RESUMO
Recent studies suggest that diets supplemented with alpha-linolenic acid (ALA)-enriched diacylglycerol (DAG) oil provide potential health benefits in preventing or managing obesity. However, available safety information about reproductive and developmental toxicities of ALA-DAG oil is limited. This study was conducted to clarify the effect, if any, of ALA-DAG oil on embryo-fetal development, following maternal exposure during the critical period of major organogenesis. ALA-DAG oil was administered via gavage to pre-mated female Sprague Dawley rats from gestation day 6 through 19, at dose levels of 0, 1.25, 2.5, and 5.0â¯mL/kg/day (equivalent to 0, 1149, 2325, and 4715â¯mg/kg/day, respectively), with total volume adjusted to 5â¯mL/kg/day with rapeseed oil. All females survived to the scheduled necropsy. There were no treatment-related changes in clinical or internal findings, maternal body weights, feed consumption, intrauterine growth, survival, and number of implantations. No ALA-DAG oil-related fetal malformations or developmental variations were noted. A maternal maximum tolerated dose for ALA-DAG oil could not be achieved in this study. Based on these results, a dose level of 5.0â¯mL/kg (4715â¯mg/kg/day), the highest dose tested, was considered as the no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity.
Assuntos
Gorduras Insaturadas na Dieta/toxicidade , Diglicerídeos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Ácido alfa-Linolênico/toxicidade , Animais , Feminino , Troca Materno-Fetal , Nível de Efeito Adverso não Observado , Gravidez , Ratos Sprague-DawleyRESUMO
Boronic acid liposomes enable triggered content release and cell delivery driven by carbohydrate binding. Dye release assays using hydrophilic and hydrophobic fluorophores validate dose-dependent release upon carbohydrate treatment. Microscopy results indicate dramatic enhancements in cell delivery, showcasing the prospects of boronic acid lipids for drug delivery.
Assuntos
Ácidos Borônicos/química , Diglicerídeos/química , Portadores de Fármacos/química , Heparina/química , Lipossomas Unilamelares/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/metabolismo , Ácidos Borônicos/toxicidade , Linhagem Celular Tumoral , Diglicerídeos/síntese química , Diglicerídeos/metabolismo , Diglicerídeos/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Oxazinas/química , Pinocitose/efeitos dos fármacos , Rodaminas/química , Lipossomas Unilamelares/síntese química , Lipossomas Unilamelares/metabolismo , Lipossomas Unilamelares/toxicidadeRESUMO
BACKGROUND: 3-monochloro-1, 2-propanediol fatty acid esters (3-MCPDEs) comprise a group of food toxicants formed during food processing. 3-MCPDEs have received increasing attention concerning their potential negative effects on human health. However, reports on the toxicity of 3-MCPD esters are still limited. To determine the effects of fatty acid substitutions on the toxicity of their esters, 1-stearic, 1-oleic, 1-linoleic, 1-linoleic-2-palmitic and 1-palmitic-2-linoleic acid esters of 3-MCPD were synthesized and evaluated with respect to their acute oral toxicities in Swiss mice. RESULTS: 3-MCPDEs were obtained through the reaction of 3-MCPD and fatty acid chlorides, and their purities and structures were characterized by ultraperformance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS), infrared, 1 H and 13 C spectroscopic analyses. Medial lethal doses of 1-stearic, 1-oleic, 1-linoleic, 1-linoleic-2-palmitic and 1-palmitic-2-linoleic acid esters were 2973.8, 2081.4, 2016.3, 5000 and > 5000 mg kg-1 body weight. For the first time, 3-MCPDEs were observed for their toxic effects in the thymus and lung. In addition, major histopathological changes, as well as blood urea nitrogen and creatinine, were examined for mice fed the five 3-MCPDEs. CONCLUSION: The results from the present study suggest that the degree of unsaturation, chain length, number of substitution and relative substitution locations of fatty acids might alter the toxicity of 3-MCPDEs. © 2016 Society of Chemical Industry.
Assuntos
Diglicerídeos/toxicidade , Contaminação de Alimentos , Hidrocarbonetos Clorados/toxicidade , Fígado/efeitos dos fármacos , Monoglicerídeos/toxicidade , Síndromes Neurotóxicas/etiologia , Timo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Diglicerídeos/síntese química , Diglicerídeos/química , Feminino , Manipulação de Alimentos , Hidrocarbonetos Clorados/síntese química , Hidrocarbonetos Clorados/química , Dose Letal Mediana , Fígado/patologia , Masculino , Camundongos , Estrutura Molecular , Monoglicerídeos/síntese química , Monoglicerídeos/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/patologia , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Relação Estrutura-Atividade , Timo/patologia , Testes de Toxicidade AgudaRESUMO
Xenobiotic diacylglycerols (DG) may induce pathological disorders by causing abnormal chromosomal segregation, which could be aneuploid. In this study, seven xenobiotic-diacylglycerols (four of drug origin and three of pesticide origin) were evaluated for their ability to induce aneuploidy in mammalian cultures using in vitro cytokinesis blocked micronucleus (CBMN) assay coupled with kinetochore labeling and interphase fluorescent in situ hybridization. Out of seven xeno-DGs, two (ibuprofen-DG and fenbufen-DG) induced statistically significant (P < 0.001) and dose-dependent increase in micronucleus induction, but this apparent micronucleus induction was very weak in case of fenbufen-DG. These MN were produced predominantly by aneugenic and clastogenic mechanisms, respectively, confirmed by immunofluorescent labeling of kinetochores. Fluorescent in situ hybridization analysis revealed that ibuprofen-DG induced significantly higher nondisjunction for chromosomes 10, 17, and 18. Other xenobiotic diacylglycerols (indomethacin-DG, salicylic acid-DG, 4-(2-methyl-4-chlorophenoxy) butanoic acid-DG (MCPB-DG), 2-(2-methyl-4-chlorophenoxy) propanoic acid-DG (MCPP-DG) and 2-(4-dichlorophenoxy)-butanoic acid-DG (2,4 DB-DG) did not induce micronuclei, but the concentrations tested did not reach levels that caused the marked growth suppression typically required for testing for regulatory testing purposes. However, the levels of growth suppression achieved were similar to that seen with ibuprofen-DG, which was positive. This study shows that xeno-DGs, which have been neglected in the past for their possible link to any pathological disorders, need serious assessment of their mutagenic potential.
Assuntos
Segregação de Cromossomos/efeitos dos fármacos , Diglicerídeos/toxicidade , Testes para Micronúcleos/métodos , Mutagênicos/toxicidade , Xenobióticos/toxicidade , Aneuploidia , Linhagem Celular Tumoral/efeitos dos fármacos , Ácido Clofíbrico/química , Ácido Clofíbrico/toxicidade , Diglicerídeos/química , Humanos , Ibuprofeno/química , Ibuprofeno/toxicidade , Modelos Moleculares , Testes de Mutagenicidade/métodos , Mutagênicos/química , Fenilbutiratos/química , Fenilbutiratos/toxicidade , Ácido Salicílico/química , Ácido Salicílico/toxicidade , Xenobióticos/químicaRESUMO
Diacylglycerol oil is an edible oil with taste and usability characteristics comparable to naturally occurring oils. The objective of this review is to examine literature on diacylglycerol oil to assess its safety-in-use. Feeding rats with unheated or heated diacylglycerol oil at levels up to 5.5% in diet for 90 days did not cause any toxic effects. In chronic studies, dietary administration of diacylglycerol oil (up to 5.3%) to rats for 2 years or at 9.5% to Beagle dogs for 1 year had no adverse effects. Genotoxicity studies of unheated and heated diacylglycerol oil did not reveal any genotoxic effects. Carcinogenicity studies in rodents demonstrate that diacylglycerol oil is non-carcinogenic. In a two-generation reproductive and developmental toxicity study, gavage administration of diacylglycerol oil at dose levels of 5.0 ml/kg body weight/day did not reveal any adverse effects. In several human clinical investigations, administration of diacylglycerol oil at levels up to 0.5 g/kg body weight/day for up to 1 year did not cause adverse effects. Collectively, there is sufficient qualitative and quantitative scientific evidence available from animal and human studies suggesting that intake of diacylglycerol oil is safe for human consumption when used in a manner similar to other edible oils.
Assuntos
Diglicerídeos/administração & dosagem , Diglicerídeos/toxicidade , Aditivos Alimentares/administração & dosagem , Aditivos Alimentares/toxicidade , Animais , Dieta , Cães , Esquema de Medicação , Humanos , RatosRESUMO
Extensive efforts have been made, recently, to find surfactants with lower irritancy potential than those presently commercially employed in pharmaceutical and cosmetic preparations. Cytotoxic and phototoxic effects of novel mono and diacylglycerol amino acid-based surfactants (glutamic acid, or arginine) were evaluated. All tested surfactants showed a clear concentration-response relationship to two immortalized cell lines, murine fibroblast cell line, 3T3, and one human keratinocyte cell line, HaCaT, demonstrated by and decrease of NR uptake. Concentrations resulting in 50% inhibition of NR uptake (IC(50)) range from 30 to 300microgmL(-1). The potential phototoxicity which could result in irritant products, was determined by modulated cytotoxicity via the resazurin reduction to resorufin and neutral red uptake (NRU) endpoints. Surfactants with two chains showed, in general, less cytotoxic but higher phototoxic effect than surfactants with only one chain.
Assuntos
Aminoácidos/farmacologia , Aminoácidos/toxicidade , Diglicerídeos/farmacologia , Diglicerídeos/toxicidade , Glicerídeos/farmacologia , Glicerídeos/toxicidade , Tensoativos/farmacologia , Tensoativos/toxicidade , Células 3T3 , Aminoácidos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Dermatite Fototóxica/patologia , Dermatite Fototóxica/prevenção & controle , Diglicerídeos/química , Fibroblastos/efeitos dos fármacos , Glicerídeos/química , Humanos , Irritantes/toxicidade , Queratinócitos/efeitos dos fármacos , Camundongos , Relação Estrutura-Atividade , Tensoativos/química , Raios UltravioletaRESUMO
Understanding the mechanisms underlying lipid-induced cell death has significant implications in both cell biology and human diseases. Previously, we showed that fission-yeast Schizosaccharomyces pombe cells deficient in triacylglycerol synthesis display apoptotic markers upon entry into stationary phase. Here, we characterize the sequential molecular events that take place at the onset of cell death in S. pombe, including a surge of diacylglycerol, post-mitotic arrest, alterations in mitochondrial activities and in intracellular redox balance, chromatin condensation, nuclear-envelope fragmentation, and eventually plasma-membrane permeabilization. Our results demonstrated active roles of mitochondria and reactive oxygen species in cell death, and identified novel cell-death regulators--including metacaspase Pca1, BH3-domain protein Rad9, and diacylglycerol-binding proteins Pck1 and Bzz1. Most importantly, we show that, under different conditions and stimuli, failure to maintain intracellular-lipid homeostasis can lead to cell death with different phenotypic manifestations, genetic criteria and cellular mechanisms, pointing to the existence of multiple lipotoxic pathways in this organism. Our study represents the first in-depth analysis of cell-death pathways in S. pombe.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/fisiologia , Lipídeos/toxicidade , Schizosaccharomyces/fisiologia , Apoptose/fisiologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ceramidas/metabolismo , Ceramidas/farmacologia , Ceramidas/toxicidade , Meios de Cultura/farmacologia , Meios de Cultivo Condicionados/farmacologia , Citotoxinas/metabolismo , Citotoxinas/farmacologia , Citotoxinas/toxicidade , Diacilglicerol O-Aciltransferase/genética , Diglicerídeos/metabolismo , Diglicerídeos/farmacologia , Diglicerídeos/toxicidade , Metabolismo dos Lipídeos/genética , Lipídeos/farmacologia , Mitose/efeitos dos fármacos , Mitose/genética , Modelos Biológicos , Organismos Geneticamente Modificados , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Diacylglycerol (DAG) oil is a novel edible oil with similar taste and usability characteristics as conventional edible oils. Recent studies suggest that DAG oil may be helpful in the prevention and management of obesity. The objective of the present two-generation study was to evaluate potential adverse effects of DAG oil on reproductive processes. DAG oil was administered via gavage to rats (30/sex/group) for at least 70 days prior to mating, at dose levels of 0, 1.25, 2.5 or 5.0 ml/kg/day (0, 1160, 2320 and 4630 mg/kg/day). An additional group received a triacylglycerol (TAG) oil with a similar fatty acid composition to DAG oil. The rats were treated throughout the mating, gestation and lactation periods. Administration of DAG or TAG oil did not reveal any toxicologically significant effects on reproductive performance (mating, fertility and copulation/conception indices). DAG oil did not affect mean gestation lengths, the process of parturition, spermatogenic parameters, organ weights, histopathologic findings, mean numbers of pups born, implantation sites and unaccounted sites. F1 and F2 pup viability, live litter sizes, body weights, mean age of attainment of balanopreputial separation and vaginal patency were similar to those in the control group. Based on the results of this study, a dose level of 5.0 ml/kg (4630 mg/kg/day) was considered as the no-observed-adverse-effect level for reproductive and systemic toxicity, and neonatal toxicity.
Assuntos
Dieta , Diglicerídeos/toxicidade , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Feminino , Lactação/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Parto/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual , Espermatogênese/efeitos dos fármacos , DesmameRESUMO
Diacylglycerol oil is an edible oil with similar taste and usability characteristics as conventional edible oil rich in triacylglycerol oil. The objective of the present study was to evaluate potential adverse effects of heated diacylglycerol and triacylglycerol oil in rats following subchronic administration. The heated diacylglycerol and triacylglycerol oils were prepared separately following deep frying potato slices at 180 degrees C for 8h per day for three days. Sprague Dawley rats were fed diets containing different ratios (concentrations) of heated to unheated diacylglycerol oil. The ratio of heated to unheated diacylglycerol was as follows: 0%/5.5% (control-1; Group 1), 1.0%/4.5% (Group 2), 2.75%/2.75% (Group 3), and 5.5%/0% (Group 4). Two additional groups received the feed containing 5.5% of unheated or 5.5% of heated triacylglycerol oil. Compared to the unheated oils, feeding of heated diacylglycerol or triacylglycerol oil did not reveal any toxicologically significant changes in clinical observation, body weights, body weight gains, feed consumption, ophthalmic examinations, functional observational battery and motor activity, clinical pathology evaluations and organ weights. Similarly, terminal necropsy did not reveal treatment-related gross or histopathology findings. Based on the results of this subchronic study, the no-observed-effect levels (NOELs) of heated diacylglycerol or triacylglycerol oil were 5.5%, the highest levels tested. The mean dietary exposure levels at the highest dose for the heated diacylglycerol and triacylglycerol oil for male and female rats ranged from 3,178 to 4,120 mg/kg/day.
Assuntos
Diglicerídeos/toxicidade , Óleos de Plantas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Contagem de Células Sanguíneas , Análise Química do Sangue , Peso Corporal/efeitos dos fármacos , Culinária , Dieta , Diglicerídeos/química , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Oftalmopatias/induzido quimicamente , Oftalmopatias/patologia , Feminino , Temperatura Alta , Masculino , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Óleos de Plantas/química , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , UrináliseRESUMO
Diacylglycerol (DAG) oil is an edible oil with similar taste and usability characteristics as conventional edible oil. Recent studies suggest that use of DAG oil may be helpful in the prevention and management of obesity. This study evaluated the potential maternal and fetal effects of DAG oil, following exposure to pregnant rats, during the critical period of major organogenesis. DAG oil was administered via gavage to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) once daily from gestation day 6 through 17, at dose levels of 0, 1.25, 2.5 or 5.0 ml/kg/day (0, 1160, 2320 and 4630 mg/kg/day) with total volume made to 5 ml/kg/day with triacylglycerol (corn) oil. No mortality or treatment-related clinical or internal findings were noted in any of the groups. Compared to animals in control group, mean maternal body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights, and food consumption were not affected by DAG oil administration. Similarly, intrauterine growth and survival were not affected by DAG oil administration. No DAG oil-related fetal malformations or developmental variations were noted. A maternal maximum tolerated dose for DAG oil was not achieved in this study. Based on the results of this study, a dose level of 5.0 ml/kg (4630 mg/kg/day) was considered as no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity.
Assuntos
Diglicerídeos/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Peso Fetal/efeitos dos fármacos , Exposição Materna , Anormalidades Induzidas por Medicamentos , Administração Oral , Animais , Fármacos Antiobesidade/toxicidade , Relação Dose-Resposta a Droga , Feminino , Nível de Efeito Adverso não Observado , Tamanho do Órgão , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Aumento de PesoRESUMO
The modifying potential of diacylglycerol (DAG) oil on tumor development was investigated in a medium-term multi-organ carcinogenesis bioassay. DAG oil is a cooking oil that contains >80% diglycerides, <20% triglycerides and <5% monoglycerides. Male 6-week-old F344 rats (20 in each group) were sequentially treated with five carcinogens for initiation in different organ target sites for 4 weeks (DMBDD treatment), and then administered DAG oil at dietary levels of 0% (control), 1.375%, 2.75% or 5.5% [triacylglycerol (TGs), with the same fatty acid composition as DAG oil were also added at dietary levels of 5.5%, 4.125%, 2.75% and 0%, respectively, to maintain the same lipid level], or 5.5% high linoleic acid TG (HLTG), 5.5% high oleic acid TG (HOTG), or 5.5% medium-chain TG (MCTG) (as reference substances, mostly consisting of triacylglycerols) admixed into AIN-93G semi-synthetic diet, for an additional 24 weeks. Controls received standard diet without any supplementation as non-treated control. All animals were killed at the end of week 28, and the major organs were carefully examined for preneoplastic and neoplastic lesions. No DAG oil treatment-related changes were noted in survival, general conditions, body weights, food consumption and organ weights. Upon quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci of the liver, DAG oil was not found to exert any effects. The incidence of colon adenomas was significantly increased in rats given 1.375% DAG oil, but not 2.75% and 5.5% DAG oil, when compared to the control (5.5% TG group) value. Furthermore, incidences and multiplicity of hyperplasias and adenomas and/or adenocarcinomas were comparable across all DAG oil-treated groups. In contrast, incidences of colon adenomas and/or adenocarcinomas were significantly increased in rats given 5.5% HOTG, and adenomas with MCTG, but not 5.5% HLTG, as compared to the 5.5% TG value. Preneoplastic and neoplastic lesions induced by DMBDD treatment in various organs other than the large intestine were comparable in all cases. Thus, the current results indicate that DAG oil may not exert modifying potential on tumor development, even in the colon because of the lack of dose-dependence. DAG oil was equivalent to HOTG (standard cocking oil composed of naturally occurring fatty acids), with regard to colon tumor development. Further dose-response study concerning HOTG may be needed to confirm whether the enhancing effect of large intestine carcinogenesis exert or not.
Assuntos
Testes de Carcinogenicidade , Carcinógenos/toxicidade , Diglicerídeos/toxicidade , Neoplasias/induzido quimicamente , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Dieta , Ingestão de Líquidos/efeitos dos fármacos , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Glutationa Transferase/metabolismo , Masculino , Neoplasias/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Análise de Sobrevida , Triglicerídeos/análiseRESUMO
The objective of the present study was to compare the effects of dietary diacylglycerol (DAG) oil with triacylglycerol (TAG) oil with a similar fatty acid composition (fatty acid chain range: C14-C22, C18 fatty acid chain: >90%) on protein kinase C (PKC) activation and on 1,2-DAG levels. Using male Wistar rats, no differences in cytosolic and membrane PKC activities in the lingual, esophageal, gastric, small intestinal, cecal, proximal colonic, and distal colonic mucosa were found between the 5% DAG and TAG oil groups, or between the 23% DAG and TAG oil groups after 1 month of feeding. The 1,2-DAG levels in the cecum and colon contents and in the feces and serum in male Wistar rats after a diet containing either 10% DAG or TAG oil feeding were similar between the groups. Moreover, exposure of Caco-2 cells to DAG and TAG oils had no effect on PKC activity in the membrane fraction, but 1,2-dioctanoyl glycerol composed of short-chain fatty acids (C8) did, suggesting the absence of an influence on PKC activity in DAG and TAG oils composed of long-chain fatty acids. In summary, the effects of DAG oil ingestion on PKC activity in the digestive tract and lingual mucosa, and on 1,2-DAG levels in the cecum and colon contents and in the feces and serum were similar to those observed for TAG oil ingestion.
Assuntos
Gorduras na Dieta/administração & dosagem , Diglicerídeos/administração & dosagem , Trato Gastrointestinal/efeitos dos fármacos , Proteína Quinase C/metabolismo , Triglicerídeos/administração & dosagem , Animais , Células CACO-2/efeitos dos fármacos , Células CACO-2/enzimologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Citosol/efeitos dos fármacos , Citosol/enzimologia , Diglicerídeos/sangue , Diglicerídeos/toxicidade , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Fezes/química , Trato Gastrointestinal/enzimologia , Humanos , Masculino , Ratos , Ratos WistarRESUMO
This study evaluated the possible carcinogenic effects of DAG (diacylglycerol) oil when given in the diet at levels up to 6.0% for 24 months to mice. Dietary fat was provided by DAG and/or the control article, TG (triacylglycerol oil). Dietary concentrations (% DAG/% TG) were 0%/6.0% (TG control), 1.5%/4.5%, 3.0%/3.0%, and 6.0%/0%. An additional control group received the standard rodent diet (fat content 4.5%). The clinical condition of the animals, ophthalmic findings, palpable mass occurrence, body weights and gross and histopathologic findings were unaffected by DAG in comparison to TG. The findings in DAG-treated groups were no different than those observed in the TG control group. The standard basal diet had 4.5% fat content. Both TG and/or DAG, when presented separately or together in the diet at a total fat level of 6.0%, resulted in some differences relative to the basal diet control (lower survival, higher body weights, lower food consumption, and higher incidences of macroscopic and microscopic findings), presumably related to the higher dietary fat content and/or the semi-purified diet. However, these parameters were similar in groups fed a diet with 6.0% dietary fat that was either DAG or TG. Thus, DAG at dietary concentrations up to 6.0% for 24 months produced no signs of systemic toxicity and had no effect on the incidence of neoplastic findings.
Assuntos
Testes de Carcinogenicidade , Carcinógenos/toxicidade , Diglicerídeos/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Carcinógenos/classificação , Dieta , Diglicerídeos/química , Diglicerídeos/classificação , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/análise , Feminino , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Triglicerídeos/química , Triglicerídeos/classificação , Triglicerídeos/toxicidadeRESUMO
The potential chronic toxic effects of DAG (diacylglycerol) when administered orally for 12 months were evaluated in this dietary study in Beagle dogs. DAG is a cooking oil which contains >80% diglycerides, <20% triglycerides and 5% monoglycerides. For this study, a special diet was prepared with no dietary fat so that all of the dietary fat could be provided by DAG, at various concentrations together with a control oil. The control oil, TG (triacylglycerol), was prepared to contain >85% triglycerides, <10% diglycerides and 5% monoglycerides. The fatty acid composition for DAG and TG was closely matched. Dietary concentrations of 0% DAG/9.5% TG (TG control), 1.5% DAG/8.0% TG, 5.5% DAG/4.0% TG, and 9.5% DAG/0% TG were presented daily, seven days per week, for 52 weeks. A second concurrent control group received the standard basal diet (Certified Canine LabDiet 5007, which has a fat content of 9.5%). The basal diet, control article-treated and DAG-treated groups each consisted of four male and four female dogs. Treatment was initiated in prejuvenile (2.5-month-old) dogs. Statistical evaluations compared the DAG-treated groups both to the basal diet and 9.5% TG control groups. The clinical condition of the animals, body weights, body weight gains and food consumption were unaffected by DAG. Hematology and urinalysis parameters were unaffected. No serum chemistry changes indicative of a toxic effect were observed. There were no effects noted on ECG data. No test article-related gross or histopathologic findings or changes in organ weights were observed. While there were no identifiable differences between the effects of TG and DAG, both caused some differences relative to the basal diet (lower food consumption, higher alkaline phosphatase, cholesterol and triglycerides). These differences were not toxicologically significant and were attributed to the differences in the diet rather than the fat source. Thus, DAG at dietary concentrations up to 9.5% for one year had no effect on normal canine growth and development, in comparison to TG.
Assuntos
Diglicerídeos/toxicidade , Testes de Toxicidade Crônica , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Testes de Química Clínica , Dieta , Diglicerídeos/química , Diglicerídeos/classificação , Cães , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/análise , Feminino , Alimentos Formulados/análise , Testes Hematológicos , Masculino , Triglicerídeos/química , Triglicerídeos/toxicidadeRESUMO
Toxicologic and carcinogenic effects of DAG (diacylglycerol) oil, administered in diet for 24 months to Crl:CD((R))(SD)-IGS BR rats, were evaluated using diet-restricted and ad libitum-fed groups. All dietary fat (consistently 5.5%) was provided by DAG and/or the control article, TG (triacylglycerol) oil. Dietary concentrations (% DAG/% TG) were 0%/5.5%, 1%/4.5%, 2.75%/2.75% and 5.5%/0%. Separate groups were fed the 0%/5.5% and 5.5%/0% diets ad libitum. Another group received the standard rodent diet (fat content 4.5%) on the restricted feeding regimen. Clinical condition, ophthalmic findings, palpable mass occurrence, body composition, clinical pathology parameters and incidence of neoplastic lesions were unaffected by DAG in comparison to TG. Groups fed the 5.5% (DAG and/or TG) fat diet when compared to the 4.5% fat diet group displayed lower survival, higher body weights, organ weights, percent body fat, higher fat-related serum chemistry parameters, incidence of microscopic changes in the heart, kidneys, liver, bone marrow, spleen, and incidences of pituitary and mammary gland neoplasms. Parameters more affected in all the ad libitum groups than in the restricted diet groups (regardless of test article) fed the same diet included survival, body weights, body fat, fat-related serum chemistry parameters, and incidences of heart, kidney and liver microscopic changes. However, the DAG and TG ad libitum-fed groups were not different from one another. Thus, DAG-treated animals had no higher risk of carcinogenic effects than rats fed on similar feeding regimens with a diet in which all dietary fat came from TG.
Assuntos
Testes de Carcinogenicidade , Carcinógenos/toxicidade , Diglicerídeos/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Carcinógenos/classificação , Dieta , Diglicerídeos/química , Diglicerídeos/classificação , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/análise , Feminino , Privação de Alimentos , Longevidade/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Triglicerídeos/química , Triglicerídeos/classificação , Triglicerídeos/toxicidadeRESUMO
Obesity is at the forefront of global health issues and directly contributes to many chronic illnesses. Several dietary components show promise in the treatment of obesity, one of which is oil rich in diacylglycerols (DAGs). Present objectives are to examine scientific knowledge concerning DAG to assess evidence supporting the effects on substrate oxidation rates, body weight and fat mass, and blood lipids, and to assess safety, as well as elucidate potential mechanisms of action. DAG can be synthesized by an enzymatic process to produce mainly 1,3-isoform DAG. This 1,3-DAG oil is believed to have the ability to increase beta-oxidation, to enhance body weight loss, to suppress body fat accumulation, and to lower serum triacylglycerol levels postprandially. While certain animal and human studies indicate that consumption of 1,3-DAG has positive physiological effects, others report no effect. The mechanisms of action of DAG are suggested to decrease the resynthesis of chylomicrons as well as shunting them directly to the liver through the portal vein, where they are oxidized. This increased fat oxidation may influence control of food intake by increasing satiety. Further study into the precise mechanism is required to understand its effects. Safety studies show no risks in consuming a diet rich in DAG oil. Overall, consumption of oils with higher amounts of DAG, specifically 1,3-DAG, may be useful in the battle against obesity.
Assuntos
Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Diglicerídeos/farmacologia , Diglicerídeos/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/toxicidade , Composição Corporal/efeitos dos fármacos , Gorduras Insaturadas na Dieta/efeitos adversos , Gorduras Insaturadas na Dieta/farmacologia , Gorduras Insaturadas na Dieta/uso terapêutico , Gorduras Insaturadas na Dieta/toxicidade , Diglicerídeos/efeitos adversos , Diglicerídeos/toxicidade , Feminino , Humanos , Lipídeos/sangue , Masculino , Obesidade/sangue , Obesidade/fisiopatologia , Oxirredução , Resultado do TratamentoRESUMO
Dietary diacylglycerol (DAG) oil is an edible oil enriched in DAG (more than 80%). A recent investigation indicated that DAG oil or its components may have beneficial effects on the prevention and management of obesity. We evaluated the genotoxic potential of DAG oil using standard genotoxicity tests. Bacterial reverse mutation assay (Ames test), the chromosomal aberration assay in cultured Chinese hamster lung cells (CHL/IU), and a bone marrow micronucleus assay in ICR CD mice were employed in the present study. In addition we have tested the possibility that genotoxic substances may be formed during cooking, heated DAG oil (HDG) was prepared by batch frying potato slices in the oil at 180 degrees C for 8 h/day for three consecutive days. Therefore, genotoxicity tests were also performed on HDG. Results obtained did not show any genotoxic effect on either unheated DAG oil (UDG) or HDG. We conclude that there are no safety concerns on the genotoxicity of DAG oil under the conditions for normal use.
Assuntos
Aberrações Cromossômicas/efeitos dos fármacos , Culinária/métodos , Gorduras na Dieta/toxicidade , Diglicerídeos/administração & dosagem , Diglicerídeos/toxicidade , Testes de Mutagenicidade/métodos , Animais , Medula Óssea/efeitos dos fármacos , Cricetinae , Cricetulus , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Temperatura Alta , Pulmão/citologia , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Microssomos Hepáticos/efeitos dos fármacos , Obesidade/dietoterapia , Segurança , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genéticaRESUMO
Three series of pyridinium cationic lipids useful as nonviral gene delivery agents were prepared by reaction of pyrylium salts with aminodiols, followed by acylation with fatty acyl chlorides. On the basis of this set of compounds, we undertook a comprehensive structure-activity relationship study at the level of the linker, hydrophobic anchor, and counterion in order to identify the structural elements that generate the highest transfection efficiency for this new type of cationic lipid. The results revealed that when formulated with cholesterol at a 1:1 molar ratio, the 1-(1,3-dimyristoyloxyprop-2-yl)-2,4,6-trimethylpyridinium, under the form of hexafluorophosphate (5AMyr) or chloride (5DMyr), was able to transfect NCI-H23 lung carcinoma with efficiencies surpassing classic DOTAP-based formulations and with lower cytotoxicity. Subsequent tests on other malignancies yielded similarly promising results.
Assuntos
Diglicerídeos/síntese química , Portadores de Fármacos/síntese química , Técnicas de Transferência de Genes , Lipídeos/síntese química , Compostos de Piridínio/síntese química , Cátions , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , DNA/administração & dosagem , DNA/química , Diglicerídeos/química , Diglicerídeos/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Humanos , Lipídeos/química , Lipossomos , Estrutura Molecular , Compostos de Piridínio/química , Compostos de Piridínio/toxicidade , Relação Estrutura-Atividade , Transfecção , UltrassomRESUMO
The lipopeptide FSL-1 [S-(2,3-bispalmitoyloxypropyl)-Cys-Gly-Asp-Pro-Lys-His-Pro-Lys-Ser-Phe, Pam(2)CGDPKHPKSF] synthesized on the basis of the N-terminal structure of a Mycoplasma salivarium lipoprotein capable of activating normal human gingival fibroblasts to induce the cell surface expression of ICAM-1 revealed an activity to induce production of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-8. FSL-1 also activated macrophages to produce tumor necrosis factor alpha as the Mycoplasma fermentans-derived lipopeptide MALP-2 (Pam(2)CGNNDESNISFKEK), a potent macrophage-activating lipopeptide, did. The level of the activity of FSL-1 was higher than that of MALP-2. This result suggests that the difference in the amino acid sequence of the peptide portion affects the activity because the framework structure other than the amino acid sequence of the former is the same as that of the latter. To determine minimal structural requirements for the activity of FSL-1, the diacylglyceryl Cys and the peptide portions were examined for this activity. Both portions did not reveal the activity. A single amino acid substitution from Phe to Arg and a fatty acid substitution from palmitic acid to stearic acid drastically reduced the activity. Similar results were obtained in measuring the NF-kappaB reporter activity of FSL-1 to human embryonic kidney 293 cells transfected with Toll-like receptor 2 and 6, together with a NF-kappaB-dependent luciferase reporter plasmid. These results suggest that both the diacylglyceryl and the peptide portions of FSL-1 are indispensable for the expression of biological activities and for the recognition by Toll-like receptors 2 and 6 and that the recognition of FSL-1 by Toll-like receptors 2 and 6 appears to be hydrophobic.
Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Diglicerídeos/química , Diglicerídeos/imunologia , Glicoproteínas de Membrana/metabolismo , Mycoplasma salivarium/imunologia , Oligopeptídeos/química , Oligopeptídeos/imunologia , Receptores de Superfície Celular/metabolismo , Acilação , Sequência de Aminoácidos , Substituição de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/toxicidade , Linhagem Celular , Diglicerídeos/genética , Diglicerídeos/toxicidade , Fibroblastos/imunologia , Gengiva/imunologia , Humanos , Lipopeptídeos , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Estrutura Molecular , Monócitos/imunologia , Mycoplasma fermentans/genética , Mycoplasma fermentans/imunologia , Mycoplasma fermentans/patogenicidade , Mycoplasma salivarium/genética , Mycoplasma salivarium/patogenicidade , Oligopeptídeos/genética , Oligopeptídeos/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Receptor 2 Toll-Like , Receptor 6 Toll-Like , Receptores Toll-LikeRESUMO
The objective of the present study was to evaluate the effects of diacylglycerol oil following long-term administration to rats. Diacylglycerol oil is an edible oil with comparable taste and physicochemical properties of several naturally occurring oils. Diacylglycerol oil can be used as a replacement for any generally used edible oil in the home and has been approved for use in cooking oil in Japan. Male and female Sprague-Dawley rats were divided into four groups and fed low-fat (1.7%) basal diets containing an edible oil composed of rapeseed, corn, high linoleic safflower and high oleic safflower oils at 5.3% (control group 1); an edible oil composed of rapeseed and soybean oils at 5.3% (control group 2); diacylglycerol oil at 2.65% plus edible oil composed of rapeseed, corn, high linoleic safflower and high oleic safflower oils at 2.65% (low-dose group); and diacylglycerol oil at 5.3% (high-dose group) for 2 years. Interim sacrifices were conducted at weeks 30 and 77 and the study was terminated following 105 weeks of feeding. No compound-related effects were noted on clinical signs, body weights, food consumption, cumulative survival rates, hematology, blood chemistry, urinalysis, organ weights or on microscopic non-neoplastic changes. Compared to control group 2, but not control group 1, there was a significant increase in the number of high-dose group females with either benign or malignant epithelial mammary gland neoplasms. These changes were not considered biologically significant, because the tumor incidence was not similar in control group 1 and 2, and the neoplastic findings were not dose related. In summary, the two-year chronic rat study revealed no toxicologically significant or treatment-related effects of diacylglycerol oil consumption at levels of up to 5.3% in the diet.