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The anti-inflammatory effects of the CRG/Ech complex in LPS-induced endotoxemia were investigated in vivo in mice and in vitro in LPS-stimulated RAW 264.7 cells and peritoneal macrophages. The results indicated that the CRG/Ech complex suppressed the LPS-induced inflammatory response by reducing the production of ROS and NO in the macrophages. Furthermore, the in vivo experiment indicated that the CRG/Ech complex minimized disorders of the physiological and metabolic processes in mice subjected to LPS intoxication and reduced the levels of proinflammatory cytokines in the mouse serum. The preventive administration of the CRG/Ech complex to mice prevented endotoxin-induced damage in the mouse model of endotoxemia, increased the mice's resistance to LPS, and prevented increases in the levels of proinflammatory cytokines (TNFα). In this work, we showed by the molecular docking that Ech interacted with carrageenan, and that H-donor and H-acceptor bonds are involved in the formation of the complex.
Assuntos
Endotoxemia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina/química , Citocinas/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Endotoxemia/metabolismo , Endotoxinas , Lipopolissacarídeos/toxicidade , Camundongos , Simulação de Acoplamento Molecular , Naftoquinonas , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Aims/hypothesis The macrophage-specific glycoprotein sCD163 has emerged as a biomarker of low-grade inflammation in the metabolic syndrome and related disorders. High sCD163 levels are seen in acute sepsis as a result of direct lipopolysaccharide-mediated shedding of the protein from macrophage surfaces including Kupffer cells. The aim of this study was to investigate if low-grade endotoxinemia in human subjects results in increasing levels of sCD163 in a cortisol-dependent manner. Methods We studied eight male hypopituitary patients and eight age- and gender-matched healthy controls during intravenous low-dose LPS or placebo infusion administered continuously over 360 min. Furthermore, we studied eight healthy volunteers with bilateral femoral vein and artery catheters during a 360-min infusion with saline and low-dose LPS in each leg respectively. Results: Systemic low-grade endotoxinemia resulted in a gradual increase in sCD163 from 1.65 ± 0.51 mg/L (placebo) to 1.92 ± 0.46 mg/L (LPS) at 220 min, P = 0.005 and from 1.66 ± 0.42 mg/L (placebo) to 2.19 ± 0.56 mg/L (LPS) at 340 min, P = 0.006. A very similar response was observed in hypopituitary patients: from 1.59 ± 0.53 mg/L (placebo) to 1.83 ± 0.45 mg/L (LPS) at 220 min, P = 0.021 and from 1.52 ± 0.53 mg/L (placebo) to 2.03 ± 0.44 mg/L (LPS) at 340 min, P < 0.001. As opposed to systemic treatment, continuous femoral artery infusion did not result in increased sCD163. Conclusion: Systemic low-grade endotoxinemia resulted in increased sCD163 to levels seen in the metabolic syndrome in both controls and hypopituitary patients. This suggests a direct and cortisol-independent effect of LPS on the shedding of sCD163. We observed no effect of local endotoxinemia on levels of serum sCD163.
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PURPOSE: The aim of our research was to study sex differences and the severity of inflammatory changes in target organs and the peculiarities of immunological disorders when low and high doses of lipopolysaccharide (LPS) were administered to rats. METHODS: Male and female 2- to 3-month-old Wistar rats (200-250 g) were injected intraperitoneally with Escherichia coli LPS in one of two doses: 1.5 or 15 mg/kg. In a day after the LPS injection, we studied endotoxin, corticosterone, sex steroids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity levels in the serum; morphological disorders in the lung, liver, thymus, and spleen; ex vivo production of IL-2, IL-4, tumor necrosis factor (TNF), and interferon γ (IFNγ) by splenic cells activated by ConA; and relative amount of T- and B-lymphocytes in the peripheral blood. RESULTS: After the injection of low-dose LPS, the serum endotoxin level increased only in males and was combined with a more pronounced inflammatory response in the lungs and thymus and an increase in ALT and AST activity levels without any changes in corticosterone level. After the injection of high-dose LPS, the inflammatory and pathological changes in the target organs manifested as severe endotoxemia and sex differences of pathological changes in the lungs and liver were not revealed. The level of production of IL-2, IL-4, IFNγ, and TNF by splenic cells and the number of T-lymphocytes, including cytotoxic cells, in the peripheral blood, decreased in males, which is an evidence of a pronounced suppression of the immune response. CONCLUSION: We have shown that the morphofunctional changes in the organs of the immune system in females and males, as well as the intensity of the sex differences of inflammation, depend on the severity of systemic inflammatory response, induced by different doses of LPS.
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BACKGROUND: Cross-sectional studies have reported a close association between serum lipopolysaccharide-binding protein (LBP) and many metabolic disorders. However, no longitudinal study has explored the relationship between LBP and type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association between serum LBP levels and the risk of developing T2DM. METHODS: A 5-year nested case-control study of 3510 individuals was performed as part of the Environment, Inflammation and Metabolic Diseases Study (EIMDS). Clinical data were collected at baseline. Serum levels of LBP and other biochemical factors, such as insulin and high-sensitivity C-reactive protein, were detected 5 years later. Subjects were diagnosed as having T2DM on the basis of results of an oral glucose tolerance test (OGTT) and 1998 World Health Organization criteria. Controls were randomly selected to match cases according to age, gender, and body mass index (BMI) in a 1:1 ratio. Odds ratios (OR) for T2DM were calculated using conditional logistic regression analysis. RESULTS: Over a 5-year follow-up period, 255 subjects developed T2DM. There was no significant difference in serum LBP levels between the T2DM and control groups at baseline (19.78 ± 6.40 versus 20.53 ± 6.99 µg/mL; P = 0.207). Subjects were divided into three groups based on tertiles of LBP concentrations (n = 170 in each group; T1 = 1.31-17.16 µg/mL LBP; T2 = 17.21-22.37 µg/mL LBP; T3 = 22.49-40.08 µg/mL LBP). There was no significant association between the risk of developing T2DM and any of the LBP tertiles in either a simple model or after adjusting for general status and biochemical factors. CONCLUSION: After matching for gender, age, and BMI, LBP does not improve prediction of the development of T2DM independently.
Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Glicoproteínas de Membrana/sangue , Proteínas de Fase Aguda , Idoso , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Levosimendan shows protective myocardial characteristics and is administered to enhance cardiac contractility in patients. However, currently little is known about levosimendan's effect on brain. The aim of this pilot study was to investigate the long-term effect of levosimendan on brain and during mild rat sepsis in comparison to its peripheral mode of action. Adult rats (n=40) were divided into four groups with n=10 per group: (I) sham, (II) levosimendan (283 µg/kg body weight i.v.), (III) lipopolysaccharide (LPS, 8 mg/kg body weight i.p.), and (IV) LPS+levosimendan. Levosimendan was given 24h after injecting LPS. Psychometric investigations were conducted using a Morris water maze (MWM) and a holeboard test. In cerebral and splenic tissue, IL-1ß, Il-6, TNFalpha levels, and apoptosis were determined; cerebral tissue corticosterone concentration was measured 6 days after injecting LPS. Blood cytokine concentrations were determined 1 day and 6 days after injecting LPS. Rats that received an LPS injection spent more time in the outer zone of the MWM according to increased cerebral corticosterone levels, and showed decreased cognitive abilities. LPS induced a reduction in body weight, increased splenic apoptosis and blood cytokine level. Levosimendan showed anti-inflammatory and anti-apoptotic properties in spleen but failed to show a long-term neuroprotective effect.