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1.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Life Sci ; 258: 118094, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32673663

RESUMO

AIMS: Docosahexaenoic acid (DHA) as an omega 3 free fatty acid has been reported to exert anti-angiogenesis effects. However, our current understanding regarding the precise mechanisms of such effects is still limited. Exosomes secreted by cancer cells may act as angiogenesis promoters. The aim of the study was to determine altered expression levels of HIF-1α, TGF-ß, VEGFR, Snail1, Snail2 and SOX2 and their regulating microRNAs in MDA-MB-231 and BT-474 cell lines after treatment with DHA in both normoxic and hypoxic conditions. MAIN METHODS: Human breast cancer cell lines including MDA-MB-231 and BT-474 were treated for 24 h with 100 uM DHA under normoxic and hypoxic conditions. Exosomes were isolated from untreated and treated cells and characterized by transmission electron microscopy (TEM) and western blotting. RNAs from cells and isolated exosomes were extracted and cDNAs were synthesized. Expression levels of miRNAs and their pro-angiogenic target genes were analyzed using quantitative real-time PCR (qRT-PCR). KEY FINDINGS: We showed significant decrease in the expression of pro-angiogenic genes including HIF1-α, TGF-ß, SOX2, Snail1, Snail2 and VEGFR in cells and also their secreted exosomes after treatment with DHA in normoxic and hypoxic conditions. Also the expression levels of tumor suppressor miRs including miR-101, miR-199, miR-342 were increased and the expression levels of oncomiRs including mir-382 and miR-21 were decreased after treatment with DHA in cells and exosomes. SIGNIFICANCE: DHA can alter the expression of pro-angiogenic genes and microRNA contents in breast cancer cells and their derived-exosomes in favor of the inhibition of angiogenesis. Our data demonstrated new insight into DHA's anti-cancer action to target not only breast cancer cells but also their derived exosomes to suppress tumor angiogenesis.


Assuntos
Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação para Baixo , Exossomos/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/ultraestrutura , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo
3.
PLoS One ; 15(6): e0235217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574225

RESUMO

In sheep, polyunsaturated fatty acid (PUFA) supplementations in late gestation increases the growth of offspring; however, there is a lack of evidence on the effect of PUFA supplementation during early gestation. Thus, the objective of this study was to evaluate the effect of dietary supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in early gestation pregnant ewes on fatty acid concentration of fetal liver (FL) and fetal central nervous system (FCNS), and relative abundance of the mRNA for genes associated with transport and metabolism of fatty acids in FL and placenta. A total of 12 ewes, block for stage of gestation were fed a diet containing 1.6% (dry matter basis) monounsaturated fatty acids (MUFA) or EPA+DHA during the first 45 days of gestation. A cesarean section was conducted on day 45 of gestation to collect placenta (caruncle and cotyledon), FL, and FCNS. Relative abundance of mRNA in FL and FCNS and fatty acid concentration were analyzed using a 2x2 factorial arrangement of treatments considering fatty acid supplementation and tissue as the main factors. Concentrations of C18:1 isomers increase (P < 0.05) in FL and FCNS with MUFA supplementation; the FL and FCNS had a greater concentration of C20:3(n-6), C20:3(n-3), C22:1, C22:5 and C22:6 (P < 0.05) with EPA+DHA supplementation. In FL, the relative abundance of LPL mRNA was greater (P = 0.02) as a result of MUFA supplementation. In placenta, there was a FA x tissue interaction for relative abundance of DNMT3b and FFAR-4 mRNA (P < 0.05). Fetus from MUFA-supplemented dams had a greater relative abundance of FABP-4 mRNA (P < 0.05). Results indicate supplementation with EPA+DHA during early gestation increases the total EPA and DHA in FL. For the placenta, EPA+DHA supplementation led to an increase in the relative abundance of lipid mRNA for transport genes.


Assuntos
Sistema Nervoso Central/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos/análise , Feto/efeitos dos fármacos , Placenta/efeitos dos fármacos , RNA Mensageiro/metabolismo , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/química , Feminino , Feto/metabolismo , Idade Gestacional , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Placenta/metabolismo , Gravidez , Ovinos
4.
Life Sci ; 254: 117773, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418896

RESUMO

The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Distribuição Aleatória , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
5.
PLoS One ; 15(5): e0233183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413078

RESUMO

Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.


Assuntos
Dieta Ocidental/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Lúpus Eritematoso Sistêmico/dietoterapia , Dióxido de Silício/toxicidade , Animais , Linfócitos B/imunologia , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Feminino , Glomerulonefrite/dietoterapia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Inflamação/imunologia , Interferon gama/metabolismo , Rim/metabolismo , Rim/patologia , Pulmão/metabolismo , Pulmão/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Camundongos , Linfócitos T/imunologia
6.
Int J Exp Pathol ; 101(1-2): 55-64, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32459025

RESUMO

Rheumatoid arthritis is a disabling autoimmune disease with a high global prevalence. Treatment with disease-modifying anti-arthritic drugs (DIMARDs) has been routinely used with beneficial effects but with adverse long-term consequences; novel targeted biologics and small-molecule inhibitors are promising options. In this study, we investigated whether purified omega unsaturated fatty acids (ω-UFAs) and dialysable leukocyte extracts (DLEs) prevented the development of arthritis in a model of collagen-induced arthritis (CIA) in mice. We also investigated whether the transcription factor NF-κB and the NLRP3 inflammasome were involved in the process and whether their activity was modulated by treatment. The development of arthritis was evaluated for 84 days following treatment with nothing, dexamethasone, DLEs, docosahexaenoic acid, arachidonic acid, and oleic acid. Progression of CIA was monitored by evaluating clinical manifestations, inflammatory changes, and histological alterations in the pads' articular tissues. Both DLEs and ω-UFAs led to an almost complete inhibition of the inflammatory histopathology of CIA and this was concomitant with the inhibition of NF-kB and the inhibition of the activation of NLRP3. These data suggest that ω-UFAs and DLEs might have NF-κB as a common target and that they might be used as ancillary medicines in the treatment of arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Cartilagem Articular/efeitos dos fármacos , Extratos Celulares/farmacologia , Ácidos Graxos Insaturados/farmacologia , Leucócitos , Animais , Ácido Araquidônico/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Colágeno Tipo II , Diálise , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oleico/farmacologia
7.
Mol Pharmacol ; 97(5): 304-313, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32132133

RESUMO

Free-fatty acid receptor-4 (FFA4), previously termed GPR120, is a G protein-coupled receptor (GPCR) for medium and long-chained fatty acids, agonism of which can regulate a myriad of metabolic, sensory, inflammatory, and proliferatory signals. Two alternative splice isoforms of FFA4 exist that differ by the presence of an additional 16 amino acids in the longer (FFA4-L) transcript, which has been suggested to be an intrinsically ß-arrestin-biased GPCR. Although the shorter isoform (FFA4-S) has been studied more extensively, very little is known about mechanisms of regulation or signaling of the longer isoform. Because ß-arrestin recruitment is dependent on receptor phosphorylation, in the current study, we used the endogenous agonist docosahexaenoic acid (DHA) to examine the mechanisms of FFA4-L phosphorylation, as well as DHA-dependent ß-arrestin recruitment and DHA-dependent extracellular-signal regulated kinase-1/2 (ERK1/2) signaling in human embryonic kidney 293 cells. Our results reveal differences in basal phosphorylation of the two FFA4 isoforms, and we show that DHA-mediated phosphorylation of FFA4-L is primarily regulated by G protein-coupled receptor kinase 6, whereas protein kinase-C can also contribute to agonist-induced and heterologous phosphorylation. Moreover, our data demonstrate that FFA4-L phosphorylation occurs on the distal C terminus and is directly responsible for recruitment and interactions with ß-arrestin-2. Finally, using CRISPR/Cas9 genome-edited cells, our data reveal that unlike FFA4-S, the longer isoform is unable to facilitate phosphorylation of ERK1/2 in cells that are devoid of ß-arrestin-1/2. Together, these results are the first to demonstrate phosphoregulation of FFA4-L as well as the effects of loss of phosphorylation sites on ß-arrestin recruitment and ERK1/2 activation. SIGNIFICANCE STATEMENT: Free-fatty acid receptor-4 (FFA4) is a cell-surface G protein-coupled receptor for medium and long-chained fatty acids that can be expressed as distinct short (FFA4-S) or long (FFA4-L) isoforms. Although much is known about FFA4-S, the longer isoform remains virtually unstudied. Here, we reveal the mechanisms of docosahexaenoic acid-induced phosphorylation of FFA4-L and subsequent ß-arrestin-2 recruitment and extracellular-signal regulated kinase-1/2 activity.


Assuntos
Processamento Alternativo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , beta-Arrestina 2/metabolismo , Processamento Alternativo/efeitos dos fármacos , Sequência de Aminoácidos , Ácidos Docosa-Hexaenoicos/farmacologia , Quinases de Receptores Acoplados a Proteína G/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Quinase C/metabolismo , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos
8.
Proc Natl Acad Sci U S A ; 117(14): 7971-7980, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32205444

RESUMO

Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes (PMNs), followed by PMN apoptosis and efferocytosis. Here we report that bacterial DNA (CpG DNA) and mitochondrial DNA impair phagocytosis and attenuate phagocytosis-induced apoptosis in human PMNs through Toll-like receptor 9 (TLR9)-mediated release of neutrophil elastase and proteinase 3 and subsequent down-regulation of the complement receptor C5aR. Consistently, CpG DNA delays pulmonary clearance of Escherichia coli in mice and suppresses PMN apoptosis, efferocytosis, and generation of proresolving lipid mediators, thereby prolonging lung inflammation evoked by E. coli Genetic deletion of TLR9 renders mice unresponsive to CpG DNA. We also show that aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 (17-epi-RvD1) through the receptor ALX/FPR2 antagonize cues from CpG DNA, preserve C5aR expression, restore impaired phagocytosis, and redirect human PMNs to apoptosis. Treatment of mice with 15-epi-LXA4 or 17-epi-RvD1 at the peak of inflammation accelerates clearance of bacteria, blunts PMN accumulation, and promotes PMN apoptosis and efferocytosis, thereby facilitating resolution of E. coli-evoked lung injury. Collectively, these results uncover a TLR9-mediated endogenous mechanism that impairs PMN phagocytosis and prolongs inflammation, and demonstrate both endogenous and therapeutic potential for 15-epi-LXA4 and 17-epi-RvD1 to restore impaired bacterial clearance and facilitate resolution of acute lung inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Infecções por Escherichia coli/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Pneumonia/imunologia , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Células Cultivadas , Ilhas de CpG/imunologia , DNA Bacteriano/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Escherichia coli/genética , Escherichia coli/imunologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Voluntários Saudáveis , Humanos , Lipoxinas/farmacologia , Lipoxinas/uso terapêutico , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Pneumonia/patologia , Cultura Primária de Células , Receptores de Formil Peptídeo/imunologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/imunologia , Receptores de Lipoxinas/metabolismo
9.
Lab Invest ; 100(7): 904-915, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32123295

RESUMO

Gram-negative bacterial infection causes an excessive inflammatory response and acute organ damage or dysfunction due to its outer membrane component, lipopolysaccharide (LPS). Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenous lipid mediator, exerts fundamental anti-inflammation and pro-resolution during infection. In the present study, we examined the properties of PCTR1 on the systemic inflammatory response, organic morphological damage and dysfunction, and serum metabolic biomarkers in an LPS-induced acute inflammatory mouse model. The results show that PCTR1 reduced serum inflammatory factors and ameliorated morphological damage and dysfunction of the lung, liver, kidney, and ultimately improved the survival rate of LPS-induced acute inflammation in mice. In addition, metabolomics analysis and high performance liquid chromatography-mass spectrometry revealed that LPS-stimulated serum linoleic acid (LA), arachidonic acid (AA), and prostaglandin E2 (PGE2) levels were significantly altered by PCTR1. Moreover, PCTR1 upregulated LPS-inhibited fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongase of very long chain fatty acids 2 (ELOVL2) expression, and downregulated LPS-stimulated phospholipase A2 (PLA2) expression to increase the intrahepatic content of AA. However, these effects of PCTR1 were partially abrogated by a lipoxin A4 receptor (ALX) antagonist (BOC-2). In summary, via the activation of ALX, PCTR1 promotes the conversion of LA to AA through upregulation of FADS1, FADS2, and ELOVL2 expression, and inhibits the conversion of bound AA into free AA through downregulation of PLA2 expression to decrease the serum AA and PGE2 levels.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/metabolismo , Ácido Linoleico/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosfolipases A2/metabolismo , Animais , Antígenos CD59 , Ácidos Docosa-Hexaenoicos/química , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfolipases A2/genética
10.
PLoS One ; 15(2): e0229435, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107491

RESUMO

A collection of evidence suggests that conjugation of double bonds of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, omega-3 polyunsaturated fatty acids (n-3 PUFAs), increases their anticarcinogenic activity; however, the effect of such conjugation on vascular tone activity remains unknown. We propose that the mixture of conjugated PUFAs exerts higher vasorelaxation activity than the corresponding mixture of nonconjugated PUFAs. The vascular response to different concentrations of conjugated and nonconjugated isomers of EPA and DHA, among other fatty acids (FAs) naturally present in shark oil, and the role of nitric oxide (NO) as a vasorelaxant agent were investigated. Both conjugated EPA (CEPA) and conjugated DHA (CDHA) were prepared by alkaline isomerization of all PUFAs contained in shark oil. Different concentrations of conjugated and nonconjugated PUFAs were placed in contact with precontracted aortic rings of Wistar rats to assess their effect on vascular tone. All tested samples exerted a vasorelaxant effect. Compared to nonconjugated PUFAs, conjugated isomers exhibited an increase in the dilatation of the aortic rings (P<0.001) in a dose-dependent manner (P<0.001). In addition, nonconjugated PUFAs produced nitric oxide (NO) in a dose-dependent manner, while conjugated PUFAs did not, suggesting that their dilatation mechanism is not totally dependent on NO.


Assuntos
Aorta Torácica/fisiologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Óleos de Peixe/farmacologia , Óxido Nítrico/metabolismo , Vasodilatação/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ácidos Graxos/metabolismo , Óleos de Peixe/química , Isomerismo , Masculino , Ratos , Ratos Wistar , Tubarões , Vasodilatação/efeitos dos fármacos
11.
Biosci Biotechnol Biochem ; 84(4): 743-756, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31889475

RESUMO

The current study aimed to investigate the antitumor and antiangiogenesis effects of apatinib in triple-negative breast cancer in vitro and also whether the combination of docosahexaenoic acid (DHA) and apatinib is more effective than apatinib monotherapy. The cell counting kit-8 assay was used to measure cell proliferation. Flow cytometry was utilized to determine the cell apoptosis rate. A wound healing assay was utilized to assess cell migration. Western blot analysis was carried out to determine the effects of apatinib and DHA on Bcl-2, BAX, cleaved caspase-3, caspase-3, phosphorylated protein kinase B (p-Akt), and Akt expression. DHA in combination with apatinib showed enhanced inhibitory effects on cell proliferation and migration compared with apatinib or DHA monotherapy. Meanwhile, DHA combined with apatinib strongly increased the cell apoptosis percentage. DHA was observed to enhance the antitumor and antiangiogenesis effects of apatinib via further downregulation of p-Akt expression.Abbreviations: FITC: fluorescein isothiocyanate; PI: propidium iodide.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Piridinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Sinergismo Farmacológico , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/administração & dosagem , Piridinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia
12.
FASEB J ; 34(1): 597-609, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914705

RESUMO

Inflammation-resolution is mediated by the balance between specialized pro-resolving mediators (SPMs) like resolvin D1 (RvD1) and pro-inflammatory factors, like leukotriene B4 (LTB4). A key cellular process of inflammation-resolution is efferocytosis. Aging is associated with defective inflammation-resolution and the accumulation of pro-inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a model of hind limb ischemia-reperfusion (I/R) remote lung injury, we present evidence that aging is associated with heightened inflammation, impaired SPM:LT ratio, defective efferocytosis, and a decrease in MerTK levels in injured lungs. Treatment with RvD1 mitigated I/R lung injury in aging, promoted efferocytosis, and prevented the decrease of MerTK in injured lungs from old mice. Old MerTK cleavage-resistant mice (MerTKCR) exhibited less neutrophils or polymorpho nuclear cells infiltration and had improved efferocytosis compared with old WT controls. Mechanistically, macrophages that were treated with conditioned media (CM) from senescent cells had increased MerTK cleavage, impaired efferocytosis, and a defective RvD1:LTB4 ratio. Macrophages from MerTKCR mice were resistant to CM-induced efferocytosis defects and had an improved RvD1:LTB4 ratio. RvD1-stimulated macrophages prevented CM-induced MerTK cleavage and promoted efferocytosis. Together, these data suggest a new mechanism and a potential therapy to promote inflammation-resolution and efferocytosis in aging.


Assuntos
Envelhecimento , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , c-Mer Tirosina Quinase/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/metabolismo , Peritonite/tratamento farmacológico , Fagocitose/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
13.
Int J Mol Sci ; 21(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952110

RESUMO

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.


Assuntos
Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Ácidos Docosa-Hexaenoicos/química , Ácidos Graxos Ômega-3/química , Hepatócitos/citologia , Hepatócitos/metabolismo , Fígado/irrigação sanguínea , Fígado/fisiopatologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Transaminases/metabolismo
14.
FASEB J ; 34(2): 2483-2496, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31909535

RESUMO

Deoxynivalenol (DON) is one of the most common mycotoxins that contaminates food or feed and cause intestinal damage. Long-chain n-3 polyunsaturated fatty acids (PUFA) such as EPA and DHA exert beneficial effects on intestinal integrity in animal models and clinical trials. Necroptosis signaling pathway plays a critical role in intestinal cell injury. This study tested the hypothesis that EPA and DHA could alleviate DON-induced injury to intestinal porcine epithelial cells through modulation of the necroptosis signaling pathway. Intestinal porcine epithelial cell 1 (IPEC-1) cells were cultured with or without EPA or DHA (6.25-25 µg/mL) in the presence or absence of 0.5 µg/mL DON for indicated time points. Cell viability, cell number, lactate dehydrogenase (LDH) activity, cell necrosis, transepithelial electrical resistance (TEER), fluorescein isothiocyanate-labeled dextran 4kDa (FD4) flux, tight junction protein distribution, and protein abundance of necroptosis related signals were determined. EPA and DHA promoted cell growth indicated by higher cell viability and cell number, and inhibited cell injury indicated by lower LDH activity in the media. EPA and DHA also improved intestinal barrier function, indicated by higher TEER and lower permeability of FD4 flux as well as increased proportions of tight junction proteins located in the plasma membrane. Moreover, EPA and DHA decreased cell necrosis demonstrated by live cell imaging and transmission electron microscopy. Finally, EPA and DHA downregulated protein expressions of necroptosis related signals including tumor necrosis factor receptor (TNFR1), receptor interacting protein kinase 1 (RIP1), RIP3, phosphorylated mixed lineage kinase-like protein (MLKL), phosphoglycerate mutase family 5 (PGAM5), dynamin-related protein 1 (Drp1), and high mobility group box-1 protein (HMGB1). EPA and DHA also inhibited protein expression of caspase-3 and caspase-8. These results suggest that EPA and DHA prevent DON-induced intestinal cell injury and enhance barrier function, which is associated with inhibition of the necroptosis signaling pathway.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Células Epiteliais , Mucosa Intestinal , Necroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tricotecenos/toxicidade , Animais , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Suínos
15.
Int J Mol Sci ; 21(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963714

RESUMO

In the case of neurodegenerative pathologies, the therapeutic arsenal available is often directed towards the consequences of the disease. The purpose of this study is, therefore, to evaluate the ability of docosahexaenoic acid (DHA), a molecule present in certain foods and considered to have health benefits, to inhibit the cytotoxic effects of very long-chain fatty acids (C24:0, C26:0), which can contribute to the development of some neurodegenerative diseases. The effect of DHA (50 µM) on very long-chain fatty acid-induced toxicity was studied by several complementary methods: phase contrast microscopy to evaluate cell viability and morphology, the MTT test to monitor the impact on mitochondrial function, propidium iodide staining to study plasma membrane integrity, and DHE staining to measure oxidative stress. A Western blot assay was used to assess autophagy through modification of LC3 protein. The various experiments were carried out on the cellular model of 158N murine oligodendrocytes. In 158N cells, our data establish that DHA is able to inhibit all tested cytotoxic effects induced by very long-chain fatty acids.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos/análise , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/citologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Modelos Animais , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
16.
Fish Shellfish Immunol ; 97: 608-616, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31614198

RESUMO

Polyunsaturated fatty acids (PUFAs) play important roles in organisms, including the structure and liquidity of cell membranes, anti-oxidation and anti-inflammation. Very little has been done in terms of the effect of PUFAs on cell death, especially on DNA virus. In this study, we demonstrated that the infectious spleen and kidney necrosis virus (ISKNV) can induce host cell death via the apoptotic cell death pathway, which correlated to modulation by PUFAs in grouper fin cell line (GF-1) cells. We screened the PUFAs, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for the ability of different dosages to prevent cell death in GF-1 cells with ISKNV infection. In the results, each 10 µM of DHA and EPA treatment enhanced host cell viability up to 80% at day 5 post-infection. Then, in Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay, DHA- and EPA-treated groups reduced TUNEL positive signals 50% in GF-1 cells with ISKNV infection. Then, through studies of the mechanism of cell death, we found that ISKNV can induce both the Bax/caspase-3 and Fas/caspase-8/tBid death signaling pathways in GF-1 cells, especially at day 5 post-infection. Furthermore, we found that DHA and EPA treatment can either prevent caspase-3 activation on 17-kDa form cleavage or Bid cleaved (15-kDa form) for activation by caspase-8, apparently. On the other hand, the anti-apoptotic gene Bcl-2 was upregulated 0.3-fold and 0.15-fold at day 3 and day 5, respectively, compared to ISKNV-infected and DHA-treated cells; that this did not happen in the EPA-treated group showed that different PUFAs trigger different signals. Finally, ISKNV-infected GF-1 cells treated with either DHA or EPA showed a 5-fold difference in viral titer at day 5. Taken together, these results suggest that optimal PUFA treatment can affect cell death signaling through both the intrinsic and extrinsic death pathways, reducing viral expression and viral titer in GF-1 cells. This finding may provide insight in DNA virus infection and control.


Assuntos
Bass/imunologia , Morte Celular/efeitos dos fármacos , Infecções por Vírus de DNA/veterinária , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Doenças dos Peixes/tratamento farmacológico , Iridoviridae/fisiologia , Nadadeiras de Animais , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Infecções por Vírus de DNA/tratamento farmacológico , Infecções por Vírus de DNA/virologia , Doenças dos Peixes/virologia , Transdução de Sinais/efeitos dos fármacos
17.
Arch Biochem Biophys ; 679: 108156, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629711

RESUMO

Recently, growing attention has been given to new classes of bioactive lipid mediators derived from ω-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), especially in the context of their role as endogenous signal modulators. One such molecule is 17-oxo-DHA, generated from DHA by the action of COX2 and a dehydrogenase. The redox-sensitive transcription factor, Nrf2 plays a key role in cellular stress responses. In the present study, the effects of 17-oxo-DHA on Nrf2-mediated expression of cytoprotective enzymes were examined in mouse skin in vivo and cultured murine epidermal JB6 cells. Topical application of 17-oxo-DHA markedly elevated the nuclear localization of Nrf2 and expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 in hairless mouse skin. In contrast to 17-oxo-DHA, the non-electrophilic metabolic precursor 17-hydroxy-DHA was a much weaker inducer of Nrf2 activation and its target protein expression. Likewise, 17-oxo-DHA significantly enhanced nuclear translocation and transcriptional activity of Nrf2 with concomitant upregulation of HO-1 expression in cultured JB6 cells. 17-Oxo-DHA was a much stronger inducer of Nrf2-mediated antioxidant response than its parent molecule, DHA. HO-1 expression was abolished in Nrf2 knockdown JB6 cells or embryo fibroblasts from Nrf2 knock out mice. 17-Oxo-DHA also markedly reduced the level of Keap1 protein by inducing ubiquitination. Mutation of Cys151 and Cys273 in Keap1 abrogated 17-oxo-DHA-induced ubiquitination and proteasome-mediated degradation of Keap1 as well as HO-1 expression, suggesting that these cysteine residues are putative sites for 17-oxo-DHA binding. Further, Keap1 degradation stimulated by 17-oxo-DHA coincided with accumulation of the autophagy substrate, p62/SQSTM1.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Epiderme/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Epiderme/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica
18.
Mol Cell Endocrinol ; 499: 110615, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628964

RESUMO

Chronic high-fat diet (HFD) consumption causes ovarian dysfunction in rodents. Acute dietary treatment with docosahexaenoic acid (DHA) increases oocyte quality and ovarian reserve at advanced reproductive age. We hypothesized that DHA supplementation after HFD exposure reverses HFD-induced ovarian defects. We conducted a dietary intervention with reversal to chow, DHA-supplemented chow, or DHA-supplemented HFD after HFD consumption. After 10 weeks, HFD-fed mice had impaired estrous cyclicity, decreased primordial follicles, and altered ovarian expression of 24 genes compared to chow controls. Diet reversal to either chow or chow + DHA restored estrous cyclicity, however only chow + DHA appeared to mitigated the impact of HFD on ovarian reserve. All dietary interventions restored HFD-dysregulated gene expression to chow levels. We found no association between follicular fluid DHA levels and ovarian reserve. In conclusion our data suggest some benefit of DHA supplementation after HFD, particularly in regards to ovarian gene expression, however complete restoration of ovarian function was not achieved.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ciclo Estral/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Ovário/efeitos dos fármacos , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Ovário/química
19.
Int J Mol Sci ; 20(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817347

RESUMO

The browning of white adipose tissue (beige adipocytes) stimulates energy expenditure. Omega-3 fatty acids have been shown to induce thermogenic action in adipocytes via G-protein coupled receptor 120 (GPR120). Atrial natriuretic peptide (ANP) is a peptide hormone that plays the role of maintaining normal blood pressure in kidneys to inhibit Na+ reuptake. Recently, ANP was found to induce adipocyte browning by binding to NPR1, an ANP receptor. However, the expression of ANP in adipocytes has not yet been studied. Therefore, in this study, we investigate the expression of ANP in beige-like adipocytes induced by docosahexaenoic acids (DHA), T3, or a PPAR agonist, rosiglitazone. First, we found that brown adipocyte-specific genes were upregulated in beige-like adipocytes. DHA promoted ANP expression in beige-like cells, whereas DHA-induced ANP expression was abolished by GPR120 knockout. ANP secretion of beige-like adipocytes was increased via PKC/ERK1/2 signaling in the GPR120 pathway. Furthermore, ANP secreted from beige-like adipocytes acted on HEK-293 cells, the recipient cells, leading to increased cGMP activity. After the NPR1 knockdown of HEK-293 cells, cGMP activity was not changed. Taken together, our findings indicate that beige-like adipocytes induce ANP secretion, which may contribute to improving obesity-associated metabolic disease.


Assuntos
Adipócitos Bege/metabolismo , Fator Natriurético Atrial/biossíntese , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células 3T3-L1 , Adipócitos Bege/citologia , Animais , Fator Natriurético Atrial/genética , GMP Cíclico/genética , GMP Cíclico/metabolismo , Técnicas de Inativação de Genes , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismo
20.
Med Sci Monit ; 25: 8181-8189, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31671079

RESUMO

BACKGROUND This study aimed to investigate the effects of maresin-1 (MaR1) in a mouse model of caerulein-induced acute pancreatitis (AP). MATERIAL AND METHODS Fifty C57BL/6 mice with caerulein-induced AP were divided into the untreated control group (N=10), the untreated AP model group (N=10), the MaR1-treated (low-dose, 0.1 µg) AP model group (N=10), the MaR1-treated (middle-dose, 0.5 µg) AP model group (N=10), and the MaR1-treated (high-dose, 1 µg) AP model group (N=10). Enzyme-linked immunoassay (ELISA) measured serum levels of amylase, lipase, tumor necrosis factor-alpha (TNF-alpha), interleukin-1ß (IL-1ß), and IL-6 and mRNA was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA), protein carbonyls, superoxide dismutase (SOD), and the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) were measured. Histology of the pancreas included measurement of acinar cell apoptosis using the terminal-deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) assay. Western blot measured Toll-like receptor 4 (TLR4), MyD88, and phospho-NF-kappaB p65, and apoptosis-associated proteins Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9. RESULTS Following treatment with MaR1, serum levels of amylase, lipase, TNF-alpha, IL-1ß, and IL-6 decreased, MDA and protein carbonyl levels decreased, SOD and the GSH/GSSG ratio increased in a dose-dependent manner. In the MaR1-treated AP mice, inflammation of the pancreas and the expression of inflammatory cytokines, pancreatic acinar cell apoptosis, Bcl-2 expression, and expression of TLR4, MyD88, and p-NF-kappaB p65 were reduced, but Bax, cleaved caspase-3, and cleaved caspase-9 expression increased. CONCLUSIONS In a mouse model of caerulein-induced AP, treatment with MaR1 reduced oxidative stress and inflammation and reduced apoptosis.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Pancreatite/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Ceruletídeo/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/fisiopatologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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