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1.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658363

RESUMO

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.


Assuntos
Acidose/sangue , Proteína HMGB1/sangue , Sepse/sangue , Sialoglicoproteínas/sangue , Zinco/sangue , Acidose/imunologia , Acidose/metabolismo , Acidose/patologia , Proteínas de Transporte , Proteína HMGB1/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata , Lipopolissacarídeos/farmacologia , Polissacarídeos/química , Sepse/imunologia , Sepse/patologia , Ácidos Siálicos/química , Sialoglicoproteínas/química , Zinco/metabolismo
2.
Medicine (Baltimore) ; 100(5): e24275, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592871

RESUMO

ABSTRACT: To investigate serum level of high mobility group box protein-1 (HMGB1) and prognosis of patients with end-stage renal disease (ESRD) on hemodialysis (HD) and peritoneal dialysis (PD).This prospective cohort observational study included a total of 253 ESRD patients who came to our hospital for HD or PD from February 2013 to February 2015. Enzyme linked immunosorbent assay (ELISA) method was used to detect the serum level of HMGB1, interleukin (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-α). The kidney disease quality of life short form (KDQOL-SF) and kidney disease targeted area (KDTA) was applied for evaluating the quality of life. Kaplan-Meier (K-M) curve was performed for survival time.Serum level of HMGB1 in patients on HD was higher than PD. HMGB1 levels were gradually decreased with the treatment of HD or PD. Furthermore, HMGB1 was positively correlated with IL-6 and TNF-α. Moreover, patients with higher HMGB1 had more complications than patients with lower HMGB1, but there was no difference for the survival rate. In addition, the quality of life was associated with different dialysis methods.The serum level of HMGB1 and prognosis of ESRD patients was associated with different dialysis methods.


Assuntos
Proteína HMGB1/sangue , Falência Renal Crônica , Diálise Peritoneal , Qualidade de Vida , Diálise Renal , China/epidemiologia , Correlação de Dados , Feminino , Humanos , Interleucina-6/sangue , Estimativa de Kaplan-Meier , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/métodos , Diálise Peritoneal/estatística & dados numéricos , Prognóstico , Estudos Prospectivos , Diálise Renal/métodos , Diálise Renal/estatística & dados numéricos , Fator de Necrose Tumoral alfa/sangue
3.
Methods Mol Biol ; 2261: 277-289, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33420996

RESUMO

Targeted protein quantification can be challenging in body fluids such as plasma with regard to sensitivity and selectivity. In this chapter, we present a protocol for the quantification of high mobility group box 1 protein (HMGB1) in plasma using an immunoaffinity liquid chromatography mass spectrometric assay (IA-LC-MSMS). The protocol provides detailed assay instructions involving sample proteolysis, peptide-targeted immunoprecipitation, and LC-MSMS-based read out.


Assuntos
Métodos Analíticos de Preparação de Amostras , Coleta de Amostras Sanguíneas , Cromatografia de Afinidade , Ácido Edético/farmacologia , Proteína HMGB1/sangue , Proteômica , Espectrometria de Massas em Tandem , Anticoagulantes/farmacologia , Humanos , Imunoprecipitação , Proteólise
4.
Int Heart J ; 62(1): 162-170, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455985

RESUMO

High-mobility group box 1 (HMGB1) is increased in the myocardium under pressure overload (PO) and is involved in PO-induced cardiac remodeling. The mechanisms of the upregulation of cardiac HMGB1 expression have not been fully elucidated. In the present study, a mouse transverse aortic constriction (TAC) model was used, and an angiotensin II (Ang II) type 1 (AT1) receptor inhibitor (losartan) or Ang II type 2 (AT2) receptor inhibitor (PD123319) was administrated to mice for 14 days. Cardiac myocytes were cultured and treated with Ang II for 5 minutes to 48 hours conditionally with the blockage of the AT1 or AT2 receptor. TAC-induced cardiac hypertrophy was observed at 14 days after the operation, which was partially reversed by losartan, but not by PD123319. Similarly, the upregulated HMGB1 expression levels observed in both the serum and myocardium induced by TAC were reduced by losartan. Elevated cardiac HMGB1 protein levels, but not mRNA or serum levels, were significantly decreased by PD123319. Furthermore, HMGB1 expression levels in culture media and cardiac myocytes were increased following Ang II treatment in vitro, positively associated with the duration of treatment. Similarly, Ang II-induced upregulation of HMGB1 in vitro was inhibited by both losartan and PD123319. These results suggest that upregulation of HMGB1 in serum and myocardium under PO, which are partially derived from cardiac myocytes, may be induced by Ang II via the AT1 and AT2 receptors. Additionally, amelioration of PO-induced cardiac hypertrophy following losartan treatment may be associated with the reduction of HMGB1 expression through the AT1 receptor.


Assuntos
Angiotensina II/farmacologia , Proteína HMGB1/efeitos dos fármacos , Losartan/farmacologia , Miocárdio/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/patologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Estudos de Casos e Controles , Constrição , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/farmacologia , Regulação para Cima , Vasoconstritores/farmacologia
5.
J Stroke Cerebrovasc Dis ; 29(9): 105055, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807461

RESUMO

BACKGROUND: To investigate the value of plasma high mobility group box protein 1 (HMGB1) in evaluating the prognosis of cerebral ischemia-reperfusion injury (CIRI) in ischemic stroke patients. METHODS: 132 ischemic stroke patients were recruited. Before and after thrombolytic therapy at 2 h, 6 h, 12 h, 24 h, and 36 h, the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) were recorded. The Modified Rankin scale (mRS) was used to assess the prognosis at 3 months. RESULTS: The NIHSS score, GCS score and plasma HMGB1 level peaked at 6 h after thrombolytic therapy, and plasma HMGB1 level was positively correlated with infarct volume and NIHSS score, and negatively correlated with GCS score. Plasma HMGB1 level at 6 h had the highest value in identifying patients with poor unfavorable functional outcome after 3 months, with a sensitivity of 86.8% and a specificity of 74.0%. Logistic regression results showed that plasma HMGB1 had a strong association with unfavorable functional outcome [odds ratio (OR) =1.621, P<0.001]. After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=1.381, P=0.005). Finally, we found that plasma HMGB1 at 6 h had the highest value in identifying patients with non-survival after 3 months (χ2=28.655, P<0.001). Logistic regression results showed that plasma HMGB1 had a strong association with non-survival (OR=2.315, P<0.001). After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=2.013, P<0.001). CONCLUSION: Plasma HMGB1 exerts a good predictive value for CIRI in ischemic stroke patients, and its increased expression is correlated with worse prognosis.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Proteína HMGB1/sangue , Traumatismo por Reperfusão/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Avaliação da Deficiência , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/fisiopatologia , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
6.
Cell Mol Immunol ; 17(9): 992-994, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32620787
7.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 39-47, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32538745

RESUMO

This study was designed to investigate the expressions and roles of MMP-9 and HMGB1 in peripheral blood of patients with epilepsy and their relationship with the cognitive function and to explore factors affecting the prognosis of epilepsy patients. A total of 127 patients with epilepsy were collected in the study group and 120 healthy subjects receiving a physical examination at the same time were collected in the control group. The MMP-9 and HMGB1 expressions and their diagnostic value for epilepsy were compared between the two groups. The relationship between MMP-9 and HMGB1 expression levels and the clinical-pathological features and the Mini-mental State Evaluation Scale (MMSE) of patients from the study group were also analyzed. The serum levels of MMP-9 and HMGB1 in the study group were significantly higher than those in the control group (P< 0.001), and were greatly decreased after the treatment (P<0.001). The ROC curve showed that MMP-9 and HMGB1 combined detection had a good diagnostic efficiency for epilepsy. MMP-9 was much related to the type and disease duration of epilepsy (P< 0.05). HMGB1 was significantly associated with disease duration, seizure, and previous treatment history of epilepsy (P< 0.050). According to the Pearson correlation coefficient analysis, the expressions of MMP-9 and HMGB1 were negatively correlated with MMSE scores of the study group (P< 0.001). Logistic regression analysis showed that the duration of disease, seizures, MMP-9, and HMGB1 were independent risk factors for the prognosis of epilepsy. The expression levels of MMP-9 and HMGB1 in peripheral blood of patients with epilepsy are significantly increased, and negatively correlated with neurological function scores. They have potential involvement in the occurrence and development of epilepsy, which makes them significant for the diagnosis and treatment of epilepsy in the future.


Assuntos
Epilepsia/sangue , Epilepsia/diagnóstico , Proteína HMGB1/sangue , Metaloproteinase 9 da Matriz/sangue , Adulto , Idoso , Cognição/efeitos dos fármacos , Cognição/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Feminino , Proteína HMGB1/metabolismo , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Análise de Regressão , Fatores de Risco , Convulsões
8.
Medicine (Baltimore) ; 99(22): e20425, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481442

RESUMO

Investigate the effect of mild hypothermia on serum inflammatory factor HMGB1 of brain-dead donors, and its significance for renal transplantation recipients.In our hospital between January 2018 and January 2019 up to the standard of brain death donor (aged 18 to 65 years old) prospective cohort study, brain death donor were randomly divided into mild hypothermia group and the non-mild hypothermia group. Serum were collected from donor at different periods, and enzyme-linked immunoassay (ELISA) was used to determine the serum HMGB1 concentration to compare the difference between the 2 donor groups. The early recovery of renal function after renal transplantation was followed up, and the incidence of delayed graft function (DGF) and early recovery of renal function were compared between the 2 groups. The correlation between donor HMGB1 and recipient DGF was analyzed.Between 17 donors in the mild hypothermia group and 17 in the non-mild hypothermia group, there were no statistically significant differences in the age, perioperative urine volume and ICU stay between the 2 groups. After mild hypothermia treatment, serum HMGB1 levels of brain death donors were significantly decreased. While in non-mild hypothermia brain death donor group without treatment, serum HMGB1 was significantly increased. There were no statistically significant differences in age and preoperative creatinine between the 2 recipient groups, including 33 patients in the mild hypothermia group and 34 patients in the non-mild hypothermia group. DGF incidence was lower in mild hypothermia group comparing with non-mild hypothermia group with statistical significance. The levels of HMGB1 from donor before procurement is correlated with the occurrence of DGF of the recipient.Mild hypothermia therapy can reduce the levels of serum HMGB1, improve the function of donor organs. The levels of HMGB1 before donor procurement can be used to predict the occurrence of DGF in kidney transplant recipients. Our study shows that HMGB1 can be potentially used as therapeutic target of early intervention for brain death donors. Furthermore, mild hypothermia therapy can be applied in the maintenance of brain death donors for kidney transplant recipient to improve the successful rate of transplantation.


Assuntos
Morte Encefálica/sangue , Proteína HMGB1/sangue , Hipotermia Induzida , Transplante de Rim , Doadores Vivos , Adulto , Função Retardada do Enxerto , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Resultado do Tratamento
9.
Sci Rep ; 10(1): 7226, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350297

RESUMO

The aim of this study was to analyse the dynamics of tissue damage and inflammatory response markers perioperatively and whether these differ between women operated with robotic and abdominal hysterectomy in treating early-stage endometrial cancer. At a Swedish university hospital fifty women with early-stage low-risk endometrial cancer were allocated to robotic or abdominal hysterectomy in a randomiszed controlled trial. Blood samples reflecting inflammatory responses (high sensitivity CRP, white blood cells (WBC), thrombocytes, IL-6, cortisol) and tissue damage (creatine kinase (CK), high-mobility group box 1 protein (HMGB1)) were collected one week preoperatively, just before surgery, postoperatively at two, 24 and 48 hours, and one and six weeks postoperatively. High sensitivity CRP (p = 0.03), WBC (p < 0.01), IL-6 (p = 0.03) and CK (p = 0.03) were significantly lower in the robotic group, but fast transitory. Cortisol returned to baseline two hours after robotic hysterectomy but remained elevated in the abdominal group comparable to the preoperative high levels for both groups just before surgery (p < 0.0001). Thrombocytes and HMGB1 were not affected by the mode of surgery. Postoperative inflammatory response and tissue damage were lower after robotic hysterectomy compared to abdominal hysterectomy. A significant remaining cortisol elevation two hours after surgery may reflect a higher stress response in the abdominal group.


Assuntos
Neoplasias do Endométrio/cirurgia , Proteína HMGB1/sangue , Hidrocortisona/sangue , Histerectomia/efeitos adversos , Interleucina-6/sangue , Complicações Pós-Operatórias/sangue , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Adulto , Biomarcadores/sangue , Neoplasias do Endométrio/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/etiologia , Contagem de Leucócitos , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos
10.
Cell Prolif ; 53(6): e12829, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32419317

RESUMO

OBJECTIVE: Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF-α/HMGB1 pathway in pyroptosis during ALF and AKI. METHODS: An ALF and AKI mouse model was generated using LPS/D-Gal, and a TNF-α inhibitor, CC-5013, was used to treat the mice. THP-1 cells were induced to differentiate into M1 macrophages, then challenged with either CC-5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX-mCMVZsGreen-PGK-Puros plasmids containing TNF-α wild-type (WT), mutation A94T of TNF-α and mutation P84L of TNF-α were transfected into M1 macrophages. RESULTS: Treatment with CC-5013 decreased the activation of TNF-α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC-5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF-α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF-α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF-α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis. CONCLUSION: The TNF-α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Proteína HMGB1/fisiologia , Falência Hepática Aguda/metabolismo , Piroptose , Fator de Necrose Tumoral alfa/fisiologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Humanos , Inflamação/metabolismo , Lenalidomida/farmacologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética
11.
J Neuroimmunol ; 345: 577266, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470565

RESUMO

High-mobility group box 1 (HMGB1) and advanced glycation end-products (RAGE) are potential mediators of inflammation. We investigate the association between levels of HMGB1 and soluble RAGE (sRAGE) following intracerebral hemorrhage (ICH) and the severity of ICH. There was a significant trend towards higher poor functional outcome rate with increasing HMGB1 and sRAGE tercile. The correlation analysis indicated that the levels of HMGB1and sRAGE were positively correlated with hematoma volume. The receiver operating curve (ROC) was 0.718 for HMGB1 and 0.631 for sRAGE to poor functional outcome. HMGB1 and sRAGE quantification provides more accurate prognostic information after ICH.


Assuntos
Hemorragia Cerebral/sangue , Hemorragia Cerebral/diagnóstico , Proteína HMGB1/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(4): 334-338, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32312371

RESUMO

OBJECTIVE: To study the association of the dynamic changes of peripheral blood human cartilage glycoprotein-39 (YKL-40) and high-mobility group box 1 (HMGB1) with bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Preterm infants, with a gestational age of 28-32 weeks and a birth weight of <1 500 g, who were admitted to the neonatal intensive care unit from July 2017 to August 2019 were prospectively selected and divided into a BPD group with 35 infants and a non-BPD group with 51 infants. ELISA was used to measure the serum concentrations of YKL-40 and HMGB1 in preterm infants on days 3, 7, and 14 after birth. RESULTS: The BPD group had a significantly lower serum YKL-40 concentration and a significantly higher serum HMGB1 concentration than the non-BPD group on days 3, 7, and 14 (P<0.001). The serum concentrations of YKL-40 and HMGB1 on days 7 and 14 were significantly higher than those on day 3 in both groups (P<0.017). In the BPD group, HMGB1 concentration on day 14 was significantly higher than that on day 7 (P<0.017), while there was no significant change in YKL-40 concentration from day 7 to day 14 (P>0.017). In the non-BPD group, YKL-40 concentration on day 14 was significantly higher than that on day 7 (P<0.017), while there was no significant change in HMGB1 concentration from day 7 to day 14 (P>0.017). CONCLUSIONS: There are significant differences in the levels of YKL-40 and HMGB1 in peripheral blood between the preterm infants with BPD and those without BPD on days 3, 7, and 14 after birth, suggesting that YKL-40 and HMGB1 might be associated with the development of BPD.


Assuntos
Displasia Broncopulmonar , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína HMGB1/sangue , Humanos , Recém-Nascido , Recém-Nascido Prematuro
13.
Mol Diagn Ther ; 24(3): 251-262, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32248387

RESUMO

This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent "homeostatic DAMP:SAMP ratio" in each case and a "homeostatic window" of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in Covid-19), administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyperresolving processes (e.g., compensatory anti-inflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.


Assuntos
Inflamação/tratamento farmacológico , Inflamação/metabolismo , Terapia de Alvo Molecular/métodos , Biomarcadores/sangue , Ácidos Nucleicos Livres/sangue , Doença Crônica , Infecções por Coronavirus/tratamento farmacológico , Proteína HMGB1/sangue , Homeostase , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Padrões Moleculares Associados a Patógenos/metabolismo , Proteínas S100/sangue , Vacinação
14.
Biol Pharm Bull ; 43(3): 399-403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115500

RESUMO

Immune checkpoint inhibitors (ICIs) exert beneficial effects in non-small cell lung cancer (NSCLC) patients. However, ICIs are only advantageous for a limited population of NSCLC patients. Therefore to enhance their effects, combination therapies with ICIs have been developed. To identify preferable chemotherapy to combine with ICIs against lung cancer, we examined immunological effects of docetaxel compared with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We found no difference in peripheral lymphocyte counts and ratio of their subpopulations in lung cancer patients before and after both treatments. On the other hand, plasma levels of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, showed significant increase after docetaxel treatment. Furthermore, we investigated effects of HMGB1 on tumor-infiltrating immune cells obtained from surgically resected tumor tissue from NSCLC patients. When the tumor infiltrating cells were stimulated with HMGB1, CD11c+ cells showed increased expression of activation markers. These findings imply that docetaxel could be involved in anti-tumor immunity via HMGB1. Therefore docetaxel might be a candidate for combination treatment with ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/farmacologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Proteína HMGB1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Antineoplásicos , Antígenos CD11/metabolismo , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Citocinas/metabolismo , Feminino , Proteína HMGB1/sangue , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Mutação , Proteínas Tirosina Quinases/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos
15.
J Stroke Cerebrovasc Dis ; 29(5): 104644, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32081495

RESUMO

BACKGROUND: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy. METHODS: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups. RESULTS: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups. CONCLUSIONS: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors.


Assuntos
Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Mediadores da Inflamação/sangue , Lamotrigina/uso terapêutico , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Ácido Valproico/uso terapêutico , Idoso , Anticonvulsivantes/efeitos adversos , Biomarcadores/sangue , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Regulação para Baixo , Quimioterapia Combinada , Epilepsia/sangue , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Proteína HMGB1/sangue , Humanos , Interleucina-6/sangue , Lamotrigina/efeitos adversos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Ácido Valproico/efeitos adversos
16.
Sci Rep ; 10(1): 1742, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015385

RESUMO

The administration of recombinant human soluble thrombomodulin (rhsTM) significantly improves liver inflammation and increases the survival rate of patients with acute liver failure (ALF). However, rhsTM is dose-dependently correlated to the risk of bleeding. Recently, ultrasound (US) was found to enhance the effect of various drugs. Thus, the present study aimed to determine the enhancement effect of US irradiation on rhsTM in ALF. rhsTM (1 mg/kg) and US (1 MHz, 0.3 W/cm2) were irradiated to the liver of lipopolysaccharide/D-galactosamine-induced ALF mice model. The post-treatment aspartate aminotransferase, alanine aminotransferase, and high-mobility group box 1 levels were significantly lower in the rhsTM + US group than in the rhsTM alone group. Histopathological findings revealed significantly reduced liver injury and apoptosis in the rhsTM + US group. By contrast, US irradiation had no effect on rhsTM and TNF-α concentration in the liver tissue. In conclusion, US irradiation enhanced the effect of rhsTM in the ALF mice model. However, further studies must be conducted to determine the exact mechanism of such enhancement effect.


Assuntos
Falência Hepática Aguda/tratamento farmacológico , Trombomodulina/uso terapêutico , Ultrassonografia de Intervenção/métodos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Modelos Animais de Doenças , Proteína HMGB1/sangue , Humanos , Fígado/metabolismo , Falência Hepática Aguda/sangue , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
17.
Blood ; 135(14): 1087-1100, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32016282

RESUMO

Bacterial infection not only stimulates innate immune responses but also activates coagulation cascades. Overactivation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), a widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC by amplifying the release of high-mobility group box 1 (HMGB1) into the bloodstream. Inhibition of the expression of type 1 IFNs and disruption of their receptor IFN-α/ßR or downstream effector (eg, HMGB1) uniformly decreased gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the procoagulant activity of tissue factor by promoting the externalization of phosphatidylserine to the outer cell surface, where phosphatidylserine assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but they also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.


Assuntos
Coagulação Intravascular Disseminada/imunologia , Endotoxemia/imunologia , Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Coagulação Sanguínea , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/etiologia , Endotoxemia/sangue , Endotoxemia/complicações , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/complicações , Proteína HMGB1/sangue , Proteína HMGB1/imunologia , Humanos , Imunidade Inata , Camundongos Endogâmicos C57BL
18.
Med Sci Monit ; 26: e919530, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31901930

RESUMO

BACKGROUND The aim of this study was to investigate the clinical significance of NLRP3 and HMGB1 in patients with active ulcerative colitis. MATERIAL AND METHODS This was a prospective observational study which included a total of 62 cases with active ulcerative colitis during January 2017 to December 2018. The patients were divided into a mild/moderate group or a severe group according to Sutherland Disease Activity Index (DAI) score. Clinical activity index and endoscopic index were used to determine the severity of UC. Serum levels of NLRP3, HMGB1, endothelin-1, IL-1ß, and TNF-alpha were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS Sutherland DAI score, clinical activity index, and endoscopic index were all significantly higher in severe patients than in the mild/moderate group. NLRP3, HMGB1, endothelin-1, IL-1ß, and TNF-alpha were significantly higher in severe UC patients. NLRP3 level was positively correlated with HMGB1, ET-1, IL-1ß, and TNF-alpha levels. Both NLRP3 and HMGB1 were positively correlated with Sutherland DAI score, clinical activity index, and endoscopic index. CONCLUSIONS Both serum NLRP3 and HMGB1 were elevated in UC patients, and the serum levels of NLRP3 were positively correlated with serum levels of HMGB1, ET-1, IL-1ß, and TNF-alpha, as well as severity of UC patients.


Assuntos
Colite Ulcerativa/sangue , Proteína HMGB1/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Adulto , Citocinas/sangue , Endotelina-1/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue
19.
Thorax ; 75(3): 209-219, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31937554

RESUMO

BACKGROUND: Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. OBJECTIVE: To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. METHODS: Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. RESULTS: The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. CONCLUSIONS: These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.


Assuntos
Lesão Pulmonar Aguda/imunologia , Proteína HMGB1/metabolismo , Imunidade Inata/imunologia , Interleucinas/metabolismo , Linfócitos/imunologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Choque Hemorrágico/sangue , Lesão Pulmonar Aguda/patologia , Animais , Antígenos de Neoplasias/sangue , Estudos de Casos e Controles , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Eosinófilos , Feminino , Proteína HMGB1/sangue , Proteína HMGB1/genética , Humanos , Interleucinas/sangue , Contagem de Linfócitos , Linfócitos/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/sangue , Receptor para Produtos Finais de Glicação Avançada/genética , Choque Hemorrágico/complicações , Transdução de Sinais
20.
Sci Rep ; 10(1): 289, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937858

RESUMO

Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Traumatismo por Reperfusão/patologia , Trombomodulina/uso terapêutico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Proteína HMGB1/sangue , Histonas/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , Traumatismo por Reperfusão/complicações , Trombomodulina/genética , Trombomodulina/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
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