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1.
Life Sci ; 254: 117786, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32433918

RESUMO

AIMS: Ovarian cancer (OC) is the most lethal gynecological malignancies and many women develop chemoresistance associated with the inflammatory process. We investigated the effects of P-MAPA and IL-12 on the inflammatory and immune responses in a chemically-induced OC model. MAIN METHODS: OCs were induced with 7,12-dimethylbenz(a)anthracene into the ovarian bursa, and the animals were given P-MAPA (5 mg/kg bw., i.p., twice a week), or IL-12 (300 ng/kg bw., i.p., one a week) for 60 days, or both P-MAPA and IL-12. Immunohistochemistry, western blot, flow cytometry, and multiplex assay were used to examine the effectiveness of immunotherapies in OC. KEY FINDINGS: The combinatory therapy improved the general OC features, reducing inflammatory cells and adipocyte accumulation, in addition to revealing a soft and mobile tissue with no adherences and peritoneal implants. P-MAPA treatment increased the levels of TLR2, TLR4 and TRIF in OCs while decreasing the number of regulatory T (Treg) cells. Additionally, the association of P-MAPA with IL-12 significantly increased the number of CD4+ and CD8+ T effector cells in draining lymph nodes. Regarding the inflammatory mediators, P-MAPA enhanced the levels of the pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased the levels of IL-1ß. Treatment with IL-12 enhanced the cytokine levels of IL-17, TNF-α, IL-1ß, and IL-2 in addition to the chemokine MIP-1α. SIGNIFICANCE: We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Also, the combination of P-MAPA with IL-12 improves the antitumor immunoresponse, opening a new therapeutic approach for fighting OC.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Interleucina-12/farmacologia , Ácidos Linoleicos/farmacologia , Ácidos Oleicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adipócitos/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL3/metabolismo , Citocinas/metabolismo , Sinergismo Farmacológico , Feminino , Inflamação/tratamento farmacológico , Interleucina-12/uso terapêutico , Ácidos Linoleicos/uso terapêutico , Ácidos Oleicos/uso terapêutico , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/metabolismo , Ratos , Linfócitos T Reguladores/efeitos dos fármacos
2.
Food Chem ; 322: 126736, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32325363

RESUMO

Fundamental nutritional studies on bioactive molecules require minimizing exposure to confounding foreign elements, like solvents. Herein, aqueous formulations of lecithin nanovesicles are proposed to study three individual trans fatty acids relevant to human nutrition: elaidic acid, trans-vaccenic acid and trans-palmitoleic acid. This proof-of-concept study describes the encapsulation of fatty acids, in vivo bioavailability, and the use of nanovesicles in behavioral experiments. The oral bioavailability of the encapsulated molecules and the selective exposure of animals to each trans-fatty acid of interest were confirmed in healthy rats. Behavioral studies also evidenced that nanovesicles can be used to evaluate the palatability of the lipids and investigate food preferences in mice. Altogether this study shows that lecithin nanovesicles offer an elegant tool to efficiently deliver hydrophobic molecules to animal models. This approach paves the way for future studies deconvoluting the nutritional effects of trans-fatty acids.


Assuntos
Lecitinas/química , Nanoestruturas/química , Nutrientes/química , Administração Oral , Animais , Disponibilidade Biológica , Dieta/veterinária , Ácidos Graxos/sangue , Ácidos Graxos/química , Feminino , Preferências Alimentares/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lecitinas/farmacocinética , Lecitinas/farmacologia , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Ratos , Ácidos Graxos Trans/análise , Ácidos Graxos Trans/química , Ácidos Graxos Trans/farmacologia
3.
Arch Med Res ; 51(5): 464-467, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32327293

RESUMO

The current outbreak of COVID-19 (coronavirus) has been identified by World Health Organization (WHO) as a global pandemic. With the emergence of the COVID-19 virus and considering the lack of effective pharmaceutical treatment for it, there is an urgent need to identify safe and effective drugs or potential adjuvant therapy in this regard. Bioactive lipids with an array of known health-promoting properties can be suggested as effective agents in alleviating acute respiratory stress induced by virus. The bioactive lipid amide, oleoylethanolamide (OEA), due to several distinctive homeostatic properties, including anti-inflammatory activities, modulation of immune response, and anti-oxidant effects can be considered as a novel potential pharmacological alternative for the management of COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Ácidos Oleicos/farmacologia , Ácidos Oleicos/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia
4.
PLoS One ; 15(3): e0230780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214349

RESUMO

Calprotectin is a heterodimeric protein complex with two subunits called S100A8/A9. The protein has an essential role in inflammation process and various human diseases. It has the ability to bind to unsaturated fatty acids including Arachidonic acid, Oleic acid and etc., which could be considered as a major carrier for fatty acids. In this study we aimed to appraise the thermodynamics and structural changes of Calprotectin in presence of Arachidonic acid/Oleic acid) using docking and molecular dynami simulation method. To create the best conformation of Calprotectin-Oleic acid/Arachidonic acid complexes, the docking process was performed. The complexes with the best binding energy were selected as the models for molecular dynamics simulation process. Furthermore, the structural and thermodynamics properties of the complexes were evaluated too. The Root Mean Square Deviation and Root Mean Square Fluctuation results showed that the binding of Arachidonic acid/Oleic acid to Calprotectin can cause the protein structural changes which was confirmed by Define Secondary Structure of Proteins results. Accordingly, the binding free energy results verified that binding of Oleic acid to Calprotectin leads to instability of S100A8/A9 subunits in the protein. Moreover, the electrostatic energy contribution of the complexes (Calprotectin-Oleic acid/Arachidonic acid) was remarkably higher than van der Waals energy. Thus, the outcome of this study confirm that Oleic acid has a stronger interaction with Calprotectin in comparison with Arachidonic acid. Our findings indicated that binding of unsaturated fatty acids to Calprotectin leads to structural changes of the S100A8/A9 subunits which could be beneficial to play a biological role in inflammation process.


Assuntos
Ácido Araquidônico/farmacologia , Complexo Antígeno L1 Leucocitário/química , Complexo Antígeno L1 Leucocitário/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácidos Oleicos/farmacologia , Ácido Araquidônico/metabolismo , Ligação de Hidrogênio , Ácidos Oleicos/metabolismo , Conformação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos
5.
J Pharmacol Exp Ther ; 373(1): 81-91, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32024803

RESUMO

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor α (PPARα) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPARα-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPARα was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor α-independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Endocanabinoides/farmacologia , Gluconeogênese/fisiologia , Glicogênio/biossíntese , Fígado/metabolismo , Ácidos Oleicos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endocanabinoides/uso terapêutico , Gluconeogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Ácidos Oleicos/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Sci Rep ; 10(1): 1463, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996706

RESUMO

Microbes develop several strategies to survive in the adverse condition such as biofilm formation, attaining non-dividing state, altering drug target or drug, thereby increases the burden of drug dosage. To combat these issues, nanoparticles have shown an alternative approach for new treatment strategy but synthesis via chemical synthetic route limits their application in biomedical field. Here, green method for the synthesis of gold nanoparticles using sophorolipid (SL) is discussed that is characterized by various techniques. Initially, the antimicrobial activity was checked against metabolically active state of microbes; Gram-positive Staphylococcus aureus and Gram-negative Vibrio cholerae using XTT assay and growth kinetics assay. Results suggested higher efficacy of nanoparticles for Gram-negative, therefore further analyzed against Escherichia coli that confirmed its potency for the same. AuNPs-SL also signifies its efficiency at least metabolically active state; non dividing cells and biofilm of these microbes. Induced morphological changes were studied by SEM that revealed AuNPs-SL led to disruption of cell membrane and leakage of intracellular fluid to the surroundings. Inhibition of respiratory enzymes activity also plays a crucial role in bactericidal action as indicated by LDH assay. Synergy of AuNPs-SL with different antibiotics was also analyzed using checkerboard assay. These results suggested the possible use of AuNPs-SL as an antimicrobial therapy in the field of nanomedicine.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/crescimento & desenvolvimento , Membrana Celular/patologia , Cólera/tratamento farmacológico , Química Verde/métodos , Ácidos Oleicos/farmacologia , Vibrio cholerae/fisiologia , Processos de Crescimento Celular , Ouro , Nanopartículas Metálicas
7.
J Appl Microbiol ; 128(6): 1754-1763, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31995843

RESUMO

AIMS: The objective of this study was to determine the effects of sophorolipids on several fungal and oomycete plant pathogens and the relationship between sophorolipids at different pH and antimicrobial activities. METHODS AND RESULTS: Sophorolipids had different solubility at different pH with a dramatic increase in solubility when pH was 6 or higher. Inhibition of mycelial growth of Phytophthora infestans by sophorolipids was affected by pH values, showing that when the pH value was higher, the inhibition rate was lower. Sophorolipids inhibited spore germination and mycelial growth of several fungal and oomycete pathogens in vitro including Fusarium sp., F. oxysporum, F. concentricum, Pythium ultimum, Pyricularia oryzae, Rhizoctorzia solani, Alternaria kikuchiana, Gaeumannomyces graminis var. tritici and P. infestans and caused morphological changes in hyphae by microscope observation. Sophorolipids reduced ß-1,3-glucanase activity in mycelia of P. infestans. In greenhouse studies, foliar application of sophorolipids at 3 mg ml-1 reduced severity of late blight of potato caused by P. infestans significantly. CONCLUSION: Sophorolipids influenced spore germination and hyphal tip growth of several plant pathogens and pH solubility of sophorolipids had an effect on their efficacy. Application of sophorolipids reduced late blight disease on potato under greenhouse conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings indicated that sophorolipids have the potential to be developed as a convenient and easy-to-use formulation for managing plant diseases.


Assuntos
Fungos/efeitos dos fármacos , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Oomicetos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Concentração de Íons de Hidrogênio , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Oomicetos/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Solanum tuberosum/microbiologia , Solanum tuberosum/parasitologia , Solubilidade , Esporos/efeitos dos fármacos , Esporos/crescimento & desenvolvimento
8.
Am J Physiol Renal Physiol ; 318(2): F457-F467, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760768

RESUMO

As an electrophilic nitroalkene fatty acid, nitro-oleic acid (OA-NO2) exerts multiple biological effects that contribute to anti-inflammation, anti-oxidative stress, and antiapoptosis. However, little is known about the role of OA-NO2 in peritoneal fibrosis. Thus, in the present study, we examined the effects of OA-NO2 on the high glucose (HG)-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs) and evaluated the morphological and immunohistochemical changes in a rat model of peritoneal dialysis-related peritoneal fibrosis. In in vitro experiments, we found that HG reduced the expression level of E-cadherin and increased Snail, N-cadherin, and α-smooth muscle actin expression levels in HPMCs. The above-mentioned changes were attenuated by pretreatment with OA-NO2. Additionally, OA-NO2 also inhibited HG-induced activation of the transforming growth factor-ß1/Smad signaling pathway and NF-κB signaling pathway. Meanwhile, OA-NO2 inhibited HG-induced phosphorylation of Erk and JNK. The results from the in vivo experiments showed that OA-NO2 notably relieved peritoneal fibrosis by decreasing the thickness of the peritoneum; it also inhibited expression of transforming growth factor-ß1, α-smooth muscle actin, N-cadherin, and vimentin and enhanced expression of E-cadherin in the peritoneum. Collectively, these results suggest that OA-NO2 inhibits the HG-induced epithelial-mesenchymal transition in HPMCs and attenuates peritoneal dialysis-related peritoneal fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose , Ácidos Oleicos/farmacologia , Diálise Peritoneal , Fibrose Peritoneal/prevenção & controle , Peritônio/efeitos dos fármacos , Actinas/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Peritônio/metabolismo , Peritônio/patologia , Ratos Wistar , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Vimentina/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-31678516

RESUMO

SR-B1 belongs to the class B scavenger receptor, or CD36 super family. SR-B1 and CD36 share an affinity for a wide array of ligands. Although they exhibit similar ligand binding specificity, SR-B1 and CD36 have some very specific lipid transport functions. Whereas SR-B1 primarily facilitates the selective delivery of cholesteryl esters (CEs) and cholesterol from HDL particles to the liver and non-placental steroidogenic tissues, as well as participating in cholesterol efflux from cells, CD36 primarily mediates the uptake of long-chain fatty acids in high fatty acid-requiring organs such as the heart, skeletal muscle and adipose tissue. However, CD36 also mediates cholesterol efflux and facilitates selective lipoprotein-CE delivery, although less efficiently than SR-B1. Interestingly, the ability or efficiency of SR-B1 to mediate fatty acid uptake has not been reported. In this paper, using overexpression and siRNA-mediated knockdown of SR-B1, we show that SR-B1 possesses the ability to facilitate fatty acid uptake. Moreover, this function is not blocked by BLT-1, a specific chemical inhibitor of HDL-CE uptake activity of SR-B1, nor by sulfo-N-succinimidyl oleate, which inhibits fatty acid uptake by CD36. Attenuated fatty acid uptake was also observed in primary adipocytes isolated from SR-B1 knockout mice. In conclusion, facilitation of fatty acid uptake is an additional function that is mediated by SR-B1.


Assuntos
Adipócitos/metabolismo , Ácidos Graxos/metabolismo , Receptores Depuradores Classe B/metabolismo , Adipócitos/efeitos dos fármacos , Animais , Antígenos CD36/antagonistas & inibidores , Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Cultivadas , Ésteres do Colesterol/metabolismo , HDL-Colesterol/metabolismo , Ciclopentanos/farmacologia , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Ácidos Oleicos/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Receptores Depuradores Classe B/antagonistas & inibidores , Receptores Depuradores Classe B/genética , Succinimidas/farmacologia , Tiossemicarbazonas/farmacologia
10.
J Biotechnol ; 309: 34-43, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31887325

RESUMO

Recent medical strategies rely on the search for effective antimicrobials as surface coatings to prevent and treat infections in humans and animals. Biosurfactants have recently been shown to have properties as antiadhesive and antibiofilm agents. Sophorolipids in particular are biosurfactant molecules known to act as therapeutic agents. This study aimed to evaluate antimicrobial properties of sophorolipids in medical-grade silicone discs using strains of clinical relevance. Sophorolipids were produced under fed batch conditions, ESI-MS analyses were carried out to confirm the congeners present in each formulation. Three different products were obtained SLA (acidic congeners), SL18 (lactonic congeners) and SLV (mixture of acidic and lactonic congeners) and were tested against Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 10145 and Candida albicans IHEM 2894. All three congener mixtures showed a biofilms disruption effect (> 0.1 % w/v) of 70 %, 75 % and 80 % for S. aureus, P. aeruginosa and C. albicans, respectively. On pre-coated silicone discs, biofilm formation of S. aureus was reduced by 75 % using SLA 0.8 % w/v. After 1.5 h the inhibition of C. albicans attachment was between 45-56 % whilst after 24 h incubation the percentage of inhibition for the cell attachment increased to 68-70 % when using SLA 0.8 % w/v. Finally, in co-incubation experiments SLA 0.05 % w/v significantly reduced the ability of S. aureus and C. albicans to form biofilms and to adhere to surfaces by 90-95 % at concentrations between 0.025-0.1 % w/v. In conclusion sophorolipids significantly reduced the cell attachment of both tested strains which suggests that these molecules could have a potential role as coating agents on medical grade silicone devices for the preventions of Gram positive bacteria and yeast infections.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Silicones/química , Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Candida glabrata/metabolismo , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Fermentação , Humanos , Ácidos Oleicos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
11.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G373-G386, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373507

RESUMO

Although steatosis (fatty liver) is a clinically well-described early stage of alcoholic liver disease, surprisingly little is known about how it promotes hepatotoxicity. We have shown that ethanol consumption leads to microtubule hyperacetylation that can explain ethanol-induced defects in protein trafficking. Because almost all steps of the lipid droplet life cycle are microtubule dependent and because microtubule acetylation promotes adipogenesis, we examined droplet dynamics in ethanol-treated cells. In WIF-B cells treated with ethanol and/or oleic acid (a fatty acid associated with the "Western" diet), we found that ethanol dramatically increased lipid droplet numbers and led to the formation of large, peripherally located droplets. Enhanced droplet formation required alcohol dehydrogenase-mediated ethanol metabolism, and peripheral droplet distributions required intact microtubules. We also determined that ethanol-induced microtubule acetylation led to impaired droplet degradation. Live-cell imaging revealed that droplet motility was microtubule dependent and that droplets were virtually stationary in ethanol-treated cells. To determine more directly whether microtubule hyperacetylation could explain impaired droplet motility, we overexpressed the tubulin-specific acetyltransferase αTAT1 to promote microtubule acetylation in the absence of alcohol. Droplet motility was impaired in αTAT1-expressing cells but to a lesser extent than in ethanol-treated cells. However, in both cases, the large immotile droplets (but not small motile ones) colocalized with dynein and dynactin (but not kinesin), implying that altered droplet-motor microtubule interactions may explain altered dynamics. These studies further suggest that modulating cellular acetylation is a potential strategy for treating alcoholic liver disease.NEW & NOTEWORTHY Chronic alcohol consumption with the "Western diet" enhances the development of fatty liver and leads to impaired droplet motility, which may have serious deletrious effects on hepatocyte function.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Acetilação , Acetiltransferases/metabolismo , Álcool Desidrogenase/metabolismo , Linhagem Celular , Complexo Dinactina/metabolismo , Dineínas/metabolismo , Humanos , Proteínas dos Microtúbulos/metabolismo , Ácidos Oleicos/farmacologia
12.
Int J Med Sci ; 16(7): 909-921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341404

RESUMO

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing worldwide. Several effective drugs for these diseases are now in development and under clinical trials. It is important to reveal the mechanism of the development of NAFLD and NASH. We investigated the role of arrestin domain-containing protein 3 (ARRDC3), which is linked to obesity in men and regulates body mass, adiposity and energy expenditure, in the progression of NAFLD and NASH. We performed knockdown of endogenous ARRDC3 in human hepatocytes and examined the inflammasome-associated gene expression by real-time PCR-based array. We also examined the effect of conditioned medium from endogenous ARRDC3-knockdown-hepatocytes on the apoptosis of hepatic stellate cells. We observed that free acids enhanced the expression of ARRDC3 in hepatocytes. Knockdown of ARRDC3 could lead to the inhibition of inflammasome-associated gene expression in hepatocytes. We also observed that conditioned medium from endogenous ARRDC3-knockdown-hepatocytes enhances the apoptosis of hepatic stellate cells. ARRDC3 has a role in the progression of NAFLD and NASH and is one of the targets for the development of the effective treatment of NAFLD and NASH.


Assuntos
Arrestinas/metabolismo , Inflamassomos/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Apoptose/efeitos dos fármacos , Arrestinas/genética , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Progressão da Doença , Regulação para Baixo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hepatócitos , Humanos , Fígado/citologia , Ácidos Oleicos/farmacologia , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
J Agric Food Chem ; 67(29): 8191-8196, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31282662

RESUMO

Conversion of free fatty acids into monoacylglycerol gives rise to new structural properties, particularly amphipathic property. Therefore, monoacylglycerols are widely used in pharmaceutical and food industries and are also reported to facilitate better absorption into the human body. A functional fatty acid when transformed into a monoacylglycerol will possibly conserve both the original functionality and amphipathic property. The compound 7,10-dihydroxy-8(E)-octadecenoic acid (DOD) was generated from oleic acid by Pseudomonas aeruginosa PR3 and was known to contain antimicrobial activities against a broad range of food-borne and plant pathogenic bacteria. Here, we attempted to convert DOD into its monoacylglycerol form using lipase for producing an amphipathic antibacterial agent. Consequently, the monoacylglycerol of DOD (DOD-MAG) was successfully produced by coincubating DOD, glycerol, and lipase at 30 °C. The maximum conversion yield reached 70% after 12 h of incubation. Antibacterial activity of DOD-MAG was enhanced by 8 times from the original activity of DOD against food-borne bacteria.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Monoglicerídeos/química , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Pseudomonas aeruginosa/química , Antibacterianos/metabolismo , Microbiologia de Alimentos , Ácidos Oleicos/metabolismo , Pseudomonas aeruginosa/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
14.
PLoS Pathog ; 15(6): e1007893, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31206555

RESUMO

Fatty acids affect a number of physiological processes, in addition to forming the building blocks of membranes and body fat stores. In this study, we uncover a role for the monounsaturated fatty acid oleate in the innate immune response of the nematode Caenorhabditis elegans. From an RNAi screen for regulators of innate immune defense genes, we identified the two stearoyl-coenzyme A desaturases that synthesize oleate in C. elegans. We show that the synthesis of oleate is necessary for the pathogen-mediated induction of immune defense genes. Accordingly, C. elegans deficient in oleate production are hypersusceptible to infection with diverse human pathogens, which can be rescued by the addition of exogenous oleate. However, oleate is not sufficient to drive protective immune activation. Together, these data add to the known health-promoting effects of monounsaturated fatty acids, and suggest an ancient link between nutrient stores, metabolism, and host susceptibility to bacterial infection.


Assuntos
Infecções Bacterianas/imunologia , Caenorhabditis elegans/imunologia , Imunidade Inata/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Animais , Ácidos Oleicos/imunologia
15.
Obes Rev ; 20(7): 1057-1069, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31111657

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Recently, some novel compounds have been investigated for the prevention and treatment of NAFLD. Oleoylethanolamide (OEA), an endogenous PPAR-α agonist, has exhibited a plethora of pharmacological properties for the treatment of obesity and other obesity-associated metabolic complications. This systematic review was performed with a focus on the effects of OEA on the risk factors for NAFLD. PubMed, Scopus, Embase, ProQuest, and Google Scholar databases were searched up to December 2018 using relevant keywords. All articles written in English evaluating the effects of OEA on the risk factors for NAFLD were eligible for the review. The evidence reviewed in this article illustrates that OEA regulates multiple biological processes associated with NAFLD, including lipid metabolism, inflammation, oxidative stress, and energy homeostasis through different mechanisms. In summary, many beneficial effects of OEA have led to the understanding that OEA may be an effective therapeutic strategy for the management of NAFLD. Although a wide range of studies have demonstrated the most useful effects of OEA on NAFLD and the associated risk factors, further clinical trials, from both in vivo studies and in vitro experiments, are warranted to verify these outcomes.


Assuntos
Endocanabinoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácidos Oleicos/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos Endogâmicos C57BL , Fatores de Risco
16.
Neurosci Lett ; 706: 189-193, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31116971

RESUMO

In this study, we have pursued to assess oleamide's potential role in reward and aversion mechanisms. To reach this goal we infused oleamide, either 1 µg into the nucleus accumbens shell (NAccS) and evaluated its effects on conditioned place preference (CCP) or 10 µg, to evaluate conditioned place aversion (CPA). Extinction and reinstatement were also evaluated in both cases. We sought to determine if CPP occurs via cannabinoid receptor 1 (CB1R) and CPA via serontoninergic 2c receptor (5HT2cR). Results revealed that 1 µg of oleamide administered bilaterally into the NAccS induced CPP, while 10 µg induced CPA. In both conditions CPP or CPA, reinstatement after extinction was induced. AM251 (CB1R inverse-agonist) prevented CPP induced with 1 µg; while SB242084 (5HT2cR antagonist) not only prevented CPA induced with 10 µg but caused a switch to CPP. These results suggest that oleamide at low doses promotes reward through CB1R, and aversion at high doses via 5HT2cR.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ácidos Oleicos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Recompensa , Aminopiridinas/farmacologia , Animais , Condicionamento Operante/fisiologia , Extinção Psicológica/efeitos dos fármacos , Indóis/farmacologia , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
17.
Int Immunopharmacol ; 72: 159-165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30981081

RESUMO

The inhibition of polymorphonuclear neutrophils' (PMNs) migration to the source of injury is among the most prominent aspects of immunosuppression following sepsis, although the precise mechanisms involved remain unclear and multifaceted. Increasing evidence connects this immunosuppression to nitric oxide (NO), as NO production is a classic feature of inflammation probably through neutrophil activation and migration. Nitrated fatty acids (NFA) such as 10-nitrooleate (OA-NO2), nitrolinoleic acid etc. produced endogenously by the non-enzymatic reaction of NO with unsaturated fatty acids, are found to be potent activators of the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ). Upregulation of PPARγ during immunosuppression and the subsequent inhibition of neutrophil migration in sepsis have been reported. However, the interplay of OA-NO2, NO and PPARγ in polymicrobial-induced immunosuppression has not been established. Hence to understand this, we have studied the role of OA-NO2 in blood PMNs migration, the effects of iNOS inhibitor on PMNs migration and PPARγ activity in cecal ligation and puncture (CLP)-induced sepsis in mice. We found increased expression of PPARγ and its DNA-binding activity in the lungs and blood PMNs from CLP mice. CLP or OA-NO2 treatment inhibited PMNs' migration in response to fMLP stimulation. Pharmacological inhibition of iNOS resulted in decreased PPARγ DNA-binding activity with a concomitant increase in the migration of PMNs to the site of infection. OA-NO2 treatment also inhibited the production of inflammatory cytokines (TNFα and IL-1ß) secretion from PMNs stimulated with lipopolysaccharide. We have also established that, OA-NO2 mediated inhibition of PMNs migration in vivo and ex vivo are regulated through PPARγ-dependent pathway. This study further highlights the fact that the activation of PPARγ by the NFA has a pivotal role in PMNs' migration and immunosuppression.


Assuntos
Quimiotaxia/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Ácidos Oleicos/farmacologia , PPAR gama/imunologia , Sepse/imunologia , Animais , Ceco/cirurgia , Feminino , Ligadura , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia
18.
Mediators Inflamm ; 2019: 7854389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30948926

RESUMO

Intestinal injury has long been considered to play a crucial role in the pathophysiology of sepsis and has even been characterized as the "motor" of it. Thus, we explored the effects of connexin43 (Cx43) on sepsis-induced intestinal injury in order to provide potential therapeutic strategies. Rat cecal ligation and puncture (CLP) models in vivo and cell models (IEC-6 cells) pretreated with LPS in vitro were used in the current study. Firstly, different methods, such as Cx43 inhibitors (18-α-GA and oleamide) or siRNA targeting Cx43 and N-acetyl cysteine (NAC) (a kind of ROS scavenger), were used to observe the effects of Cx43 channels mediating ROS transfer on intestinal injury. Secondly, the influence of ROS content on the activity of the JNK1/Sirt1/FoxO3a signaling pathway was explored through the application of NAC, sp600125 (a JNK1 inhibitor), and nicotinamide (a Sirt1 inhibitor). Finally, luciferase assays and ChIP were used to determine the direct regulation of FoxO3a on proapoptotic proteins, Bim and Puma. The results showed that sepsis-induced intestinal injury presented a dynamic change, coincident with the alternation of Cx43 expression. The inhibition of Cx43 attenuated CLP-induced intestinal injury in vivo and LPS-induced IEC-6 injury in vitro. The changes of Cx43 channel function regulated ROS transfer between the neighboring cells, which mediated the activation of the JNK1/Sirt1/FoxO3a signaling pathway. FoxO3a directly affected its downstream target genes, Bim and Puma, which are responsible for cell or tissue apoptosis. In summary, our results suggest that Cx43 inhibition suppresses ROS transfer and inactivates the JNK1/Sirt1/FoxO3a signaling pathway to protect against sepsis-induced intestinal injury.


Assuntos
Conexina 43/metabolismo , Proteína Forkhead Box O3/metabolismo , Intestinos/lesões , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sirtuína 1/metabolismo , Animais , Conexina 43/antagonistas & inibidores , Conexina 43/genética , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Ácidos Oleicos/farmacologia , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico
19.
PLoS One ; 14(4): e0215812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002699

RESUMO

Osteoarthritis (OA) is a multifactorial joint disease and a common disabling condition in the elderly population. The associated pain and pathohistological changes in cartilage are common features of OA in both humans and animal models. Shea nut oil extract (SheaFlex75) contains a high triterpenoid concentration and has demonstrated anti-inflammatory and antiarthritic effects in both human and animal studies. In this study, we aim to investigate the potential of SheaFlex75 to prevent articular cartilage deterioration in a rat model of chronic OA progression. By employing anterior cruciate ligament transection (ACLT) with medial meniscectomy (MMx)-induced OA, we found attenuation of both early and chronic onset OA pain and cartilage degeneration in ACLT+MMx rats receiving SheaFlex75 dietary supplementation. Under long-term oral administration, the rats with induced OA presented sustained protection of both pain and OA cartilage integrity compared to the OA-control rats. Moreover, rats subjected to long-term SheaFlex75 ingestion showed normal biochemical profiles (AST, BUN and total cholesterol) and presented relatively lower triglycerides (TGs) and body weights than the OA-control rats, which suggested the safety of prolonged use of this oil extract. Based on the present evidence, preventive management is advised to delay/prevent onset and progression in OA patients. Therefore, we suggest that SheaFlex75 may be an effective management strategy for symptom relief and cartilage protection in patients with both acute and chronic OA.


Assuntos
Lesões do Ligamento Cruzado Anterior/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Ácidos Oleicos/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Dor/prevenção & controle , Óleos Vegetais/farmacologia , Triterpenos/farmacologia , Administração Oral , Animais , Ligamento Cruzado Anterior/efeitos dos fármacos , Ligamento Cruzado Anterior/patologia , Lesões do Ligamento Cruzado Anterior/patologia , Anti-Inflamatórios/isolamento & purificação , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Colesterol/sangue , Modelos Animais de Doenças , Progressão da Doença , Esquema de Medicação , Humanos , Masculino , Meniscectomia/métodos , Nozes/química , Ácidos Oleicos/isolamento & purificação , Osteoartrite do Joelho/patologia , Dor/fisiopatologia , Óleos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Triglicerídeos/sangue , Triterpenos/isolamento & purificação
20.
J Pharmacol Exp Ther ; 369(3): 503-510, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894457

RESUMO

Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated nuclear factor-κ B, nuclear factor-κ B, and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids that covalently modify proteins to limit inflammation and oxidant stress. In the present study, we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) in the uninephrectomized deoxycorticosterone acetate-high-salt mouse model of CKD. After 4 weeks of treatment, CXA-10 [2.5 millligrams per kilogram (mpk), p.o.] significantly attenuated increases in plasma cholesterol, heart weight, and kidney weight observed in the model without impacting systemic arterial blood pressure. CXA-10 also reduced albuminuria, nephrinuria, glomerular hypertrophy, and glomerulosclerosis in the model. Inflammatory MCP-1 and fibrosis (collagen, fibronectin, plasminogen activator inhibitor-1, and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and antifibrotic effects, as well as glomerular protection, were not observed in the enalapril-treated group. Also, CXA-10 appears to exhibit hormesis as all protective effects observed in the low-dose group were absent in the high-dose group (12.5 mpk). Taken together, these findings demonstrate that, at the appropriate dose, the nitrated fatty acid CXA-10 exhibits anti-inflammatory and antifibrotic effects in the kidney and limits renal injury in a model of CKD.


Assuntos
Citoproteção/efeitos dos fármacos , Acetato de Desoxicorticosterona/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Rim/efeitos dos fármacos , Rim/patologia , Nitrocompostos/farmacologia , Ácidos Oleicos/farmacologia , Sais/efeitos adversos , Animais , Acetato de Desoxicorticosterona/farmacocinética , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Nitrocompostos/farmacocinética , Ácidos Oleicos/farmacocinética , Estresse Oxidativo/efeitos dos fármacos , Distribuição Tecidual
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