Einfluss von Hypergravitation auf den cGMP-Efflux in Stickstoffmonoxid-stimulierten humanen Melanozyten und Melanomzellen

Gravity alteration is known to affect cell proliferation, morphology, gene expression, and me-tabolism. To our knowledge, studies concerning the gravity influence on melanocyte physiol-ogy with respect to activation and cellular responses that are important for malignant trans-formation have been rarely reported. Since melanocytes are able to sense mechanical forces and transform them into biochemical signals it was assumed that these cells likewise respond to gravity alteration. We examined whether hypergravity (up to 5g for 24 h) modulates the efflux of the second messenger cGMP under conditions of stimulated cGMP-synthesis. Due to the differential expression of functional guanylyl cyclase (GC) isoforms in normal human melanocytes (NHM) and melanoma cell lines we used direct NO donors (NONOates) which differ in their kinetics of NO release as stimulators of sGC and ANP as a GC-A modulator. Our results demonstrate that long-term application of hypergravity (5g for 24 h) in the presence of DETA/NO induced a decrease in intracellular cGMP in NHMs and non-metastatic 1F6 melanoma cells compared to cGMP levels at 1g. The corresponding extracellular cGMP levels increased suggesting that hypergravity enhances the cGMP efflux. This efflux was re-duced in the presence of trequinsin as a selective phosphodiesterase 5 inhibitor and additionally a highly selective inhibitor of multidrug resistance protein 4/5, indicating that in melanocytes the hypergravity-stimulated cGMP efflux under PDE5 inhibition is most proba-bly mediated by endogenous anion transporters and/or selective cGMP transporters like MRP 4/5. Short-term application (5g up to 6 h) was not effective. Compared to the 1g-controls there existed no differences between intra- and extracellular cGMP-levels. These results indicate that short-term centrifugation did not affect cGMP efflux in melanocytic cells. Interestingly, highly metastatic melanoma cells were apparently insensitive to a 24 hour centrifugation in the presence of ANP. These cells that do not express the NO-sensitive GC isoforms, showed no alteration in intra- and extracellular cGMP concentrations. Application of hypergravity did not alter the cAMP efflux in melanocytic cells, but the production of cAMP appeared to be stimulated by centrifugal acceleration. In summary, the presented in vitro experiments demonstrate that long-term exposure to hypergravity increases the cGMP efflux in NO-stimulated NHMs and non-metastatic melanoma cells, whereas highly metastatic melanoma cells are not sensitive. Thus an altered acceleration vector may induce cGMP-dependent signalling events in NO-stimulated human melanocytic cells

Hypergravity stimulates cyclic GMP efflux in melanocytic cells

hypergravity, cGMP, melanocyte

Clinical Practice Guidelines for Vaccine Management in Ambulatory Care - A Systematic Review following the AGREE II Approach

Vaccine storage to maintain the cold chain is of utmost importance to assure vaccines´ effectiveness. This review compares the reporting quality and the content of international guidelines/practice recommendations on this issue

Significance of Bone Alkaline Phosphatase, CA 15-3 and CEA in the Detection of Bone Metastases During the Follow-Up of Patients Suffering from Breast Carcinoma

Peer Reviewe

A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project

We provide a systematic review to support the European Palliative Care Research Collaboration development of clinical guidelines for cancer patients suffering from cachexia. CENTRAL, MEDLINE, PsycINFO, ClinicalTrials.gov, and a selection of cancer journals have been searched up until 15 April 2016. The systematic literature research yielded 4214 publications with 21 of these included in the final evaluation. Regarding minerals, our search identified only one study examining the use of magnesium with no effect on weight loss. As far as vitamins are concerned, vitamin E in combination with omega-3 fatty acids displayed an effect on survival in a single study, vitamin D showed improvement of muscle weakness in prostate cancer patients, and vitamin C supplementation led to an improvement of various quality of life aspects in a sample with a variety of cancer diagnoses. For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. L-carnitine led to an increase of body mass index and an increase in overall survival in advanced pancreatic cancer patients. Adverse effects of food supplementation were rare and showed mild intensity. There is not enough solid evidence for the use of minerals, vitamins, proteins, or other supplements in cancer. No serious adverse effects have been reported with dietary supplementation