Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Background Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. Methods In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). Results In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. Conclusions Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. Trial registration: NCT01425580

Newly synthesized Ionic Liquids as potent lubricants and additives to existing lubricant oils

Ionic Liquids are promising candidates for next generation green lubricants. We have synthesized 39 Tetraalkylammonium Alkyl Ether Carboxylate Ionic Liquids and tested them for their lubricant capabilities. We measured friction coefficient to assess the transition from the boundary to the hydrodynamic lubrication, the hydrodynamic area and the minimum friction value. Some Ionic Liquids are capable of forming a hydrodynamic layer fully separating two specimens. Compounds with short C-chain of the cationic part show poor tribological behaviour. Similarly, increasing the PO-degree of the anionic part lowers the lubrication power. An increase of the C-chain length improves the tribological behaviour, i.e. the minimum friction value becomes lower. This is due to the formation of a uniform tribolayer of the long-chain carboxylic acids. Higher viscosity of the Ionic Liquids results in low friction coefficients and the development of a hydrodynamic layer. This is due to a strong hydrodynamic pressure, which is formed by the more viscous compound. Addition of small amounts of Ionic Liquids to low performance oils increases their capability to from tribolayers and thus improves their lubricant capability.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities

<b><i>Introduction:</i></b> The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. <b><i>Methods:</i></b> The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic <i>db</i>/<i>db</i> mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. <b><i>Results:</i></b> From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound <b>14b)</b> improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic <i>db</i>/<i>db</i> mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound <b>14b</b> treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound <b>14b</b> decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound <b>14b</b> were associated with the activation of the G-protein-coupled bile acid receptor TGR5. <b><i>Conclusion:</i></b> Compound <b>14b</b> exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Changes in the distribution of membrane lipids during growth of Thermotoga maritima at different temperatures: Indications for the potential mechanism of biosynthesis of ether-bound diabolic acid (membrane-spanning) lipids

Membrane-spanning lipids are present in a wide variety of archaea but they are rarely in bacteria. Nevertheless, the (hyper)thermophilic members of the order Thermotogales harbor tetraester, tetraether, and mixed ether/ester membrane-spanning lipids mostly composed of core lipids derived from diabolic acids, C 30, C 32 and C 34 dicarboxylic acids with two adjacent mid-chain methyl substituents. Lipid analysis of Thermotoga maritima across growth phases revealed a decrease of the relative abundance of fatty acids together with an increase of diabolic acids with independence of growth temperature. We also identified isomers of C 30 and C 32 diabolic acids, i.e. dicarboxylic acids with only one methyl group at C-15. Their distribution suggests they are products of the condensation reaction but preferably produced when the length of the acyl chains is not optimal. In comparison with growth at the optimal temperature of 80°C, an increase of glycerol ether-derived lipids was observed at 55°C. Besides, our analysis only detected diabolic acid-containing intact polar lipids with phosphoglycerol (PG) headgroups. Considering these findings, we hypothesize a biosynthetic pathway for the synthesis of membrane-spanning lipids based on PG polar lipid formation, suggesting that the protein catalyzing this process could be a membrane protein. We also identified, by genomic and protein domain analyses, a gene coding for a putative plasmalogen synthase homologue in T. maritima , which is also present in other bacteria producing sn 1-alkyl ether lipids but not plasmalogens, suggesting it could be involved in the conversion of the ester to ether bond in the diabolic acids bound in membrane-spanning lipids. Importance Membrane-spanning lipids are unique compounds found in most archaeal membranes, but they are also present in specific bacterial groups like the Thermotogales. The synthesis and physiological role of membrane-spanning lipids in bacteria represent an evolutionary and biochemical open question that points to the differentiation of the membrane lipids composition. Understanding the formation of membrane-spanning lipids is crucial to solving this question and identifying the enzymatic and biochemical mechanism performing this procedure. In the present work, we found changes at the core lipid level, and we propose that the growth phase drives the biosynthesis of these lipids rather than temperature. Our results identified physiological conditions influencing the membrane-spanning lipids biosynthetic process which can further clarify the pathway leading to the biosynthesis of these compounds.

Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.

A Multistate Adsorption Model for the Adsorption of C14EO4 and C14EO8 at the Solution/Air Interface

The dynamic and equilibrium properties of adsorption layers of poly (oxyethylene) alkyl ether (CnEOm) can be well described by the reorientation model. In its classical version, it assumes two adsorption states; however, there are obviously surfactants that can adsorb in more than two possible conformations. The experimental data for C14EO4 and C14EO8 (dynamic and equilibrium surface tensions and surface dilational visco-elasticity as measured by bubble profile analysis tensiometry) are used to verify if a reorientation model with more than two possible adsorption states can better describe the complete set data of CnEOm adsorption layers at the water/air interface. The proposed refined theoretical model allows s different states of the adsorbing molecules at the interface. The comparison between the model and experiment demonstrates that, for C14EO4, the assumption of s = 5 adsorption states provides a much better agreement than for s = 2, while for C14EO8, a number of s = 10 adsorption states allows an optimum data description.

Synthesis and Anticancer Activity of Triazole Linked Macrocycles and Heterocycles

Synthesis of macrocylic enones starting from alkyl ether and triazole as a linker was achieved using click reaction and intramolecular aldol condensation. The newly synthesized macrocyclic enone was successfully utilized as a dipolarophile in 1,3-dipolar cycloaddition. The dipoles generated from hydrazine hydrochloride, hydroxylamine and guanidine hydrochloride were reacted with macrocyclic enone to give a new class of spiro aminopyrimidines, phenyl pyrazoles and isoxazoles grafted macrocycles in good yield. The structures of newly synthesized compounds were confirmed with IR, NMR and mass spectroscopy and evaluated for their anti cancer activity.