.
Diabetes Res Clin Pract ; 74(2): 148-53, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16828917

ABSTRACT

Mitochondrial respiratory function in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with heteroplasmic mitochondrial DNA (mtDNA) C3310T mutation, which replaces the second amino acid of NADH dehydrogenase 1 (ND1) from a hydrophobic Proline to a hydrophilic Serine, was investigated. Mitochondrial respiratory function solely due to mtDNA C3310T mutation was investigated in cybrid system by the fusion of mtDNA-deleted (rho(0)) HeLa cells and exogenous mtDNA either from the proband or from controls. Total oxygen consumption of the proband cybrid cells was significantly decreased compared with those of controls (2.468+/-0.475 versus 2.871+/-0.484 micromol/h/10(7) cells, p=0.0392). Mitochondrial respiratory chain complex I activity of the proband cybrid cells was also significantly decreased compared with those of controls (0.191+/-0.080 versus 0.288+/-0.113 micromol/h/mg protein, p=0.0223). Furthermore, ATP content in the proband cybrid cells was also significantly decreased compared with those in controls (1.119+/-0.344 versus 1.419+/-0.378 pmol/10(5) cells, p=0.044). The present study indicates that mtDNA C3310T mutation may be a pathogenic mutation of maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy in the proband and the family.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , DNA, Mitochondrial/genetics , Diabetes Mellitus, Type 2/genetics , Diabetic Angiopathies/genetics , Electron Transport Complex I/genetics , Polymorphism, Single Nucleotide , Blotting, Southern , Cardiomyopathy, Hypertrophic/enzymology , Diabetes Mellitus, Type 2/enzymology , Diabetic Angiopathies/enzymology , HeLa Cells , Humans , Male , Middle Aged , Mutation , Oxygen Consumption
2.
Endocrinology ; 145(11): 5397-405, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15271884

ABSTRACT

Loss of thyroid-specific gene expression and functions accompanied by loss of thyroid transcription factors render them unresponsive to radioiodide therapy in poorly differentiated and anaplastic thyroid cancer. In anticipation of reactivation of thyroid functions, we investigated the effect of thyroid transcription factor-1 (TTF-1) gene transfer on thyroid cancer cells. Reexpression of thyroperoxidase (TPO) and thyroglobulin (Tg) mRNA and protein was detected in poorly differentiated human thyroid cancer cells that were infected with an adenovirus vector containing TTF-1 (AdTTF-1). Although TTF-1 gene transfer faintly induced iodide uptake, the induction of sodium/iodide symporter (NIS) mRNA was not observed in AdTTF-1-infected cells. To analyze the effect of TTF-1 on iodide metabolism, we transfected an NIS expression vector into BHP18-21v cells and cloned a cell line (N-BHP18-21v) that stably expressed NIS. The treatment of N-BHP18-21v cells with AdTTF-1 significantly increased the amount of protein-bound radioiodide and prolonged the iodide efflux. AdTTF-1 injections significantly induced iodide retention and organification in tumors formed from N-BHP18-21v cells in nude mice. These results indicate that AdTTF-1 specifically induces iodide organification and retards iodide efflux in thyroid cancer cells in vitro and in vivo.


Subject(s)
Carcinoma, Papillary , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Thyroid Neoplasms , Transcription Factors/genetics , Transcription Factors/metabolism , Adenoviridae/genetics , Autoantigens/genetics , Gene Transfer Techniques , Humans , Iodide Peroxidase/genetics , Iodides/pharmacokinetics , Iodine Radioisotopes/pharmacokinetics , Iron-Binding Proteins/genetics , Thyroglobulin/genetics , Thyroid Nuclear Factor 1 , Tumor Cells, Cultured
3.
Diabetes Res Clin Pract ; 64(1): 11-8, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15036822

ABSTRACT

In order to investigate the effect of high carbohydrate/low fat diet on glucose tolerance and on lipid profiles, we performed a 4-week crossover study. Japanese subjects (30 patients with type 2 diabetes mellitus, 15 subjects with impaired glucose tolerance and 8 subjects with normal glucose tolerance) were allocated either 55% standard carbohydrate/30% fat (sc) or 70% high carbohydrate/15% low fat (hc) diet for four weeks, and evaluated by OGTT and various parameters. Then, the diet was crossed over to another diet, and identical parameters were re-evaluated after four weeks. Area under the glucose concentration-time curve (AUG) or triglyceride did not show significant changes between the two diets. HDL-Cholesterol and body mass index decreased significantly by hc diet. Free fatty acids and homeostasis model assessment insulin resistance index showed a tendency to be decreased by hc diet. AUG hc/sc ratio was inversely correlated with AUG or free fatty acids on standard carbohydrate diet. In conclusion, the present 4-week high carbohydrate/low fat diet may be useful to reduce body weight and insulin resistance. The 4-week high carbohydrate/low fat diet did not affect glucose tolerance as a whole. Although the 4-week high carbohydrate/low fat diet decreased HDL-Chol, it did not increase triglyceride.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diet, Fat-Restricted , Dietary Carbohydrates/pharmacology , Lipids/blood , Body Mass Index , Diabetes Mellitus, Type 2/diet therapy , Fatty Acids, Nonesterified/blood , Female , Glucose Tolerance Test , Humans , Male , Middle Aged
4.
Endocrinology ; 145(6): 2865-75, 2004 Jun.
Article in English | MEDLINE | ID: mdl-14976143

ABSTRACT

Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.


Subject(s)
Carcinoma, Papillary/metabolism , Depsipeptides , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Iodide Peroxidase/metabolism , Symporters/metabolism , Thyroglobulin/metabolism , Thyroid Neoplasms/metabolism , Animals , Carcinoma, Papillary/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cycloheximide/pharmacology , Gene Expression/drug effects , Humans , Immunohistochemistry , Iodide Peroxidase/genetics , Iodine Radioisotopes/pharmacokinetics , Mice , Mice, Nude , Peptides, Cyclic/pharmacology , Protein Synthesis Inhibitors/pharmacology , RNA, Messenger/metabolism , Symporters/genetics , Thyroglobulin/genetics , Thyroid Neoplasms/pathology
5.
Clin Exp Nephrol ; 7(1): 27-32, 2003 Mar.
Article in English | MEDLINE | ID: mdl-14586740

ABSTRACT

BACKGROUND: It has been recently reported that peroxisome proliferator-activated receptors (PPARs)gamma exist in various tissues and that they exibit anti-inflammatory effects. METHODS: We investigated the effects of PPARgamma activators on the development of crescentic glomerulonephritis. Crescentic glomerulonephritis was induced by the injection of rabbit anti-rat glomerular basement membrane antibody in WKY rats. RESULTS: Administration of troglitazone suppressed urinary protein excretion and crescent formation as indicated by crescent scores. Pioglitazone, a PPARgamma activator, mimicked the effect of troglitazone, but bezafibrate, a PPARalpha-activator, did not. Immunohistology revealed that troglitazone and pioglitazone inhibited the infiltration of ED-1-positive monocyte/macrophages and CD8-positive cells into glomeruli. CONCLUSIONS: In the present study, we demonstrated that PPARgamma activators exert antinephritic effects by suppressing the recruitment of inflammatory cells via a PPARgamma-dependent mechanism.


Subject(s)
Anti-Glomerular Basement Membrane Disease/prevention & control , Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/drug effects , Transcription Factors/physiology , Animals , Anti-Glomerular Basement Membrane Disease/immunology , Anti-Glomerular Basement Membrane Disease/pathology , Antibodies/administration & dosage , Autoantibodies , CD8-Positive T-Lymphocytes/pathology , Chromans/therapeutic use , Kidney Glomerulus/immunology , Kidney Glomerulus/pathology , Kinetics , Macrophages/pathology , Male , Monocytes/pathology , Pioglitazone , Proteinuria , Rabbits , Rats , Rats, Inbred WKY , Thiazolidinediones/therapeutic use , Troglitazone
6.
Exp Nephrol ; 10(5-6): 393-401, 2002.
Article in English | MEDLINE | ID: mdl-12381924

ABSTRACT

Peroxisome proliferator-activated receptor-gamma (PPARgamma) belongs to a superfamily of nuclear receptors, which plays important roles in lipid and glucose metabolism. However, expression of PPARgamma in extra-adipose tissues and stimulation of apoptosis by PPARgamma activators has been previously reported. We investigated the functions of PPARgamma using a clonal kidney cell line (LLC-PK1). RT-PCR revealed the expression of PPARgamma in LLC-PK1 cells. The cells accumulated fat droplets and increased beta-oxidation of free fatty acids in response to troglitazone, a ligand for PPARgamma. At physiological concentrations, ligands for PPARgamma including troglitazone, BRL49653, and 15-deoxy-delta-12,14-prostaglandin J(2) inhibited serum-deprivation-induced apoptosis of the cells. On the other hand, PPARalpha activators did not inhibit the apoptosis. Apoptosis of LLC-PK1 cells was determined by a cell viability assay, condensation of the nucleus on fluorescent and electron microscopy, and DNA fragmentation as indicated by the appearance of nucleosomal ladders on an agarose gel. Troglitazone also suppressed serum-deprivation-induced activation of Caspase 3. However, troglitazone did not suppress apoptosis induced by ATP deprivation. Anti-apoptotic effects of troglitazone were partially blocked by a phosphatidylinositol-3-kinase (PI3K) inhibitor, wortmannin, but not by other kinase inhibitors such as PD98059 and AG490. These results suggest that PPARgamma is functionally expressed in LLC-PK1 cells, and its activation inhibits apoptosis induced by serum deprivation, at least in part, through the PI3K pathway.


Subject(s)
Apoptosis/physiology , Culture Media, Serum-Free/pharmacology , Receptors, Cytoplasmic and Nuclear/physiology , Thiazolidinediones , Transcription Factors/physiology , Adenosine Triphosphate/deficiency , Androstadienes/pharmacology , Animals , Apoptosis/drug effects , Caspase 3 , Caspases/metabolism , Cell Survival/physiology , Chromans/pharmacology , Enzyme Inhibitors/pharmacology , LLC-PK1 Cells/physiology , Swine , Thiazoles/pharmacology , Troglitazone , Wortmannin
7.
Diabetes Res Clin Pract ; 57(3): 163-70, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12126765

ABSTRACT

The effect of high carbohydrate (hc) diet on glucose tolerance and on lipid profiles in patients with type 2 diabetes mellitus is contradicted. Japanese patients with mild type 2 diabetes mellitus were allocated either 55% standard carbohydrate (sc) or 80% high carbohydrate diets for 1 week, and OGTT and lipid profiles were examined. Then the diet was crossed over for another week, and OGTT and other identical parameters were re-evaluated. High carbohydrate diet improved the area under the glucose concentration-time curve (AUG) in 16/24 patients, and significantly increased and decreased 1,5-anhydroglucitol and homeostasis model assessment insulin resistance (HOMA-R) as a whole, respectively. Fasting plasma glucose (FPG) hc/sc ratio was inversely correlated with HOMA-R on a standard carbohydrate diet. High carbohydrate diet significantly decreased LDL- and HDL-cholesterol, whereas it significantly increased triglyceride. Furthermore, hc/sc ratios of the lipid parameters were inversely correlated with the respective parameters on standard carbohydrate diet. The present study indicates that high carbohydrate diet improved glucose tolerance depending on patients and the improvement in FPG was predicted by HOMA-R on a standard carbohydrate diet. The effect of high carbohydrate diet on glucose tolerance and lipid profiles should be investigated through a long-term study in the future.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Dietary Carbohydrates/pharmacology , Adult , Aged , Blood Glucose/drug effects , Body Mass Index , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Female , Glucose Tolerance Test , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Regression Analysis , Triglycerides/blood
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