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1.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
2.
J Anim Sci ; 97(7): 3071-3088, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31063536

RESUMO

The objective of this study was to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation to ewes during late gestation on finishing lamb liver and adipose tissue fatty acid (FA) profile and gene expression. Lambs born from ewes supplemented with Ca salts of EPA + DHA, or palm FA distillate (PFAD) high in palmitic and oleic acid at 0.39% DM during the last 50 d of gestation were used. Lambs were weaned at 61 d of age and adapted to a high concentrate diet for 1.5 mo. After adaptation, 74 lambs (28 pens) were blocked by sex and BW and used in a 2 × 2 factorial arrangement of treatments using the factors of dam supplementation (DS) and lamb supplementation (LS) of Ca salts of EPA + DHA or PFAD at 1.48% DM. Lambs were slaughtered after 42 d and liver and adipose tissue collected for FA and gene expression analysis. Liver concentrations of EPA and DHA were greater (P < 0.01) with LS of EPA + DHA vs. PFAD during the finishing period. In adipose tissue, a lamb × dam interaction was observed for EPA (P = 0.02) and DHA (P = 0.04); LS of EPA + DHA increased EPA and DHA, but the increase was greatest in lambs born from ewes supplemented with PFAD. No lamb × dam treatment interactions were observed for gene expression in liver tissue (P > 0.10). Hepatic mRNA abundance of hormone-sensitive lipase (HSL; P = 0.01) was greater in lambs born from EPA + DHA ewes vs. lambs from PFAD ewes. mRNA expression of stearoyl-CoA desaturase (P < 0.01), fatty acid synthase (P = 0.01), Δ5-desaturase (P < 0.01), and Δ6-desaturase (P < 0.01) were decreased in liver of EPA + DHA lambs. A significant lamb × dam diet interaction was observed for elongation of very long chain fatty acid 2 in adipose tissue (P = 0.01); lambs supplemented with the same FA as their dams had lower expression. Expression of HSL tended (P = 0.08) to be decreased in adipose of EPA + DHA lambs born from EPA + DHA ewes. The changes in mRNA expression suggest that lipogenesis decreased, and lipolysis increased in lamb liver with EPA + DHA vs. PFAD supplementation during the finishing period. In adipose tissue, changes suggest that lipogenesis decreased in lambs born from EPA + DHA supplemented dams and supplemented with EPA + DHA during the finishing period. In addition, these results suggest an interaction between supplementation of FA to dams during late gestation on lamb response of adipose tissue, but not liver, to FA supplementation during the finishing period.


Assuntos
Suplementos Nutricionais/análise , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos/farmacologia , Ovinos/fisiologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Ração Animal/análise , Animais , Cálcio/farmacologia , Dieta/veterinária , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos não Esterificados/metabolismo , Feminino , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Parto/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ovinos/genética , Desmame
3.
Anim Reprod Sci ; 205: 150-155, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31076217

RESUMO

As oocytes and embryos of pigs have greater lipid content in the cytoplasm than those of other species, supplementation of the medium for in vitro maturation (IVM) of oocytes with omega-3 polyunsaturated fatty acids (PUFA) may help to improve embryo development. This study was conducted to evaluate effects of the inclusion of the docosaexaenoic (DHA) and of the eicosapentaenoic acids (EPA) in the IVM medium on the development of pig oocytes and on the lipid content of oocytes and embryos. In all experiments, control media consisted of porcine follicular fluid and oocytes were activated through parthenogenesis. In Experiment 1, there were four treatments for each PUFA: one control; and three treatments including EPA or DHA in the IVM medium at 12.5 µM, 25.0 µM and 50.0 µM). In Experiment 2, inclusion of 50 µM DHA was compared against the control. Cleavage rates in the IVM medium including 12.5 µM EPA and blastocyst development rates in media at any EPA concentration were less than for the control in Experiment 1 (P < 0.05). Compared to the control, inclusion of 50 µM DHA in the IVM medium was related to greater cleavage rates and greater number of embryo cells, in Experiment 1, and lesser lipid content in oocytes after 22 and 44 h and in embryos after 7 days, in Experiment 2 (both P < 0.05). Addition of DHA in the IVM medium may benefit the development of pig oocytes, but EPA appears to be cytotoxic.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Embrião de Mamíferos/química , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/efeitos dos fármacos , Suínos/embriologia , Animais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Relação Dose-Resposta a Droga , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Metabolismo dos Lipídeos , Partenogênese , Suínos/fisiologia
4.
J Anim Sci ; 97(6): 2631-2643, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31073599

RESUMO

Omega-3 long chain fatty acids have a positive impact on production. When consumed during late gestation, it might have fetal programming effects on the fetus, which will have lifelong impacts on development and production. The objectives of the present study were to evaluate the effect of increasing doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the diet of ewes in the last third of gestation on their body weight (BW), subcutaneous adipose tissue relative mRNA abundance of genes associated with adipose tissue metabolism, and growth performance and plasma metabolites and hormones of their offspring during the finishing phase. Ewes (n = 72) were blocked by BW and allotted to pens (8 per treatment) with 3 ewes per pen. Ewes were supplemented with an EPA and DHA source (Strata G113) at concentrations of 0, 1, or 2% of dry matter intake during the last 50 d of gestation. At lambing, all ewes were penned together and offered the same diet. After weaning at 60 d of age, lambs were blocked by BW and sex and fed for 56 d. All lambs were fed the same pellet diet (61.09% ground corn, 24.08% soy hulls, 11.09% soybean meal, 1.48% Ca salt of palm oil, and 2.26% mixed mineral vitamin), and were weighed every 14 d until the end of the trial. Blood samples were collected on the weight sampling days. Dry matter intake and refusals were weighed daily. Data were analyzed as a randomized complete block design with repeated measurements (SAS 9.4). Polynomial contrast (linear-L and quadratic-Q) was used for mean separation. There were no differences in ewe body condition score, milk production, milk fat, or milk protein, but there was a trend for increased (L, P = 0.06) lactose concentration, and also differences in DGAT1 (L, P = 0.04), Δ5-desaturase (Q, P = 0.06) and Δ6-desaturase (Q, P = 0.07), PPARα (Q, P = 0.03), ELOVL2 and 5 (Q, P < 0.07), FABP4 (Q, P = 0.04), FATP1 (Q, P = 0.06), leptin (Q, P = 0.02), and resistin (L, P = 0.05). Feeding pregnant ewes an increased amount of EPA and DHA in late gestation increased final BW (L, P = 0.01), ADG (L, P = 0.04; Q, P = 0.01), DMI (Q, P ≤ 0.01), plasma glucose concentration (L, P = 0.04), and trended to decrease ghrelin concentrations (L, P = 0.07) in offspring during the finishing period. Dam supplementation did not affect G:F, nor plasma NEFA concentration (P ≥ 0.53) of lambs. Therefore, increasing supplementation of EPA and DHA in pregnant ewes has an impact on offspring performance, increasing DMI, ADG, and BW.


Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Grelina/análise , Ovinos/fisiologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta/veterinária , Ácido Eicosapentaenoico/farmacologia , Feminino , Gravidez , Desmame
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(2): 215-218, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-31106542

RESUMO

OBJECTIVE: To investigate the therapeutic effects of resolvin D1 (RvD1) on cerulein and lipopolysaccharide (LPS)-induced severe acute pancreatitis in mice. METHODS: The model of severe acute pancreatitis was induced by cerulein combined with LPS in mice. Mice were treated with RvD1 at a dose of 150 mg/kg for 4 h after the last injection of cerulein. Pathological changes and scores were assessed by HE staining, serum amylase and lipase levels were detected by ELISA, serum tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) levels were determined by Luminex Assay. RESULTS: Cerulein combined with LPS successfully induced severe acute pancreatitis model in mice. RvD1 reduced the pathological changes of pancreas in severe acute pancreatitis mice, decreased the serum levels of amylase and lipase, as well as attenuated the serum levels of TNF-α and IL-6. CONCLUSION: RvD1 can reduce the severity of severe acute pancreatitis induced by cerulein and LPS in mice.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Pancreatite/tratamento farmacológico , Doença Aguda , Amilases/sangue , Animais , Ceruletídeo , Interleucina-6/sangue , Lipase/sangue , Lipopolissacarídeos , Camundongos , Pâncreas , Pancreatite/induzido quimicamente , Fator de Necrose Tumoral alfa
6.
Nat Immunol ; 20(5): 626-636, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936495

RESUMO

Muscle damage elicits a sterile immune response that facilitates complete regeneration. Here, we used mass spectrometry-based lipidomics to map the mediator lipidome during the transition from inflammation to resolution and regeneration in skeletal muscle injury. We observed temporal regulation of glycerophospholipids and production of pro-inflammatory lipid mediators (for example, leukotrienes and prostaglandins) and specialized pro-resolving lipid mediators (for example, resolvins and lipoxins) that were modulated by ibuprofen. These time-dependent profiles were recapitulated in sorted neutrophils and Ly6Chi and Ly6Clo muscle-infiltrating macrophages, with a distinct pro-resolving signature observed in Ly6Clo macrophages. RNA sequencing of macrophages stimulated with resolvin D2 showed similarities to transcriptional changes found during the temporal transition from Ly6Chi macrophage to Ly6Clo macrophage. In vivo, resolvin D2 increased Ly6Clo macrophages and functional improvement of the regenerating muscle. These results reveal dynamic lipid mediator signatures of innate immune cells and provide a proof of concept for their exploitable effector roles in muscle regeneration.


Assuntos
Mediadores da Inflamação/imunologia , Lipídeos/imunologia , Macrófagos/imunologia , Músculo Esquelético/imunologia , Regeneração/imunologia , Animais , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Metabolismo dos Lipídeos/imunologia , Lipídeos/análise , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/lesões , Músculo Esquelético/fisiopatologia , Regeneração/genética
7.
J Dairy Sci ; 102(6): 5054-5065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954254

RESUMO

This study aimed to evaluate the effects of increasing dietary levels of microalgae (ALG), rich in docosahexaenoic acid (DHA; All-G-Rich, Alltech, Nicholasville, KY), in isolipidic diets, on animal performance, nutrient digestibility, ruminal fermentation, milk fatty acid profile, energy balance, microbial protein synthesis, and blood serum metabolites in mid-lactating dairy cows. Twenty-four Holstein cows [130.3 ± 15.4 d in milk, and 30.8 ± 0.543 kg/d of milk yield (mean ± standard error)] were used in a 4 × 4 Latin square design experiment to evaluate the following treatments: control diet, without addition of ALG; and increasing levels of ALG [2, 4, and 6 g/kg of dry matter (DM)]. The ALG decreased DM intake and increased total-tract DM apparent digestibility. A tendency was observed for a quadratic effect on total-tract NDF digestibility by ALG inclusion, with peak value of the quadratic response at 4.13 g/kg of DM dose. Moreover, ALG increased ruminal pH and decreased acetate and total volatile fatty acid concentrations. Fat-corrected milk and energy-corrected milk were quadratically affected, and a tendency for a milk yield effect was observed when ALG levels increased, whereas maximal yields were observed with intermediate doses. Milk fat, protein, and lactose concentrations were diminished, whereas productive efficiency was improved by the increase of ALG levels. Saturated fatty acid proportions were decreased, whereas polyunsaturated fatty acid proportions were increased when ALG was fed. There was low DHA transfer into milk; however, ALG inclusion decreased C18:0, C18:1 cis-9, C18:2 cis-9,12, and C18:3 cis-9,12,15 proportions, and increased C18:2 cis-9,trans-11, C18:1 trans-9, and C18:1 trans-11 proportions. Gross energy intake was decreased, whereas no effect was observed on digestible, metabolizable, or net energy intake. The ALG inclusion quadratically affected the microbial protein synthesis, with maximal enhancement at 3.24 g/kg of DM dose, and also increased serum cholesterol concentration. Under the conditions of this experiment, the inclusion of ALG in diets for mid-lactating dairy cows decreased feed intake and increased nutrient digestibility, improving productive efficiency and modifying milk fatty acid profile. Estimated intermediate doses (1.22 to 2.90 g/kg of DM) of DHA-rich ALG may be beneficial to milk, fat-corrected milk, and energy-corrected milk yields, and is recommended for dairy cows.


Assuntos
Ração Animal , Bovinos , Dieta/veterinária , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Voláteis/metabolismo , Microalgas , Leite/metabolismo , Ruminação Digestiva , Ração Animal/análise , Animais , Indústria de Laticínios , Feminino , Fermentação , Lactação , Lactose/metabolismo , Distribuição Aleatória , Rúmen/metabolismo
8.
Int J Mol Med ; 43(6): 2523-2531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017264

RESUMO

Docosahexaenoic acid (DHA) is an omega­3 polyunsaturated fatty acid, derived mainly from fish oil. It is well known that DHA is present in high concentrations in nervous tissue and plays an important role in brain development and neuroprotection. However, the molecular mechanisms underlying its role remain to be fully elucidated. In this study, to enhance our understanding of the pathophysiological role of DHA, we investigated the possible neuroprotective mechanisms of action of DHA against hydrogen peroxide (H2O2)­induced oxidative damage in a rat pheochromocytoma cell line (PC12). Specifically, we evaluated the viability, oxidation potential, and the expression and production of antioxidant/cytoprotective enzymes, and eventual apoptosis. We found that pre­treatment with DHA (24 h) protected the cells from H2O2­induced oxidative damage. In particular, pre­treatment with DHA: i) Antagonized the consistent decrease in viability observed following exposure to H2O2 for 24 h; ii) reduced the high levels of intracellular reactive oxygen species (ROS) associated with H2O2­induced oxidative stress; iii) increased the intracellular levels of enzymatic antioxidants [superoxide dismutase (SOD) and glutathione peroxidase (GSH­Px)] both under basal conditions and following H2O2 exposure; iv) augmented the intracellular levels of reduced glutathione (GSH) and ascorbic acid, while it reduced the malondialdehyde (MDA) levels under conditions of oxidative stress; v) upregulated the expression of nuclear factor (erythroid­derived 2)­like 2 (NFE2L2) and its downstream target protein, heme­oxygenase­1 (HO­1); and vi) induced an anti­apoptotic effect by decreasing Bax and increasing Bcl2 expression. These findings provide evidence suggesting that DHA is able to prevent H2O2­induced oxidative damage to PC12 cells, which is attributed to its antioxidant and anti­apoptotic effects via the regulation NFE2L2/HO­1 signaling. Therefore, DHA may play protective role in neurodegenerative diseases associated with oxidative stress.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Fármacos Neuroprotetores/metabolismo , Células PC12 , Ratos , Superóxido Dismutase/metabolismo
9.
Nutrients ; 11(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991731

RESUMO

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is implicated in theregulation of both lipid and carbohydrate metabolism. Thus, we questioned whether dietary DHAand low or high content of sucrose impact on metabolism in mice deficient for elongation of verylong-chain fatty acids 2 (ELOVL2), an enzyme involved in the endogenous DHA synthesis. Wefound that Elovl2 -/- mice fed a high-sucrose DHA-enriched diet followed by the high sucrose, highfat challenge significantly increased body weight. This diet affected the triglyceride rich lipoproteinfraction of plasma lipoproteins and changed the expression of several genes involved in lipidmetabolism in a white adipose tissue. Our findings suggest that lipogenesis in mammals issynergistically influenced by DHA dietary and sucrose content.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Sacarose na Dieta/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Lipogênese/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Ácidos Docosa-Hexaenoicos/deficiência , Lipogênese/genética , Lipoproteínas/sangue , Camundongos Knockout , Triglicerídeos/sangue
10.
Biomed Pharmacother ; 114: 108811, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965235

RESUMO

OBJECTIVES: We aimed to determine whether bone remodeling and vessel formation in the osteochondral unit are suppressed by supplementing with docosahexaenoic acid in anterior cruciate ligament transection (ACLT)-induced rats. METHODS: Twelve-week-old male Sprague Dawley rats were randomized to sham-operated, ACLT-operated and treated with vehicle, or ACLT-operated and treated with DHA groups. Micro-architecture and vasculature in the tibial osteochondral unit were examined by micro-CT, as well as by histomorphometry. To evaluate the effects of DHA in vitro, we conducted functional and expressional assays in RAW264.7 cells and HUVECs. Finally, we used OARSI-modified Mankin criteria and histological analyses to assess the status of the cartilage layer. RESULTS: Microstructural parameters in the osteochondral unit showed that bone mass loss and angiogenesis were less in DHA-treated rats than in vehicle-treated rats. Immunofluorescence-positive cells labeled with TRAP, RANKL, CD31, and endomucin agents in the osteochondral unit of ACLT-operated rats were reduced in the DHA-treated group compared with the vehicle-treated group. Furthermore, the number of TRAP-stained cells, areas of bone resorption pits, and mRNA expression of TRAP, CTSK, MITF, and NFATC1 were reduced in RAW264.7 cells treated with RANKL + DHA compared with those treated with only RANKL. Tube formation, proliferation and migration of HUVECs, and VEGF-C mRNA and VEGFR2 protein expression were inhibited by DHA. The decrease in OARSI score, and MMP-13 and collagen X expression suggested that DHA attenuated cartilage degeneration. CONCLUSIONS: DHA has the ability to restrain bone remodeling and vessel formation in the osteochondral unit, which may contribute to protection of cartilage.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Células RAW 264.7 , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
J Clin Neurosci ; 64: 227-233, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948313

RESUMO

Traumatic brain injury (TBI) is followed by a secondary inflammation in the brain. Neuroprotectin D1 (NPD1) is synthesized from docosahexaenoic acid (DHA) and has anti-inflammatory and antiapoptotic effects in experimental models of neurodegenerative disease and brain ischemia-reperfusion. It is not known whether intralesional administration of NPD1 ameliorates inflammation and cell death after severe TBI. We therefore investigated the effects of NPD1 following a severe form of focal penetrating TBI. A total of 30 male Sprague-Dawley rats weighing between 350 and 450 g were exposed to focal penetrating TBI or sham surgery. The rats were randomized to NPD1 treatment (50 ng intralesionally, immediately following TBI) or no treatment. The rats were sacrificed at 24 or 72 h. All subgroups consisted of 5 rats. Brains were removed, fresh frozen, cut in 14-µm coronal sections and subjected to Fluoro-Jade, TUNEL, MnSOD, 3-NT, COX-2, Ox-42 and NF-κB immuno-staining and lesion size analyses. NPD1 decreased the lesion area at 72 h compared to no treatment with a mean change 42% (NPD1 14.1 mm2; no treatment 24.5 mm2) (p < 0.01). No difference was detected in markers for neuronal degeneration, apoptosis, anti-inflammatory or antioxidative enzymes, or immune cells. In conclusion, single-dose intralesional administration of NPD1 had brain tissue sparing effects after focal penetrating TBI, which may be beneficial in preventing brain tissue damage, making NPD1 a potential candidate for further clinical applications. Exact mechanisms of action could not be determined and it is possible that continuous or multiple administration regimens may increase efficacy in sequential preclinical studies.


Assuntos
Anti-Inflamatórios/farmacologia , Lesões Encefálicas Traumáticas/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Traumatismos Cranianos Penetrantes/patologia , Inflamação , Masculino , Ratos , Ratos Sprague-Dawley
12.
Oxid Med Cell Longev ; 2019: 1280987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949290

RESUMO

Introduction: The omega-3 polyunsaturated fatty acids, as docosahexaenoic acid (DHA), are considered mediators regulating the resolution of inflammation during cancer and may be associated with better outcomes. Epoxydocosapentaenoic acids (EDPs), metabolites of the DHA, are hypothesized to be responsible for some beneficial effects. In the present study, we aimed to assess the circulating 19,20-EDP levels in breast cancer (BC) patients and in healthy controls before and after DHA oral supplementation and the potential differences in the DHA conversion in 19,20-EDPs between patients with different BC presentations. Methods: BC patients and healthy controls were supplemented with DHA (algal oil) for 10 days (2 g/day). Blood samples were collected at baseline (T0) and after supplementation (T1) to assess EDP (19,20-EDP) serum levels by liquid chromatography spectrometry. Results: 33 BC patients and 10 controls were studied. EDP values at T0 were not different between patients and controls. At T1, we found an increase in 19,20-EDP levels in BC patients (P < 0.00001) and in controls (P < 0.001), whereas no differences in 19,20-EDPs were present between the two groups; when considering the type of BC presentation, patients with BRCA1/2 mutation showed lower 19,20-EDPs levels with respect to BC patients without the mutation (P = 0.03). According to immunohistochemical subtype, luminal A-like BC patients showed at T1 higher 19,20-EDP levels compared to nonluminal A (P = 0.02). Conclusions: DHA oral supplementation was associated with increased 19,20-EDP serum levels in BC patients, independent of the type of BC presentation, and in controls. Patients carrier of BRCA1/2 mutation seem to possess lower ability of DHA epoxidation, whereas luminal A-like BC patients showed higher EDP conversion. This behavior should be tested in a larger population.


Assuntos
Neoplasias da Mama/dietoterapia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Inflamação/tratamento farmacológico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade
13.
J Anim Physiol Anim Nutr (Berl) ; 103(3): 925-934, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816602

RESUMO

Adipose-derived stem cells (ADSCs) possess multipotent properties, and their proper functionality is essential for further development of metabolic disorders. In the current study, we explored the impact of two n-3 LC-PUFAs (long-chain polyunsaturated fatty acids, DHA-docosahexaenoic; C22:6, and EPA-eicosapentaenoic; C20:5) on a specific profile of lipolytic-related gene expressions in the in vitro-differentiated subcutaneous and visceral ADSCs from rabbits. The subcutaneous and visceral ADSCs were obtained from 28-day-old New Zealand rabbits. The primary cells were cultured up to passage 4 and were induced for adipogenic differentiation. Thereafter, the differentiated cells were treated with 100 µg EPA or DHA for 48 hr. The total mRNA was isolated and target genes expression evaluated by real-time RCR. The results demonstrated that treatment of rabbit ADSCs with n-3 PUFAs significantly enhanced mRNA expression of Perilipin A, while the upregulation of leptin and Rab18 genes was seen mainly in ADSCs from visceral adipose tissue. Moreover, the EPA significantly enhanced PEDF (Pigment Derived Epithelium Factor) mRNA expression only in visceral cells. Collectively, the results suggest activation of an additional lipolysis pathway most evident in visceral cells. The data obtained in our study indicate that in vitro EPA up-regulates the mRNA expression of the studied lipolysis-associated genes stronger than DHA mainly in visceral rabbit ADSCs.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Coelhos/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Células Cultivadas , Células-Tronco Mesenquimais/metabolismo
14.
Eur J Pharmacol ; 853: 41-48, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878386

RESUMO

At arterial sites of endothelial denudation and dysfunction, activated platelets contribute to vascular injury through the release of potent contracting factors such as serotonin (5-HT). This study evaluated whether omega-3 polyunsaturated fatty acids (PUFAs), known to protect the vascular system, are able to prevent platelets-induced contractile responses in isolated arteries and, if so, to investigate the underlying mechanism and the importance of the omega-3 PUFAs formulation. Porcine coronary arteries (PCA), human internal mammary arteries (IMA) and washed human platelets were prepared and vascular reactivity was studied in organ chambers. In PCA rings, aggregating platelets caused concentration-dependent contractions that were significantly inhibited by the 5-HT2A receptor antagonist ketanserin, and by EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v. EPA:DHA 6:1 also prevented the 5-HT-induced contractions but affected only slightly those to the thromboxane A2 analogue U46619. The inhibitory effect of EPA:DHA 6:1 on platelets-induced contractions was not observed in rings without endothelium, and prevented by an eNOS inhibitor but not by inhibitors of endothelium-dependent hyperpolarization. In IMA rings, EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v significantly prevented the 5-HT-induced contraction, and induced greater endothelium-dependent relaxations than bradykinin and acetylcholine sensitive to an eNOS inhibitor. EPA:DHA 6:1 strongly inhibits platelets- and 5-HT-induced contractions in PCA rings and those to 5-HT in IMA rings most likely through an increased endothelial formation of NO. These findings suggest that the omega-3 PUFAs EPA:DHA 6:1 formulation may be of interest to prevent platelets-induced vascular injury at arterial sites of endothelial dysfunction.


Assuntos
Plaquetas/fisiologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Artéria Torácica Interna/efeitos dos fármacos , Óxido Nítrico/biossíntese , Serotonina/metabolismo , Vasoconstrição/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Animais , Ácidos Docosa-Hexaenoicos/química , Composição de Medicamentos , Ácido Eicosapentaenoico/química , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Artéria Torácica Interna/fisiologia , Pessoa de Meia-Idade , Suínos
15.
Drug Des Devel Ther ; 13: 739-745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863013

RESUMO

Background: Inflammation and oxidative stress play a crucial role in the pathogenesis of renal ischemia/reperfusion injury (IRI). Maresin 1 (MaR1), which has shown strong anti-inflammatory and antioxidant effects, was recently reported to have protective properties in several different animal models. Aim: The objectives of our study were to determine whether MaR1 alleviates renal IRI and to identify the underlying mechanisms. Materials and methods: The mouse model in this study was induced by ischemia of the left kidney for 45 minutes and by nephrectomy of the right kidney. All mice were intravenously injected with a vehicle or MaR1. Renal histopathologic changes, function, proinflammatory cytokines, and oxidative stress were assessed. The expression of proteins was measured by Western blot. Results: The results indicated that MaR1 markedly protected against renal IRI. The protective effects were accompanied by the reduction of histologic changes and reduction of renal dysfunction. Meanwhile, MaR1 remarkably mitigated renal IRI-induced inflammation and oxidative stress. In addition, our results showed that MaR1 significantly inhibited the expression of TLR4 and the expression of phosphorylated Erk, JNK, and P38. Furthermore, MaR1 decreased the nuclear translocation of NF-κB and increased the nuclear translocation of Nrf2. Conclusion: MaR1 protects against renal IRI by inhibiting the TLR4/MAPK/NF-κB pathways, which mediate anti-inflammation, and by activating the Nrf2 pathway, which mediates antioxidation.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Nefropatias/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Receptor 4 Toll-Like/antagonistas & inibidores
16.
Fish Physiol Biochem ; 45(3): 1091-1099, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903378

RESUMO

Our previous study has shown that overload of lipid accumulation results in cell apoptosis and inflammation in grass carp (Ctenopharyngodon idella). In this study, we investigated the potential protective effects of docosahexaenoic acid (DHA) on inhibiting oleic acid (OA)-induced apoptosis and inflammation in grass carp hepatocytes. Firstly, the hepatocyte of grass carp were treated with OA (800 µM) and different concentration (0, 50, 100 and 200 µM) of DHA for 24 h, the apoptotic ratio, gene expression levels of apoptosis such as caspase 3, caspase 8, and caspase 9, protein levels of Caspase3, and mRNA levels of inflammation genes such as nf-kb, tnf-α, and il-8 were detected. Furthermore, the mRNA levels of lipogenesis genes srebp1c, fas, acc, and scd and a key enzyme of lipolysis Atgl were also detected. These results showed that the cell apoptosis and the inflammation increased by OA were significantly attenuated by DHA (P < 0.05). Furthermore, DHA could significantly decrease fatty acid synthesis gene expression levels which were induced by OA (P < 0.05). However, the hepatocytes exposed with DHA had no significant influence on the expression of Atgl. Taken together, the study indicated that DHA protects the hepatocytes against apoptosis and inflammation induced by OA might via inhibiting fatty acid synthesis, instead of promoting lipolysis. These results call for further studies to assess the effectiveness of DHA.


Assuntos
Apoptose/efeitos dos fármacos , Carpas , Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/efeitos dos fármacos , Inflamação/induzido quimicamente , Ácido Oleico/toxicidade , Animais , Células Cultivadas , Hepatócitos/metabolismo , Inflamação/metabolismo , Substâncias Protetoras/farmacologia
17.
Vet Immunol Immunopathol ; 209: 53-60, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30885306

RESUMO

Fatty acids are well known metabolic intermediaries but also have a role in the immune response. Long-chain fatty acids such as omega-6 and -9 activate neutrophil function through free fatty acid (FFA)-1 receptor in bovines. Although omega-3 has also been suggested to influence neutrophil function, the details remain unclear. The goal of this study was to determine the presence of the bovine FFA4 receptor and its effect on neutrophil responses. We treated bovine neutrophils with the natural and synthetic agonists of FFA4 receptor docosahexaenoic acid (DHA) and TUG-891, respectively, and assessed oxidative and no oxidative response. We detected protein and mRNA FFA4 receptor expression through immunofluorescence, immunoblot, and RT-PCR analysis. DHA and TUG-891 both increased intracellular calcium mobilisation in bovine neutrophils, with 50% effective concentrations of 99 µM and 73 µM, respectively, which was partially reduced after treatment with the FFA4 antagonist AH7614. Furthermore, DHA and TUG-891 increased matrix metalloproteinase (MMP)-9 granules release and superoxide production. AH7614 and the intracellular calcium chelator BAPTA-AM decreased the superoxide production induced by TUG-891 and by both DHA and TUG-891, respectively, suggesting a key role of intracellular calcium in FFA4 agonists-induced superoxide production. These results highlight an important mechanism of bovine neutrophil responses mediated via FFA4 receptor, which can further inform the development of new formulations for DHA-enriched feed supplements to enhance innate immunity in dairy cattle.


Assuntos
Compostos de Bifenilo/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Cálcio/metabolismo , Bovinos , Feminino , Metaloproteinase 9 da Matriz/metabolismo , Receptores Acoplados a Proteínas-G/agonistas
18.
Ann Clin Lab Sci ; 49(1): 72-78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814080

RESUMO

OBJECTIVE: This study aims to investigate the effect of different concentrations of docosahexaenoic acid (DHA) on proliferation and apoptosis in HepG2 cell lines, and to research the possible molecular mechanisms. METHODS: DHA concentration was 0 g/mL in the negative control group, and 15, 30, 45, 60 and 75 ug/mL, respectively, in the experimental groups. CCK-8 and flow cytometry methods were used to observe the growth inhibition and apoptosis rates of HepG2 cells cultured in vitro, which were treated with different concentrations of DHA. The level of ß-catenin and c-myc mRNA and protein were measured by real-time PCR and western blot, respectively. RESULTS: In the concentration range of 0-45 ug/mL, the action time was 24 hours. DHA could inhibit the growth of HepG2 cells, and there were significant differences between the experimental and control groups (P<0.01). The same was observed in each of the two groups in experimental groups. As drug concentration or action time increased, results revealed no statistical differences. Furthermore, flow cytometric analysis indicated that DHA could promote HepG2 cell apoptosis; and the apoptosis rate was greatly different between the experimental and control groups (P<0.01). The same was observed in each of the two groups in the experimental groups. Real-time PCR could detect low c-myc expression in HepG2 cells disposed by DHA, and c-myc expression was significantly different between the experimental and control groups (P<0.01). The same was observed in each of the two groups in the experimental groups. There was no obvious difference in ß-catenin expression between the experimental and control groups, and the experimental groups were all identical. Western blot demonstrated that DHA could decrease ß-catenin and c-myc protein expression in HepG2 cells. CONCLUSION: DHA could promote apoptosis and inhibit the proliferation of HepG2 cells. The possible mechanism was related with the down-regulated protein expression of ß-catenin and the mRNA expression of c-myc.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
Nutrients ; 11(3)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866528

RESUMO

Τhe effect of docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) upon the proliferation of EoL-1 (Eosinophilic leukemia) cell line was assessed, while additional cellular events during the antiproliferative action were recorded. DHA inhibited EoL-1 cells growth dose-dependently by inducing growth arrest at G0/1 phase of the cell cycle. After DHA addition to the cells, the expression of MYC oncogene was decreased, PTAFR-mRNA overexpression was observed which was used as a marker of differentiation, and PLA2G4A-mRNA increase was recorded. The enzymatic activities of phospholipase A2 (PLA2), a group of hydrolytic enzymes, whose action precedes and leads to PAF biosynthesis through the remodeling pathway, as well as platelet activating factor acetylhydrolase (PAFAH) which hydrolyses and deactivates PAF, were also measured. DHA had an effect on the levels of both the intracellular and secreted activities of PLA2 and PAFAH. The inflammatory cytokines IL-6 and TNF-α were also detected in high levels. In conclusion, DHA-induced EoL-1 cells differentiation was correlated with downregulation of MYC oncogene, overexpression of PTAFR and PLA2G4A-mRNAs, increase of the inflammatory cytokines production, and alteration of the enzymatic activities that regulate PAF levels. DHA is a natural substance and the understanding of its action on EoL-1 cells on molecular level could be useful in further investigation as a future therapeutic tool against F/P ⁺ hypereosinophilic syndrome.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Leucemia/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Fosfolipases A2 do Grupo IV/genética , Fosfolipases A2 do Grupo IV/metabolismo , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
20.
Mol Cells ; 42(3): 252-261, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30764601

RESUMO

The omega-3 fatty acid docosahexaenoic acid (DHA) is known to induce apoptosis and cell cycle arrest via the induction of reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress in many types of cancers. However, the roles of DHA in drug-resistant cancer cells have not been elucidated. In this study, we investigated the effects of DHA in cisplatin-resistant gastric cancer SNU-601/cis2 cells. DHA was found to induce ROS-dependent apoptosis in these cells. The inositol 1,4,5-triphosphate receptor (IP3R) blocker 2-aminoethyl diphenylboninate (2-APB) reduced DHA-induced ROS production, consequently reducing apoptosis. We also found that G-protein-coupled receptor 120 (GPR120), a receptor of long-chain fatty acids, is expressed in SNU-601/cis2 cells, and the knockdown of GPR120 using specific shRNAs alleviated DHA-mediated ROS production and apoptosis. GPR120 knockdown reduced the expression of ER stress response genes, similar to the case for the pre-treatment of the cells with N-acetyl-L-cysteine (NAC), an ROS scavenger, or 2-APB. Indeed, the knockdown of C/EBP homologous protein (CHOP), a transcription factor that functions under ER stress conditions, markedly reduced DHA-mediated apoptosis, indicating that CHOP plays an essential role in the anti-cancer activity of DHA. These results suggest that GPR120 mediates DHA-induced apoptosis by regulating IP3R, ROS, and ER stress levels in cisplatin-resistant cancer cells, and that GPR120 is an effective chemotherapeutic target for cisplatin resistance.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Fator de Transcrição CHOP/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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