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Background: Recent studies have suggested that metabolic syndrome (MS) encompasses a group of risk factors for developing chronic kidney disease (CKD). This work aimed to evaluate the antioxidant and anti-inflammatory effects of allicin in the kidney from an experimental model of MS. Methods: Male Wistar rats (220-250 g) were used, and three experimental groups (n = 6) were formed: control (C), metabolic syndrome (MS), and MS treated with allicin (16 mg/Kg/day, gastric gavage) (MS+A). MS was considered when an increase of 20% in at least three parameters (body weight, systolic blood pressure (SBP), fasting blood glucose (FBG), or dyslipidemia) was observed compared to the C group. After the MS diagnosis, allicin was administered for 30 days. Results: Before the treatment with allicin, the MS group showed more significant body weight gain, increased SBP, and FBG, glucose intolerance, and dyslipidemia. In addition, increased markers of kidney damage in urine and blood. Moreover, the MS increased oxidative stress and inflammation in the kidney compared to group C. The allicin treatment prevented further weight gain, reduced SBP, FBG, glucose intolerance, and dyslipidemia. Also, markers of kidney damage in urine and blood were decreased. Further, the oxidative stress and inflammation were decreased in the renal cortex of the MS+A compared to the MS group. Conclusion: Allicin exerts its beneficial effects on the metabolic syndrome by considerably reducing systemic and renal inflammation as well as the oxidative stress. These effects were mediated through the Nrf2 pathway. The results suggest allicin may be a therapeutic alternative for treating kidney injury induced by the metabolic syndrome risk factors.
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Intolerância à Glucose , Síndrome Metabólica , Insuficiência Renal Crônica , Ratos , Animais , Masculino , Antioxidantes/farmacologia , Síndrome Metabólica/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Ratos Wistar , Rim , Insuficiência Renal Crônica/tratamento farmacológico , Peso Corporal , Modelos Teóricos , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologiaRESUMO
Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFß1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFß1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1ß increased at 1.5-6 h and TGFß1 at 12 h; in females, TNF decrease at 6 h and TGFß1 increased from 6 h; in CLP females, TNF and IL-1ß decreased at 12 h and 1.5 h, respectively, and TGFß1 increased from 6 h; in males, TGFß1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFß1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFß1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFß1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice.
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Endotoxemia , Sepse , Feminino , Masculino , Camundongos , Animais , Interleucina-6 , Lipopolissacarídeos , Modelos Animais de Doenças , Inflamação , Imunoglobulina M , Fator de Necrose Tumoral alfa , Camundongos Endogâmicos C57BLRESUMO
Introduction: Challenges of diverse origin in childhood can alter the growth and development of the central nervous system, affecting structures and functions. As a consequence of the damage suffered during the perinatal period, long periods of dysfunctionality may occur, such as regulatory disorders, which may result in remaining in a process of low-grade inflammation. We previously found that perinatal risks and neurological signs are associated with long-term changes in circulating concentrations of molecules of the inflammatory process, findings that are consistent with the postulate that long periods of dysfunction may condition long-lasting low-grade inflammation or parainflammation. The aim of this study was to assess whether different expressions of neurological disorders show variations in their inflammatory molecule profiles or whether there is a common pattern. Methods: We included screening for (a) caregiver-perceived risk detection of regulatory disturbances, using the DeGangi instrument; (b) dysautonomia or asymmetries, through neurodevelopmental assessments; (c) cognitive developmental disturbances (using the Bailey instrument). We assessed protein molecules on a multiplex system, and lipid molecules by ELISA. Results: We found a similar, although not identical, pattern of cytokine profiles with the presence of risk of regulatory disturbances, dysautonomia and asymmetries; but an opposite inflammatory profile was associated with cognitive impairment. Discussion: Our results suggest that there are diverse, probably limited, molecular footprints associated with impaired function, and that these footprints may depend on the response requirements necessary to adjust to the altered internal environment. Here we propose a theoretical model that suggests possible scenarios for inflammatory outcomes associated with chronic challenges.
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The aim of this work was to obtain insights of the participation of the autonomic nervous system in different stages of calcific aortic valve disease (CAVD) by heart rate variability (HRV) analysis. Studying subjects with no valve impairments and CAVD patients, we also sought to quantify the independent contribution or explanatory capacity of the aortic valve echocardiographic parameters involved in the HRV changes caused by active standing using hierarchical partitioning models to consider other variables or potential confounders. We detected smaller adjustments of the cardiac autonomic response at active standing caused specifically by the aortic valve deterioration. The highest association (i.e., the highest percentage of independent exploratory capacity) was found between the aortic valve area and the active standing changes in the short-term HRV scaling exponent α1 (4.591%). The valve's maximum pressure gradient echocardiographic parameter was present in most models assessed (in six out of eight models of HRV indices that included a valve parameter as an independent variable). Overall, our study provides insights with a wider perspective to explore and consider CAVD as a neurocardiovascular pathology. This pathology involves autonomic-driven compensatory mechanisms that seem generated by the aortic valve deterioration.
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COVID-19, caused by SARS-CoV-2, is a primarily pulmonary disease that can affect several organs, directly or indirectly. To date, there are many questions about the different pathological mechanisms. Here, we generate an approach to identify the cellular-level tropism of SARS-CoV-2 using human proteomics, virus-host interactions, and enrichment analysis. Through a network-based approach, the molecular context was visualized and analyzed. This procedure was also performed for SARS-CoV-1. We obtained proteomes and interactomes from 145 different cells corresponding to 57 different tissues. We discarded the cells without the proteins known for interacting with the virus, such as ACE2 or TMPRSS2. Of the remaining cells, a gradient of susceptibility to infection was observed. In addition, we identified proteins associated with the coagulation cascade that can be directly or indirectly affected by viral proteins. As a whole we identified 55 cells that could be potentially controlled by the virus, with different susceptibilities, mainly being pneumocytes, heart, kidney, liver, or small intestine cells. These results help to explain the molecular context and provide elements for possible treatments in the current situation. This strategy may be useful for other viruses, especially those with limited reported PPI, such as a new virus.
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COVID-19 , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Interações entre Hospedeiro e Microrganismos , Humanos , TropismoRESUMO
BACKGROUND: Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-ß signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. RESULTS: Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. CONCLUSIONS: The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.
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Doença de Chagas , MicroRNAs , Animais , Biomarcadores , Doença de Chagas/genética , Biologia Computacional , Feminino , Fibrose , Camundongos , MicroRNAs/genéticaRESUMO
Aortic stenosis is a progressive heart valve disorder characterized by calcification of the leaflets. Heart rate variability (HRV) analysis has been proposed for assessing the heart response to autonomic activity, which is documented to be altered in different cardiac diseases. The objective of the study was to evaluate changes of HRV in patients with aortic stenosis by an active standing challenge. Twenty-two volunteers without alterations in the aortic valve (NAV) and twenty-five patients diagnosed with moderate and severe calcific aortic valve stenosis (AVS) participated in this cross-sectional study. Ten minute electrocardiograms were performed in a supine position and in active standing positions afterwards, to obtain temporal, spectral, and scaling HRV indices: mean value of all NN intervals (meanNN), low-frequency (LF) and high-frequency (HF) bands spectral power, and the short-term scaling indices (α1 and αsign1). The AVS group showed higher values of LF, LF/HF and αsign1 compared with the NAV group at supine position. These patients also expressed smaller changes in meanNN, LF, HF, LF/HF, α1, and αsign1 between positions. In conclusion, we confirmed from short-term recordings that patients with moderate and severe calcific AVS have a decreased cardiac parasympathetic supine response and that the dynamic of heart rate fluctuations is modified compared to NAV subjects, but we also evidenced that they manifest reduced autonomic adjustments caused by the active standing challenge.
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Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-ß were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.
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Angina Pectoris/terapia , Doença da Artéria Coronariana/terapia , Tratamento por Ondas de Choque Extracorpóreas/métodos , Insuficiência Cardíaca/fisiopatologia , Revascularização Miocárdica/métodos , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Angina Pectoris/complicações , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/metabolismo , Proteína 1 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/metabolismo , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/metabolismo , Citocinas/metabolismo , Células Progenitoras Endoteliais , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lipoxinas/metabolismo , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio , Estudos Prospectivos , Índice de Gravidade de Doença , Volume Sistólico , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo , Teste de CaminhadaRESUMO
AIMS: Little is known regarding acute heart failure (AHF) clinical characteristics and its hospital outcome in Latin America. This study sought to assess the prevalence of, and identify differences among, in-hospital outcomes in patients hospitalized for AHF who were stratified by clinical phenotype at a hospital in Latin America. METHODS AND RESULTS: This is a retrospective cohort study of patients with AHF who were hospitalized in the coronary care unit of a Latin American teaching hospital from January 2006 to December 2018. Cox regression analysis was used to identify predictors of mortality. Of 21 042 patients admitted, 7759 (36.6%) had AHF. Their median age was 62 years, and 35% were women. De novo heart failure was seen in 39.4% of patients. Most common was AHF-associated acute coronary syndromes (ACS-HF) in 43.0%, decompensated heart failure (DHF) in 33.7%, hypertensive heart failure (HT-HF) in 11.8%, and cardiogenic shock (CS) in 5.2%. Pulmonary oedema (PO) (3.3%) and right heart failure (RHF) (3.0%) were least frequent. Coronary artery disease was the most frequent aetiology in 56.5% of patients, valvular heart disease in 22.4%, and cardiomyopathies in 12.3%. Other less frequent aetiology included adult congenital heart disease (2.5%), lung diseases (2.1%), acute aortic syndromes (1.4%), pericardial diseases (0.8%), and intracardiac tumours (0.3%). Aetiology could not be established in 1.6% of patients. Before admission, patients with worsening chronic heart failure and reduced ejection fraction were treated with renin-angiotensin system blockers (60.4%), beta-blockers (42.5%), or spironolactone (34.4%). The percentages of patients given in-hospital management with intravenous diuretics, vasodilators, inotropes, and vasopressors were 81.2%, 33.4%, 18.9%, and 20.4%, respectively. The overall in-hospital mortality was 17.9% (71.3%, 43.9%, 23.8%, 14.9%, 13.6%, and 10.1% for CS, PO, RHF, DHF, ACS-HF, and HT-HF, respectively; P < 0.0001). Multivariate analysis revealed that PO (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.73-4.14, P < 0.0001) and CS (HR 3.37, 95% CI 2.12-5.35, P < 0.0001) were independent predictors of in-hospital mortality. Use of intravenous diuretics was linked to reduction of in-hospital mortality (HR 0.70, 95% CI 0.59-0.59, P < 0.0001). By contrast, increased in-hospital mortality was associated with the use of intravenous inotrope or vasopressor (HR 1.49, 95% CI 1.27-1.76 and HR 2.91, 95% CI 2.41-3.51, P < 0.0001, respectively). CONCLUSIONS: Real-world evidence from a university hospital in Latin America shows that the high mortality among patients with AHF may depend, among other factors, on patients' AHF clinical phenotypes. The clinical characteristics and aetiologies of AHF appear to differ between these data from Mexico and those from European and US registries.
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Cardiopatias Congênitas , Insuficiência Cardíaca , Doença Aguda , Adulto , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , América Latina/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Estudos RetrospectivosRESUMO
BACKGROUND: Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. Micro-RNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-ß signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. RESULTS: Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. CONCLUSIONS: The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.
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Animais , Feminino , Camundongos , Doença de Chagas/genética , MicroRNAs/genética , Fibrose , Biomarcadores , Biologia ComputacionalRESUMO
Disorders in the child's neurological development caused by perinatal risks can lead to long-term altered neurological signs that begin at an early age and involve persistent functional disorders. Recent data suggest that tissue dysfunction, not just acute damage, may initiate or perpetuate an inflammatory response. The aim of this study was to find out if any neurological dysfunction in preschool children secondary to damage generated during the perinatal period is associated with the magnitude of perinatal risks and long-term modifications in the serum concentrations of inflammatory molecules. The participants, aged 1-4 years, were on neurodevelopmental follow-up and rehabilitation therapy from the first three months of life and had no acute disease data. We classified the children into three groups according to the importance of their perinatal risks: low, medium, and high. The results show that 1) the magnitude of perinatal risks correlated with the severity of neurological dysfunction; 2) the greatest changes in the concentrations of the molecules of the inflammatory process were associated with the most altered neurological signs. This suggests that persistent nervous system dysfunction keeps inflammatory responses active even in the absence of an acute process of infection or damage.
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Citocinas/sangue , Ácidos Docosa-Hexaenoicos/sangue , Doenças do Sistema Nervoso/sangue , Lesões Pré-Natais/sangue , Pré-Escolar , Feminino , Humanos , Lactente , Inflamação/sangue , Inflamação/imunologia , Masculino , Doenças do Sistema Nervoso/imunologia , Lesões Pré-Natais/imunologia , Reflexo , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Inflammation can be grouped into three phases: proinflammatory, anti-inflammatory, and resolution. The latter, mainly attributed to lipid mediators, is the most recently described, and has been studied little in coronary ischemic diseases. OBJECTIVE: To evaluate 1) if acute coronary syndromes (ACS) manifest different circulating levels of resolution mediators compared with stable angina (SA); 2) if their concentrations are related to those of pro and anti-inflammatory mediators; and 3) if such concentrations are associated with the severity of the disease and the damage produced. METHOD: LTB4, RvD1, LXA4, ET-1, MMP-2, MMP-9, TIMP-1, IL-1ß, IL-6, IL-8 and IL-10 were measured in serum. The GRACE score was established as parameter of gravity, and LVEF as a damage parameter. RESULTS: Thirty patients with SA, 37 with NEST-ACS, 38 with STEMI, and 10 individuals with non-cardiogenic chest pain were included. Patients with coronary artery disease showed elevated levels of inflammatory cytokines and low levels of resolution mediators. CONCLUSIONS: The low resolution response even in patients with acute coronary disease suggests an inability to repair damage. Testing this hypothesis would have the potential to suggest new therapies for the management of chronic cardiovascular inflammation.
ANTECEDENTES: La inflamación puede agruparse en tres fases: proinflamatoria, antiinflamatoria y de resolución. Esta última, principalmente atribuida a mediadores lipídicos, es la de más reciente descripción y se ha estudiado poco en las enfermedades isquémicas coronarias. OBJETIVOS: Evaluar 1) si los síndromes coronarios agudos (SICA) manifiestan niveles circulantes distintos de mediadores de resolución comparados con la angina estable (AE); 2) si sus concentraciones se relacionan con las de mediadores proinflamatorios y antiinflamatorios; y 3) si dichas concentraciones se asocian con la gravedad de la enfermedad y el daño producido. MÉTODO: Se midieron LTB4, RvD1, LXA4, ET-1, MMP-2, MMP-9, TIMP-1, IL-1ß, IL-6, IL-8 e IL-10 en suero. Se establecieron la puntuación GRACE como parámetro de gravedad y la fracción de eyección del ventrículo izquierdo (FEVI) como parámetro de daño. RESULTADOS: Se incluyeron 30 pacientes con AE, 37 con SICA sin elevación del segmento ST (SICA-SEST), 38 con Infarto agudo del miocardio con elevación del segmetno ST(IAM-CEST) y 10 con dolor torácico no cardiogénico. Los pacientes con enfermedad coronaria mostraron niveles elevados de citocinas inflamatorias y bajos de mediadores de resolución. CONCLUSIONES: La escasa respuesta de resolución aun en pacientes con enfermedad coronaria aguda sugiere una incapacidad para reparar daños. Probar esta hipótesis tendría el potencial de sugerir nuevas terapias para el manejo de la inflamación cardiovascular crónica.
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Síndrome Coronariana Aguda/fisiopatologia , Angina Estável/fisiopatologia , Inflamação/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Idoso , Dor no Peito/etiologia , Doença da Artéria Coronariana/fisiopatologia , Estudos Transversais , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Sleep has a fundamental role in the regulation of homeostasis. The aim of this study was to assess the effect of different periods of paradoxical sleep deprivation (PSD) and recovery on serum levels of cytokines and miRNAs related to inflammatory responses. METHODS: Male Wistar rats were submitted to a PSD of 24, 96, or 192 h, or of 192 h followed by 20 days of recovery (192 h PSD+R). The concentrations of corticosterone, cytokines (IL-6, TNF, IL-10, Adiponectin) and miRNAs (miR-146a, miR-155, miR-223, miR-16, miR-126, miR-21) in serum were evaluated. RESULTS: At PSD 24 h a significant increase of IL-6 and decrease of IL-10 were observed. At PSD 96h adiponectin increased. At 192 h of PSD IL-6 increased significantly again, accompanied by a threefold increase of IL-10 and an increase of serum corticosterone. After 20 days of recovery (192 h PSD+R) corticosterone, IL-6 and TNF levels increased significantly, while IL-10 decreased also significantly. Regarding the miRNAs at 24 h of PSD serum miR-146a, miR-155, miR-223, and miR-16 levels all increased. At 96 h of PSD miR-223 decreased. At 192 h of PSD decreases in miR-16 and miR-126 were observed. After recovery serum miR-21 increased and miR-16 decreased. CONCLUSION: PSD induces a dynamic response likely reflecting the induced cellular stress and manifested as variating hormonal and inflammatory responses. Sleep deprivation disturbed corticosterone, cytokine and miRNA levels in serum related to the duration of sleep deprivation, as short-term PSD produced effects similar to those of an acute inflammatory response and long-term PSD induced long-lasting disturbances of biological mediators.
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Psoriasis is triggered by several stimuli that share a systemic production of interferon (IFN)-γ and other inflammatory mediators, which are key to regulate the production of matrix metalloproteinase (MMP)-9 and its inhibitor (TIMP)-1 by cells of monocytic lineage. This study evaluates the effect of the sera of 55 patients with psoriasis and 41 non-psoriatic individuals on the production of MMP-9 and TIMP-1 in cultured monocytes from a single healthy blood donor and in U937 cells. The effect of IFN-γ stimulation was also evaluated. Serum and supernatant concentrations of IFN-γ, MMP-9, and TIMP-1 were measured by enzyme-linked immunoassays, and the MMP-9/TIMP-1 ratios were calculated. In monocytes, incubation with psoriasis' sera increased the production of MMP-9 and TIMP-1 in comparison with both baseline and monocytes incubated with non-psoriatic sera. Although the MMP-9/TIMP-1 ratio was significantly higher compared to the baseline, no differences between groups were observed. In contrast, IFN-γ stimulation in monocytes previously exposed to psoriasis' sera increased MMP-9 levels and decreased TIMP-1 levels, whereas stimulation in monocytes exposed to non-psoriatic sera did not further modify the levels of MMP-9 or TIMP-1. Consequently, the MMP-9/TIMP-1 ratio in cells exposed to psoriatic serum was significantly higher than in cells exposed to non-psoriatic sera (24.5 versus 16.7; P < 0.05). Similar results were observed in U937 cells. Therefore, our results suggest that soluble mediators in psoriatic sera may enhance the proteolytic phenotype of monocytes when stimulated with IFN-γ, which supports the existence of a primed state in the inflammatory cells of patients with psoriasis.
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Inflamação/imunologia , Metaloproteinase 9 da Matriz/sangue , Monócitos/fisiologia , Psoríase/imunologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto , Linhagem da Célula , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Proteólise , Soro , Células U937RESUMO
BACKGROUND: Fresh frozen plasma (FFP) administration may increase the risk of nosocomial infections in parallel with the development of immune modulation. This could be driven by soluble mediators, possibly influencing the in vitro activation of human U937 monocyte cells, in a manner dependent on the age of the donors. METHODS: FFP donors were stratified into groups of 19-30 years, 31-40 years or 41-50 years, and U937 cells were cultured with FFP (alone or plus lipopolysaccharide-LPS) for 24 h. Both in FFP and supernatants, TNF, IL-1ß, IL-6, and IL-10 levels were measured by ELISA. Additionally, CD11B, TLR2, and CASP3 gene expression were measured by qtPCR in U937 cells. Total phagocytic activity was also assayed. RESULTS: Elevated IL-10, but low TNF and IL-1ß levels were measured in FFP from individuals aged 19-40 years, whereas in individuals aged 41-50 years FFP were characterized by equalized TNF and IL-10 levels. Elevated IL-6 levels were found in all FFP samples, especially in those from the oldest individuals. FFP stimulation was associated with striking modifications in cytokine production in an age-dependent way. Exposure to FFP attenuates the response to LPS. TLR2 and CD11B expression were enhanced regardless of the age of plasma donors, although CASP3 expression was increased only when FFP from individuals aged 19-40 years were tested. Phagocytosis decreased after exposure to FFP regardless of donor age. CONCLUSION: Our results suggest that soluble mediators in FFP may modulate the functioning of monocytes. Interestingly, this effect appears to be partially influenced by the age of donors.
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Doadores de Sangue , Citocinas/imunologia , Monócitos/imunologia , Plasma/imunologia , Células U937/imunologia , Adulto , Fatores Etários , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
BACKGROUND: National health surveys have revealed an outstandingly high prevalence of obesity, hypertension, and diabetes in Mexico. OBJECTIVE: To assess whether serum uric acid levels on admission may predict short-term mortality in patients with ST-segment elevation myocardial infarction in a population with an unusually high prevalence of classic cardiovascular risks. METHODS: A total of 795 ST-segment elevation myocardial infarction patients undergoing primary reperfusion therapy were classified as having normouricemia or hyperuricemia according to serum uric acid levels at admission, and the occurrence of mortality and major adverse cardiovascular events during coronary care unit stay was assessed. RESULTS: Patients with hyperuricemia (n = 291; mean age 61.2 ± 11.9 years; 74.8% males) were older, obese, hypertensive, and had a higher Killip class at admission than those with normouricemia (n = 504; mean age 57.6 ± 11.3 years; 88.9% males). Mortality rates were 1.7 and 0.7 cases/100 patients per day of coronary care unit stay in hyperuricemic and normouricemic patients, respectively. Comparatively, no association was observed for the occurrence of major adverse cardiovascular events. After multivariate adjustments, independent predictors for short-term mortality were only Killip class ≥ 2 (HR: 13.15; 95% CI: 5.29-29.85; p < 0.0001) and elevated serum uric acid levels (HR: 1.99; 95% CI: 1.08-3.66; p = 0.026). CONCLUSIONS: Hyperuricemia on admission remains associated with short-term mortality in ST-segment elevation myocardial infarction patients from a population with an unusually high prevalence of cardiovascular risk factors.
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Doenças Cardiovasculares/epidemiologia , Hiperuricemia/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Ácido Úrico/sangue , Idoso , Doenças Cardiovasculares/etiologia , Unidades de Cuidados Coronarianos , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Reperfusão Miocárdica/métodos , Prevalência , Prognóstico , Sistema de Registros , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
OBJECTIVE: The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE). METHODS: Serum levels of IFN-λ1, IFN-λ2, and IFN-λ3 were measured in 93 SLE patients and 67 healthy individuals. The associations with overall disease activity, organ-specific damage, and SLE-related antibodies were assessed. RESULTS: Median IFN-λ1 levels were 0 pg/mL (range, 0-510 pg/mL) and 0 pg/mL (0-171 pg/mL; P = 0.814) in SLE patients and control subjects, respectively. These figures were 0 pg/mL (0-28 pg/mL) and 0 pg/mL (0-43 pg/mL; P = 0.659) for IFN-λ2, as well as 83 pg/mL (0-965 pg/mL) and 42 pg/mL (0-520 pg/mL; P = 0.002) for IFN-λ3, respectively. According to the Systemic Lupus Erythematosus Disease Activity Index categories, IFN-λ3 levels were 44 pg/mL (0-158 pg/mL) in quiescent, 117 pg/mL (0-344 pg/mL) in mild, 79 pg/mL (0-965 pg/mL) in moderate, and 78 pg/mL (0-329 pg/mL) in severe disease, with the highest levels found in patients with serosal or cutaneous involvement. In line with this, IFN-λ3 levels were inversely correlated with C3 (ρ = -0.44; 95% confidence interval, -0.62 to -0.20; P = 0.0003) and C4 (ρ = -0.40; 95% confidence interval, -0.59 to -0.15; P = 0.0001) complement proteins. In addition, higher IFN-λ3 levels were found in patients positive for anti-Ro/SSA antibodies than in those negative for that antibody (122 pg/mL [0-965 pg/mL] vs. 0 pg/mL [0-165 pg/mL]; P = 0.001). The concentration of IFN-λ3 also was higher in patients receiving glucocorticoids (104 pg/mL [0-965 pg/mL] vs. 30 pg/mL [0-165 pg/mL]; P = 0.009), and a dose-related effect was observed. CONCLUSIONS: Interferon λ3, a subtype of type III IFNs, is associated with the extent of lupus activity, in particular with active serosal and cutaneous disease. This association could be mechanistically related to anti-Ro/SSA antibodies.
Assuntos
Anticorpos Antinucleares/imunologia , Glucocorticoides/administração & dosagem , Interferons/imunologia , Lúpus Eritematoso Sistêmico , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , México , Pessoa de Meia-Idade , Gravidade do Paciente , Estatística como AssuntoRESUMO
BACKGROUND: Acute Kidney Injury (AKI), a common complication of acute coronary syndromes (ACS), is associated with higher mortality and longer hospital stays. The role of cytokines and other mediators is unknown in AKI induced by an ACS (ACS-AKI), leading to several unanswered questions. The worsening of renal function is usually seen as a dichotomous phenomenon instead of a dynamic change, so evaluating changes of the renal function in time may provide valuable information in the ACS-AKI setting. The aim of this study was to explore inflammatory factors associated to de novo kidney injury induced by de novo cardiac injury secondary to ACS. METHODS: One hundred four consecutive patients with ACS were initially included on the time of admission to the Coronary Unit of the Instituto Nacional de Cardiología in Mexico City, from February to May 2016, before any invasive procedure, imaging study, diuretic or anti-platelet therapy. White blood count, hemoglobin, NT-ProBNP, troponin I, C-reactive protein, albumin, glucose, Na+, K+, blood urea nitrogen (BUN), total cholesterol, HDL, LDL, triglycerides, creatinine (Cr), endothelin-1 (ET-1), leukotriene-B4, matrix metalloproteinase-2 and -9, tissue inhibitor of metalloproteinases-1, resolvin-D1 (RvD1), lipoxin-A4 (LXA4), interleukin-1ß, -6, -8, and -10 were measured. We finally enrolled 78 patients, and subsequently we identified 15 patients with ACS-AKI. Correlations were obtained by a Spearman rank test. Low-rank regression, splines regressions, and also protein-protein/chemical interactions and pathways analyses networks were performed. RESULTS: Positive correlations of ΔCr were found with BUN, admission Cr, GRACE score, IL-1ß, IL-6, NT-ProBNP and age, and negative correlations with systolic blood pressure, mean-BP, diastolic-BP and LxA4. In the regression analyses IL-10 and RvD1 had positive non-linear associations with ΔCr. ET-1 had also a positive association. Significant non-linear associations were seen with NT-proBNP, admission Cr, BUN, Na+, K+, WBC, age, body mass index, GRACE, SBP, mean-BP and Hb. CONCLUSION: Inflammation and its components play an important role in the worsening of renal function in ACS. IL-10, ET-1, IL-1ß, TnI, RvD1 and LxA4 represent mediators that might be associated with ACS-AKI. IL-6, ET-1, NT-ProBNP might represent crossroads for several physiopathological pathways involved in "de novo cardiac injury leading to de novo kidney injury".
Assuntos
Síndrome Coronariana Aguda/complicações , Injúria Renal Aguda/etiologia , Síndrome Cardiorrenal/etiologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Inflamação/etiologia , Rim/fisiopatologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Idoso , Biomarcadores/sangue , Síndrome Cardiorrenal/sangue , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/fisiopatologia , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/fisiopatologia , Masculino , México , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Fatores de Risco , Transdução de SinaisRESUMO
Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and indicators for glucose metabolism, circulating lipids, and markers for inflammation were analyzed before and after intervention. An overall decrease in triglycerides (TG) and an increase in HS-ω3 index were observed in all subjects [-4.1 mg/dL, (SD:±51.7), P=.02 and 2.6%, (SD:±1.2), P<.001 respectively]. Mean fasting insulin and glycated hemoglobin (HbA1c%) were significantly decreased in all subjects [-0.547mlU/L, (SD:±10.29), P=.034 and-0.07%, (SD:±0.3), P<.001 respectively], whereas there was no change in body composition, fasting glucose, adiponectin and inflammatory markers. Subjects carrying the minor alleles of PPARα L162V and PPARγ2 P12A had higher responses in reduction of TG and fasting insulin respectively. Interestingly, doses below 2.7 g/day (1.8 g/day) were sufficient to induce a significant reduction in fasting insulin and HbA1c% from baseline (P=.019 and P<.001). The observed responses in triglycerides and fasting insulin in the Mexican population give further evidence of the importance of FO supplementation in young people as an early step towards the prevention of cardiometabolic disease.
Assuntos
Biomarcadores/sangue , Óleos de Peixe/farmacologia , Lipídeos/sangue , PPAR alfa/genética , PPAR gama/genética , Adulto , Composição Corporal/efeitos dos fármacos , Sacarose Alimentar , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Frequência do Gene , Humanos , Masculino , México , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.