Cem Ekmekcioglu

Coexpression of the melatonin receptor 1 and nestin in human breast cancer specimens

Abstract:u2002 Activation of the G‐protein‐coupled receptor (GPCR) for melatonin (MT1) suppresses breast cancer cell growth in experimental models. To elucidate whether MT1 might play a role in cancer cells positive for the stem cell marker nestin, we assessed paired carcinomatous (Ca) and adjacent noncancerous (NCa) samples from 42 patients with primary breast cancer for MT1 and nestin by double immunofluorescence staining and quantitative image analysis with Tissue‐Quest® software. MT1 was located in luminal and myoepithelial cells in milk ducts and in tumor cells in 40/42 and 39/42 of NCa and Ca specimens, respectively, independent of hormone receptor and HER‐2 status. Nestin was located together with MT1 in myoepithelial cells in 38 NCa specimens (total nu2003=u200342) and in 18 Ca specimens with intact milk ducts. Quantitative evaluation of selected 16 NCa and Ca samples revealed that MT1 levels were higher in invasive Ca sections than in NCa specimens in eight and lower in six cases. Specimens from higher tumor stages (TII/III) with a higher risk of relapse were associated with MT1/nestin co‐staining in more than 10% of tumor cells, whereas a lack of co‐staining correlated with lower tumor stages. Abundant expression of MT1 and, particularly, coexpression of MT1 with nestin in invading tumor cells in more advanced tumors suggest an important role for this GPCR in the pathogenesis of breast cancer.

Expression of the melatonin receptor (MT) 1 in benign and malignant human bone tumors

Abstract:u2002 The beneficial effects of melatonin on bone homeostasis have been shown in various diseases. As this indoleamine causes dose‐dependent modulation of bone‐forming osteoblast and bone‐resorbing osteoclast activities by receptor‐independent and ‐dependent pathways, we investigated the expression of G‐protein‐coupled melatonin receptors (MTs) in malignant and non‐malignant human bone lesions. By TaqMan polymerase chain reaction (PCR), we analyzed 30 specimens from osteosarcoma and 11 from benign bone tumors for MT1‐mRNA expression. Furthermore, we determined mRNA expression levels of the osteoclast activity‐stimulating receptor activator of nuclear factor‐κ B ligand (RANKL) and its counterpart osteoprotegerin (OPG). Although mean MT1‐mRNA levels were similar (Pu2003=u20030.596) in malignant (4.39u2003±u20034.98‐fold) and benign samples (4.64u2003±u20036.81‐fold), the highest MT1‐mRNA levels (up to 27‐fold) were observed in individual osteosarcomas, particularly, in two specimens of patients with local recurrence of the tumor. Moreover, mean RANKL‐ and OPG‐mRNA levels were similar in malignant and benign specimens (RANKL: 7.38u2003±u20039.61‐fold versus 3.57u2003±u20033.11‐fold, Pu2003=u20030.207; OPG: 23.45u2003±u200332.76 versus 8.07u2003±u20037.23‐fold, Pu2003=u20030.133). Again, highest RANKL‐ and OPG‐mRNA levels (up to 41‐ and 160‐fold, respectively) were observed in individual osteosarcomas. Expression of MT1‐mRNA was confirmed in two human osteosarcoma cell lines (HOS, MG63). High expression levels of MT1‐mRNA together with low OPG‐mRNA were found in both osteosarcoma cell lines, while in normal human osteoblasts and bone marrow stromal cells, high OPG‐mRNA levels were associated with low MT1‐mRNA levels. These data on the abundant expression of MT1‐mRNA in human bone tumors and osteosarcoma cells lines suggest an important role for MT1 in bone pathology.

The role of dietary potassium in hypertension and diabetes

Potassium is an essential mineral which plays major roles for the resting membrane potential and the intracellular osmolarity. In addition, for several years, it has been known that potassium also affects endothelial and vascular smooth muscle functions and it has been repeatedly shown that an increase in potassium intake shifts blood pressure to a more preferable level. Meanwhile, the blood pressure lowering effects of potassium were presented in several intervention trials and summarized in a handful of meta-analyses. Furthermore, accumulating epidemiological evidence from, especially, the last decade relates low dietary potassium intake or serum potassium levels to an increased risk for insulin resistance or diabetes. However, intervention trials are required to confirm this association. So, in addition to reduction of sodium intake, increasing dietary potassium intake may positively affect blood pressure and possibly also glucose metabolism in many populations. This concise review not only summarizes the studies linking potassium to blood pressure and diabetes but also discusses potential mechanisms involved, like vascular smooth muscle relaxation and endothelium-dependent vasodilation or stimulation of insulin secretion in pancreatic β-cells, respectively.

Impact of Salt Intake on the Pathogenesis and Treatment of Hypertension

Excessive dietary salt (sodium chloride) intake is associated with an increased risk for hypertension, which in turn is especially a major risk factor for stroke and other cardiovascular pathologies, but also kidney diseases. Besides, high salt intake or preference for salty food is discussed to be positive associated with stomach cancer, and according to recent studies probably also obesity risk. On the other hand a reduction of dietary salt intake leads to a considerable reduction in blood pressure, especially in hypertensive patients but to a lesser extent also in normotensives as several meta-analyses of interventional studies have shown. Various mechanisms for salt-dependent hypertension have been put forward including volume expansion, modified renal functions and disorders in sodium balance, impaired reaction of the renin-angiotensin-aldosterone-system and the associated receptors, central stimulation of the activity of the sympathetic nervous system, and possibly also inflammatory processes.Not every person reacts to changes in dietary salt intake with alterations in blood pressure, dividing people in salt sensitive and insensitive groups. It is estimated that about 50-60u2009% of hypertensives are salt sensitive. In addition to genetic polymorphisms, salt sensitivity is increased in aging, in black people, and in persons with metabolic syndrome or obesity. However, although mechanisms of salt-dependent hypertensive effects are increasingly known, more research on measurement, storage and kinetics of sodium, on physiological properties, and genetic determinants of salt sensitivity are necessary to harden the basis for salt reduction recommendations.Currently estimated dietary intake of salt is about 9-12xa0g per day in most countries of the world. These amounts are significantly above the WHO recommended level of less than 5xa0g salt per day. According to recent research results a moderate reduction of daily salt intake from current intakes to 5-6xa0g can reduce morbidity rates. Potential risks of salt reduction, like suboptimal iodine supply, are limited and manageable. Concomitant to salt reduction, potassium intake by higher intake of fruits and vegetables should be optimised, since several studies have provided evidence that potassium rich diets or interventions with potassium can lower blood pressure, especially in hypertensives.In addition to dietary assessment the gold standard for measuring salt intake is the analysis of sodium excretion in the 24xa0h urine. Spot urine samples are appropriate alternatives for monitoring sodium intake. A weakness of dietary evaluations is that the salt content of many foods is not precisely known and information in nutrient databases are limited. A certain limitation of the urine assessment is that dietary sources contributing to salt intake cannot be identified.Salt reduction strategies include nutritional education, improving environmental conditions (by product reformulation and optimization of communal catering) up to mandatory nutrition labeling and regulated nutrition/health claims, as well as legislated changes in the form of taxation.Regarding dietary interventions for the reduction of blood pressure the Dietary Approaches to Stop Hypertension (DASH) diet can be recommended. In addition, body weight should be normalized in overweight and obese people (BMI less than 25xa0kg/m2), salt intake should not exceed 5xa0g/day according to WHO recommendations (<2xa0g sodium/day), no more than 1.5xa0g sodium/d in blacks, middle- and older-aged persons, and individuals with hypertension, diabetes, or chronic kidney disease, intake of potassium (~4.7xa0g/day) should be increased and alcohol consumption limited. In addition, regular physical activity (endurance, dynamic resistance, and isometric resistance training) is very important.

Red meat, diseases, and healthy alternatives: A critical review

ABSTRACT Meat is an important food for human nutrition, by especially providing high-quality protein and also some essential micronutrients, in front iron, zinc, and vitamin B12. However, a high intake of red and processed meat is associated with an increased risk for diseases, especially type 2 diabetes and colorectal cancer, as several epidemiological studies and meta-analyses have shown. This review summarizes meta-analyses of publications studying the association between red and processed meat intake and type 2 diabetes, cardiovascular diseases, colorectal and other cancers, and all-cause mortality. Various potential mechanisms involved in the increased disease risk are discussed. Furthermore, the beneficial effects of healthy alternatives for meat, like fish, nuts, vegetables and fruits, pulses and legumes, whole grains, and dairy products are reviewed by including selected papers and recent meta-analyses.

25-Hydroxyvitamin D Status and Risk for Colorectal Cancer and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Epidemiological Studies

Epidemiological evidence suggests an association between low vitamin D status and risk for various outcomes including cardiovascular diseases, cancer, and type 2 diabetes mellitus (T2DM). Analyzing serum 25-hydroxyvitamin D [25(OH)D] is the most established means to evaluate an individual’s vitamin D status. However, cutoff values for 25(OH)D insufficiency as well as for optimal 25(OH)D levels are controversial. This systematic review critically summarizes the epidemiological evidence regarding 25(OH)D levels and the risk for colorectal cancer and T2DM. The meta-analytical calculation revealed a pooled relative risk (RR) of 0.62 (CI 0.56–0.70; I2 = 14.7%) for colorectal cancer and an RR of 0.66 (CI 0.61–0.73; I2 = 38.6%) for T2DM when comparing individuals with the highest category of 25(OH)D with those in the lowest. A dose–response analysis showed an inverse association between 25(OH)D levels and RR for both outcomes up to concentrations of about 55 ng/mL for colorectal cancer and about 65 ng/mL for T2DM. At still higher 25(OH)D levels the RR increases slightly, consistent with a U-shaped association. In conclusion, a higher 25(OH)D status is associated with a lower risk for colorectal cancer and T2DM; however, this advantage is gradually lost as levels increase beyond 50–60 ng/mL.

Melatonin receptors, melatonin metabolizing enzymes and cyclin D1 in human breast cancer

Background. Melatonin suppresses breast cancer cell proliferation by inhibiting the upregulation of estrogen-induced cyclin D1 via its G-protein-coupled receptor MT1. Additionally, melatonin stimulates the expression of the estrogen sulfotransferase, SULT1E1. However, metabolism of melatonin via 6-hydroxylation by CYP1A1/1A2 and subsequent sulfonation by SULT1A1/1A3 decreases its intracellular concentration. This could have a negative impact on its oncostatic action in breast cancer. Patients and methods. In this pilot study, we performed immunohistochemical (IHC) analysis of MT1 and cyclin D1 in breast cancer specimens from 33 patients. Also, we investigated the expression of CYP1A1/1A2, SULT1A1/1A3/1E1, and cyclin D1 in cancer (CANC) and adjacent non-cancer (NCANC) specimens from 10 representative breast cancer patients using quantitative real-time reverse transcription polymerase chain reaction. Results. CYP1A1-mRNA-expression was found only in three CANC and in one NCANC. CYP1A2 mRNA was below the detection limit in all patients. SULT1A1 was observed only in two of the 10 CANC and one of the 10 NCANC specimens. But, all 10 CANC and NCANC samples showed high SULT1A3 levels. Cyclin D1 mRNA levels were found in all 10 CANC and NCANC specimens. Furthermore, IHC-staining of cyclin D1 was observed in 27 of 33 CANC and correlated positively with estrogen receptor positivity (pu2009=u20090.015). Conclusion. The low or even absent expression of CYP1A1 or CYP1A2 in breast cancer specimens suggested that melatonin might be involved in cell cycle arrest.

The effect of vegetarian diets on iron status in adults: A systematic review and meta-analysis

ABSTRACT Background: Vegetarian diets exclude meat, seafood, and products containing these foods. Although the vegetarian lifestyle could lead to a better health status in adults, it may also bear risks for certain nutritional deficiencies. Cross-sectional studies and narrative reviews have shown that the iron status of vegetarians is compromised by the absence of highly bioavailable haem-iron in meatless diets and the inhibiting effect of certain components present in plant foods on non-haem iron bioavailability. Methods: The databases Pubmed, Scopus, Embase, and Cochrane CentralRegister of Controlled Trials were searched for studies comparing serum ferritin, as the major laboratory parameter for iron status of adult vegetarians with non-vegetarian control groups. A qualitative review was conducted as well as an inverse-variance random-effects meta-analysis to pool available data. In addition the effect of vegetarian diets according to gender was investigated with a subgroup analysis. The results were validated using a sensitivity analysis. Results: A total of 27 cross-sectional studies and three interventional studies were selected for the systematic review. The meta-analysis which combined data of 24 cross-sectional studies showed that adult vegetarians have significantly lower serum ferritin levels than their non-vegetarian controls (−29.71 µg/L, 95% CI [−39.69, −19.73], p < 0.01). Inclusion of semi-vegetarian diets did not change the results considerably (−23.27 µg/L, 95% CI [−29.77, −16.76], p < 0.01). The effects were more pronounced in men (−61.88 µg/L, 95% CI [−85.59, −38.17], p < 0.01) than in both premenopausal women (−17.70 μg/L, 95% CI [−29.80, −5.60], p < 0.01) and all women (−13.50 μg/L, 95% CI [−22.96, −4.04], p < 0.01), respectively. Conclusions: In conclusion our results showed that vegetarians are more likely to have lower iron stores compared with non-vegetarians. However, since high iron stores are also a risk factor for certain non-communicable diseases, such as type 2 diabetes, it is recommended that not only vegetarians but also non-vegetarians should regularly control their iron status and improve their diet regarding the content and bioavailability of iron by consuming more plants and less meat.

Expression and putative functions of melatonin receptors in malignant cells and tissues

SummaryMelatonin, the popular hormone of the darkness, is primarily synthesized in the pineal gland, and acts classically through the G-protein coupled plasma membrane melatonin receptors MT1 and MT2, respectively. Although some of the receptor mediated functions of melatonin, especially those on the (central) circadian system, have been more or less clarified, the functional meaning of MT-receptors in various peripheral organs are still not sufficiently investigated yet. There is, however, accumulating evidence for oncostatic effects of melatonin with both, antioxidative and MT-receptor mediated mechanisms possibly playing a role. This review briefly summarizes the physiology of melatonin and MT-receptors, and discusses the expression and function of MT-receptors in human cancer cells and tissues.ZusammenfassungMelatonin, das populäre Hormon der Dunkelheit, wird primär in der Zirbeldrüse gebildet und wirkt klassischerweise über die G-Protein gekoppelten Melatonin-Rezeptoren MT1 and MT2. Obwohl gewisse Rezeptor-vermittelte Funktionen des Melatonins, insbesondere auf das (zentrale) circadiane System, mehr oder minder aufgeklärt wurden, ist die funktionelle Bedeutung der MT-Rezeptoren in verschiedenen peripheren Organen noch unzureichend untersucht. In letzter Zeit mehren sich die Hinweise, dass Melatonin onkostatische Wirkungen aufweist, wobei sowohl antioxidative als auch Rezeptor- induzierte Mechanismen beteiligt zu sein scheinen. Diese Übersichtsarbeit fasst in komprimierter Form die Physiologie des Melatonins und der Melatonin-Rezeptoren zusammen und gibt einen Überblick über die Expression und mögliche Funktionen von Melatonin-Rezeptoren in humanen Karzinomzellen und im Krebsgewebe.

Salt taste after bariatric surgery and weight loss in obese persons

Background. Little is known about the perception of salty taste in obese patients, especially after bariatric surgery. Therefore, the aim of this study was to analyse possible differences in salt detection thresholds and preferences for foods differing in salt content in obese persons before and after bariatric surgery with weight loss compared to non-obese individuals. Methods. Sodium chloride detection thresholds and liking for cream soups with different salt concentrations were studied with established tests. Moreover, a brief salt food questionnaire was assessed to identify the usage and awareness of salt in food. Results. The results showed similar mean sodium chloride detection thresholds between non-obese and obese participants. After bariatric surgery a non-significant increase in the salt detection threshold was observed in the obese patients (mean ± SD: 0.44 ± 0.24 g NaCl/L before OP vs. 0.64 ± 0.47 g NaCl/L after OP, p = 0.069). Cream soup liking between controls and obese patients were not significantly different. However, significant sex specific differences were detected with the tested women not liking the soups (p < 0.001). Results from the food questionnaire were similar between the groups. Conclusion. No differences between non-obese persons and obese patients were shown regarding the salt detection threshold. However, due to highly significant differences in soup liking, sex should be taken into consideration when conducting similar sensory studies.