Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 175
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Infect Dis ; 21(1): 1073, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663245

RESUMO

BACKGROUND: Several inflammatory molecules participate in the immune response to malaria. Interleukin (IL)-18 is an inflammatory cytokine activated by NLRP3 inflammasomes. In clinical falciparum malaria, with and without HIV co-infection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce. METHODS: Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells using hemozoin crystals. RESULTS: (i) IL-18 and IL-18bp were markedly up-regulated during falciparum malaria with particular high levels in malaria patients co-infected with HIV and severe malaria disease. (ii) In the malaria group as a whole, both IL-18 and IL-18bp were positively correlated with disease severity, parasitemia, and endothelial cell activation as assessed by vWF in plasma. (iii) Whereas there was no change in IL-18 levels in malaria patients co-infected with HIV during follow-up, the patients with malaria only had slightly increased IL-18 levels. Further, the IL-18pb levels declined and thereby contributed to an increase in IL-18/IL-18bp ratio in all subgroups of malaria patients. (iv) IL-27, previously shown to be up-regulated in this malaria cohort, markedly induced a release of IL-18bp from endothelial cells in vitro, and notably, this presumably anti-inflammatory effect was counteracted by hemozoin. CONCLUSIONS: Our findings suggest that the IL-18 system could be an important mediator in the immune pathogenesis during falciparum malaria, potentially also representing a target for therapy.


Assuntos
Interleucina-18 , Malária , Células Endoteliais , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Parasitemia , Índice de Gravidade de Doença
2.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343089

RESUMO

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.


Assuntos
Reparo do DNA , DNA Mitocondrial/metabolismo , Cardiopatias/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , NAD/metabolismo , Animais , Dano ao DNA , Células HeLa , Humanos , Camundongos , Mitocôndrias/metabolismo , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Compostos de Piridínio/efeitos adversos , Sirtuínas/antagonistas & inibidores
3.
Sci Rep ; 10(1): 21006, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273482

RESUMO

Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. NLRP3 inflammasome activation may underlie obesity-induced inflammation and insulin resistance, and NLRP3 deficient mice exposed to high fat diet (HFD) appear to be protected from left ventricle (LV) concentric remodeling. Herein, we investigated if these beneficial effects were associated with alterations in plasma metabolites, using metabolomic and lipidomic analysis, and gut microbiota composition, using 16S rRNA sequencing of cecum content, comparing NLRP3 deficient and wild type (WT) mice on HFD and control diet. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. Our findings support a role of NLRP3 inflammasome in the interface between metabolic and inflammatory stress, involving an altered gut microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal , Metaboloma , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Ceramidas/sangue , Metabolismo Energético , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Lipopolissacarídeos/sangue , Fígado/metabolismo , Masculino , Metilaminas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
4.
EBioMedicine ; 60: 102985, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927275

RESUMO

BACKGROUND: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. METHODS: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. FINDINGS: Transcripts of interleukin (IL)-1beta(ß) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1ß protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1ß, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. INTERPRETATION: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.


Assuntos
Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/metabolismo , Colesterol/metabolismo , Proteínas do Sistema Complemento/imunologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Doenças das Artérias Carótidas/patologia , Complemento C5a/imunologia , Biologia Computacional/métodos , Doença da Artéria Coronariana/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Cristais Líquidos , Placa Aterosclerótica
6.
Sci Rep ; 10(1): 5397, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214138

RESUMO

The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Rosuvastatina Cálcica/farmacologia , Adulto , Idoso , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Microbiota/efeitos dos fármacos , Microbiota/genética , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Rosuvastatina Cálcica/metabolismo
7.
Cell Rep ; 30(12): 4165-4178.e7, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209476

RESUMO

Oxidation resistance gene 1 (OXR1) protects cells against oxidative stress. We find that male mice with brain-specific isoform A knockout (Oxr1A-/-) develop fatty liver. RNA sequencing of male Oxr1A-/- liver indicates decreased growth hormone (GH) signaling, which is known to affect liver metabolism. Indeed, Gh expression is reduced in male mice Oxr1A-/- pituitary gland and in rat Oxr1A-/- pituitary adenoma cell-line GH3. Oxr1A-/- male mice show reduced fasting-blood GH levels. Pull-down and proximity ligation assays reveal that OXR1A is associated with arginine methyl transferase PRMT5. OXR1A-depleted GH3 cells show reduced symmetrical dimethylation of histone H3 arginine 2 (H3R2me2s), a product of PRMT5 catalyzed methylation, and chromatin immunoprecipitation (ChIP) of H3R2me2s shows reduced Gh promoter enrichment. Finally, we demonstrate with purified proteins that OXR1A stimulates PRMT5/MEP50-catalyzed H3R2me2s. Our data suggest that OXR1A is a coactivator of PRMT5, regulating histone arginine methylation and thereby GH production within the pituitary gland.


Assuntos
Arginina/metabolismo , Histonas/metabolismo , Proteínas Mitocondriais/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Hormônio do Crescimento/sangue , Hormônio do Crescimento/metabolismo , Hormônios/metabolismo , Imunidade/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/química , Proteínas Mitocondriais/deficiência , Especificidade de Órgãos , Hipófise/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Domínios Proteicos , Ratos , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/metabolismo , Relação Estrutura-Atividade , Transcriptoma/genética
8.
Biochem Biophys Res Commun ; 523(4): 867-873, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31955888

RESUMO

Inflammation is centrally involved in the development of cardiac hypertrophy and the processes of remodelling. The complement system and Toll-like receptor (TLR) family, two upstream arms of the innate immune system, have previously been reported to be involved in cardiac remodelling. However, the role of complement component 3 (C3), TLR co-receptor CD14 and the synergy between them have not been addressed during pressure overload-induced cardiac remodelling. Here, we examined angiotensin II-induced cardiac hypertrophy and remodelling for 7 days in male C57Bl/6 J mice deficient in C3, CD14, or both (C3CD14), and WT controls. Angiotensin II infusion induced a mild concentric hypertrophic phenotype in WT mice with increased left ventricle weight, wall thicknesses and reduced ventricular internal diameter, associated with increased cardiac fibrosis. However, there were no differences between WT mice and mice deficient for C3, CD14 or C3CD14, as systolic blood pressure, cardiac function and structure and levels of fibrosis were comparable between WT mice and the three other genotypes. C5a did not change in angiotensin II treated mice, whereas Mac2 levels were increased in angiotensin II treated mice, but did not differ between genotypes. The inflammatory IL-6 response was comparable between WT and C3 deficient mice, however, it was decreased in CD14 and C3CD14 deficient mice. We conclude that deficiency in C3, CD14 or C3CD14 had no effect on cardiac remodelling following angiotensin II-induced pressure overload. This suggests that C3 and CD14 are not involved in angiotensin II-induced adverse cardiac remodelling.


Assuntos
Angiotensina II/farmacologia , Complemento C3/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Receptores Toll-Like/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/sangue , Cardiomegalia/genética , Fibrose , Hipertrofia , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sístole/efeitos dos fármacos
9.
BMC Infect Dis ; 20(1): 65, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964363

RESUMO

BACKGROUND: The immune response during falciparum malaria mediates both harmful and protective effects on the host; however the participating molecules have not been fully defined. Interleukin (IL)-27 is a pleiotropic cytokine exerting both inflammatory and anti-inflammatory effects, but data on IL-27 in malaria patients are scarce. METHODS: Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV-1 co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells and PBMC using hemozoin crystals. Samples were analyzed using enzyme immunoassays and quantitative PCR. RESULTS: (i) IL-27 was markedly up-regulated in malaria patients compared with controls and HIV-infected patients without malaria, showing no relation to HIV co-infection. (ii) IL-27 was correlated with P. falciparum parasitemia and von Willebrand factor as a marker of endothelial activation, but not with disease severity. (iii) In vitro, IL-27 modulated the hemozoin-mediated cytokine response in endothelial cells and PBMC with enhancing effects on IL-6 and attenuating effects on IL-8. CONCLUSION: Our findings show that IL-27 is regulated during falciparum malaria, mediating both inflammatory and anti-inflammatory effects, potentially playing an immune-regulatory role during falciparum malaria.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Coinfecção/imunologia , HIV-1 , Interleucinas/sangue , Interleucinas/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Coinfecção/sangue , Estudos Transversais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Hemeproteínas/farmacologia , Humanos , Interleucinas/genética , Interleucinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Malária Falciparum/sangue , Masculino , Pessoa de Meia-Idade , Moçambique , Parasitemia/imunologia , Estudos Prospectivos , Adulto Jovem
10.
ESC Heart Fail ; 7(2): 456-466, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31978943

RESUMO

AIMS: Recent reports have suggested that patients with heart failure (HF) have an altered gut microbiota composition; however, associations with diet remain largely uninvestigated. We aimed to explore differences in the gut microbiota between patients with HF with reduced ejection fraction and healthy controls, focusing on associations with diet and disease severity. METHODS AND RESULTS: The microbiota composition of two cross-sectional cohorts (discovery, n = 40 and validation, n = 44) of patients with systolic HF and healthy controls (n = 266) was characterized by sequencing of the bacterial 16S rRNA gene. The overall microbial community (beta diversity) differed between patients with HF and healthy controls in both cohorts (P < 0.05). Patients with HF had shifts in the major bacterial phyla, resulting in a lower Firmicutes/Bacteroidetes (F/B) ratio than controls (P = 0.005). Patients reaching a clinical endpoint (listing for heart transplant or death) had lower bacterial richness and lower F/B ratio than controls (P < 0.01). Circulating levels of trimethylamine-N-oxide were associated with meat intake (P = 0.016), but not with gut microbiota alterations in HF. Low bacterial richness and low abundance of several genera in the Firmicutes phylum were associated with low fibre intake. CONCLUSIONS: The gut microbiota in HF was characterized by decreased F/B ratio and reduced bacterial diversity associated with clinical outcome. The gut microbiota alterations in HF were partly related to low fibre intake, emphasizing the importance of diet as a covariate in future studies. Our data could provide a rationale for targeting the gut microbiota in HF with high-fibre diet.


Assuntos
Microbioma Gastrointestinal , Insuficiência Cardíaca , Microbiota , Estudos Transversais , Humanos , RNA Ribossômico 16S
11.
J Infect Dis ; 221(4): 506-509, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31077280

RESUMO

People with human immunodeficiency virus (HIV) infection (PWH) have an increased risk of cardiovascular disease (CVD), compared with the general population. In a nested case-control study of 55 PWH with first-time myocardial infarction (MI; cases) and 182 PWH with no CVD (controls), we measured soluble markers of interleukin 1 (IL-1) activation at 4 different time points before the case's MI. Cases had higher levels of IL-1 receptor antagonist (IL-1Ra) at all time points leading up to first-time MI, and higher levels of IL-1Ra were associated with an approximately 1.5-fold increased risk of MI, supporting the rationale to target IL-1 activation to reduce cardiovascular risk in PWH.


Assuntos
Infecções por HIV/sangue , Infecções por HIV/complicações , HIV/genética , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-1beta/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Interleucina-1beta/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Prognóstico , RNA Viral/sangue , Fatores de Risco
12.
Atherosclerosis ; 296: 74-82, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31870625

RESUMO

BACKGROUND AND AIMS: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events. METHODS: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry. RESULTS: In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome. CONCLUSIONS: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.


Assuntos
Doenças Cardiovasculares/metabolismo , Cisteína Endopeptidases/biossíntese , Macrófagos/enzimologia , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Doença Aguda , Sequência de Aminoácidos , Plaquetas/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Estudos Transversais , Cisteína Endopeptidases/sangue , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/farmacologia , Citocinas/farmacologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Seguimentos , Humanos , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Intervenção Coronária Percutânea , Placa Aterosclerótica/química , Ativação Plaquetária , Proteínas Recombinantes/farmacologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Suécia/epidemiologia , Células THP-1
13.
Int J Cancer ; 146(1): 223-235, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444972

RESUMO

Angiogenesis is necessary for tumor growth and has been targeted in breast cancer; however, it is unclear which patients will respond and benefit from antiangiogenic therapy. We report noninvasive monitoring of patient response to neoadjuvant chemotherapy given alone or in combination with anti-vascular endothelial growth factor (bevacizumab) in a randomized clinical trial. At four time points during neoadjuvant chemotherapy ± bevacizumab of receptor tyrosine-protein kinase erbB-2-negative breast cancers, we measured metabolites and inflammation-related markers in patient's serum. We report significant changes in the levels of several molecules induced by bevacizumab, the most prominent being an increase in pentraxin 3 (PTX3) and von Willebrand factor (VWF). Serum levels of AXL, VWF and pulmonary and activation-regulated cytokine (PARC/CCL18) reflected response to chemotherapy alone or in combination with bevacizumab. We further analyzed serum cytokines in relation to tumor characteristics such as gene expression, tumor metabolites and tumor infiltrating leukocytes. We found that VWF and growth-differentiation factor 15 tumor mRNA levels correlated with their respective serum protein levels suggesting that these cytokines may be produced by tumors and outflow to the bloodstream while influencing the tumor microenvironment locally. Finally, we used binomial logistic regression which allowed to predict patient's response using only 10 noninvasive biomarkers. Our study highlights the potential of monitoring circulating levels of cytokines and metabolites during breast cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Mediadores da Inflamação/sangue , Bevacizumab/administração & dosagem , Biomarcadores/metabolismo , Neoplasias da Mama/sangue , Citocinas/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante
16.
JACC Basic Transl Sci ; 5(12): 1210-1224, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33426377

RESUMO

An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3 -/- mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1ß and -18) in MI patients.

17.
Open Heart ; 6(2): e001098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798913

RESUMO

Objective: The aetiology of thoracic aortic aneurysm (TAA) is largely unknown, but inflammation is likely to play a central role in the pathogenesis. In this present study, we aim to investigate the complement receptors in TAA. Methods: Aortic tissue and blood from 31 patients with non-syndromic TAA undergoing thoracic aortic repair surgery were collected. Aortic tissue and blood from 36 patients with atherosclerosis undergoing coronary artery bypass surgery or aortic valve replacement were collected and served as control material. The expression of the complement anaphylatoxin receptors C3aR1, C5aR1 and C5aR2 in aortic tissue were examined by quantitative RT-PCR and C5aR2 protein by immunohistochemistry. Colocalisation of C5aR2 to different cell types was analysed by immunofluorescence. Complement activation products C3bc and sC5b-9 were measured in plasma. Results: Compared with controls, TAA patients had substantial (73%) downregulated gene expression of C5aR2 as seen both at the mRNA (p=0.005) level and protein (p=0.03) level. In contrast, there were no differences in the expression of C3aR1 and C5aR1 between the two groups. Immunofluorescence examination showed that C5aR2 was colocalised to macrophages and T cells in the aortic media. There were no differences in the degree of systemic complement activation between the two groups. Conclusion: Our findings suggest downregulation of the C5aR2, regarded to act mainly anti-inflammatory, in electively operated TAA as compared with non-aneurysmatic aortas of patients with aortic stenosis and/or coronary artery disease. This may tip the balance towards a relative increase in the inflammatory responses induced by C5aR1 and thus enhance the inflammatory processes in TAA.

18.
J Cardiovasc Pharmacol ; 74(4): 276-284, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31584530

RESUMO

Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems are evolutionarily conserved throughout species. As a result, the immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interaction between metabolic disturbances and the immune system has been most extensively studied in disorders related to obesity such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease. Metabolically induced inflammation seems also to play a role in the development and progression of atherosclerosis including its complications such as myocardial infarction (MI) and post-MI remodeling. There are several lines of evidence suggesting that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a sensor of metabolic stress linking metabolic disturbances to inflammation. Here, we will discuss the role of the NLRP3 inflammasome in the pathogenesis of obesity and diabetes, 2 important risk factors for atherosclerosis and MI. We will also discuss the role of NLRP3 inflammasome in the interaction between metabolic disturbances and myocardial inflammation during MI and during metabolically induced myocardial remodeling.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/metabolismo , Animais , Aterosclerose/epidemiologia , Aterosclerose/imunologia , Aterosclerose/patologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Metabolismo Energético , Microbioma Gastrointestinal , Humanos , Inflamassomos/imunologia , Inflamação/epidemiologia , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/imunologia , Resistência à Insulina , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Obesidade/epidemiologia , Obesidade/imunologia , Obesidade/patologia , Fatores de Risco , Transdução de Sinais
19.
J Immunol ; 203(7): 1973-1980, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492744

RESUMO

Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.


Assuntos
Estenose da Valva Aórtica/imunologia , Estenose da Valva Aórtica/mortalidade , Fator B do Complemento/imunologia , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Fator B do Complemento/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/imunologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/imunologia , Índice de Gravidade de Doença , Troponina T/sangue , Troponina T/imunologia
20.
J Am Coll Cardiol ; 74(6): 774-782, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31395128

RESUMO

BACKGROUND: The chemokines CCL19 and CCL21 are up-regulated in atherosclerotic disease and heart failure, and increased circulating levels are found in unstable versus stable coronary artery disease. OBJECTIVES: The purpose of this study was to evaluate the prognostic value of CCL19 and CCL21 in acute coronary syndrome (ACS). METHODS: CCL19 and CCL21 levels were analyzed in serum obtained from ACS patients (n = 1,146) on the first morning after hospital admission. Adjustments were made for GRACE (Global Registry of Acute Coronary Events) score, left ventricular ejection fraction, pro-B-type natriuretic peptide, troponin I, and C-reactive protein levels. RESULTS: The major findings were: 1) those having fourth quartile levels of CCL21 on admission of ACS had a significantly higher long-term (median 98 months) risk of major adverse cardiovascular events (MACE) and myocardial infarction in fully adjusted multivariable models; 2) high CCL21 levels at admission were also independently associated with MACE and cardiovascular mortality during short-time (3 months) follow-up; and 3) high CCL19 levels at admission were associated with the development of heart failure. CONCLUSIONS: CCL21 levels are independently associated with outcome after ACS and should be further investigated as a promising biomarker in these patients.


Assuntos
Síndrome Coronariana Aguda/sangue , Quimiocina CCL19/sangue , Quimiocina CCL21/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Biomarcadores/sangue , Causas de Morte/tendências , Ecocardiografia , Feminino , Seguimentos , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Suécia/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...