Phosphatidylcholine (18:0/20:4), a potential biomarker to predict ethionamide-induced hepatic steatosis in rats.

Ethionamide (ETH), a second-line drug for multidrug-resistant tuberculosis, is known to cause hepatic steatosis in rats and humans. To investigate predictive biomarkers for ETH-induced steatosis, we performed lipidomics analysis using plasma and liver samples collected from rats treated orally with ETH at 30 and 100 mg/kg for 14 days. The ETH-treated rats developed hepatic steatosis with Oil Red O staining-positive vacuolation in the centrilobular hepatocytes accompanied by increased hepatic contents of triglycerides (TG) and decreased plasma TG and total cholesterol levels. A multivariate analysis for lipid profiles revealed differences in each of the 35 lipid species in the plasma and liver between the control and the ETH-treated rats. Of those lipids, phosphatidylcholine (PC) (18:0/20:4) decreased dose-dependently in both the plasma and liver. Moreover, serum TG-rich very low-density lipoprotein (VLDL) levels, especially the large particle fraction of VLDL composed of PC containing arachidonic acid (20:4) involved in hepatic secretion of TG, were decreased dose-dependently. In conclusion, the decreased PC (18:0/20:4) in the liver, possibly leading to suppression of hepatic TG secretion, was considered to be involved in the pathogenesis of the ETH-induced hepatic steatosis. Therefore, plasma PC (18:0/20:4) levels are proposed as mechanism-related biomarkers for ETH-induced hepatic steatosis.

Amended Safety Assessment of Triglycerides as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 51 triglycerides; 25 of these ingredients were previously reviewed by the Panel, and 26 are reviewed herein for the first time. The majority of the ingredients named in this assessment have several functions, with most reported to function as skin conditioning agents (occlusive or emollient) and/or viscosity increasing agents in cosmetics; some are also reported to function as a fragrance or solvent. The Panel reviewed relevant new data, including frequency and concentration of use, and considered the data from previous reports. The Panel concluded the 51 triglycerides reviewed in this report are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension.

Exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. Exenatide QW suspension was developed for use with an autoinjector device, in which the microspheres are suspended in Miglyol 812, a mixture of medium chain triglycerides (MCTs). MCTs are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or MCFAs). While MCTs are edible oils present in many foods, including foodstuffs containing coconut and palm kernel oils, limited information is available regarding the oral and subcutaneous bioavailability of MCTs as well as safety following subcutaneous injection. These studies were designed to investigate the non-clinical pharmacokinetics and safety of MCTs. In a single dose pharmacokinetic study, MCFAs were rapidly detected in the plasma of rats following oral administration of either Miglyol 812 or tricaprylin at doses of 10 or 9.48 g kg-1 , respectively. Following subcutaneous dosing with Miglyol 812, MCFAs were rapidly absorbed with a similar profile to that following oral dosing. Furthermore, the toxicity of Miglyol 812 alone was evaluated in a 3 month repeat dose toxicology studies in cynomolgus monkeys. In this study, weekly subcutaneous doses of 0.15 g kg-1 did not elicit any treatment-related effects in cynomolgus monkeys. In conclusion, these studies alongside the available literature data show that Miglyol 812 is a safe excipient for use in subcutaneously administered therapeutics.

Safety assessment of medium- and long-chain triacylglycerols containing 30% (w/w) medium-chain fatty acids in mice and rats.

A novel medium- and long-chain triacylglycerols (MLCT), with 30% (w/w) medium-chain fatty acids (MCFA) was evaluated for its safety as a dietary fat in mice and rats. The subacute oral toxicity study showed that the maximum tolerated dose exceeded 54.33 g/kg body weight (kg bw)/day. In the 90-day feeding study, no dose-related adverse effects were observed in rats administered diets formulated with different levels of MLCT (2.0, 4.0, and 8.0 g/kg bw/day) as compared to the rapeseed oil control diet. Further safety assessment in pregnant rats did not reveal any significant difference relative to the control at a treatment level up to 8.0 g MLCT/kg bw/day. The results from this study indicated the safe use of MLCT with high contents of MCFA in food products for improving human health.

Evaluation of the effects of polymeric chitosan/tripolyphosphate and solid lipid nanoparticles on germination of Zea mays, Brassica rapa and Pisum sativum.

Although the potential toxicity of many metallic and carbon nanoparticles to plants has been reported, few studies have evaluated the phytotoxic effects of polymeric and solid lipid nanoparticles. The present work described the preparation and characterization of chitosan/tripolyphosphate (CS/TPP) nanoparticles and solid lipid nanoparticles (SLN) and evaluated the effects of different concentrations of these nanoparticles on germination of Zea mays, Brassica rapa, and Pisum sativum. CS/TPP nanoparticles presented an average size of 233.6±12.1nm, polydispersity index (PDI) of 0.30±0.02, and zeta potential of +21.4±1.7mV. SLN showed an average size of 323.25±41.4nm, PDI of 0.23±0.103, and zeta potential of -13.25±3.2mV. Nanotracking analysis enabled determination of concentrations of 1.33×1010 (CS/TPP) and 3.64×1012 (SLN) nanoparticles per mL. At high concentrations, CS/TPP nanoparticles caused complete inhibition of germination, and thus negatively affected the initial growth of all tested species. Differently, SLN presented no phytotoxic effects. The different size and composition and the opposite charges of SLN and CS/TPP nanoparticles could be associated with the differential phytotoxicity of these nanomaterials. The present study reports the phytotoxic potential of polymeric CS/TPP nanoparticles towards plants, indicating that further investigation is needed on the effects of such formulations intended for future use in agricultural systems, in order to avoid damage to the environment.

Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.

Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity.

We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPARγ; ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (EIF2a). Both ACSL1 and PPARγ adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterified free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress.

Oral toxicity of Miglyol 812(®) in the Göttingen(®) minipig.

Miglyol 812(®), a mixture of medium-chain triglycerides, has been identified as an oral vehicle that could improve the solubility and possibly the bioavailability of orally administered drugs during the non-clinical safety assessment. The toxicity of Miglyol was assessed in Göttingen(®) minipigs upon daily oral administration (gavage) for six weeks, at dosing-volumes of 0.5 and 2 mL/kg/day, compared to controls receiving 0.5% CarboxyMethylCellulose/0.1% Tween(®) 80 in water at 2 mL/kg/day. The control vehicle did not induce any findings. Miglyol at 0.5 and 2 mL/kg/day induced transient tremors, abnormal color of feces and increase in triglycerides. Miglyol at 2 ml/kg/day also induced reduced motor activity, decreased food intake, respiratory signs (2/6 animals) and increased total and LDL-cholesterol. At necropsy, the lung of 3/6 animals treated at 2 mL/kg/day presented abnormal color and/or irregular surface correlated with a chronic bronchiolo-alveolar inflammation. This finding is probably due to aspiration pneumonia in relation to the administration method and the high viscosity of Miglyol. Overall, the oral administration of pure Miglyol 812(®) for six weeks up to 2 mL/kg was less tolerated than that of the control vehicle. Miglyol as vehicle for sub-chronic oral toxicity studies in minipigs should be used with a limited dosing-volume.

Comparison of cytotoxicity in vitro and irritation in vivo for aqueous and oily solutions of surfactants.

The in vivo model on rabbit eyes and the in vitro cytotoxicity on fibroblasts were used to compare irritation effect of aqueous and oily (Miglyol 812) solutions of surfactants. Tween 20, Tween 80 and Cremophor EL were tested in different concentrations (0.1, 1 or 5%) and the in vitro test demonstrated that surfactants in oil are less cytotoxic than in aqueous solutions. In the in vivo study, the aqueous solutions of surfactants were characterized as non-irritant while small changes in conjunctiva were observed after application the oily solutions of surfactants and the preparations were classified as slightly irritant, however this effect was similar when Miglyol was applied alone. In conclusion, it is reported that the MTT assay does not correlate well with the Draize scores.

Molecular cloning of a novel bioH gene from an environmental metagenome encoding a carboxylesterase with exceptional tolerance to organic solvents.

BACKGROUND: BioH is one of the key enzymes to produce the precursor pimeloyl-ACP to initiate biotin biosynthesis de novo in bacteria. To date, very few bioH genes have been characterized. In this study, we cloned and identified a novel bioH gene, bioHx, from an environmental metagenome by a functional metagenomic approach. The bioHx gene, encoding an enzyme that is capable of hydrolysis of p-nitrophenyl esters of fatty acids, was expressed in Escherichia coli BL21 using the pET expression system. The biochemical property of the purified BioHx protein was also investigated. RESULTS: Screening of an unamplified metagenomic library with a tributyrin-containing medium led to the isolation of a clone exhibiting lipolytic activity. This clone carried a 4,570-bp DNA fragment encoding for six genes, designated bioF, bioHx, fabG, bioC, orf5 and sdh, four of which were implicated in the de novo biotin biosynthesis. The bioHx gene encodes a protein of 259 aa with a calculated molecular mass of 28.60 kDa, displaying 24-39% amino acid sequence identity to a few characterized bacterial BioH enzymes. It contains a pentapeptide motif (Gly76-Trp77-Ser78-Met79-Gly80) and a catalytic triad (Ser78-His230-Asp202), both of which are characteristic for lipolytic enzymes. BioHx was expressed as a recombinant protein and characterized. The purified BioHx protein displayed carboxylesterase activity, and it was most active on p-nitrophenyl esters of fatty acids substrate with a short acyl chain (C4). Comparing BioHx with other known BioH proteins revealed interesting diversity in their sensitivity to ionic and nonionic detergents and organic solvents, and BioHx exhibited exceptional resistance to organic solvents, being the most tolerant one amongst all known BioH enzymes. This ascribed BioHx as a novel carboxylesterase with a strong potential in industrial applications. CONCLUSIONS: This study constituted the first investigation of a novel bioHx gene in a biotin biosynthetic gene cluster cloned from an environmental metagenome. The bioHx gene was successfully cloned, expressed and characterized. The results demonstrated that BioHx is a novel carboxylesterase, displaying distinct biochemical properties with strong application potential in industry. Our results also provided the evidence for the effectiveness of functional metagenomic approach for identifying novel bioH genes from complex ecosystem.

Safety of medium-chain triglycerides used as an intraocular tamponading agent in an experimental vitrectomy model rabbit.

PURPOSE: To evaluate safety of medium-chain triglycerides used as a possible intraocular tamponading agent. METHODS: A 20-gauge pars plana vitrectomy was performed in the right eye of 28 rabbits. An ophthalmologic examination was performed every week until rabbits were killed. At days 7, 30, 60, and 90, rabbits were killed and the treated eyes were examined macroscopically and prepared for histologic examination. Principal outcome was retinal toxicity evaluated by light and electron microscopy, and secondary outcomes were the presence of medium-chain triglyceride emulsification, inflammatory reactions, and the development of cataract. RESULTS: Histologic examination did not reveal any retinal toxicity. Two cases of moderate emulsification were observed, but in these cases, emulsification was caused by the perioperative injection of the agent and did not increase during the postoperative period. We noted 13 cases of inflammatory reaction in vitreous cavity and no case of inflammatory reaction in anterior chamber. Two eyes developed cataract as a result of perioperative trauma to the lens with the vitreous cutter and not secondary to the presence of medium-chain triglycerides in the vitreous cavity. CONCLUSION: Medium-chain triglycerides did not induce morphologic evidence of retinal toxicity. The results suggest that medium-chain triglycerides could be a promising alternative intraocular tamponading agent for the treatment of retinal detachments.

Comparison of adjuvant mechanisms of medium-chain triacylglycerol in a mouse FITC-induced contact hypersensitivity model.

The number of allergy sufferers has been increasing with the increase in chemicals to which we are potentially exposed. We have discovered that tributyrin, a short-chain triacylglycerol (TAG), enhanced fluorescein isothiocyanate (FITC)-induced contact hypersensitivity in a mouse model. Medium-chain triacylglycerols (MCTs) are used in cosmetics, with which we come into direct contact frequently, to maintain skin conditions and as a thickening agent for cosmetics. In this study, we examined whether MCTs with different side chain lengths enhanced skin sensitization to FITC in the mouse model. During skin sensitization to FITC, the presence of tributyrin (side chain carbon number, 4; C4) as well as that of each MCT, tricaproin (C6), tricaprylin (C8), or tricaprin (C10), resulted in enhanced skin sensitization, whereas that of trilaurin (C12) did not. As to the mechanism underlying the enhanced sensitization, three MCTs (C6, C8 and C10) facilitated migration of FTIC-presenting CD11c+ dendritic cells to draining lymph nodes. These results indicated that not only tributyrin but also MCTs, up to side chain carbon number 10, have an adjuvant effect on FITC-induced skin hypersensitivity in mice.

Safety assessment of EPA-rich triglyceride oil produced from yeast: genotoxicity and 28-day oral toxicity in rats.

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820 mg EPA oil/kg/day, or fish oil (sardine/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were increased in the medium and high-dose EPA (male only), and fish oil groups but were considered non-adverse physiologically adaptive responses. Increased thyroid follicular cell hypertrophy was observed in male high-dose EPA and fish oil groups, and was considered to be an adaptive response to high levels of polyunsaturated fatty acids. No adverse test substance-related effects were observed on body weight, nutritional, or other clinical or anatomic pathology parameters. The oil was not mutagenic in the in vitro Ames or mouse lymphoma assay, and was not clastogenic in the in vivo mouse micronucleus test. In conclusion, exposure for 28 days to EPA oil derived from yeast did not produce adverse effects at doses up to 2820 mg/kg/day and was not genotoxic. The safety profile of the EPA oil in these tests was comparable to a commercial fish oil.

Toxicity of three types of arsenolipids: species-specific effects in Caenorhabditis elegans.

Although fish and seafood are well known for their nutritional benefits, they contain contaminants that might affect human health. Organic lipid-soluble arsenic species, so called arsenolipids, belong to the emerging contaminants in these food items; their toxicity has yet to be systematically studied. Here, we apply the in vivo model Caenorhabditis elegans to assess the effects of two arsenic-containing hydrocarbons (AsHC), a saturated arsenic-containing fatty acid (AsFA), and an arsenic-containing triacylglyceride (AsTAG) in a whole organism. Although all arsenolipids were highly bioavailable in Caenorhabditis elegans, only the AsHCs were substantially metabolized to thioxylated or shortened metabolic products and induced significant toxicity, affecting both survival and development. Furthermore, the AsHCs were several fold more potent as compared to the toxic reference arsenite. This study clearly indicates the need for a full hazard identification of subclasses of arsenolipids to assess whether they pose a risk to human health.

Triacylglycerol-induced impairment in mitochondrial biogenesis and function in J774.2 and mouse peritoneal macrophage foam cells.

The aim of this study was to detect mitochondrial alterations in J774.2 macrophages and mouse peritoneal macrophages (MPM) foam cells. J774.2 and MPM cells were exposed to triacylglycerol (TG) emulsion (1 mg/ml) for induction of fat accumulation. Impairment of mitochondrial function was reflected by reduced cellular ATP production and decreased expression of subunits of mitochondrial complexes I and III. The expression of subunit IV of complex IV remained unchanged, however, the content of its precursor in cells increased. Inhibitors of mitochondrial complexes, rotenone (0.1 microM) and myxothiazol (25 nM), protected the viability in TG-loaded macrophages. The exposure to TG caused downregulation of PPARgamma coactivator (PGC)-1alpha and nuclear respiratory factor (NRF)-1. Activation of peroxisome proliferator-activated receptors attenuated reactive oxygen species production in the foam cells. Treatment with antioxidant N-acetylcysteine (NAC) prevented lipid-mediated mitochondrial and cellular damage. In conclusion, this study demonstrates the important role of mitochondrial biogenesis dysfunction in TG-induced lipotoxicity in macrophages.

Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha.

High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-alpha. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia. TGRL induced membrane upregulation of the low-density lipoprotein family receptors LRP and LR11, which was inhibited by the low-density lipoprotein receptor-associated protein-1. TGRLs alone did not elicit inflammation in HAECs but enhanced the inflammatory response via a 10-fold increase in sensitivity to cytokine stimulation. This was reflected by increased mitogen-activated protein kinase activation, nuclear translocation of NF-kappaB, amplified expression of endothelial selectin and VCAM-1, and a subsequent increase in monocyte-specific recruitment under shear flow as quantified in a microfabricated vascular mimetic device.

Lipid-dependent cytotoxicity by the lipase PLRP2 and by PLRP2-positive cytotoxic T lymphocytes (CTLs).

IL-4 induces a lipase, pancreatic lipase related protein 2 (PLRP2), in cytotoxic T lymphocytes (CTLs). Because PLRP2 in semen can mediate lipid-dependent toxicity to sperm, we questioned whether CTL-derived PLRP2 could support similar cytotoxicity toward tumor cells. Recombinant PLRP2 was toxic to P815 tumor cells in 48 h when lipid and another protein, colipase, were present. However, PLRP2-positive CTLs (induced with many lots of IL-4) were unable to mediate lipid-dependent cytotoxicity. Notably, CTLs induced with only one lot of IL-4 had lipid-dependent cytotoxicity. The exceptional lot of IL-4 was effective in multiple experiments at inducing lipid-dependent cytotoxicity. The lipid-dependent cytotoxicity it induced was determined to be perforin-independent. CTLs induced with IL-4 that was unable to induce lipid-dependent cytotoxicity had mRNA for PLRP2 but not mRNA for colipase. Therefore, we added exogenous colipase to the CTL assays but still cytotoxicity was unchanged. We conclude (1) that lipid-dependent cytotoxicity, promoted by the lipase PLRP2 and colipase, will kill tumor cells and (2) that more than PLRP2 alone is required for lipid-dependent cytotoxicity mediated by CTLs.

Cytotoxicity and permeability enhancement of Capmul®MCM in nanoemulsion formulation.

This study aimed to investigate the following factors affecting the cytotoxicity of Capmul®MCM (C8/10MD) in self-emulsified nanoemulsions (SENs): concentration, triglycerides, and droplet size, and how these factors influence permeability of lipid droplets. Two triglycerides (C8T and C18T) and six formulations were used: SEN1(C18T:C8/10MD:Kolliphor®RH40 = 7:3:10, 257 nm), SEN2(C8T:C8/10MD:Kolliphor®RH40 = 1:1:2, 30 nm), SEN3(C18T:Kolliphor®RH40 = 1:4, 26 nm), SEN4(C8T:Kolliphor®RH40 = 1:4, 27 nm), SEN5(C8/10MD:Kolliphor®RH40 = 1:1, 120 nm) and SEN6(C8/10MD:Kolliphor®RH40 = 1:4, 15 nm). There was no cytotoxicity from SEN3-4 (5% preconcentrate), but there was concentration-dependent cytotoxicity from the SENs containing C8/10MD. The presence of triglycerides in SEN1-2 reduced the toxicity of C8/10MD as compared to SEN5-6. SEN2 and SEN6 showed higher toxicity than SEN1 and SEN5, respectively, due to the smaller size. 14C-Triolein-loaded droplets from SEN1 (0.45-0.6% C8/10MD) and SEN2 (0.3-0.6% C8/10MD) could permeate across the MDCK monolayer, resulted in intact droplets and radioactivity in the receiver chamber. The TEER was reduced as the C8/10MD concentration increased, and not recovered after 24 h from SEN1 (0.6% C8/10MD) and SEN2 (0.45-0.6% C8/10MD), resulted in significantly higher (p < 0.05) permeability of 14C-mannitol and 3H-propranolol compared to the treatment by the medium. In conclusion, Capmul®MCM caused concentration-dependent cytotoxicity and permeation enhancement, which were reduced with the presence of triglycerides and increase in droplet size.

Green Formulation of Triglyceride/Phospholipid-Based Nanocarriers as a Novel Vehicle for Oral Coenzyme Q10 Delivery.

This study was aimed to develop a novel nanocarrier for coenzyme Q10 (CoQ10) by a green process that prevented the use of surfactants and organic solvents. Triglyceride/phospholipid-based nanocarriers were developed through high-pressure homogenization (an industrial feasible process), and a 25-1 fractional factorial design was adopted to assess the influences of formulation variables on the considered responses, including vesicle size, entrapment efficiency, loading capacity, and solubility of the vehicles in simulated gastrointestinal fluids. The optimized formulation was further in-depth characterized in terms of morphology, release behavior, biocompatibility (Caco-2 cell cytotoxicity and histological examination), thermal behavior, and Fourier transform infrared analysis. Optimal nanocarriers were found to have mean particle size of 75 nm, narrow particle distribution, and CoQ10 entrapment of 95%. The optimized formulation was stable upon incubation in simulated gastrointestinal fluids without considerable leakage of cargo, which was in agreement with their sustained release behavior. Microscopic observations also confirmed nanosized nature of the vesicles and revealed their spherical shape. Moreover, toxicity evaluations at the cellular and tissue levels revealed their nontoxic nature. In conclusion, triglyceride/phospholipid-based nanocarriers proved to be a green safe vehicle for delivery of CoQ10 with industrial-scale production capability and could provide a new horizon for delivery of hydrophobic nutraceuticals. PRACTICAL APPLICATION: Green nanostructure formulation approaches have recently gained tremendous attraction for their safe profile especially when it comes to supplements, which are generally recommended for daily use. However, their sufficient association with cargoes and industrial-scale production have remained considerable challenges. This study focuses on the development of lipid-based nanocarriers for CoQ10 by an industrial feasible process that prevents the use of any surfactants or organic solvents.

Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila.

Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. The incidence of obesity has reached alarming proportions worldwide, and increasing evidence suggests that the parents' nutritional status may predispose their offspring to lipotoxic cardiomyopathy. However, to date, mechanisms underlying intergenerational heart disease risks have yet to be elucidated. Here we report that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations.