BioMed Research International: Endocrinology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Evaluation of Parotid Salivary Glucose Level for Clinical Diagnosis and Monitoring Type 2 Diabetes Mellitus Patients Tue, 31 Jan 2017 10:04:02 +0000 Background. To investigate the relationships among blood glucose, mixed saliva glucose, and parotid glucose in type 2 diabetes patients and to evaluate the diagnostic and monitoring value of salivary gland glucose in patients with type 2 diabetes (type 2DM). Material and Methods. Thirty patients with type 2DM and 30 healthy age- and sex-matched individuals were included in this study. Glucose levels in unstimulated mixed saliva and in unstimulated parotid saliva were measured by the glucose oxidase peroxidase method. Results. The blood glucose and parotid salivary glucose levels in type 2DM patients were significantly higher than those in the controls (). The blood glucose, parotid salivary glucose, and mixed salivary glucose were  mmol/L,  mmol/L, and  mmol/L, respectively, in the type 2DM group; the corresponding glucose levels in the control group were  mmol/L,  mmol/L, and  mmol/L. The parotid salivary and blood glucose levels in type 2DM patients were strongly correlated; the linear regression equation for blood glucose and parotid salivary glucose was , with . However, mixed salivary glucose levels were not significantly different in the type 2 diabetes group compared with the control group. Conclusion. Our results suggest that parotid salivary glucose has potential as a biomarker to monitor type 2DM and as a painless, noninvasive method for the management of type 2DM. Beibei Wang, Juan Du, Zhao Zhu, Zhihong Ma, Songlin Wang, and Zhaochen Shan Copyright © 2017 Beibei Wang et al. All rights reserved. Effects of Tibolone on the Central Nervous System: Clinical and Experimental Approaches Mon, 16 Jan 2017 11:09:03 +0000 Hormone replacement therapy (HRT) increases the risk of endometrial and breast cancer. A strategy to reduce this incidence is the use of tibolone (TIB). The aim of this paper was to address the effects of TIB on the central nervous system (CNS). For the present review, MEDLINE (via PubMed), LILACS (via BIREME), Ovid Global Health, SCOPUS, Scielo, and PsycINFO (ProQuest Research Library) electronic databases were searched for the results of controlled clinical trials on peri- and postmenopausal women published from 1990 to September 2016. Also, this paper reviews experimental studies performed to analyze neuroprotective effects, cognitive deficits, neuroplasticity, oxidative stress, and stroke using TIB. Although there are few studies on the effect of this hormone in the CNS, it has been reported that TIB decreases lipid peroxidation levels and improves memory and learning. TIB has important neuroprotective effects that could prevent the risk of neurodegenerative diseases in postmenopausal women as well as the benefits of HRT in counteracting hot flashes, improving mood, and libido. Some reports have found that TIB delays cognitive impairment in various models of neuronal damage. It also modifies brain plasticity since it acts as an endocrine modulator regulating neurotransmitters, Tau phosphorylation, and decreasing neuronal death. Finally, its antioxidant effects have also been reported in different animal models. Rodolfo Pinto-Almazán, Julia J. Segura-Uribe, Eunice D. Farfán-García, and Christian Guerra-Araiza Copyright © 2017 Rodolfo Pinto-Almazán et al. All rights reserved. Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells Thu, 12 Jan 2017 10:41:52 +0000 Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM) from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12–48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells. Araceli Gutiérrez-Rodríguez, Valeria Hansberg-Pastor, and Ignacio Camacho-Arroyo Copyright © 2017 Araceli Gutiérrez-Rodríguez et al. All rights reserved. Conservative Nonhormonal Options for the Treatment of Male Infertility: Antibiotics, Anti-Inflammatory Drugs, and Antioxidants Mon, 09 Jan 2017 00:00:00 +0000 The nonhormonal medical treatment can be divided into empirical, when the cause has not been identified, and nonempirical, if the pathogenic mechanism causing male infertility can be solved or ameliorated. The empirical nonhormonal medical treatment has been proposed for patients with idiopathic or noncurable oligoasthenoteratozoospermia and for normozoospermic infertile patients. Anti-inflammatory, fibrinolytic, and antioxidant compounds, oligo elements, and vitamin supplementation may be prescribed. Infection, inflammation, and/or increased oxidative stress often require a specific treatment with antibiotics, anti-inflammatory drugs, and/or antioxidants. Combined therapies can contribute to improve sperm quality. Aldo E. Calogero, Rosita A. Condorelli, Giorgio Ivan Russo, and Sandro La Vignera Copyright © 2017 Aldo E. Calogero et al. All rights reserved. Hypothyroidism Reduces the Size of Ovarian Follicles and Promotes Hypertrophy of Periovarian Fat with Infiltration of Macrophages in Adult Rabbits Wed, 04 Jan 2017 07:05:31 +0000 Ovarian failure is related to dyslipidemias and inflammation, as well as to hypertrophy and dysfunction of the visceral adipose tissue (VAT). Although hypothyroidism has been associated with obesity, dyslipidemias, and inflammation in humans and animals, its influence on the characteristics of ovarian follicles in adulthood is scarcely known. Control and hypothyroid rabbits were used to analyze the ovarian follicles, expression of aromatase in the ovary, serum concentration of lipids, leptin, and uric acid, size of adipocytes, and infiltration of macrophages in the periovarian VAT. Hypothyroidism did not affect the percentage of functional or atretic follicles. However, it reduced the size of primary, secondary, and tertiary follicles considered as large and the expression of aromatase in the ovary. This effect was associated with high serum concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-C). In addition, hypothyroidism induced hypertrophy of adipocytes and a major infiltration of CD68+ macrophages into the periovarian VAT. Our results suggest that the reduced size of ovarian follicles promoted by hypothyroidism could be associated with dyslipidemias, hypertrophy, and inflammation of the periovarian VAT. Present findings may be useful to understand the influence of hypothyroidism in the ovary function in adulthood. J. Rodríguez-Castelán, M. Méndez-Tepepa, Y. Carrillo-Portillo, A. Anaya-Hernández, J. Rodríguez-Antolín, E. Zambrano, F. Castelán, and E. Cuevas-Romero Copyright © 2017 J. Rodríguez-Castelán et al. All rights reserved. Uric Acid Induces Endothelial Dysfunction by Activating the HMGB1/RAGE Signaling Pathway Sun, 01 Jan 2017 09:27:45 +0000 Uric acid (UA) is a risk factor for endothelial dysfunction, a process in which inflammation may play an important role. UA increases high mobility group box chromosomal protein 1 (HMGB1) expression and extracellular release in endothelial cells. HMGB1 is an inflammatory cytokine that interacts with the receptor for advanced glycation end products (RAGE), inducing an oxidative stress and inflammatory response, which leads to endothelial dysfunction. In this study, human umbilical vein endothelial cells (HUVECs) were incubated with a high concentration of UA (20 mg/dL) after which endothelial function and the expression of HMGB1, RAGE, nuclear factor kappa B (NF-κB), inflammatory cytokines, and adhesion molecules were evaluated. UA inhibited endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in HUVECs, increased intracellular HMGB1 expression and extracellular HMGB1 secretion, and upregulated RAGE expression. UA also activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the upregulation of RAGE and HMGB1 and prevented the increase in DNA binding activity of NF-κB and the levels of inflammatory cytokines. It also blocked the decrease in eNOS expression and NO production induced by UA. Our results suggest that high concentrations of UA cause endothelial dysfunction via the HMGB1/RAGE signaling pathway. Wei Cai, Xi-Mei Duan, Ying Liu, Jiao Yu, Yun-Liang Tang, Ze-Lin Liu, Shan Jiang, Chun-Ping Zhang, Jian-Ying Liu, and Ji-Xiong Xu Copyright © 2017 Wei Cai et al. All rights reserved. Influence of Estradiol-17beta on Progesterone and Estrogen Receptor mRNA Expression in Porcine Follicular Granulosa Cells during Short-Term, In Vitro Real-Time Cell Proliferation Mon, 26 Dec 2016 13:29:59 +0000 Progesterone (P4) and estradiol (E2) play a significant role in mammalian reproduction. Our study demonstrated that separated porcine cumulus cells (CCs) and/or granulosa cells (GCs) might proliferate in vitro during short-term, real-time primary culture. The GCs were analyzed according to gene expression of the progesterone receptor (nuclear form) (pgr), progesterone receptor membrane component 1 (pgrmc1), and estrogen-related receptor beta 3 (esrrb3) in relation to two housekeeping genes: actb and pbgd. GCs were cultivated in medium with the E2. Both pgr/actb and pgr/pbgd revealed higher expression between 24 and 168 h of IVC of prolonged E2 treatment and at 48 h of IVC after acute E2 administration. The pgrmc1/actb and pgrmc1/pbgd displayed increased expression after prolonged E2 treatment between 24 and 120 h of IVC. The highest level of esrrb3/actb at 120 and 144 h, as well as esrrb3/pbgd at 120 h, in untreated controls as compared to the hormone-stimulated group, was observed. We suggest that E2 significantly influences the upregulation of pgr, pgrmc1, and esrrb3 expression in porcine GCs during real-time cell proliferation. Since esrrb3 expression is stimulated by E2 in both an acute and prolonged manner, estradiol may be recognized as a potential estrogen receptor agonist in GCs. Sylwia Ciesiółka, Joanna Budna, Karol Jopek, Artur Bryja, Wiesława Kranc, Adrian Chachuła, Sylwia Borys, Marta Dyszkiewicz Konwińska, Agnieszka Ziółkowska, Paweł Antosik, Dorota Bukowska, Klaus P. Brüssow, Małgorzata Bruska, Michał Nowicki, Maciej Zabel, and Bartosz Kempisty Copyright © 2016 Sylwia Ciesiółka et al. All rights reserved. The Value of the Model and Quantitative Parameters of Contrast-Enhanced Ultrasound in Judging the Severity of SHPT Mon, 19 Dec 2016 09:31:36 +0000 Using the model and quantitative parameters of contrast-enhanced ultrasound (CEUS) to assess the severity of secondary hyperparathyroidism (SHPT) was proposed. 42 SHPT patients who underwent CEUS examination were divided into three groups, light, moderate, and heavy as per parathyroid hormone (PTH). The process of CEUS was divided into two phases, wash-in phase and wash-out phase. The three groups were analyzed with their enhancing model in the two phases. The quantitative parameters of CEUS such as Arrival Time (AT), Time to Peak (TTP), Mean Transit Time (MTT), and Maximum Intensity (IMAX) were measured by time-intensity curve (TIC) and compared among the three groups. The enhancing model of light SHPT, moderate SHPT, and heavy SHPT showed statistical significance in wash-in phase and wash-out phase (). No difference was observed in AT and TTP among the three groups while MTT and IMAX showed statistical significance . The CEUS of light SHPT was characterized by “slow-in, fast-out, and lower-enhancement” with short enhancement time; the CEUS of moderate SHPT was characterized by “fast-in, fast-out, and higher-enhancement” with slightly long enhancement time; the CEUS of heavy SHPT was characterized by “fast-in, slow-out, and higher-enhancement” with long enhancement time. Therefore, the model and quantitative parameters of CEUS can be benefit for the assessment of the severity of SHPT. Xing-xin Liang, Fan Li, Feng Gao, Yang Liu, Xiao-hui Qiao, Zheng Zhang, and Lian-fang Du Copyright © 2016 Xing-xin Liang et al. All rights reserved. Gender-Specific Associations between Socioeconomic Status and Psychological Factors and Metabolic Syndrome in the Korean Population: Findings from the 2013 Korean National Health and Nutrition Examination Survey Mon, 05 Dec 2016 12:44:14 +0000 We aimed to assess the gender-specific associations between psychological factors and socioeconomic status (SES) and metabolic syndrome (MetS) in Korean adults. We examined 4,689 Korean adults aged 20–79 years who participated in the 2013 Korean National Health Examination and Nutrition Survey. With regard to SES, occupation status (none, manual, and nonmanual), marital status (single, married, divorced, and widowed), and psychological factors (detection of stress, depressive symptoms, and suicidal thoughts) were determined via questionnaires. Compared with married men, single and divorced men exhibited ORs (95% confidence interval [CIs]) for MetS of 0.45 (0.31–0.65) and 1.61 (1.02–2.55), respectively, after adjusting for covariates. However, this association was not significant in women. Compared with those in the lowest household income group and least educated group in women, the ORs for MetS in the highest income group and the most educated group were 0.63 (CI 0.46–0.86) and 0.46 (CI 0.32–0.67), respectively. Suicidal thoughts in men (OR 1.64, CI 1.03–2.61) and perceived stress in women (OR 1.26, CI 1.01–1.59) were associated with MetS. In this study, MetS has gender-specific associations with lower SES and psychological factors. Thus, gender-specific public health interventions based on SES and psychological factors are needed to prevent and treat MetS and reduce additional cardiovascular disease risk. Kyoung Im Cho, Bo Hyun Kim, Hyung Gon Je, Jae Sik Jang, and Yong Hyun Park Copyright © 2016 Kyoung Im Cho et al. All rights reserved. Is Laparoendoscopic Single-Site Adrenalectomy a Feasible Alternative in Treating Aldosterone-Producing Adenoma? Wed, 16 Nov 2016 14:25:20 +0000 Objective. To compare laparoendoscopic single-site (LESS) and conventional multiport adrenalectomy in patients with aldosterone-producing adenoma (APA). Material and Methods. We retrospectively reviewed patients who had been clinically confirmed with unilateral APA and who underwent LESS or multiport adrenalectomy between 2009 and 2014. Perioperative data were obtained for all patients. Blood pressure and the levels of serum aldosterone, renin, and potassium were checked periodically. Results. We identified 45 APA patients in the LESS group and 71 in the multiport group. The baseline characteristics were matched between two groups. All adrenalectomies were completed successfully, except one with laparoscopic conversion in the single-port group and one open conversion in the multiport group. After a mean follow-up around one year, there were no significant group differences in the improvement of hypertension, number of types of medication taken, and cure of hypokalemia after operation. Conclusions. Our study confirm that LESS adrenalectomy achieved similar clinical and functional outcomes as conventional multiport adrenalectomy for management of unilateral APA. Che-Hsiung Wu, Leay-Kiaw Er, Ya-Hui Hu, Chia Da Lin, Shih-Chieh Chueh, and Yao-Chou Tsai Copyright © 2016 Che-Hsiung Wu et al. All rights reserved. The Association between VDR Gene Polymorphisms and Diabetic Retinopathy Susceptibility: A Systematic Review and Meta-Analysis Sun, 06 Nov 2016 07:06:57 +0000 Aims. Studies on the associations of vitamin D receptor (VDR) gene polymorphisms with diabetic retinopathy (DR) susceptibility reported conflicting results. A systematic meta-analysis was undertaken to clarify this topic. Methods. A systematic search of electronic databases (PubMed, EMBASE, and CNKI) was carried out until March 31, 2016. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association. Results. A total of 7 studies fulfilling the inclusion criteria were included in this meta-analysis (649 cases and 707 controls). Pooled ORs showed a significant association between FokI polymorphism and DR risk in all the four genetic models ( (1.354~1.921), 1.988 (1.481~2.668), 1.889 (1.424~2.505), and 2.674 (1.493~4.790) in allelic, dominant, recessive, and additive models, resp., ), but not for TaqI or BsmI polymorphism (). Similar results were found in the subgroup analysis. Sensitivity analysis indicated that the results were relatively stable and reliable. Results of Begg’s and Egger’s tests suggested a lack of publication bias. Conclusions. Our meta-analysis demonstrated that DR was significantly associated with VDR gene FokI polymorphism. However, due to the relatively small sample size in this meta-analysis, further studies with a larger sample size should be done to confirm the findings. Yun Zhang, Wei Xia, Ping Lu, and Huijuan Yuan Copyright © 2016 Yun Zhang et al. All rights reserved. Associations of A-FABP with Anthropometric and Metabolic Indices and Inflammatory Cytokines in Obese Patients with Newly Diagnosed Type 2 Diabetes Thu, 13 Oct 2016 13:45:00 +0000 The study aimed to evaluate the relationship between anthropometric and metabolic indices, inflammatory cytokines, and adipocyte fatty acid-binding protein (A-FABP) in obese patients with newly diagnosed type 2 diabetes. The study included 48 nonobese subjects with newly diagnosed type 2 diabetes, 42 obese subjects with newly diagnosed type 2 diabetes, 30 simple obese subjects, and 30 matched normal subjects. Serum A-FABP was assessed by enzyme-linked immunosorbent assay. Pearson’s correlations and multiple linear regression stepwise analysis were used to analyze correlations of A-FABP with anthropometric and metabolic indices and inflammatory cytokines. Obese subjects with newly diagnosed type 2 diabetes had elevated A-FABP compared to normal control, nondiabetic obese patients, and nonobese diabetic patients. A-FABP was significantly correlated with glycated hemoglobin A1C (HbA1C), BMI, triglyceride, Homeostasis Model Assessment Index (HOMA-IR), waist hip rate, C-reactive protein, IL-6, and HDL-C in obese subjects with type 2 diabetes. In multiple linear regression stepwise analysis, BMI, HbA1C, and HOMA-IR were significantly independent determinants for A-FABP. BMI, HbA1C, and HOMA-IR are independently associated with A-FABP in obese subjects with newly diagnosed type 2 diabetes. A-FABP may be related to insulin resistance and inflammation in type 2 diabetes and concomitant obesity. Guifen Niu, Jian Li, Huaiguo Wang, Yuan Ren, and Jie Bai Copyright © 2016 Guifen Niu et al. All rights reserved. Endothelial Microparticles Act as Novel Diagnostic and Therapeutic Biomarkers of Diabetes and Its Complications: A Literature Review Mon, 10 Oct 2016 10:50:07 +0000 Diabetes mellitus- (DM-) related vascular diseases attract increased attention due to their high morbidity and mortality. The incidence of obesity, atherosclerosis, coronary heart disease, hypertension, and dyslipidemia is significantly higher in DM patients, with an earlier onset and faster progression compared with non-DM patients. DM-related vascular diseases including macrovascular and microvascular complications are characterized by endothelial dysfunction. Therefore, a better understanding of the etiology and mechanisms of endothelial dysfunction is important for the diagnosis and treatment of DM. Endothelial microparticles (EMPs) are new diagnostic and therapeutic targets and biomarkers in DM-related vascular disease. Circulating EMPs containing biologically active substances act as intercellular signals under physiological and pathological conditions. They serve as biological markers of altered vascular endothelium and reflect the pathological progression and diminished endothelial function of blood vessels. Recent evidence suggests that the plasma level of EMPs is significantly higher in DM patients than in healthy population and is significantly correlated with DM-related complications. These observations have prompted speculation that EMPs play a crucial role in the pathophysiology of DM. This review summarizes the known and potential roles of EMPs in the diagnosis, staging, treatment, and clinical prognosis of DM and related vascular diseases. Fan Deng, Shuang Wang, and Liangqing Zhang Copyright © 2016 Fan Deng et al. All rights reserved. Network Based Approach in the Establishment of the Relationship between Type 2 Diabetes Mellitus and Its Complications at the Molecular Level Coupled with Molecular Docking Mechanism Tue, 06 Sep 2016 17:09:52 +0000 Diabetes mellitus (DM) is one of the major metabolic disorders that is currently threatening the world. DM is seen associated with obesity and diabetic retinopathy (DR). In the present paper we tried to evaluate the relationship between the three aliments at the gene level and further performed the molecular docking to identify the common drug for all the three diseases. We have adopted several software programs such as Phenopedia, VennViewer, and CDOCKER to accomplish the objective. Our results revealed six genes that commonly associated and are involved in the signalling pathway. Furthermore, evaluation of common gene association from the selected set of genes projected the presence of SIRT1 in all the three aliments. Therefore, we targeted protein 4KXQ which was produced from the gene SIRT1 and challenged it with eight phytochemicals, adopting the CDOCKER. C1 compound has displayed highest -CDOCKER energy and -CDOCKER interaction energy of 43.6905 and 43.3953, respectively. Therefore, this compound is regarded as the most potential lead molecule. Shailima Rampogu and Mary Rampogu Lemuel Copyright © 2016 Shailima Rampogu and Mary Rampogu Lemuel. All rights reserved. Association of Polymorphisms in STRA6 and RARRES2 Genes with Type 2 Diabetes in Southern Han Chinese Sun, 03 Jul 2016 12:00:29 +0000 Stimulated by retinoic acid gene homolog 6 (STRA6) and retinoic acid receptor responder 2 (RARRES2) are candidate genes involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Three tag-SNPs in STRA6 and one in RARRES2 gene were selected and genotyped with TaqMan or PCR-RFLP method in 603 populations (571 patients with T2D versus 632 control subjects) in Southern Han Chinese. We estimated the interactions between T2DM risk and genetic variants in the STRA6 and RARRES2 genes using polymerase chain reaction. Rs736118 in STRA6 gene were significantly associated with T2DM occurrence in the recessive genetic model. The genotype of rs974456 was significantly associated with T2DM in the dominant genetic model correlated to sex, MBI, and triglyceride. However, the association of other SNPs with T2DM was not found. Furthermore, smoking history and other factors may be independent risk factors for the incidence of T2DM. This study suggested that a role of STRA6 polymorphism could also be of value in predicting the risk of T2DM while RARRES2 polymorphism could not predict the risk of T2DM. Han-Wei Huang, Bi-Yu Liang, and Yun-Xi Li Copyright © 2016 Han-Wei Huang et al. All rights reserved. Circulating Betatrophin Is Increased in Patients with Overt and Subclinical Hypothyroidism Tue, 26 Apr 2016 09:24:13 +0000 Thyroid hormone (TH) affects many metabolic processes such as promoting oxidation of sugar, fat, and protein in many tissues. Thyroid dysfunction is associated with metabolic disorders. The newly discovered adipocyte- and hepatocyte-derived cytokine, betatrophin, has been reported to be involved in metabolic diseases, but its influence on thyroid dysfunction is uncertain. Therefore, the present study aims to evaluate circulating betatrophin levels in subjects with different thyroid function status and to predict the factors associated with betatrophin levels, especially whether thyroid stimulating hormone (TSH), TH, or thyroid autoantibodies are associated with betatrophin levels. In the study, serum betatrophin was measured in the subjects grouped as overt hypothyroidism (OH), subclinical hypothyroidism (SCH), euthyroid with isolated thyroid peroxidase antibody positivity (isolated Ab), and healthy control (HC), according to their thyroid functions. From our results, we found that betatrophin may be associated with thyroid insufficiency but not thyroid autoimmunity. Thus, when interpreting the results of betatrophin, thyroid functions should also be taken into consideration. Cheng Han, Xinghai Xia, Aihua Liu, Xiaowen Zhang, Mi Zhou, Chuhui Xiong, Xin Liu, Jie Sun, Xiaoguang Shi, Zhongyan Shan, and Weiping Teng Copyright © 2016 Cheng Han et al. All rights reserved. Prevalence of Diabetic Foot Disease in Patients with Diabetes Mellitus under Renal Replacement Therapy in Lleida, Spain Thu, 14 Apr 2016 07:56:00 +0000 Aim. To assess the prevalence of diabetic foot and other associated conditions in patients with diabetes mellitus under renal replacement in the region of Lleida, Spain. Methods. This was an observational, cross-sectional study of 92 dialysis-treated diabetic patients. Besides a podiatric examination, we explored the presence of cardiovascular risk factors, late diabetes complications, including peripheral neuropathy, atherosclerotic disease, and peripheral artery disease. We assessed risk factors for foot ulceration and amputation by logistic regression. Results. Prevalent diabetic foot was found in 17.4% of patients, foot deformities were found in 54.3%, previous ulcer was found in 19.6%, and amputations were found in 16.3%; and 87% of them had some risk of suffering diabetic foot in the future. We observed a high prevalence of patients with peripheral neuropathy and peripheral artery disease (89.1% and 64.2%, resp.). Multivariable analysis identified diabetic retinopathy and advanced atherosclerotic disease (stenosing carotid plaques) as independent risk factors for foot ulceration ( and , resp.) and diabetic retinopathy also as an independent risk factor for lower-limb amputations (). Moreover, there was a temporal association between the initiation of dialysis and the incidence of amputations. Conclusion. Diabetic patients receiving dialysis therapy are at high risk of foot complications and should receive appropriate and intensive foot care. Montserrat Dòria, Verónica Rosado, Linda Roxana Pacheco, Marta Hernández, Àngels Betriu, Joan Valls, Josep Franch-Nadal, Elvira Fernández, and Dídac Mauricio Copyright © 2016 Montserrat Dòria et al. All rights reserved. Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol Tue, 15 Mar 2016 12:39:49 +0000 The effects of high-fructose diet on adipose tissue insulin signaling and inflammatory process have been poorly documented. In this study, we examined the influences of long-term fructose intake and resveratrol supplementation on the expression of genes involved in insulin signaling and the levels of inflammatory cytokines and sex hormones in the white adipose tissues of male and female rats. Consumption of high-fructose diet for 24 weeks increased the expression of genes involved in insulin signaling including IR, IRS-1, IRS-2, Akt, PI3K, eNOS, mTOR, and PPAR, despite induction of proinflammatory markers, iNOS, TNF, IL-1, IL-18, MDA, and ALT, as well as anti-inflammatory factors, IL-10 and Nrf2 in adipose tissues from males and females. Total and free testosterone concentrations of adipose tissues were impaired in males but increased in females, although there were no changes in their blood levels. Resveratrol supplementation markedly restored the levels of MDA, IL6, IL-10, and IL-18, as well as iNOS, Nrf2, and PI3K mRNA, in adipose tissues of both genders. Dietary fructose activates both insulin signaling and inflammatory pathway in the adipose tissues of male and female rats proposing no correlation between the tissue insulin signaling and inflammation. Resveratrol has partly modulatory effects on fructose-induced changes. Mehmet Bilgehan Pektas, Halit Bugra Koca, Gokhan Sadi, and Fatma Akar Copyright © 2016 Mehmet Bilgehan Pektas et al. All rights reserved. Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model Mon, 07 Mar 2016 12:31:47 +0000 Premature ovarian failure (POF) is one of the most common causes of infertility in women. In our present study, we established cyclophosphamide- (CTX-) induced POF rat model and elucidated its effect on ovarian function. We detected the serum estrogen, follicle stimulating hormone, and anti-Müllerian hormone of mice models by ELISA and evaluated their folliculogenesis by histopathology examination. Our study revealed that CTX administration could severely disturb hormone secretion and influence folliculogenesis in rat. This study also detected ovarian cells apoptosis by deoxy-UTP-digoxigenin nick end labeling (TUNEL) and demonstrated marked ovarian cells apoptosis in rat models following CTX administration. In order to explore the potential of human umbilical cord mesenchymal stem cells (UCMSCs) in POF treatment, the above indexes were used to evaluate ovarian function. We found that human UCMSCs transplantation recovered disturbed hormone secretion and folliculogenesis in POF rat, in addition to reduced ovarian cell apoptosis. We also tracked transplanted UCMSCs in ovaries by fluorescence in situ hybridization (FISH). The results manifested that the transplanted human UCMSCs could reside in ovarian tissues and could survive for a comparatively long time without obvious proliferation. Our present study provides new insights into the great clinical potential of human UCMSCs in POF treatment. Dan Song, Yun Zhong, Chunfeng Qian, Qinyan Zou, Jian Ou, Yichao Shi, Liang Gao, Gaigai Wang, Zhenxing Liu, Haibo Li, Hailei Ding, Huihua Wu, Fuxin Wang, Jing Wang, and Hong Li Copyright © 2016 Dan Song et al. All rights reserved. The Significance of Ultrasound in Determining Whether SHPT Patients Are Sensitive to Calcitriol Treatment Mon, 29 Feb 2016 09:27:22 +0000 This study was to explore the significance of ultrasound in determining whether the patients with secondary hyperparathyroidism (SHPT) are sensitive to calcitriol treatment. According to the decrease value of parathyroid hormone (PTH), 42 SHPT patients were divided into two groups: drug susceptible group and drug insusceptible group. These 42 SHPT patients’ ultrasound images were retrospectively analyzed. The morphology, size, number, blood flow, elastic modulus, and perfusion of the parathyroid glands were correlated with drug therapeutic outcome (oral calcitriol). Most SHPT patients with drug susceptible showed volume <438.50 mm3 and number ≤2, with 0-1 structural and vascular patterns, associated with Relative Maximum Intensity (RIMAX) <1.59 and elastic modulus <18.8 kPa, whereas most SHPT patients with drug insusceptible showed volume ≥438.50 mm3 and number ≥3, with 2-3 structural and vascular patterns, associated with Relative Maximum Intensity (RIMAX) ≥1.59 and elastic modulus ≥18.8 kPa. Therefore, ultrasonography in SHPT allows an accurate definition of the morphology, size, number, blood flow, elastic modulus, and perfusion of the parathyroid glands and is useful in determining whether SHPT patients are sensitive to calcitriol treatment. Xing-xin Liang, Fan Li, Feng Gao, Chun-xiao Li, Xiao-hui Qiao, Jia-jie Zhang, and Lian-fang Du Copyright © 2016 Xing-xin Liang et al. All rights reserved. Update on Mechanisms of Renal Tubule Injury Caused by Advanced Glycation End Products Mon, 29 Feb 2016 06:51:00 +0000 Diabetic nephropathy (DN) caused by advanced glycation end products (AGEs) may be associated with lipid accumulation in the kidneys. This study was designed to investigate whether Nε-(carboxymethyl) lysine (CML, a member of the AGEs family) increases lipid accumulation in a human renal tubular epithelial cell line (HK-2) via increasing cholesterol synthesis and uptake and reducing cholesterol efflux through endoplasmic reticulum stress (ERS). Our results showed that CML disrupts cholesterol metabolism in HK-2 cells by activating sterol regulatory element-binding protein 2 (SREBP-2) and liver X receptor (LXR), followed by an increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) mediated cholesterol synthesis and low density lipoprotein receptor (LDLr) mediated cholesterol uptake and a reduction in ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, ultimately causing lipid accumulation in HK-2 cells. All of these responses could be suppressed by an ERS inhibitor, which suggests that CML causes lipid accumulation in renal tubule cells through ERS and that the inhibition of ERS is a potential novel approach to treating CML-induced renal tubular foam cell formation. Hong Sun, Yang Yuan, and Zilin Sun Copyright © 2016 Hong Sun et al. All rights reserved. Treatment of Endometriosis with the GnRHa Deslorelin and Add-Back Estradiol and Supplementary Testosterone Thu, 31 Dec 2015 16:24:20 +0000 Background. This randomized, multicenter, open-label clinical trial was intended to generate pilot data on the efficacy and safety of the gonadotropin-releasing hormone agonist (GnRHa) deslorelin (D) with low-dose estradiol ± testosterone (E2  ± T) add-back for endometriosis-related pelvic pain. Methods. Women with pelvic pain and laparoscopically confirmed endometriosis were treated with a six-month course of daily intranasal D with concurrent administration of either transdermal E2, intranasal E2, or intranasal E2  + T. Efficacy data included evaluation of dyspareunia, dysmenorrhea, pelvic pain, tenderness, and induration. Cognition and quality of life were also assessed. Safety parameters included assessment of endometrial hyperplasia, bone mineral density (BMD), and hot flashes. Results. Endometriosis symptoms and signs scores decreased in all treatment arms from a baseline average of 7.4 to 2.5 after 3 months of treatment and 3.4 after 6 months. BMD changes and incidence of hot flashes were minimal, and no endometrial hyperplasia was observed. Patient-reported outcomes showed significant improvement across multiple domains. Conclusions. Daily intranasal D with low dose E2  ± T add-back resulted in significant reduction in severity of endometriosis symptoms and signs with few safety signals and minimal hypoestrogenic symptoms that would be expected with the use of a GnRHa alone. Sanjay K. Agarwal, AnnaMarie Daniels, Steven R. Drosman, Laurence Udoff, Warren G. Foster, Malcolm C. Pike, Darcy V. Spicer, and John R. Daniels Copyright © 2015 Sanjay K. Agarwal et al. All rights reserved. Exploring the Link between the Components of Metabolic Syndrome and the Risk of Depression Mon, 07 Dec 2015 14:24:33 +0000 Background. Metabolic syndrome (MetS) has been reported with an increased risk of depression. MetS was also associated with insulin resistance. This study aimed to evaluate whether MetS components might contribute to depression in participants with insulin resistance (IR) or not. Methods. This study included 3,331 participants ≥18 years in the NHANES 2009-2010. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). MetS components were measured using blood chemistry and body measurements. IR was identified using the homeostasis model assessment method. Results. Predicted PHQ-9 scores significantly increased as the number of MetS components increased in patients with IR. The adjusted β coefficients of the predicted PHQ-9 score with 2, 4, and 5 MetS components were 1.803, 2.081, and 3.048, respectively ( for trend < 0.05). Low HDL-C levels were significantly associated with higher predicted total PHQ-9 scores in fully adjusted models in the IR group (). Conclusion. The results indicated that the presence of a greater number of components of MetS was significantly associated with higher predicted total PHQ-9 scores in participants with IR. Among the components of MetS, the most apparent association was observed between low HDL and higher predicted total PHQ-9 scores. Fang-Yih Liaw, Tung-Wei Kao, Ju-Ting Hsueh, Yi-Hsin Chan, Yaw-Wen Chang, and Wei-Liang Chen Copyright © 2015 Fang-Yih Liaw et al. All rights reserved. N-Acetylneuraminic Acid Supplementation Prevents High Fat Diet-Induced Insulin Resistance in Rats through Transcriptional and Nontranscriptional Mechanisms Wed, 25 Nov 2015 12:00:52 +0000 N-Acetylneuraminic acid (Neu5Ac) is a biomarker of cardiometabolic diseases. In the present study, we tested the hypothesis that dietary Neu5Ac may improve cardiometabolic indices. A high fat diet (HFD) + Neu5Ac (50 or 400 mg/kg BW/day) was fed to rats and compared with HFD + simvastatin (10 mg/kg BW/day) or HFD alone for 12 weeks. Weights and serum biochemicals (lipid profile, oral glucose tolerance test, leptin, adiponectin, and insulin) were measured, and mRNA levels of insulin signaling genes were determined. The results indicated that low and high doses of sialic acid (SA) improved metabolic indices, although only the oral glucose tolerance test, serum triglycerides, leptin, and adiponectin were significantly better than those in the HFD and HFD + simvastatin groups (). Furthermore, the results showed that only high-dose SA significantly affected the transcription of hepatic and adipose tissue insulin signaling genes. The data suggested that SA prevented HFD-induced insulin resistance in rats after 12 weeks of administration through nontranscriptionally mediated biochemical changes that may have differentially sialylated glycoprotein structures at a low dose. At higher doses, SA induced transcriptional regulation of insulin signaling genes. These effects suggest that low and high doses of SA may produce similar metabolic outcomes in relation to insulin sensitivity through multiple mechanisms. These findings are worth studying further. Zhang Yida, Mustapha Umar Imam, Maznah Ismail, Norsharina Ismail, Nur Hanisah Azmi, Waiteng Wong, Hadiza Altine Adamu, Nur Diyana Md Zamri, Aini Ideris, and Maizaton Atmadini Abdullah Copyright © 2015 Zhang Yida et al. All rights reserved. Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management Sun, 15 Nov 2015 11:13:46 +0000 Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6–12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation. Gong-bin Lan, Xu-biao Xie, Long-kai Peng, Lei Liu, Lei Song, and He-long Dai Copyright © 2015 Gong-bin Lan et al. All rights reserved. Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis Tue, 10 Nov 2015 11:49:26 +0000 We systematically identified the prevalence of hyperuricemia and gout in mainland China and provided informative data that can be used to create appropriate local public health policies. Relevant articles from 2000 to 2014 were identified by searching 5 electronic databases: PubMed, Google Scholar, Chinese Wanfang, CNKI, and Chongqing VIP. All of the calculations were performed using the Stata 11.0 and SPSS 20.0 software. The eligible articles (; 3 in English and 33 in Chinese) included 44 studies (38 regarding hyperuricemia and 6 regarding gout). The pooled prevalence of hyperuricemia and gout was 13.3% (95% CI: 11.9%, 14.6%) and 1.1% (95% CI: 0.7%, 1.5%), respectively. Although publication bias was observed, the results did not change after a trim and fill test, indicating that that impact of this bias was likely insignificant. The prevalence of hyperuricemia and gout was high in mainland China. The subgroup analysis suggested that the geographical region, whether the residents dwell in urban or rural and coastal or inland areas, the economic level, and sex may be associated with prevalence. Rui Liu, Cheng Han, Di Wu, Xinghai Xia, Jianqiu Gu, Haixia Guan, Zhongyan Shan, and Weiping Teng Copyright © 2015 Rui Liu et al. All rights reserved. Glycated Albumin Levels in Patients with Type 2 Diabetes Increase Relative to HbA1c with Time Mon, 21 Sep 2015 11:51:53 +0000 We recently reported that glycated albumin (GA) is increased in subjects with longer duration of diabetes and with decreased insulin secretory function. Based on this, we investigated whether GA increases with time relative to glycated hemoglobin () and the association between GA and beta-cell function. We analyzed 340 type 2 diabetes patients whose serum GA and HbA1c levels had been repeatedly measured over 4 years. We assessed the pattern of changes with time in glycemic indices (GA, , and GA/ ratio) and their relationship with beta-cell function. In all patients, glycemic indices decreased and maintained low levels around 15 and 27 months. However, from 39 months to 51 months, GA significantly increased but tended to increase without statistical significance. We defined ΔGA/ as the difference between the nadir point (at 15 to 27 months) and the end point (at 39 to 51 months) and found that ΔGA/ was positively correlated with diabetes duration and negatively related to beta-cell function. In multivariable linear regression analyses, ΔGA/ was independently associated with diabetes duration. In conclusion, this study demonstrated that serum GA levels increase relative to levels with time. Hye-jin Yoon, Yong-ho Lee, Kwang Joon Kim, So Ra Kim, Eun Seok Kang, Bong-Soo Cha, Hyun Chul Lee, and Byung-Wan Lee Copyright © 2015 Hye-jin Yoon et al. All rights reserved. POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells Wed, 02 Sep 2015 14:25:35 +0000 POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers. Monica Malheiros França, Bruno Ferraz-de-Souza, Antonio Marcondes Lerario, Maria Candida Barisson Villares Fragoso, and Claudimara Ferini Pacicco Lotfi Copyright © 2015 Monica Malheiros França et al. All rights reserved. Evaluation of Nutritional Status of Patients with Depression Thu, 27 Aug 2015 12:33:39 +0000 Aims and Objectives. Our goal was to determine nutritional status, body composition, and biochemical parameters of patients diagnosed with depression based on DSM-IV-TR criteria. Methods. A total of 59 individuals, aged 18–60 years admitted to Mental Health Centre of Kayseri Education and Research Hospital, were included in the study. The participants were randomly assigned to two groups; depression group () and control group (). Anthropometric measurements, some biochemical parameters, demographic data, and 24-hour dietary recall were evaluated. Results. 65.5% of depression and 60.0% of control group were female. Intake of vitamins A, thiamine, riboflavin, B6, folate, C, Na, K, Mg, Ca, P, Fe, Zn, and fibre () were lower in depression group. Median levels of body weight, waist circumference, hip circumference, waist-to-hip ratio () were significantly higher in depression group. Fasting blood glucose levels, serum vitamins B12, and folic acid () in depression group were lower than controls. Serum insulin and HOMA levels of two groups were similar. Conclusion. Some vitamin B consumption and serum vitamin B12 and folic acid levels were low while signs of abdominal obesity were high among patients with depression. Future research exploring nutritional status of individuals with depression is warranted. Gülşah Kaner, Meltem Soylu, Nimet Yüksel, Neriman Inanç, Dilek Ongan, and Eda Başmısırlı Copyright © 2015 Gülşah Kaner et al. All rights reserved. Interplay between the Endocrine System and Immune Cells Wed, 05 Aug 2015 08:54:40 +0000 Livia A. Carvalho, Jantje M. Gerdes, Carina Strell, Graham R. Wallace, and Joilson O. Martins Copyright © 2015 Livia A. Carvalho et al. All rights reserved. Mycophenolate Mofetil Ameliorates Diabetic Nephropathy in db/db Mice Tue, 04 Aug 2015 11:26:35 +0000 Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Mycophenolate mofetil (MMF) has an anti-inflammatory effect, inhibiting lymphocyte proliferation. Previous studies showed attenuation of diabetic nephropathy with MMF, but the underlying mechanisms were unclear. This study aimed to identify the effect of MMF on diabetic nephropathy and investigate its action mechanisms in type 2 diabetic mice model. Eight-week-old db/db and control mice (db/m mice) received vehicle or MMF at a dose of 30 mg/kg/day for 12 weeks. MMF-treated diabetic mice showed decreased albuminuria, attenuated mesangial expansion, and profibrotic mRNA expressions despite the high glucose level. The number of infiltrated CD4+ and CD8+ T cells in the kidney was significantly decreased in MMF-treated db/db mice and it resulted in attenuating elevated intrarenal TNF-α and IL-17. The renal chemokines expression and macrophages infiltration were also attenuated by MMF treatment. The decreased expression of glomerular nephrin and WT1 was recovered with MMF treatment. MMF prevented the progression of diabetic nephropathy in db/db mice independent of glycemic control. These results suggest that the effects of MMF in diabetic nephropathy are mediated by CD4+ T cell regulation and related cytokines. Jung-Woo Seo, Yang Gyun Kim, Sang Ho Lee, Arah Lee, Dong-Jin Kim, Kyung-Hwan Jeong, Kyung Hye Lee, Seung Joon Hwang, Jong Shin Woo, Sung Jig Lim, Weon Kim, and Ju-Young Moon Copyright © 2015 Jung-Woo Seo et al. All rights reserved. Modulation of Intrathymic Sphingosine-1-Phosphate Levels Promotes Escape of Immature Thymocytes to the Periphery with a Potential Proinflammatory Role in Chagas Disease Tue, 04 Aug 2015 11:07:22 +0000 The sphingosine-1-phosphate (S1P) system regulates both thymic and lymph nodes T cell egress which is essential for producing and maintaining the recycling T cell repertoire. Infection with the protozoan parasite Trypanosoma cruzi induces a hormonal systemic deregulation that has impact in the thymic S1P homeostasis that ultimately promotes the premature exit of immature CD4−CD8− T cells expressing TCR and proinflamatory cytokines to peripheral lymphoid organs, where they may interfere with adaptive immune responses. In what follows, we review recent findings revealing escape of these immature T cells exhibiting an activation profile to peripheral compartments of the immune system in both experimental murine and human models of Chagas disease. Ana Flávia Nardy, Leonardo Santos, Célio Geraldo Freire-de-Lima, and Alexandre Morrot Copyright © 2015 Ana Flávia Nardy et al. All rights reserved. Role of Inhibitors of Apoptosis Proteins in Testicular Function and Male Fertility: Effects of Polydeoxyribonucleotide Administration in Experimental Varicocele Tue, 04 Aug 2015 10:49:16 +0000 Neuronal apoptosis inhibitory protein (NAIP) and survivin might play an important role in testicular function. We investigated the effect of PDRN, an agonist of adenosine A2A receptor, on testicular NAIP and survivin expression in an experimental model of varicocele. After the creation of experimental varicocele (28 days), adolescent male Sprague-Dawley rats were randomized to one of the following treatments lasting 21 days: vehicle, PDRN (8 mg/kg i.p., daily), PDRN + 3,7-dimethyl-propargylxanthine (DMPX, a specific adenosine A2A-receptor antagonist, 0.1 mg/kg i.p., daily), varicocelectomy, and varicocelectomy + PDRN (8 mg/kg i.p., daily). Sham-operated animals were used as controls. Animals were then euthanized and testis expression of NAIP and survivin was evaluated through qRT-PCR, western blot, and immunohistochemical analysis. Spermatogenetic activity was also assessed. NAIP and survivin expressions were significantly reduced following varicocele induction when compared to sham animals whereas PDRN-treated rats showed an increase in NAIP and survivin levels. Immunohistochemistry revealed an enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization following PDRN treatment. Moreover, administration of PDRN significantly restored spermatogenic function in varicocele rats. PDRN may represent a rational therapeutic option for accelerating recovery from depressed testicular function through a strategic modulation of apoptosis in experimental varicocele. Letteria Minutoli, Salvatore Arena, Pietro Antonuccio, Carmelo Romeo, Alessandra Bitto, Carlo Magno, Mariagrazia Rinaldi, Antonio Micali, Natasha Irrera, Gabriele Pizzino, Federica Galfo, Francesco Squadrito, Domenica Altavilla, and Herbert Marini Copyright © 2015 Letteria Minutoli et al. All rights reserved. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease Mon, 03 Aug 2015 13:46:59 +0000 Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance. Paloma Almeda-Valdes, Nancy E. Aguilar Olivos, Beatriz Barranco-Fragoso, Misael Uribe, and Nahum Méndez-Sánchez Copyright © 2015 Paloma Almeda-Valdes et al. All rights reserved. Interleukin-1 β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study Mon, 03 Aug 2015 13:27:38 +0000 The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1β, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1β (75 pg/mL), or (4) NE + IL-1β. It was found that IL-1β abolished () NE-induced increase in melatonin release. Treatment with IL-1β also reduced () expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1β treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated () expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1β suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression. A. P. Herman, J. Bochenek, J. Skipor, K. Król, A. Krawczyńska, H. Antushevich, B. Pawlina, E. Marciniak, and D. Tomaszewska-Zaremba Copyright © 2015 A. P. Herman et al. All rights reserved. MicroRNAs: Novel Players in the Dialogue between Pancreatic Islets and Immune System in Autoimmune Diabetes Mon, 03 Aug 2015 12:53:25 +0000 MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and response to antigens. Indeed, it is not surprising that microRNA alterations can lead to the development of several diseases, including type 1 diabetes (T1D). Type 1 diabetes is the result of a selective autoimmune destruction of insulin-producing beta-cells, characterized by islet inflammation (insulitis), which leads to chronic hyperglycemia. Given the growing importance of microRNA in the pathophysiology of T1D, the aim of this review is to summarize the most recent data on the potential involvement of microRNAs in autoimmune diabetes. Specifically, we will focus on three different aspects: (i) microRNAs as regulators of immune homeostasis in autoimmune diabetes; (ii) microRNA expression in pancreatic islet inflammation; (iii) microRNAs as players in the dialogue between the immune system and pancreatic endocrine cells. Giuliana Ventriglia, Laura Nigi, Guido Sebastiani, and Francesco Dotta Copyright © 2015 Giuliana Ventriglia et al. All rights reserved. High Body Mass Index Is an Indicator of Maternal Hypothyroidism, Hypothyroxinemia, and Thyroid-Peroxidase Antibody Positivity during Early Pregnancy Mon, 27 Jul 2015 13:01:13 +0000 Background. Maternal thyroid dysfunction in early pregnancy may increase the risk of adverse pregnancy complications and neurocognitive deficiencies in the developing fetus. Currently, some researchers demonstrated that body mass index (BMI) is associated with thyroid function in nonpregnant population. Hence, the American Thyroid Association recommended screening thyroid function in obese pregnant women; however, the evidence for this is weak. For this purpose, our study investigated the relationship between high BMI and thyroid functions during early pregnancy in Liaoning province, an iodine-sufficient region of China. Methods. Serum thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb) concentration, urinary iodine concentration (UIC), and BMI were determined in 6303 pregnant women. Results. BMI ≥ 25 kg/m2 may act as an indicator of hypothyroxinemia and TPOAb positivity and BMI ≥ 30 kg/m2 was associated with increases in the odds of hypothyroidism, hypothyroxinemia, and TPOAb positivity. The prevalence of isolated hypothyroxinemia increased among pregnant women with BMI > 24 kg/m2. Conclusions. High BMI during early pregnancy may be an indicator of maternal thyroid dysfunction; for Asian women whose BMI > 24 kg/m2 and who are within 8 weeks of pregnancy, thyroid functions should be assessed especially. Cheng Han, Chenyan Li, Jinyuan Mao, Weiwei Wang, Xiaochen Xie, Weiwei Zhou, Chenyang Li, Bin Xu, Lihua Bi, Tao Meng, Jianling Du, Shaowei Zhang, Zhengnan Gao, Xiaomei Zhang, Liu Yang, Chenling Fan, Weiping Teng, and Zhongyan Shan Copyright © 2015 Cheng Han et al. All rights reserved. Severe Ketoacidosis (pH ≤ 6.9) in Type 2 Diabetes: More Frequent and Less Ominous Than Previously Thought Sun, 21 Jun 2015 11:37:21 +0000 Diabetic ketoacidosis is a life-threatening acute metabolic complication of uncontrolled diabetes. Severe cases of DKA (pH ≤ 7.00, bicarbonate level ≤ 10.0, anion gap > 12, positive ketones, and altered mental status) are commonly encountered in patients with type 1 diabetes and are thought to carry an ominous prognosis. There is not enough information on the clinical course of severely acidotic type 2 diabetes (pH ≤ 6.9) patients with DKA, possibly because this condition is rarely seen in developed countries. In this series, we present 18 patients with type 2 diabetes, DKA, and a pH ≤ 6.9 that presented to a tertiary university hospital over the past 11 years. The objective was to describe their clinical characteristics, the triggering cause, and emphasis on treatment, evolution, and outcomes. The majority of the patients were female (61%). Mean age was 40.66 years (23–59). The patients had been first diagnosed with type 2 diabetes on average 5.27 ± 3.12 years before admission. Glutamic acid decarboxylase (GAD65) antibodies were negative in all patients. The origin of DKA could be attributed to two main causes: treatment omission in 8 (44.4%) patients and infections in 7 (38.8%) patients. The most common symptoms described were general malaise, dyspnea, altered mental status, and abdominal pain. Mean serum glucose on admission was 613.8 ± 114.5 mg/dL. Mean venous pH was 6.84 ± 0.03 with an anion gap of 30.3 ± 2.9 and a venous HCO3 level of 3.62 ± 1.35 mmol/L. All patients had acute renal failure on admission, with a mean serum creatinine of 1.57 ± 0.35 mg/dL compared to 0.55 ± 0.21 mg/dL at discharge. All patients received regular insulin infusion, aggressive fluid repletion, and 12 patients (66%) received bicarbonate infusion. Mean total insulin infusion dose was 181.7 ± 90.4 U (on average 0.14 ± 0.05 U/Kg/h). Mean time on infusion was 24.4 ± 12.6 hours. We recorded no mortality in this case series. Mean in-hospital stay was 5.0 ± 4.1 days. In conclusion, very severe DKA in type 2 diabetes is not uncommon in our population, shares many features with non-very-severe cases of DKA (bicarbonate therapy did not make a difference in mortality), and can be managed following standard published or institutional guidelines. René Rodríguez-Gutiérrez, Carlos R. Cámara-Lemarroy, Dania L. Quintanilla-Flores, Emanuel I. González-Moreno, Juan Manuel González-Chávez, Fernando Javier Lavalle-González, Jose Gerardo González-González, and A. Enrique Caballero Copyright © 2015 René Rodríguez-Gutiérrez et al. All rights reserved. Association between Hyperhomocysteinemia and Thyroid Hormones in Euthyroid Diabetic Subjects Sun, 21 Jun 2015 11:37:20 +0000 Objectives. The concept now emerging is that higher thyroid-stimulating hormone (TSH) and lower thyroid hormone levels within the euthyroid range may adversely affect atherosclerosis. The present study aimed to investigate the potential associations between thyroid parameters and hyperhomocysteinaemia in a cohort of euthyroid diabetic subjects. Material and Methods. Two hundred and seventy-three euthyroid diabetic subjects (167 males and 106 females) were consecutively recruited in this cross-sectional study. Clinical and biomedical data was collected. Results. TSH level was higher in females than males. Compared to normal-homocysteine group, hyperhomocysteinaemia group was more likely to be elderly, males, with longer diabetes history, and with lower diastolic blood pressure. Free thyroxine (FT4) level was lower in hyperhomocysteinaemia group than in normal-homocysteine group; however, it was not statistically significant. Adjusted for age, sex, body mass index, duration of diabetes, blood pressure, fasting glucose, total cholesterol, and triglyceride in logistic regression analyses, hyperhomocysteinaemia was significantly correlated with FT4 (). No significant association was found with TSH or free triiodothyronine. When analyzed in subjects with TSH < 2.5 uIU/mL separately, we got similar results. Conclusions. In conclusion, we identified a relation between hyperhomocysteinemia and FT4 in a group of euthyroid diabetic patients. Yun Zhang, Qiong Wang, Quanzhong Li, and Ping Lu Copyright © 2015 Yun Zhang et al. All rights reserved. Serum Soluble Adhesion Molecules and Markers of Systemic Inflammation in Elderly Diabetic Patients with Mild Cognitive Impairment and Depressive Symptoms Thu, 18 Jun 2015 06:40:26 +0000 The aim of the study was to determine the serum levels of soluble adhesion molecules and hs-CRP in elderly diabetics with mild cognitive impairment (MCI) alone or with depressive symptoms. Methods. 219 diabetics elders were screened for psychiatric disorders and divided: group 1, MCI without depressive mood; group 2, MCI with depressive mood; group 3, controls. Data of biochemical parameters and biomarkers were collected. Results. In groups 1 and 2 levels of all biomarkers were significantly higher as compared to controls. The highest level of hs-CRP and sICAM-1 was detected in group 2. SVCAM-1 and sE-selectin levels were also the highest in group 2; however they did not significantly differ as compared to group 1. MoCA score was negatively correlated with all biomarkers in group 1. The logistic regression model showed that variables which increased the likelihood of having depressive syndrome in MCI patients were older age, stroke, neuropathy, increased number of comorbidities, and higher sICAM-1 level. Conclusions. We first demonstrated that elderly diabetic patients with MCI, particularly those with depressive mood have higher levels of soluble adhesion molecules and markers of low-grade systemic inflammation. Coexisting depressive syndrome in patients with MCI through common inflammatory pathways may result in augmentation of psychiatric disorders. Malgorzata Gorska-Ciebiada, Malgorzata Saryusz-Wolska, Anna Borkowska, Maciej Ciebiada, and Jerzy Loba Copyright © 2015 Malgorzata Gorska-Ciebiada et al. All rights reserved. Cloning and Characterization of Spliced Variants of the Porcine G Protein Coupled Receptor 120 Sun, 17 May 2015 12:55:51 +0000 The polyunsaturated fatty acids (PUFAs) receptor GPR120 exerts a significant impact on systemic nutrient homeostasis in human and rodents. However, the porcine GPR120 (pGPR120) has not been well characterized. In the current study, we found that pGPR120 had 3 spliced variants. Transcript 1 encoded 362-amino acids (aa) wild type pGPR120-WT, which shared 88% homology with human short form GPR120. Transcript 1 was the mainly expressed transcript of pGPR120. It was expressed predominantly in ileum, jejunum, duodenum, spleen, and adipose. Transcript 3 (coding 320-aa isoform) was detected in spleen, while the transcript 2 (coding 310-aa isoform) was only slightly expressed in spleen. A selective agonist for human GPR120 (TUG-891) and PUFAs activated SRE-luc and NFAT-luc reporter in HEK293T cells transfected with construct for pGPR120-WT but not pGPR120-V2. However, 320-aa isoform was not a dominant negative isoform. The extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation levels in cells transfected with construct for pGPR120-WT were well activated by PUFAs, especially n-3 PUFA. These results showed that although pGPR120 had 3 transcripts, transcript 1 which encoded pGPR120-WT was the mainly expressed transcript. TUG-891 and PUFAs, especially n-3 PUFA, well activated pGPR120-WT. The current study contributed to dissecting the molecular regulation mechanisms of n-3 PUFA in pigs. Tongxing Song, Jie Peng, Jiao Ren, Hong-kui Wei, and Jian Peng Copyright © 2015 Tongxing Song et al. All rights reserved. Insulin Resistance-Associated Interhemispheric Functional Connectivity Alterations in T2DM: A Resting-State fMRI Study Thu, 30 Apr 2015 12:41:12 +0000 We aim to investigate whether decreased interhemispheric functional connectivity exists in patients with type 2 diabetes mellitus (T2DM) by using resting-state functional magnetic resonance imaging (rs-fMRI). In addition, we sought to determine whether interhemispheric functional connectivity deficits associated with cognition and insulin resistance (IR) among T2DM patients. We compared the interhemispheric resting state functional connectivity of 32 T2DM patients and 30 healthy controls using rs-fMRI. Partial correlation coefficients were used to detect the relationship between rs-fMRI information and cognitive or clinical data. Compared with healthy controls, T2DM patients showed bidirectional alteration of functional connectivity in several brain regions. Functional connectivity values in the middle temporal gyrus (MTG) and in the superior frontal gyrus were inversely correlated with Trail Making Test-B score of patients. Notably, insulin resistance (log homeostasis model assessment-IR) negatively correlated with functional connectivity in the MTG of patients. In conclusion, T2DM patients exhibit abnormal interhemispheric functional connectivity in several default mode network regions, particularly in the MTG, and such alteration is associated with IR. Alterations in interhemispheric functional connectivity might contribute to cognitive dysfunction in T2DM patients. Wenqing Xia, Shaohua Wang, Andrea M. Spaeth, Hengyi Rao, Pin Wang, Yue Yang, Rong Huang, Rongrong Cai, and Haixia Sun Copyright © 2015 Wenqing Xia et al. All rights reserved. The Role of Vaspin in the Development of Metabolic and Glucose Tolerance Disorders and Atherosclerosis Mon, 06 Apr 2015 11:46:40 +0000 In recent years, most research efforts have been focused on studying insulin-sensitizing adipokines. One of the most recently discovered adipokines is vaspin, a visceral adipose tissue-derived serine protease inhibitor. Vaspin levels have been found significantly increased in mice with obesity and insulin resistance. It has been assumed that vaspin serves as an insulin sensitizer with anti-inflammatory effects and might act as a compensatory mechanism in response to decreased insulin sensitivity. Most studies in humans have shown a positive correlation between vaspin gene expression and serum levels, and metabolic syndrome parameters. Vaspin gene expression is influenced by age and gender, and the administration of insulin sensitizers enhances it in mice, whereas the use of metformin decreases serum vaspin levels in humans, probably due to different regulatory mechanisms. Presumably vaspin plays local and endocrine role in the development of initial and advanced atherosclerosis in obese subjects and might be used as a predictor of coronary and cerebrovascular disease. It is believed that vaspin could be regarded as a new link between obesity and related metabolic disorders, including glucose intolerance. The entire understanding of vaspin intimate mechanism of action might enable the development of novel etiology-based treatment strategies, targeting metabolic and glucose tolerance disorders. Rumyana Dimova and Tsvetalina Tankova Copyright © 2015 Rumyana Dimova and Tsvetalina Tankova. All rights reserved. Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines Wed, 01 Apr 2015 08:10:59 +0000 The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide) oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight) were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-α and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and sterol regulatory element-binding protein-1c (SREBP-1c) were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines. Yi Tan, Xing Liang Jin, Weiguo Lao, Jane Kim, Linda Xiao, and Xianqin Qu Copyright © 2015 Yi Tan et al. All rights reserved. Oxidative/Antioxidative Status in Obese and Sport Trained Children: A Comparative Study Tue, 31 Mar 2015 08:16:45 +0000 The aim of the study was to compare oxidative/antioxidative status in obese and sport trained children and to correlate obtained redox markers with anthropometrical measurements, body composition parameters, and adipokines levels. 78 (44 males) obese (SG) and 80 (40 males) normal weight sport trained (CG) children matched for age and Tanner stage were recruited for the study. Body composition parameters and basal metabolic rate (BMR) were assessed by bioelectrical impedance analysis (BIA). Oxidative/antioxidative status was evaluated in plasma by total oxidative status (PerOX), oxidized-LDL cholesterol (oxLDL), total antioxidative capacity (ImAnOx), and glutathione peroxidase activity (GPx). Leptin and adiponectin levels and adiponectin/leptin ratio (A/L) were also investigated. OxLDL was higher in SG versus CG (P < 0.05), but ImAnOx and GPx were reduced in SG versus CG (P < 0.01). Redox markers correlated significantly with BMI Z-score, WHR, WHtR, body composition parameters, leptin (in boys only), and A/L ratio (in boys only) in SG and in a whole studied population. PerOX significantly correlated with BMR in the CG. Antioxidative/oxidative status in obese children is significantly impaired and related adipose tissue excess and its hormonal activity. Oxidative status assessed by PerOx is also high in sport trained children but antioxidative defense is significantly more efficient with no overproduction of oxidized LDL. Pawel Matusik, Zofia Prokopowicz, Berenika Norek, Magdalena Olszanecka-Glinianowicz, Jerzy Chudek, and Ewa Malecka-Tendera Copyright © 2015 Pawel Matusik et al. All rights reserved. Environmental Trigger(s) of Type 1 Diabetes: Why Is It So Difficult to Identify? Mon, 30 Mar 2015 06:11:43 +0000 Kjersti S. Rønningen, Jill M. Norris, and Mikael Knip Copyright © 2015 Kjersti S. Rønningen et al. All rights reserved. Can Exposure to Environmental Chemicals Increase the Risk of Diabetes Type 1 Development? Thu, 26 Mar 2015 10:50:43 +0000 Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged. Johanna Bodin, Lars Christian Stene, and Unni Cecilie Nygaard Copyright © 2015 Johanna Bodin et al. All rights reserved. Role of Nutritional Factors at the Early Life Stages in the Pathogenesis and Clinical Course of Type 1 Diabetes Thu, 26 Mar 2015 09:31:18 +0000 Nutrition has been suggested as an important environmental factor other than viruses and chemicals in the pathogenesis of type 1 diabetes (T1D). Whereas various maternal dietary nutritional elements have been suggested and examined in T1D of both humans and experimental animals, the results largely remain controversial. In a series of studies using T1D model nonobese diabetic (NOD) mice, maternal dietary n-6/n-3 essential fatty acid ratio during pregnancy and lactation period, that is, early life stages of the offspring, has been shown to affect pathogenesis of insulitis and strongly prevent overt T1D of the offspring, which is consistent with its preventive effects on other allergic diseases. Yukiko Kagohashi and Hiroki Otani Copyright © 2015 Yukiko Kagohashi and Hiroki Otani. All rights reserved. Chinese Medicine for Treating Endocrinology-Related Disease Thu, 26 Mar 2015 09:02:00 +0000 Yizhou Xin, Ying Zhang, and Chunchao Han Copyright © 2015 Yizhou Xin et al. All rights reserved. Therapeutic Effect of Agaricus brasiliensis on Phenylhydrazine-Induced Neonatal Jaundice in Rats Wed, 25 Mar 2015 13:24:17 +0000 The present study was designed to investigate the effect of Agaricus brasiliensis extract (ABE) on phenylhydrazine-induced neonatal jaundice in rats. Administration of ABE dose-dependently reduced the elevated bilirubin level induced by phenylhydrazine. It can be somewhat supported from the results of in vitro bilirubin degradation experiment. ABE treatment also reduced the total antioxidant status (TAOS), cascade /SOD, level of NF-κB protein, and adrenomedullin (AM). Overall, the results of this study demonstrated that Agaricus brasiliensis extract may be beneficial to reducing bilirubin level without causing hepatotoxicity in neonatal jaundice. Lan Zhang, Bo Yuan, HuiPing Wang, and Ya Gao Copyright © 2015 Lan Zhang et al. All rights reserved. Environmental Trigger(s) of Type 1 Diabetes: Why So Difficult to Identify? Wed, 25 Mar 2015 11:14:13 +0000 Type 1 diabetes (T1D) is one of the most common chronic diseases with childhood onset, and the disease has increased two- to fivefold over the past half century by as yet unknown means. T1D occurs when the body’s immune system turns against itself so that, in a very specific and targeted way, it destroys the pancreatic β-cells. T1D results from poorly defined interactions between susceptibility genes and environmental determinants. In contrast to the rapid progress in finding T1D genes, identification and confirmation of environmental determinants remain a formidable challenge. This review article will focus on factors which have to be evaluated and decision to take before starting a new prospective cohort study. Considering all the large ongoing prospective studies, new and more conclusive data than that obtained so far should instead come from international collaboration on the ongoing cohort studies. Kjersti S. Rønningen Copyright © 2015 Kjersti S. Rønningen. All rights reserved. Assessing Age-Related Etiologic Heterogeneity in the Onset of Islet Autoimmunity Wed, 25 Mar 2015 08:52:50 +0000 Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases. Brittni N. Frederiksen, Miranda Kroehl, Anna Barón, Molly M. Lamb, Tessa L. Crume, Marci K. Sontag, Marian Rewers, and Jill M. Norris Copyright © 2015 Brittni N. Frederiksen et al. All rights reserved. Daycare Attendance, Breastfeeding, and the Development of Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young Wed, 25 Mar 2015 07:37:12 +0000 Background. The hygiene hypothesis attributes the increased incidence of type 1 diabetes (T1D) to a decrease of immune system stimuli from infections. We evaluated this prospectively in the Diabetes Autoimmunity Study in the Young (DAISY) by examining daycare attendance during the first two years of life (as a proxy for infections) and the risk of T1D. Methods. DAISY is a prospective cohort of children at increased T1D risk. Analyses were limited to 1783 children with complete daycare and breastfeeding data from birth to 2 years of age; 58 children developed T1D. Daycare was defined as supervised time with at least one other child at least 3 times a week. Breastfeeding duration was evaluated as a modifier of the effect of daycare. Cox proportional hazards regression was used for analyses. Results. Attending daycare before the age of 2 years was not associated with T1D risk (HR: 0.89; CI: 0.54–1.47) after adjusting for HLA, first degree relative with T1D, ethnicity, and breastfeeding duration. Breastfeeding duration modified this association, where daycare attendance was associated with increased T1D risk in nonbreastfed children and a decreasing T1D risk with increasing breastfeeding duration (interaction P value = 0.02). Conclusions. These preliminary data suggest breastfeeding may modify the effect of daycare on T1D risk. Katelyn Hall, Brittni Frederiksen, Marian Rewers, and Jill M. Norris Copyright © 2015 Katelyn Hall et al. All rights reserved. Luminex and Other Multiplex High Throughput Technologies for the Identification of, and Host Response to, Environmental Triggers of Type 1 Diabetes Wed, 25 Mar 2015 07:12:10 +0000 Complex interactions between a series of environmental factors and genes result in progression to clinical type 1 diabetes in genetically susceptible individuals. Despite several decades of research in the area, these interactions remain poorly understood. Several studies have yielded associations of certain foods, infections, and immunizations with the onset and progression of diabetes autoimmunity, but most findings are still inconclusive. Environmental triggers are difficult to identify mainly due to (i) large number and complex nature of environmental exposures, including bacteria, viruses, dietary factors, and environmental pollutants, (ii) reliance on low throughput technology, (iii) less efforts in quantifying host response, (iv) long silent period between the exposure and clinical onset of T1D which may lead to loss of the exposure fingerprints, and (v) limited sample sets. Recent development in multiplex technologies has enabled systematic evaluation of different classes of molecules or macroparticles in a high throughput manner. However, the use of multiplex assays in type 1 diabetes research is limited to cytokine assays. In this review, we will discuss the potential use of multiplex high throughput technologies in identification of environmental triggers and host response in type 1 diabetes. Sharad Purohit, Ashok Sharma, and Jin-Xiong She Copyright © 2015 Sharad Purohit et al. All rights reserved. The Advances in Research on the Pharmacological Effects of Fructus Ligustri Lucidi Sun, 22 Mar 2015 09:29:17 +0000 Fructus Ligustri Lucidi is a well-known invigorator in Chinese materia medica with hepatoprotective effect, anticancer activity, antioxidant activity, and so on. And oleanolic acids are the major pharmacologically active components in Fructus Ligustri Lucidi. So it has great value in medical health, and may be developed to a complementary and alternative medicine through further research. In this paper, the advances in research on pharmacological effects of Fructus Ligustri Lucidi were summarized by reviewing the recent related literature. Zunting Pang, Zhou Zhi-yan, Wei Wang, Yanni Ma, Niu Feng-ju, Xuelan Zhang, and Chunchao Han Copyright © 2015 Zunting Pang et al. All rights reserved. Osteoprotective Effect of Cordycepin on Estrogen Deficiency-Induced Osteoporosis In Vitro and In Vivo Sun, 22 Mar 2015 08:54:37 +0000 The purpose of this study was to verify the effect of cordycepin on ovariectomized osteopenic rats. Fifty Wistar female rats used were divided into 5 groups: (1) sham-operation rats (control), (2) ovariectomized (OVX) rats with osteopenia, and (3) OVX’d rats with osteopenia treated with cordycepin (5 mg, 10 mg, and 20 mg) for 8 weeks. After the rats were treated orally with cordycepin, serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY) , C-terminal crosslinked telopeptides of collagen type I (CTX) level, and oxidative stress were examined, respectively. The femoral neck was used for mechanical compression testing. At the same time, we further investigated the effect of cordycepin in vitro assay. The beneficial effects of cordycepin on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, and CTX level. At the same time, cordycepin also increases the OC level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary cordycepin can prevent bone loss caused by estrogen deficiency. These experimental results suggest that complement cordycepin is protective after ovariectomized osteopenic in specific way. Da-wei Zhang, Hualiang Deng, Wei Qi, Guang-yue Zhao, and Xiao-rui Cao Copyright © 2015 Da-wei Zhang et al. All rights reserved. Crocetin Downregulates the Proinflammatory Cytokines in Methylcholanthrene-Induced Rodent Tumor Model and Inhibits COX-2 Expression in Cervical Cancer Cells Sun, 22 Mar 2015 08:52:18 +0000 The effect of crocetin (C20H24O4) on methylcholanthrene- (MCA-) induced uterine cervical cancer in mice was studied in this paper. After the mice were treated orally with crocetin, maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1 (IL-1), and tumor necrosis factor- (TNF-) were examined by ELISA or immunohistochemistry. The inducible nitric oxide synthase (iNOS) activation in HeLa cells was analyzed using fluorescence microscopy for light microscopic examination. The MCA mice showed a significant increase in plasma MDA, PMN, IL-1, TNF-, and nitrates levels. At the same time, the mRNA level of COX-2 in HeLa cells was also significantly increased. These changes were attenuated by crocetin supplementation in the MCA mice. Crocetin supplementation in the MCA mice also showed protection against cervical cancer. These results suggest that crocetin may act as a chemopreventive and an anti-inflammatory agent. Bing Chen, Zhao-Hui Hou, Zhe Dong, and Chun-Dong Li Copyright © 2015 Bing Chen et al. All rights reserved. Combined Therapy of Diabetic Peripheral Neuropathy with Breviscapine and Mecobalamin: A Systematic Review and a Meta-Analysis of Chinese Studies Thu, 19 Mar 2015 14:29:47 +0000 Objective. A meta-analysis on combined therapy of diabetic peripheral neuropathy (DPN) with breviscapine and mecobalamin was performed to evaluate the efficacy of this therapy. Methods. Six English databases (Medline, Cochrane Library, PubMed, EMBASE, Web of Science, and CINAHL) and four Chinese databases (China National Knowledge Infrastructure, VIP Journals Database, CBM, and Wanfang database) were searched for studies on the clinical trials in which DPN was treated with breviscapine and mecobalamin, and RevMan 5.1 package was employed for analyzing pooled trials and publication bias. Results. A total of 17 articles including 1398 DPN patients were identified. Homogeneity was observed among different studies (). The efficacy of combined therapy with breviscapine and mecobalamin was significantly better than that in control group [ (, 95% CI: 3.70–6.78)]. Conclusion. Available findings suggest that the therapeutic efficacy of breviscapine combining mecobalamin is superior to mecobalamin alone, and this strategy is required to be popularized in clinical practice. Chanjiao Zheng, Weilin Ou, Huanyu Shen, Zhiheng Zhou, and Jiaji Wang Copyright © 2015 Chanjiao Zheng et al. All rights reserved. A Novel Rat Model of Vitamin D Deficiency: Safe and Rapid Induction of Vitamin D and Calcitriol Deficiency without Hyperparathyroidism Sat, 28 Feb 2015 11:48:29 +0000 Vitamin D deficiency is associated with a range of clinical disorders. To study the mechanisms involved and improve treatments, animal models are tremendously useful. Current vitamin D deficient rat models have important practical limitations, including time requirements when using, exclusively, a vitamin D deficient diet. More importantly, induction of hypovitaminosis D causes significant fluctuations in parathyroid hormone (PTH) and mineral levels, complicating the interpretation of study results. To overcome these shortcomings, we report the successful induction of vitamin D deficiency within three weeks, with stable serum PTH and minerals levels, in Wistar rats. We incorporated two additional manoeuvres compared to a conventional diet. Firstly, the vitamin D depleted diet is calcium (Ca) enriched, to attenuate the development of secondary hyperparathyroidism. Secondly, six intraperitoneal injections of paricalcitol during the first two weeks are given to induce the rapid degradation of circulating vitamin D metabolites. After three weeks, serum 25-hydroxyvitamin D3 (25D) and 1,25-dihydroxyvitamin D3 (1,25D) levels had dropped below detection limits, with unchanged serum PTH, Ca, and phosphate (P) levels. Therefore, this model provides a useful tool to examine the sole effect of hypovitaminosis D, in a wide range of research settings, without confounding changes in PTH, Ca, and P. Andrea W. D. Stavenuiter, Maria Vittoria Arcidiacono, Evelina Ferrantelli, Eelco D. Keuning, Marc Vila Cuenca, Piet M. ter Wee, Robert H. J. Beelen, Marc G. Vervloet, and Adriana S. Dusso Copyright © 2015 Andrea W. D. Stavenuiter et al. All rights reserved. Association of IL-6 Polymorphism -174G/C and Metabolic Syndrome in Hypertensive Patients Sat, 28 Feb 2015 07:10:53 +0000 Introduction. Visceral obesity, the central core of metabolic syndrome (MetS), is conceived as the pathogenic basis of an increased cardiovascular burden and is related with changes in cytokines. We investigated whether IL-6-174G/C gene polymorphism is associated with MetS prevalence in hypertensive patients. Method. A population of hypertensive patients was included and stratified by the presence of MetS according to IDF criteria and evaluated by Framingham risk score. The IL-6-174G/C genotyping was performed by polymerase chain reaction and the prevalence of MetS was compared between “C” carrier and “non-C” carrier groups. Results. From an original sample of 664 patients, 612 (34.2% men, age 57.3 ± 10.1, 30.4% diabetics) were included. MetS was diagnosed in 51.3% of total population and “C” carriers demonstrated high prevalence of MetS () and each of its components. On binary logistic regression, it was observed that the IL-6 polymorphism was independently associated with occurrence of MetS, even after adjusting for covariates (OR 1.13–2.37, 95% CI, ). Conclusion. The C allele at the -174 locus of IL-6 gene is independently associated with the occurrence of metabolic syndrome, emphasizing the importance of inflammatory genetic background in the pathogenesis of visceral obesity and related cardiovascular burden. Andrei Alkmim Teixeira, Beata Marie Redublo Quinto, Maria Aparecida Dalboni, Cassio Jose de Oliveira Rodrigues, and Marcelo Costa Batista Copyright © 2015 Andrei Alkmim Teixeira et al. All rights reserved. Effects of Berberine on Amelioration of Hyperglycemia and Oxidative Stress in High Glucose and High Fat Diet-Induced Diabetic Hamsters In Vivo Sun, 01 Feb 2015 14:06:51 +0000 This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet-induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg·kg−1) for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes. Cong Liu, Zhuo Wang, Yulong Song, Dan Wu, Xuan Zheng, Ping Li, Jin Jin, Nannan Xu, and Ling Li Copyright © 2015 Cong Liu et al. All rights reserved. Polymorphic Basal Rates of Continuous Subcutaneous Insulin Infusion among Taiwanese Children with Type 1 Diabetes Sat, 31 Jan 2015 11:17:28 +0000 Introduction. The basal dose of insulin, proportion of total daily insulin, and circadian variation during continuous subcutaneous insulin infusion (CSII) therapy among children with type 1 diabetes mellitus (T1D) have not been fully elucidated. Materials and Methods. A total of 45 childhood patients with T1D receiving CSII therapy at Pediatrics Department of Chang Gung Memorial Hospital between 2004 and 2012 were analyzed. Patients were classified according to Tanner stage. Results. HbA1c was significantly reduced in all Tanner groups within three months of CSII therapy (from 67 mmol/mol (8.3%) to 54 mmol/mol (7.1%), ). The actual basal proportion of total daily insulin use was 34–40%. The circadian distribution of basal insulin differed markedly between the five Tanner groups. Basal insulin requirement was highest between 3:00 and 7:00 h in Tanner stages 1-2. In stages 3-4, a lower nocturnal basal insulin that increased gradually until daytime was noted. Adolescents (stage 5) displayed a high insulin peak between 6:00 and 11:00 h, and a smaller peak between 19:00 and 23:00 h. Conclusions. A smaller proportion of basal insulin to total daily insulin use, as well as varied circadian patterns of insulin use, characterized these children with T1D. Chia-Hung Lin, Feng-Ju Hsieh, Yang-Hau Van, and Fu-Sung Lo Copyright © 2015 Chia-Hung Lin et al. All rights reserved. Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH Wed, 28 Jan 2015 08:40:51 +0000 Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass. Rafael Pacheco-Costa, Jenifer Freitas Campos, Eduardo Katchburian, Valquíria Pereira de Medeiros, Helena Bonciani Nader, Keico Okino Nonaka, Lilian Irene Plotkin, and Rejane Daniele Reginato Copyright © 2015 Rafael Pacheco-Costa et al. All rights reserved. R990G Polymorphism of Calcium Sensing Receptor Gene Is Associated with High Parathyroid Hormone Levels in Subjects with Vitamin D Deficiency: A Cross-Sectional Study Wed, 28 Jan 2015 08:38:04 +0000 Single nucleotide polymorphisms (SNPs), R990G and A986S of the calcium sensing receptor (CaSR) gene, are shown to influence response of parathyroid hormone (PTH) in subjects with optimal vitamin D levels. This cross-sectional study was conducted in subjects with vitamin D deficiency (VDD) to observe associations between CaSR polymorphisms, plasma iPTH, and serum calcium levels. Adult females () with known VDD, intact parathyroid hormone (iPTH), and calcium levels were recruited for genotype analysis. The frequencies of the 986 alleles GG, GT, and TT were 68%, 25%, and 7%, respectively, whereas the frequencies of the 990 alleles AA, AG, and GG were 80%, 8.9%, and 11.1%, respectively. The subjects with GG genotype of R990G polymorphism had higher iPTH levels (148.65 versus 91.47 and 86.1 pg/mL for GG versus AA, AG, resp., ) and lower calcium levels (8.4 versus 9.04 and 9.07 mg/dL for GG versus AA, AG, resp., ). No such association of A986S polymorphism with plasma iPTH or serum calcium levels was observed in the present study. Patients with VDD bearing the GG genotype of R990G SNPs are prone to have higher iPTH levels and lower calcium. Hafsa Majid, Aysha Habib Khan, and Tariq Moatter Copyright © 2015 Hafsa Majid et al. All rights reserved. A Protective Role of Arecoline Hydrobromide in Experimentally Induced Male Diabetic Rats Wed, 28 Jan 2015 06:20:10 +0000 Objectives. Arecoline, the most potent and abundant alkaloid of betel nut, causes elevation of serum testosterone and androgen receptor expression in rat prostate, in addition to increase in serum insulin levels in rats, leading to insulin resistance and type 2 diabetes-like conditions. This study investigated the role of arecoline on the reproductive status of experimentally induced type 1 diabetic rats. Methods. Changes in the cellular architecture were analyzed by transmission electron microscopy. Blood glucose, serum insulin, testosterone, FSH, and LH were assayed. Fructose content of the coagulating gland and sialic acid content of the seminal vesicles were also analyzed. Results. Arecoline treatment for 10 days at a dose of 10 mg/kg of body weight markedly facilitated β-cell regeneration and reversed testicular and sex accessory dysfunctions by increasing the levels of serum insulin and gonadotropins in type 1 diabetic rats. Critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (pdx-1) and glucose transporter 2 (GLUT-2), were found to be activated by arecoline at the protein level. Conclusion. It can thus be suggested that arecoline is effective in ameliorating the detrimental effects caused by insulin deficiency on gonadal and male sex accessories in rats with type 1 diabetes. Indraneel Saha, Joydeep Das, Biswaranjan Maiti, and Urmi Chatterji Copyright © 2015 Indraneel Saha et al. All rights reserved. Dependence of Thyroid Sonographic Markers of Malignancy and Its Influence on the Diagnostic Value of Sonographic Findings Thu, 22 Jan 2015 12:38:58 +0000 Introduction. Thyroid nodules constitute frequent medical condition. Ultrasonographic (US) examination remains the basis in the diagnostics of nodular goiter and selection of the suspected ones requiring fine-needle aspiration biopsy (FNAB). The aim of this study was to evaluate if the features so far considered to be US malignancy markers are dependent or independent variables and to check if these data are clinically relevant. Materials and Methods. Patients with diagnosed thyroid nodular goiter admitted for thyroidectomy, irrespectively of the indications for surgery, were involved. The following parameters were assessed: echogenicity, the presence of calcifications, presence of halo, shape, margins, structure (solid, partially or pure cystic), and elasticity of the nodules (assessed quantitatively). Results. 122 consecutive patients with 393 thyroid nodules were included. There were significant associations between halo absence and irregular borders, micro- and macrocalcifications, taller-than-wide feature and macrocalcifications, irregular margins and macrocalcifications, and also decreased elasticity of nodules and several attributes (partially cystic character, micro- and macrocalcifications). Conclusions. Not only diagnostic value of particular sonographic features but also data about cooccurrence and associations between them are clinically relevant. Although most of these features turned out to be independent, omitting significant association can lead to incorrect assessment of the risk of malignancy. Kosma Woliński, Adam Stangierski, Ewelina Szczepanek-Parulska, Edyta Gurgul, and Marek Ruchała Copyright © 2015 Kosma Woliński et al. All rights reserved. Experimental Gestational Diabetes Mellitus Induces Blunted Vasoconstriction and Functional Changes in the Rat Aorta Sun, 28 Dec 2014 07:59:10 +0000 Diabetic conditions increase vascular reactivity to angiotensin II in several studies but there are scarce reports on cardiovascular effects of hypercaloric diet (HD) induced gestational diabetes mellitus (GDM), so the objective of this work was to determine the effects of HD induced GDM on vascular responses. Angiotensin II as well as phenylephrine induced vascular contraction was tested in isolated aorta rings with and without endothelium from rats fed for 7 weeks (4 before and 3 weeks during pregnancy) with standard (SD) or hypercaloric (HD) diet. Also, protein expression of AT1R, AT2R, COX-1, COX-2, NOS-1, and NOS-3 and plasma glucose, insulin, and angiotensin II levels were measured. GDM impaired vasoconstrictor response versus SD) in intact (e+) but not in endothelium-free (e−) vessels. Losartan reduced GDM but not SD e− vasoconstriction versus SD). AT1R, AT2R, and COX-1 and COX-2 protein expression were significantly increased in GDM vessels versus SD). Results suggest an increased participation of endothelium vasodilator mediators, probably prostaglandins, as well as of AT2 vasodilator receptors as a compensatory mechanism for vasoconstrictor changes generated by experimental GDM. Considering the short term of rat pregnancy findings can reflect early stage GDM adaptations. Cecilia Tufiño, Cleva Villanueva-López, Maximiliano Ibarra-Barajas, Ismael Bracho-Valdés, and Rosa Amalia Bobadilla-Lugo Copyright © 2014 Cecilia Tufiño et al. All rights reserved. Lifestyle Modification Strategies to Counteract the World Epidemic Growth of Obesity and Diabetes Sun, 28 Dec 2014 06:27:46 +0000 Pierpaolo De Feo, Jean-Michel Boris, and Claudio Maffeis Copyright © 2014 Pierpaolo De Feo et al. All rights reserved. Intraportal Infusion of Ghrelin Could Inhibit Glucose-Stimulated GLP-1 Secretion by Enteric Neural Net in Wistar Rat Tue, 26 Aug 2014 12:01:51 +0000 As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect. Xiyao Zhang, Wensong Li, Ping Li, Manli Chang, Xu Huang, Qiang Li, and Can Cui Copyright © 2014 Xiyao Zhang et al. All rights reserved. Investigation on Carbohydrate Counting Method in Type 1 Diabetic Patients Sun, 17 Aug 2014 08:45:48 +0000 Objective. The results from Diabetes Control and Complications Trial (DCCT) have propounded the importance of the approach of treatment by medical nutrition when treating diabetes mellitus (DM). During this study, we tried to inquire carbohydrate (Kh) count method’s positive effects on the type 1 DM treatment’s success as well as on the life quality of the patients. Methods. 22 of 37 type 1 DM patients who applied to Eskişehir Osmangazi University, Faculty of Medicine Hospital, Department of Endocrinology and Metabolism, had been treated by Kh count method and 15 of them are treated by multiple dosage intensive insulin treatment with applying standard diabetic diet as a control group and both of groups were under close follow-up for 6 months. Required approval was taken from the Ethical Committee of Eskişehir Osmangazi University, Medical Faculty, as well as informed consent from the patients. The body weight of patients who are treated by carbohydrate count method and multiple dosage intensive insulin treatment during the study beginning and after 6-month term, body mass index, and body compositions are analyzed. A short life quality and medical research survey applied. At statistical analysis, t-test, chi-squared test, and Mann-Whitney U test were used. Results. There had been no significant change determined at glycemic control indicators between the Kh counting group and the standard diabetic diet and multiple dosage insulin treatment group in our study. Conclusion. As a result, Kh counting method which offers a flexible nutrition plan to diabetic individuals is a functional method. Osman Son, Belgin Efe, Nazan Erenoğlu Son, Aysen Akalin, and Nur Kebapçi Copyright © 2014 Osman Son et al. All rights reserved. The Wedelolactone Derivative Inhibits Estrogen Receptor-Mediated Breast, Endometrial, and Ovarian Cancer Cells Growth Wed, 13 Aug 2014 09:14:02 +0000 Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers. Defeng Xu, Tzu-Hua Lin, Chiuan-Ren Yeh, Max A. Cheng, Lu-Min Chen, Chawnshang Chang, and Shuyuan Yeh Copyright © 2014 Defeng Xu et al. All rights reserved. Description of the EUROBIS Program: A Combination of an Epode Community-Based and a Clinical Care Intervention to Improve the Lifestyles of Children and Adolescents with Overweight or Obesity Mon, 04 Aug 2014 11:36:37 +0000 The present paper describes the Epode Umbria Region Obesity Prevention Study (EUROBIS) and aims to implement the C.U.R.I.A.MO. model through the EPODE methodology. The main goal of the EUROBIS is to change the pendency of slope of the actual trend towards the increase in the yearly rates of childhood overweight and obesity in Umbria and to improve healthy lifestyles of children and their parents. The project is the first EPODE program to be performed in Italy. The aims of the Italian EUROBIS study are: (1) a community-based intervention program (CBP) carrying out activities in all primary schools of the Umbria Region and family settings as first step, to reverse the current obesity trend on a long-term basis, and (2) a clinical care program for childhood and adolescent by C.U.R.I.A.MO. model. C.U.R.I.A.MO. model is a multidisciplinary approach to improve three key aspects of healthy lifestyles: nutrition, exercise, and psychological aspects with the strategy of a family-based approach. The community-based intervention and clinical trial provide an innovative valuable model to address the childhood obesity prevention and treatment in Italy. Claudia Mazzeschi, Chiara Pazzagli, Loredana Laghezza, Dalila Battistini, Elisa Reginato, Chiara Perrone, Claudia Ranucci, Cristina Fatone, Roberto Pippi, Maria Donata Giaimo, Alberto Verrotti, Giovanni De Giorgi, and Pierpaolo De Feo Copyright © 2014 Claudia Mazzeschi et al. All rights reserved. Influence of Electric, Magnetic, and Electromagnetic Fields on the Circadian System: Current Stage of Knowledge Tue, 22 Jul 2014 11:23:03 +0000 One of the side effects of each electrical device work is the electromagnetic field generated near its workplace. All organisms, including humans, are exposed daily to the influence of different types of this field, characterized by various physical parameters. Therefore, it is important to accurately determine the effects of an electromagnetic field on the physiological and pathological processes occurring in cells, tissues, and organs. Numerous epidemiological and experimental data suggest that the extremely low frequency magnetic field generated by electrical transmission lines and electrically powered devices and the high frequencies electromagnetic radiation emitted by electronic devices have a potentially negative impact on the circadian system. On the other hand, several studies have found no influence of these fields on chronobiological parameters. According to the current state of knowledge, some previously proposed hypotheses, including one concerning the key role of melatonin secretion disruption in pathogenesis of electromagnetic field induced diseases, need to be revised. This paper reviews the data on the effect of electric, magnetic, and electromagnetic fields on melatonin and cortisol rhythms—two major markers of the circadian system as well as on sleep. It also provides the basic information about the nature, classification, parameters, and sources of these fields. Bogdan Lewczuk, Grzegorz Redlarski, Arkadiusz Żak, Natalia Ziółkowska, Barbara Przybylska-Gornowicz, and Marek Krawczuk Copyright © 2014 Bogdan Lewczuk et al. All rights reserved. The Impact of Strenuous Group Physical Activity on Mood States, Personal Views, Body Composition, and Markers of Myocardial Damage in Overweight/Obese Adults: The “Step-by-Step Italy’s Coast to Coast” Trek Tue, 22 Jul 2014 00:00:00 +0000 It is clinically relevant to understand whether it is safe to recommend to trained overweight/obese people long-distance treks and whether these experiences could have a negative psychological impact or become even dangerous exposing the trekkers to the risk of clinically silent myocardial damage. To answer these questions we have performed a quantitative/qualitative study comparing the changes in mood profiles, personal views, body composition, and plasma troponin levels of 40 overweight/obese subjects with those of 36 healthy normal weight subjects after the participation in a trek of 388 km from the Adriatic to the Tyrrhenian seas trek: the “Step by step…Italy’s coast to coast”. The results of this study demonstrate that long-distance treks are a safe activity for trained overweight/obese people which should be recommended because they improve mood, health status, and the relationship of participants with themselves and with the regular practice of exercise with effects similar to those obtained by healthy normal weight subjects. Claudia Mazzeschi, Natalia Piana, Daniela Capezzali, Antonella Mommi, Cristina Aiello, Michela Gatti, Giannermete Romani, Livia Buratta, Dalila Battistini, Giovanni Nasini, Elisa Reginato, Lorena Urbani, Chiara Pazzagli, Carla Ferri, Giuseppe Ambrosio, and Pierpaolo De Feo Copyright © 2014 Claudia Mazzeschi et al. All rights reserved. The Effects of Vitamin E and Omega-3 PUFAs on Endothelial Function among Adolescents with Metabolic Syndrome Sun, 20 Jul 2014 08:55:17 +0000 Aim. The present study aims to explore the effects of vitamin E and omega-3 on endothelial function indicators among adolescents with metabolic syndrome. Method. In a randomized, double blind, and placebo-controlled trial, 90 young individuals, aged 10 to 18 years, with metabolic syndrome were randomly assigned to receive either vitamin E tablets (400 IU/day) or omega-3 tablets (2.4 gr/day) or placebo. For assessing endothelial functional state, the serum level of vascular endothelial growth factor (VEGF) was measured by ELISA test. Results. The use of omega-3 supplementation for eight weeks led to significant increase in serum HDL level compared with the group treated with vitamin E or placebo group. In this regard, no significant correlations were found between the change in VEGF and baseline levels of other markers including anthropometric indices and serum lipids. Omega-3 could significantly reduce VEGF with the presence of other baseline variables (; ). Conclusion. The administration of omega-3 can effectively improve endothelial function in adolescents with metabolic syndrome by reducing the level of serum VEGF, as a major index for atherosclerosis progression and endothelial destabilization. Omega-3 can be proposed as a VEGF antagonist for improving endothelial function in metabolic syndrome. The clinical implications of our findings should be assessed in future studies. Alireza Ahmadi, Mojgan Gharipour, Gholamreza Arabzadeh, Payam Moin, Mahin Hashemipour, and Roya Kelishadi Copyright © 2014 Alireza Ahmadi et al. All rights reserved. Consumption of Green Coffee Reduces Blood Pressure and Body Composition by Influencing 11β-HSD1 Enzyme Activity in Healthy Individuals: A Pilot Crossover Study Using Green and Black Coffee Wed, 16 Jul 2014 00:00:00 +0000 Dietary polyphenols may have a protective role against the development of CVD. Thus, we aimed to investigate the effects of green coffee (GC), rich in chlorogenic acid, and black coffee (BC) on cardiovascular markers. A randomised pilot crossover study was performed on healthy subjects who consumed both coffees for 2 weeks. We measured anthropometry, blood pressure, and arterial elasticity after each intervention and collected urine samples to monitor antioxidant capacity. Free cortisol and cortisone levels were obtained from urine and analysed by specific ELISA methods. Systolic blood pressure () and arterial elasticity () were significantly reduced after GC. BMI ( for BC; for GC) and abdominal fat ( for BC; for GC) were also significantly reduced with no changes in energy intake. Urinary free cortisol was significantly reduced from  nmol/day to  nmol/day following GC and increased to  nmol/day after BC. Urinary free cortisone increased by 18% following BC and 9% following GC (nonsignificant). Cortisol/cortisone ratio (indicating 11β-HSD1 activity) was reduced after GC (from to , ). This suggests that GC can play a role in reducing cardiovascular risk factors. Further research including hypertensive and overweight individuals will now be justified to clarify whether GC could have a therapeutic role in CVD. R. Revuelta-Iniesta and E. A. S. Al-Dujaili Copyright © 2014 R. Revuelta-Iniesta and E. A. S. Al-Dujaili. All rights reserved. Adrenergic Activation of Melatonin Secretion in Ovine Pineal Explants in Short-Term Superfusion Culture Occurs via Protein Synthesis Independent and Dependent Phenomena Tue, 15 Jul 2014 08:36:24 +0000 The ovine pineal is generally considered as an interesting model for the study on adrenergic regulation of melatonin secretion due to some functional similarities with this gland in the human. The present investigations, performed in the superfusion culture of pineal explants, demonstrated that the norepinephrine-induced elevation of melatonin secretion in ovine pinealocytes comprised of two subsequent periods: a rapid increase phase and a slow increase phase. The first one included the quick rise in release of N-acetylserotonin and melatonin, occurring parallel to elevation of NE concentration in the medium surrounding explants. This rapid increase phase was not affected by inhibition of translation. The second, slow increase phase began after NE level had reached the maximum concentration in the culture medium and lasted about two hours. It was completely abolished by the treatment with translation inhibitors. The obtained results showed for the first time that the regulation of N-acetylserotonin synthesis in pinealocytes of some species like the sheep involves the on/off mechanism, which is completely independent of protein synthesis and works very fast. They provided strong evidence pointing to the need of revision of the current opinion that arylalkylamines N-acetyltransferase activity in pinealocytes is controlled exclusively by changes in enzyme abundance. Bogdan Lewczuk, Natalia Ziółkowska, Magdalena Prusik, and Barbara Przybylska-Gornowicz Copyright © 2014 Bogdan Lewczuk et al. All rights reserved. Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression Thu, 10 Jul 2014 07:32:29 +0000 Context. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing’s syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors. Tamaya Castro Ribeiro, Alexander Augusto Jorge, Madson Q. Almeida, Beatriz Marinho de Paula Mariani, Mirian Yumi Nishi, Berenice Bilharinho Mendonca, Maria Candida Barisson Villares Fragoso, and Ana Claudia Latronico Copyright © 2014 Tamaya Castro Ribeiro et al. All rights reserved. The Protective Effect of Agaricus blazei Murrill, Submerged Culture Using the Optimized Medium Composition, on Alcohol-Induced Liver Injury Thu, 10 Jul 2014 00:00:00 +0000 Agaricus blazei Murrill (ABM), an edible mushroom native to Brazil, is widely used for nonprescript and medicinal purposes. Alcohol liver disease (ALD) is considered as a leading cause for a liver injury in modern dietary life, which can be developed by a prolonged or large intake of alcohol. In this study, the medium composition of ABM was optimized using response surface methodology for maximum mycelial biomass and extracellular polysaccharide (EPS) production. The model predicts to gain a maximal mycelial biomass and extracellular polysaccharide at 1.047 g/100 mL, and 0.367 g/100 mL, respectively, when the potato is 29.88 g/100 mL, the glucose is 1.01 g/100 mL, and the bran is 1.02 g/100 mL. The verified experiments showed that the model was significantly consistent with the model prediction and that the trends of mycelial biomass and extracellular polysaccharide were predicted by artificial neural network. After that, the optimized medium was used for the submerged culture of ABM. Then, alcohol-induced liver injury in mice model was used to examine the protective effect of ABM cultured using the optimized medium on the liver. And the hepatic histopathological observations showed that ABM had a relatively significant role in mice model, which had alcoholic liver damage. Hang Wang, Gang Li, Wenyu Zhang, Chunchao Han, Xin Xu, and Yong-Ping Li Copyright © 2014 Hang Wang et al. All rights reserved. Ameliorative Effect of Saffron Aqueous Extract on Hyperglycemia, Hyperlipidemia, and Oxidative Stress on Diabetic Encephalopathy in Streptozotocin Induced Experimental Diabetes Mellitus Wed, 09 Jul 2014 11:19:53 +0000 Diabetic encephalopathy is one of the severe complications in patients with diabetes mellitus. Findings indicate that saffron extract has antioxidant properties but its underlying beneficial effects on diabetic encephalopathy were unclear. In the present study, the protective activities of saffron were evaluated in diabetic encephalopathy. Saffron at 40 and 80 mg/kg significantly increased body weight and serum TNF-α and decreased blood glucose levels, glycosylated serum proteins, and serum advanced glycation endproducts (AGEs) levels. Furthermore, significant increase in HDL and decrease () in cholesterol, triglyceride, and LDL were observed after 28 days of treatment. At the end of experiments, the hippocampus tissue was used for determination of glutathione content (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Furthermore, saffron significantly increased GSH, SOD, and CAT but remarkably decreased cognitive deficit, serum TNF-α, and induced nitric oxide synthase (iNOS) activity in hippocampus tissue. Our findings indicated that saffron extract may reduce hyperglycemia and hyperlipidemia risk and also reduce the oxidative stress in diabetic encephalopathy rats. This study suggested that saffron extract might be a promising candidate for the improvement of chemically induced diabetes and its complications. Saeed Samarghandian, Mohsen Azimi-Nezhad, and Fariborz Samini Copyright © 2014 Saeed Samarghandian et al. All rights reserved. Perceived Difficulty with Physical Tasks, Lifestyle, and Physical Performance in Obese Children Sun, 06 Jul 2014 00:00:00 +0000 We estimated perceived difficulty with physical tasks, lifestyle, and physical performance in 382 children and adolescents (163 obese, 54 overweight, and 165 normal-weight subjects) and the relationship between perceived physical difficulties and sports participation, sedentary behaviors, or physical performance. Perceived difficulty with physical tasks and lifestyle habits was assessed by interview using a structured questionnaire, while physical performance was assessed through the six-minute walking test (6MWT). Obese children had higher perceived difficulty with several activities of daily living, were less engaged in sports, and had lower physical performance than normal-weight or overweight children; on the contrary, they did not differ with regard to time spent in sedentary behaviors. Perceived difficulty in running and hopping negatively predicted sports participation ( and <0.01, resp.), while perceived difficulty in almost all physical activities negatively predicted the 6MWT, independently of BMI (). Our results indicate that perception of task’s difficulty level may reflect an actual difficulty in obese children. These findings may have practical implications for approaching physical activity in obese children. Exploring both the perception of a task’s difficulty level and physical performance may be useful to design exercise programs that allow safe and successful participation. Giuliana Valerio, Valeria Gallarato, Osvaldo D’Amico, Maura Sticco, Paola Tortorelli, Eugenio Zito, Rosa Nugnes, Enza Mozzillo, and Adriana Franzese Copyright © 2014 Giuliana Valerio et al. All rights reserved. Selected Factors Determining a Way of Coping with Stress in Type 2 Diabetic Patients Thu, 03 Jul 2014 11:50:31 +0000 Objectives. The aim of the study was to examine factors which determine stress coping styles in type 2 diabetic (T2D) patients, with regard to selected demographic variables, clinical diabetes-related variables and selected psychical variables (anxiety level and assessment of depressive disorders). Methods. 50 T2D patients, aged 59.9 ± 10.2 years were assessed by Coping Inventory for Stressful Situations (CISS), Spielberger State-Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). In the statistical analysis simple and multivariable logistic regression models were used. Results. Variables significantly increasing the selection risk of stress coping style different from preferred task-oriented strategy in a simple logistic regression model are: hypoglycemia within three months prior to the research: odds ratio (OR) = 6.86 (95% confidence interval (CI) 1.25–37.61), taking antidepressants or neuroleptics: OR =15.42 (95% CI 2.42–98.33), severe depression in Beck’s scale: OR = 84.00 (95% CI 6.51–1083.65), high state-anxiety level: OR = 9.60 (95% CI 1.08–85.16), and high trait-anxiety level: OR = 18.40 (95%CI 2.96–114.31), but in a multivariable model, diagnosed depression is the strongest factor: OR = 32.38 (95% CI 4.94–212.13). Conclusions. In T2D patients, the strategy to cope with stress appears to be mostly influenced by psychical predisposition. Anna Beata Sobol-Pacyniak, Wiesław Szymczak, Paulina Kwarta, Jerzy Loba, and Tadeusz Pietras Copyright © 2014 Anna Beata Sobol-Pacyniak et al. All rights reserved. Effect of Exercise Intensity on Isoform-Specific Expressions of NT-PGC-1α mRNA in Mouse Skeletal Muscle Wed, 02 Jul 2014 12:15:53 +0000 PGC-1α is an inducible transcriptional coactivator that regulates mitochondrial biogenesis and cellular energy metabolism in skeletal muscle. Recent studies have identified two additional PGC-1α transcripts that are derived from an alternative exon 1 (exon 1b) and induced by exercise. Given that the PGC-1α gene also produces NT-PGC-1α transcript by alternative 3′ splicing between exon 6 and exon 7, we have investigated isoform-specific expression of NT-PGC-1α mRNA in mouse skeletal muscle during physical exercise with different intensities. We report here that NT-PGC-1α-a mRNA expression derived from a canonical exon 1 (exon 1a) is increased by high-intensity exercise and AMPK activator AICAR in mouse skeletal muscle but not altered by low- and medium-intensity exercise and β2-adrenergic receptor agonist clenbuterol. In contrast, the alternative exon 1b-driven NT-PGC-1α-b (PGC-1α4) and NT-PGC-1α-c are highly induced by low-, medium-, and high-intensity exercise, AICAR, and clenbuterol. Ectopic expression of NT-PGC-1α-a in C2C12 myotube cells upregulates myosin heavy chain (MHC I, MHC II a) and Glut4, which represent oxidative fibers, and promotes the expression of mitochondrial genes (Cyc1, COX5B, and ATP5B). In line with gene expression data, citrate synthase activity was significantly increased by NT-PGC-1α-a in C2C12 myotube cells. Our results indicate the regulatory role for NT-PGC-1α-a in mitochondrial biogenesis and adaptation of skeletal muscle to endurance exercise. Xingyuan Wen, Jing Wu, Ji Suk Chang, Pengcheng Zhang, Jianzhu Wang, Yaliang Zhang, Thomas W. Gettys, and Yubin Zhang Copyright © 2014 Xingyuan Wen et al. All rights reserved. Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency Thu, 26 Jun 2014 06:49:09 +0000 Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology. Mariza G. Santos, Aline Z. Machado, Conceição N. Martins, Sorahia Domenice, Elaine M. F. Costa, Mirian Y. Nishi, Bruno Ferraz-de-Souza, Soraia A. C. Jorge, Carlos A. Pereira, Fernanda C. Soardi, Maricilda P. de Mello, Andrea T. Maciel-Guerra, Gil Guerra-Junior, and Berenice B. Mendonca Copyright © 2014 Mariza G. Santos et al. All rights reserved. MicroRNA Era: The Importance for Diagnosis and Prognosis of Adrenocortical Tumors Mon, 23 Jun 2014 12:33:21 +0000 MicroRNAs play an essential role in posttranscriptional regulation of gene expression. They are evolutionary conserved, small, noncoding, 19–22-nucleotide RNAs, whose abnormalities, such as up- or downregulated expression, have been associated with several neoplasms, including adrenocortical tumors. Expression levels of distinct microRNAs can distinguish benign from malignant adrenal tumors. This current review provides recent data on the miRNAs profile in benign and malignant adrenocortical tumors diagnosed in adult and pediatric patients. João Evangelista Bezerra and Ana Claudia Latronico Copyright © 2014 João Evangelista Bezerra and Ana Claudia Latronico. All rights reserved. The Ratio of Estimated Average Glucose to Fasting Plasma Glucose Level Is Superior to Glycated Albumin, Hemoglobin A1c, Fructosamine, and GA/A1c Ratio for Assessing β-Cell Function in Childhood Diabetes Tue, 10 Jun 2014 06:10:18 +0000 Objective. This study investigated the use of the estimated average glucose to fasting plasma glucose ratio (eAG/fPG ratio) to screen for β-cell function in pediatric diabetes. Methods. Glycated hemoglobin (HbA1c), glycated albumin (GA), fructosamine, insulin, and C-peptide levels were measured. The ratio of GA to HbA1c (GA/A1c ratio) was calculated, and the homeostasis model assessment of β-cell function (HOMA-β) was determined. Results. Median values of C-peptide, insulin, and HOMA-β levels were significantly higher in patients with an increased eAG/fPG ratio than in those with a decreased eAG/fPG ratio. C-peptide and HOMA-β levels were more closely correlated with the eAG/fPG ratio than with GA, HbA1c, the GA/A1c ratio, and fructosamine. In contrast, body mass index was significantly associated with GA, GA/A1c ratio, and fructosamine, but not with the eAG/fPG ratio and HbA1c levels. To test the diagnostic accuracies of the eAG/fPG ratio for identifying HOMA-β > 30.0% in patients with type 2 diabetes, the area under the ROC curve of the eAG/fPG ratio was significantly larger than that of the GA/A1c ratio [0.877 (95% CI, 0.780–0.942) versus 0.775 (95% CI, 0.664–0.865), ]. Conclusions. A measurement of the eAG/fPG ratio may provide helpful information for assessing β-cell function in pediatric patients with diabetes. Ji Eun Lee, Ji Woo Lee, Tatsuyoshi Fujii, Noriyoshi Fujii, and Jong Weon Choi Copyright © 2014 Ji Eun Lee et al. All rights reserved. The Role of Genetic Factors and Kidney and Liver Function in Glycemic Control in Type 2 Diabetes Patients on Long-Term Metformin and Sulphonylurea Cotreatment Mon, 09 Jun 2014 16:03:27 +0000 This study investigated the influence of genetic polymorphisms of metformin transporters on long-term glycemic control and lipid status in type 2 diabetes patients in the everyday clinical setting. In total 135 patients treated with combination of metformin and sulphonylurea for at least 6 months were genotyped for SLC22A1 rs628031 and SLC47A1 rs2289669 polymorphisms. Relatively good blood glucose control with median HbA1c 6.9 (6.4–7.6) % was achieved on prescribed metformin dosage of 2550 (2000–2550) mg per day. Only 28 (20.7%) patients experienced mild hypoglycemia events, while no severe hypoglycemia events were observed. Most patients had normal or mildly impaired renal function. Parameters indicating renal function were not correlated with fasting glucose, HbA1c, or lipid parameters. Rs628031 and rs2289669 had minor allele frequencies of 0.385 and 0.355, respectively, and were not associated with HbA1c levels. Rs628031 was marginally associated with risk for hypoglycemia events (; OR = 0.51; 95% CI 0.26–0.99), while significant correlation was observed between rs2289669 and total cholesterol levels (). In conclusion, in patients on long-term metformin and sulphonylurea combination treatment, metformin transporters polymorphisms do not play a major role in glycemic control; however, they may influence lipid status. Jasna Klen, Katja Goričar, Andrej Janež, and Vita Dolžan Copyright © 2014 Jasna Klen et al. All rights reserved. 4-Hydroxychalcone Attenuates Hyperaldosteronism, Inflammation, and Renal Injury in Cryptochrome-Null Mice Mon, 09 Jun 2014 13:13:03 +0000 In the present study, we aimed to investigate the preventive effects of 4-hydroxychalcone (4HCH) on resistant hypertension. We used cryptochrome-null mice, which characteristically show high plasma aldosterone levels, inflammation, and renal injury. The cryptochrome-null mice received high-salt treatment and were treated orally with 4HCH 10 mg/kg, 4HCH 20 mg/kg, and 4HCH 40 mg/kg, respectively. The salt administration in cryptochrome-null mice is able to induce an increase in systolic pressure which is associated with hyperaldosteronism, inflammation, and kidney injury. Treatment with 40 mg/kg 4HCH reduced systolic hypertension, serum IL-1β, and TNF-α levels and suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and renal injury. The impact of 4HCH on the hyperaldosteronism, inflammation, and kidney injury provides new insights for future development of therapeutic strategies in resistant hypertension. Qi Qu, Bingguang Dai, Bo Yang, Xuelian Li, Yimin Liu, and Fuling Zhang Copyright © 2014 Qi Qu et al. All rights reserved. Prevalence of Anti-Neu5Gc Antibodies in Patients with Hypothyroidism Mon, 09 Jun 2014 05:49:04 +0000 Background. N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by animals, but not by humans or birds. However, it can be incorporated in human cells and can trigger immune response. In the present study, we detected anti-Neu5Gc antibodies in samples of the general population and of patients suffering from hypothyroidism/Hashimoto’s disease, which is known to have autoimmune origin. Methods. Antibodies were measured using enzyme-immunosorbent techniques. Results. Serum anti-Neu5Gc IgG antibodies were higher in patients with hypothyroidism (mean:  μg/mL, median: 10.0 μg/mL, , Mann-Whitney) and even higher in the group with Hashimoto’s thyroiditis (mean:  μg/mL, median: 27.2 μg/mL, , Mann-Whitney) compared to the general population (mean:   μg/mL, median : 4 μg/mL). All anti-TPO positive samples had anti-Neu5Gc antibody concentration higher than the mean value of the general population while anti-TPO concentration was increased as anti-Neu5Gc concentration increased. Low concentrations of IgA and IgM antibodies were measured in both general population and patient groups. Conclusion. The increased values of anti-Neu5Gc antibodies in patients with hypothyroidism/Hashimoto’s disease and the correlation of anti-TPO incidence with increased anti-Neu5Gc concentration raise the possibility of an association between anti-Neu5Gc antibody development and autoimmune hypothyroidism. Phaedra Eleftheriou, Stavros Kynigopoulos, Alexandra Giovou, Alexandra Mazmanidi, John Yovos, Petros Skepastianos, Eleni Vagdatli, Christos Petrou, Dafni Papara, and Maria Efterpiou Copyright © 2014 Phaedra Eleftheriou et al. All rights reserved. Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus Wed, 04 Jun 2014 11:18:30 +0000 The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFα synthesis. Intravenous injection of SB203580 successfully inhibited () synthesis of IL-1β and reduced () the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased () gene expression of TNFα but its effect was not observed at the level of TNFα protein synthesis. SB203580 also reduced () LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment. Andrzej P. Herman, Agata Krawczyńska, Joanna Bochenek, Hanna Antushevich, Anna Herman, and Dorota Tomaszewska-Zaremba Copyright © 2014 Andrzej P. Herman et al. All rights reserved. Serum IL-17, IL-23, and TGF-β Levels in Type 1 and Type 2 Diabetic Patients and Age-Matched Healthy Controls Wed, 04 Jun 2014 09:09:27 +0000 Type 1 diabetes is recognized as an autoimmune inflammatory disease and low grade inflammation is also observed in type 2 diabetic patients. Interleukin 17 (IL-17) is a new player in inflammation. Th17 cells, as the main source of IL-17, require transforming growth factor β (TGF-β) and interleukin 23 (IL-23). The aim of this study was to investigate serum IL-17, IL-23 and TGF-β levels in diabetic patients and controls. In this case-control study, serum levels of IL-17, IL-23, and TGF-β were measured in 24 type 1 diabetic patients and 30 healthy controls using the ELISA method. Simultaneously, the same methodology was used to compare serum concentration of these three cytokines in 38 type 2 diabetic patients and 40 healthy controls. There was no significant difference between serum levels of IL-17 and IL-23 cytokines between cases and controls. However, TGF-β was significantly lower in type 1 diabetic patients (). Serum IL-17 and IL-23 levels demonstrate no association with type 1 and type 2 diabetes, but, in line with previous studies, TGF-β levels were lower in type 1 diabetic patients. Azam Roohi, Mina Tabrizi, Farzaneh Abbasi, Asal Ataie-Jafari, Behrouz Nikbin, Bagher Larijani, Mostafa Qorbani, Alipasha Meysamie, Hossein Asgarian-Omran, Bahram Nikmanesh, Arezou Bajouri, Novin Shafiey, and Akram Maleki Copyright © 2014 Azam Roohi et al. All rights reserved. Polymorphisms of β1-Adrenoreceptor Gene and Cardiovascular Complications in Patients with Thyrotoxicosis Sun, 25 May 2014 07:12:00 +0000 Human cardiac β1-AR perform a crucial role in mediating the cardiostimulating effects of norepinephrine. Gly389Arg and Ser49Gly polymorphisms of β1-adrenoreceptors (β1-AR) can influence the cardiovascular prognosis. However, the possible effect of Gly389Arg and Ser49Gly polymorphisms on heart function in thyrotoxicosis has not been studied. We investigated the possible link between Gly389Arg and Ser49Gly polymorphisms and echocardiography parameters in 165 normotensive patients with a thyrotoxicosis without any cardiovascular disorders. Echo-CG was performed according to standard protocol before and during the thyreostatic treatment. Our data demonstrate that both Gly389Arg and Ser49Gly polymorphisms have very moderate influence on the risk of left ventricular hypertrophy and atrial fibrillation with no statistically significant effects on cardiac function and the development of cardiovascular complications. A. Y. Babenko, E. N. Grineva, D. A. Savitskaja, E. N. Kravchuk, V. N. Solncev, and A. A. Kostareva Copyright © 2014 A. Y. Babenko et al. All rights reserved. Validation of Reference Genes for Normalization Gene Expression in Reverse Transcription Quantitative PCR in Human Normal Thyroid and Goiter Tissue Sun, 11 May 2014 13:38:09 +0000 Reverse transcription quantitative polymerase chain reaction (RT-qPCR) has been recognized as the most accurate method for quantifying mRNA transcripts, but normalization of samples is a prerequisite for correct data interpretation. So, this study aimed to evaluate the most stable reference gene for RT-qPCR in human normal thyroid and goiter tissues. Beta-actin (ACTB); glyceraldehyde-3-phosphate dehydrogenase (GAPDH); succinate dehydrogenase, subunit A, flavoprotein (Fp) (SDHA); hypoxanthine phosphoribosyltransferase I (HPRTI); tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (YWHAZ); and beta-2-microglobulin (B2M) were evaluated in 14 thyroid tissue samples (7 normal and 7 goiter tissues) by RT-qPCR. The mean Cq and the maximum fold change (MFC) and NormFinder software were used to assess the stability of the genes. As a result, ACTB gene was more stable than GAPDH, SDHA, HPRTI, YWHAZ, and B2M. In conclusion, ACTB could be used to normalize RT-qPCR data in normal thyroid and goiter tissues. Raquel Weber, Ana Paula Santin Bertoni, Laura Walter Bessestil, Beatriz Maria de Azevedo Assis Brasil, llma Simoni Brum, and Tania Weber Furlanetto Copyright © 2014 Raquel Weber et al. All rights reserved. Frequency and Clinical Implication of the R450H Mutation in the Thyrotropin Receptor Gene in the Japanese Population Detected by Smart Amplification Process 2 Mon, 05 May 2014 10:02:26 +0000 In Japanese pediatric patients with thyrotropin (TSH) resistance, the R450H mutation in TSH receptor gene (TSHR) is occasionally observed. We studied the frequency and clinical implication of the R450H mutation in TSHR in the general population of Japanese adults using smart amplification process 2 (SmartAmp2). We designed SmartAmp2 primer sets to detect this mutation using a drop of whole blood. We analyzed thyroid function, antithyroid antibodies, and this mutation in 429 Japanese participants who had not been found to have thyroid disease. Two cases without antithyroid antibodies were heterozygous for the R450H mutation in TSHR. Thus, the prevalence of this mutation was 0.47% in the general population and 0.63% among those without antithyroid antibodies. Their serum TSH concentrations were higher than the average TSH concentration not only in subjects without antithyroid antibodies but also in those with antithyroid antibodies. The R450H mutation in TSHR is relatively common in the Japanese population and potentially affects thyroid function. The present study demonstrates that the SmartAmp2 method is useful to detect the R450H mutation in TSHR, which is one of the common causes of TSH resistance in the Japanese population. Katsuhiko Tsunekawa, Yoshimaro Yanagawa, Tomoyuki Aoki, Tadashi Morimura, Osamu Araki, Takao Kimura, Takayuki Ogiwara, Nobuo Kotajima, Masumi Yanagawa, and Masami Murakami Copyright © 2014 Katsuhiko Tsunekawa et al. All rights reserved. Analysis of the Associations between Vitamin D and Albuminuria or β-Cell Function in Chinese Type 2 Diabetes Wed, 23 Apr 2014 14:11:04 +0000 Objective. To investigate the associations of 25-(OH)D and β-cell function or insulin resistance or albuminuria in Chinese type 2 diabetic patients. Methods. In total, 1408 type 2 diabetic patients without vitamin D supplement were included in this retrospective study. Results. Comparison between patients with and without 25-(OH)D deficiency indicated that, compared with patients with 25-(OH)D ≥ 50 nmol/L, patients with 25-(OH)D < 50 nmol/L showed a higher level of urine albumin-creatinine ratio (ACR) ( mg/g versus  mg/g). Multiple regression analysis indicated that 25-(OH)D was independently and negatively correlated with urine ACR (, 95%CI 0.972–0.999, ), adjusted by age, diabetic duration, HBP duration, SBP, HbA1c, creatinine, LDL-C, triglyceride, total cholesterol, and HDL-C. Compared with patients with normal level of urine ACR, patients with higher level of urine ACR showed a significant lower level of 25-(OH)D ( nmol/L versus  nmol/L, ). Analysis of the associations of 25-(OH)D and β-cell function or insulin resistance showed that 25-(OH)D may not correlate with β-cell function or insulin resistance. Conclusion. 25-(OH)D was independently associated with albuminuria in Chinese type 2 diabetic patients but was not associated with β-cell function or insulin resistance. Xiaoling Cai, Zhaoheng Hu, Ling Chen, Xueyao Han, and Linong Ji Copyright © 2014 Xiaoling Cai et al. All rights reserved. Liraglutide Suppresses Obesity and Hyperglycemia Associated with Increases in Hepatic Fibroblast Growth Factor 21 Production in KKAy Mice Mon, 07 Apr 2014 10:03:42 +0000 Social isolation contributes to the development of obesity and insulin-independent diabetes in KK mice. Here we show that systemic administration of liraglutide, a long-acting human glucagon-like peptide-1 (GLP-1) analog, significantly decreased food intake, body weight, and blood glucose levels at 24 h after its administration while having no significant effects on plasma insulin and glucagon levels in individually housed KK mice. In addition, the systemic administration of liraglutide significantly increased plasma fibroblast growth factor (Fgf) 21 levels (1.8-fold increase) associated with increases in the expression of hepatic Fgf21 (1.9-fold increase) and Ppar (1.8-fold increase), while having no effects on the expression of hepatic Ppar and Fgf21 in white adipose tissue. Moreover, systemic administration of liraglutide over 3 days significantly suppressed food intake, body weight gain, and hyperglycemia in KK mice. On the other hand, despite remarkably increased plasma active GLP-1 levels (4.2-fold increase), the ingestion of alogliptin, a selective dipeptidyl peptidase-4 inhibitor, over 3 days had no effects on food intake, body weight, blood glucose levels, and plasma Fgf21 levels in KK mice. These findings suggest that systemic administration of liraglutide induces hepatic Fgf21 production and suppresses the social isolation-induced obesity and diabetes independently of insulin, glucagon, and active GLP-1 in KK mice. Katsunori Nonogaki, Miki Hazama, and Noriko Satoh Copyright © 2014 Katsunori Nonogaki et al. All rights reserved. Obesity and Headache/Migraine: The Importance of Weight Reduction through Lifestyle Modifications Thu, 03 Apr 2014 12:47:47 +0000 The aim of this study is to determine a possible relationship between prevalence, frequency, and severity of migraine and obesity. All pertinent data from the literature have been critically examined and reviewed in order to assess the possible relationship between obesity and migraine, in particular migraine frequency and disability in children, as well as in adult population studies. Prevalence, frequency, and severity of migraine appear to increase in relation to the body mass index, although this evidence is not supported by all the studies examined. Data from literature suggest that obesity can be linked with migraine prevalence, frequency, and disability both in pediatric and adult subjects. These data have important clinical implications and suggest that clinicians should have a special interest for weight reduction of obese children suffering from migraine, prescribing and supporting intensive lifestyle modifications (dietary, physical activities, and behavioral) for the patient and the entire family. Alberto Verrotti, Alessia Di Fonzo, Laura Penta, Sergio Agostinelli, and Pasquale Parisi Copyright © 2014 Alberto Verrotti et al. All rights reserved. NMR-Based Metabolomic Profiling of Overweight Adolescents: An Elucidation of the Effects of Inter-/Intraindividual Differences, Gender, and Pubertal Development Thu, 27 Mar 2014 16:31:18 +0000 The plasma and urine metabolome of 192 overweight 12–15-year-old adolescents (BMI of 25.4 ± 2.3 kg/m2) were examined in order to elucidate gender, pubertal development measured as Tanner stage, physical activity measured as number of steps taken daily, and intra-/interindividual differences affecting the metabolome detected by proton NMR spectroscopy. Higher urinary excretion of citrate, creatinine, hippurate, and phenylacetylglutamine and higher plasma level of phosphatidylcholine and unsaturated lipid were found for girls compared with boys. The results suggest that gender differences in the metabolome are being commenced already in childhood. The relationship between Tanner stage and the metabolome showed that pubertal development stage was positively related to urinary creatinine excretion and negatively related to urinary citrate content. No relations between physical activity and the metabolome could be identified. The present study for the first time provides comprehensive information about associations between the metabolome and gender, pubertal development, and physical activity in overweight adolescents, which is an important subject group to approach in the prevention of obesity and life-style related diseases. While this study is preliminary, these results may have the potential to translate into clinical applicability upon further investigations; if biomarkers for Tanner stage can be established, these might be used for identification of individuals susceptible to an early pubertal development. Hong Zheng, Christian C. Yde, Karina Arnberg, Christian Mølgaard, Kim F. Michaelsen, Anni Larnkjær, and Hanne C. Bertram Copyright © 2014 Hong Zheng et al. All rights reserved. Functional Analyses of c.2268dup in Thyroid Peroxidase Gene Associated with Goitrous Congenital Hypothyroidism Mon, 17 Mar 2014 13:52:45 +0000 The c.2268dup mutation in thyroid peroxidase (TPO) gene was reported to be a founder mutation in Taiwanese patients with dyshormonogenetic congenital hypothyroidism (CH). The functional impact of the mutation is not well documented. In this study, homozygous c.2268dup mutation was detected in two Malaysian-Chinese sisters with goitrous CH. Normal and alternatively spliced TPO mRNA transcripts were present in thyroid tissues of the two sisters. The abnormal transcript contained 34 nucleotides originating from intron 12. The c.2268dup is predicted to generate a premature termination codon (PTC) at position 757 (p.Glu757X). Instead of restoring the normal reading frame, the alternatively spliced transcript has led to another stop codon at position 740 (p.Asp739ValfsX740). The two PTCs are located at 116 and 201 nucleotides upstream of the exons 13/14 junction fulfilling the requirement for a nonsense-mediated mRNA decay (NMD). Quantitative RT-PCR revealed an abundance of unidentified transcripts believed to be associated with the NMD. TPO enzyme activity was not detected in both patients, even though a faint TPO band of about 80 kD was present. In conclusion, the c.2268dup mutation leads to the formation of normal and alternatively spliced TPO mRNA transcripts with a consequential loss of TPO enzymatic activity in Malaysian-Chinese patients with goitrous CH. Ching Chin Lee, Fatimah Harun, Muhammad Yazid Jalaludin, Chor Yin Lim, Khoon Leong Ng, and Sarni Mat Junit Copyright © 2014 Ching Chin Lee et al. All rights reserved. Estrogen Deficiency and the Origin of Obesity during Menopause Thu, 06 Mar 2014 09:25:08 +0000 Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women. Fernando Lizcano and Guillermo Guzmán Copyright © 2014 Fernando Lizcano and Guillermo Guzmán. All rights reserved. Inhibition of Ceramide De Novo Synthesis with Myriocin Affects Lipid Metabolism in the Liver of Rats with Streptozotocin-Induced Type 1 Diabetes Wed, 19 Feb 2014 10:09:28 +0000 Nowadays diabetes is one of the most common metabolic diseases. Sphingolipids, which are vitally important constituents of intracellular signal transduction pathways, may be among the most pathogenic lipid moieties intermingled in the origin and development of diabetes. It is now well established that inhibition of de novo ceramide synthesis with myriocin exerts positive effects on lipid metabolism and glucose homeostasis in type 2 diabetes mellitus animal models. However, its influence on type I diabetes still remains unknown. Therefore, the scope of this paper is to fulfill that particular gap in our knowledge. Krzysztof Kurek, Patrycja Wiesiołek-Kurek, Dominika M. Piotrowska, Bartłomiej Łukaszuk, Adrian Chabowski, and Małgorzata Żendzian-Piotrowska Copyright © 2014 Krzysztof Kurek et al. All rights reserved. Decreased Thioredoxin-1 and Increased HSP90 Expression in Skeletal Muscle in Subjects with Type 2 Diabetes or Impaired Glucose Tolerance Tue, 04 Feb 2014 08:00:31 +0000 In diabetes, the endogenous defence systems are overwhelmed, causing various types of stress in tissues. In this study, newly diagnosed or diet-treated type 2 diabetics (T2D) () were compared with subjects with impaired glucose tolerance (IGT) (). In both groups, at resting conditions, blood samples were drawn for assessing metabolic indices and skeletal muscle samples (m. vastus lateralis) were taken for the measurements of cellular defence markers: thioredoxin-1 (TRX-1) and stress proteins HSP72, HSP90. The protein level of TRX-1 was 36.1% lower () and HSP90 was 380% higher () in the T2D than in the IGT subjects, with no significant changes in HSP72. However, after the adjustment of both analyses with HOMA-IR only HSP90 difference remained significant. In conclusion, level of TRX-1 in skeletal muscle tissue was lower while that of HSP90 was higher in T2D than in IGT subjects. This may impair antioxidant defence and lead to disruptions of protein homoeostasis and redox regulation of cellular defences. Because HSP90 may be involved in sustaining functional insulin signalling pathway in type 2 diabetic muscles and higher HSP90 levels can be a consequence of type 2 diabetes, our results are potentially important for the diabetes research. M. Venojärvi, A. Korkmaz, S. Aunola, K. Hällsten, K. Virtanen, J. Marniemi, J.-P. Halonen, O. Hänninen, P. Nuutila, and M. Atalay Copyright © 2014 M. Venojärvi et al. All rights reserved. Plasma miR-126 Is a Potential Biomarker for Early Prediction of Type 2 Diabetes Mellitus in Susceptible Individuals Wed, 25 Dec 2013 17:03:50 +0000 Type 2 diabetes mellitus (T2DM) is a major public health problem in China. Diagnostic markers are urgently needed to identify individuals at risk of developing T2DM and encourage them to adapt to a healthier life style. Circulating miRNAs present important sources of noninvasive biomarkers of various diseases. Recently, a novel plasma microRNA signature was identified in T2DM. Here, we evaluated the T2DM-related miRNA signature in plasma of three study groups: normal (fasting glucose (FG), 4.8–5.2 mmol/L), T2DM-susceptible (FG, 6.1–6.9 mmol/L), and T2DM individuals (FG, ≥7.0 mmol/L) and tested the feasibility of using circulating miRNAs to identify individuals at risk of developing T2DM. Among the 5 miRNAs included in the signature, miR-29b and miR-28-3p are not detectable. miR-15a and miR-223 have comparable expression levels among three groups. Notably, miR-126 is the only miRNA that showed significantly reduced expression in susceptible individuals and T2DM patients compared to normal individuals, suggesting that miR-126 in circulation may serve as a potential biomarker for early identification of susceptible individuals to T2DM. Tao Zhang, Chunfang Lv, Liling Li, Sihan Chen, Shenglin Liu, Changyi Wang, and Bing Su Copyright © 2013 Tao Zhang et al. All rights reserved. Resistance Training for Diabetes Prevention and Therapy: Experimental Findings and Molecular Mechanisms Sun, 22 Dec 2013 11:54:47 +0000 Type 2 diabetes mellitus (T2D) is characterized by insulin resistance, impaired glycogen synthesis, lipid accumulation, and impaired mitochondrial function. Exercise training has received increasing recognition as a cornerstone in the prevention and treatment of T2D. Emerging research suggests that resistance training (RT) has the power to combat metabolic dysfunction in patients with T2D and seems to be an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients. However, there is limited mechanistic insight into how these adaptations occur. This review provides an overview of the intervention data on the impact of RT on glucose metabolism. In addition, the molecular mechanisms that lead to adaptation in skeletal muscle in response to RT and that are associated with possible beneficial metabolic responses are discussed. Some of the beneficial adaptations exerted by RT include increased GLUT4 translocation in skeletal muscle, increased insulin sensitivity and hence restored metabolic flexibility. Increased energy expenditure and excess postexercise oxygen consumption in response to RT may be other beneficial effects. RT is increasingly establishing itself as an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients. Barbara Strasser and Dominik Pesta Copyright © 2013 Barbara Strasser and Dominik Pesta. All rights reserved. Baseline Obesity Status Modifies Effectiveness of Adapted Diabetes Prevention Program Lifestyle Interventions for Weight Management in Primary Care Wed, 04 Dec 2013 14:40:16 +0000 Objective. To examine whether baseline obesity severity modifies the effects of two different, primary care-based, technology-enhanced lifestyle interventions among overweight or obese adults with prediabetes and/or metabolic syndrome. Patients and Methods. We compared mean differences in changes from baseline to 15 months in clinical measures of general and central obesity among participants randomized to usual care alone () or usual care plus a coach-led group () or self-directed individual () intervention, stratified by baseline body mass index (BMI) category. Results. Participants with baseline BMI had greater reductions in mean BMI, body weight (as percentage change), and waist circumference in the coach-led group intervention, compared to usual care and the self-directed individual intervention ( for all). In contrast, the self-directed intervention was more effective than usual care only among participants with baseline BMIs between . Mean weight loss exceeded 5% in the coach-led intervention regardless of baseline BMI category, but this was achieved only among self-directed intervention participants with baseline BMIs . Conclusions. Baseline BMI may influence behavioral weight-loss treatment effectiveness. Researchers and clinicians should take an individual’s baseline BMI into account when developing or recommending lifestyle focused treatment strategy. This trial is registered with NCT00842426. Kristen M. J. Azar, Lan Xiao, and Jun Ma Copyright © 2013 Kristen M. J. Azar et al. All rights reserved. Effects of Water Extracts of Graptopetalum paraguayense on Blood Pressure, Fasting Glucose, and Lipid Profiles of Subjects with Metabolic Syndrome Mon, 25 Nov 2013 10:49:35 +0000 This study was aimed to investigate the effects of water extracts of Graptopetalum paraguayense (WGP, 4 g/d) on blood pressure, blood glucose level, and lipid profiles in subjects with metabolic syndrome (MS). Participants with MS () were randomly assigned to the placebo () and WGP groups (), and the intervention was administered for 12 weeks. Systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose (FG), lipid profiles (total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein (HDL-C)), and antioxidant enzymes activities (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)) were measured. Forty-two subjects completed the study (placebo, ; WGP, ). FG, SBP, and LDL-C levels were significantly lower and HDL-C level and antioxidant enzymes activities (CAT and SOD) were significantly higher after WGP supplementation. Blood pressure, FG, and lipid profiles were significantly correlated with antioxidant enzymes activities after supplementation (). The present study demonstrated a significant reduction in blood pressure, blood glucose, and lipid profiles and an increase in antioxidant enzymes activities in subjects with MS after WGP supplementation. Taken together, the antioxidative capacity of WGP might exert a beneficial effect on MS. This trial is registered with NCT01463748. Chi-Hua Yen, Shu-Ju Chen, Jen-Tzu Liu, Yu-Fen Tseng, and Ping-Ting Lin Copyright © 2013 Chi-Hua Yen et al. All rights reserved. IRS1, TCF7L2, ADRB1, PPARG, and HHEX Polymorphisms Associated with Atherogenic Risk in Mexican Population Mon, 25 Nov 2013 08:48:51 +0000 Objective. We aimed to explore the association between polymorphisms of IRS1 (rs1801278), TCF7L2 (rs7903146 and rs12255372), ADRB1 (rs1801253), PPARG (rs1801282), and HHEX (rs5015480) genes with atherogenic risk (AI = Total cholesterol/HDL) in MetS, T2D, and healthy populations from the Mexican Social Security Institute. Methodology and Results. Four hundred thirty-five MetS, 517 T2D, and 547 healthy individuals were selected. The association between the SNPs and the atherogenic index was evaluated by multiple linear regression and multinomial logistic regression models. The ADRB1 gene showed a statistically significant association with high-risk atherogenic index, (IC 95% 1.64–5.24; ) for the Arg/Gly variant, under the dominant model an (IC 95% 1.67–5.25; ), and under the Log additive model an (IC 95% 1.54–4.15; ). Conclusions. The Arg389Gly polymorphism of the ADRB1 gene may be a worthy biological marker to predict the risk of developing cardiovascular diseases given a high-risk atherogenic index. B. I. Estrada-Velasco, M. Cruz, V. Madrid-Marina, G. A. Martínez-Nava, J. Gomez-Zamudio, and A. I. Burguete-García Copyright © 2013 B. I. Estrada-Velasco et al. All rights reserved. Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment Sun, 27 Oct 2013 17:42:20 +0000 Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST), a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level. Hala Ahmadieh and Ibrahim Salti Copyright © 2013 Hala Ahmadieh and Ibrahim Salti. All rights reserved. The Incidence of Hypogonadotropic Hypogonadism in Type 2 Diabetic Men in Polish Population Thu, 10 Oct 2013 09:56:29 +0000 The aim of this study was to investigate the incidence of hypogonadotropic hypogonadism (HH) in type 2 diabetic men (T2DM) in population of Polish men and examine the possible influence of estradiol levels and glycemic control. We evaluated TT, cfT, estradiol, and glycemic control (HbA1c) in 184 diabetic men and in 149 nondiabetic control group. The mean HbA1c was 8.6 ± 0.2% and 6.1 ± 0.3% and cfT concentration was 0.315 ± 0.08 nmol/L and 0.382 ± 0.07 nmol/L, respectively. T2DM had higher E2 concentration than nonobese control men (29.4 ± 3.7 pg/mL versus 24.5 ± 2.9 pg/mL). Forty-six percent of T2DM were hypogonadal and 93% had HH. We observed inverse relationship between BMI and cfT (, ) and positive between BMI and E2 (, ). E2 concentration was higher in T2DM with HH versus T2DM with normal TT/cfT concentration (34.5 ± 5.2 versus 27.4 ± 3.4 pg/mL). We observed negative correlation between HbA1c and cfT (, ) but positive between HbA1c and E2 levels (, ). The prevalence of obesity, hypertension, and CVD was higher in men with hypogonadism. High incidence of hypogonadotropic hypogonadism in type 2 diabetic men in Polish population is associated with poor glycemic control and can be secondary to an increase in estradiol concentrations. Michał Rabijewski, Lucyna Papierska, Wojciech Zgliczyński, and Paweł Piątkiewicz Copyright © 2013 Michał Rabijewski et al. All rights reserved. Potential Utility of Sodium Selenate as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats: A Perspective on Protein Tyrosine Phosphatase Wed, 11 Sep 2013 13:57:25 +0000 Metformin is widely regarded as the standard first-line antidiabetic agent, in terms of efficacy and safety profiles. However, in most patients with type II diabetes mellitus (T2DM), it was found that metformin alone is not enough to adequately control hyperglycemia. Thus, we designed this study with the aim to investigate the effect of sodium selenate, a protein tyrosine phosphatase (PTP) inhibitor, individually and as an adjunct to metformin, on a rat model that simulates the metabolic characteristics of human T2DM. T2DM model was achieved by feeding the rats with high-fat, high-fructose diet (HFFD) for 8 weeks followed by a low dose of streptozotocin (STZ) (35 mg/kg/day, i.p.). Changes in serum glucose, insulin, adiponectin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and the lipid profile were assessed. In addition, the level of reduced glutathione (GSH) and the activity of PTP were determined in the liver. Results showed that the addition of sodium selenate to metformin was able to restore hepatic GSH back to normal levels. Also, this combination therapy corrected the altered serum total cholesterol (TC), triglycerides (TG), and adiponectin levels. In conclusion, additive therapeutic effect was recorded when sodium selenate was used as an adjunct to metformin. Rania M. Salama, Mona F. Schaalan, Alaaeldin A. Elkoussi, and Amani E. Khalifa Copyright © 2013 Rania M. Salama et al. All rights reserved. Time Course of Improvement of Metabolic Parameters after a 12 Week Physical Exercise Programme in Patients with Type 2 Diabetes: The Influence of Gender in a Nigerian Population Thu, 29 Aug 2013 15:42:06 +0000 Gender is a major determinant of the outcomes of many health interventions. This study documents the order of significant improvements in metabolic parameters of patients with type 2 diabetes mellitus (T2DM) having metabolic syndrome within 12 weeks of physical exercise programmes. Twenty-nine patients, mean age 49.6 ± 3.7 years, presenting with high fasting plasma glucose, high triglycerides, hypertension, and high waist circumference undertook a thrice weekly aerobic and endurance exercise programme in addition to their drugs and diet. Variables were assessed at baseline and end of every two weeks for twelve weeks. Compared with baseline, significant improvement () in the metabolic parameters occurred in this order for the male participants: fasting glucose (2nd week), triglycerides and waist circumference (4th week), and systolic blood pressure (12th week). For the female participants, it was fasting glucose (4th week), triglycerides (6th week), and waist circumference (10th week). Regardless of the gender, fasting glucose was the first to improve significantly, followed by triglycerides. Hypertension did not improve significantly at all in the female participants as they may require more than twelve weeks of therapeutic exercise for any significant improvement in hypertension. A. F. Adeniyi, A. E. Uloko, O. O. Ogwumike, A. O. Sanya, and A. A. Fasanmade Copyright © 2013 A. F. Adeniyi et al. All rights reserved. Modulation of Pineal Melatonin Synthesis by Glutamate Involves Paracrine Interactions between Pinealocytes and Astrocytes through NF-B Activation Mon, 05 Aug 2013 08:54:42 +0000 The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF-κB activation were analyzed in astrocytes and pinealocytes. TNF-α's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF-α. Moreover, the activation of the astrocytic NF-κB seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF-κB transcription factor and possibly by subsequent TNF-α release. Darine Villela, Victoria Fairbanks Atherino, Larissa de Sá Lima, Anderson Augusto Moutinho, Fernanda Gaspar do Amaral, Rafael Peres, Thais Martins de Lima, Andréa da Silva Torrão, José Cipolla-Neto, Cristóforo Scavone, and Solange Castro Afeche Copyright © 2013 Darine Villela et al. All rights reserved. Chronic Exposure to Cadmium Disrupts the Adrenal Gland Activity of the Newt Triturus carnifex (Amphibia, Urodela) Mon, 22 Jul 2013 13:20:28 +0000 We intended to verify the safety of the freshwater values established for cadmium by the European Community and the Italian Ministry of Health in drinking water (5 μg/L) and sewage waters (20 μg/L). Therefore, we chronically exposed the newt Triturus carnifex to 5 μg/L and 20 μg/L doses of cadmium, respectively, during 3 and 9 months and verified the effects on the adrenal gland. We evaluated the serum concentrations of adrenocorticotropic hormone (ACTH), corticosterone, aldosterone, norepinephrine, and epinephrine. During the 3-month exposure, both doses of cadmium decreased ACTH and corticosterone serum levels and increased aldosterone and epinephrine serum levels. During the 9-month exposure, the 5 μg/L dose decreased ACTH and increased aldosterone and epinephrine serum levels; the 20 μg/L dose decreased norepinephrine and epinephrine serum levels, without affecting the other hormones. It was concluded that (1) chronic exposure to the safety values established for cadmium disrupted the adrenal gland activity and (2) the effects of cadmium were related both to the length of exposure and the dose administered. Moreover, our results suggest probable risks to human health, due to the use of water contaminated by cadmium. Flaminia Gay, Vincenza Laforgia, Ivana Caputo, Carla Esposito, Marilena Lepretti, and Anna Capaldo Copyright © 2013 Flaminia Gay et al. All rights reserved. The Role of PTPN22 C1858T Gene Polymorphism in Diabetes Mellitus Type 1: First Evaluation in Greek Children and Adolescents Mon, 15 Jul 2013 10:48:55 +0000 Type 1 diabetes mellitus (T1DM) is an autoimmune multifactorial disease. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. PTPN22 C1858T polymorphism was associated with T1DM in populations of Caucasian origin. The aim of this study was the investigation for the first time of the association of PTPN22 C1858T polymorphism with T1DM in Greek population. We studied 130 children and adolescents with T1DM and 135 healthy individuals of Greek origin. The polymorphism was genotyped using polymerase chain reaction with restriction fragment length polymorphism. C1858T and T1858T genotypes as well as 1858T allele were found more frequently in patients (10.8% and 5.8%, resp.) than in healthy individuals (5.9% and 3.0%, resp.) but at non statistically significant level. There was no statistically significant association found with gender, age at diagnosis, severity of onset, history of Hashimoto thyroiditis or family history of T1DM. Increased frequency of 1858T allele in patients than in controls, implying a probable association, agrees with results of similar studies on other populations. The inability to find a statistically significant difference is probably due to the decreased frequency of minor allele in Greek population, indicating the need for a larger sample. Styliani Giza, Antonios Goulas, Emmanouela Gbandi, Smaragda Effraimidou, Efimia Papadopoulou-Alataki, Maria Eboriadou, and Assimina Galli-Tsinopoulou Copyright © 2013 Styliani Giza et al. All rights reserved. Prevalence of Overweight and Obesity in Urban Elementary School Children in Northeastern Romania: Its Relationship with Socioeconomic Status and Associated Dietary and Lifestyle Factors Sun, 14 Jul 2013 07:53:44 +0000 The purpose of this paper is to estimate the prevalence of obesity and to identify its potential determinants to optimize the methods of prevention to combat further increases in childhood overweight. The study was carried out on 3444 school children of 6–10 years of age attending 30 schools in northeast Romania. Schools were classified by geographical location and socioeconomic status (SES). Overweight and obesity status were determined using IOTF BMI cut-off points. Prevalence of overweight (including obesity) was found to be 24.6% among boys and 22.6% among girls, whereas the prevalence of obesity was 7.8% in boys and 6.3% in girls. High SES (OR: 1.46; 95% CI: 1.10–1.93) and eating French fries and chips (OR: 1.81; 95% CI: 1.24–2.67) were associated with increased risk of overweight. In high- and medium-SES children, overweight was positively associated with the consumption of French fries and chips (2.93, 95% CI: 1.54–5.60 and 1.82, 95% CI: 1.04–3.21). In low-SES children, overweight was associated with low fruit consumption (0.21, 95% CI: 0.05–1.00) and sedentary behavior (3.37, 95% CI: 1.13–10.05). Therefore, the social and environmental determinants should be considered when constructing and implementing preventive measures regarding overweight and obesity. Veronica Mocanu Copyright © 2013 Veronica Mocanu. All rights reserved. Leptin Modulates Norepinephrine-Mediated Melatonin Synthesis in Cultured Rat Pineal Gland Mon, 01 Jul 2013 15:46:07 +0000 Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE (1 µM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception. Rodrigo Antonio Peliciari-Garcia, Jéssica Andrade-Silva, José Cipolla-Neto, and Carla Roberta de Oliveira Carvalho Copyright © 2013 Rodrigo Antonio Peliciari-Garcia et al. All rights reserved. Lipoprotein(a) Serum Levels in Diabetic Patients with Retinopathy Wed, 05 Jun 2013 10:02:31 +0000 Background. Atherogenic lipoproteins, such as total cholesterol, LDL cholesterol, oxidized low density lipoprotein, and triglycerides, are associated with progression of retinopathy. Aim. To evaluate the relationship between lipoprotein(a) and retinopathy in patients with type 2 diabetes mellitus. Materials and Methods. We enrolled 145 diabetic consecutive patients (82 females, 63 males; mean age years, mean duration of diabetes years). Presence and severity of retinopathy were evaluated. Serum lipid profile, including Lp(a) level, was assessed. Results. High Lp(a) levels have been observed in 54 (78.3%) subjects and normal levels in 13 (18.85%) subjects as regards diabetic patients with retinopathy. Lp(a) levels were high in 15 subjects (21.75%) and normal in 63 subjects (91.35%) as regards patients without retinopathy. Conclusions. Lp(a) levels are increased in a significant percentage of patients with retinopathy compared to diabetic patients without retinopathy. The impact of Lp(a) levels on diabetic retinopathy needs to be further investigated. Giulia Malaguarnera, Caterina Gagliano, Claudio Bucolo, Marco Vacante, Salvatore Salomone, Michele Malaguarnera, Daniela Giovanna Leonardi, Massimo Motta, Filippo Drago, and Teresio Avitabile Copyright © 2013 Giulia Malaguarnera et al. All rights reserved. In Vivo Determination of Vitamin D Function Using Transgenic Mice Carrying a Human Osteocalcin Luciferase Reporter Gene Wed, 27 Mar 2013 15:44:28 +0000 Vitamin D is an essential factor for ossification, and its deficiency causes rickets. Osteocalcin, which is a noncollagenous protein found in bone matrix and involved in mineralization and calcium ion homeostasis, is one of the major bone morphogenetic markers and is used in the evaluation of osteoblast maturation and osteogenic activation. We established transgenic mouse line expressing luciferase under the control of a 10-kb osteocalcin enhancer/promoter sequence. Using these transgenic mice, we evaluated the active forms of vitamins D2 and D3 for their bone morphogenetic function by in vivo bioluminescence. As the result, strong activity for ossification was observed with 1α,25-hydroxyvitamin D3. Our mouse system can offer a feasible detection method for assessment of osteogenic activity in the development of functional foods and medicines by noninvasive screening. Tomoko Nakanishi, Rumiko Saito, Makoto Taniguchi, Haruka Oda, Atsumi Soma, Mayu Yasunaga, Mariko Yamane, and Kenzo Sato Copyright © 2013 Tomoko Nakanishi et al. All rights reserved. Vitamin D and Bone Disease Thu, 27 Dec 2012 09:20:15 +0000 Vitamin D is important for normal development and maintenance of the skeleton. Hypovitaminosis D adversely affects calcium metabolism, osteoblastic activity, matrix ossification, bone remodeling and bone density. It is well known that Vit. D deficiency in the developing skeleton is related to rickets, while in adults is related to osteomalacia. The causes of rickets include conditions that lead to hypocalcemia and/or hypophosphatemia, either isolated or secondary to vitamin D deficiency. In osteomalacia, Vit. D deficiency leads to impairment of the mineralisation phase of bone remodeling and thus an increasing amount of the skeleton being replaced by unmineralized osteoid. The relationship between Vit. D and bone mineral density and osteoporosis are still controversial while new evidence suggests that Vit. D may play a role in other bone conditions such as osteoarthritis and stress fractures. In order to maintain a “good bone health” guidelines concerning the recommended dietary intakes should be followed and screening for Vit. D deficiency in individuals at risk for deficiency is required, followed by the appropriate action. S. Christodoulou, T. Goula, A. Ververidis, and G. Drosos Copyright © 2013 S. Christodoulou et al. All rights reserved. Altered Polarization, Morphology, and Impaired Innate Immunity Germane to Resident Peritoneal Macrophages in Mice with Long-Term Type 2 Diabetes Wed, 03 Oct 2012 10:34:02 +0000 Type 2 diabetes (T2D) is associated with perturbed innate immunity. Macrophages, bridging innate immunity and metabolic disturbances, play important roles in controlling immune homeostasis. However, the effect of long-term diabetic milieu (DM) on the functions and phenotypes of macrophages is still not clear. In this study, we used resident peritoneal macrophages (RPMs) from 5-month-old db/db mice to investigate the changes of macrophages. It was found that RPMs in db/db mice significantly reduced phagocytosis and adhesion capacity. After standardization with body weight, the number of F4/80+ RPMs markedly reduced in db/db mice, and, furthermore, the macrophages skewed to M2-polarizated macrophages. The results of morphology found that the RPMs shape of db/db mice was nearly round, but the RPMs shape of control mice was spindle-shaped and irregular. In this study, we found the cell numbers, morphology, and innate immunity functions of RPMs in 5-month-old type 2 diabetic mice (db/db mice) obtained by abdominal cavity lavage were significantly altered. Importantly, we also found the remarkably increased M2-RPMs in diabetic mice for the first time. Hui-Fang Liu, Hui-Jie Zhang, Qi-Xian Hu, Xiao-Yan Liu, Zhi-Quan Wang, Jia-Yan Fan, Ming Zhan, and Feng-Ling Chen Copyright © 2012 Hui-Fang Liu et al. All rights reserved. Effects of Norepinephrine and Acetylcholine on the Development of Cultured Leydig Cells in Mice Tue, 02 Oct 2012 13:35:49 +0000 Few data have suggested how norepinephrine (NE) and acetylcholine (Ach) regulate the development of Leydig cells in mice at prepuberty, except for data indicating endocrine effects. The present study aims to elucidate the roles of NE and Ach on the differentiation and proliferation of Leydig cells. Firstly, the expression of adrenergic receptors and muscarinic acetylcholine receptors in Leydig cells was investigated. It was found that adrenergic receptors (β1AR, β2AR, and α1D) and muscarinic acetylcholine receptors (M1 and M3) mRNA are expressed in adult Leydig cells. Then, the effects of NE and Ach on the differentiation and proliferation of Leydig cells were analyzed. The results showed that NE and Ach at 10 μM significantly increased the number of 3β-hydroxysteroid-dehydrogenase- (3β-HSD-) positive Leydig cells and improved the expression of proliferating cell nuclear antigen (PCNA) in Leydig cells on postnatal day (PD) 15 (𝑃<0.05). NE and Ach at 10 μM had no impact on the expression of PCNA mRNA (𝑃>0.05), but reduced the expression of 3β-HSD mRNA in adult Leydig cells and a murine Leydig tumor cell line (MLTC-1) (𝑃<0.05). Therefore, a conclusion may be reached that NE and Ach participated in stimulating the development of Leydig cells in mice from prepuberty to adult stage. Shuying Huo, Xiuhui Zhong, Xianjun Wu, and Yurong Li Copyright © 2012 Shuying Huo et al. All rights reserved. Psychological Stress Alters Ultrastructure and Energy Metabolism of Masticatory Muscle in Rats Sun, 31 Oct 2010 14:18:32 +0000 To investigate the effects of psychological stress on the masticatory muscles of rats, a communication box was applied to induce the psychological stress (PS) in rats. The successful establishment of psychological stimulation was confirmed by elevated serum levels of adrenocorticotropic hormone (ACTH) and changed behaviors in the elevated plusmaze apparatus. The energy metabolism of the bilateral masseter muscles was tested via chemocolorimetric analysis, whereas muscle ultrastructure was assessed by electron microscopy. In comparison to the control group, the PS group showed evidence of swollen mitochondria with cristae loss and reduced matrix density in the masticatory muscles after three weeks of stimulation; after five weeks of stimulation, severe vacuolar changes to the mitochondria were observed. Increased vascular permeability of the masticatory muscle capillaries was found in the five-week PS rats. In addition, there was decreased activity of -ATPase and -ATPase and a simultaneous increase in the activity of lactate dehydrogenase and lactic acid in the masticatory muscles of PS rats. Together, these results indicate that psychological stress induces alterations in the ultrastructure and energy metabolism of masticatory muscles in rats. Yong-Jin Chen, Fei Huang, Min Zhang, and Hai-Yan Shang Copyright © 2010 Yong-Jin Chen et al. All rights reserved. Endocrine Disruptors and Leydig Cell Function Wed, 25 Aug 2010 08:01:59 +0000 During the past decades, a large body of information concerning the effects of endocrine disrupting compounds (EDCs) on animals and humans has been accumulated. EDCs are of synthetic or natural origin and certain groups are known to disrupt the action of androgens and to impair the development of the male reproductive tract and external genitalia. The present overview describes the effects of the different classes of EDCs, such as pesticides, phthalates, dioxins, and phytoestrogens, including newly synthesized resveratrol analogs on steroidogenesis in Leydig cells. The potential impact of these compounds on androgen production by Leydig cells during fetal development and in the adult age is discussed. In addition, the possible role of EDCs in connection with the increasing frequency of abnormalities in reproductive development in animals and humans is discussed. K. Svechnikov, G. Izzo, L. Landreh, J. Weisser, and O. Söder Copyright © 2010 K. Svechnikov et al. All rights reserved. FSHR Single Nucleotide Polymorphism Frequencies in Proven Fathers and Infertile Men in Southeast Turkey Thu, 29 Apr 2010 07:19:10 +0000 The influence of FSH receptor (FSHR) variants on male infertility is not completely understood. The present investigation is the first screening study for SNP at nucleotide position −29 in the core promoter region and codon 680 in exon 10 of the FSHR and the effect of the serum levels of FSH on male infertility in Southeast Turkey. The SNPs in codon 680 and at position −29 of the FSHR gene were analyzed by PCR-RFLP technique in 240 men with proven fathers, and 270 infertile men (150 nonobstructive azoospermic and 120 severe oligozoospermic). The separate analysis for SNP at nucleotide position −29 did not show any difference in genotypic frequencies and serum FSH levels. The genotype distribution of SNP at position 680 was different but does not influence serum FSH levels. Together the two SNPs form four discrete haplotypes (A-Thr-Asn, G-Thr-Asn, A-Ala-Ser, and G-Ala-Ser) occurring in 10 combinations. A statistically significant difference in the allelic distribution of G-Asn/G-Ser and G-Ser/G-Ser genotype between proven fathers and infertile men but there were not any statistically significant difference in the overall frequency of the four FSHR haplotypes. We conclude that the FSHR haplotype does not associate with different serum FSH levels but it is differently distributed in proven fathers and infertile men. Mahmut Balkan, Abdullah Gedik, Hasan Akkoc, Ozlem Izci Ay, M. Emin Erdal, Hilmi Isi, and Turgay Budak Copyright © 2010 Mahmut Balkan et al. All rights reserved. Testosterone Depletion by Castration May Protect Mice from Heat-Induced Multiple Organ Damage and Lethality Mon, 12 Apr 2010 10:11:22 +0000 When the vehicle-treated, sham-operated mice underwent heat stress, the fraction survival and core temperature at +4 h of body heating were found to be 5 of 15 and , respectively. Castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero, protected the mice from heat-induced death (fraction survival, 13/15) and reduced the hypothermia (core temperature, ). The beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl- transferase- mediatedUDP-biotin nick end-labeling staining, were significantly prevented by castration. In addition, heat-induced neuronal damage, as indicated by cell shrinkage and pyknosis of nucleus, to the hypothalamus was also castration-prevented. Again, the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke, were significantly reversed by testosterone replacement. The data indicate that testosterone depletion by castration may protect mice from heatstroke-induced multiple organ damage and lethality. Chian-Yuh Lin, Mao-Tsun Lin, Ruei-Tang Cheng, and Sheng-Hsien Chen Copyright © 2010 Chian-Yuh Lin et al. All rights reserved. In Vivo Bioassay of Recombinant Human Growth Hormone Synthesized in B. mori Pupae Thu, 18 Mar 2010 10:28:18 +0000 The human growth hormone (hGH) has been expressed in prokaryotic expression system with low bioactivity previously. Then the effective B. mori baculovirus system was employed to express hGH identical to mature hGH successfully in larvae, but the expression level was still limited. In this work, the hGH was expressed in B. mori pupae by baculovirus system. Quantification of recombinant hGH protein (BmrhGH) showed that the expression of BmrhGH reached the level of approximately 890 g/mL pupae supernatant solution, which was five times more than the level using larvae. Furthermore, Animals were gavaged with BmrhGH at the dose of 4.5 mg/, and the body weight gain (BWG) of treated group had a significant difference () compared with the control group. The other two parameters of liver weight and epiphyseal width were also found to be different between the two groups (). The results suggested that BmrhGH might be used as a protein drug by oral administration. Hanglian Lan, Zuoming Nie, Yue Liu, Zhengbing Lv, Yingshuo Liu, Yanping Quan, Jianqing Chen, Qingliang Zhen, Qin Chen, Dan Wang, Qing Sheng, Wei Yu, Jian Chen, Xiangfu Wu, and Yaozhou Zhang Copyright © 2010 Hanglian Lan et al. All rights reserved. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System Wed, 02 Aug 2006 00:00:00 +0000 Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity. Suyeon Kim, Morvarid Soltani-Bejnood, Annie Quignard-Boulange, Florence Massiera, Michele Teboul, Gerard Ailhaud, Jung Han Kim, Naima Moustaid-Moussa, and Brynn H. Voy Copyright © 2006 Suyeon Kim et al. All rights reserved.