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1.
Chem Biol Interact ; 311: 108794, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421115

RESUMO

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.


Assuntos
Diterpenos/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
2.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 445-449, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357761

RESUMO

Objective: To observe whether liraglutide protects HepG2 cells from lipotoxicity by affecting mitogen-activated protein kinase (MAPKs) pathway. Methods: HepG2 cells were induced with 400µmol/L palmitic acid, and cells were treated with a final concentration of 100 nmol/L liraglutide. In addition, JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580) were added in advance, respectively. Apoptosis rate, malondialdehyde (MDA) content, and caspase3 activity were detected. Western blot was used to detect p38 mitogen-activated protein kinase (p38 MAPK), c-jun amino terminal kinase (JNK), cytochrome oxidase P450 2E1 (CYP2E1), glucose regulatory protein 78 (GRP78), activated caspase 3, B cell lymphoma associated Protein X (Bax), B cell lymphoma 2 (Bcl-2), and expression of C/EBP homologous protein (CHOP) protein. LSD or Dunnett's T3 test were used to compare the mean of multiple samples. Results: Palmitic acid increased the phosphorylation of p38 MAPK and JNK in HepG2 cells (P< 0.05). Furthermore, it increased the expression of GRP78, CHOP, CYP2E1, MDA, Bax, caspase3 and apoptosis rate, but inhibited the expression of Bcl-2 (Pvalue < 0.05). SP600125 and SB203580 had inhibited oxidative stress and apoptosis induced by palmitic acid (including CYP2E1, MDA, Bax, Bcl-2, caspase3, CHOP) (P< 0.05). The phosphorylation level of p38 MAPK and JNK was reduced with liraglutide and the expression of apoptosis-related proteins (Bax, Bcl-2, caspase3, CHOP) (P< 0.05) was regulated. There was no significant difference in the effect of liraglutide on apoptotic proteins (Bax, Bcl-2, caspase-3, CHOP) (P> 0.05) after pretreatment with those two inhibitors. Conclusion: Palmitic acid has strong lipotoxicity to HepG2 cells and induces apoptosis. Glucagon-like peptide-1 analogue, liraglutide may improve lipotoxicity of palmitic acid by mediating p38 MAPK and JNK pathways.


Assuntos
Apoptose , Carcinoma Hepatocelular , Liraglutida , Neoplasias Hepáticas , Ácido Palmítico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/fisiopatologia , Células Hep G2 , Humanos , Liraglutida/farmacologia , Neoplasias Hepáticas/fisiopatologia , MAP Quinase Quinase 4/metabolismo , Ácido Palmítico/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Mol Med Rep ; 19(6): 5087-5096, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059046

RESUMO

The present study aimed to investigate the inhibitory effects and the mechanisms underlying 17ß­estradiol (E2) effects on triglyceride synthesis and insulin resistance in skeletal muscle tissues and cells. Ovariectomy (OVX) was performed on 6­month­old female rats treated with or without E2. Subsequently, various serum biochemical markers were measured. Additionally, pathological alterations of the uterus, liver and skeletal muscle were analyzed, and the content of triglycerides (TG) in muscle was detected. Differentiated myotubes formed by C2C12 cells were treated with palmitic acid (PA) or pretreated with E2, estrogen receptor (ESR) 1 agonist propylpyrazoletriol (PPT) and ESR2 agonist diarylpropionitrile (DPN). Subsequently, the mRNA or protein expression levels of ESR1/2, peroxisome proliferator activated receptor α (PPARα), CD36 molecule (CD36), fatty acid synthase (FASN), perilipin 2 (PLIN2), phosphorylated acetyl­CoA carboxylase α (p­ACACA), p­AKT serine/threonine kinase (p­AKT) and p­mitogen­activated protein kinase 8 (p­MAPK8) were analyzed in skeletal muscle or in C2C12 cells by reverse transcription­semi­quantitative polymerase chain reaction and western blotting. The present results suggested that treatment with E2 inhibited OVX­induced body weight gain, TG accumulation and insulin resistance. The protein or mRNA expression levels of ESR1, CD36, PPARα, p­ACACA and p­AKT were decreased, whereas the protein or mRNA expression levels of ESR2, PLIN2, FASN and p­MAPK8 were increased in the OVX group. Of note, treatment with E2 restored the expression levels of the aforementioned factors. In C2C12 cells, treatment with E2 or PPT reversed the alterations induced by treatment with PA. In contrast, pretreatment with DPN did not influence the effect of PA. Collectively, E2 was able to interact with ESR1, thus activating the CD36­PPARα pathway, decreasing the level of TG in the muscles and improving insulin resistance in skeletal muscles and C2C12 cells.


Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Resistência à Insulina , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ovariectomia , Ácido Palmítico/farmacologia , Perilipina-2/genética , Perilipina-2/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
4.
J Ovarian Res ; 12(1): 43, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077207

RESUMO

BACKGROUND: Palmitic acid (PA), the main component of dietary saturated fat, causes apoptosis in many cell types, including mouse granulosa cell. Melatonin, an important endogenous hormone, has beneficial effects on female reproductive processes. Since elevated PA levels are present in follicular fluid (FF) of patients with infertility and are shown to be toxic for granulosa cells, we investigated the molecular mechanisms of PA toxicity in mouse granulosa cells and explored the effects of melatonin on PA-induced apoptosis. METHODS: Granulosa cells from immature female mice were cultured for 24 h in medium containing PA and/or melatonin. Then, the effects of PA alone or combined with melatonin on viability, apoptosis and endoplasmic reticulum (ER) stress in granulosa cells were detected by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry assay and western blot. After 48 h of PA and/or melatonin treatment, the concentrations of estradiol (E2) and progesterone (P4) in the culture supernatants were measured with ELISA kits. RESULTS: In this study, we explored the effects of melatonin on cell viability and apoptosis in PA-treated mouse granulosa cells and uncovered the signaling pathways involved in these processes. Our results showed that 200-800 µM PA treatment reduces cell viability, induces cell apoptosis, enhances the expression of apoptosis-related genes (Caspase 3 and B-cell lymphoma-2 (BCL-2) associated X protein (BAX)), and activates the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Melatonin treatment (1-10 µM) suppresses 400 µM PA-induced cell viability decrease, cell apoptosis, Caspase 3 activation, and BAX, CHOP, and GRP78 expression. In addition, we found that 10 µM melatonin successfully attenuated the 400 µM PA-induced estrogen (E2) and progesterone (P4) decreases. CONCLUSIONS: This study suggests that PA triggers cell apoptosis via ER stress and that melatonin protects cells against apoptosis by inhibiting ER stress in mouse granulosa cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Melatonina/farmacologia , Ácido Palmítico/farmacologia , Animais , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Células da Granulosa/citologia , Humanos , Camundongos , Modelos Animais
5.
Neurochem Res ; 44(7): 1745-1754, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073968

RESUMO

Increased levels of circulating fatty acids, such as palmitic acid (PA), are associated with the development of obesity, insulin resistance, type-2 diabetes and metabolic syndrome. Furthermore, these diseases are linked to an increased risk of cancer, cardiovascular diseases, mild cognitive impairment and even Alzheimer's disease (AD). However, the precise actions of elevated PA levels on neurons and their association with neuronal metabolic disruption that leads to the expression of pathological markers of AD, such as the overproduction and accumulation of the amyloid-ß peptide, represent an area of intense investigation. A possible molecular mechanism involved in the effects of PA may be through dysfunction of the NAD+ sensor enzyme, SIRT1. Therefore, the aim of the present study was to analyze the relationship between the effects of PA metabolism on the function of SIRT1 and the upregulation of BACE1 in cultured hippocampal neurons. PA reduced the total amount of NAD+ in neurons that caused an increase in p65 K310 acetylation due to inhibition of SIRT1 activity and low protein content. Furthermore, BACE1 protein and its activity were increased, and BACE1 was relocated in neurites after PA exposure.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Hipocampo/metabolismo , NAD/metabolismo , Neurônios/metabolismo , Ácido Palmítico/farmacologia , Sirtuína 1/metabolismo , Acetilação , Animais , Ratos Wistar , Fator de Transcrição RelA/química , Fator de Transcrição RelA/metabolismo , Regulação para Cima
6.
Mol Cell Biochem ; 458(1-2): 113-124, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993495

RESUMO

Lipotoxicity, an accumulation of intracellular lipid metabolites, has been proposed as an important pathogenic mechanism contributing to kidney dysfunction in the context of metabolic disease. Palmitic acid, a predominant lipid derivative, can cause lipoapoptosis and the release of inflammatory extracellular vesicles (EVs) in hepatocytes, but the effect of lipids on EV production in chronic kidney disease remains vaguely explored. This study was aimed to investigate whether palmitic acid would stimulate EV release from renal proximal tubular epithelial cells. Human and rat proximal tubular epithelial cells, HK-2 and NRK-52E, were incubated with 1% bovine serum albumin (BSA), BSA-conjugated palmitic acid (PA), and BSA-conjugated oleic acid (OA) for 24-48 h. The EVs released into conditioned media were isolated by ultracentrifugation and quantified by nanoparticle-tracking analysis (NTA). According to NTA, the size distribution of EVs was 30-150 nm with similar mode sizes in all experimental groups. Moreover, BSA-induced EV release was significantly enhanced in the presence of PA, whereas EV release was not altered by the addition of OA. In NRK-52E cells, PA-enhanced EV release was associated with an induction of cell apoptosis reflected by an increase in cleaved caspase-3 protein by Western blot and Annexin V positive cells analyzed by flow cytometry. Additionally, confocal microscopy confirmed the uptake of lipid-induced EVs by recipient renal proximal tubular cells. Collectively, our results indicate that PA stimulates EV release from cultured proximal tubular epithelial cells. Thus, extended characterization of lipid-induced EVs may constitute new signaling paradigms contributing to chronic kidney disease pathology.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/metabolismo , Vesículas Extracelulares/metabolismo , Túbulos Renais Proximais/metabolismo , Ácido Palmítico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Células Epiteliais/citologia , Humanos , Túbulos Renais Proximais/citologia , Ácido Palmítico/química , Ratos
7.
J Antibiot (Tokyo) ; 72(6): 498-506, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30988370

RESUMO

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a growing class of natural products found in organisms ranging from plants to humans. The roles these endogenous derivatives of fatty acids play in biology and their novel pathways for controlling inflammation have increased our understanding of basic human physiology. FAHFAs incorporate diverse fatty acids into their structures, however, given their recent discovery non-natural derivatives have not been a focus and as a result structure-activity relationships remain unknown. The importance of the long chain hydrocarbons extending from the ester linkage as they relate to anti-inflammatory activity is unknown. Herein the systematic removal of carbons from either the hydroxy fatty acid or fatty acid regions of the most studied FAHFA, palmitic acid ester of 9-hydroxystearic acid (9-PAHSA), was achieved and these synthetic, abridged analogs were tested for their ability to attenuate IL-6 production. Reduction of the carbon chain lengths of the 9-hydroxystearic acid portion or palmitic acid hydrocarbon chain resulted in lower molecular weight analogs that maintained anti-inflammatory activity or in one case enhanced activity.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácido Palmítico/química , Ácido Palmítico/farmacologia , Ácidos Esteáricos/química , Ácidos Esteáricos/farmacologia , Animais , Anti-Inflamatórios/química , Camundongos , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
8.
Mol Med Rep ; 19(6): 4797-4805, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957183

RESUMO

Perivascular adipose tissue (PVAT) is considered to serve a vital role during the development of endothelial dysfunction. The current study investigated the effect of exosomes derived from mangiferin­stimulated PVAT on endothelial function, including regeneration, migration, apoptosis and inflammation. The number of exosomes secreted by PVAT was increased by stimulation with mangiferin (0.1, 1 or 10 µM), and uptake of these exosomes by endothelial cells was observed. Exosomes produced by stimulation of PVAT with mangiferin reversed the effects of inflammation­induced endothelial dysfunction following palmitic acid (PA) treatment. Furthermore, nuclear factor (NF)­κB signaling in endothelial cells was significantly increased when treated with PA­induced PVAT­derived exosomes, whereas exosomes from the supernatant of PVAT stimulated with mangiferin reduced p65 and p50 phosphorylation levels in the cells, and inhibited p65 transportation to the nucleus. Taken together, the present study demonstrated that exosomes derived from mangiferin­stimulated PVAT supernatant inhibited inflammation­induced endothelial dysfunction via modulation of NF­κB signaling.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Exossomos/metabolismo , Doenças Vasculares/metabolismo , Xantonas/farmacologia , Tecido Adiposo/patologia , Animais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Inflamação , Masculino , NF-kappa B , Ácido Palmítico/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
9.
Cell Physiol Biochem ; 52(2): 212-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30816669

RESUMO

BACKGROUND/AIMS: MIP-1α (macrophage inflammatory protein 1α)/CCL3 chemokine is associated with the adipose tissue inflammation in obesity. Both MIP-1α and free fatty acids are elevated in obesity/T2D. We asked if free fatty acid palmitate could modulate MIP1α expression in the human monocytic cells. METHODS: Human monocytic THP-1 cells and macrophages were stimulated with palmitate and TNF-α (positive control). MIP-1α expression was measured with real time RT-PCR, Flow Cytometry and ELISA. Signaling pathways were identified by using THP-1-XBlue™ cells, THP-1-XBlue™-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. RESULTS: Our data show that palmitate induced significant increase in MIP1α production in monocytic THP-1 cells/macrophages. MIP-1α induction was significantly suppressed when cells were treated with anti-TLR4 antibody prior stimulation with palmitate. Using TLR4 siRNA, we further demonstrate that palmitate-induced MIP-1α expression in monocytic cells requires TLR4. Moreover, THP1 cells defective in MyD88, a major adaptor protein involved in TLR4 signaling, were unable to induce MIP-1α production in response to palmitate. Palmitate-induced MIP-1α expression was suppressed by inhibition of MAPK, NFkB and PI3K signaling pathways. In addition, palmitate-induced NF-κB/AP-1 activation was observed while production of MIP-1α. However, this activation of NF-κB/AP-1 was abrogated in MyD88 deficient cells. CONCLUSION: Overall, these results show that palmitate induces TLR4dependent MIP-1α expression requiring the MyD88 recruitment and activation of MAPK, NF-κB/AP-1 and PI3K signaling. It implies that the increased systemic levels of free fatty acid palmitate in obesity/T2D may contribute to metabolic inflammation through excessive production of MIP-1a.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/metabolismo , Ácido Palmítico/farmacologia , Receptor 4 Toll-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Macrófagos/patologia , Monócitos/patologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Células THP-1 , Receptor 4 Toll-Like/genética
10.
Cell Physiol Biochem ; 52(3): 486-502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873823

RESUMO

BACKGROUND/AIMS: Cross-talk between different pancreatic islet cell types regulates islet function and somatostatin (SST) released from pancreatic delta cells inhibits insulin secretion from pancreatic beta cells. In other tissues SST exhibits both protective and pro-apoptotic properties in a tissue-specific manner, but little is known about the impact of the peptide on beta cell survival. Here we investigate the specific role of SST in the regulation of beta cell survival in response to physiologically relevant inducers of cellular stress including palmitate, cytokines and glucose. METHODS: Pancreatic MIN6 beta cells and primary mouse islet cells were pre-treated with SST with or without the Gi/o signalling inhibitor, pertussis toxin, and exposed to different cellular stress factors. Apoptosis and proliferation were assessed by measurement of caspase 3/7 activity, TUNEL and BrdU incorporation, respectively, and expression of target genes was measured by qPCR. RESULTS: SST partly alleviated upregulation of cellular stress markers (Hspa1a and Ddit3) and beta cell apoptosis in response to factors such as lipotoxicity (palmitate), pro-inflammatory cytokines (IL1ß and TNFα) and low glucose levels. This effect was mediated via a Gi/o protein-dependent pathway, but did not modify transcriptional upregulation of the specific NFκB-dependent genes, Nos2 and Ccl2, nor was it associated with transcriptional changes in SST receptor expression. CONCLUSION: Our results suggest an underlying protective effect of SST which modulates the beta cell response to ER stress and apoptosis induced by a range of cellular stressors associated with type 2 diabetes.


Assuntos
Proliferação de Células/efeitos dos fármacos , Glucose/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Toxina Pertussis/antagonistas & inibidores , Somatostatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica , Glucose/farmacologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/farmacologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Toxina Pertussis/farmacologia , Técnicas de Cultura de Tecidos , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
11.
Molecules ; 24(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901967

RESUMO

Enfuvirtide (T20) is the first U.S. FDA-approved HIV fusion inhibitor-based anti-HIV drug. Its clinical application is limited because of its low potency and short half-life. We previously reported that peptide HP23-E6-IDL, containing both N- and C-terminal anchor-tails, exhibited stronger potency and a better resistance profile than T20. Here we designed an analogous peptide, YIK, by introducing a mutation, T639I, and then a lipopeptide, YIK-C16, by adding palmitic acid (C16) at the C-terminus of YIK. We found that YIK-C16 was 4.4- and 3.6-fold more potent than HP23-E6-IDL and YIK against HIV-1IIIB infection and 13.3- and 10.5-fold more effective than HP23-E6-IDL and YIK against HIV-1Bal infection, respectively. Consistently, the ex vivo anti-HIV-1IIIB activity, as determined by the highest dilution-fold of the serum causing 50% inhibition of HIV-1 infection, of YIK-C16 in the sera of pretreated mice was remarkably higher than that of YIK or HP23-E6-IDL. The serum half-life (t1/2 = 5.9 h) of YIK-C16 was also significantly longer than that of YIK (t1/2 = 1.3 h) and HP23-E6-IDL (t1/2 = 1.0 h). These results suggest that the lipopeptide YIK-C16 shows promise for further development as a new anti-HIV drug with improved anti-HIV-1 activity and a prolonged half-life.


Assuntos
Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Ácido Palmítico/farmacologia , Peptídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Dicroísmo Circular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Ácido Palmítico/química , Ácido Palmítico/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética
12.
J Dairy Sci ; 102(5): 4155-4164, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879815

RESUMO

The objective of our study was to evaluate the effects of feeding triglyceride and fatty acid (FA) supplements enriched in palmitic acid (PA; C16:0) on production and nutrient digestibility responses of mid-lactation dairy cows. Fifteen Holstein cows (137 ± 49 d in milk) were randomly assigned to a treatment sequence in a 3 × 3 Latin square design. Treatments consisted of a control diet (CON; no added PA) or 1.5% FA added as either a FA supplement (PA-FA) or a triglyceride supplement (PA-TG). The PA supplements replaced soyhulls, and diets were balanced for glycerol content. Periods were 21 d in length with sample and data collection occurring during the final 5 d. Compared with CON, PA treatments increased dry matter (66.5 vs. 63.9%) and neutral detergent fiber (NDF) apparent digestibility (42.0 vs. 38.2%). Although PA treatments tended to increase 18-carbon FA apparent digestibility (79.1 vs. 77.9%), PA treatments decreased 16-carbon (63.1 vs. 75.8%) and total FA (72.0 vs. 76.5%) apparent digestibilities compared with CON. The PA treatments increased milk fat content (3.60 vs. 3.41%), milk fat yield (1.70 vs. 1.60 kg/d), yield of 16-carbon milk FA (570 vs. 471 g/d), 3.5% fat-corrected milk (47.6 vs. 46.5 kg/d), and energy-corrected milk (47.4 vs. 46.6 kg/d) compared with CON. The PA treatments did not affect dry matter intake (28.5 vs. 29.2 kg/d), milk yield (47.0 vs. 47.4 kg/d), milk protein yield (1.42 vs. 1.45 kg/d), milk lactose yield (2.29 vs. 2.31 kg/d), yield of <16-carbon milk FA (360 vs. 370 g/d), yield of >16-carbon milk FA (642 vs. 630 g/d), body weight (720 vs. 723 kg), or body condition score (3.14 vs. 3.23). We did not observe differences in digestibilities of dry matter, NDF, and 18-carbon FA between PA-TG and PA-FA. In contrast, PA-FA increased 16-carbon (68.6 vs. 57.6%) and total FA apparent digestibility (73.8 vs. 70.1%) compared with PA-TG. This resulted in PA-FA supplementation increasing the apparent digestibility of the PA supplement by ∼10 percentage points compared with PA-TG. Compared with PA-TG, PA-FA increased 16-carbon FA intake by 60 g/d, absorbed 16-carbon FA by 86 g/d, and absorbed total FA by 85 g/d. Compared with PA-TG, PA-FA increased dry matter intake (29.1 vs. 27.8 kg/d), yield of 16-carbon milk FA (596 vs. 545 g/d), and tended to increase milk yield (47.6 vs. 46.4 kg/d), milk fat yield (1.70 vs. 1.66 kg/d), and 3.5% fat-corrected milk (48.1 vs. 47.2 kg/d). In conclusion, the production response of dairy cows to PA tended to be greater for a FA supplement compared with a triglyceride supplement. Overall, PA increased NDF digestibility, milk fat yield, energy-corrected milk, and feed efficiency in mid-lactation dairy cows.


Assuntos
Ração Animal , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Ácidos Graxos/farmacologia , Ácido Palmítico/farmacologia , Triglicerídeos/farmacologia , Ração Animal/análise , Animais , Peso Corporal , Fibras na Dieta/metabolismo , Digestão , Ácidos Graxos/administração & dosagem , Ácidos Graxos/metabolismo , Feminino , Lactação , Lactose/metabolismo , Leite , Proteínas do Leite/metabolismo , Nutrientes/metabolismo , Ácido Palmítico/administração & dosagem , Ácido Palmítico/metabolismo , Distribuição Aleatória , Triglicerídeos/administração & dosagem , Triglicerídeos/metabolismo
13.
Fish Shellfish Immunol ; 88: 518-527, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30880233

RESUMO

The objective of this work was to investigate the effect of berberine (BBR) on the Cell viability, lipid accumulation, apoptosis, cytochrome c, caspase-9 and caspase-3 in lipid accumulation-hepatocytes induced by sodium palmitate in vitro. The lipid accumulation-hepatocytes (induced by 0.5 mM sodium palmitate for 24 h) were treated with 5 µM berberine for 12 h. Then, the Cell viability, intracellular triglyceride (TG) content, lipid peroxide (LPO), malonaldehyde (MDA) content, cytochrome c, caspase-9, caspase-3 and apoptosis were detected. Sodium palmitate decreased Cell viability and increased intracellular TG content, lipid droplet accumulation, LPO and MDA concentrations, caused caspase-3 and caspase-9 activation, then led to apoptosis accompanied by cytochrome c release from mitochondria into the cytoplasm. Beberine could improve intracellular lipid droplet accumulation and oxidative stress, while reduce apoptosis induced by sodium palmitate.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/farmacologia , Carpas , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/farmacologia , Animais , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromos c/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Triglicerídeos/metabolismo
14.
Lipids Health Dis ; 18(1): 71, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909920

RESUMO

BACKGROUND: Obesity increases the risk of developing diabetes mellitus. Clinical studies suggest that risk factors like palmitic acid (PA) and lipopolysaccharide (LPS) exist simultaneously in diabetes with obesity. Combination of PA and LPS even at low concentration can induce strong inflammatory reaction. Monocyte chemoattractant protein-1 (MCP-1) is an important inflammatory chemokine related to insulin resistance and type II diabetes. Our previous study using PCR array revealed that LPS and PA synergistically induce MCP-1 mRNA expression in macrophage cells RAW264.7, while the protein expression of MCP-1 in this case was not investigated. Moreover, the underling mechanism in the synergistic effect of MCP-1 expression or production induced by treatment of LPS and PA combination remains unclear. METHODS: Protein secretion of MCP-1 was measured by the enzyme-linked immunosorbent assay (ELISA) and mRNA levels of MCP-1 and Toll-like receptor 4 (TLR4) were measured by real-time PCR. Statistical analysis was conducted using SPSS software. RESULTS: LPS could increase MCP-1 transcription as well as secretion in RAW264.7, and PA amplified this effect obviously. Meanwhile, combination of LPS with PA increased TLR4 mRNA expression while LPS alone or PA alone could not, TLR4 knockdown inhibited MCP-1 transcription/secretion induced by LPS plus PA. Moreover, not NF-κB inhibitor but inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways, including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPK were found to block MCP-1 generation stimulated by LPS plus PA. CONCLUSION: LPS and PA synergistically induced MCP-1 secretion in RAW264.7 macrophage cells, in which MCP-1 transcription mediated by MAPK/TLR4 signaling pathways was involved. Combined treatment of PA and LPS in RAW264.7 cells mimics the situation of diabetes with obesity that has higher level of PA and LPS, MAPK/TLR4/ MCP-1 might be potential therapeutic targets for diabetes with obesity.


Assuntos
Quimiocina CCL2/genética , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase 1/genética , Ácido Palmítico/farmacologia , Receptor 4 Toll-Like/genética , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/patologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
15.
Life Sci ; 221: 341-347, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802511

RESUMO

AIMS: The aim of this study was to assess the effects of enterolactone (ENL) on lipid fractions fatty acids composition affecting hepatocyte inflammation development. MAIN METHODS: The experiments were conducted in HepG2 cells incubated with ENL and/or palmitic acid (16 h). Intracellular contents of free fatty acids (FFA), di- (DAG) and tri- (TAG) acylglycerol as well as their fatty acids compositions were assessed by Gas-Liquid Chromatography. Moreover, the ω-6/ω-3 ratios in the above mentioned lipids fractions were estimated. The expression of proteins involved in eicosanoids and prostanoids production (COX-2, 15-LOX), inflammatory process (TNFα), as well as the proteins participating in the desaturation (SCD 1) and elongation (Elovl 3, Elovl 6) of fatty acids were evaluated by Western Blot. KEY FINDINGS: Enterolactone modified fatty acids composition in FFA, DAG and TAG fractions. In conjunction with lipid overload, it increased the content of ω-6 more than ω-3 PUFA. Moreover, it enhanced the expressions of Elovl 3, Elovl 6, COX-2 and TNFα, whereas it had no influence on SCD 1 and 15-LOX level. SIGNIFICANCE: Our study revealed that the supplementation with ENL affected intracellular hepatic composition of saturated as well as unsaturated fatty acids in each of the investigated lipid fractions. Based on the shift in the ω-6/ω-3 balance towards ω-6, as well as the increase in COX-2 and TNFα protein expressions, we may postulate a pro-inflammatory nature of the examined polyphenol. Moreover, our findings could prove to be useful in the future research in the topic of widespread diseases such as NASH.


Assuntos
4-Butirolactona/análogos & derivados , Ácidos Graxos não Esterificados/metabolismo , Inflamação/tratamento farmacológico , Lignanas/metabolismo , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologia , Eicosanoides , Ácidos Graxos , Ácidos Graxos não Esterificados/análise , Ácidos Graxos Ômega-3 , Ácidos Graxos Insaturados , Células Hep G2/efeitos dos fármacos , Hepatócitos , Humanos , Inflamação/metabolismo , Lignanas/farmacologia , Metabolismo dos Lipídeos , Lipídeos , Fígado/efeitos dos fármacos , Ácido Palmítico/farmacologia , Prostaglandinas , Triglicerídeos/análise
16.
J Dairy Sci ; 102(4): 3000-3009, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30799102

RESUMO

The effects of feeding rumen-inert fat sources on production responses of lactating dairy cows have been well reported but less thoroughly described in lactating dairy buffalo. The objective of this study was to investigate the effect of oil and 2 different rumen-inert fat sources on dry matter intake, milk yield, milk composition, and milk fatty acid (FA) profile in Nili Ravi buffalo. Twelve multiparous mid-lactating Nili Ravi buffaloes received 4 treatments in a 4 × 4 Latin square design with a period length of 21 d. The treatments were (1) the basal diet without supplementation of oil or fats (CTRL), (2) the basal diet supplemented with canola oil (CO), (3) the basal diet supplemented with calcium salts of palm FA (Ca-FA), and (4) the basal diet supplemented with high palmitic acid (PA). Dry matter intake was decreased by 4.4% in the CO compared with Ca-FA and PA. Milk yield and milk fat yield were increased by 7.8 and 14.3%, respectively, in CO, Ca-FA, and PA compared with the CTRL. Milk fat content increased by 7.5%, whereas milk fat yield tended to increase with the supplementation of Ca-FA and PA compared with CO. No effect on milk yield and milk composition was observed in Ca-FA versus PA treatments. The yield of medium-chain FA was increased by Ca-FA and PA versus CO. The CO treatment increased the yield of long-chain FA compared with Ca-FA and PA treatments. Plasma glucose level was higher in CO, Ca-FA, and PA compared with the CTRL. In conclusion, feeding rumen-inert fats in the lactating buffalo diet proved to be a useful strategy to increase the 3.5% fat-corrected milk yield due to the higher milk fat content in this study.


Assuntos
Ração Animal , Búfalos/fisiologia , Dieta/veterinária , Gorduras na Dieta/farmacologia , Lactação , Leite , Animais , Suplementos Nutricionais , Ácidos Graxos/análise , Feminino , Leite/química , Ácido Palmítico/farmacologia , Distribuição Aleatória , Óleo de Brassica napus/farmacologia , Rúmen
17.
J Exp Clin Cancer Res ; 38(1): 52, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717785

RESUMO

BACKGROUND: Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. METHODS: Immunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays. RESULTS: PA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of ß-catenin through inactivation of GSK-3ß via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data. CONCLUSIONS: Our experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3ß/ß-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.


Assuntos
Antígenos CD36/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Ácido Palmítico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , beta Catenina/metabolismo , Animais , Antígenos CD36/biossíntese , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Ácido Palmítico/farmacologia
18.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717198

RESUMO

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Chalconas/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Resistência à Insulina , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células 3T3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aspalathus/química , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Chalconas/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Açúcares da Dieta/efeitos adversos , Regulação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hiperglicemia/etiologia , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hipoglicemiantes/isolamento & purificação , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ácido Palmítico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais
19.
J Diabetes Res ; 2019: 2052675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809553

RESUMO

Elevated free fatty acid (FFA) is a key risk factor for insulin resistance (IR). Our previous studies found that mangiferin could decrease serum FFA levels in obese rats induced by a high-fat diet. Our research was to determine the effects and mechanism of mangiferin on improving IR by regulating FFA metabolism in HepG2 and C2C12 cells. The model was used to quantify PA-induced lipid accumulation in the two cell lines treated with various concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased insulin-stimulated glucose uptake, via phosphorylation of protein kinase B (P-AKT), glucose transporter 2 (GLUT2), and glucose transporter 4 (GLUT4) protein expressions, and markedly decreased glucose content, respectively, in HepG2 and C2C12 cells induced by PA. Mangiferin significantly increased FFA uptake and decreased intracellular FFA and triglyceride (TG) accumulations. The activity of the peroxisome proliferator-activated receptor α (PPARα) protein and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) and the fatty acid ß-oxidation rate corresponding to FFA metabolism were also markedly increased by mangiferin in HepG2 and C2C12 cells. Furthermore, the effects were reversed by siRNA-mediated knockdown of PPARα. Mangiferin ameliorated IR by increasing the consumption of glucose and promoting the FFA oxidation via the PPARα pathway in HepG2 and C2C12 cells.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Xantonas/farmacologia , Animais , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Humanos , Insulina/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
Lipids Health Dis ; 18(1): 52, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764838

RESUMO

BACKGROUND: This study was designed to test the hypothesis that κ-opioid receptor (κ-OR) stimulation reduces palmitate-induced HUVECs apoptosis and to investigate its mechanisms. METHODS: HUVECs were subjected to sodium palmitate, apoptosis and cell viability were determined, HUVECs were treated with specific inhibitors to PI3K, Akt, eNOS and siRNAs targeting κ-OR and Akt. Groups were divided as follows: the control group, the sodium palmitate group, the sodium palmitate+U50,488H (a selective κ-OR agonist) group and the sodium palmitate+U50,488H + nor-BNI (a selective κ-OR antagonist) group. RESULTS: Treatment with sodium palmitate significantly reduced cell viability and increased apoptosis rate which were significantly alleviated by pretreatment with U50,488H, the effect of U50,488H was abolished by nor-BNI. Phosphorylation of Akt and eNOS, as well as NO production were attenuated and accompanied by an increased expression of caspase 3 when HUVECs were subjected to sodium palmitate, and all these changes were restored by pretreatment with U50,488H, the effects of U50,488H were abolished by nor-BNI, and specific inhibitors to PI3K, Akt, eNOS, respectively. SiRNAs targeting κ-OR or Akt abolished the effects of U50,488H on phosphorylation of Akt and eNOS as well as the expressions of caspase 3, Bax and Bcl-2. SiRNAs targeting Akt elicited no effect on the expression of κ-OR. CONCLUSION: This study provides the evidence for the first time that κ-OR stimulation possesses anti-palmitate-induced apoptosis effect, which is mediated by PI3K/Akt/eNOS signaling pathway.


Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Opioides kappa/genética , Analgésicos Opioides/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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