Polymorphism of Pro12Ala in the peroxisome proliferator-activated receptor 2 gene in Iranian diabetic and obese subjects

Background: Peroxisome proliferator-activated receptor 2 (PPAR2) is a nuclear receptor that regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. The aim of this study was to investigate the association between the Pro12Ala single nucleotide polymorphism (SNP) at the PPAR2 gene and type II diabetes (T2DM) and obesity in an Iranian population. Methods: The genomic DNA of the 312 subjects included four groups: (1) nonobese with type II diabetes, (2) obese without type II diabetes, (3) obese with type II diabetes, and (4) nondiabetic nonobese controls. The Pro12Ala polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results: Frequencies of the Ala allele in obese subjects were significantly different from those control subjects (odds ratio [OR], 2.358; 95% confidence interval [CI], 1.101-5.05) (P = 0.025). In contrast, no significant association was detected between the Pro12Ala polymorphism and type II diabetes (OR, 0.652; 95% CI, 0.261-1.628). In all subjects, the Ala carriers had a higher body mass index (BMI) compared with the common allele. Conclusions: Our results showed that the Pro12Ala polymorphism in the PPAR2 gene is associated with obesity in Iranian subjects and the presence of the Ala allele could predict higher BMI. © 2009 Mary Ann Liebert, Inc

Human lung carcinoma reaction against metabolic serum deficiency stress

Cancer treatment is still of the greatest challenges that health care providers and patients are facing. One of the unsolved problems in cancer treatment is cells� reaction to metabolic stress caused by harsh nutritional conditions around tumor. In order to be able to treat this disease properly, it is important to understand the true nature of the disease. In fact, the cells inside the central part of the tumor lack sufficient access to blood vessels, nutrients, and growth signals. After tumor shrinkage, the cells are exposed to favorable environmental conditions and might regrow and cause tumor recurrence. The main purpose of this study was to investigate the effect of serum starvation, as a type of metabolic stress, on human lung cancer cell line, A549. These cells were treated with 10 (control), 0.5 and 0.25 serum for 1 to 5 days. At 24 h intervals, the cells were released with 10 serum supplemented media. Starved or released cells were studied for their cycle and morphology. The results showed that the cells were actually arrested at G1 phase and following exposure to optimal conditions, the cells could be back to their cycle again. Furthermore, sub-G1 apoptotic cells population was not increased within the starvation period, while control cells had significant increase in sub-G1 cells. Morphological studies also showed that starved cells could make denser colonies while control cells were entering death phase. These observations provide some evidence for the generation of some effective resistance phenomena in cancer cells against harsh metabolic conditions © 2016 by School of Pharmacy

IMPROVEMENT IN REDOX HOMEOSTASIS AFTER CYTOREDUCTIVE SURGERY IN COLORECTAL ADENOCARCINOMA

colorectal cancer (CRC) as one the most common cancer type is associated with oxidative stress. Surgery is the only curative modality for early-stage CRC. The aim of this study was to evaluate the oxidative damage biomarkers as well as enzymatic and nonenzymatic antioxidants in patients with CRC before and after tumor resection in healthy controls. 60 patients with stage I/II colorectaL adenocarcinoma and 43 healthy controls were recruited in this study. We measured plasma levels of oxidative damage biomarkers, including advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), malondialdehyde (MDA), and oxized low-density lipoprotein (ox-LDL) at baseline and after tumor removal. We also evaluated the plasma activuty of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as enzymatic antioxidants and the ferric reducing antioxidants power (FRAP) assay for nonenzymatic antioxidant capacity. Patients with CRC had significantly higher AGE, AOPP, MDA, and ox-LDL and also FRAP levels and higher SOD and GPx and lower CAT activity levels compared to healthy controls (p<0,05). We did not observe any statistically significant correlation between redox biomarkers and the size and stage of tumor. AGEs (72,49 +/- 7.7 vs. 67.93 +/- 8.8, p< 0,001), AOPP (137.64 +/- 21.9 vs. 119.08 +/- 33.1 p<0,001), MDA (3.56 +/- 0.30 vs. 3.05 +/- 0.33 p< 0,001), and ox-LDL (19.78 +/- 0.97 vs. 16.94 +/- 1.02, p< 0,001) concentrations reduced significantly after tumor removal. The largest effect sizes were found in ox-LDL (d = - 2.853, 95% CI 2.50 - 3.19) and MDA (d = - 0.43 - 0.57). Serum FRAP lelvels (1097.5 +/-156.7 vs. 1239.3 +/- 290, p< 0,001) and CAT (2.34 +/- 0.34 vs. 2.63 +/- 0.38, p< 0,001), GPx (102.37 +/- 6.58 vs. 108.03 +/- 6.95, p< 0,001), and SOD (5.13 +/- 0.39 vs. 5.53 +/- 0,31 p< 0,001) activity levels increased significantly after surgery. The largest effect sizes among antioxidants were seen in SOD (d = 1.135, 95% CI 0.46 - 0.34) and GPx (d = 0.836, 95% CI 0.35 - 0.23>). This study indicated that patients with colorectal cancer high higher levels of oxidative stress and antioxidants activity compared to healthy controls. After surgical resection of tumor, we observed a substantial improvement in redox homeostasis

Neuroendocrine tumors presenting with thyroid gland metastasis: a case series

<p>Abstract</p> <p>Introduction</p> <p>Autopsy series have shown that metastasis to the thyroid gland has occurred in up to 24% of patients who have died of cancer. Neuroendocrine tumors may metastasize to thyroid gland.</p> <p>Case presentations</p> <p>Case 1 was a 17-year-old Turkish woman who was referred from our Endocrinology Department for a thyroidectomy for treatment of neuroendocrine tumor metastasis. She was treated with a bilateral total thyroidectomy. Histopathological examination results were consistent with a neuroendocrine tumor; neoplastic cells showed strong immunoreactivity to chromogranin A and synaptophysin, but the immunohistochemical profile was inconsistent with medullary thyroid carcinoma in that the tumor was negative for calcitonin, carcinoembryonic antigen, and thyroid transcription factor-1.</p> <p>Case 2 was a 54-year-old Turkish woman who presented with a 3-cm nodule on her right thyroid lobe. She had undergone surgery for a right lung mass four years previously. After a right pneumonectomy, thymectomy and lymph node dissection, a typical carcinoid tumor was diagnosed. Under ultrasonographic guidance, fine needle aspiration biopsy of her right thyroid pole nodule was performed and the biopsy was compatible with a neuroendocrine tumor metastasis. She was treated with a bilateral total thyroidectomy. Histopathological examination indicated three nodular lesions, 5 cm and 0.4 cm in diameter in her right lobe and 0.1 cm in diameter in her left lobe. The tumors were consistent with a neuroendocrine phenotype, showing strong immunoreactivity to chromogranin A and synaptophysin.</p> <p>Conclusion</p> <p>Thyroid nodules detected during follow-up of neuroendocrine tumor patients should be thoroughly investigated. A fine needle aspiration biopsy of the thyroid confirms the diagnosis in most cases and leads to appropriate management of those patients and may prevent unnecessary treatment approaches.</p

Association between serum keptin concentrations and insulin resistance: A population-based study from China

BACKGROUND Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported. METHODS A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance. RESULTS In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001). CONCLUSIONS There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.Hui Zuo, Zumin Shi, Baojun Yuan, Yue Dai, Gaolin Wu, Akhtar Hussai

A multinodular goiter as the initial presentation of a renal cell carcinoma harbouring a novel VHL mutation

BACKGROUND: Secondary involvement of the thyroid gland is rare. Often the origin of the tumor is difficult to identify from the material obtained by fine-needle aspiration cytology. Renal cell carcinoma of the clear-cell type is one of the more common carcinomas to metastasize to the thyroid gland. Somatic mutations of the von Hippel-Lindau tumor suppressor gene are associated with the sporadic form of this tumor. We aimed to illustrate the potential utility of DNA based technologies to search for specific molecular markers in order to establish the anatomic site of origin. CASE PRESENTATION: A 54-yr-old Caucasian male complaining of a rapidly increasing neck tumor was diagnosed as having a clear-cell tumor by fine-needle aspiration cytology. A positive staining for cytokeratin as well as for vimentin and CD10 in the absence of staining for thyroglobulin, calcitonin and TTF1 suggested a renal origin confirmed by computed tomography. Using frozen RNA, obtained from cells left inside the needle used for fine needle aspiration cytology, it was possible to identify a somatic mutation (680 delA) in the VHL gene. CONCLUSION: In the presence of a clear-cell tumor of the thyroid gland, screening for somatic mutations in the VHL gene in material derived from thyroid aspirates might provide additional information to immunocytochemical studies and therefore plays a contributory role to establish the final diagnosis. Moreover, in a near future, this piece of information might be useful to define a targeted therapy

Metabolic syndrome is linked to a mild elevation in liver aminotransferases in diabetic patients with undetectable non-alcoholic fatty liver disease by ultrasound

<p>Abstract</p> <p>Background</p> <p>Despite ongoing findings on the relationship between elevated levels of alanine and aspartate aminotransferases (ALT and AST) and metabolic syndrome (MetS), this association in diabetic patients without a known cause for liver enzymes elevation other than diabetes, per se, remains unclear. In this study, we aimed to assess the relationship between circulating liver enzymes and MetS in a relatively large sample of patients with diabetes.</p> <p>Methods</p> <p>A total of 670 diabetic patients, without known causes of hepatocellular injury, were enrolled. Patients with ultrasonographic signs of fatty liver disease were not included. Fasting blood samples were obtained and biochemical characteristics were measured. MetS was defined according to the international diabetes federation criteria.</p> <p>Results</p> <p>Serum ALT and AST were significantly higher in patients with MetS (p < 0.001). High waist circumference and low HDL-cholesterol were significantly associated with elevated ALT (OR = 2.56 and 2.0, respectively) and AST (OR = 2.23 and 2.21, respectively). ALT and AST were significantly associated with MetS (OR = 2.17 and 2.31, respectively). These associations remained significant after multiple adjustments for age, sex, BMI, diabetes duration, HbA1c and medications. There was a significant (p < 0.01) positive association between the number of the MetS features and the level of ALT or AST.</p> <p>Conclusion</p> <p>In diabetic patients without ultrasonographic evidence of fatty liver, elevated aminotransferases are independently associated with MetS. Despite negative ultrasound results in diabetic patients with MetS, the serum level of liver aminotransferases may be elevated and should be more thoroughly monitored.</p

High Density Lipoprotein (HDL) Promotes Glucose Uptake in Adipocytes and Glycogen Synthesis in Muscle Cells

Background: High density lipoprotein (HDL) was reported to decrease plasma glucose and promote insulin secretion in type 2 diabetes patients. This investigation was designed to determine the effects and mechanisms of HDL on glucose uptake in adipocytes and glycogen synthesis in muscle cells. Methods and Results: Actions of HDL on glucose uptake and GLUT4 translocation were assessed with 1- [ 3 H]-2deoxyglucose and plasma membrane lawn, respectively, in 3T3-L1 adipocytes. Glycogen analysis was performed with amyloglucosidase and glucose oxidase-peroxidase methods in normal and palmitate-treated L6 cells. Small interfering RNA was used to observe role of scavenger receptor type I (SR-BI) in glucose uptake of HDL. Corresponding signaling molecules were detected by immunoblotting. HDL stimulated glucose uptake in a time- and concentration-dependent manner in 3T3-L1 adipocytes. GLUT4 translocation was significantly increased by HDL. Glycogen deposition got enhanced in L6 muscle cells paralleling with elevated glycogen synthase kinase3 (GSK3) phosphorylation. Meanwhile, increased phosphorylations of Akt-Ser473 and AMP activated protein kinase (AMPK) a were detected in 3T3-L1 adipocytes. Glucose uptake and Akt-Ser473 activation but not AMPK-a were diminished in SR-BI knock-down 3T3-L1 cells. Conclusions: HDL stimulates glucose uptake in 3T3-L1 adipocytes through enhancing GLUT4 translocation by mechanisms involving PI3K/Akt via SR-BI and AMPK signaling pathways, and increases glycogen deposition in L6 muscle cells throug

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease