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Keiko KATO, Hitomi MURAKAMI, Osamu ISOZAKI, Toshio TSUSHIMA, Kazue TAK ...
2009 Volume 56 Issue 1 Pages
17-27
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 01, 2008
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Serum BNP (brain naturiuretic peptide) and ANP (atrial natriuretic peptide) levels are reportedly elevated in patients with thyrotoxicosis. The increases may not be due to thyrotoxicosis itself but to secondary cardiovascular changes such as chronic heart failure (HF) or atrial fibrillation (AF) which frequently accompany thyrotoxicosis. We measured serum ANP and BNP levels in 130 patients with thyrotoxicosis and correlated them with HF severity and thyroid function. Thirty-seven normal subjects served as controls. Serum BNP levels in thyrotoxic patients were significantly higher than those in control subjects and significantly correlated with serum free T4, free T3 and ANP levels. In untreated Graves' disease serum BNP level was significantly elevated in patients with HF or AF. Multiple regression analysis revealed that HF, free T4, female gender and AF are independent contributing factors to the elevated BNP level, and that these four factors contributed about 40%. On the other hand, HF and AF were contributing variables for ANP level but the overall contribution of these factors was only 10%. After normalization of thyroid function, serum BNP levels were normalized in 70.5% of Graves' patients. BNP level in euthyroid state was dependent on the presence of HF and the BNP value before therapy, but not on thyroid hormone levels or AF. These data suggest that the cardiovascular condition is the major factor responsible for the elevated serum BNP and ANP levels in thyrotoxic patients, while thyrotoxicosis itself is an independent but minor contributing factor. Thus, the determination of serum BNP levels in thyrotoxic patients is useful for monitoring cardiovascular conditions of HF.
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Kaori OYAMA, Yoshihisa SUGIMURA, Takashi MURASE, Akira UCHIDA, Shizu H ...
2009 Volume 56 Issue 1 Pages
29-37
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: September 10, 2008
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It is well known that maternal diabetes causes various congenital malformations. Although there are many reports that folic acid (FA) administration in pregnancy reduces the risk of birth defects including neural tube defects (NTDs), a precise analysis on the preventive effect of FA against diabetic embryopathy has not been done yet. In this study, we analyzed the preventive effects of FA on congenital malformations including NTDs, cardiovascular, and skeletal malformations using a diabetic mouse model. Female mice were rendered hyperglycemic by streptozotocin and then mated. Pregnant diabetic mice were treated daily with FA (3 mg/kg body weight) or saline between gestational days (GD) 6 and 10. On GD 18, fetuses were examined for congenital malformations. FA did not affect plasma glucose levels. In the DM control group, the incidence of NTDs, cardiovascular, and skeletal malformations was 28.4%, 28.5%, and 29.7%, respectively. In the FA-treated group, the corresponding proportions reduced to 6.0%, 2.5% and 12.5%, respectively. A whole-mount TUNEL revealed an increased apoptosis in the hindbrain region of embryos from DM control group on day 9.5, and the apoptosis was decreased by FA treatment. Maternal plasma homocysteine levels on GD 9.5 were significantly lowered in DM control group compared with those in non-DM group, and FA treatment did not show a significant effect. These results indicate that FA is effective for the prevention of various diabetic embryopathy including NTDs, cardiovascular, and skeletal malformations, and suggested that this effect is independent from homocysteine metabolism and possibly mediated by decreasing the abnormal apoptosis during organogenesis.
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Yasuhiro NAKAMURA, Takashi SUZUKI, Yoichi ARAI, Hironobu SASANO
2009 Volume 56 Issue 1 Pages
39-44
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 01, 2008
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The orphan nuclear receptor DAX1 (dosage-sensitive sex reversal-AHC critical region on the X chromosome gene 1;
NR0B1) has been known for its various roles in human development, specifically sex determination and steroidogenesis. Its expression has been reported in endocrine and sex steroid-dependent neoplasms such as human adrenocortical, pituitary, endometrial, and ovarian tumors. Prostate cancer is also sex steroid-dependent tumor in which androgens play important roles in the pathogenesis and development via androgen receptor (AR). DAX1 is also reported to repress AR activity in human prostate cancer cell line (LNCaP) but its biological roles have remained unclear in the human prostate cancer. The aim of this study is to examine the expression of DAX1 in human prostate cancer using immunohistochemistry in order to evaluate its possible biological and/or clinical significance. In this study, we examined the DAX1 immunoreactivity in human prostate cancer obtained from surgery (n = 40), and correlated the findings with clinicopathological features of the patients. Twenty-one cases were defined as positive cases for DAX1 immunoreactivity (53%). Immunoreactivity for DAX1 was inversely and significantly correlated with Gleason score (
P<0.05). However, DAX1 immunoreactivity was not significantly correlated with the status of sex steroid receptors we examined. DAX1 immunoreactivity is considered a new biological modulator of human prostate cancer, but independent to the status of sex steroid receptors in human prostate cancer tissues.
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Koji NAKASHIMA, Yukiko KANDA, Yasushi HIROKAWA, Fumiko KAWASAKI, Michi ...
2009 Volume 56 Issue 1 Pages
45-53
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 09, 2008
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MIN6 cells retains glucose-stimulated insulin secretion (GSIS) as isolated islets. We comprehensively evaluated the gene expression and production of other islet hormones in MIN6 cells. Islet hormones were demonstrated by immunohistochemical staining and measured by ELISA. The gene expression profiles of MIN6 cells were compared with those in the mouse islets obtained by the laser capture micro-dissection (LCM). MIN6 cells excreted insulin, glucagon, somatostatin and ghrelin. They expressed mRNAs of insulin I and II, proglucagon, somatostatin, pancreatic polypeptide (PP) and ghrelin which were shown in the mouse pancreatic islet core and periphery obtained by LCM. A variety of genes closely related to the islet hormone producing cells were expressed in MIN6. Confocal laser scanning microscopy revealed that MIN6 cells included not only insulin positive cells but also insulin and glucagon or somatostin double positive cells. Glucagon, somatostatin and ghrelin were detectable in the culture medium. The present study clearly demonstrated that MIN6 produce pancreatic endocrine cells. It would be possible to use this cell line as a model to research the development, cell differentiation and function of pancreatic islets.
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Junfeng HAN, Tianhong LUO, Yanyun GU, Guo LI, Weiping JIA, Min LUO
2009 Volume 56 Issue 1 Pages
55-63
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 08, 2008
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We previously found that cathepsin K (CTSK) played an important role in adipocyte differentiation. However, the underlying molecular mechanism is not clear. Through the time window study, it was observed that CTSK activities were required mainly in the early phases of adipogenic process. At the same time, the expression of type I collagen disappeared. However, type I collagen can still be observed during the whole process when the CTSK inhibitor-E64 was added. The mRNA levels of peroxisome proliferator-activated receptor γ (PPAR- γ) and CCAAT/enhancer binding protein α (C/EBP- α) was also declining. These imply that CTSK may play a role in adipogenesis in early differentiation phases and produce an effect at least partly by degrading type I collagen, which may provides a basis for developing novel therapeutic approaches to treat obesity and the diseases associated with it.
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Noritaka ONODA, Yoshiyuki KATO, Toshiro SEKI, Makiko KURIMOTO, Kazue T ...
2009 Volume 56 Issue 1 Pages
65-72
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 08, 2008
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We report two cases with painful Hashimoto's thyroiditis, who developed recurrent fever and painful thyroid. Glucocorticoid treatment was transiently successful but tenderness in the thyroid gland and fever developed when glucocorticoid was tapered. One patient underwent total thyroidectomy uneventfully. As is well known, it is frequently difficult to make differential diagnosis between painful Hashimoto's thyroiditis and subacute thyroiditis particularly at the initial phase. Interestingly, color flow doppler sonography of patient 1 revealed an increased thyroid blood flow in the hypoechoic lesions at the time of acute exacerbation although the serum level of TSH was suppressed. In the other patient, thyroid blood flow was also increased mainly in the hypoechoic lesions when the serum level of TSH was moderately increased, and it disappeared completely after supplementation of prednisolone and L-T4. Since thyroid blood flow in subacute thyroiditis is always decreased, such an increased blood flow in the hypoechoic lesion may be one of clinical characteristics of painful Hashimoto's thyroiditis, and useful for differential diagnosis from subacute thyroiditis.
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Jae Woong SULL, Hee Jin KIM, Ji Eun YUN, Eun Jung PARK, Grace KIM, Sun ...
2009 Volume 56 Issue 1 Pages
73-78
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 08, 2008
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Objective: To measure the association between smoking and serum adiponectin, taking into consideration insulin resistance and obesity. Material and Methods: The cross-sectional study was carried out in Seoul, Korea in 2006. Waist circumference (WC), body mass index (BMI), and serum adiponectin were measured in 2,500 healthy Korean men. Multiple linear regression models were used to assess the association of smoking status with serum adiponectin level. WC, BMI, and homeostasis model assessment (HOMA) were classified into two groups according to median values. Results: The mean adiponectin concentrations were 6.6 μg/ml and 7.3 μg/ml in current smokers and non-smokers. After adjusting for age, BMI, and alcohol consumption, mean log adiponectin levels decreased by 0.064 μg/ml in current smokers compared with non-smokers (P = 0.0190). Mean log adiponectin levels also decreased by 0.030 and 0.095 μg/ml in moderate and heavy smokers compared to non-smokers. The relationship between adiponectin and smoking was similar between the high and low insulin resistance, BMI, and WC groups. Conclusions: These results suggest that serum adiponectin levels are associated with smoking status. These data also support that lower serum adiponectin concentrations in smokers may not be dependent on insulin resistance status or obesity.
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Shiko ASAI, Takuyuki KATABAMI, Naoko OBI, Tomoya MATSUI, Hiroyuki KATO ...
2009 Volume 56 Issue 1 Pages
79-87
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 22, 2008
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To investigate the role of ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, in diabetic gastroparesis, we evaluated the plasma ghrelin profile during the oral glucose tolerance test in 55 patients with diabetes (men/women: 36/19, mean ± SE of age: 55.1 ± 1.7 years) with or without gastroparesis (diagnosed by the
13C-acetate breath test). We also further examined cardiac autonomic neuropathy by assessing 24-hour variation of the R-R interval in randomly selected 32 patients with diabetes (men/women: 23/9, mean ± SE of age: 54.2 ± 2.5 years), and evaluated the influence of autonomic neuropathy on ghrelin. The fasting plasma ghrelin level was significantly lower in diabetes mellitus with gastroparesis than in healthy controls (7.9 ± 0.7 fmol/ml versus 16.6 ± 5.3 fmol/ml, p = 0.006). Patients with diabetes with gastroparesis showed no decrease of plasma ghrelin after glucose loading, unlike patients without gastroparesis or healthy controls. Diabetes mellitus with autonomic neuropathy, but not those without it, also showed no decrease of plasma ghrelin after glucose loading. Diabetic gastroparesis may be related to ghrelin-associated neurohormonal abnormalities, but the pathophysiological meaning of this abnormal ghrelin response needs further clarification.
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Yasuhiro ITO, Hiroshi YOSHIDA, Rie MARUO, Shinji MORITA, Toru TAKANO, ...
2009 Volume 56 Issue 1 Pages
89-97
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 08, 2008
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Recent studies have demonstrated that BRAF
V600E mutation is a common event in papillary thyroid carcinoma and a majority of these lesions have shown a direct relationship between BRAF
V600E mutation and aggressive characteristics, including a worse patient prognosis. However, there are no studies from Japan regarding this issue in a large series with adequate postoperative follow-up periods. We investigated BRAF
V600E mutation in 631 patients with papillary carcinoma having median follow-up periods of 83 months. The prevalence of BRAF
V600E mutation was 38.4%, and the rate was higher in carcinoma larger than 1.0 cm but did not successively increase with tumor size. Furthermore, the prevalence did not significantly increase in cases demonstrating high-risk biological features such as clinically apparent lymph node metastasis, massive extrathyroid extension, advanced age, distant metastasis at surgery, and advanced Stage. The disease-free survival of patients with BRAF
V600E mutation did not differ from that of those without BRAF
V600E mutation. These findings indicate that, although BRAF
V600E mutation may play some roles in local carcinoma development, there is no evidence that BRAF
V600E mutation significantly reflects the aggressive characteristics and poor prognosis of patients with papillary carcinoma in Japan.
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Bin YAO, Xue LIU, Hua LIANG, Ting-ting DONG, Zhi-min HUANG, Xiong CHEN ...
2009 Volume 56 Issue 1 Pages
99-104
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 09, 2008
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Germline mutations in the RET proto-oncogene (RET gene) are well documented as the genetic causes of multiple endocrine neoplasia type 2A (MEN2A). We performed genetic analysis by direct RET gene mutation analysis in a Chinese MEN2A family and compared these results with biochemical screening tests and pathological examinations. Twenty-one exons and flanking introns of the RET gene were amplified using polymerase chain reaction (PCR). The PCR products were subjected to sequencing directly, or cloned into pGEM-T plasmids and sequenced. Restriction fragment length polymorphism (RFLP) was employed to confirm the mutation on the RET sequence. A novel heterozygous mutation of a 3-bp (GAC) deletion at codon 631 (D631del) of exon 11, resulting in the deletion of an aspartic acid at the locus, was identified in four MEN2A patients and one phenotypically normal family member. The average clinical onset-age of four MEN2A patients was 33.7 years, no cervical lymph node metastasis was found in MEN2A patients with medullary thyroid carcinoma in the family. The study indicated that the novel heterozygous deletion mutation at D631 of RET gene was co-segregated with MEN2A phenotype and promoted the development of MEN2A. This report is the first description of the D631del mutation in the family with MEN2A.
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Won Gu KIM, Eui Young KIM, Tae Yong KIM, Jin-Sook RYU, Suck Joon HONG, ...
2009 Volume 56 Issue 1 Pages
105-112
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 11, 2008
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Radioiodine (I-131) therapy is of proven efficacy for treatment of differentiated thyroid carcinoma (DTC). However, loss of differentiation in recurrent or metastatic DTC which decrease I-131 uptake may decrease the efficacy of I-131 therapy. Therefore, strategies to improve I-131 uptake are mandatory. This study is an open label clinical study to evaluate the effectiveness of 13-
cis retinoic acid (13-
cis RA) for improving I-131 uptake in recurrent or metastatic of DTC with defective I-131 uptake. Eleven patients (Age 27-66 years, M : F=4 : 7) were given 13-
cis RA (1.5 mg/kg daily for 5 weeks), followed by 200 mCi (7.4 GBq) I-131 treatment. The differences of serum thyroglobulin (Tg) level and I-131 uptake on the post-treatment whole body scan (RxWBS) were compared before and after 13-
cis RA therapy. Six out of 11 patients showed significantly increased (above 50%) Tg levels just after RA therapy. However, Tg levels a year after I-131 therapy were increased, stable and decreased in 7, 2 and 1 patients, respectively. Iodine uptake on RxWBS showed marginal improvement in only 2 patients and their Tg levels after one year follow-up increased. Most frequent adverse events were dry skin and lips. 13-
cis RA partially restores I-131 uptake in few patients with recurrent or metastatic DTC. The use of 13-
cis RA in current protocol has only limited usefulness and is not routinely recommended as currently used protocol.
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Chikari TAKEO, Kazuhiro IKEDA, Kuniko HORIE-INOUE, Satoshi INOUE
2009 Volume 56 Issue 1 Pages
113-120
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 22, 2008
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Estrogen has an important effect on higher brain function such as memory, learning, and emotion in which the hippocampus plays a critical role. The hippocampus expresses estrogen receptors, ER α and ERβ, which are ligand-dependent transcription factors; however, the precise mechanism of estrogen action is not fully understood. We explored genes which are up-regulated by estrogen in the hippocampus using ovariectomized rat models. Microarray analysis revealed that mRNA levels of ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2), insulin like growth factor 2 (Igf2) and insulin-like growth factor binding protein 2 (Igfbp2) were increased by estrogen in the hippocampus. Quantitative-PCR analysis demonstrated that the levels of Enpp2, Igf2 and Igfbp2 mRNA were elevated by estrogen administration in the hippocampus but not in the hypothalamus. On the other hand, ERα, ERβ and progesterone receptor (PR) mRNA expression was up-regulated by estrogen only in the hypothalamus. We further analyzed the time-dependent regulation of these genes using rat pituitary adenoma, MtT/S and GH3 cells, which are known to express ERα. In both MtT/S and GH3 cells, Igfbp2 and Enpp2 mRNAs were up- and down-regulated by estrogen, respectively, whereas Igf2 mRNA was increased only in GH3 cells. These results demonstrate a brain region- and cell type-specific responses to estrogen in rat brain, suggesting that Igf signaling may mediate the estrogen function in the hippocampus.
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Hiroshi TAKEMORI, Yoshiko KATOH HASHIMOTO, Jun NAKAE, Eric N. OLSON, M ...
2009 Volume 56 Issue 1 Pages
121-130
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: October 22, 2008
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Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. The activated SIK1 then auto-phosphorylates its Ser186 located at the +4 position of Thr182. The phospho-Ser186 is essential for sustained activity of SIK1, which is maintained by sequential phosphorylation at Ser186-Thr182 by glycogen synthase kinase (GSK)-3β. Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein (CREB) by phosphorylating its co-activator transducer of regulated CREB activity (TORC). Recently, histone deacetylase (HDAC) 5 was identified as a new substrate of SIK1. Inhibition of SIK1 or AMPK results in the stimulation of glyconeogensis in the liver by enhancing dephosphorylation of TORC2 followed by up-regulation of peroxisome proliferator-activated receptor coactivator (PGC)-1α gene expression. However, expression of the
PGC-1α gene has been found to be repressed in LKB1-defective muscle cells. Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-dependent expression of
PGC-1α is diminished by inhibitors of GSK-3β or SIKs in C2C12 myoblasts. Treatment with AICAR or the overexpression of SIK1 induces nuclear export of HDAC5 followed by the activation of myogenic transcription factor (MEF)-2C. The levels of phosphorylation at Thr182 and Ser186 of SIK1 in AICAR-treated C2C12 cells are elevated, and GSK-3β enzyme purified from AICAR-treated cells shows enhanced phosphorylation activity of SIK1
in vitro. These observations suggest that GSK-3 β and SIK1 may play important roles in the regulation of
PGC-1α gene expression by inactivating HDAC5 followed by activation of MEF2C.
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Koji SATO, Hideki FUKATA, Yasushi KOGO, Jun OHGANE, Kunio SHIOTA, Chis ...
2009 Volume 56 Issue 1 Pages
131-139
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: November 08, 2008
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Perinatal exposure to diethylstilbestrol (DES) can have numerous adverse effects on the reproductive organs later in life, such as vaginal clear-cell adenocarcinoma. Epigenetic processes including DNA methylation may be involved in the mechanisms. We subcutaneously injected DES to neonatal C57BL/6 mice. At days 5, 14, and 30, expressions of DNA methyltransferases (Dnmts) Dnmt1, Dnmt3a, and Dnmt3b, and transcription factors Sp1 and Sp3 were examined. We also performed restriction landmark genomic scanning (RLGS) to detect aberrant DNA methylation. Real-time RT-PCR revealed that expressions of Dnmt1, Dnmt3b, and Sp3 were decreased at day 5 in DES-treated mice, and that those of Dnmt1, Dnmt3a, and Sp1 were also decreased at day 14. RLGS analysis revealed that 5 genomic loci were demethylated, and 5 other loci were methylated by DES treatment. Two loci were cloned, and differential DNA methylation was quantified. Our results indicated that DES altered the expression levels of Dnmts and DNA methylation.
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Dong-Sun KIM, Emina ITOH, Keiji IIDA, Michael O THORNER
2009 Volume 56 Issue 1 Pages
141-147
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: November 08, 2008
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GH plays an important role in lipid metabolism as a partitioning hormone. PPARδ regulates lipid oxidation in skeletal muscle and is activated by several physiological ligands including fatty acids. To investigate whether GH has an effect on the regulation of transcription of PPARδ and other genes involved in energy metabolism in skeletal muscle, mRNA levels were studied by real-time RT-PCR in
lit/lit mice (isolated GH deficiency) and
lit/+ mice controls (normal GH levels). Mice received either a single bolus (120 ng/g) of rat GH or vehicle, and skeletal muscle was collected 4h later. PPARδ mRNA was increased in vehicle-treated
lit/lit mice compared to vehicle-treated
lit/+ mice (1.67 fold,
P<0.05).
lit/lit mice treated with GH showed a further increase in PPARδ mRNA levels (2.83 fold vs. vehicle-treated
lit/+ mice,
P<0.001). mRNA levels of Foxo1 were increased in vehicle-treated
lit/lit mice compared to vehicle-treated
lit/+ mice (1.74 fold,
P<0.05).
lit/lit mice treated with GH showed a further increase in Foxo1 mRNA levels (6.30 fold vs. vehicle-treated
lit/+ mice,
P<0.001). mRNA levels of acyl CoA-oxidase showed a trend to be higher in vehicle-treated
lit/lit mice compared to vehicle-treated
lit/+ mice. This reached statistical significance in GH-treated
lit/lit mice compared to vehicle-treated
lit/+ mice (2.11 fold,
P<0.05). In summary, mRNA levels of PPARδ and Foxo1 were increased in skeletal muscle of GH-deficient mice, and further acutely increased by GH administration. These results suggest that GH plays a relevant role in the lipid catabolism in skeletal muscle.
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Chie OHMURA, Hirotaka WATADA, Kosuke AZUMA, Tomoaki SHIMIZU, Akio KANA ...
2009 Volume 56 Issue 1 Pages
149-156
Published: 2009
Released on J-STAGE: March 12, 2009
Advance online publication: November 08, 2008
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The increased flux of polyol pathway induced by hyperglycemia is implicated in the pathogenesis of various complications associated with diabetic, which results in increased oxidative stress. Because oxidative stress causes tissue damage in patients with diabetes, searching for an effective strategy to reduce oxidative stress in clinical setting is important in order to prevent diabetic complications. The aim of this study was to evaluate the effects of aldose reductase inhibition on oxidative stress in patients with type 2 diabetes mellitus. The subjects of this study were 21 patients with type 2 diabetes. We compared the levels of various oxidative stress markers and antioxidants including plasma thiobarbituric acid-reactive substances, malondialdehyde-modified low-density lipoprotein, vitamin E, β-carotene and lipid hydroperoxides in erythrocytes at baseline with those measured after a 3-month course of epalrestat (150 mg/day), an aldose reductase inhibitor. While administration of epalrestat did not result in significant changes in plasma thiobarbituric acid-reactive substances, malondialdehyde-modified low-density lipoprotein, vitamin E, or β-carotene, it significantly reduced lipid hydroperoxides in erythrocytes. Given the importance of measuring lipid hydroperoxides in erythrocytes as an index of oxidative stress, these results highlight the potential usefulness of epalrestat in reducing oxidative stress in type 2 diabetes mellitus.
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