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Chronic consumption of hyperpalatable and hypercaloric foods has been pointed out as a factor associated with cognitive decline and memory impairment in obesity. In this context, the integration between peripheral and central inflammation may play a significant role in the negative effects of an obesogenic environment on memory. However, little is known about how obesity-related peripheral inflammation affects specific neurotransmission systems involved with memory regulation. Here, we test the hypothesis that chronic exposure to a highly palatable diet may cause neuroinflammation, glutamatergic dysfunction, and memory impairment. For that, we exposed C57BL/6J mice to a high sugar and butter diet (HSB) for 12 weeks, and we investigated its effects on behavior, glial reactivity, blood-brain barrier permeability, pro-inflammatory features, glutamatergic alterations, plasticity, and fractalkine-CX3CR1 axis. Our results revealed that HSB diet induced a decrease in memory reconsolidation and extinction, as well as an increase in hippocampal glutamate levels. Although our data indicated a peripheral pro-inflammatory profile, we did not observe hippocampal neuroinflammatory features. Furthermore, we also observed that the HSB diet increased hippocampal fractalkine levels, a key chemokine associated with neuroprotection and inflammatory regulation. Then, we hypothesized that the elevation on glutamate levels may saturate synaptic communication, partially limiting plasticity, whereas fractalkine levels increase as a strategy to decrease glutamatergic damage.
Assuntos
Quimiocina CX3CL1 , Hipocampo , Animais , Camundongos , Quimiocina CX3CL1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Inflamação/complicações , Camundongos Endogâmicos C57BL , Obesidade/complicações , Fármacos Atuantes sobre Aminoácidos ExcitatóriosRESUMO
Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter.
Assuntos
Fibrilação Atrial , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Interleucina-10 , Interleucina-6 , Interferon gama , Quimiocina CXCL10 , Interleucina-4 , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Atrial fibrillation (AF) is an arrhythmia that involves structural and electrophysiological abnormalities. Many of the AF-related clinical conditions are associated with an increase in inflammatory and oxidative factors. Haptoglobin (Hp) is an acute phase protein whose biological role is to promote clearance of free hemoglobin (Hb). In addition, for being considered an inflammatory marker, Hp represents a protective mechanism against the oxidative effects of Hb. The Hp1-Hp2 polymorphism at Hp locus can lead to three phenotypes related to structural and functional differences in the protein. The objective of this study were to evaluate Hp levels and Hp1-Hp2 polymorphism at Hp locus in patients with AF compared to a control group. METHODS AND RESULTS: This study included 65 patients with AF and 54 individuals without the arrhythmia. Biochemical parameters were determined using Vitros system, plasma levels of Hp were measured in serum samples by using ELISA method and polymorphisms were verified by PCR technique. Plasma Hp levels, as well as allelic and genotypic frequency, were not associated with AF. The levels of Hp also did not differ among the genotypes according to the applied models. CONCLUSIONS: The results suggest that Hp levels and Hp1-Hp2 polymorphism are not associated to AF.
Assuntos
Fibrilação Atrial , Haptoglobinas , Fibrilação Atrial/genética , Genótipo , Haptoglobinas/química , Haptoglobinas/genética , Hemoglobinas , Humanos , Polimorfismo GenéticoRESUMO
Abstract The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.
Assuntos
Humanos , Masculino , Feminino , Proteínas Quinases , Leucemia Linfocítica Crônica de Células B/patologia , Pacientes , Expressão Gênica/genética , Apoptose , MicroRNAs/farmacologia , Voluntários SaudáveisRESUMO
Abstract Background Traditionally, the most effective therapy in the prevention of stroke in patients with atrial fibrillation (AF) has been oral anticoagulation with vitamin K inhibitors, particularly warfarin, whose disadvantages and adverse effects have led to their replacement by "direct oral anticoagulants", as factor X inhibitor. Objectives This study aimed to conduct a brief approach on atrial fibrillation (AF) and use of Rivaroxaban, and to comparatively evaluate the prothrombin time / International Normalized Ratio (PT/INR) in patients with AF in use of this oral anticoagulant, depending on the time elapsed between the last administration of the drug and the time of blood sample venipuncture. Methods We evaluated 34 patients with AF in use of Rivaroxaban by using PT / INR, distributed into a subgroup with blood collection time ≤ 12 hours (n = 7) and > 12 hours after the last drug intake (n = 27). Mann-Whitney test was used to compare the groups and p < 0.05 was considered significant. Results An analysis as a function of time between the Rivaroxaban intake and blood collection, revealed that PT / INR suffers the greatest effect up to 12 hours after ingestion of the drug, dropping to levels close to normal in subsequent hours before the next dose. Conclusion We concluded that, in contrast to warfarin, the knowledge of the time interval between drug intake and blood collection from patients taking Rivaroxaban is essential to properly interpret a laboratory test to assess hemostasis, particularly PT and its derivatives. Int J Cardiovasc Sci. 2020; [online].ahead print, PP.0-0
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Fibrilação Atrial/tratamento farmacológico , Rivaroxabana/farmacologia , Tempo de Protrombina , Fibrilação Atrial/prevenção & controle , Varfarina/farmacologia , Medição de Risco , Coeficiente Internacional NormatizadoRESUMO
Patients with atrial fibrillation (AF) present hyperactivation of both platelets and coagulation leading to a hypercoagulable state which contributes to an increased risk of thromboembolism. Therefore, one of the main strategies for treatment of AF is prevention of these events through the use of oral anticoagulants (OAC). The aim of this study was to evaluate hemostasis as a whole in patients with non-valvular AF undergoing warfarin or rivaroxaban by thrombin generation test (TGT), in addition to monocyte-platelet aggregates (MPA), glycoprotein IIb/IIIa (GPIIb/IIIa), and platelet (PMP) and endothelium (EMP) microparticles, compared to age and sex matched controls. PT/INR for OAC use was also determined. In patients taking OAC, compared to control group, a decrease in TGT (p = 0.000 for all parameters) were observed. Patients taking warfarin showed to be more hypocoagulable, presenting lower levels of ETP (p = 0.000) and peak (p = 0.002) than patients using rivaroxaban. Patients on warfarin use with INR > 3 had also lower levels of ETP (p = 0.01) and peak (p = 0.006). A decrease in ETP (p = 0.03) and peak (p = 0.02) values was also observed in patients using rivaroxaban with PT > 21.4 s. Patients using warfarin (p = 0.000) and rivaroxaban (p = 0.000) presented lower levels of MPA in relation to control group. It was also observed in patients using warfarin, lower GPIIb/IIIa levels in relation to control group (p = 0.011). Patients taking rivaroxaban (p = 0.003) and warfarin (p = 0.001) had higher PMP levels compared to control group. There was no difference in levels of EMP between the groups (p = 0.0536). The present study reinforces the usefulness of OAC in AF, which decisively contribute to a better management of the disease preventing possible complications.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Rivaroxabana/uso terapêutico , Trombina/análise , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemostasia/efeitos dos fármacos , Humanos , MasculinoRESUMO
Background: Atrial fibrillation (AF) is the most common arrhythmia associated with high risk of venous thromboembolism. Inflammatory mechanisms may be involved in the pathophysiology of AF and in the AF-related thrombogenesis, and patients with AF might benefit from the use of anticoagulants with anti-inflammatory properties. However, the evidence is still scarce, and it points out the need of trials seeking to investigate the levels of inflammatory mediators in patients with AF under different anticoagulant therapies. Therefore, this study was designed to define whether patients with AF treated either with an activated coagulation factor X (FXa) inhibitor (rivaroxaban) or with a vitamin K inhibitor (warfarin) present changes in peripheral levels of inflammatory mediators, mainly cytokines and chemokines. Methods: A total of 127 subjects were included in this study, divided into three groups: patients with non-valvular atrial fibrillation (NVAF) using warfarin (N = 42), patients with NVAF using rivaroxaban (N = 29), and controls (N = 56). Plasma levels of inflammatory mediators were quantified by immunoassays. Results: Patients with AF (both warfarin and rivaroxaban groups) presented increased levels of inflammatory cytokines in comparison with controls. The use of rivaroxaban was associated with decreased levels of inflammatory cytokines in comparison with warfarin. On the other hand, patients with AF using rivaroxaban presented increased levels of the chemokines (MCP-1 in comparison with warfarin users; MIG and IP-10 in comparison with controls). Conclusions: AF is associated with an inflammatory profile that was less pronounced in patients on rivaroxaban in comparison with warfarin users. Further studies are necessary to assess the clinical implications of our results and whether patients with AF would benefit from rivaroxaban anti-inflammatory effects.
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Atrial fibrillation (AF) is one of the most prevalent forms of arrhythmia that carries an increased risk of stroke which, in turn, is strongly associated with cognitive decline. The majority of dementia cases are caused by Alzheimer's disease (AD) with obscure pathogenesis. While the exact mechanisms are unknown, the role of inflammatory processes and infectious agents have recently been implicated in both AD and AF, suggesting a common link between these maladies. Here, we present the main shared pathways underlying arrhythmia and memory loss. The overlapping predictive biomarkers and emerging joint pharmacological approaches are also discussed.
Assuntos
Doença de Alzheimer/fisiopatologia , Fibrilação Atrial/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Infecções/fisiopatologia , Inflamação/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Demência/fisiopatologia , Humanos , Modelos Biológicos , Fatores de RiscoRESUMO
Chronic inflammation contributes to neuronal death in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here we evaluated inflammatory and pro-resolving mediators in AD and behavioural variant of FTD (bvFTD) patients compared with controls, since neuroinflamamtion is a common feature in both diseases. Ninety-eight subjects were included in this study, divided into AD (nâ¯=â¯32), bvFTD (nâ¯=â¯30), and control (nâ¯=â¯36) groups. The levels of hsCRP, IL-1ß, IL-6, TNF, and TGF-ß1, as well as annexin A1 (AnxA1) and lipoxin A4 (LXA4) were measured in blood and cerebrospinal fluid (CSF). The expression profile of AnxA1 was evaluated in peripheral blood mononuclear cells (PBMCs) as well the distribution of ANXA1 rs2611228 polymorphism. We found reduced peripheral levels of hsCRP and TNF in AD compared with bvFTD patients and controls, and increased levels of TGF-ß1 in AD compared to controls. Moreover, reduced plasma levels of AnxA1 were observed in bvFTD compared to AD and controls. There was a significant cleavage of AnxA1 in PBMCs in both dementia groups. The results suggest differential regulation of inflammatory and pro-resolving mediators in bvFTD and AD, while AnxA1 cleavage may impair pro-resolving mechanisms in both groups.
Assuntos
Doença de Alzheimer/metabolismo , Anexina A1/metabolismo , Citocinas/metabolismo , Demência Frontotemporal/metabolismo , Lipoxinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/imunologia , Anexina A1/sangue , Anexina A1/líquido cefalorraquidiano , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/imunologia , Genótipo , Voluntários Saudáveis , Humanos , Inflamação , Lipoxinas/sangue , Lipoxinas/líquido cefalorraquidiano , Masculino , Pessoa de Meia-IdadeRESUMO
Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-ß (Aß) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aß induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aß injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aß accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aß stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.