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1.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502470

RESUMO

Bacterial endotoxin is a potent inflammatory antigen abundant in the human intestine. Endotoxins circulate in the blood at low concentrations in all healthy individuals. Elevated levels of circulatory endotoxins may cause inflammation with the development of chronic disease, either affecting metabolism, neurological disease, or resistance to viral and bacterial infections. The most important endotoxin is LPS, being a superantigen. In this narrative review, the effect of various food components to postprandially elevate circulating LPS and inflammatory markers is described. There is evidence that the intake of food enriched in fat, in particular saturated fat, may elevate LPS and pro-inflammatory markers. This occurs in both normal-weight and obese subjects. In obese subjects, inflammatory markers are already elevated before meal consumption. The importance of food choice for endotoxemia and inflammatory response is discussed.


Assuntos
Gorduras na Dieta , Endotoxemia/sangue , Contaminação de Alimentos , Lipopolissacarídeos/toxicidade , Obesidade/sangue , Biomarcadores/sangue , Endotoxemia/etiologia , Humanos , Inflamação/sangue , Inflamação/etiologia
2.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443679

RESUMO

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endotoxemia/patologia , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Ansiedade/complicações , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/complicações , Cicloexanóis/administração & dosagem , Teste de Labirinto em Cruz Elevado , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/sangue , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hipotermia Induzida , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Estereoisomerismo , Sulfonamidas/administração & dosagem
3.
Vet Immunol Immunopathol ; 237: 110267, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993048

RESUMO

In veterinary medicine, inflammation in swine is evaluated principally by clinical signs. This method is often unreliable when assessing large animal populations because of inconsistent interpretations of clinical observations. This study examined whether changes in miRNA expression can predict the severity of the inflammatory response in swine after administration of Escherichia coli lipopolysaccharide (LPS). Whole blood from swine challenged with LPS at 0.125 µg/kg to 2.0 µg/kg body weight was collected at 0, 1, 3, and 8 h post LPS-challenge. Mature miRNAs were extracted from plasma and quantitative real-time-PCR (qRT-PCR) was used to evaluate the 84 most abundant swine miRNAs found in plasma. The miRNA changes in expression were assessed using the comparative CT Method (ΔΔCT method) for normalization with an exogenous control. The results revealed that expression of ssc-let-7e-5p, ssc-mir-22-3p, and ssc-miR-146a-5p were the most significantly changed miRNA over the time course. At 1 h post-LPS, ssc-let-7e-5p decreased as the LPS dosage levels increased from 0.125 to 1.0 µg/kg. Similarly, as the LPS doses increased from 0.125 to 0.5 µg/kg, ssc-miR-22-3p levels significantly decreased at 1 h post-LPS. In the 2.0 µg/kg LPS, ssc-miR-146a-5p levels increased between 0 and 3 h post-LPS; however, expression was downregulated with a 145 % decrease from 3 to 8 h. The three miRNA biomarkers suggest potentially useful surrogate endpoints for the evaluation of inflammatory and endotoxemia responses in swine.


Assuntos
Inflamação/veterinária , Lipopolissacarídeos/farmacologia , MicroRNAs/sangue , Doenças dos Suínos/genética , Transcriptoma/efeitos dos fármacos , Animais , Biomarcadores/sangue , Endotoxemia/sangue , Endotoxemia/diagnóstico , Endotoxemia/veterinária , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Suínos , Doenças dos Suínos/sangue
4.
Br J Anaesth ; 126(6): 1111-1118, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33896590

RESUMO

BACKGROUND: Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. METHODS: Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg-1) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. RESULTS: In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x109 L-1([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. CONCLUSION: In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.


Assuntos
Coagulação Sanguínea , Coagulação Intravascular Disseminada/prevenção & controle , Endotoxemia/terapia , Hipotermia Induzida , Adolescente , Adulto , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Estudos de Casos e Controles , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/etiologia , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Endotoxemia/diagnóstico , Endotoxinas/administração & dosagem , Voluntários Saudáveis , Humanos , Hipotermia Induzida/efeitos adversos , Infusões Parenterais , Masculino , Fatores de Tempo , Adulto Jovem
5.
Int J Mol Sci ; 22(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672437

RESUMO

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy.


Assuntos
Fibra de Algodão , Endotoxinas/sangue , Endotoxinas/isolamento & purificação , Hemoperfusão/métodos , Imobilização/métodos , Polimixina B/química , Sepse/terapia , Choque Séptico/terapia , Adsorção , Animais , COVID-19/terapia , Endotoxemia/sangue , Endotoxemia/terapia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/terapia , Imobilização/instrumentação , Sepse/sangue , Choque Séptico/sangue
6.
Cells ; 10(1)2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430014

RESUMO

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.


Assuntos
Angiotensina I/administração & dosagem , Angiotensina I/uso terapêutico , Endotoxemia/tratamento farmacológico , Hipotensão/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Vasopressinas/metabolismo , Animais , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxemia/genética , Regulação da Expressão Gênica , Hipotensão/sangue , Hipotensão/complicações , Hipotensão/genética , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Lipopolissacarídeos , Masculino , Concentração Osmolar , Proteínas Proto-Oncogênicas/metabolismo , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismo , Sódio/sangue , Vasopressinas/genética
7.
J Leukoc Biol ; 109(5): 877-890, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33438263

RESUMO

Neutrophil-macrophage interplay is a fine-tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti-inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin αD ß2 , in the development of acute inflammation. αD ß2 is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that αD -knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS-induced endotoxemia. This pathologic outcome of αD -deficient mice is associated with a reduced number of monocyte-derived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild-type (WT) and αD -/- monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to αD -deficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of αD -/- mice markedly increased migration of monocyte-derived macrophage to lungs and dramatically improves survival. αD -deficient neutrophils demonstrate increased necrosis/pyroptosis. αD ß2 -mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin αD ß2 implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophil-dependent pathway.


Assuntos
Endotoxemia/imunologia , Cadeias alfa de Integrinas/metabolismo , Neutrófilos/metabolismo , Sepse/imunologia , Transferência Adotiva , Animais , Ceco/patologia , Contagem de Células , Movimento Celular , Citocinas/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/complicações , Cadeias alfa de Integrinas/deficiência , Ligadura , Lipopolissacarídeos , Pulmão/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/patologia , Necrose , Neutrófilos/patologia , Fagocitose , Punções , Piroptose , Sepse/sangue , Sepse/complicações , Análise de Sobrevida , Regulação para Cima
8.
Methods Mol Biol ; 2261: 247-262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33420994

RESUMO

The comprehensive analysis of serum cytokine levels can be challenging due to low sample volumes and time consuming when using single-target methods like enzyme-linked immunosorbent assay (ELISA). Bead-based detection systems allow the simultaneous detection of multiple analytes using minimal sample volumes. Here we describe the use of a multiplex cytokine, chemokine, and growth factor assay for mouse cytokines in a 96-well format. This assay is based on antibody-coupled fluorescent magnetic beads combined with biotinylated secondary detection antibody followed by fluorescent-tagged streptavidin in a sandwich-like composition. Final assay readout provides the concentrations of 23 different cytokines, chemokines, and growth factors in up to 76 samples.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Endotoxemia/sangue , Técnica Indireta de Fluorescência para Anticorpo , Fluorimunoensaio , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Proteômica , Animais , Biotinilação , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Endotoxemia/genética , Lipopolissacarídeos , Camundongos Knockout , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética
9.
Am J Respir Crit Care Med ; 203(11): 1419-1430, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33320799

RESUMO

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.


Assuntos
Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Endotélio/patologia , Endotoxemia/sangue , Fator 2 de Diferenciação de Crescimento/sangue , Sepse/sangue , Lesão Pulmonar Aguda/etiologia , Animais , Estudos de Casos e Controles , Células Endoteliais/metabolismo , Endotoxemia/etiologia , Endotoxemia/patologia , Feminino , Humanos , Masculino , Camundongos , Edema Pulmonar/sangue , Edema Pulmonar/etiologia , Edema Pulmonar/patologia , Sepse/etiologia , Sepse/patologia
10.
Int J Sports Physiol Perform ; 16(5): 704-710, 2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33361496

RESUMO

PURPOSE: The risk of exercise-induced endotoxemia is increased in the heat and is primarily attributable to changes in gut permeability resulting in the translocation of lipopolysaccharides (LPS) into the circulation. The purpose of this study was to quantify the acute changes in gut permeability and LPS translocation during submaximal continuous and high-intensity interval exercise under heat stress. METHODS: A total of 12 well-trained male runners (age 37 [7] y, maximal oxygen uptake [VO2max] 61.0 [6.8] mL·min-1·kg-1) undertook 2 treadmill runs of 2 × 15-minutes at 60% and 75% VO2max and up to 8 × 1-minutes at 95% VO2max in HOT (34°C, 68% relative humidity) and COOL (18°C, 57% relative humidity) conditions. Venous blood samples were collected at the baseline, following each running intensity, and 1 hour postexercise. Blood samples were analyzed for markers of intestinal permeability (LPS, LPS binding protein, and intestinal fatty acid-binding protein). RESULTS: The increase in LPS binding protein following each exercise intensity in the HOT condition was 4% (5.3 µg·mL-1, 2.4-8.4; mean, 95% confidence interval, P < .001), 32% (4.6 µg·mL-1, 1.8-7.4; P = .002), and 30% (3.0 µg·mL-1, 0.03-5.9; P = .047) greater than in the COOL condition. LPS was 69% higher than baseline following running at 75% VO2max in the HOT condition (0.2 endotoxin units·mL-1, 0.1-0.4; P = .011). Intestinal fatty acid-binding protein increased 43% (2.1 ng·mL-1, 0.1-4.2; P = .04) 1 hour postexercise in HOT compared with the COOL condition. CONCLUSIONS: Small increases in LPS concentration during exercise in the heat and subsequent increases in intestinal fatty acid-binding protein and LPS binding protein indicate a capacity to tolerate acute, transient intestinal disturbance in well-trained endurance runners.


Assuntos
Endotoxemia/sangue , Exercício Físico/fisiologia , Transtornos de Estresse por Calor , Mucosa Intestinal/metabolismo , Consumo de Oxigênio , Corrida/fisiologia , Adulto , Teste de Esforço , Temperatura Alta , Humanos , Masculino , Esforço Físico
11.
Psychoneuroendocrinology ; 122: 104864, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33166799

RESUMO

OBJECTIVE: Cross-sectional data have linked gut barrier abnormalities and endotoxemia with depression, even among those without gastrointestinal symptoms. This study examined longitudinal associations between endotoxemia markers and depressive symptoms, as well as the role of inflammation in this relationship. DESIGN: At three annual visits, 315 women (n=209 breast cancer survivors, n = 106 non-cancer patient controls, M=55 years old) completed the Center for Epidemiological Studies Depression questionnaire (CES-D) and provided blood samples to assess inflammatory markers - interleukin-6, tumor necrosis factor-alpha, and C-reactive protein - and endotoxemia markers - lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and their ratio. RESULTS: Adjusting for key demographic variables, health behaviors, visit 1 depressive symptoms, and cancer status and treatment, women with higher visit 1 LBP and LBP/sCD14 had more depressive symptoms at the two subsequent annual visits. Illustrating the notable impact, a woman at the 75th percentile for LBP or LBP/sCD14 at visit 1 was 18 % more likely to report clinically significant depressive symptoms (CES-D ≥16) at follow-up than a woman in the lowest quartile. Cancer status and treatment type did not modulate this relationship. In contrast, visit 1 depressive symptoms did not predict endotoxemia at follow-up. A significant interaction between LBP/sCD14 and inflammatory burden suggested that visit 1 endotoxemia fueled depressive symptoms only in the context of elevated inflammation. CONCLUSION: These results suggest that endotoxemia, combined with systemic inflammation, can drive depressive symptoms. These findings may implicate bacterial endotoxin translocation from the gut to the bloodstream in depression etiology. Interventions that reduce endotoxemia and inflammation may lessen the risk of depression.


Assuntos
Depressão/etiologia , Endotoxemia/psicologia , Inflamação/fisiopatologia , Adulto , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos Transversais , Depressão/metabolismo , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Feminino , Humanos , Interleucina-6/sangue , Receptores de Lipopolissacarídeos/sangue , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Fator de Necrose Tumoral alfa/sangue
12.
BMC Vet Res ; 16(1): 422, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148245

RESUMO

BACKGROUND: Paraoxonase-1 (PON-1) is an antioxidant enzyme, whose activity decreases during the acute phase response in many species. Little is known about PON-1 and its role as a negative acute phase protein during septic inflammation in horses, but promising findings about its utility in diagnosing SIRS and predicting the outcome in diseased horses, were recently highlighted. The objective of the study was to investigate the behaviour of PON-1 in horses after experimentally induced endotoxemia. To this aim, PON-1 activity was measured on 66 plasma samples collected from six clinically healthy mares, previously included in another study, before and at multiple time points between 12 and 240 h after intravenous infusion of Escherichia coli O55:B5 lipopolysaccharide (LPS). RESULTS: Compared with baseline values, a progressive transient decrease of PON-1 activity was observed starting from 24 h post-infusion, with lowest values observed between 3 to 7 days post-infusion, followed by a normalisation to pre-infusion levels the tenth day. CONCLUSIONS: The results of this study suggest that measurement and monitoring of PON-1 activity might be useful to evaluate progression and recovery from endotoxemia in horses. Further studies in horses with naturally occurring sepsis are warranted.


Assuntos
Arildialquilfosfatase/sangue , Endotoxemia/induzido quimicamente , Doenças dos Cavalos/diagnóstico , Animais , Endotoxemia/sangue , Endotoxemia/diagnóstico , Endotoxemia/enzimologia , Escherichia coli , Feminino , Doenças dos Cavalos/sangue , Doenças dos Cavalos/enzimologia , Cavalos , Lipopolissacarídeos/administração & dosagem
13.
Front Immunol ; 11: 595282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224150

RESUMO

Background: Selenium (Se) levels decrease in the circulation during acute inflammatory states and sepsis, and are inversely associated with morbidity and mortality. A more specific understanding of where selenoproteins and Se processing are compromised during insult is needed. We investigated the acute signaling response in selenoenzymes and Se processing machinery in multiple organs after innate immune activation in response to systemic lipopolysaccharide (LPS). Methods: Wild type (WT) adult male C57/B6 mice were exposed to LPS (5 mg/kg, intraperitoneal). Blood, liver, lung, kidney and spleen were collected from control mice as well as 2, 4, 8, and 24 h after LPS. Plasma Se concentration was determined by ICP-MS. Liver, lung, kidney and spleen were evaluated for mRNA and protein content of selenoenzymes and proteins required to process Se. Results: After 8 h of endotoxemia, plasma levels of Se and the Se transporter protein, SELENOP were significantly decreased. Consistent with this timing, the transcription and protein content of several hepatic selenoenzymes, including SELENOP, glutathione peroxidase 1 and 4 were significantly decreased. Furthermore, hepatic transcription and protein content of factors required for the Se processing, including selenophosphate synthetase 2 (Sps2), phosphoseryl tRNA kinase (Pstk), selenocysteine synthase (SepsecS), and selenocysteine lyase (Scly) were significantly decreased. Significant LPS-induced downregulation of these key selenium processing enzymes was observed in isolated hepatocytes. In contrast to the acute and dynamic changes observed in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. Conclusion: Hepatic selenoenzyme production and Se processing factors decreased after endotoxemia. This was temporally associated with decreased circulating Se. In contrast to these active changes in the regulation of Se processing in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. These findings highlight the need to further study the impact of innate immune challenges on Se processing in the liver and the impact of targeted therapeutic Se replacement strategies during innate immune challenge.


Assuntos
Endotoxemia/imunologia , Fígado/imunologia , Selenoproteínas/imunologia , Animais , Endotoxemia/sangue , Glutationa Peroxidase , Hepatócitos , Rim/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Selênio/sangue , Baço/imunologia
14.
Nutrients ; 12(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019697

RESUMO

Despite the updated knowledge of the impact of gut dysbiosis on diabetes, investigations into the beneficial effects of individual bacteria are still required. This study evaluates the antihyperglycemic efficacy of Lactobacillus paracasei HII01 and its possible mechanisms in diabetic rats. Diabetic rats were assigned to receive vehicle, L. paracasei HII01 (108 CFU/day), metformin 30 (mg/kg) or a combination of L. paracasei HII01 and metformin. Normal rats given vehicle and L. paracasei HII01 were included. Metabolic parameters, including in vitro hemi-diaphragm glucose uptake, skeletal insulin-signaling proteins, plasma lipopolysaccharide (LPS), gut permeability, composition of gut microbiota and its metabolites, as well as short-chain fatty acids (SCFAs), were assessed after 12 weeks of experiment. The results clearly demonstrated that L. paracasei HII01 improved glycemic parameters, glucose uptake, insulin-signaling proteins including pAktSer473, glucose transporter 4 (GLUT4) and phosphorylation of AMP-activated protein kinase (pAMPKThr172), tumor necrosis factor (TNF-α) and nuclear factor-κB (NF-kB) in diabetic rats. Modulation of gut microbiota was found together with improvement in leaky gut, endotoxemia and SCFAs in diabetic rats administered L. paracasei HII01. In conclusion, L. paracasei HII01 alleviated hyperglycemia in diabetic rats primarily by modulating gut microbiota along with lessening leaky gut, leading to improvement in endotoxemia and inflammation-disturbed insulin signaling, which was mediated partly by PI3K/Akt signaling and AMPK activation.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Microbioma Gastrointestinal/fisiologia , Hipoglicemiantes/administração & dosagem , Lactobacillus paracasei/fisiologia , Adipocinas/sangue , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Endotoxemia/sangue , Glucose/metabolismo , Teste de Tolerância a Glucose , Lipídeos/sangue , Masculino , Metformina/administração & dosagem , Músculo Esquelético/metabolismo , Probióticos/administração & dosagem , Ratos , Ratos Wistar
15.
Toxicol Lett ; 335: 28-36, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091562

RESUMO

Endotoxic manifestations are diminished in female populations due to immune boosting actions of sex steroids. Considering that tobacco constituents including nicotine inhibit estrogen synthesis, we tested the hypothesis that nicotine exposure unveils cardiovascular anomalies of endotoxemia in female rats. Studies were undertaken in conscious female rats treated with i.v. lipopolysaccharide (LPS, 10 mg/kg) in absence and presence of nicotine. In contrast to no effects for LPS when used alone, dose-related decreases in blood pressure (BP) and serum estrogen were noted in endotoxic rats treated consequently with nicotine (25, 50, or 100 µg/kg i.v.). Signs of cardiac autonomic dysfunction appeared in LPS/nicotine-treated rats such as (i) decreased time-domain indices of heart rate variability (HRV), e.g. standard deviation of R-R intervals (SDNN) and root mean square of successive differences in R-R interval durations (rMSSD), and (ii) reduced total power of the frequency spectrum and shifted cardiac sympathovagal balance toward sympathetic dominance. Nicotine reversed the LPS-evoked modest rises in serum TNFα and IL-1ß while had no effect on associated arterial baroreflex dysfunction, inferring no roles for inflammation or baroreflexes in LPS-nicotine interaction. Estrogen or aminoguanidine (iNOS inhibitor), but not pentoxifylline (TNFα inhibitor), abolished LPS/nicotine hypotension. Together, nicotine acts probably via reducing estrogen availability to uncover nitric oxide-dependent hypotension and autonomic dysregulation in endotoxic female rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Endotoxemia/induzido quimicamente , Estrogênios/sangue , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Nicotina/toxicidade , Óxido Nítrico/sangue , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Endotoxemia/sangue , Endotoxemia/imunologia , Endotoxemia/fisiopatologia , Endotoxinas/toxicidade , Feminino , Coração/inervação , Interleucina-1beta/sangue , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue
16.
J Cell Mol Med ; 24(20): 11903-11911, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896106

RESUMO

The suppression of energy metabolism is one of cornerstones of cardiac dysfunction in sepsis/endotoxaemia. To investigate the role of fatty acid oxidation (FAO) in the progression of inflammation-induced cardiac dysfunction, we compared the effects of FAO-targeting compounds on mitochondrial and cardiac function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia. In LPS-treated mice, endotoxaemia-induced inflammation significantly decreased cardiac FAO and increased pyruvate metabolism, while cardiac mechanical function was decreased. AMP-activated protein kinase activation by A769662 improved mitochondrial FAO without affecting cardiac function and inflammation-related gene expression during endotoxaemia. Fatty acid synthase inhibition by C75 restored both cardiac and mitochondrial FAO; however, no effects on inflammation-related gene expression and cardiac function were observed. In addition, the inhibition of carnitine palmitoyltransferase 2 (CPT2)-dependent FAO by aminocarnitine resulted in the accumulation of FAO intermediates, long-chain acylcarnitines, in the heart. As a result, cardiac pyruvate metabolism was inhibited, which further exacerbated inflammation-induced cardiac dysfunction. In conclusion, although inhibition of CPT2-dependent FAO is detrimental to cardiac function during endotoxaemia, present findings show that the restoration of cardiac FAO alone is not sufficient to recover cardiac function. Rescue of cardiac FAO should be combined with anti-inflammatory therapy to ameliorate cardiac dysfunction in endotoxaemia.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Progressão da Doença , Endotoxemia/enzimologia , Endotoxemia/fisiopatologia , Coração/fisiopatologia , Inflamação/enzimologia , Inflamação/patologia , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Temperatura Corporal , Carnitina O-Palmitoiltransferase/metabolismo , Endotoxemia/sangue , Metabolismo Energético , Ácidos Graxos/metabolismo , Feminino , Inflamação/sangue , Inflamação/complicações , Lipopolissacarídeos , Camundongos , Mitocôndrias Cardíacas/metabolismo
17.
Front Immunol ; 11: 1893, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973784

RESUMO

Excessive nitric oxide (NO) production and NO-mediated nitrative stress contribute to vascular dysfunction, inflammation, and tissue injury in septic shock. New therapeutic targets are urgently needed to provide better control of NO level during septic shock. In the present study, we investigated the role of HDAC6 in the regulation of NO production and nitrative stress in a mouse model of endotoxin-induced septic shock. HDAC6 deficient mice and a specific HDAC6 inhibitor were utilized in our studies. Our data clearly indicate that HDAC6 is an important mediator of NO production in macrophages. HDAC6 mediates NO production through the regulation of iNOS expression in macrophages. HDAC6 up-regulates iNOS expression in macrophages by modulating STAT1 activation and IRF-1 expression. HDAC6 inhibition potently blocked endotoxin-induced STAT1 activation and iNOS expression in macrophages. Furthermore, HDAC6 contributes to excessive NO production and nitrotyrosine level in the blood and promotes iNOS expression in the lung tissues during septic shock. Our data reveal a novel HDAC6/STAT1/iNOS pathway that mediates excessive NO production and nitrative stress in septic shock.


Assuntos
Endotoxemia/enzimologia , Desacetilase 6 de Histona/metabolismo , Macrófagos Peritoneais/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/sangue , Animais , Células Cultivadas , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/genética , Endotoxemia/prevenção & controle , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/deficiência , Desacetilase 6 de Histona/genética , Inibidores de Histona Desacetilases/farmacologia , Fator Regulador 1 de Interferon/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Tirosina/análogos & derivados , Tirosina/sangue
18.
Sci Rep ; 10(1): 14094, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839476

RESUMO

The aim of this study was to analyze the metabolic and molecular profile according to physical fitness status (Low or High VO2max) and its impacts on peripheral and cellular inflammatory responses in healthy men. First (Phase I), inflammatory profile (TNF-α, IL-6, IL-10) was analyzed at baseline and post-acute exercise sessions performed at low (< 60% VO2max) and high (> 90% VO2max) intensities considering the individual endotoxin concentrations. Next (Phase II), monocyte cell cultures were treated with LPS alone or associated with Rosiglitazone (PPAR-γ agonist drug) to analyze cytokine production and gene expression. Monocyte subsets were also evaluated by flow cytometry. A positive relationship was observed between LPS concentrations and oxygen uptake (VO2max) (r = 0.368; p = 0.007); however, in the post-exercise an inverse correlation was found between LPS variation (Δ%) and VO2max (r = -0.385; p = 0.004). With the low-intensity exercise session, there was inverse correlation between LPS and IL-6 concentrations post-exercise (r = -0.505; p = 0.046) and a positive correlation with IL-10 in the recovery (1 h post) (r = 0.567; p = 0.011), whereas with the high-intensity exercise an inverse correlation was observed with IL-6 at pre-exercise (r = -0.621; p = 0.013) and recovery (r = -0.574; p = 0.016). When monocyte cells were treated with LPS, High VO2max individuals showed higher PPAR-γ gene expression whereas Low VO2max individuals displayed higher IL-10 production. Additionally, higher TLR-4, IKK1, and PGC-1α gene expression were observed in the High VO2max group than Low VO2max individuals. In conclusion, even with elevated endotoxemia, individuals with High VO2max exhibited higher IL-6 concentration in peripheral blood post-acute aerobic exercise and lower IL-10 concentration during recovery (1 h post-exercise). The anti-inflammatory effects linked with exercise training and physical fitness status may be explained by a greater gene expression of IKK1, TLR-4, and PGC-1α, displaying an extremely efficient cellular framework for the PPAR-γ responses.


Assuntos
Exercício Físico/fisiologia , Lipopolissacarídeos/metabolismo , Consumo de Oxigênio/fisiologia , PPAR gama/sangue , PPAR gama/metabolismo , Aptidão Física/fisiologia , Adulto , Células Cultivadas , Endotoxemia/sangue , Humanos , Hipoglicemiantes/farmacologia , Interleucina-10/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/citologia , Lipopolissacarídeos/sangue , Masculino , PPAR gama/agonistas , Rosiglitazona/farmacologia , Fator de Necrose Tumoral alfa/sangue
19.
Nat Metab ; 2(10): 1034-1045, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32839596

RESUMO

Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.


Assuntos
Frutose/farmacologia , Inflamação/metabolismo , Lipogênese/efeitos dos fármacos , Acetilcoenzima A/farmacologia , Animais , Endotoxemia/sangue , Feminino , Frutosefosfatos/farmacologia , Microbioma Gastrointestinal , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Lipidômica , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Regeneração/efeitos dos fármacos , Receptores Toll-Like/agonistas
20.
Thromb Haemost ; 120(8): 1173-1181, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32604425

RESUMO

BACKGROUND: Portal vein thrombosis (PVT) is the most common thrombotic complication in cirrhosis; however, local risk factors involved in its pathogenesis are still not fully investigated. The aim of the study was to evaluate hemostasis and endothelial damage in the portal vein in patients with cirrhosis and portal hypertension. METHODS: Adult cirrhotics undergoing transjugular intrahepatic portosystemic shunt were consecutively enrolled. Rotational thromboelastometry (ROTEM), dosage of total circulating glycosaminoglycans (GAGs), and endotoxemia levels (lipopolysaccharide [LPS]), along with evaluation of endothelial dysfunction by quantification of circulating endothelial microparticles (MPs), were performed on citrated peripheric and portal venous blood samples from each enrolled patient. RESULTS: Forty-five cirrhotics were enrolled. ROTEM analysis revealed the presence of a significant heparin-like effect in portal blood (median ɑ angle NATEM 50° vs. HEPTEM 55°, p = 0.027; median coagulation time NATEM 665 s vs. HEPTEM 585 s, p = 0.006), which was not detected in peripheral blood, and was associated with a higher concentration of circulating GAGs. Even though total annexin V-MP circulating MPs were less concentrated in the splanchnic district, the proportion of MPs of endothelial origin, with respect to annexin V-MP, was significantly increased in the portal district (p = 0.036). LPS concentration was higher in portal (197 pg/mL) compared with peripheral blood (165 pg/mL) (p < 0.001). CONCLUSION: Evidences of a damage of glycocalyx along with increased concentration of endothelial MPs suggest the presence of a significant endothelial alteration in the portal vein with respect to peripheral veins. Portal site-specific endothelial damage could hamper its antithrombotic properties and may represent an important local risk factor in the pathogenesis of PVT.


Assuntos
Endotélio Vascular/patologia , Cirrose Hepática/patologia , Veia Porta/patologia , Adulto , Coagulação Sanguínea , Micropartículas Derivadas de Células , Endotélio Vascular/fisiopatologia , Endotoxemia/sangue , Feminino , Glicocálix/patologia , Glicosaminoglicanos/sangue , Heparina Liase/farmacologia , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/cirurgia , Masculino , Pessoa de Meia-Idade , Derivação Portossistêmica Cirúrgica , Tromboelastografia , Trombose Venosa/prevenção & controle
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