Lysophosphatidylcholines Enriched with cis and trans Palmitoleic Acid Regulate Insulin Secretion via GPR119 Receptor.

Among lipids, lysophosphatidylcholines (LPCs) with various fatty acyl chains have been identified as potential agonists of G protein-coupled receptors (GPCRs). Recently, targeting GPCRs has been switched to diabetes and obesity. Concomitantly, our last findings indicate the insulin secretagogue properties of cis and trans palmitoleic acid (16:1, n-7) resulting from GPCR activation, however, associated with different signaling pathways. We here report the synthesis of LPCs bearing two geometrical isomers of palmitoleic acids and investigation of their impact on human pancreatic ß cells viability, insulin secretion, and activation of four GPCRs previously demonstrated to be targeted by free fatty acids and LPCs. Moreover, molecular modeling was exploited to investigate the probable binding sites of tested ligands and calculate their affinity toward GPR40, GPR55, GPR119, and GPR120 receptors.

Dually Active Apigenin-Loaded Nanostructured Lipid Carriers for Cancer Treatment.

Purpose: Cancer is one of the major causes of death worldwide affecting more than 19 million people. Traditional cancer therapies have many adverse effects and often result in unsatisfactory outcomes. Natural flavones, such as apigenin (APG), have demonstrated excellent antitumoral properties. However, they have a low aqueous solubility. To overcome this drawback, APG can be encapsulated in nanostructured lipid carriers (NLC). Therefore, we developed dual NLC encapsulating APG (APG-NLC) with a lipid matrix containing rosehip oil, which is known for its anti-inflammatory and antioxidant properties. Methods: Optimisation, physicochemical characterisation, biopharmaceutical behaviour, and therapeutic efficacy of this novel nanostructured system were assessed. Results: APG-NLC were optimized obtaining an average particle size below 200 nm, a surface charge of -20 mV, and an encapsulation efficiency over 99%. The APG-NLC released APG in a sustained manner, and the results showed that the formulation was stable for more than 10 months. In vitro studies showed that APG-NLC possess significant antiangiogenic activity in ovo and selective antiproliferative activity in several cancer cell lines without exhibiting toxicity in healthy cells. Conclusion: APG-NLC containing rosehip oil were optimised. They exhibit suitable physicochemical parameters, storage stability for more than 10 months, and prolonged APG release. Moreover, APG-NLC were internalised inside tumour cells, showing the capacity to cause cytotoxicity in cancer cells without damaging healthy cells.

Precision Medicines for Retinal Lipid Metabolism-Related Pathologies.

Oxidation of lipids and lipoproteins contributes to inflammation processes that promote the development of eye diseases. This is a consequence of metabolism dysregulation; for instance, that of the dysfunctional peroxisomal lipid metabolism. Dysfunction of lipid peroxidation is a critical factor in oxidative stress that causes ROS-induced cell damage. Targeting the lipid metabolism to treat ocular diseases is an interesting and effective approach that is now being considered. Indeed, among ocular structures, retina is a fundamental tissue that shows high metabolism. Lipids and glucose are fuel substrates for photoreceptor mitochondria; therefore, retina is rich in lipids, especially phospholipids and cholesterol. The imbalance in cholesterol homeostasis and lipid accumulation in the human Bruch's membrane are processes related to ocular diseases, such as AMD. In fact, preclinical tests are being performed in mice models with AMD, making this area a promising field. Nanotechnology, on the other hand, offers the opportunity to develop site-specific drug delivery systems to ocular tissues for the treatment of eye diseases. Specially, biodegradable nanoparticles constitute an interesting approach to treating metabolic eye-related pathologies. Among several drug delivery systems, lipid nanoparticles show attractive properties, e.g., no toxicological risk, easy scale-up and increased bioavailability of the loaded active compounds. This review analyses the mechanisms involved in ocular dyslipidemia, as well as their ocular manifestations. Moreover, active compounds as well as drug delivery systems which aim to target retinal lipid metabolism-related diseases are thoroughly discussed.

Studies on the Anticancer and Antioxidant Activities of Resveratrol and Long-Chain Fatty Acid Esters.

Resveratrol (RES) is gaining recognition as a natural bioactive compound. To expand the possible applications of RES with its enhanced bioactivity as well as to increase the health benefits of long-chain fatty acids, a lipophilization process of RES was performed using three fatty acids: palmitic acid (PA), oleic acid (OA), and conjugated linoleic acid (CLA). The obtained mono-, di-, and tri-esters of RES were evaluated for their anticancer and antioxidant properties against lung carcinoma (A549), colorectal adenocarcinoma (HT29), and pancreatic ductal adenocarcinoma (BxPC3) cell lines. Human fibroblast (BJ) cells were used as a control. Several parameters were investigated: cell viability and apoptosis, including the expression of major pro- and anti-apoptotic markers, as well as the expression of superoxide dismutase, a key enzyme of the body's antioxidant barrier. Three of the obtained esters: mono-RES-OA, mono-RES-CLA, and tri-RES-PA, which significantly reduced the tumor cell viability up to 23%, at concentrations 25, 10, 50 µg/mL, respectively, turned out to be particularly interesting. The above-mentioned resveratrol derivatives similarly increased the tumor cells' apoptosis by modifying their caspase activity of pro-apoptotic pathways (p21, p53, and Bax). Moreover, among the mentioned esters, mono-RES-OA induced apoptosis of the analyzed cell lines most strongly, reducing the number of viable cells up to 48% for HT29 cells versus 36% for pure RES. Furthermore, the selected esters exhibited antioxidant properties towards the normal BJ cell line by regulating the expression of major pro-antioxidant genes (superoxide dismutases-SOD1 and SOD2) without the effect on their expression in the tumor, and therefore reducing the defense of cancer cells against increased oxidative stress induced by high ROS accumulation. The obtained results indicate that the esters of RES and long-chain fatty acids allow enhancement of their biological activity. The RES derivatives have the potential for being applied in cancer prevention and treatment, as well as for oxidative stress suppression.

Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.

Antifeedant Potential of Geranylacetone and Nerylacetone and Their Epoxy-Derivatives against Myzus persicae (Sulz.).

Geranylacetone and nerylacetone are natural sesquiterpenoids, which play various roles in plant-insect interactions, including the deterrent and repellent effects on herbivores. The structural modifications of natural compounds often change their biological activities. The aim of the study was to evaluate the effect of geranylacetone, nerylacetone and their epoxy-derivatives on the probing and settling behavior of Myzus persicae (Sulz.) (Hemiptera: Aphididae). The no-choice test using the Electrical Penetration Graph (EPG) technique showed that the probes before the first phloem phase were usually shorter than 3 min, which means that they were terminated within the epidermis and/or outer layers of mesophyll. This resulted in a tendency to delay the initiation of the phloem phase in aphids, which reflects a weak preingestive deterrent activity of the studied compounds at the level of non-vascular tissues. Most M. persicae showed bouts of sustained phloem sap ingestion. However, the 24-h free-choice test demonstrated that aphids did not settle on the leaves treated with geranylacetone, nerylacetone, and their epoxy-derivatives. The refusal to settle after the consumption of phloem sap on treated plants indicated that the studied compounds had postingestive deterrent activity. The epoxidation of geranylacetone and nerylacetone did not evoke significant changes in their activity profiles.

Novel Strategies against Cancer: Dexibuprofen-Loaded Nanostructured Lipid Carriers.

The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using high-pressure homogenization. A two-level factorial design 24 was applied to optimize the formulation, and physicochemical properties such as particle size, zeta potential, polydispersity index and entrapment efficiency were measured. Optimized parameters of DXI-NLCs exhibited a mean particle size of 152.3 nm, a polydispersity index below 0.2, and high DXI entrapment efficiency (higher than 99%). Moreover, DXI-NLCs provided a prolonged drug release, slower than the free DXI. DXI-NLCs were stable for 2 months and their morphology revealed that they possess a spherical shape. In vitro cytotoxicity and anticancer potential studies were performed towards prostate (PC-3) and breast (MDA-MB-468) cancer cell lines. The highest activity of DXI-NLCs was observed towards breast cancer cells, which were effectively inhibited at 3.4 µM. Therefore, DXI-NLCs constitute a promising antiproliferative therapy that has proven to be especially effective against breast cancer.

Elevating Phospholipids Production Yarrowia lipolytica from Crude Glycerol.

Phospholipids (PLs) are a class of lipids with many proven biological functions. They are commonly used in lipid replacement therapy to enrich cell membranes damaged in chronic neurodegenerative diseases, cancer, or aging processes. Due to their amphipathic nature, PLs have been widely used in food, cosmetic, and pharmaceutical products as natural emulsifiers and components of liposomes. In Yarrowia lipolytica, PLs are synthesized through a similar pathway like in higher eukaryotes. However, PL biosynthesis in this yeast is still poorly understood. The key intermediate in this pathway is phosphatidic acid, which in Y. lipolytica is mostly directed to the production of triacylglycerols and, in a lower amount, to PL. This study aimed to deliver a strain with improved PL production, with a particular emphasis on increased biosynthesis of phosphatidylcholine (PC). Several genetic modifications were performed: overexpression of genes from PL biosynthesis pathways as well as the deletion of genes responsible for PL degradation. The best performing strain (overexpressing CDP-diacylglycerol synthase (CDS) and phospholipid methyltransferase (OPI3)) reached 360% of PL improvement compared to the wild-type strain in glucose-based medium. With the substitution of glucose by glycerol, a preferred carbon source by Y. lipolytica, an almost 280% improvement of PL was obtained by transformant overexpressing CDS, OPI3, diacylglycerol kinase (DGK1), and glycerol kinase (GUT1) in comparison to the wild-type strain. To further increase the amount of PL, the optimization of culture conditions, followed by the upscaling to a 2 L bioreactor, were performed. Crude glycerol, being a cheap and renewable substrate, was used to reduce the costs of PL production. In this process 653.7 mg/L of PL, including 352.6 mg/L of PC, was obtained. This study proved that Y. lipolytica is an excellent potential producer of phospholipids, especially from waste substrates.

Diclofenac Loaded Biodegradable Nanoparticles as Antitumoral and Antiangiogenic Therapy.

Cancer is identified as one of the main causes of death worldwide, and an effective treatment that can reduce/eliminate serious adverse effects is still an unmet medical need. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), has demonstrated promising antitumoral properties. However, the prolonged use of this NSAID poses several adverse effects. These can be overcome by the use of suitable delivery systems that are able to provide a controlled delivery of the payload. In this study, Diclofenac was incorporated into biodegradable polymeric nanoparticles based on PLGA and the formulation was optimized using a factorial design approach. A monodisperse nanoparticle population was obtained with a mean size of ca. 150 nm and negative surface charge. The release profile of diclofenac from the optimal formulation followed a prolonged release kinetics. Diclofenac nanoparticles demonstrated antitumoral and antiangiogenic properties without causing cytotoxicity to non-tumoral cells, and can be pointed out as a safe, promising and innovative nanoparticle-based formulation with potential antitumoral effects.

Evaluation of the Physico-Chemical Properties of Liposomes Assembled from Bioconjugates of Anisic Acid with Phosphatidylcholine.

The aim of this work was the evaluation of the physico-chemical properties of a new type of liposomes that are composed of DPPC and bioconjugates of anisic acid with phosphatidylcholine. In particular, the impact of modified anisic acid phospholipids on the thermotropic parameters of liposomes was determined, which is crucial for using them as potential carriers of active substances in cancer therapies. Their properties were determined using three biophysical methods, namely differential scanning calorimetry (DSC), steady-state fluorimetry and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Moreover, temperature studies of liposomes composed of DPPC and bioconjugates of anisic acid with phosphatidylcholine provided information about the phase transition, fluidity regarding chain order, hydration and dynamics. The DSC results show that the main phase transition peak for conjugates of anisic acid with phosphatidylcholine molecules was broadened and shifted to a lower temperature in a concentration- and structure-dependent manner. The ATR-FTIR results and the results of measurements conducted using fluorescent probes located at different regions in the lipid bilayer are in line with DSC. The results show that the new bioconjugates with phosphatidylcholine have a significant impact on the physico-chemical properties of a membrane and cause a decrease in the temperature of the main phase transition. The consequence of this is greater fluidity of the lipid bilayer.

Phospholipid Derivatives of Cinnamic Acid Restore Insulin Sensitivity in Insulin Resistance in 3T3-L1 Adipocytes.

BACKGROUND: Insulin resistance (IR) is a condition in which the physiological amount of insulin is insufficient to evoke a proper response of the cell, that is, glucose utilization. Metformin is the first choice for therapy, thanks to its glycemic efficacy and general tolerability. In addition, various natural compounds from plant extracts, spices, and essential oils have been shown to provide health benefits regarding insulin sensitivity. In the present study, we analyzed the effect of phospholipid derivatives of selected natural aromatic acids on insulin action and their potential use to overcome insulin resistance. METHODS: The 3T3-L1 fibroblasts were differentiated into mature adipocytes; next, insulin resistance was induced by palmitic acid (16:0). Cells were further cultured with phenophospholipids at appropriate concentrations. To assess insulin sensitivity, we measured the insulin-stimulated glucose uptake, using a glucose uptake test. RESULTS: We showed that cinnamic acid (CA) and 3-methoxycinnamic acid (3-OMe-CA) restored the proper insulin response. However, 1,2-dicinnamoyl-sn-glycero-3-phosphocholine (1,2-diCA-PC) and 1-cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine (1-CA-2-PA-PC) improved insulin sensitivity in insulin-resistant adipocytes even stronger, exhibiting more beneficial effects. CONCLUSIONS: The binding of aromatic acids to phosphatidylcholine increases their beneficial effect on insulin sensitivity in adipocytes and expands their potential practical application as nutraceutical health-promoting agents.

Conjugation with Phospholipids as a Modification Increasing Anticancer Activity of Phenolic Acids in Metastatic Melanoma-In Vitro and In Silico Studies.

Phenolic acids possess many beneficial biological activities, including antioxidant and anti-inflammatory properties. Unfortunately, their low bioavailability restricts their potential medical uses, as it limits the concentration of phenolic acids achievable in the organism. The conjugation with phospholipids constitutes one of the most effective strategies to enhance compounds bioavailability in biological systems. In the present study, the conjugates of anisic (ANISA) and veratric acid (VA) with phosphatidylcholine (PC) were investigated. Since both ANISA and VA are inhibitors of tyrosinase, a melanocyte enzyme, the expression of which increases during tumorigenesis, anticancer potential of the conjugates was tested in several metastatic melanoma cell lines. The conjugates proved to be antiproliferative, apoptosis-inducing and cell-cycle-affecting agents, selective for cancerous cells and not affecting normal fibroblasts. The conjugates substituted by ANISA and VA, respectively, at both the sn-1 and sn-2 positions of PC, appeared the most promising, since they were effective against the vast majority of metastatic melanoma cell lines. Additionally, the conjugation of phenolic acids to PC increased their antioxidant activity. Molecular modeling was employed for the first time to estimate the features of the investigated conjugates relevant to their anticancer properties and membrane permeation. Again, the conjugates substituted by phenolic acid at both the sn-1 and sn-2 positions of PC seemed to be presumably most bioavailable.

Recent Developments in Therapeutic and Nutraceutical Applications of p-Methoxycinnamic Acid from Plant Origin.

The p-methoxycinnamic acid (p-MCA) is one of the most studied phenylpropanoids with high importance not only in the wide spectrum of therapeutic activities but also its potential application for the food industry. This natural compound derived from plants exhibits a wide range of biologically useful properties; therefore, during the last two decades it has been extensively tested for therapeutic and nutraceutical applications. This article presents the natural sources of p-MCA, its metabolism, pharmacokinetic properties, and safety of its application. The possibilities of using this dietary bioactive compound as a nutraceutical agent that may be used as functional food ingredient playing a vital role in the prevention and treatment of many chronic diseases is also discussed. We present the antidiabetic, anticancer, antimicrobial, hepato-, and neuroprotective activities of p-MCA and methods of its lipophilization that have been developed so far to increase its industrial application and bioavailability in the biological systems.

Biological Properties, Health Benefits and Enzymatic Modifications of Dietary Methoxylated Derivatives of Cinnamic Acid.

Methoxylated derivatives of cinnamic acid play an important role in the formation of the pro-health potential of food products. Numerous reports present them as molecules with strong antimicrobial, antidiabetic, anticancer as well as hepato-, cardio-, and neuroprotective activities. In the last three decades, many research groups have tried to extend the practical application of these molecules as therapeutic and antioxidant agents extensively studying the methods of their lipophilization as the solution of problems of their low oral bioavailability and rapid metabolism. This article summarizes the latest data of natural sources of occurrence, biological potential and bioavailability of methoxy derivatives of cinnamic acids. Metabolism and pharmacokinetics of this group of dietary compounds are also extensively discussed as well as reviewing the methods of their chemical and enzymatic lipophilization in the aspect of their use in food and pharmaceutical industries.

Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs.

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic ß-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Dexibuprofen Therapeutic Advances: Prodrugs and Nanotechnological Formulations.

S-(+) enantiomer of ibuprofen (IBU) dexibuprofen (DXI) is known to be more potent than its R-(-) form and exhibits many advantages over the racemic mixture of IBU such as lower toxicity, greater clinical efficacy, and lesser variability in therapeutic effects. Moreover, DXI potential has been recently advocated to reduce cancer development and prevent the development of neurodegenerative diseases in addition to its anti-inflammatory properties. During the last decade, many attempts have been made to design novel formulations of DXI aimed at increasing its therapeutic benefits and minimizing the adverse effects. Therefore, this article summarizes pharmacological information about DXI, its pharmacokinetics, safety, and therapeutic outcomes. Moreover, modified DXI drug delivery approaches are extensively discussed. Recent studies of DXI prodrugs and novel DXI nanoformulations are analyzed as well as reviewing their efficacy for ocular, skin, and oral applications.

Lipid Formulations and Bioconjugation Strategies for Indomethacin Therapeutic Advances.

Indomethacin (IND) is a drug which after successful clinical trials became available for general prescription in 1965 and from that time is one of the most widely used anti-inflammatory drug with the highest potencies in the in vitro and in vivo models. However, despite its high therapeutic efficacy in relieving the symptoms of certain arthritis and in treating gout or collagen diseases, administration of IND causes a number of adverse effects, such as gastrointestinal ulceration, frequent central nervous system disorders and renal toxicity. These obstacles significantly limit the practical applications of IND and make that 10-20% of patients discontinue its use. Therefore, during the last three decades many attempts have been made to design novel formulations of IND aimed to increase its therapeutic benefits minimizing its adverse effects. In this review we summarize pharmacological information about IND and analyze its new lipid formulations and lipid bioconjugates as well as discuss their efficacy and potential application.

Synthesis of novel phytol-derived γ-butyrolactones and evaluation of their biological activity.

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Products were obtained in good yields (19-96%) and their structures were fully characterized by spectroscopic data (NMR, HRMS). Four synthesized δ-halo-γ-lactones (4-7) are new and have not been previously described in the literature. In the choice test phytol (1) appeared deterrent to M. persicae, whereas modifications of its structure did not cause the avoidance of the treated leaves by the aphids. In contrast, aphids were attracted to the leaves treated with the new trans-δ-chloro-γ-lactone (6). Electrical Penetration Graph (EPG) technique applied to explore the aphid probing and feeding activity revealed that neither phytol nor lactone 6 affected aphid probing and the consumption of phloem sap, which means that both phytol and the lactone 6 might have acted as postingestive modifiers of aphid behavior. The results of in vitro antitumor assays showed that obtained phytol derivatives exhibit cytotoxic activity against studied cancer cell lines (leukemia, lung and colon carcinoma and its doxorubicin resistant subline). Halolactones 4-6 were identified as the compounds, which arrest cell cycle of leukemia cells mainly in G2/M and S phases.

Enzymatic Production of Biologically Active 3-Methoxycinnamoylated Lysophosphatidylcholine via Regioselctive Lipase-Catalyzed Acidolysis.

Enzymatic acidolysis of egg-yolk phosphatidylcholine (PC) with 3-methoxycinnamic acid (3-OMe-CA) was investigated to produce biologically active 3-methoxycinnamoylated phospholipids. Four commercially available lipases were screened for their ability to incorporate 3-OMe-CA into PC. The results showed that Novozym 435 is the most effective biocatalyst for this process, while during the examination of organic solvents, heptane was found propriate reaction medium. The other reaction parameters including the substrate molar ratio, enzyme load and reaction time were designed using an experimental factorial design method. According to three-level-3-factor Box-Behnken model it was shown that all of studied parameters are crucial variables for the maximization of the synthesis of structured PLs. The optimum conditions derived via response surface methodology (RSM) were: 30% of lipase of the total weight of substrates, 1:15 molar ration of PC/3-OMe-CA and reaction time 4 days. The process of acidolysis performed on the increased scale at optimized parameters afforded two products. The major product, 3-methoxycinnamoylated lysophosphatidylcholine (3-OMe-CA-LPC) was isolated in high 48% yield, while 3-methoxycinnamoylated phosphatidylcholine (3-OMe-CA-PC) was produced in trace amount only in 1.2% yield. Obtained results indicate that presented biotechnological method of synthesis of 3-methoxycinnamoylated lysophosphatidylcholine is competitive to the previously reported chemical one.

Lysophosphatidylcholine Containing Anisic Acid Is Able to Stimulate Insulin Secretion Targeting G Protein Coupled Receptors.

Diabetes mellitus is a worldwide health problem with high rates of mortality and morbidity. Management of diabetes mellitus by dietary components is achievable especially at the initial stage of the disease. Several studies confirmed the antidiabetic activities of simple phenolic acids and lysophosphatidylcholine (LPC). The main goal of this study was to identify new potential insulin secretion modulators obtained by combining the structures of two natural compounds, namely O-methyl derivatives of phenolic acids and phospholipids. LPC and phosphatidylcholine bearing methoxylated aromatic carboxylic acids were tested as potential agents able to improve glucose-stimulated insulin secretion (GSIS) and intracellular calcium mobilization in MIN6 ß pancreatic cell line. Our results show that LPC with covalently bonded molecule of p-anisic acid at the sn-1 position was able to induce GSIS and intracellular calcium flux. Notably, 1-anisoyl-2-hydroxy-sn-glycero-3-phosphocholine did not affect the viability of MIN6 cells, suggesting its potential safe use. Furthermore, we have shown that three G protein coupled receptors, namely GPR40, GPR55, and GPR119, are targeted by this LPC derivative.