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Monocyte chemoattractant protein-1 (MCP-1) participates in the initiation and progression of atherosclerosis. In vitro studies have reported that the MCP-1 rs1024611 polymorphism is associated with increased MCP-1 concentrations. The study aimed to define whether MCP-1 concentrations are associated with premature coronary artery disease (pCAD) and to establish whether variations in the rs1024611 polymorphism increase MCP-1 concentrations. MCP-1 rs1024611 polymorphism was determined in 972 pCAD patients and 1070 control individuals by real-time PCR. MCP-1 concentrations were determined by the Bio-Plex system. In the total population, men had higher MCP-1 concentrations when compared to women (p < 0.001). When stratified by rs1024611 genotypes, higher MCP-1 concentrations were observed in AA individuals compared to GG subjects (p = 0.023). When performing the analysis considering sex, the differences remained significant in women (AA vs. GG, p = 0.028 and GA vs. GG, p = 0.008). MCP-1 concentrations were similar in pCAD patients and controls (p = 0.782). However, the independent analysis of the studied groups showed that in patients with the AA genotype, MCP-1 concentrations were significantly higher when compared to patients with the GG genotype (p = 0.009). Considering that the AA genotype increases MCP-1 concentration, we evaluated whether, in AA genotype carriers, MCP-1 concentrations were associated with pCAD. The results showed that for every ten pg/mL increase in MCP-1 concentration, the risk of presenting pCAD increases by 2.7% in AA genotype individuals. Individuals with the MCP-1 rs1024611 AA genotype present an increase in MCP-1 concentration. In those individuals, increased MCP-1 concentrations increase the risk of presented pCAD.
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The epidermal growth factor receptor (EGFR) signaling pathway is one of the main pathways responsible for propagating the luteinizing hormone (LH) signal throughout the cumulus cells and the oocyte. Recently, we have proposed the C-C motif chemokine receptor 2 (CCR2) and its main ligand (monocyte chemoattractant protein-1, MCP1) as novel mediators of the ovulatory cascade. Our previous results demonstrate that the gonadotropins (GNT), amphiregulin (AREG), and prostaglandin E2 (PGE2) stimulation of periovulatory gene mRNA levels occurs, at least in part, through the CCR2/MCP1 pathway, proposing the CCR2 receptor as a novel mediator of the ovulatory cascade in a feline model. For that purpose, feline cumulus-oocyte complexes (COCs) were cultured in the presence or absence of an EGFR inhibitor, recombinant chemokine MCP1, and gonadotropins [as an inducer of cumulus-oocyte expansion (C-OE), and oocyte maturation] to further assess the mRNA expression of periovulatory key genes, C-OE, oocyte nuclear maturation, and steroid hormone production. We observed that MCP1 was able to revert the inhibition of AREG mRNA expression by an EGFR inhibitor within the feline COC. In accordance, the confocal analysis showed that the GNT-stimulated hyaluronic acid (HA) synthesis, blocked by the EGFR inhibitor, was recovered by the addition of recombinant MCP1 in the C-OE culture media. Also, MCP1 was able to revert the inhibition of progesterone (P4) production by EGFR inhibitor in the C-OE culture media. Regarding oocyte nuclear maturation, recombinant MCP1 could also revert the inhibition triggered by the EGFR inhibitor, leading to a recovery in the percentage of metaphase II (MII)-stage oocytes. In conclusion, our results confirm the chemokine receptor CCR2 as a novel intermediate in the ovulatory cascade and demonstrate that the EGFR/AREG and the CCR2/MCP1 signaling pathways play critical roles in regulating feline C-OE and oocyte nuclear maturation, with CCR2/MCP1 signaling pathway being downstream EGFR/AREG pathway within the ovulatory cascade.
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OBJECTIVES: To assess the prevalence of leukocyte cell-derived chemotactic 2 (LECT2), its organ involvement, and its clinical association in autopsies from an ethnically biased population. METHODS: The tissues from all autopsies of individuals diagnosed with amyloidosis were reassessed and typed for amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, transthyretin amyloidosis (ATTR), and leukocyte chemotactic factor 2 amyloidosis (ALECT2) by immunohistochemistry. Organ involvement was described and correlated with its clinical associations. RESULTS: Of 782 autopsies, 27 (3.5%) had a confirmed diagnosis of amyloidosis. Of these, 14 (52%) corresponded to ALECT2, 5 (19%) to AL amyloidosis, 2 (7%) to ATTR amyloidosis, 1 (4%) to AA amyloidosis, and 5 (21%) as undetermined-type amyloidosis. The LECT2 amyloid deposits were found in the kidneys, liver, spleen, and adrenal glands in most individuals. Except for the kidneys, there were no clinical signs suggestive of amyloid deposition in most of the affected organs. LECT2 amyloidosis was not associated with the cause of death in any case. No cases had heart or brain involvement. Potential subclinical effects of amyloid deposition in organs such as adrenal glands and spleen require further study. CONCLUSIONS: This autopsy study confirms the high prevalence of LECT2 amyloidosis in the Mexican population, with frequent amyloid deposition in the kidneys, liver, spleen, and adrenal glands.
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Neuropatias Amiloides Familiares , Rim , Humanos , Fatores Quimiotáticos , Leucócitos , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
OBJECTIVES: The present study aims to assess the course of uMCP-1 and its association with response to therapy and long-term kidney function in a prospective cohort of adults who received a kidney biopsy for suspicion of active lupus nephritis (LN). METHODS: Subjects were segregated into a histologically active LN group and a histologically chronic LN group. Both groups were followed for > = 36 months and urine were collected at flare, 3, 6, and 12 months of follow-up. The association between the course of uMCP-1, response to treatment, and progression to 30% loss of the eGFR was evaluated by linear mixed models for repeated measures. RESULTS: A kidney biopsy was performed on 125 subjects. In 114, the report was consistent with histologically active LN; in 11, with histologically chronic LN. Urine MCP-1 levels were significantly higher in the active LN than in the chronic LN group. Urine MCP-1 levels correlated with the histological findings of cellular crescents, endocapillary hypercellularity, interstitial inflammation, glomerular sclerosis, interstitial fibrosis, and tubular atrophy. The mean estimates of uMCP-1 at flare were higher in the non-response group than in the complete response group, and decreased in the complete/partial response groups by the third month, while they remained elevated in the non-response group. The mean estimates for uMCP-1 were higher at LN flare and remained elevated in patients who progressed to loss of 30% of the eGFR, while they decreased in patients with stable kidney function. CONCLUSION: The first-year course of uMCP-1 is associated with response to therapy and kidney survival in LN. Key Points â¢Urine MCP-1 levels differentiate histologically-active lupus nephritis from histologically-chronic lupus nephritis â¢Urine MCP-1 levels decrease by 3 months of therapy in subjects with a favorable response whose kidney function remains stable long-term â¢Urine MCP-1 levels remain elevated during the first year of therapy in subjects the will later lose kidney function.
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Nefrite Lúpica , Adulto , Humanos , Biomarcadores , Rim/patologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/complicações , Prognóstico , Estudos ProspectivosRESUMO
Several factors are associated with the progression of chronic hepatitis C: comorbidities, lifestyle, and pathogenic factors, including immune response, apoptosis and heredity. Single nucleotide polymorphisms (SNPs) in the PNPLA3 and TM6SF2 genes are more widely studied genetic risk factors, while CXCL9-11 chemokines produced by hepatocytes in the process of infection are less well studied. Our aim was to evaluate the influence of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 in liver fibrosis when analysed together with PNPLA3 rs738409 and TM6SF2 rs58542926. The study included 219 patients with chronic hepatitis C. SNP genotyping was performed by real-time PCR. Univariate and multivariate analyses were used to detect the association between SNPs and advanced fibrosis in a recessive genetic model. All SNPs had a minimum allele frequency >5%, and CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 were in high linkage disequilibrium (D' ≥ 0.84). In the multivariate analysis, we observed that male gender (P = 0.000), older age (P = 0.025), moderate to intense inflammatory activity (P = 0.002), moderate to accentuated hepatic steatosis (P = 0.026) and the CT genotype of the TM6SF2 rs58542926 SNP (P = 0.014) presented significant associations with advanced fibrosis. Overall, the CXCL9 rs10336, CXCL10 rs3921, CXCL11 rs4619915 and PNPLA3 rs738409 SNPs did not influence liver fibrosis among patients with chronic hepatitis C.
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Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Hepacivirus , Hepatite C Crônica/genética , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Hepatócitos/metabolismo , Humanos , Lipase/genética , Lipase/metabolismo , Cirrose Hepática/virologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. METHODS: Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc). RESULTS: For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence. CONCLUSION: Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.
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Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.
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OBJECTIVE: To describe the main neurological manifestations related to coronavirus infection in humans. METHODOLOGY: A systematic review was conducted regarding clinical studies on cases that had neurological manifestations associated with COVID-19 and other coronaviruses. The search was carried out in the electronic databases PubMed, Scopus, Embase, and LILACS with the following keywords: "coronavirus" or "Sars-CoV-2" or "COVID-19" and "neurologic manifestations" or "neurological symptoms" or "meningitis" or "encephalitis" or "encephalopathy," following the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Seven studies were included. Neurological alterations after CoV infection may vary from 17.3% to 36.4% and, in the pediatric age range, encephalitis may be as frequent as respiratory disorders, affecting 11 % and 12 % of patients, respectively. The Investigation included 409 patients diagnosed with CoV infection who presented neurological symptoms, with median age range varying from 3 to 62 years. The main neurological alterations were headache (69; 16.8 %), dizziness (57, 13.9 %), altered consciousness (46; 11.2 %), vomiting (26; 6.3 %), epileptic crises (7; 1.7 %), neuralgia (5; 1.2 %), and ataxia (3; 0.7 %). The main presumed diagnoses were acute viral meningitis/encephalitis in 25 (6.1 %) patients, hypoxic encephalopathy in 23 (5.6 %) patients, acute cerebrovascular disease in 6 (1.4 %) patients, 1 (0.2 %) patient with possible acute disseminated encephalomyelitis, 1 (0.2 %) patient with acute necrotizing hemorrhagic encephalopathy, and 2 (1.4 %) patients with CoV related to Guillain-Barré syndrome. CONCLUSION: Coronaviruses have important neurotropic potential and they cause neurological alterations that range from mild to severe. The main neurological manifestations found were headache, dizziness and altered consciousness.
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Expression of immune function genes within follicle cells has been reported in ovaries from many species. Recent work from our laboratory showed a direct effect of the monocyte chemoattractant protein 1/C-C motif chemokine receptor 2 system within the feline cumulus oocyte complex, by increasing the mRNA levels of key genes involved in the ovulatory cascade in vitro. Studies were designed to evaluate if C-C motif chemokine receptor 2 acts as a novel mediator of the ovulatory cascade in vitro. Therefore, feline cumulus oocyte complexes were cultured in the presence or absence of a highly selective C-C motif chemokine receptor 2 antagonist together with known inducers of cumulus-oocyte expansion and/or oocyte maturation to assess mRNA expression of key genes related to periovulatory events in other species as well as oocyte maturation. Also, the effects of recombinant monocyte chemoattractant protein 1 on spontaneous or gonadotrophin-induced oocyte maturation were assessed. This is an in vitro system using isolated cumulus oocyte complexes from feline ovaries. The present study reveals the modulation of several key ovulatory genes by a highly selective C-C motif chemokine receptor 2 antagonist. However, this antagonist was not enough to block the oocyte maturation induced by gonadotropins or amphiregulin. Nonetheless, recombinant monocyte chemoattractant protein 1 had a significant effect on spontaneous oocyte maturation, increasing the percentage of metaphase II stage oocytes in comparison to the control. This is the first study in any species to establish C-C motif chemokine receptor 2 as a mediator of some actions of the mid-cycle gonadotrophin surge.
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Ovulação/genética , Receptores CCR2/fisiologia , Animais , Gatos , Células Cultivadas , Células do Cúmulo/metabolismo , Células do Cúmulo/fisiologia , Feminino , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/metabolismo , Oócitos/fisiologia , Oogênese/genética , Folículo Ovariano/metabolismo , Folículo Ovariano/fisiologiaRESUMO
Lupus nephropathy is a severe and frequent complication of systemic lupus erythematosus. Here, we assessed the biomarkers of oxidative stress, inflammation and disease activity in patients with lupus nephritis. Thirty-four patients with active lupus nephritis, 31 patients with inactive lupus nephritis and 20 lupus patients without renal damage (non-lupus nephritis) were studied. Oxidative stress biomarkers malonyldialdehyde, oxidized-to-total glutathione, catalase, superoxide dismutase and total antioxidant status were assessed, as well as inflammation biomarkers CRP, interleukin 6 and monocyte chemoattractant protein 1. Renal tubular disease biomarkers neutrophil gelatinase-associated lipocalin and ß2-microglobulin were assessed, together with the classic disease activity biomarkers urinary protein/creatinine ratio, anti-dsDNA, anti-C1q antibody and complement proteins C3 and C4. Significant differences were found between active lupus nephritis and inactive lupus nephritis patients and between active lupus nephritis and non-lupus nephritis patients for all the assessed biomarkers (P < 0.05), except for catalase, superoxide dismutase and interleukin 6. There is an imbalance in the redox status in active lupus nephritis patients that would be involved in lipid peroxidation of the glomerular basal membrane that would alter its integrity and could also affect renal tubular function in these patients.
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Biomarcadores/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Nefrite Lúpica/diagnóstico , Estresse Oxidativo/imunologia , Adolescente , Adulto , Quimiocina CCL2/sangue , Complemento C3/análise , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Testes de Função Renal , Lipocalina-2/sangue , Modelos Logísticos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/sangue , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
In many species, sperm must locate the female gamete to achieve fertilization. Molecules diffusing from the egg envelope, or the female genital tract, guide the sperm toward the oocyte through a process called chemotaxis. Sperm chemotaxis has been studied for more than 100 years being a widespread phenomenon present from lower plants to mammals. This process has been mostly studied in external fertilizers where gametes undergo a significant dilution, as compared to internal fertilizers where the encounter is more defined by the topology of the female tract and only a small fraction of sperm appear to chemotactically respond. Here, we summarize the main methods to measure sperm swimming responses to a chemoattractant, both in populations and in individual sperm. We discuss a novel chemotactic index (CI) to score sperm chemotaxis in external fertilizers having circular trajectories. This CI is based on the sperm progressive displacement and its orientation angle to the chemoattractant source.
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Quimiotaxia/genética , Fertilização/genética , Motilidade dos Espermatozoides/genética , Animais , Células Germinativas/crescimento & desenvolvimento , Células Germinativas/metabolismo , Mamíferos/genética , Mamíferos/crescimento & desenvolvimento , Desenvolvimento VegetalRESUMO
Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable in the first-line defense to kill invading pathogens in the early stage of disease. However, on the other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible damage to the infected joint, which is known as an important complication in septic arthritis patients. Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an efficient therapy to reduce tissue damage in septic arthritis.
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Artrite Infecciosa/terapia , Articulações/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Infecções Estafilocócicas/terapia , Antibacterianos/uso terapêutico , Artrite Infecciosa/imunologia , Artrite Infecciosa/microbiologia , Artrite Infecciosa/cirurgia , Artrocentese/métodos , Artroscopia/métodos , Movimento Celular/imunologia , Quimiocinas/imunologia , Quimiocinas/metabolismo , Humanos , Inflamação , Articulações/imunologia , Articulações/microbiologia , Articulações/cirurgia , Leucotrienos/imunologia , Leucotrienos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/cirurgia , Staphylococcus aureus , Sucção/métodosRESUMO
Background Information regarding urinary biomarkers in Mestizo and Afro-Latin-American patients is very limited. We investigated whether levels of urinary neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein 1 (MCP-1) are good biomarkers to differentiate patients with lupus nephritis among Latin-American systemic lupus erythematosus (SLE) patients. Methods SLE patients meeting the revised American College of Rheumatology classification criteria for SLE were recruited. Urinary levels of NGAL and MCP-1 were measured using a commercial ELISA kit. Serum anti-C1q antibodies were measured by ELISA. SLE activity was measured with the systemic lupus erythematosus disease activity index (SLEDAI). Mann-Whitney tests were used to compare data and Spearman's rank correlations were used to examine associations between continuous variables. In addition, receiver operating characteristic curves were performed. Results One hundred and twenty SLE patients were recruited (87% women) with a median age of 32.8 ± 12.1 years and median disease duration of 7.3 ± 6.9 years. Afro-Latin-Americans had a significantly higher prevalence of lupus nephritis and higher SLEDAI scores than Mestizos. The three biomarkers were significantly higher in patients with lupus nephritis than in patients without lupus nephritis. In addition, urinary NGAL and MCP-1 were significantly higher in patients with active lupus nephritis than in inactive lupus nephritis. Urinary NGAL levels were significantly higher in Afro-Latin-American patients. A receiver operating characteristic curve for urinary biomarkers for lupus nephritis in all SLE patients showed a good level of sensitivity and specificity. Conclusion In our cohort of SLE patients, we found that urinary NGAL and MCP-1 in addition to anti-C1q antibodies were useful biomarkers for the identification of renal involvement and discrimination of active lupus nephritis among patients with renal disease.
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Quimiocina CCL2/urina , Lipocalina-2/urina , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/urina , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Biomarcadores/urina , População Negra , Colômbia/epidemiologia , Complemento C1q/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Indígenas Sul-Americanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/etnologia , Nefrite Lúpica/etiologia , Masculino , Valor Preditivo dos Testes , Prevalência , Regulação para Cima , Urinálise/métodos , Adulto JovemRESUMO
Lamina propria dendritic cells (DCs) have a permanent turnover with constitutive migration to mesenteric lymph nodes and replenishment by progenitors. Luminal bacteria and dietary constituents provide key signals that endow DCs their unique properties in vivo. Taking into account that the intestinal immune system is greatly influenced by retinoids, we evaluated in B6 mice 3, 8, 16 and 24 h after feeding a single dose of vitamin A phenotype and function of cells present in mesenteric afferent lymph nodes as well as signals involved in migration. We studied the frequency of CD11c+MHC-II+CD103+CD86+ and RALDH+ DCs by flow cytometry, we determined CCL-21 and D6 levels in tissue homogenates by Western blot, and we co-cultured cells isolated from afferent lymphatics with sorted CD4+ lymphocytes to assess Foxp-3 induction and homing receptor expression. Sixteen hours after vitamin A administration, DCs isolated from afferent lymphatics were able to induce homing receptors and Foxp3 expression in CD4+ lymphocytes. Our results show that a single dose of vitamin A generated a stream of signals and amplified the tolerogenic activity of DCs migrating to lymphoid tissue.
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Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Suplementos Nutricionais , Fatores de Transcrição Forkhead/agonistas , Regulação da Expressão Gênica , Receptores de Retorno de Linfócitos/agonistas , Vitamina A/administração & dosagem , Animais , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Tolerância Imunológica , Linfa/citologia , Linfa/imunologia , Linfa/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Mesentério , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Retorno de Linfócitos/genética , Receptores de Retorno de Linfócitos/metabolismo , Organismos Livres de Patógenos EspecíficosRESUMO
Monocytes circulate in the blood and migrate to inflammatory tissues, but their functions can be either detrimental or beneficial, depending on their phenotypes. In humans, classical monocytes are inflammatory cluster of differentiation (CD)14++CD16-CCR2++ cells originated from the bone marrow or spleen reservoirs and comprise ≥92% of monocytes. Intermediate monocytes (CD14++CD16+CCR2+) are involved in the production of anti-inflammatory cytokines [such as interleukin (IL)-10], reactive oxygen species (ROS), and proinflammatory mediators [such as tumor necrosis factor-α (TNF-α) and IL-1ß). Nonclassical monocytes (CD14+CD16++CCR2-) are patrolling cells involved in tissue repair and debris removal from the vasculature. Many studies in both humans and animals have shown the importance of monocyte chemoattractant protein-1 (MCP-1) and its receptor [chemokine receptor of MCP-1 (CCR2)] in pathologies, such as atherosclerosis and myocardial infarction (MI). This review presents the importance of these monocyte subsets in cardiovascular diseases (CVDs), and sheds light on new strategies for the blocking of the MCP-1/CCR2 axis as a therapeutic goal for treating vascular disorders.
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Doenças Cardiovasculares/metabolismo , Quimiocina CCL2/metabolismo , Monócitos/metabolismo , Receptores CCR2/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Quimiocina CCL2/antagonistas & inibidores , Humanos , Ligantes , Monócitos/classificação , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fenótipo , Receptores CCR2/antagonistas & inibidores , Transdução de SinaisRESUMO
Organic anion transporters (OATs) are involved in the uptake of uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), which play a role in endothelial dysfunction in patients with chronic kidney diseases (CKD). In this study, we investigated the role of OAT1 and OAT3 in the uptake of PCS and IS into human endothelial cells. PCS was synthesized via p-cresol sulfation and characterized using analytical methods. The cells were treated with PCS and IS in the absence and presence of probenecid (Pb), an OAT inhibitor. Cell viability was assessed using the MTT assay. The absorbed toxins were analyzed using chromatography, OAT expression using immunocytochemistry and western blot, and monocyte chemoattractant protein-1 (MCP-1) expression using enzyme-linked immunosorbent assay. Cell viability decreased after toxin treatment in a dose-dependent manner. PCS and IS showed significant internalization after 60 min treatment, while no internalization was observed in the presence of Pb, suggesting that OATs are involved in the transport of both toxins. Immunocytochemistry and western blot demonstrated OAT1 and OAT3 expression in endothelial cells. MCP-1 expression increased after toxins treatment but decreased after Pb treatment. PCS and IS uptake were mediated by OATs, and OAT blockage could serve as a therapeutic strategy to inhibit MCP-1 expression.
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Quimiocina CCL2/metabolismo , Células Endoteliais/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Uremia/metabolismo , Transporte Biológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cresóis/metabolismo , Cresóis/toxicidade , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Indicã/metabolismo , Indicã/toxicidade , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Probenecid/farmacologia , Ésteres do Ácido Sulfúrico/metabolismo , Ésteres do Ácido Sulfúrico/toxicidade , Fatores de Tempo , Regulação para Cima , Uremia/patologiaRESUMO
Abstract Background: Hypertension is a chronic, low-grade inflammation process associated with the release of cytokines and development of target organ damage. Deregulated monocyte chemoattractant protein-1 (MCP-1) levels have been associated with high blood pressure and cardiovascular complications; however, the mechanisms involved are complex and not fully understood. Objective: This study aimed to compare the levels of MCP-1 in patients with resistant (RH) versus mild-to-moderate (HTN) hypertension and their association with the presence or absence of left ventricular hypertrophy (LVH) in all hypertensive subjects. Methods: We enrolled 256 hypertensive subjects: 120 RH and 136 HTN, investigating the relationship between circulating MCP-1 levels and blood pressure, biochemical data, hematologic profile, and cardiac damage within the RH and HTN groups. Plasma MCP-1 levels were measured by ELISA and LVH was assessed by echocardiography. Results: We found no difference in MCP-1 levels between RH and HTN subjects. On the other hand, we encountered lower MCP-1 levels in patients with LVH (105 pg/mL [100 - 260 pg/mL] versus 136 pg/mL (100 - 200 pg/mL), p = 0.005, respectively] compared with those without LVH. A logistic regression model adjusted for body mass index (BMI), age, race, aldosterone levels, and presence of diabetes and RH demonstrated that median levels of MCP-1 (2.55 pg/mL [1.22 - 5.2 pg/mL], p = 0.01) were independently associated with LVH in the entire hypertensive population. Conclusion: Since MCP-1 levels were similar in both RH and HTN subjects and decreased in hypertensive patients with existing LVH, our study suggests a possible downregulation in MCP-1 levels in hypertensive individuals with LVH, regardless of hypertension strata.
Resumo Fundamentos: A hipertensão arterial é um processo crônico de baixo grau inflamatório, associado com liberação de citocinas e desenvolvimento de lesão em órgãos-alvo. A desregulação dos níveis de proteína quimiotática de monócitos-1 (MCP-1) tem sido associada com elevação da pressão arterial e complicações cardiovasculares; porém, os mecanismos envolvidos são complexos e ainda não foram inteiramente elucidados. Objetivo: O objetivo deste estudo foi comparar os níveis de MCP-1 em pacientes com hipertensão resistente (HR) versus pacientes com hipertensão de grau leve a moderado (HAS) e sua associação com a presença ou ausência de hipertrofia ventricular esquerda (HVE) em todos os indivíduos hipertensos. Métodos: Foram incluídos 256 indivíduos hipertensos: 120 com HR e 136 com HAS. Foi investigada a relação entre os níveis circulantes de MCP-1 e pressão arterial, dados bioquímicos, perfil hematológico e dano cardíaco nos grupos HR e HAS. Os níveis plasmáticos de MCP-1 foram medidos por ELISA e a HVE foi avaliada por ecocardiografia. Resultados: Não encontramos diferença nos níveis de MCP-1 entre indivíduos com HR e HAS. Por outro lado, encontramos níveis mais baixos de MCP-1 em pacientes com HVE (105 pg/mL [100 - 260 pg/mL] versus 136 pg/mL [100 - 200 pg/mL], respectivamente, p = 0,005] em comparação a pacientes sem HVE. Um modelo de regressão logística ajustado para o índice de massa corporal (IMC), idade, raça, níveis de aldosterona e presença de diabetes e HR mostrou que os níveis medianos de MCP-1 (2,55 pg/mL [1,22 - 5,2 pg/mL], p = 0,01) estiveram independentemente associados com HVE em toda a população de hipertensos. Conclusão: Como os níveis de MCP-1 foram semelhantes em indivíduos tanto com HR quanto HAS e estiveram diminuídos em pacientes hipertensos com HVE, nosso estudo sugere uma possível redução nos níveis de MCP-1 em indivíduos hipertensos com HVE, independe do grau da hipertensão.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Hipertrofia Ventricular Esquerda/fisiopatologia , Quimiocina CCL2/análise , Remodelação Ventricular/fisiologia , Hipertensão/fisiopatologia , Índice de Gravidade de Doença , Estudos Transversais , Monitorização Ambulatorial da Pressão ArterialRESUMO
OBJECTIVES: Henoch-Schönlein purpura nephritis and immunoglobulin A nephropathy are two diseases with similar clinical presentations but very different prognoses. Transforming growth factor β1 and monocyte chemoattractant protein-1 have been associated with the development of tissue fibrosis. We examined the development of tubulointerstitial fibrosis and its relationship with Transforming growth factor β1 and monocyte chemoattractant protein-1 expression in these patients. METHODS: Renal tissue samples were collected by renal biopsy from 50 children with Henoch-Schönlein purpura nephritis and 50 children with immunoglobulin A nephropathy. Hematoxylin and eosin and Masson's trichrome-stained tissues were examined using light microscopy. Tubulointerstitial fibrosis was graded using the method described by Bohle et al. (1). The immunohistochemical detection of Transforming growth factor β1 and monocyte chemoattractant protein-1 expression was correlated with the tubulointerstitial fibrosis grade. Clinical Trial registration number: ZJCH-2012-0105. RESULTS: Transforming growth factor β1 and monocyte chemoattractant protein-1 expression in the renal tissues was significantly greater in the patients with immunoglobulin A nephropathy than in the patients with Henoch-Schönlein purpura nephritis (both p<0.001). The immunoglobulin A nephropathy patients had a higher tubulointerstitial fibrosis grade than the Henoch-Schönlein purpura nephritis patients (p<0.001). The tubulointerstitial fibrosis grade was in accordance with the Transforming growth factor β1 and monocyte chemoattractant protein-1 expression levels in both diseases (both p<0.001). CONCLUSION: Transforming growth factor β1 and monocyte chemoattractant protein-1 expression was associated with the development of immunoglobulin A nephropathy and Henoch-Schönlein purpura nephritis. Further studies are needed to better evaluate this association.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Vasculite por IgA/metabolismo , Quimiocina CCL2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Glomerulonefrite por IGA/metabolismo , Túbulos Renais/metabolismo , Prognóstico , Vasculite por IgA/patologia , Fibrose , Glomerulonefrite por IGA/patologia , Túbulos Renais/patologiaRESUMO
We evaluated the effects of chronic oral supplementation with l-glutamine and l-alanine in their free form or as the dipeptide l-alanyl-l-glutamine (DIP) on muscle damage, inflammation and cytoprotection, in rats submitted to progressive resistance exercise (RE). Wistar rats (n 8/group) were submitted to 8-week RE, which consisted of climbing a ladder with progressive loads. In the final 21 d before euthanasia, supplements were delivered in a 4 % solution in drinking water. Glutamine, creatine kinase (CK), lactate dehydrogenase (LDH), TNF-α, specific IL (IL-1ß, IL-6 and IL-10) and monocyte chemoattractant protein-1 (MCP-1) levels were evaluated in plasma. The concentrations of glutamine, TNF-α, IL-6 and IL-10, as well as NF-κB activation, were determined in extensor digitorum longus (EDL) skeletal muscle. HSP70 level was assayed in EDL and peripheral blood mononuclear cells (PBMC). RE reduced glutamine concentration in plasma and EDL (P<0·05 v. sedentary group). However, l-glutamine supplements (l-alanine plus l-glutamine (GLN+ALA) and DIP groups) restored glutamine levels in plasma (by 40 and 58 %, respectively) and muscle (by 93 and 105 %, respectively). GLN+ALA and DIP groups also exhibited increased level of HSP70 in EDL and PBMC, consistent with the reduction of NF-κB p65 activation and cytokines in EDL. Muscle protection was also indicated by attenuation in plasma levels of CK, LDH, TNF-α and IL-1ß, as well as an increase in IL-6, IL-10 and MCP-1. Our study demonstrates that chronic oral l-glutamine treatment (given with l-alanine or as dipeptide) following progressive RE induces cyprotective effects mediated by HSP70-associated responses to muscle damage and inflammation.
Assuntos
Alanina/farmacologia , Anti-Inflamatórios/farmacologia , Suplementos Nutricionais , Dipeptídeos/farmacologia , Glutamina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Treinamento Resistido/efeitos adversos , Alanina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Creatina Quinase/sangue , Citocinas/sangue , Dipeptídeos/uso terapêutico , Glutamina/sangue , Glutamina/metabolismo , Glutamina/uso terapêutico , Proteínas de Choque Térmico HSP70/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , L-Lactato Desidrogenase/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Músculo Esquelético/metabolismo , NF-kappa B/metabolismo , Ratos WistarRESUMO
Resumo Objetivo Investigar a relação entre os números de células progenitoras endoteliais circulantes e a ativação endotelial em uma população pediátrica com obesidade. Métodos Estudo observacional e transversal, que incluiu 120 crianças e adolescentes com obesidade primária de ambos de sexos, entre seis e 17 anos, recrutados de nossa Clínica de Riscos Cardiovasculares. O grupo de controle contou com 41 crianças e adolescentes com índice de massa corporal normal. As variáveis analisadas foram: idade, sexo, índice de massa corporal, pressão arterial sistólica e diastólica, proteína C reativa de alta sensibilidade, perfil lipídico, leptina, adiponectina, resistência à insulina para avaliação do modelo de homeostase, proteína quimiotática de monócitos-1, E-seleticna, dimetilarginina assimétrica e números de células endoteliais progenitoras circulantes. Resultados A resistência à insulina foi correlacionada à dimetilarginina assimétrica (p = 0,340; p = 0,003), que foi diretamente correlacionada, porém de forma muita amena, à E-seleticna (ρ = 0,252; p = 0,046). Não constatamos que a proteína C reativa de alta sensibilidade estivesse correlacionada a marcadores de ativação endotelial. A pressão arterial sistólica foi diretamente correlacionada ao índice de massa corporal ρ = 0,471; p < 0,001) e à resistência à insulina para avaliação do modelo de homeostase (ρ = 0,230; p = 0,012) e inversamente correlacionada à adiponectina (ρ = −0,331; p < 0,001) e à lipoproteína de alta densidade-colesterol ρ = −0,319; p < 0,001). Os números de células progenitoras endoteliais circulantes foram diretamente correlacionados, porém de forma muito amena, ao índice de massa corporal (r = 0,211; p = 0,016), à leptina (ρ = 0,245; p = 0,006), aos níveis de triglicerídeos (r = 0,241; p = 0,031) e à E-seleticna ρ = 0,297; p = 0,004). Conclusão Os números de células progenitoras endoteliais circulantes são elevados em crianças e adolescentes obesos com comprovação de ativação endotelial. Isso sugere que, na infância, os mecanismos de reparação endotelial estão presentes no contexto da ativação endotelial.
Abstract Objective This study aimed to investigate the relationship between circulating endothelial progenitor cell count and endothelial activation in a pediatric population with obesity. Methods Observational and transversal study, including 120 children and adolescents with primary obesity of both sexes, aged 6-17 years, who were recruited at this Cardiovascular Risk Clinic. The control group was made up of 41 children and adolescents with normal body mass index. The variables analyzed were: age, gender, body mass index, systolic and diastolic blood pressure, high-sensitivity C-reactive protein, lipid profile, leptin, adiponectin, homeostasis model assessment-insulin resistance, monocyte chemoattractant protein-1, E-selectin, asymmetric dimethylarginine and circulating progenitor endothelial cell count. Results Insulin resistance was correlated to asymmetric dimethylarginine (ρ = 0.340; p = 0.003), which was directly, but weakly correlated to E-selectin (ρ = 0.252; p = 0.046). High sensitivity C-reactive protein was not found to be correlated to markers of endothelial activation. Systolic blood pressure was directly correlated to body mass index (ρ = 0.471; p < 0.001) and the homeostasis model assessment-insulin resistance (ρ = 0.230; p = 0.012), and inversely correlated to adiponectin (ρ = −0.331; p < 0.001) and high-density lipoprotein cholesterol (ρ = −0.319; p < 0.001). Circulating endothelial progenitor cell count was directly, but weakly correlated, to body mass index (r = 0.211; p = 0.016), leptin (ρ = 0.245; p = 0.006), triglyceride levels (r = 0.241; p = 0.031), and E-selectin (ρ = 0.297; p = 0.004). Conclusion Circulating endothelial progenitor cell count is elevated in obese children and adolescents with evidence of endothelial activation, suggesting that, during infancy, endothelial repairing mechanisms are present in the context of endothelial activation.