RESUMO
OBJECTIVE: Obesity is a chronic multisystem disease associated with increased morbidity and mortality. Obesity, which is a complex, multifactorial, and heterogeneous condition, is thought to result from the interaction of environmental, physiological, and genetic factors. In this study, the relationship between serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB in obese and healthy cohorts was evaluated along with biochemical and gene expressions and with demographic and clinical covariates, and their effects on obesity were evaluated. METHODS: This case-control study included a total of 80 individuals, 40 healthy controls and 40 obesity patients, consisting of female and male aged between 18 and 63 years. Hemoglobin A1c, mucin-1, and nuclear factor κB levels were determined by ELISA in serum samples obtained from patients. In addition, aspartate aminotransferase, alanine transaminase, low density lipoprotein, and glucose values were measured. The gene expressions of the same markers were analyzed by quantitative real-time polymerase chain reaction, and their regulation status was defined. RESULTS: Serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB were found to be high in obese individuals (p<0.05). The gene expression of these serum markers was found to be upregulated. Of the anthropometric measurements, waist circumference and body mass index were correlated with both serum markers and gene expressions (p<0.05). CONCLUSION: In addition to the known association of hemoglobin A1c and nuclear factor κB with obesity, serum levels of mucin-1 as well as upregulation of genes point to its modifier effect on obesity. These parameters can be the powerful markers in the diagnosis of obesity.
Assuntos
Biomarcadores , Índice de Massa Corporal , Hemoglobinas Glicadas , Mucina-1 , NF-kappa B , Obesidade , Humanos , Masculino , Obesidade/sangue , Feminino , Hemoglobinas Glicadas/análise , Adulto , NF-kappa B/sangue , Estudos de Casos e Controles , Pessoa de Meia-Idade , Adulto Jovem , Mucina-1/sangue , Adolescente , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Reação em Cadeia da Polimerase em Tempo RealRESUMO
C-X-C motif chemokine receptor 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) affect bone cells and play an important role in bone and joint diseases, but the data on CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB in the serum of skeletal fluorosis (SF) patients are inconclusive. Thus, according to the "Diagnostic Criteria for Endemic Skeletal Fluorosis" (WS 192-2008), we enrolled patients with SF (n = 60) as the SF group and those without SF as the controls (n = 60). Serum levels of CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB were detected by enzyme-linked immunosorbent assays (ELISAs). Serum SDF-1, CXCR4, MCP-1 and NF-κB levels were significantly higher in the SF group than in the control group. Within the serum of SF patients, CXCR4 and SDF-1 levels were positively correlated with NF-κB levels. There was no correlation between MCP-1 levels and those of ERK1/2 or NF-κB. SDF-1 and CXCR4 may activate the NF-κB pathway, and MCP-1 affects the occurrence and development of SF by regulating osteocytes through other pathways. The SDF-1/CXCR4 axis and MCP-1 signalling pathway provide a new theoretical basis for the occurrence and development of SF.
Assuntos
Doenças Ósseas , Sistema de Sinalização das MAP Quinases , NF-kappa B , Humanos , Quimiocina CCL2/sangue , Proteína Quinase 3 Ativada por Mitógeno/sangue , NF-kappa B/sangue , Receptores CXCR4/sangue , Transdução de Sinais , Doenças Ósseas/sangue , Doenças Ósseas/diagnósticoRESUMO
Objective: To assess the prognostic value of serum interleukin-6 (IL-6), nuclear factor-κB (NF-κB), and monocyte chemoattractant protein 1(MCP-1) assay in patients with diabetic nephropathy. Methods: From May 2019 to March 2020, 104 patients with diabetic nephropathy treated in our institution assessed for eligibility were recruited and assigned at a ratio of 1 : 1 to either the observation group ([urinary albumin excretion rate (UAER)] of 30 mg-300 mg/24 h) or the research group ([UAER] >300 mg/24 h). IL-6, MCP-1, renal function indices, and NF-κB levels were determined, and their correlation with DN was analyzed. Logistic regression was used to analyze the influencing factors of end-stage renal disease in patients with diabetic nephropathy. The receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to analyze the predictive value of combined detection of IL-6, MCP-1, and NF-κB in the prognosis of patients with diabetic nephropathy. Results: The eligible patients with UAER of 30 mg-300 mg/24 h were associated with significantly higher levels of IL-6, MCP-1, NF-κB, blood urea nitrogen (BUN), and serum creatinine (Scr) versus those with UAER >300 mg/24 h (P < 0.05). During the follow-up, a total of 38 patients progressed to end-stage renal diseases. Eligible patients with end-stage renal diseases showed significantly higher serum IL-6, MCP-1, and NF-κB levels versus those without end-stage renal diseases (P < 0.05). Serum IL-6, MCP-1, and NF-κB are independent risk factors for the occurrence of end-stage renal disease in patients with diabetic nephropathy. The AUCs of IL-6, MCP-1, and NF-κB for predicting the prognosis of patients with diabetic nephropathy were 0.562, 0.634, and 0.647, respectively, and the AUC of the three combined detection for predicting the prognosis of patients with diabetic nephropathy was 0.889. Conclusion: Serum IL-6, NF-κB, and MCP-1 levels are closely related to renal injury and poor prognosis in patients with diabetic nephropathy, and the combined assay is valuable for assessing patients' condition and prognosis.
Assuntos
Quimiocina CCL2 , Diabetes Mellitus , Nefropatias Diabéticas , Interleucina-6 , NF-kappa B , Quimiocina CCL2/sangue , Diabetes Mellitus/sangue , Nefropatias Diabéticas/sangue , Humanos , Interleucina-6/sangue , Falência Renal Crônica/sangue , NF-kappa B/sangue , PrognósticoRESUMO
Obesity is a risk factor for insulin resistance, type 2 diabetes, and cardiovascular diseases. Reticulon-4 (Nogo) is an endoplasmic reticulum-resident protein with unclear functions in obesity. Herein, we investigated the effect of Nogo on obesity and associated metabolic disorders. Human serum samples were collected to explore the relationship between circulating Nogo-B and body mass index value. Nogo-deficient and WT littermate control mice were fed normal chow or high-fat diet (HFD) for 14 weeks, and HFD-induced obese C57BL/6J mice were injected scrambled or Nogo siRNA for 2 weeks. We found that in human and mouse serum, Nogo-B was positively correlated to body mass index/bodyweight and lipid profiles. Reduced Nogo (by genetic deletion or siRNA transfection) protected mice against HFD-induced obesity and related metabolic disorders. We demonstrate that Nogo deficiency reversed HFD-induced whitening of brown adipose tissue, thereby increasing thermogenesis. It also ameliorated lipid accumulation in tissues by activating the adiponectin-adiponectin receptor 1-AMP-activated kinase α signaling axis. Finally, Nogo deficiency potently reduced HFD-induced serum proinflammatory cytokines and infiltration of macrophages into metabolic organs, which is related to enhanced NF-κB p65 degradation via the lysosome pathway. Collectively, our study suggests that reduced levels of Nogo protect mice against HFD-induced obesity by increasing thermogenesis and energy metabolism while inhibiting NF-κB-mediated inflammation. Our results indicate that inhibition of Nogo may be a potential strategy for obesity treatment.
Assuntos
Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Resistência à Insulina , Proteínas Nogo , Obesidade , Animais , Diabetes Mellitus Tipo 2/sangue , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , NF-kappa B/sangue , Proteínas Nogo/sangue , Obesidade/sangue , RNA Interferente Pequeno/sangueRESUMO
BACKGROUND: Bone marrow myelofibrosis (BMF) that develop on top of Polycythaemia vera (PV) and essential thrombocythemia leads to shortening of the patient's overall survival. This study aimed to address the impact of miR-146a rs2431697 polymorphism on inflammatory biomarkers and genes expression and the hazards of myelofibrosis progression. PATIENTS AND METHODS: The study included 88 myeloproliferative neoplasm (40 PV; 27 ET; 21 MF) and 90 healthy controls. For all investigated subjects miR-146a rs2431697 genotypes were identified by sequencing and the expression of miR-146a; IL-1ß; NF-κB; a NOD-like receptor family, pyrin domain containing 3 (NLRP3) (NLRP3) genes were estimated by real time PCR. RESULTS: miR146a genotypes revealed that there was significant association between TT and TC genotypes with MF. The degree of miR146a expression was significantly reduced in MF as compared to both PV and ET. In contrast; the levels of IL-1ß; NF-κB; NLRP3 genes expression were significantly elevated in MF patients group as compared to PV and ET patients' group. Multivariate analysis identified TT genotype as poor predictor of MF progression. CONCLUSION: miR-146a rs2431697 TT genotype is associated with high risk of MF progression in MPN patients. Targeting of IL-1ß; NF-κB; NLRP3 genes might help in hindering of MF progression in MPN patients,
.
Assuntos
Neoplasias da Medula Óssea/genética , MicroRNAs/genética , Transtornos Mieloproliferativos/genética , Polimorfismo Genético/genética , Idoso , Biomarcadores/sangue , Neoplasias da Medula Óssea/sangue , Estudos de Casos e Controles , Progressão da Doença , Feminino , Expressão Gênica , Genótipo , Humanos , Interleucina-1beta/sangue , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , NF-kappa B/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Valor Preditivo dos TestesRESUMO
Age-related macular degeneration (AMD) causes the degeneration of photoreceptors and retinal cells leading to vision loss in older subjects. Among possible exogenous risk factors, it has been recently proposed that long-term exposure to blue light could aggravate the course of AMD. In the search for therapeutic options, plasma rich in growth factors (PRGF) has been shown to enhance cell antioxidant pathways and protect photoreceptors against the harm produced by blue light, although its mechanism of action remains unknown. One possible mechanism, autophagy, is one of the most conservative cell renewal systems used in eukaryotes to destroy cellular components that have been damaged by some kind of insult. The oxidative stress of exposure to blue light is known to induce cell autophagy. In this study, we examined the combined effects on autophagy of blue light and PRGF in a retinal cell line, ARPE19. In response to treatment with both PRGF and blue light, we detected the modulated expression of autophagy markers such as NF-kB, p62/sqstm1, Atg5, LC3 and Beclin1, and inflammatory markers such as IL1B and IL18. Our findings suggest that PRGF promotes cell autophagy in response to exposure to blue light.
Assuntos
Autofagia/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Luz/efeitos adversos , Estresse Oxidativo/fisiologia , Retina/metabolismo , Adulto , Autofagia/efeitos da radiação , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/efeitos da radiação , Linhagem Celular , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/efeitos da radiação , Masculino , NF-kappa B/sangue , NF-kappa B/efeitos da radiação , Estresse Oxidativo/efeitos da radiaçãoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Type 2 diabetes (T2DM) is a multigenic disease that develops with impaired ß-cell function and insulin sensitivity and has a high prevalence worldwide. A cause often postulated for type 2 diabetes is chronic inflammation. It has been suggested that inflammatory regulators can inhibit insulin signal transduction and that inflammation is involved in insulin resistance (IR) and the pathogenesis of type 2 diabetes. In this direction, we aimed to investigate the gene variants of MyD88 (rs1319438, rs199396), IRAK4 (rs1461567, rs4251513, rs4251559) and TRAF6 (rs331455, rs331457) and serum levels of COX-2, NF-κB, iNOS in T2DM and IR. METHODS: The MyD88, IRAK4 and TRAF6 variations were genotyped in 100 newly diagnosed T2DM patients and 100 non-diabetic individuals using The MassARRAY® Iplex GOLD SNP genotyping method. The COX-2, iNOS and NF-κB levels were measured in serum samples with the sandwich-ELISA method. Results were analysed using SPSS Statistics software and the online FINNETI program. RESULTS AND DISCUSSION: In our study, a total of the 7 variants in the MyD88, IRAK4 and TRAF6 genes were genotyped, and as a result, no relationship was found between most of these variants and the risk of type 2 diabetes and insulin resistance (p > 0.05). Only, the rs1461567 variant of the IRAK4 gene was significant in the heterozygous model (CC vs. CT), and the CT genotype was most frequent in diabetic individuals compared with the non-diabetics (p = 0.033). Additionally, COX-2 and iNOS levels were found to be associated with diabetes and insulin resistance (p < 0.05). WHAT IS NEW AND CONCLUSION: Our results show that high COX-2 and iNOS levels are associated with T2DM, besides MyD88, IRAK4 and TRAF6 gene variations may not be closely related to type 2 diabetes and insulin resistance. Nevertheless, studies in this pathway with a different population and a large number of patients are important.
Assuntos
Diabetes Mellitus Tipo 2/genética , Mediadores da Inflamação/metabolismo , Inflamação/genética , Resistência à Insulina/genética , Adulto , Idoso , Ciclo-Oxigenase 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Genótipo , Humanos , Inflamação/fisiopatologia , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/sangue , Óxido Nítrico Sintase Tipo II/sangue , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Neuroprotection strategies after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) remain key areas of basic and clinical research. This study was designed to investigate the neuroprotective effects of dexmedetomidine following resuscitation and potential mechanisms. METHODS: Anesthetized rats underwent 6-min asphyxia-based cardiac arrest and resuscitation, after which the experimental group received a single intravenous dose of dexmedetomidine (25 µg/kg). Neurological outcomes and ataxia were assessed after the return of spontaneous circulation. The serum levels and brain expression of inflammation markers was examined, and apoptotic cells were quantified by TUNEL staining. RESULTS: Neuroprotection was enhanced by dexmedetomidine post-conditioning after the return of spontaneous circulation. This enhancement was characterized by the promotion of neurological function scores and coordination. In addition, dexmedetomidine post-conditioning attenuated the serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α at 2 h, as well as interleukin IL-1ß at 2, 24, and 48 h. TUNEL staining showed that the number of apoptotic cells in the dexmedetomidine post-conditioning group was significantly reduced compared with the control group. Further western blot analysis indicated that dexmedetomidine markedly reduced the levels of caspase-3 and nuclear factor-kappa B (NF-κB) in the brain. CONCLUSIONS: Dexmedetomidine post-conditioning had a neuroprotective effect against cerebral injury following asphyxia-induced cardiac arrest. The mechanism was associated with the downregulation of apoptosis and neuroinflammation.
Assuntos
Isquemia Encefálica/prevenção & controle , Dexmedetomidina/farmacologia , Parada Cardíaca/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Asfixia/complicações , Reanimação Cardiopulmonar , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Interleucina-1beta/sangue , Masculino , NF-kappa B/sangue , Doenças Neuroinflamatórias/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Long noncoding RNAs (lncRNAs) as potential disease biomarkers might be related to severe course of multiple sclerosis (MS). We evaluated expression levels of NF-κB-associated lncRNAs including HOTAIR, THRIL, H19, NKILA, and ANRIL; as well as expression of IL-6, TNF-α and MMP9, in peripheral blood mononuclear cells (PBMCs) from 60 relapse-remitting MS (RRMS) patients. At relapse phase of RRMS, up-regulation of ANRIL and H19 was positively correlated with the overexpression of IL-6; high levels of THRIL and HOTAIR was positively correlated with increased levels of TNF-α and MMP9, respectively; however, the NKILA expression was negatively correlated with the expression of TNF-α.
Assuntos
Perfilação da Expressão Gênica/métodos , Leucócitos Mononucleares/fisiologia , Esclerose Múltipla Recidivante-Remitente/genética , NF-kappa B/genética , RNA Longo não Codificante/genética , Adulto , Biomarcadores/sangue , Feminino , Expressão Gênica , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/epidemiologia , NF-kappa B/sangue , RNA Longo não Codificante/sangue , Adulto JovemRESUMO
OBJECTIVES: Clinical practice lacks biomarkers to predict the severity of acute pancreatitis (AP). We studied if intracellular signaling of circulating leukocytes could predict persistent organ dysfunction (OD) and secondary infections in AP. METHODS: A venous blood sample was taken from 174 patients with AP 72 hours or less from onset of symptoms and 31 healthy controls. Phosphorylation levels (p) of appropriately stimulated signal transducer and activator of transcription 1 (STAT1), STAT6, nuclear factor-κB (NF-κB), Akt, and nonstimulated STAT3 in monocytes, neutrophils, and lymphocytes was measured using phosphospecific flow cytometry. RESULTS: The patients showed higher pSTAT3 and lower pSTAT1, pSTAT6, pNF-κB, and pAkt than healthy controls. pSTAT3 in all leukocyte subtypes studied increased, and pSTAT1 in monocytes and T cells decreased in an AP severity-wise manner. In patients without OD at sampling, high pSTAT3 in monocytes and T lymphocytes were associated with development of persistent OD. In patients with OD, low interleukin-4-stimulated pSTAT6 in monocytes and neutrophils and Escherichia coli-stimulated pNF-κB in neutrophils predicted OD persistence. High pSTAT3 in monocytes, CD8+ T cells, and neutrophils; low pSTAT1 in monocytes and T cells; and low pNF-κB in lymphocytes predicted secondary infections. CONCLUSIONS: Leukocyte STAT3, STAT1, STAT6, and NF-κΒ phosphorylations are potential predictors of AP severity.
Assuntos
Leucócitos/metabolismo , NF-kappa B/sangue , Pancreatite/sangue , Fatores de Transcrição STAT/sangue , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Fosforilação , Valor Preditivo dos Testes , Estudos Prospectivos , Fator de Transcrição STAT1/sangue , Fator de Transcrição STAT3/sangue , Fator de Transcrição STAT6/sangue , Índice de Gravidade de Doença , Adulto JovemRESUMO
The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.
Assuntos
Aconitina/análogos & derivados , Fibrilação Atrial/fisiopatologia , Neuroimunomodulação/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Acetilcolina/sangue , Aconitina/administração & dosagem , Aconitina/farmacologia , Animais , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/métodos , Estudos de Casos e Controles , Modelos Animais de Doenças , Cães , Átrios do Coração/inervação , Átrios do Coração/fisiopatologia , Interleucina-6/sangue , NF-kappa B/sangue , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Veias Pulmonares/inervação , Veias Pulmonares/fisiopatologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Fator de Transcrição STAT3/sangue , Fator de Necrose Tumoral alfa/sangue , Estimulação do Nervo Vago/efeitos adversos , Estimulação do Nervo Vago/métodosRESUMO
BACKGROUND: This study aimed to evaluate the protective effects of alamandine, a new member of the angiotensin family, against doxorubicin (DOX)-induced nephrotoxicity in rats. METHODS: Rats were intraperitoneally injected with DOX (3.750 mg/kg/week) to reach a total cumulative dose of 15 mg/kg by day 35. Alamandine (50 µg/kg/day) was administered to the rats via mini-osmotic pumps for 42 days. At the end of the experiment, rats were placed in the metabolic cages for 24 h so that their water intake and urine output could be measured. After scarification, the rats' serum and kidney tissues were collected, and biochemical, histopathological, and immunohistochemical studies were carried out. RESULTS: DOX administration yielded increases in pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6, pro-fibrotic proteins transforming growth factor-ß (TGF-ß), pro-inflammatory transcription factor nuclear kappa B (NF-κB), kidney malondialdehyde (MDA), creatinine clearance, blood urea nitrogen (BUN), and water intake. On the other hand, the DOX-treated group exhibited decreased renal superoxide dismutase (SOD), renal glutathione peroxidase (GPx) activity, and urinary output. Alamandine co-therapy decreased these effects, as confirmed by histopathology and immunohistochemical analysis. CONCLUSIONS: The results suggest that alamandine can prevent nephrotoxicity induced by DOX in rats.
Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/análise , Citocinas/sangue , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/sangue , Oligopeptídeos/farmacologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Albumina Sérica/análise , Superóxido Dismutase/metabolismo , Ureia/sangueRESUMO
IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.
Assuntos
COVID-19/imunologia , Interleucina-1beta/sangue , Subpopulações de Linfócitos T/imunologia , COVID-19/sangue , COVID-19/complicações , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Interleucina-1beta/farmacologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Monócitos/classificação , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/sangue , Pandemias , Fosforilação , Receptores CCR6/sangue , SARS-CoV-2 , Fatores de Transcrição STAT/sangue , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/sangueRESUMO
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/sangueRESUMO
Objective:To investigate the expression of plasma NF-κB and the inhibitory subunit IκB-α in HIV-associated pre-eclampsia. Method: This retrospective study examined plasma NF-κB and IκB-α expression expressed as Mean Fluorescence Intensity (MFI) in normotensive (n = 32) and pre-eclamptic (n = 34) pregnant women stratified by HIV status. Results: A significant decrease in the level of plasma NF-κB expression between pre-eclamptic and normotensive pregnant women was observed, irrespective of HIV status (MFI = 82.8 vs 134.3; p = 0.03). Similarly, a significant decline in the level of plasma IκB-α expression was noted in the pre-eclamptic compared to normotensive pregnant women, irrespective of HIV status (MFI = 91.2 vs 120.1; p = 0.04). Plasma NF-κB (p = 0.7) and IκB-α (p = 0.8) expression was similar between HIV positive and HIV negative pregnant women, irrespective of pregnancy type. Conclusion: This study demonstrates decreased plasma NF-κB and IκB-α expression in preeclampsia compared to normotensive pregnant women irrespective of HIV status.
Assuntos
Biomarcadores/sangue , Infecções por HIV/sangue , Inibidor de NF-kappaB alfa/sangue , NF-kappa B/sangue , Complicações Infecciosas na Gravidez/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/virologia , Estudos RetrospectivosRESUMO
BACKGROUND: The role of serum S100A8/A9 in intestinal inflammation has been confirmed, and its role in food allergy is currently being investigated. OBJECTIVE: To explore the levels of S100A8/A9 and inflammatory factors, including Toll-like receptors 4 (TLR4), Nuclear transcription factors (NF-κB) and Tumor necrosis factor α (TNF-α), in mild food allergies. METHODS: Eighty 3-week-old male Brown Norway rats were used. Forty rats were randomly assigned to the ovalbumin-sensitized experimental group, while 40 rats were assigned to the normal saline sham-sensitized control group. Body weight and length and the levels of serum ovalbumin-specific IgE (OVA-IgE), histamine, Th1-associated and Th2-associated factors, S100A8/A9 and inflammation-associated cytokines were compared. RESULTS: Through the evaluation of OVA-IgE level and Th1/Th2 balance in the experimental group, a successful IgE-mediated food allergy model was constructed. Compared with the control group, the experimental group had higher serum S100A8/A9 levels on days 21, 28, 35 and 42 (all P < 0.05); higher TLR4 levels on days 28, 35 and 42 (all P < 0.05); higher TNF-α levels on days 28, 35 and 42 (all P < 0.05); higher NF-κB levels on days 35 and 42 (all P < 0.05); and higher IL-1ß and IL-6 levels on days 7 to 42 (all P < 0.05). Moreover, positive correlations were found between the serum levels of S100A8/A9 and inflammation-associated cytokines [TNF-α: r = 0.378, P = 0.039; IL-1ß: r = 0.679, P = 0.000; IL-6: r = 0.590, P = 0.001]. CONCLUSION: S100A8/A9 and inflammatory-related factors, including TLR4, NF-κB, TNF-α, IL-6 and IL-1ß, is closely related to food allergies. Moreover, immune and inflammatory factors interact with each other in food allergies, which may provide insight into food allergy causes and treatments.
Assuntos
Hipersensibilidade Alimentar/imunologia , Mediadores da Inflamação/sangue , Ratos Endogâmicos BN , Animais , Calgranulina A/sangue , Calgranulina B/sangue , Citocinas/sangue , Hipersensibilidade Alimentar/sangue , Imunoglobulina E/sangue , Inflamação , Masculino , NF-kappa B/sangue , Ovalbumina/imunologia , Ratos , Equilíbrio Th1-Th2 , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.
Assuntos
COVID-19/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , DNA/sangue , Desoxirribonuclease I/uso terapêutico , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Neutrófilos/efeitos dos fármacos , SARS-CoV-2 , Sepse/tratamento farmacológico , Animais , COVID-19/sangue , COVID-19/imunologia , Síndrome da Liberação de Citocina/etiologia , Desoxirribonuclease I/administração & dosagem , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Indóis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , NF-kappa B/sangue , Neutrófilos/enzimologia , Peroxidase/sangue , Polietilenoglicóis , Poliglactina 910 , Polímeros , Sepse/etiologia , Sepse/imunologiaRESUMO
BACKGROUND: The overall clinical outcome of inflammatory conditions is the result of the balance between pro-inflammatory and anti-inflammatory mediators. Because nuclear factor kappa B (NF-ĸB) is at the bottom of many inflammatory conditions, methods to evaluate the net effect of inflammation modulators on this master regulator have been conceptualized for years. METHODS: Using an ex vivo NF-ĸB reporter cell line-based assay, plasma samples of patients with rheumatoid arthritis (n = 27), psoriasis (n = 15), or severe coronavirus disease-19 (COVID-19) (n = 21) were investigated for NF-ĸB activation compared to plasma samples from 9 healthy volunteers. RESULTS: When separated by C-reactive protein (CRP) threshold levels, samples of patients exhibiting increased CRP levels (≥5 mg/l) activated NF-ĸB more efficiently than samples from patients with levels below 5 mg/l (P = 0.0001) or healthy controls (P = 0.04). Overall, there was a moderate association of CRP levels with NF-ĸB activation (Spearman r = 0.66; p < 0.0001). Plasma from COVID-19 patients activated NF-ĸB more efficiently (mean 2.4-fold compared to untreated reporter cells) than samples from any other condition (healthy controls, 1.8-fold, P = 0.0025; rheumatoid arthritis, 1.7-fold, P < 0.0001; psoriasis, 1.7-fold, P < 0.0001). In contrast, effects of rheumatoid arthritis, psoriasis, or healthy volunteer samples did not differ. CONCLUSION: This study shows that a NF-ĸB reporter cell line can be used to evaluate the net inflammatory effect of clinical plasma samples. Patients with chronic but stable rheumatoid arthritis or psoriasis do not exhibit increased plasma levels of NF-ĸB-activating compounds as opposed to COVID-19 patients with high inflammatory burden.
Assuntos
Artrite Reumatoide/patologia , COVID-19/patologia , NF-kappa B/sangue , NF-kappa B/metabolismo , Psoríase/patologia , Artrite Reumatoide/sangue , Proteína C-Reativa/análise , Linhagem Celular , Ativação Enzimática/fisiologia , Feminino , Células HEK293 , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , SARS-CoV-2/imunologiaRESUMO
Environmental risk factors that operate at foetal or neonatal levels increase the vulnerability to schizophrenia, plausibly via stress-immune activation that perturbs the epidermal growth factor (EGF) system, a system critical for neurodevelopment. We investigated potential associations between environmental insults and immune and EGF system changes through a maternal immune activation (MIA) model, using the precocial spiny mice (Acomys cahirinus). After mid-gestation MIA prepubescent offspring showed elevated NF-κB1 protein in nucleus accumbens, decreased EGFR in caudate putamen and a trend for increased PI3K-110δ in ventral hippocampus. Thus, prenatal stress may cause a heightened NF-κB1-mediated immune attenuation of EGF system signalling.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Fator de Crescimento Epidérmico/sangue , NF-kappa B/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Esquizofrenia/imunologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Genes erbB-1 , Hipocampo/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Neuritos/metabolismo , Gravidez , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Transdução de SinaisRESUMO
AIMS: Tobacco smoking is a major health problem associated with lung and liver damage. Lung and liver damage secondary to tobacco smoking is mediated through nicotine-induced oxidative stress. Therefore, we hypothesized that antioxidant treatment with tiron may improve nicotine-induced lung and liver damage. MATERIALS AND METHODS: Rats were divided into six groups, a control, nicotine (10 mg/kg/day, i.p.; for 8 weeks) and tiron (100 or 200 mg/kg/day, i.p.; for 8 weeks) with or without nicotine administration. KEY FINDINGS: Tiron improved survival rate and attenuated lung and liver damage as reflected by decreased total and differential cell counts, lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) and decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum; also histopathological examination confirmed the protective effect of tiron in lung and liver tissues of nicotine treated rats. Tiron attenuated dyslipidemia, which is associated with nicotine. These ameliorative effects of tiron may be mainly due to its antioxidant effect as proved by a significant decrease in malondialdehyde (MDA) content, reactive oxygen species (ROS) and total nitrite/nitrate (NOx) levels, and increase in reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) activities. This is likely related to suppression of protein levels of NADPH oxidase enzyme (NOX1), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α); and up-regulation of protein levels of nuclear factor erythroid-2 (Nrf2). SIGNIFICANCE: This makes tiron (synthetic analogue of vitamin E) good candidate for future use to minimize nicotine's hazards among smokers.