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1.
JAMA ; 325(11): 1061-1073, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33724323

RESUMO

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Colecalciferol/uso terapêutico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Vitaminas/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Deficiência de Vitamina D/tratamento farmacológico
2.
Nat Commun ; 12(1): 1704, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731716

RESUMO

GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37-/- mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.


Assuntos
Macrófagos/metabolismo , Dor/prevenção & controle , Receptores Acoplados a Proteínas-G/metabolismo , Sepse/prevenção & controle , Transferência Adotiva , Animais , Artesunato/metabolismo , Artesunato/farmacologia , Artesunato/uso terapêutico , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Listeria monocytogenes/patogenicidade , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Macrófagos/transplante , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Dor/imunologia , Dor/mortalidade , Fagocitose/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Receptores Acoplados a Proteínas-G/deficiência , Sepse/imunologia , Sepse/mortalidade , Sepse/terapia
3.
Clin Sports Med ; 40(1): 123-131, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33187603

RESUMO

The medications used in postconcussion syndrome are typically used to help manage or minimize disruptive symptoms while recovery proceeds. These medications are not routinely used in most concussions that recover within days to weeks. However, it is beneficial to be aware of medication options that may be used in athletes with prolonged concussion symptoms or for those that have symptom burdens that preclude entry into basic concussion protocols. Medications and supplements remain a small part of the concussion treatment plan, which may include temporary academic adjustments, physical therapy, vestibular and ocular therapy, psychological support, and graded noncontact exercise.


Assuntos
Traumatismos em Atletas/terapia , Concussão Encefálica/terapia , Síndrome Pós-Concussão/terapia , Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/tratamento farmacológico , Concussão Encefálica/diagnóstico , Concussão Encefálica/tratamento farmacológico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Humanos , Modalidades de Fisioterapia , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/tratamento farmacológico , Psicoterapia
4.
Cochrane Database Syst Rev ; 12: CD011679, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320335

RESUMO

BACKGROUND: Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition. OBJECTIVES: To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease. SEARCH METHODS: We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review. SELECTION CRITERIA: We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks. DATA COLLECTION AND ANALYSIS: Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD. MAIN RESULTS: We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mild and mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid. AUTHORS' CONCLUSIONS: Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.


Assuntos
Doença de Alzheimer/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Fosfolipídeos/uso terapêutico , Viés , Cognição , Demência/prevenção & controle , Suplementos Nutricionais/efeitos adversos , Progressão da Doença , Ácidos Docosa-Hexaenoicos/efeitos adversos , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/efeitos adversos , Ácido Eicosapentaenoico/química , Humanos , Fosfolipídeos/efeitos adversos , Fosfolipídeos/química , Placebos/uso terapêutico , Sintomas Prodrômicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
5.
Front Immunol ; 11: 1997, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983141

RESUMO

Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Ácidos Docosa-Hexaenoicos/deficiência , Ácido Eicosapentaenoico/metabolismo , Ácido Linoleico/deficiência , Lipoxinas/deficiência , Obesidade/epidemiologia , Obesidade/imunologia , Pneumonia Viral/epidemiologia , Comorbidade , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inflamação/metabolismo , Ácido Linoleico/uso terapêutico , Lipoxinas/uso terapêutico , Morbidade , Obesidade/metabolismo , Pandemias , Pneumonia Viral/dietoterapia , Pneumonia Viral/virologia , Fatores de Risco
6.
Medicina (Kaunas) ; 56(9)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32825011

RESUMO

It is proposed that the bioactive lipid, arachidonic acid (AA, 20:4 n-6), can inactivate severe acute respiratory syndrome(SARS-CoV-2), facilitate M1 and M2 macrophage generation, suppress inflammation, prevent vascular endothelial cell damage, and regulate inflammation resolution processes based on the timely formation of prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) based on the context. Thus, AA may be useful both to prevent and manage coronavrus disease-2019(COVID-19).


Assuntos
Ácido Araquidônico/uso terapêutico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inflamação , Macrófagos/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Inativação de Vírus
7.
Cochrane Database Syst Rev ; 6: CD008428, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32573764

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead to blindness. Symptoms may become manifest during childhood or adulthood which include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). Visual field loss is progressive and affects central vision later in the disease course. The worldwide prevalence of RP is approximately 1 in 4000, with 100,000 individuals affected in the USA. At this time, there is no proven therapy for RP. OBJECTIVES: The objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (2020, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP); and OpenGrey. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 February 2020. SELECTION CRITERIA: We included randomized controlled trials that enrolled participants of any age diagnosed with any degree of severity or type of RP, and evaluated the effectiveness of vitamin A, fish oils (DHA), or both compared to placebo, vitamins (other than vitamin A), or no therapy, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials. DATA COLLECTION AND ANALYSIS: We prespecified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one-year follow-up, and mean change in visual acuity, at five-year follow-up. Two review authors independently extracted data and evaluated risk of bias for all included trials. We also contacted study investigators for further information when necessary. MAIN RESULTS: In addition to three trials from the previous version of this review, we included a total of four trials with 944 participants aged 4 to 55 years. Two trials included only participants with X-linked RP and the other two included participants with RP of all forms of genetic predisposition. Two trials evaluated the effect of DHA alone; one trial evaluated vitamin A alone; and one trial evaluated DHA and vitamin A versus vitamin A alone. Two trials recruited participants from the USA, and the other two recruited from the USA and Canada. All trials were at low risk of bias for most domains. We did not perform meta-analysis due to clinical heterogeneity. Four trials assessed visual field sensitivity. Investigators found no evidence of a difference in mean values between the groups. However, one trial found that the annual rate of change of visual field sensitivity over four years favored the DHA group in foveal (-0.02 ± 0.55 (standard error (SE)) dB versus -0.47 ± 0.03 dB, P = 0.039), macular (-0.42 ± 0.05 dB versus -0.85 ± 0.03 dB, P = 0.031), peripheral (-0.39 ± 0.02 versus -0.86 ± 0.02 dB, P < 0.001), and total visual field sensitivity (-0.39 ± 0.02 versus -0.86 ± 0.02 dB, P < 0.001). The certainty of the evidence was very low. The four trials evaluated visual acuity (LogMAR scale) at a follow-up of four to six years. In one trial (208 participants), investigators found no evidence of a difference between the two groups, as both groups lost 0.7 letters of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity per year. In another trial (41 participants), DHA showed no evidence of effect on visual acuity (mean difference -0.01 logMAR units (95% confidence interval -0.14 to 0.12; one letter difference between the two groups; very low-certainty evidence). In the third trial (60 participants), annual change in mean number of letters correct was -0.8 (DHA) and 1.4 letters (placebo), with no evidence of between-group difference. In the fourth trial (572 participants), which evaluated (vitamin A + vitamin E trace) compared with (vitamin A trace + vitamin E trace), decline in ETDRS visual acuity was 1.1 versus 0.9 letters per year, respectively. All four trials reported electroretinography (ERG). Investigators of two trials found no evidence of a difference between the DHA and placebo group in yearly rates of change in 31 Hz cone ERG amplitude (mean ± SE) (-0.028 ± 0.001 log µV versus -0.022 ± 0.002 log µV; P = 0.30); rod ERG amplitude (mean ± SE) (-0.010 ± 0.001 log µV versus -0.023 ± 0.001 log µV; P = 0.27); and maximal ERG amplitude (mean ± SE) (-0.042 ± 0.001 log µV versus -0.036 ± 0.001 log µV; P = 0.65). In another trial, a slight difference (6.1% versus 7.1%) in decline of ERG per year favored vitamin A (P = 0.01). The certainty of the evidence was very low. One trial (51 participants) that assessed optical coherence tomography found no evidence of a difference in ellipsoid zone constriction (P = 0.87) over two years, with very low-certainty evidence. The other three trials did not report this outcome. Only one trial reported adverse events, which found that 27/60 participants experienced 42 treatment-related emergent adverse events (22 in DHA group, 20 in placebo group). The certainty of evidence was very low. The rest of the trials reported no adverse events, and no study reported any evidence of benefit of vitamin supplementation on the progression of visual acuity loss. AUTHORS' CONCLUSIONS: Based on the results of four studies, it is uncertain if there is a benefit of treatment with vitamin A or DHA, or both for people with RP. Future trials should also take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Retinite Pigmentosa/terapia , Vitamina A/uso terapêutico , Vitaminas/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada/métodos , Progressão da Doença , Ácidos Docosa-Hexaenoicos/efeitos adversos , Eletrorretinografia , Feminino , Óleos de Peixe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Retinite Pigmentosa/genética , Acuidade Visual , Campos Visuais/fisiologia , Vitamina A/efeitos adversos , Vitaminas/efeitos adversos , Adulto Jovem
8.
Arch Med Res ; 51(6): 492-503, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32451116

RESUMO

OBJECTIVE: To study whether resolvin D1 (RvD1), a metabolite of docosahexaenoic acid (DHA), prevents NA-STZ-induced type 2 diabetes mellitus (type 2 DM) in vivo and if so, what could be the mechanism of this action. MATERIAL AND METHODS: Single intra-peritoneal (i.p) injection of NA-STZ (175 mg/kg body weight of NA and 65 mg/kg of STZ) was injected simultaneously with RvD1 (60 ng/animal) (injected for 5 consecutive days) to Wistar rats. The effect of RvD1 on plasma glucose levels and apoptotic (Bcl2/Bax) and inflammatory (NF-κB/iNOS) protein expression, plasma lipoxin A4 and BDNF (brain-derived neurotrophic factor) were studied. Protein expressions of PI3k-Akt-mTOR pathway along with histopathological studies of brain were also evaluated. RESULTS: NA-STZ-induced type 2 DM rats showed hyperglycemia, enhanced plasma IL-6/TNF-α (p ≤0.01), reduced plasma BDNF (p ≤0.01) and LXA4 (p ≤0.01) levels and low BDNF in pancreatic, hepatic and brain tissues (p <0.001), which were restored to near normal (p ≤0.01) in RvD1 treated group. RvD1 increased insulin sensitivity by suppressing inflammation (NF-κB/iNOS) (p ≤0.01) and decreasing apoptosis (Bcl2/Bax) and restoring BDNF and LXA4 levels to near normal. RvD1 treatment increased phosphorylation of Akt (Ser473), and subsequent activation (phosphorylation) of downstream signaling molecules of PI3K and mTOR indicating that RvD1 acts through PI3K/Akt/mTOR axis. DISCUSSION: RvD1 is effective in preventing NA-STZ-induced type 2 DM in vivo by suppressing oxidative damage, enhancing the production of anti-inflammatory LXA4 and enhancing neuronal cell survival by augmenting the production of BDNF. Thus, RvD1 may be of benefit not only in preventing diabetes mellitus but also diabetes associated Alzheimer's disease and memory loss.


Assuntos
Anti-Inflamatórios/uso terapêutico , Encéfalo/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Niacinamida/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Diabetes Mellitus Tipo 2/induzido quimicamente , Humanos , Masculino , Ratos , Ratos Wistar
9.
Sci Rep ; 10(1): 6692, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317678

RESUMO

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of incompletely understood pathophysiology predominantly affecting premature infants. While NEC is associated with microbial invasion of intestinal tissues, and mucus modulates interactions between microbes and underlying tissues, variations in mucus barrier properties with NEC-associated risk factors have not been investigated. This study explored differences in mucus composition (total protein, DNA, mucin content, sialic acid, and immunoregulatory proteins), as well as structural and transport properties, assessed by tracking of particles and bacteria (E. coli and E. cloacae) with developmental age and exposure to NEC stressors in Sprague Dawley rats. Early developmental age (5 day old) was characterized by a more permeable mucus layer relative to 21 day old pups, suggesting immaturity may contribute to exposure of the epithelium to microbes. Exposure to NEC stressors was associated with reduced mucus permeability, which may aid in survival. Feeding with breastmilk as opposed to formula reduces incidence of NEC. Thus, NEC-stressed (N-S) rat pups were orally dosed with breastmilk components lysozyme (N-S-LYS) or docosahexaenoic acid (N-S-DHA). N-S-LYS and N-S-DHA pups had a less permeable mucus barrier relative to N-S pups, which suggests the potential of these factors to strengthen the mucus barrier and thus protect against disease.


Assuntos
Envelhecimento/patologia , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/uso terapêutico , Enterocolite Necrosante/tratamento farmacológico , Muco/metabolismo , Muramidase/administração & dosagem , Muramidase/uso terapêutico , Estresse Fisiológico , Administração Oral , Animais , DNA/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Enterobacter cloacae/fisiologia , Enterocolite Necrosante/microbiologia , Escherichia coli/fisiologia , Fucose/metabolismo , Íleo/patologia , Íleo/ultraestrutura , Imunoglobulina G/metabolismo , Mucinas/metabolismo , Muco/efeitos dos fármacos , Muramidase/farmacologia , Ácido N-Acetilneuramínico/metabolismo , Permeabilidade , Polietilenoglicóis/química , Ratos Sprague-Dawley , Estresse Fisiológico/efeitos dos fármacos
11.
Cochrane Database Syst Rev ; 3: CD003177, 2020 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-32114706

RESUMO

BACKGROUND: Omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess the effects of increased intake of fish- and plant-based omega-3 fats for all-cause mortality, cardiovascular events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily). Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high-certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate-certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high-certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate-certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low-certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low-certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low-certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre-planned subgrouping or meta-regression. There is little evidence of effects of eating fish. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate-certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate-certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate-certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low-certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low-certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate-certainty evidence). Effects on stroke are unclear. Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose-dependent way (high-certainty evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and low-certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Prevenção Primária , Prevenção Secundária , Adiposidade , Adulto , Arritmias Cardíacas/epidemiologia , Doenças Cardiovasculares/dietoterapia , Doenças Cardiovasculares/mortalidade , Causas de Morte , Doença das Coronárias/mortalidade , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Ácidos Graxos Ômega-3/efeitos adversos , Hemorragia/epidemiologia , Humanos , Embolia Pulmonar/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Acidente Vascular Cerebral/epidemiologia , Resultado do Tratamento , Ácido alfa-Linoleico/uso terapêutico
12.
Proc Natl Acad Sci U S A ; 117(14): 7971-7980, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32205444

RESUMO

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


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Infecções por Escherichia coli/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Pneumonia/imunologia , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Células Cultivadas , Ilhas de CpG/imunologia , DNA Bacteriano/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Escherichia coli/genética , Escherichia coli/imunologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Voluntários Saudáveis , Humanos , Lipoxinas/farmacologia , Lipoxinas/uso terapêutico , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Pneumonia/patologia , Cultura Primária de Células , Receptores de Formil Peptídeo/imunologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/imunologia , Receptores de Lipoxinas/metabolismo
13.
Trials ; 21(1): 137, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019575

RESUMO

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a ß-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the ß-blocker effect, could prevent related cardiotoxicity. However, carvedilol's antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo. METHODS/DESIGN: We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing. DISCUSSION: We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antibióticos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carvedilol/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Doxorrubicina/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Neoplasias da Mama/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Método Duplo-Cego , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Adulto Jovem
14.
Trials ; 21(1): 79, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937352

RESUMO

BACKGROUND: Knee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA. METHODS/DESIGN: We will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016. Universal Trial Number (UTN) U1111-1181-7087.


Assuntos
Euphausiacea/química , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Placebos/administração & dosagem , Adulto , Animais , Austrália/epidemiologia , Estudos de Casos e Controles , Progressão da Doença , Ácidos Docosa-Hexaenoicos/efeitos adversos , Ácidos Docosa-Hexaenoicos/economia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Medição da Dor/métodos , Medição da Dor/estatística & dados numéricos , Segurança , Sinovite/complicações , Sinovite/diagnóstico por imagem , Sinovite/tratamento farmacológico , Resultado do Tratamento
15.
Trials ; 21(1): 93, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948466

RESUMO

BACKGROUND: This trial addresses the global problem of chronic venous leg ulcers (CVLUs), wounds that cause significant infirmity for an estimated 9.7 million people annually, mainly older adults with comorbidities. Advanced therapies are needed because standard topical therapies are often ineffective or yield only short-term wound healing. Thus, we are testing a new oral therapy containing the bioactive elements of fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for targeting and reducing the high numbers of activated polymorphonuclear leukocytes (PMN) in wound microenvironments that keep CVLUs "trapped" in a chronic inflammatory state. METHODS: This double-blind RCT will include 248 eligible adults ≥ 55 years of age with CVLUs receiving standard care at a large Midwest outpatient wound clinic. Participants are randomized to two groups: 12 weeks of daily oral therapy with EPA + DHA (1.87 g/day of EPA + 1.0 g/day of DHA) or daily oral therapy with placebo. At 0, 4, 8, and 12 weeks, across the two groups, we are pursuing three specific aims: Aim 1. Compare levels of EPA + DHA-derived lipid mediators, and inflammatory cytokines in blood and wound fluid; Subaim 1a. Compare inflammatory cytokine gene expression by PMNs in blood; Aim 2. Compare PMN activation in blood and wound fluid, and PMN-derived protease levels in wound fluid; Aim 3. Compare reduction in wound area, controlling for factors known to impact healing, and determine relationships with lipid mediators, cytokines, and PMN activation. Subaim 3a. Compare frequency of CVLU recurrence and levels of study variables in blood between the randomly assigned two subgroups (continuing EPA + DHA therapy versus placebo therapy beyond week 12) within the EPA + DHA group with healed CVLUs after 3 months of therapy. Subaim 3b. Compare symptoms of pain at all time points and quality of life at first and last time points across the two groups and two subgroups. DISCUSSION: This trial will provide new evidence about the effectiveness of EPA + DHA oral therapy to target and reduce excessive PMN activation systemically and locally in patients with CVLUs. If effective, this therapy may facilitate healing and thus be a new adjunct treatment for CVLUs in the aging population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03576989; Registered on 13 June 2018.


Assuntos
Citocinas/efeitos dos fármacos , Ácidos Graxos Ômega-3/uso terapêutico , Neutrófilos/efeitos dos fármacos , Úlcera Varicosa/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Crônica , Citocinas/sangue , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/uso terapêutico , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Óleos de Peixe/administração & dosagem , Óleos de Peixe/uso terapêutico , Humanos , Úlcera da Perna/epidemiologia , Úlcera da Perna/patologia , Reguladores do Metabolismo de Lipídeos/administração & dosagem , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Qualidade de Vida
16.
Biosci Biotechnol Biochem ; 84(4): 743-756, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31889475

RESUMO

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


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Piridinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Sinergismo Farmacológico , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/administração & dosagem , Piridinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia
17.
Int Immunopharmacol ; 78: 106018, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31780371

RESUMO

OBJECTIVE: Ulcerative colitis (UC) is one of the most common gastrointestinal diseases, characterized as a chronic, relapsing inflammation that causes damage to the colonic mucosa. Maresin 1 (MaR1), a specialized proresolving mediator, has powerful anti-inflammatory activity that prevents the occurrence of various inflammatory diseases. The aim of this study was to explore the role and potential mechanism of MaR1 in DSS-induced ulcerative colitis. METHODS: In the present study, we established dextran sulfate sodium (DSS)-induced ulcerative colitis rat model in vivo. Rats with colitis received tail vein injection of MaR1, with or without intraperitoneal injection of ML385. The changes of body weight, colon length, disease activity index (DAI), colonic histopathology, inflammatory cytokines, the activity of myeloperoxidase (MPO) and reactive oxygen species (ROS), and infiltration of macrophages expressing F4/80 were analyzed for the evaluation of colitis severity. In addition, protein expressions were detected using western blot. RESULTS: MaR1 significantly reduced inflammatory cytokines production, and restored body weight, DAI and colonic histopathology. Besides, MaR1 improved the expression of tight junction (TJ) proteins and reduced the infiltration of neutrophil and macrophages, as well as a decreased activity of MPO and ROS. Meanwhile, MaR1 activated Nrf2 signaling and decreased toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB) activation. Furthermore, ML385, an inhibitor of Nrf2, significantly reversed the protective effect of MaR1. CONCLUSION: MaR1 play a protective role in DSS-induced colitis by activating Nrf2 signaling and inactivating Nrf2-mediated TLR4/NF-κB signaling pathway, which mediate proinflammatory mediators and intestinal TJ proteins in rats, providing novel insights into the therapeutic strategy of colitis.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/citologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/uso terapêutico , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Substâncias Protetoras/uso terapêutico , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/imunologia , Proteínas de Junções Íntimas/metabolismo , Receptor 4 Toll-Like/metabolismo
18.
Br J Nutr ; 123(2): 190-197, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31554528

RESUMO

A mixture of natural ingredients, namely, DHA, phosphatidylcholine, silymarin, choline, curcumin and d-α-tocopherol, was studied in subjects with non-alcoholic fatty liver disease (NAFLD). Primary endpoints were serum levels of hepatic enzymes, and other parameters of liver function, the metabolic syndrome and inflammation were the secondary endpoints. The coagulation-fibrinolysis balance was also thoroughly investigated, as NAFLD is associated with haemostatic alterations, which might contribute to increased cardiovascular risk of this condition. The present study involved a double-blind, randomised, multicentre controlled trial of two parallel groups. Subjects with NAFLD (18-80 years, either sex) received the active or control treatment for 3 months. All assays were performed on a total of 113 subjects before and at the end of supplementation. The hepatic enzymes aspartate aminotransferase (AST), alanine aminotransferase and γ-glutamyl transpeptidase decreased from 23·2 to 3·7 % after treatment, only the AST levels reaching statistical significance. However, no differences were found between control and active groups. Metabolic and inflammatory variables were unchanged, except for a slight (less than 10 %) increase in cholesterol and glucose levels after the active treatment. Coagulation-fibrinolytic parameters were unaffected by either treatment. In conclusion, chronic supplementation with the mixture of dietary compounds was well tolerated and apparently safe in NAFLD subjects. The trial failed to demonstrate any efficacy on relevant physiopathological markers, but its protocol and results may be useful to design future studies with natural compounds.


Assuntos
Suplementos Nutricionais , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Colina/uso terapêutico , Curcumina/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolinas/uso terapêutico , Silimarina/uso terapêutico , Tocoferóis/uso terapêutico , gama-Glutamiltransferase/sangue
19.
Int Immunopharmacol ; 78: 106043, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837574

RESUMO

Protectin DX (PDX) has been reported to have extensive anti-inflammatory effects. However, it is unknown whether PDX acts as an anti-inflammatory agent in the context of osteoarthritis (OA). This study aimed to evaluate the anti-inflammatory activity of PDX in vitro and in vivo in a model of OA. Primary rat chondrocytes were preincubated with PDX 1 h prior to IL-1ß treatment for 24 h. We found that PDX was nontoxic, and pretreatment with PDX increased cell viability in IL-1ß-induced chondrocytes. Preincubation with PDX also efficiently inhibited the degradation of type II collagen dose-dependently. Additionally, the expression of MMP-3, MMP-13, ADAMTS4, iNOS, COX-2, NO, and PGE2 decreased after IL-1ß stimulation when cells were preincubated with PDX. Moreover, PDX inhibited the increase in phosphorylated NF-κB p65 and IκBα upon IL-1ß stimulation, and the negative effects of IL-1ß on chondrocytes were partially blocked by treatment with pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor. In addition, we found that PDX increased AMPK phosphorylation in IL-1ß-mediated chondrocytes. The phosphorylation of AMPK could be inhibited by compound C, a classic AMPK inhibitor. Compound C also remarkably reversed the decrease in p65 phosphorylation and MMP-13 expression caused by PDX. Furthermore, nuclear translocation of NF-κB was visible by immunofluorescence after PDX-induced AMPK activation. Additionally, we verified that PDX ameliorated cartilage degradation in monosodium iodoacetate (MIA)-induced OA rats through histological evaluation and ELISA of TNF-α in the serum and intra-articular lavage fluid. In conclusion, we have shown that PDX suppresses inflammation in chondrocytes in vitro and in vivo, likely through the AMPK/NF-κB signaling pathway. Our results suggest that PDX could be a useful novel therapeutic agent for OA treatment.


Assuntos
Artrite Experimental/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Osteoartrite/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Condrócitos/imunologia , Progressão da Doença , Ácidos Docosa-Hexaenoicos/uso terapêutico , Humanos , Injeções Intra-Articulares , Ácido Iodoacético/administração & dosagem , Ácido Iodoacético/toxicidade , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/imunologia , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Cultura Primária de Células , Ratos , Transdução de Sinais/imunologia , Fator de Transcrição RelA/metabolismo
20.
Matronas prof ; 20/21(4/1): e1-e9, 2019-2020. tab
Artigo em Espanhol | IBECS | ID: ibc-192426

RESUMO

OBJETIVO: Examinar la evidencia sobre los efectos de la suplementación con ácido docosahexaenoico (DHA) en el embarazo, el parto y la descendencia. METODOLOGÍA: Revisión bibliográfica de investigaciones de menos de 5 años desde la publicación sobre los efectos de la suplementación con DHA durante el embarazo, el parto y la descendencia. Bases de datos consultadas: Medline, IBECS, IME y Biblioteca Cochrane. RESULTADOS: Se analizaron 41 trabajos de investigación: 34 ensayos clínicos y 7 revisiones bibliográficas. CONCLUSIONES: Existe acuerdo sobre los beneficios de la suplementación con DHA en las embarazadas que padecen diabetes mellitus y obesidad, así como en la duración de la gestación. Se necesitan nuevos estudios para investigar sobre otros probables beneficios de dicha suplementación en el embarazo, el parto y la descendencia, así como la dosis óptima y el mejor momento de inicio


OBJECTIVE: To examine the evidence on the effects of docosahexaenoic acid (DHA) supplementation in pregnancy, delivery and offspring. METHODOLOGY: Bibliographic review of research with less than 5 years since the publication, about the effects of supplementation with DHA during pregnancy, delivery and offspring. Databases consulted: Medline, IBECS, IME and Cochrane Library. RESULTS: 41 Investigation works were analyzed: 34 clinical trials and 7 literature reviews. CONCLUSIONS: There is agreement on the beneficial effects of prenatal DHA supplementation in pregnant women who suffer from diabetes, obesity and in the duration of pregnancy. New studies are needed to investigate other likely benefits in pregnancy, childbirth and offspring, as well as the optimal dose and the best time to start supplementation


Assuntos
Humanos , Feminino , Gravidez , Suplementos Nutricionais , Gravidez/fisiologia , Trabalho de Parto/fisiologia , Nutrição Pré-Natal , Ácidos Docosa-Hexaenoicos/uso terapêutico , Fenômenos Fisiológicos da Nutrição Materna , Cuidado Pré-Natal , Ácidos Docosa-Hexaenoicos/metabolismo
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