MAPK pathway and NIS in B-CPAP human papillary thyroid carcinoma cells treated with resveratrol.

BACKGROUND: Resveratrol, a herbal phytoalexin, is known to have anti-tumor effects in several tumors including thyroid cancer cells. AIM: The aim of this study was to determine the effects of resveratrol on the expression of BRAF, ERK and NIS mRNA levels and protein expression in B-CPAP human thyroid papillary cancer cell line. METHODS: B-CPAP cells were treated with resveratrol at concentrations of 10-100 µM for 24-48-72 h. Cell viability was assessed by XTT Cell Proliferation Assay. BRAF, ERK and NIS mRNA levels were evaluated by rt-PCR method. Protein expressions were evaluated by Western Blot method. RESULTS: Resveratrol was found to inhibit cell proliferation in a time and dose dependent manner. The IC50 values of resveratrol were 18.7 µM and 56.8 µM after 48 h and 72 h respectively. Resveratrol treatment of B-CPAP cells resulted in up to 1.5-fold reduction in BRAF mRNA and up to 5.5 fold reduction in ERK mRNA levels. NIS mRNA levels showed up to 3-fold increase. Western Blot studies confirmed the rt- PCR results with a decrease in BRAF and ERK, and increase in NIS protein expressions. CONCLUSION: This study demonstrated that resveratrol inhibits thyroid papillary carcinoma cell proliferation and reduces poor prognostic BRAF and ERK mRNA and protein expressions, while increasing NIS mRNA and protein expression suggesting a redifferentiating effect. More studies are needed to evaluate resveratrol as a novel therapeutic agent in the treatment of papillary thyroid cancer.

Endocrine disruptor chemicals as obesogen and diabetogen: Clinical and mechanistic evidence.

Obesity is becoming an inevitable pandemic all over the world. The World Obesity Federation predicts in the 2022 World Obesity Atlas that one billion people worldwide, including 1 in 5 women and 1 in 7 men, will be living with obesity by 2030. Moreover, the prevalence of diabetes is increasing worldwide, and diabetes is becoming more of a public health problem. Increased insulin resistance due to obesity and deficiency in insulin secretion are the two main causes of type 2 diabetes mellitus (T2DM). An exogenous chemical or mixture of chemicals that interferes with any aspect of hormone action was defined as endocrine-disrupting chemicals (EDCs). Bisphenol A (BPA), the first known EDC, was synthesized and was considered to be estrogenic. Global production of BPA has increased progressively from 5 to 8 million tons (MT) between 2010 and 2016. Furthermore, researchers estimated that the production should reach 10.2 MT by 2022. The human population is exposed to EDCs in daily life in such forms as pesticides/herbicides, industrial and household products, plastics, detergents, and personal care products. The term obesogen was used for chemicals that promote weight gain and obesity by increasing the number of adipocytes and fat storage in existing adipocytes, changing the energy balance, and finally regulating appetite and satiety. Besides the obesogenic effect, EDCs can cause T2DM through alteration in ß cell function and morphology and insulin resistance. In this review, we provide clinical and mechanistic evidence regarding EDCs as obesogen and diabetogen. However, those studies are not enough methodologically to indicate causality. In this respect, randomized clinical trials are needed to investigate the association between obesogen, diabetogen and the related metabolic clinical picture.

Probiotic kefir consumption improves serum apolipoprotein A1 levels in metabolic syndrome patients: a randomized controlled clinical trial.

Metabolic syndrome has become a major health hazard of the modern world. Studies investigating the effects of traditional fermented foods on metabolic syndrome are limited. We hypothesized that regular kefir consumption could improve the anthropometrical measurements, glycemic control, lipid profile, blood pressure, and inflammatory status in patients with metabolic syndrome. Sixty-two participants were randomly assigned to receive either 180 mL/d probiotic kefir or unfermented milk for 12 weeks. Dietary intake, anthropometrical measurements, biochemical status, and blood pressure were assessed at baseline and the end of weeks 4, 8, and 12. Serum apolipoprotein A1 concentration increased by 3.4% in the kefir group, whereas it decreased by 2.4% in the milk group in 12 weeks (P = .03). A subgroup analysis for participants with low-density lipoprotein cholesterol (LDL-C) levels >130 mg/dL showed that serum LDL-C and apolipoprotein B concentrations (7.6% and 5.4%, respectively) significantly decreased with kefir consumption compared with the baseline values at the 12th week (P < .05), but not compared with milk consumption (P > .05). Both milk and kefir consumption was associated with lower systolic and diastolic blood pressure compared with the baseline (P < .05). The 12-weeks of kefir administration also decreased serum tumor necrosis factor-α, interleukin 6, interleukin 10, interferon-gamma, and homocysteine concentrations significantly (P < .05). In conclusion, regular dairy consumption as part of a well-balanced diet can provide favorable effects in the management of metabolic syndrome, and probiotic kefir may deserve a special interest among dairy products. This trial was registered at clinicaltrials.gov (NCT03966846).

Determining the Cardiovascular Disease Risk Factor Knowledge and Related Factors Among Adults With Type 2 Diabetes Mellitus.

In this study was to determine knowledge of cardiovascular disease (CVD) risk factors and to explore related factors among adults with type 2 diabetes mellitus (DM) who have not been diagnosed with CVD. This descriptive study was conducted with 175 adults. Data were collected individual identification form and Cardiovascular Disease Risk Factors Knowledge Level (CARRF-KL) scale. A negative correlation was found between age and CARRF-KL score. A significant difference was found between educational status and CARRF-KL score. The individuals described their health status as good, managed their condition with diet and exercise, received information from nurses, adults with DM in their family and those with no DM complications had significantly higher scores in CARRF-KL. The knowledge of an individual with DM about CVD risk factors should be assessed, CVD risks should be identified at an early stage, and individuals at risk should be subjected to screening.

Magnetic resonance spectroscopy to assess hepatic steatosis in patients with lipodystrophy.

BACKGROUND/AIMS: Lipodystrophy is a rare metabolic disorder characterized by near total or partial lack of subcutaneous adipose tissue and associated with insulin resistance. We aimed to evaluate the efficacy of magnetic resonance spectroscopy imaging (MRS) to explore the fat content of the liver in patients with lipodystrophy and to determine the relationship between the liver fat accumulation and clinical presentations of lipodystrophy. MATERIALS AND METHODS: Between July 2014 and February 2016, 34 patients with lipodystrophy were assessed by MRS for quantification of hepatic steatosis. All patients had metabolic abnormalities associated with insulin resistance. Metabolic parameters and the MRS findings were analyzed to identify potential correlations between the liver fat content and disease severity. RESULTS: The MRS fat ratios (MRS-FR) were markedly higher, indicating severe hepatic steatosis in lipodystrophy. Patients with generalized and partial lipodystrophy had comparable levels of MRS-FRs, although patients with generalized lipodystrophy were significantly younger. Patients with genetically based lipodystrophy had elevated MRS-FR compared to those with acquired lipodystrophy (p=0.042). The MRS-FR was positively correlated with liver enzyme alanine aminotransferase (p=0.028) and serum adiponectin (p=0.043). CONCLUSION: Our data suggest that MRS might be an effective, noninvasive imaging method to quantify hepatic fat content in patients with lipodystrophy. Further studies are needed to validate the technique and threshold values which would allow accurate comparison of data acquired by different machines and centers.

Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells.

Anaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers. Treatment options are external radiation therapy and/or chemotherapy. The success rate with these treatment modalities is not satisfactory. We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells. In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC. Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT2 Profiler PCR Array. In C643 and SW1736 cell lines, IC50 doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 µM, and 23.17 µM. Also, the combination of MET and PIO was determined as an additive according to isobologram analyses. We have found the downregulation of the expression levels of oncogenic genes: AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, and RICTOR genes, in the MET and PIO combination-treated cells. In addition, expression levels of tumor suppressor genes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, and ULK2, were found to have increased significantly. The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected. The decreases, particularly, in AKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, and PRKCA expressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets.

Effects of Regular Kefir Consumption on Gut Microbiota in Patients with Metabolic Syndrome: A Parallel-Group, Randomized, Controlled Study.

Several health-promoting effects of kefir have been suggested, however, there is limited evidence for its potential effect on gut microbiota in metabolic syndrome This study aimed to investigate the effects of regular kefir consumption on gut microbiota composition, and their relation with the components of metabolic syndrome. In a parallel-group, randomized, controlled clinical trial setting, patients with metabolic syndrome were randomized to receive 180 mL/day kefir (n = 12) or unfermented milk (n = 10) for 12 weeks. Anthropometrical measurements, blood samples, blood pressure measurements, and fecal samples were taken at the beginning and end of the study. Fasting insulin, HOMA-IR, TNF-α, IFN-γ, and systolic and diastolic blood pressure showed a significant decrease by the intervention of kefir (p ≤ 0.05, for each). However, no significant difference was obtained between the kefir and unfermented milk groups (p > 0.05 for each). Gut microbiota analysis showed that regular kefir consumption resulted in a significant increase only in the relative abundance of Actinobacteria (p = 0.023). No significant change in the relative abundance of Bacteroidetes, Proteobacteria or Verrucomicrobia by kefir consumption was obtained. Furthermore, the changes in the relative abundance of sub-phylum bacterial populations did not differ significantly between the groups (p > 0.05, for each). Kefir supplementation had favorable effects on some of the metabolic syndrome parameters, however, further investigation is needed to understand its effect on gut microbiota composition.

A Distinct Clinical Phenotype in Two Siblings with X-linked Adrenoleukodystrophy.

OBJECTIVES: X-linked adrenoleukodystrophy(X-ALD) is a rare X-linked recessive metabolic disorder. The mutations in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene account for the underlying molecular mechanism. Herein, we present two siblings with X-ALD due to a missense, presumably identical, ABCD1 mutation, who had extremely distinct clinical phenotypes. MATERIAL AND METHODS: Patient 1 (6y/o) was admitted with primary adrenal insufficiency (PAI). His VLCFA analysis and cranial MRI suggested the diagnosis of X-ALD with no cranial involvement. Although the PAI was successfully managed using hydrocortisone replacement therapy, during follow-up he was admitted with the complaints of perception impairment, seizures, loss of vision and deafness suggesting cranial involvement which was not able to be recovered despite intensive supportive therapies; in the end patient died. Patient 2 (21y/o) had mild symptoms of PAI with no organ manifestation. He was undertaken to a molecular genetics analysis for ABCD1 gene due to history of his brother. His VLCFA analysis revealed mildly elevated C26, C22 and C26/C22 ratio suggesting ALD diagnosis. However, his cranial imaging and other results were within normal limits. CONCLUSION: Two siblings with X-ALD due to presumably an identical, missense ABCD1 mutation and distinct clinical phenotype have confirmed the lack of phenotype-genotype correlation and proved the essential role of molecular genetics analysis in the early diagnosis. It is crucial to follow up for the development of cranial involvement and decide a bone marrow transplantation which is the only option that can prevent the progression of the disease, thus extend the lifespan.

Therapeutic plasma exchange in hypertriglyceridemic patients

Background/aim: High triglyceride (TG) levels are associated with increases in atherosclerotic cardiovascular disease (CVD), hepatic steatosis, and pancreatitis. Acute pancreatitis is a condition with high mortality. Therapeutic plasma exchange (TPE) in the treatment of hypertriglyceridemic pancreatitis (HTGP) is a rapid and effective treatment modality. In this study, the results of TPE were evaluated and the frequency of lipoprotein lipase (LPL) mutation in these patients was determined. Materials and methods: TPE was performed in 31 patients with HTGP at the Adult Therapeutic Apheresis Center. Results: A TG level under 500 mg/dL was achieved by applying apheresis at a median of 2 times (IQR 2­2, min 1, max 6) in the 31 cases. LPL mutation was detected in 8 (25.8%) of the 31 hypertriglyceridemia cases. When TG levels before and after TPE were evaluated, the mean TG level before TPE was significantly higher (3132 ± 1472 mg/dL) than the mean TG level afterwards (948 ± 465 mg/dL, P < 0.001). This result represented a decrease of 69.7% TG after TPE. Conclusion: TPE is a safe, fast, and effective treatment modality in experienced centers.

Plasma Levels of Antioxidant Vitamins in Patients with Acromegaly: A Case-Control Study.

OBJECTIVE: The aim of this study was to compare antioxidant vitamin C and vitamin E levels in the non-acromegaly control group and in patients with acromegaly with and without remission. MATERIAL AND METHODS: In this study, 100 cases, acromegaly patients of 57% (n=57, 29F, 28M, mean ages of 49.5±12.1) and control subjects of 43% (n=43, 29F, 14M, mean ages of 49.6±9.2). Acromegaly patients were classified into two groups; active acromegaly (AA; n=33) and controlled acromegaly (CA; n=24). RESULTS: Vitamin C levels were significantly lower in the acromegaly group [7.6 (4.7) mg/L, as median (IQR)] when compared to the control group [12.2 (5.5) mg/L, as median (IQR)] (p <0.001). Vitamin E levels didn't show a significant difference between the acromegaly and the control groups (14.2±3.6 vs. 14.8±3.7, as mean±SD, respectively, p = 0.439). Correlation analysis showed that vitamin C levels were not significantly associated with clinical, anthropometric and laboratory parameters in the acromegaly group. Vitamin E levels were significantly associated with the total cholesterol, triglyceride, LDL-C, HDL-C, APO A1, APO B both in the acromegaly and the control groups. CONCLUSION: This study is the first one to investigate the relationship between the levels of vitamin C & E and anthropometric & metabolic parameters in acromegaly patients and control group. In our study, vitamin C level was significantly lower in the acromegaly group compared to the level in the control group. There was no significant difference in vitamin E levels between the acromegaly and control group.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Polycystic ovary syndrome is associated with increased osteopontin levels.

OBJECTIVE: Osteopontin (OPN) is a multi-functional secreted glycoprotein that plays a crucial role in glucose metabolism and inflammatory process. Growing evidence suggests that there is a link between OPN and ovarian function. However, no such link has yet been found for OPN in polycystic ovary syndrome (PCOS). Our aim was to ascertain whether circulating OPN levels are altered in women with PCOS and to determine whether OPN levels differ between the follicular phase and mid-cycle of the menstrual cycle in eumenorrheic women. DESIGN AND METHODS: In total, 150 women with PCOS and 150 age- and BMI-matched controls without PCOS were recruited for this prospective observational study. OPN levels were measured using ELISA. Metabolic parameters were also determined. RESULTS: Circulating OPN levels were significantly elevated in PCOS women compared with controls (69.12±31.59  ng/ml vs 42.66±21.28  ng/ml; P<0.001). OPN levels were significantly higher at mid-cycle than in the follicular phase in eumenorrheic women. OPN was positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA-IR), free testosterone, and high sensitivity C-reactive protein (hs-CRP). Multivariate logistic regression analyses revealed that the odds ratio (OR) for PCOS was 3.64 for patients in the highest quartile of OPN compared with those in the lowest quartile (OR=3.64; 95% CI=2.42-5.57; P=0.011). Our findings indicate that BMI, HOMA-IR, hs-CRP, and free testosterone are independent factors influencing serum OPN levels and that OPN is an independent predictor for HOMA-IR. CONCLUSION: PCOS is associated with increased OPN levels.

Characteristics and Treatment Results of 5 Patients with Fibrous Dysplasia and Review of the Literature.

Aim. Fibrous dysplasia is a rare bone disease caused by missense mutation leading to abnormal fibroblast and osteoblast proliferation and increased bone resorption. FD can present in monostotic or polyostotic forms. About 3% of FD could be in association with McCune-Albright syndrome (MAS). Because FD is a rare disease, there is limited data in the literature about characteristics of disease and response to treatment. Methods. We present our five cases of FD with general properties and their responses to medical treatment. Results. Two of our patients had polyostotic and three had monostotic FD. One of the polyostotic patients had MAS. One of our patients had surgery for femur fractures, facial asymmetry, and findings of compression. Four patients were given pamidronate; one was given zoledronic acid as bisphosphonate treatment. Bone pain was relieved in all patients with medical treatment. Conclusion. There was a decrease in bone turnover markers to some degree with medical treatment but no radiological improvement was observed.