Biological and chemical characterization of new isolated halophilic microorganisms from saltern ponds of Trapani, Sicily

Halophilic microorganisms inhabiting hypersaline environments such as salt lakes, Dead Sea, or salt evaporation ponds, have acquired specific cell adaptation to grow within stressful conditions. In this study, we isolated heterotrophic and autotrophic microorganisms from several saltern ponds located at the Natural Reserve “Saline di Trapani e Paceco”, Sicily, Italy. The aim of the study was to investigate the biotechnological potential of new microbial strains from saltern ponds, by capturing their biological and chemical diversity. After the isolation and identification of the sampled strains, their growth capacity was determined under low and high salinity conditions. The metabolomic profiles of heterotrophs and pigments production of photosynthetic organisms were analyzed. In parallel, antiproliferative tests on human cell lines were conducted with total extracts coming from the microorganism cultures, together with repair activity assessment of non-cytotoxic extracts. Some of the isolated strains were found to synthetize known bioactive molecules and to exert bioactivity on human cells. In particular, the high salinity increases cell repair activity, probably due to an higher production of antioxidants pigments (e.g. lutein and fucoxanthin) from photosynthetic microorganisms; same culture condition augment also concentration of molecules with interesting bioactivities, such as ectoine, betaine, trigonelline, amino acids and oxiglutathione from heterotrophic microorganisms. In conclusion, this work represents the first study on the isolation of halophilic microorganisms populating the ‘Trapani-Paceco’ saltern and shows how an interdisciplinary investigation based on marine microbiology, cell biology, and modern metabolomics can disclose their biotechnological potential

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B12 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400–700 mg m−2). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration–time curve (AUC) (r2=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r2=0.58, P<0.001) and leucocytes (r2=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r2=0.37, P<0.01 and r2=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation

Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for beta-Cell Imaging

Item does not contain fulltextDiabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of beta-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on beta-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used beta-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful beta-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis

Synthesis of GPR40 targeting 3 H- and 18 F-probes towards selective beta cell imaging

Item does not contain fulltextDiabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of beta-cells in vivo is expected to contribute to an improved understanding of the underlying pathophysiology, improved diagnosis, and development of new treatment options for diabetes. Here, we describe the first radiosyntheses of [3 H]-TAK875 and [18 F]-TAK875 derivatives to be used as beta-cell imaging probes addressing the free fatty acid receptor 1 (FFAR1/GPR40). The fluorine-labeled derivative showed similar agonistic activity as TAK875 in a functional assay. The radiosynthesis of the 18 F-labelled tracer 2a was achieved with 16.7 +/- 5.7% radiochemical yield in a total synthesis time of 60-70 min

Organische Chemie 2004

Bruckner R, Wurthner F, Tschierske C, et al. Organische Chemie 2004. Nachrichten aus der Chemie. 2005;53(3):251-272