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1.
Int J Mol Sci ; 22(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34639088

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies in the Western world and intestinal dysbiosis might contribute to its pathogenesis. The mucosal colon microbiome and C-C motif chemokine 2 (CCL2) were investigated in 20 healthy controls (HC) and 20 CRC patients using 16S rRNA sequencing and immunoluminescent assay, respectively. A total of 10 HC subjects were classified as overweight/obese (OW/OB_HC) and 10 subjects were normal weight (NW_HC); 15 CRC patients were classified as OW/OB_CRC and 5 patients were NW_CRC. Results: Fusobacterium nucleatum and Escherichia coli were more abundant in OW/OB_HC than in NW_HC microbiomes. Globally, Streptococcus intermedius, Gemella haemolysans, Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were significantly increased in CRC patient tumor/lesioned tissue (CRC_LT) and CRC patient unlesioned tissue (CRC_ULT) microbiomes compared to HC microbiomes. CCL2 circulating levels were associated with tumor presence and with the abundance of Fusobacterium nucleatum, Bacteroides fragilis and Gemella haemolysans. Our data suggest that mucosal colon dysbiosis might contribute to CRC pathogenesis by inducing inflammation. Notably, Fusobacterium nucleatum, which was more abundant in the OW/OB_HC than in the NW_HC microbiomes, might represent a putative link between obesity and increased CRC risk.


Assuntos
Bactérias/genética , Biomarcadores/análise , Quimiocina CCL2/sangue , Neoplasias Colorretais/diagnóstico , Microbioma Gastrointestinal , Mucosa Intestinal/patologia , RNA Ribossômico 16S/genética , Idoso , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/análise
2.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638546

RESUMO

Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.


Assuntos
Anti-Inflamatórios/farmacologia , Endotoxemia/tratamento farmacológico , Indazóis/farmacologia , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Linhagem Celular , Quimiocina CCL2/sangue , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Reposicionamento de Medicamentos , Endotoxemia/mortalidade , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ativação Plaquetária/efeitos dos fármacos , Células RAW 264.7 , Transcriptoma/genética
3.
Nutrients ; 13(10)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684577

RESUMO

Hyperhomocysteneinemia (HHcy) is common in the general population and is a risk factor for atherosclerosis by mechanisms that are still elusive. A hypomethylated status of epigenetically relevant targets may contribute to the vascular toxicity associated with HHcy. Ketogenic diets (KD) are diets with a severely restricted amount of carbohydrates that are being widely used, mainly for weight-loss purposes. However, studies associating nutritional ketosis and HHcy are lacking. This pilot study investigates the effects of mild HHcy induced by nutritional manipulation of the methionine metabolism in the absence of dietary carbohydrates on disease progression and specific epigenetic changes in the apolipoprotein-E deficient (apoE-/-) mouse model. ApoE-/- mice were either fed a KD, a diet with the same macronutrient composition but low in methyl donors (low methyl KD, LMKD), or control diet. After 4, 8 or 12 weeks plasma was collected for the quantification of: (1) nutritional ketosis, (i.e., the ketone body beta-hydroxybutyrate using a colorimetric assay); (2) homocysteine by HPLC; (3) the methylating potential S-adenosylmethionine to S-adenosylhomocysteine ratio (AdoHcy/AdoMet) by LC-MS/MS; and (4) the inflammatory cytokine monocyte chemoattractant protein 1 (MCP1) by ELISA. After 12 weeks, aortas were collected to assess: (1) the vascular AdoHcy/AdoMet ratio; (2) the volume of atherosclerotic lesions by high-field magnetic resonance imaging (14T-MRI); and (3) the content of specific epigenetic tags (H3K27me3 and H3K27ac) by immunofluorescence. The results confirmed the presence of nutritional ketosis in KD and LMKD mice but not in the control mice. As expected, mild HHcy was only detected in the LMKD-fed mice. Significantly decreased MCP1 plasma levels and plaque burden were observed in control mice versus the other two groups, together with an increased content of one of the investigated epigenetic tags (H3K27me3) but not of the other (H3K27ac). Moreover, we are unable to detect any significant differences at the p < 0.05 level for MCP1 plasma levels, vascular AdoMet:AdoHcy ratio levels, plaque burden, and specific epigenetic content between the latter two groups. Nevertheless, the systemic methylating index was significantly decreased in LMKD mice versus the other two groups, reinforcing the possibility that the levels of accumulated homocysteine were insufficient to affect vascular transmethylation reactions. Further studies addressing nutritional ketosis in the presence of mild HHcy should use a higher number of animals and are warranted to confirm these preliminary observations.


Assuntos
Apolipoproteínas E/deficiência , Metilação de DNA/genética , Dieta Cetogênica , Epigênese Genética , Acetilação , Animais , Peso Corporal , Quimiocina CCL2/sangue , Histonas/metabolismo , Homocisteína/sangue , Cetose/sangue , Cetose/genética , Lisina/metabolismo , Masculino , Metaboloma , Camundongos , Projetos Piloto , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Processamento de Proteína Pós-Traducional
4.
Nutrients ; 13(10)2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34684629

RESUMO

Melatonin, the hormone of circadian rhythm regulation, is involved in the modulation of mitochondrial activity through its antioxidant and anti-inflammatory properties. Alteration of circadian rhythms such as sleep is related to obesity and metabolic pathogenesis in adulthood, but studies during childhood are scarce. The present study investigated the association of melatonin with metabolic and inflammatory markers in children with (n = 113) and without obesity (n = 117). Melatonin was measured in saliva four and two hours before bedtime, and after one hour of sleep. Cardiometabolic factors, high sensitivity C-reactive protein, immune markers (monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, tumor necrosis α and interferon-γ), leptin and ghrelin were determined. Sleep duration was recorded by a questionnaire. The melatonin level at 1 h after sleep was found to be increased more than twofold in children with obesity (90.16 (57.16-129.16) pg/mL) compared to controls (29.82 (19.05-61.54) pg/mL, p < 0.001) and was related to fat mass (rho = 0.294, p < 0.001); melatonin levels at 1 h after sleep were inversely correlated with high-density lipoprotein cholesterol. Positive correlation was found with apolipoprotein B, adipokines, high sensitivity C-reactive protein, plasminogen activator inhibitor-1 and tumor necrosis factor-α. Shorter sleep duration and earlier waking times were recorded in children with obesity. In conclusion, melatonin in children with obesity appears to be involved in the global metabolic and inflammatory alteration of this condition.


Assuntos
Inflamação/sangue , Melatonina/análise , Obesidade Pediátrica/sangue , Saliva/química , Sono , Adipocinas/sangue , Adolescente , Proteína C-Reativa/análise , Quimiocina CCL2/sangue , Criança , Ritmo Circadiano , Feminino , Grelina/sangue , Humanos , Inflamação/metabolismo , Interferon gama/sangue , Leptina/sangue , Masculino , Obesidade Pediátrica/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Fator de Necrose Tumoral alfa/sangue
5.
Nutrients ; 13(9)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34578925

RESUMO

Monocyte chemotactic protein-1 (MCP-1) plays an important role in the entire atherosclerotic process, from atherogenesis to destabilisation of the atherosclerotic plaque. The purpose of this study is to evaluate the effect of the dietary approaches to stop hypertension (DASH) diet in patients with coronary artery disease on the MCP-1 plasma concentration and to evaluate the potential usefulness of this chemokine as a marker of change in the volume and composition of coronary plaque. MATERIAL AND METHOD: As part of the dietary intervention to stop coronary atherosclerosis in computed tomography (DISCO-CT) study, patients were randomised to an intervention group (n = 40) in which the DASH diet was introduced, and to a control group (n = 39) with no dietary intervention. In the DASH group, dietary counselling was provided at all follow-up visits within 12 months of the follow-up period. MCP-1 plasma concentration was determined using enzyme-linked immunosorbent assay (ELISA). Coronary plaque analysis was performed using a semi-automated plaque analysis software system (QAngioCT, Medis, The Netherlands). RESULTS: In the DASH group, MCP-1 plasma concentration significantly decreased by 34.1 pg/mL (p = 0.01), while in the control group, the change in MPC-1 was not significant. Significant inverse correlations were revealed for the change in MCP-1 plasma concentration and change in the consumption of vitamin C and dietary fibre both in the DASH (r = -0.519, p = 0.0005; r = -0.353, p = 0.025, respectively) and in the control group (r = -0.488 p = 0.001; r = -0.502, p = 0.001, respectively). In patients with the highest decrease in percent atheroma volume (PAV), a significant positive correlation was observed between the change in MCP-1 plasma concentration and changes in PAV (r = 0.428, p = 0.033) and calcified plaque component (r = 0.468, p = 0.018), while the change in noncalcified plaque component correlated inversely with change in MCP1 (r = -0.459, p = 0.021). CONCLUSION: Dietary intervention based on the DASH diet model reduces the MCP-1plasma concentration, mostly due to an increased intake of plant-derived, fibre-rich foods and antioxidants. The change in MCP-1 plasma concentration seems to reflect changes in the atheroma volume and proportions between the calcified and non-calcified plaque elements.


Assuntos
Quimiocina CCL2/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/dietoterapia , Abordagens Dietéticas para Conter a Hipertensão/métodos , Biomarcadores/sangue , Quimiocinas/sangue , Angiografia por Tomografia Computadorizada , Doença da Artéria Coronariana/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
6.
Nutrients ; 13(9)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34578989

RESUMO

Inflammation plays a role in development of diabetic complications. The postprandial state has been linked to chronic low grade inflammation. We therefore aimed to investigate the acute effects of fructose loading, with and without a pizza, on metabolic and inflammatory markers in patients with type 2 diabetes (T2D) (n = 7) and in healthy subjects (HS) (n = 6), age 47-76 years. Drinks consumed were blueberry drink (18 g fructose), Coca-Cola (17.5 g fructose), and fructose drink (35 g fructose). The levels of glucose, insulin, insulin-like growth factor binding protein-1 (IGFBP-1) and inflammatory markers: Interleukin-6 (IL-6), Monocyte chemoattractant protein-1 (MCP-1), Interleukin-18 (IL-18), Intercellular Adhesion Molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and bacterial lipopolysaccharides (LPS) were analyzed in blood. The postprandial responses were assessed using Wilcoxon's matched-pairs test, Friedman's ANOVA and Mann-Whitney U test. There was no difference in baseline levels of inflammatory markers between the groups. In T2D, MCP-1 decreased following blueberry drink and Coca-Cola (p = 0.02), Coca-Cola + pizza and fructose + pizza (p = 0.03). In HS, IL-6 increased following blueberry + pizza and fructose + pizza (p = 0.03), there was a decrease in MCP-1 following blueberry drink and Coca-Cola (p = 0.03), and in ICAM-1 following blueberry + pizza (p = 0.03). These results may indicate a role for MCP-1 as a link between postprandial state and diabetes complications, however further mechanistic studies on larger population of patients with T2D are needed for confirmation of these results.


Assuntos
Frutose/efeitos adversos , Inflamação/induzido quimicamente , Idoso , Biomarcadores/sangue , Glicemia/análise , Bebidas Gaseificadas/efeitos adversos , Quimiocina CCL2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Frutose/administração & dosagem , Sucos de Frutas e Vegetais , Humanos , Inflamação/sangue , Insulina/sangue , Molécula 1 de Adesão Intercelular/sangue , Interleucina-18/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Molécula 1 de Adesão de Célula Vascular/sangue
7.
Front Immunol ; 12: 646673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367126

RESUMO

Background: Infliximab is effective in inducing and maintaining remission in patients with Crohn's disease (CD), but primary non-response (PNR) occurs in 10-30% of cases. We investigated whether serum biomarkers are effective in predicting PNR in patients with CD. Methods: From January 2016 to April 2020, a total of 260 patients were recruited to this prospective and retrospective cohort study. Serum samples were collected at baseline and week 2 of infliximab treatment. Serum levels of 35 cytokines were assessed in 18 patients from the discovery cohort and were further evaluated in the 60-patient cohort 1. Then, candidate cytokines and other serological biomarkers were used to construct a predictive model by logistic regression in a 182-patient cohort 2. PNR was defined based on the change of CD activity index or clinical symptoms. Results: Among the 35 cytokines, matrix metalloproteinase 3(MMP3) and C-C motif ligand 2 (CCL2) were two effective serum biomarkers associated with PNR in both the discovery cohort and cohort 1. In cohort 2, serum level of MMP3, CCL2 and C-reactive protein (CRP) at 2 weeks after infliximab injection were independent predictors of PNR, with odds ratios (95% confidence interval) of 1.108(1.059-1.159), 0.940(0.920-0.965) and 1.102(1.031-1.117), respectively. A PNR classifier combining these three indicators had a large area under the curve [0.896(95% CI:0.895-0.897)] and negative predictive value [0.918(95%CI:0.917-0.919)] to predict PNR to infliximab. Conclusions: MMP3, CCL2, and CRP are promising biomarkers in prediction of PNR to infliximab, and PNR classifier could accurately predict PNR and may be useful in clinical practice for therapy selection.


Assuntos
Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Quimiocina CCL2/sangue , Doença de Crohn/tratamento farmacológico , Infliximab/uso terapêutico , Metaloproteinase 3 da Matriz/sangue , Adolescente , Adulto , Estudos de Coortes , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Citocinas/sangue , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Modelos Logísticos , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Curva ROC , Adulto Jovem
8.
Biomed Res Int ; 2021: 5544264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195267

RESUMO

Background: Rheumatoid arthritis (RA) is a chronic condition that manifests as inflammation of synovial joints, leading to joint destruction and deformity. Methods: We identified single-cell RNA-seq data of synovial fibroblasts from RA and osteoarthritis (OA) patients in GSE109449 dataset. RA- and OA-specific cellular subpopulations were identified, and enrichment analysis was performed. Further, key genes for RA and OA were obtained by combined analysis with differentially expressed genes (DEGs) between RA and OA in GSE56409 dataset. The diagnostic role of key genes for RA was predicted using receiver operating characteristic (ROC) curve. Finally, we identified differences in immune cell infiltration between RA and OA patients, and utilized flow cytometry, qRT-PCR, and Western blot were used to examine the immune cell and key genes in RA patients. Results: The cluster 0 matched OA and cluster 3 matched RA and significantly enriched for neutrophil-mediated immunity and ECM receptor interaction, respectively. We identified 478 DEGs. In the top 20 degrees of connection in the PPI network, the key genes for RA were obtained by comparing with the gene markers of cluster 0 and cluster 3, respectively. ROC curve showed that CCL2 and MMP13 might be diagnostic markers for RA. We found aberrant levels of CD8+T, neutrophil, and B cells in RA fibroblasts, which were validated in clinical samples. Importantly, we also validated the differential expression of key genes between RA and OA. Conclusion: High expression of CCL2 and MMP13 in RA may be a diagnostic and therapeutic target.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Algoritmos , Linfócitos B/metabolismo , Biomarcadores/sangue , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/sangue , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Sistema Imunitário , Inflamação , Metaloproteinase 13 da Matriz/sangue , Mapas de Interação de Proteínas/genética , Curva ROC
9.
J Pediatr ; 238: 33-41.e4, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34273357

RESUMO

OBJECTIVES: To utilize a Luminex platform to examine multiple cytokines simultaneously as well as clinical laboratory testing to identify markers that predict acute pancreatitis severity in the pediatric population on admission. STUDY DESIGN: Patients (<19 years of age) prospectively enrolled over a 4-year period in a single institution acute pancreatitis database were included in separate derivation and validation cohorts. Plasma samples were obtained within 48 hours of admission and stored for analysis. Samples from mild acute pancreatitis and severe acute pancreatitis (moderately severe and severe combined) were analyzed using Luminex panels and C-reactive protein (CRP) testing. RESULTS: The derivation cohort examined 62 cytokines in 66 subject samples (20 control, 36 mild acute pancreatitis, 10 severe acute pancreatitis) and identified interleukin 6 (IL-6) (P = .02) and monocyte chemotactic protein-1 (MCP-1) (P = .02) as cytokines that were differentially expressed between mild and severe acute pancreatitis. Our validation cohort analyzed 76 cytokines between 10 controls, 19 mild acute pancreatitis, and 6 severe acute pancreatitis subjects. IL-6 (P = .02) and MCP-1 (P = .007) were again found to differentiate mild acute pancreatitis from severe acute pancreatitis. CRP values were obtained from 53 of the subjects, revealing a strong association between elevated CRP values and progression to severe disease (P < .0001). CONCLUSIONS: This study identified and validated IL-6 and MCP-1 as predictors of severe acute pancreatitis using 2 distinct cohorts and showed that CRP elevation is a marker of progression to severe acute pancreatitis. These biomarkers have not been extensively studied in the pediatric acute pancreatitis population. Our data allows for risk-stratification of patients with acute pancreatitis, and represent novel insight into the immunologic response in severe acute pancreatitis.


Assuntos
Quimiocina CCL2/sangue , Interleucina-6/sangue , Pancreatite/sangue , Receptores Imunológicos/sangue , Adolescente , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Pancreatite/diagnóstico , Estudos Prospectivos , Curva ROC
10.
Front Immunol ; 12: 646516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079541

RESUMO

Objectives: To investigate vascular macrophage phenotype as well as vascular and peripheral chemokine (C-C motif) ligand 2 (CCL2) expression during different stages of disease progression in patients with Takayasu Arteritis (TA). Methods: In this study, 74 patients with TA and 50 controls were recruited. TA disease activity was evaluated with Kerr scores. Macrophage phenotype and CCL2 expression were examined by immunohistochemistry in vascular specimens from 8 untreated and 7 treated TA patients, along with 4 healthy controls. Serum CCL2 were quantified by enzyme-linked immune-absorbent assay from TA patients at baseline (n=59), at 6-months (n=38), and from 46 healthy volunteers. Vascular macrophage phenotype, vascular CCL2 expression and serum CCL2 levels during different stages, as well as the relationship between serum CCL2 and disease activity or other inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin 6 (IL-6)) were investigated. Results: In untreated patients, vascular M1 macrophages and CCL2 showed increased expression, mainly in the adventitia. In contrast, in treated patients, vascular adventitial M1 and CCL2 expression were decreased, while vascular medial M2 macrophages and CCL2 levels were increased. Distribution of macrophages and CCL2 was consistent within the TA vascular lesions regardless of the disease stage. Furthermore, peripheral CCL2 was elevated in patients with TA (TA: 160.30 ± 120.05 vs. Control: 65.58 ± 54.56 pg/ml, P < 0.001). CCL2 levels were found to correlate with ESR, CRP, and IL-6 (all R values between 0.55 and 0.6, all P < 0.001). Receiver operating curve analysis demonstrated that CCL2 (at the cut-off value of 100.36 pg/ml) was able to predict disease activity (area under the curve = 0.74, P = 0.03). Decrease in CCL2 level was observed in patients with clinical remission (CR), but not in patients without CR, after 6 months of treatment (CR patients: baseline 220.18 ± 222.69 vs. post-treatment 88.71 ± 55.89 pg/ml, P = 0.04; non-CR patients: baseline 142.45 ± 104.76 vs. post-treatment 279.49 ± 229.46 pg/ml, P = 0.02). Conclusions: Macrophages contribute to vascular pathological changes in TA by undergoing phenotype transformation. CCL2 is an important factor for recruiting macrophages and a potential biomarker for disease activity.


Assuntos
Biomarcadores/sangue , Quimiocina CCL2/imunologia , Macrófagos/imunologia , Arterite de Takayasu/imunologia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Quimiocina CCL2/sangue , Quimiocina CCL2/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-6/sangue , Macrófagos/classificação , Masculino , Fenótipo , Arterite de Takayasu/patologia , Arterite de Takayasu/terapia
11.
Biomed Res Int ; 2021: 1752904, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124239

RESUMO

Background: Acute kidney injury (AKI) is one of most prevalent and serious complications of leptospirosis, a prevalent zoonotic disease in tropical countries. Prompt diagnosis of the leptospirosis-associated AKI is a challenge as there are no proper diagnostic tools that can identify patients in the early stage. Kidney injury molecule-1 (KIM-1) and monocyte chemoattractant protein-1 (MCP-1) are widely used novel AKI biomarkers that are studied in various disease conditions with AKI, but not in leptospirosis. Thus, this study is aimed at seeking the importance of KIM-1 and MCP-1 in determining the leptospirosis-associated AKI. Methods: Leptospirosis-suspected patients who were admitted to medical wards of two selected hospitals in the Western province of Sri Lanka were recruited. Leptospirosis was confirmed by three diagnostic tests: PCR, MAT, and culture, and the status of AKI was determined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Results: Of 170 leptospirosis-suspected patients, 79 were leptospirosis confirmed, and among them, 24.05% of patients were diagnosed to have AKI according to KDIGO criteria. Median serum KIM-1 (p < 0.0001), urine KIM-1 (0.0053), serum MCP-1 (0.0080), and urine MCP-1 (0.0019) levels in those developing AKI were significantly higher than in patients not developing AKI. The biomarker levels associated with leptospirosis AKI had AUC-ROC of 0.8565, 0.7292, 0.7024, and 0.7282 for serum KIM-1, urine KIM-1, serum MCP-1, and urine MCP-1, respectively. Conclusion: This study revealed serum KIM-1 as a promising marker for leptospirosis-associated AKI among the tested biomarkers. Thus, further validation is recommended with a larger study group.


Assuntos
Injúria Renal Aguda , Quimiocina CCL2/sangue , Receptor Celular 1 do Vírus da Hepatite A/sangue , Leptospirose , Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Leptospirose/sangue , Leptospirose/complicações , Leptospirose/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sri Lanka
12.
Int Immunopharmacol ; 97: 107685, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33951560

RESUMO

BACKGROUND: The 2019 Coronavirus (COVID-19) pandemic poses a huge threat internationally; however, the role of the host immune system in the pathogenesis of COVID-19 is not well understood. METHODS: Cytokine and chemokine levels and characterisation of immune cell subsets from 20 COVID-19 cases after hospital admission (17 critically ill and 3 severe patients) and 16 convalescent patients were determined using a multiplex immunoassay and flow cytometry, respectively. RESULTS: IP-10, MCP-1, MIG, IL-6, and IL-10 levels were significantly higher in acute severe/critically ill patients with COVID-19, whereas were normal in patients who had reached convalescence. CD8 T cells in severe and critically ill COVID-19 patients expressed high levels of cytotoxic granules (granzyme B and perforin)and was hyperactivated as evidenced by the high proportions of CD38. Furthermore, the cytotoxic potential of natural killer (NK) cells, and the frequencies of myeloid dendritic cells and plasmacytoid dendritic cells was reduced in patients with severe and critical COVID-19; however, these dysregulations were found to be restored in convalescent phases. CONCLUSION: Thus, elicitation of the hyperactive cytokine-mediated inflammatory response, dysregulation of CD8 T and NK cells, and deficiency of host myeloid and plasmacytoid DCs, may contribute to COVID-19 pathogenesis and provide insights into potential therapeutic targets and strategies.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Convalescença , Inflamação/etiologia , ADP-Ribosil Ciclase 1/sangue , Doença Aguda , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL9/sangue , Estado Terminal , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Células Dendríticas/imunologia , Feminino , Granzimas/metabolismo , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Células Matadoras Naturais/enzimologia , Células Matadoras Naturais/imunologia , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Perforina/metabolismo
13.
Sci Rep ; 11(1): 8272, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859290

RESUMO

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Interferon Tipo I/fisiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Quimiocina CXCL10/sangue , Quimiocina CXCL10/genética , Citocinas/sangue , Citocinas/genética , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Interferon Tipo I/metabolismo , Resultados Negativos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Ubiquitinas/sangue , Ubiquitinas/genética
15.
Mediators Inflamm ; 2021: 5513690, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776571

RESUMO

Kidney allograft transplantation improved the prognosis and quality of life of patients with end-stage renal diseases but the occurrence of acute rejection represents a limitation of the final outcome. Noninvasive biomarkers are needed as well as further advancements in the understanding of immune mechanisms of reaction to the allograft. Our study of 138 patients focused on one-year monitoring of serum concentrations of 12 chemokines regulating the recruitment of different immune cells into transplanted allograft and on in vitro regulation of the same chemokines release by interactions of renal proximal epithelial cells with monocyte/macrophage cell line stimulated with TNF alpha. In a group of 44 patients with acute rejection, higher serum pretransplant levels of CXCL1, CXCL5, CXCL6, CCL2, CCL21, and particularly CXCL10 and CX3CL1(both p < 0.001) were found suggesting their higher proinflammatory status as compared to subjects with the uncomplicated outcome. In samples collected at the day of biopsy positive for acute rejection, chemokines CXCL9 and CXCL11 attracting preferentially Th1 lymphocytes were found to be upregulated. In our in vitro model with TNF alpha induction, renal proximal epithelial cells seemed to be a more potent source of chemokines attracting neutrophils as compared to monocyte/macrophage cell line but the coculture of these cells potentiated release of neutrophilic chemokines CXCL5 and CXCL6. Similar augmentation of chemokine production was found also in the case of CCL2. On the other hand, adding of monocytes/macrophages to a culture of renal epithelial cells suppressed the release of CXCL10 and CXCL11 attracting T lymphocytes. We assume from our data that in kidney allograft transplantation, chemokines attracting neutrophils, T lymphocytes, and monocytes are induced simultaneously and measurement some of them in combination might be used as biomarkers of acute rejection. Mutual cell-cell interactions of immune cells with renal parenchyma seem to be important for fine regulation of chemokine release.


Assuntos
Quimiocinas/sangue , Rejeição de Enxerto/sangue , Transplante de Rim/efeitos adversos , Aloenxertos , Quimiocina CCL2/sangue , Quimiocina CCL21/sangue , Quimiocina CX3CL1/sangue , Quimiocina CXCL1/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL5/sangue , Quimiocina CXCL6/sangue , Quimiocina CXCL9/sangue , Rejeição de Enxerto/imunologia , Humanos , Qualidade de Vida , Células Th1/metabolismo
16.
Mediators Inflamm ; 2021: 6684120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776576

RESUMO

Bletilla striata is a well-known traditional Chinese herb with anti-inflammatory properties that is widely used in the treatment of lung conditions such as silicosis, tuberculosis, and pneumogastric hemorrhage. However, little information on the anti-inflammatory ingredients and their activities is available. In this study, an effect fraction of Bletilla striata (EFBS) was enriched, and its anti-inflammatory activities and underlying mechanisms were investigated. EFBS was enriched by polyamide column chromatography and characterized by HPLC; an LPS-induced acute lung injury model was used to evaluate the anti-inflammatory activities of EFBS. Meanwhile, the main anti-inflammation-contributing ingredients and possible molecular mechanism of anti-inflammatory activity in EFBS were verified by component-knockout method combined with LPS-induced RAW264.7 cell model. The EFBS mainly consisted of coelonin (15.88%), batatasin III (32.49%), 3'-O-methylbatatasin III (6.96%), and 3-hydroxy-5-methoxy bibenzyl (2.51%). Pretreatment with the EFBS (20 mg/kg and 60 mg/kg) for five days prior to the administration of LPS resulted in decreases in wet-to-dry lung weight ratio, neutrophil number, MPO activity, total protein concentration, NO level, and MDA level, as well as IL-1ß, IL-6, MCP-1, and TNF-α concentrations in the bronchoalveolar lavage fluid. Western blot analysis demonstrated the increased expressions of iNOS, COX-2, and NF-κB p65 in the LPS treatment group, all of which were ameliorated by EFBS pretreatment. Histological examination confirmed the protective effect of the EFBS. Additionally, component-knockout assay confirmed that these four quantitative components contributed significantly to the anti-inflammatory effect of EFBS. Coelonin, batatasin III, 3'-O-methylbatatasin III and 3-hydroxy-5-methoxy bibenzyl were the main anti-inflammatory components of EFBS and could regulate the expression of downstream inflammatory cytokines by inhibiting p65 nuclear translocation. These findings uncover, in part, the molecular basis underlying the anti-inflammatory activity of Bletilla striata.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Lipopolissacarídeos/toxicidade , Lesão Pulmonar Aguda/sangue , Animais , Quimiocina CCL2/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/sangue , Fator de Necrose Tumoral alfa/sangue
17.
Front Immunol ; 12: 623430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746960

RESUMO

Idiopathic pulmonary fibrosis (IPF) is the most severe form of chronic lung fibrosis. Circulating monocytes have been implicated in immune pathology in IPF but their phenotype is unknown. In this work, we determined the immune phenotype of monocytes in IPF using multi-colour flow cytometry, RNA sequencing and corresponding serum factors, and mapped the main findings to amount of lung fibrosis and single cell transcriptomic landscape of myeloid cells in IPF lungs. We show that monocytes from IPF patients displayed increased expression of CD64 (FcγR1) which correlated with amount of lung fibrosis, and an amplified type I IFN response ex vivo. These were accompanied by markedly raised CSF-1 levels, IL-6, and CCL-2 in serum of IPF patients. Interrogation of single cell transcriptomic data from human IPF lungs revealed increased proportion of CD64hi monocytes and "transitional macrophages" with higher expression of CCL-2 and type I IFN genes. Our study shows that monocytes in IPF patients are phenotypically distinct from age-matched controls, with a primed type I IFN pathway that may contribute to driving chronic inflammation and fibrosis. These findings strengthen the potential role of monocytes in the pathogenesis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Interferon Tipo I/metabolismo , Pulmão/imunologia , Monócitos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/sangue , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imunofenotipagem , Interferon Tipo I/genética , Interleucina-6/sangue , Pulmão/metabolismo , Pulmão/patologia , Fator Estimulador de Colônias de Macrófagos/sangue , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/metabolismo , Fenótipo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Análise de Célula Única
18.
BMC Ophthalmol ; 21(1): 133, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711968

RESUMO

BACKGROUND: The purpose of the study was to investigate whether dynamic monocyte chemoattractant protein-1 (MCP-1) level might be as predictors of perceived pain during the first and second phacoemulsification eye surgeries in patients with bilateral cataract. METHODS: Consecutive bilateral cataract patients undergoing bilateral sequential phacoemulsification were retrospectively enrolled. Patients' preoperative anxiety score and intraoperative pain score were registered. Aqueous humor samples were obtained during surgery. MCP-1 level in the aqueous humor was measured by enzyme linked immunosorbent assay (Elisa). Patients were assigned to seven subgroups based on the interval between first-eye and second-eye cataract surgery. Comparisons were performed for a subjective sensation and MCP-1 levels among different subgroups. RESULTS: pain score during second-eye surgery was significantly higher than during first-eye surgery. Whereas there was no statistical difference in anxiety score between both surgeries. Result from subgroups comparison showed that the visual analog scale (VAS) pain score was statistically greater in 1-group and 6-group during the second eye surgery. Anxiety score did not statistically differ in subgroups. Additionally, the second-eye MCP-1 level was significantly higher at week 1and 6 intervals. Preoperative MCP-1 level was positively correlated with perceiving pain score during both surgeries. CONCLUSIONS: MCP-1 level in aqueous humor significantly correlated with perceived pain during cataract surgery. Dynamic MCP-1 level could function as predictors of perceived pain during the first and second phacoemulsification eye surgeries in patients with bilateral cataract, which might support clinicians in treatment optimization and clinical decision-making.


Assuntos
Catarata , Quimiocina CCL2/sangue , Dor , Facoemulsificação/efeitos adversos , Catarata/complicações , Humanos , Medição da Dor , Percepção da Dor , Estudos Retrospectivos
19.
Medicine (Baltimore) ; 100(11): e24762, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725942

RESUMO

ABSTRACT: Chemokines are majorly involved in inflammatory and immune responses. The interferon-γ-inducible chemokines C-X-C motif chemokines 9 and 10 (CXCL9 and CXCL10) are considerably associated with Th1 cells and monocytes, and their expression levels rapidly increase during the early episodes of renal allograft rejection and various infectious diseases. CXCL13 is one of the most potent B-cell and T follicular helper-cell chemoattractants. The expression of CXCL13 in the presence of infection indicates an important chemotactic activity in multiple infectious diseases. C-C motif chemokine ligand 2 (CCL2) can attract monocytes and macrophages during inflammatory responses. However, there are no studies on the role of these chemokines in posttransplant infection in kidney transplant recipients.In this study, CXCL9, CXCL10, CXCL13, and CCL2 were analyzed using the Bio-Plex suspension array system before transplant and 30 days after transplant.The serum levels of CXCL9 and CXCL13 30 days after kidney transplant were associated with infection within 1 year after transplant (P = .021 and P = .002, respectively). The serum levels of CXCL9 and CXCL13 before surgery and those of CCL2 and CXCL10 before and after surgery were not associated with infection within 1 year after transplant (P > .05). The combination of postoperative day (POD) 30 CXCL9 and postoperative day 30 CXCL13 provided the best results with an area under the curve of 0.721 (95% confidence interval, 0.591-0.852), with a sensitivity of 71.4% and specificity of 68.5% at the optimal cutoff value of 52.72 pg/mL.As important chemokines, CXCL9 and CXCL13 could be used to predict the occurrence of infection after kidney transplant.


Assuntos
Quimiocina CXCL13/sangue , Quimiocina CXCL9/sangue , Infecções/etiologia , Nefropatias/sangue , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/etiologia , Adulto , Biomarcadores/sangue , Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Feminino , Humanos , Nefropatias/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Retrospectivos
20.
J Int Soc Sports Nutr ; 18(1): 19, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653365

RESUMO

BACKGROUND: In this study, we investigated the effects of supplementation and exercise on the expression of genes associated with inflammation like CCL2, CRP, IL1, IL6, IL10 mRNA in elderly women. METHODS: Twenty four participants divided randomly into two groups were subjected to 6 weeks of the same health training program (three times per week). SUP group (supplemented, n = 12, mean age 72.8 ± 5.26 years and mean body mass 68.1 ± 8.3 kg) received 1000 mg of Vitamin C/day during the training period, while CON group (control, n = 12, mean age 72.4 ± 5.5 years and body mass 67.7 ± 7.5 kg) received placebo. RESULTS: No significant changes in IL-1, IL-6, IL-10 and CRP mRNA were observed within and between groups. However, there was a clear tendency of a decrease in IL-6 (two-way ANOVA, significant between investigated time points) and an increase in IL-10 mRNA noted in the supplemented group. A significant decrease in CCL2 mRNA was observed only in the CON group (from 2^0.2 to 2^0.1, p = 0.01). CONCLUSIONS: It can be concluded, that 6 weeks of supplementation and exercise was too short to obtain significant changes in gene expression in leukocytes, but supplementation of 1000 mg vitamin C positively affected IL-6 and IL-10 expression - which are key changes in the adaptation to training. However, changes in body mass, IL1 and CCL2 were positive in CON group. It is possible that Vitamin C during 6 weeks of supplementation could have different effects on the expression of individual genes involved in the immune response. TRIAL REGISTRATION: Retrospectively registered.


Assuntos
Ácido Ascórbico/administração & dosagem , Expressão Gênica , Imunidade/genética , Condicionamento Físico Humano/fisiologia , Vitaminas/administração & dosagem , Idoso , Ácido Ascórbico/sangue , Composição Corporal , Índice de Massa Corporal , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Feminino , Humanos , Interleucina-1/sangue , Interleucina-1/genética , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Estresse Oxidativo , Consumo de Oxigênio , RNA Mensageiro/sangue , Receptores Imunológicos/sangue , Receptores Imunológicos/genética , Fatores de Tempo , Vitaminas/sangue
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