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1.
Clin Interv Aging ; 14: 1481-1492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616139

RESUMO

Nutritional factors can influence the risk of developing Alzheimer's disease (AD) and its rate of progression, and there is, therefore, increasing interest in nutrition as a modifiable risk factor for the disease. Synaptic loss is an important feature of early AD, and the formation of new synapses is dependent on key nutritional elements that are known to be deficient in patients with AD. The daily medical food, Souvenaid, contains Fortasyn Connect, a multinutrient combination developed to specifically address these deficiencies, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, phospholipids, selenium, folic acid, and vitamins B12, B6, C, and E. Although yielding heterogeneous findings, clinical studies of Fortasyn Connect provide preliminary evidence of clinically relevant benefits on cognitive outcomes in prodromal and early AD. The LipiDiDiet trial investigated the effects of Fortasyn Connect on cognition and related measures in prodromal AD, and is the first randomized, controlled, double-blind, multicenter trial study of a non-pharmacological intervention in this setting. The primary efficacy endpoint was change over 24 months in a composite score of cognitive performance using a neuropsychological test battery. Fortasyn Connect had no significant effect on this endpoint, but demonstrated a significant benefit on secondary endpoints, including domains of cognition affected by AD (attention, memory, executive function) and hippocampal atrophy, suggesting a potential benefit on disease progression. Other studies have demonstrated benefits for Fortasyn Connect on nutritional markers and levels of plasma homocysteine. Taken together, current evidence indicates that Fortasyn Connect may show benefit on domains of cognition affected by AD and nutritional measures that influence risk factors for its progression; that it has greater potential for benefit earlier rather than later in the disease; and that it is safe and well tolerated, alone or in combination with AD medications. Further research into its potential role in AD management is therefore warranted.


Assuntos
Doença de Alzheimer/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Estado Nutricional , Fosfolipídeos/uso terapêutico , Idoso , Doença de Alzheimer/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos
2.
Yakugaku Zasshi ; 139(9): 1169-1175, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31474633

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of fat in the liver in the absence of any other disease related to liver steatosis, which includes a wide spectrum ranging from mild asymptomatic fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the pathogenesis of NASH has not been established. In this study, we investigated the involvement of the G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4) in the pathogenesis of NASH. Mice fed a 0.1% methionine- and choline-deficient l-amino acid-defined, high-fat (CDAHF) diet showed a significant increase in plasma aspartate aminotransferase and alanine aminotransferase levels, fatty deposition, inflammatory cell infiltration, and slight fibrosis. Docosahexanoic acid (DHA, a GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in hepatic tissues and prevented liver fibrosis. On the other hand, GPR120/FFAR4-deficient CDAHF-fed mice showed increments in the number of hepatic crown-like structures and immunoreactivity to F4/80-positive cells compared with wild-type mice. Furthermore, the levels of hepatic TNF-α mRNA expression increased in GPR120-deficient mice. These findings suggest that the GPR120/FFAR4-mediating system could be a key signaling pathway to prevent the development of NASH. In this review, we describe our recent data showing that GPR120/FFAR4 could be a therapeutic target in NASH/NAFLD.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
3.
Int Immunopharmacol ; 75: 105788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377587

RESUMO

Depression has become a common mental illness, and studies have shown that neuroinflammation is associated with depression. Ketamine is a rapid antidepressant. In order to obtain better antidepressant effects, it is necessary to explore the efficacy of combination therapy with ketamine and other antidepressants. DHA is an unsaturated fatty acid with excellent application prospects due to its safety and antidepressant effects. This study was designed to investigate the effect of ketamine combined with DHA on lipopolysaccharide-induced depression-like behavior. In behavioral experiments, lipopolysaccharide prolongs the immobility time of the forced swimming and tail suspension tests in rats and reduces the sucrose preference. The combination of ketamine and DHA can reverse these changes and work better than the single application. Nissl staining showed that ketamine combined with DHA can reverse the nerve damage caused by lipopolysaccharide. Cell morphology observation the combination of ketamine and DHA group was more complete than that of LPS group. The combination of ketamine and DHA significantly decreased the levels of IL-1, IL-6 and TNF-ɑin hippocampus and PC12 cells and increased the content of BDNF. Immunofluorescence results showed that ketamine combined with DHA can effectively inhibit PP65 nuclear translocation. Western blot results showed that ketamine combined with DHA can effectively inhibit the expression of NF-KB in hippocampus and PC12 cells, and increase the expression of P-CREB and BDNF. In summary, the combination of ketamine with DHA may be a more effective treatment for depression caused by inflammation and is mediated by inhibition of the inflammatory pathway.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ketamina/uso terapêutico , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocinas/metabolismo , Depressão/induzido quimicamente , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/farmacologia , Lipopolissacarídeos , Masculino , NF-kappa B/metabolismo , Células PC12 , Ratos , Ratos Wistar
4.
Int Immunopharmacol ; 75: 105825, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437789

RESUMO

Mechanical ventilation (MV) is a major support for patients with severe clinical disease, surgery and anesthesia. However, complications of mechanical ventilation especially ventilator-induced lung injury(VILI) can make the course and prognosis worse. Resolvin D1(RvD1) is a class of endogenous polyunsaturated fatty acid derivative, which has protective effects on various pulmonary inflammatory diseases. However, the mechanism of RvD1 in the process of VILI has not been fully elucidated. Our study found that RvD1 does have a protective effect on VILI including inhibiting inflammatory responses, reducing tissue damage and improving pulmonary function. The protective effect of RvD1 is positively related to its dose. Our research suggested RvD1 plays a role that increases the expression of heme oxygenase­1 (HO-1) and decreases the expression of the high mobility group chromosomal protein B1 (HMGB-1) in VILI. HO-1 can exert the protective effect of organism through multiple mechanisms such as anti-inflammatory, anti-oxidation, anti-apoptosis, etc. HMGB1 is a potent inflammatory response factor in the body, which can aggravate the inflammatory response of the body. Our study demonstrated that RvD1 can ameliorate lung inflammation and reduce pathological changes in lung tissue in a model of lung injury induced by mechanical ventilation. The protective role of RvD1 is closely linked to the increased expression of HO-1 and the decreased expression of HMGB1. Moreover, we found that RvD1 can increase the expression of Nrf2 and inhibit the expression of NF-κB. We found the specific inhibitor of HO-1, ZnPP, can significantly inhibit the protective role of RvD1 in VILI. When HO-1 is inhibited, pathological damage and inflammatory reaction in the lungs are considerably aggravated, and pulmonary function is significantly weakened. In addition, the expression of HMGB1 is drastically increased. This indicates that the HO-1-HMGB1 pathway plays an important role in the protective effect of RvD1 on mechanical ventilation lung injury.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Proteína HMGB1/imunologia , Heme Oxigenase-1/imunologia , Proteínas de Membrana/imunologia , Substâncias Protetoras/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Ventiladores Mecânicos/efeitos adversos
5.
Int Immunopharmacol ; 75: 105816, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437794

RESUMO

Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPARγ by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPARγ via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPARγ in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPARγ to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPARγ activation was required for DHA to attenuate liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , PPAR gama/imunologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Células Estreladas do Fígado/imunologia , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos ICR
6.
Biomed Res Int ; 2019: 6254587, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275979

RESUMO

As one of the basic treatment modalities in the intensive care unit (ICU), mechanical ventilation can cause or aggravate acute lung injury or ventilator-induced lung injury (VILI). Resolvin D1 (RvD1) is an endogenous polyunsaturated fatty acid derivative with strong anti-inflammatory action. In this study, we explored if RvD1 possesses a protective effect on VILI. Mice were ventilated with high tidal volume (40 mL/kg, HVT) for 4 h and were then intraperitoneally administered RvD1 at the beginning of high tidal volume ventilation and given GW9662 (a PPAR-γ antagonist) intraperitoneally 30 min before ventilation. RvD1 attenuated VILI, as evidenced by improved oxygenation and reduced histological injury, compared with HVT -induced lung injury. Similarly, it could ameliorate neutrophil accumulation and production of proinflammatory cytokines in lung tissue. In contrast, the protective effect of RvD1 on lung tissue could be reversed by GW9662. RvD1 mitigated VILI by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibiting nuclear factor-kappa B (NF-κB) signaling pathways in mice. In conclusion, RvD1 could reduce the inflammatory response in VILI by activating PPAR-γ and inhibiting NF-κB signaling pathways.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , NF-kappa B/metabolismo , PPAR gama/metabolismo , Transdução de Sinais , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , DNA/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Subunidades Proteicas/metabolismo , Testes de Função Respiratória , Fator de Transcrição RelA/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
7.
Urologiia ; (1): 78-83, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31184022

RESUMO

AIM: docosahexaenoic acid is one of the most common fatty acids in the cell membranes of sperm. This substance is a structural component of cell membranes, and is responsible for such properties as plasticity and fluidity which are necessary for the implementation of the process of capacitation and acrosome reaction. In addition, docosahexaenoic acid has antioxidant properties. Aim of our study was to assess the effect of dietary supplement docosahexaenoic acid (Brudi PLUS) on such markers of male fertility as the sperm DNA integrity, standard indicators of semen analysis and cryotolerance in infertile men. MATERIALS AND METHODS: a randomized, multicenter, double-blind, placebo-controlled study was conducted. A total of 109 infertile men were recruited to participate in the study. All patients underwent different analyzes, including semen analysis, sperm DNA fragmentation, MAR-test, test of cryotolerance and electron microscopy analysis of spermatozoa. In active treatment group patients were prescribed to drug containing 350 mg of docosahexaenoic acid 3 times a day for 90 days. In the control group, patients were administered to a placebo with a similar scheme. All analyzes were repeatedly performed after 3-months of therapy. RESULTS: An increase in the progressive mobility and sperm viability was determined after the test of cryotolerance in the active treatment group. According to electron microscopy analysis of spermatozoa, positive changes were observed in the number of heads of the normal form with the normal structure of chromatin and acrosome, as well as a decrease in the number of spermatozoa with insufficiently condensed chromatin. CONCLUSIONS: the therapy with drug Brudi PLUS in patients with male infertility allows to increase in cryotolerance of sperms as well as decrease in number of sperm ultrastructure defects.


Assuntos
Ácidos Docosa-Hexaenoicos , Infertilidade Masculina , Adulto , DNA/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Humanos , Infertilidade Masculina/tratamento farmacológico , Masculino , Análise do Sêmen , Espermatozoides/efeitos dos fármacos
8.
Food Funct ; 10(7): 4010-4021, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31214670

RESUMO

Acute gouty inflammation could be triggered by phagocytosis of monosodium urate (MSU) by immune cells. This study investigated the protective effect and underlying mechanism of docosahexaenoic acid (DHA) on MSU-induced inflammation in vitro and in vivo. Results showed that DHA effectively inhibited MSU-induced expression and secretion of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in THP-1 cells. Intracellular reactive oxygen species (ROS) production triggered by MSU was alleviated by DHA treatment. Furthermore, DHA promoted the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), wherein Nrf2 further mediated the expression of multiple antioxidant enzymes such as, heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1) and catalase, which are closely related with redox homeostasis. DHA treatment also restored MSU-induced impairment of mitochondrial transmembrane potential. In addition, oral administration of DHA-rich microalgal oil to C57BL/6 mice effectively reduced the infiltration of neutrophils, and decreased the expression and secretion of inflammatory cytokines. Altogether, our results suggest that DHA or DHA-rich microalgal oil may be a promising natural agent for the prevention of MSU-induced inflammation and potentially acute gout at least partly by attenuating oxidative stress.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ácido Úrico/efeitos adversos , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Gota , Heme Oxigenase-1/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Interleucina-1beta/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo
9.
BMJ Case Rep ; 12(5)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31110063

RESUMO

Acute pancreatitis in pregnancy is rare and can be caused by hypertriglyceridaemia. The management of hypertriglyceridaemia in pregnancy is complex and challenging as many lipid-lowering medications have been found to be unsafe in pregnancy. Patients who present with hypertriglyceridaemia commonly have multiple risk factors such as, diabetes, alcohol excess and hypothyroidism which pose a greater challenge to the management of these patients. We present a case of a 31-year-old woman presenting with familial hypertriglyceridaemia and type 2 diabetes mellitus in her third pregnancy. She had an uneventful pregnancy with the use of omega-3 fatty acids nutritional support, low-fat diet and tight glucose control with insulin and metformin.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Dieta com Restrição de Gorduras , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Hiperlipoproteinemia Tipo IV/terapia , Pancreatite/prevenção & controle , Adulto , Diabetes Mellitus Tipo 2/complicações , Combinação de Medicamentos , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/complicações , Gravidez , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez , Triglicerídeos/sangue
10.
Optom Vis Sci ; 96(6): 387-396, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31116166

RESUMO

SIGNIFICANCE: Identification of the association of specific signs of dry eye disease with specific visual function deficits may allow for more targeted approaches to treatment. PURPOSE: The purpose of this study was to explore the association of dry eye signs and symptoms with visual acuity (VA) and contrast sensitivity in the Dry Eye Assessment and Management study. METHODS: Baseline data from participants in the Dry Eye Assessment and Management study were used in this secondary cross-sectional analysis. Standardized procedures were used to obtain results on the Ocular Surface Disease Index (OSDI), high-contrast logMAR VA, contrast sensitivity, tear film debris, tear breakup time (TBUT), corneal fluorescein staining, meibomian gland evaluation, conjunctival lissamine green staining, and Schirmer test scores. Generalized linear models that included age, refractive error status, and cataract status were used to assess the association between VA and contrast sensitivity with OSDI score and each dry eye sign. The Hochberg procedure was used to account for multiple comparisons. RESULTS: Among 487 participants (974 eyes), worse VA was associated with worse mean score on the OSDI vision subscale (39.4 for VA 20/32 or worse vs. 32.4 for VA 20/16 or better; adjusted linear trend, P = .02); scores were not associated with contrast sensitivity. Severe meibomian gland plugging and abnormal secretions were associated with worse mean log contrast sensitivity (1.48 for severe vs. 1.54 for not plugged [P = .04] and 1.49 for obstructed vs. 1.57 for clear [P = .002], respectively). Longer TBUT was associated with better mean log contrast sensitivity (1.57 for TBUT >5 seconds and 1.51 for TBUT ≤2 seconds, P < .0001). CONCLUSIONS: Worse VA rather than worse contrast sensitivity drives vision-related symptoms in dry eye. Greater tear film instability was associated with worse contrast sensitivity.


Assuntos
Sensibilidades de Contraste/fisiologia , Síndromes do Olho Seco/fisiopatologia , Acuidade Visual/fisiologia , Adulto , Idoso , Estudos Transversais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Síndromes do Olho Seco/diagnóstico , Síndromes do Olho Seco/tratamento farmacológico , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Humanos , Masculino , Glândulas Tarsais/fisiopatologia , Pessoa de Meia-Idade , Lágrimas/fisiologia
11.
Mar Drugs ; 17(5)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072006

RESUMO

Lipids used in intravenous nutrition support (i.e., parenteral nutrition) provide energy, building blocks, and essential fatty acids. These lipids are included as emulsions since they need to be soluble in an aqueous environment. Fish oil is a source of bioactive omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid). Lipid emulsions, including fish oil, have been used for parenteral nutrition for adult patients post-surgery (mainly gastrointestinal). This has been associated with alterations in biomarkers of inflammation and immune defense, and in some studies, a reduction in length of intensive care unit and hospital stay. These benefits, along with a reduction in infections, are emphasized through recent meta-analyses. Perioperative administration of fish oil may be superior to postoperative administration, but this requires further exploration. Parenteral fish oil has been used in critically ill adult patients. Here, the influence on inflammatory processes, immune function, and clinical endpoints is less clear. However, some studies found reduced inflammation, improved gas exchange, and shorter length of hospital stay in critically ill patients if they received fish oil. Meta-analyses do not present a consistent picture but are limited by the small number and size of studies. More and better trials are needed in patient groups in which parenteral nutrition is used and where fish oil, as a source of bioactive omega-3 fatty acids, may offer benefits.


Assuntos
Emulsões Gordurosas Intravenosas/administração & dosagem , Ácidos Graxos Ômega-3/uso terapêutico , Óleos de Peixe/uso terapêutico , Nutrição Parenteral/métodos , Adulto , Estado Terminal/terapia , Procedimentos Cirúrgicos do Sistema Digestório , Ácidos Docosa-Hexaenoicos/biossíntese , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/biossíntese , Ácido Eicosapentaenoico/uso terapêutico , Ácidos Graxos Ômega-3/biossíntese , Humanos , Inflamação/terapia , Assistência Perioperatória , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Nano Lett ; 19(6): 3548-3562, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31026397

RESUMO

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Metformina/administração & dosagem , Metástase Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Pulmão/irrigação sanguínea , Metformina/sangue , Metformina/uso terapêutico , Camundongos , Micelas , Metástase Neoplásica/patologia , Neoplasias/patologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Ratos Sprague-Dawley
13.
Oxid Med Cell Longev ; 2019: 1280987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949290

RESUMO

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


Assuntos
Neoplasias da Mama/dietoterapia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Inflamação/tratamento farmacológico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade
14.
Am J Clin Nutr ; 109(5): 1380-1392, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004139

RESUMO

BACKGROUND: Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid that has been linked to improved vision and cognition in postnatal feeding studies and has been consistently associated with reduction of early preterm birth in prenatal supplementation trials. This is a report of the first long-term follow-up of infants from mothers receiving prenatal DHA supplementation in a US cohort. OBJECTIVE: Our objective was to evaluate the efficacy of the prenatal supplementation on both global and granular longitudinal assessments of cognitive and behavioral development. METHODS: In a randomized double-blind clinical trial, mothers received either 600 mg/d of DHA or a placebo beginning at 14.5 weeks of gestation and capsules were provided until delivery. Children from those pregnancies were followed by cognitive and behavioral assessments administered from 10 mo through 6 y of age. From 301 mothers in the initial study, ∼200 infants completed the longitudinal schedule. RESULTS: Although this intervention had been shown to reduce high-risk pregnancies and improve visual attention in infants during the first year, only a few positive long-term effects of prenatal DHA supplementation emerged from analyses of this follow-up. Increases in maternal blood DHA during pregnancy were related to verbal and full scale intelligence quotient (IQ) scores at 5 and 6 y, but these effects disappeared after controlling for SES. Maternal blood DHA concentrations at delivery were unrelated to outcomes, although maternal DHA at enrollment was related to productive vocabulary at 18 mo. CONCLUSIONS: Although prenatal DHA supplementation substantially reduced early preterm birth and improved visual attention in infancy in this sample, no consistent long-term benefits were observed into childhood. Increases in maternal blood DHA concentration in pregnancy were related to higher IQs but this effect was confounded with SES and disappeared when SES was statistically controlled. This trial was registered at http://www.clinicaltrials.gov as NCT00266825 and NCT02487771.


Assuntos
Atenção/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Cognição/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Cuidado Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal , Adulto , Criança , Comportamento Infantil/efeitos dos fármacos , Pré-Escolar , Estudos de Coortes , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactente , Kansas , Masculino , Mães , Gravidez , Nascimento Prematuro/prevenção & controle , Estados Unidos , Universidades
15.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986970

RESUMO

Cognitive impairment is strongly associated with functional outcomes in psychiatric patients. Involvement of n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), in particular docosahexaenoic acid (DHA), in brain functions is largely documented. DHA is incorporated into membrane phospholipids as structural component, especially in the central nervous system where it also has important functional effects. The aim of this review is to investigate the relationship between DHA and cognitive function in relation to mental disorders. Results from few randomized controlled trials (RCTs) on the effects of DHA (alone or in combination) in psychotic, mood and neurodevelopmental disorders, respectively, suggest that no conclusive remarks can be drawn.


Assuntos
Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Afeto/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Transtornos do Humor/fisiopatologia , Transtornos do Humor/psicologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia
16.
Rheumatology (Oxford) ; 58(7): 1285-1292, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877775

RESUMO

OBJECTIVES: SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset. METHODS: Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined. RESULTS: Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice. CONCLUSION: AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Saliva/fisiologia , Síndrome de Sjogren/tratamento farmacológico , Animais , Aspirina/farmacologia , Citocinas/biossíntese , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Mediadores da Inflamação/metabolismo , Contagem de Linfócitos , Masculino , Camundongos Endogâmicos NOD , Salivação/efeitos dos fármacos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Células Th17/efeitos dos fármacos
17.
Biofactors ; 45(3): 427-438, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907984

RESUMO

One of the major issues in cell therapy of myocardial infarction (MI) is early death of engrafted cells in a harsh oxidative stress environment, which limits the potential therapeutic utility of this strategy in the clinical setting. Increasing evidence implicates beneficial effects of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and ascorbic acid (AA) in cardiovascular diseases, in particular their role in ameliorating fibrosis. In the current study, we aim to assess the cytoprotective role of EPA + DHA and AA in protecting embryonic stem cell (ESC)-derived cardiac lineage cells and amelioration of fibrosis. Herein, we have shown that preincubation of the cells with EPA + DHA + AA prior to H2 O2 treatment attenuated generation of reactive oxygen species (ROS) and enhanced cell viability. Gene expression analysis revealed that preincubation with EPA + DHA + AA followed by H2 O2 treatment, upregulated heme oxygenase-1 (HO-1) along with cardiac markers (GATA4, myosin heavy chain, α isoform [MYH6]), connexin 43 [CX43]) and attenuated oxidative stress-induced upregulation of fibroblast markers (vimentin and collagen type 1 [Col1]). Alterations in gene expression patterns were followed by marked elevation of cardiac troponin (TNNT2) positive cells and reduced numbers of vimentin positive cells. An injection of EPA + DHA + AA-pretreated ESC-derived cardiac lineage cells into the ischemic myocardium of a rat model of MI significantly reduced fibrosis compared to the vehicle group. This study provided evidence that EPA + DHA + AA may be an appropriate preincubation regimen for regenerative purposes. © 2019 BioFactors, 45(3):427-438, 2019.


Assuntos
Ácido Ascórbico/uso terapêutico , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Ácidos Graxos Ômega-3/uso terapêutico , Animais , Biomarcadores/metabolismo , Western Blotting , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ecocardiografia , Ácido Eicosapentaenoico/uso terapêutico , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
18.
Artigo em Inglês | MEDLINE | ID: mdl-30836143

RESUMO

Omega-3 fatty acid (n-3 PUFA) supplementation may have beneficial effects in certain chronic diseases, potentially including osteoarthritis. Favorable effects are attributed, in part, to downstream pro-resolving oxylipid metabolites. We investigated the role of n-3 PUFA and docosahexaenoic acid (DHA)-derived oxylipids (docosanoids) on equine synoviocyte metabolism. We hypothesized that n-3 PUFA and selected docosanoids would modulate inflammatory mediator gene expression by recombinant equine (re)IL-1ß-stimulated synovial fibroblasts. Synoviocyte monolayer cultures were prepared from grossly normal equine carpal synovium. Cellular incorporation of eicosapentaenoic acid (EPA) and DHA was determined using LC-MS and docosanoid biosynthesis by LC-MS-MS. The influence of n-3 PUFA and docosanoids on osteoarthritis marker gene expression was determined by quantitative real time polymerase chain reaction (qPCR). Synoviocytes incorporated EPA and DHA in significant amounts and DHA treatment augmented the synthesis of several docosanoids. Synoviocyte cultures pre-treated with EPA or DHA followed by reIL-1ß stimulation had significant reductions in expression of ADAMTS4, MMP-1, MMP-13, IL-1ß, IL-6 and COX-2. The docosanoids resolvin D1 and D2, maresin 1 and protectin DX, alone and in combination, abrogated ADAMTS4, MMP-1, MMP-13, and IL-6 gene expression in reIL-1ß-stimulated synoviocytes. Similarly, both resolvins and maresin 1 stifled COX-2 expression. Our results demonstrate that synoviocytes readily incorporate n-3 PUFA. DHA incorporation was sufficient for biosynthesis of significant concentrations of several docosanoids which modulated the synovial inflammatory response in vitro. These data indicate n-3 PUFA supplementation may prove useful in the prevention or treatment of osteoarthritis.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/farmacologia , Proteínas Recombinantes/farmacologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Animais , Citocinas/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Cavalos , Inflamação/metabolismo , Inflamação/patologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/patologia
19.
Oxid Med Cell Longev ; 2019: 5080798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728886

RESUMO

Prostate cancer development has been associated with changes in mitochondrial activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 µM and MLT at 1 µM for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p < 0.01). These alterations affected the area and perimeter of mitochondria, since DHA increased whereas MLT decreased, but such hormone has no effect on coincubation. DHA isolated did not change the oxidative phosphorylation rate (OXPHOS), but decreased (p < 0.001) the mitochondrial bioenergetic reserve capacity (MBRC) which is closely related to cell responsiveness to stress conditions. MLT, regardless of DHA, ameliorated OXPHOS and recovered MBRC after coincubation. All incubations decreased AKT phosphorylation; however, only MLT alone inhibited p-mTOR. MLT increased p-ERK1/2 and, when combined to DHA, increased GSTP1 expression (p < 0.01). DHA did not change the testosterone levels in the medium, whereas MLT alone or coincubated decreased by about 20%; however, any incubation affected AR expression. Moreover, incubation with luzindole revealed that MLT effects were MTR1/2-independent. In conclusion, DHA increased ROS production and impaired mitochondrial function which was probably related to AKT inactivation; MLT improved OXPHOS and decreased ROS which was related to AKT/mTOR dephosphorylation, and when coincubated, the antiproliferative action was related to mitochondrial bioenergetic modulation associated to AKT and ERK1/2 regulation. Together, these findings point to the potential application of DHA and MLT towards the prevention of proliferative prostate diseases.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Metabolismo Energético/fisiologia , Melatonina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Masculino , Melatonina/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Espécies Reativas de Oxigênio , Transdução de Sinais
20.
Lipids ; 54(1): 39-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740707

RESUMO

In this study, the effect of n-3 fatty acids (FA) [α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] on the intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic bile acid transporters (BAT) was assessed in young and aged dyslipidemic rats. Dyslipidemia was induced in young and aged rats by feeding a high-fat (HF) diet. Experimental groups received diets containing canola oil (HF + CNO) and fish oil (HF + FO) as a source of ALA and EPA + DHA, respectively. After 60 days of feeding, intestinal BA uptake and expression of apical sodium-dependent bile acid transporter (Asbt), organic solute transporter-alpha/beta (Osta/b) messenger RNA (mRNA), and hepatic expression of Na+ taurocholate cotransporting polypeptide (Ntcp), bile salt export pump (Bsep), cholesterol 7-α hydroxylase A1 (Cyp7a1), Farnesoid X receptor (Fxr), small heterodimer partner-1 (Shp), liver receptor homolog-1 (Lrh-1), and hepatic nuclear factor-4 alpha (Hnf4a) mRNA were measured. Hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity and total BA in serum, liver, and feces were assessed. The dyslipidemic HF group had: (1) increased intestinal BA uptake and Asbt and Osta/b mRNA expression, (2) increased BA in serum, (3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, (4) increased activity of HMG-CoA reductase, (5) increased hepatic expression of Fxr and Shp mRNA, (6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and (7) decreased BA in feces, when compared to control, HF + CNO, and HF + FO groups. Immunostaining revealed increased expression of intestinal Asbt and hepatic Ntcp protein in the HF group when compared to control, HF + CNO, and HF + FO groups. n-3 FA abrogated dyslipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in both young and aged rats. EPA + DHA was more effective than ALA in modulating dyslipidemia-induced changes.


Assuntos
Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Glicoproteínas de Membrana/metabolismo , Animais , Ácidos e Sais Biliares/sangue , Colesterol 7-alfa-Hidroxilase/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Dislipidemias/sangue , Ácido Eicosapentaenoico/uso terapêutico , Fezes/química , Fator 4 Nuclear de Hepatócito/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Ácido alfa-Linoleico/uso terapêutico
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