RESUMO
SCOPE: The main phenolic secoiridoid oleuropein and active constituent from olive tree (Olea europaea, Oleaceae), has demonstrated anti-inflammatory properties in intestinal inflammation and anti-tumoral effects in different cancer cells. In this study, we evaluated the chemoprevention of oleuropein in a model of azoxymethane (AOM)/Dextran sulfate sodium (DSS)-induced colorectal cancer (CRC) in C57BL/6 mice and the modulatory effect on the Th17 response in DSS acute colitis. METHODS AND RESULTS: Oleuropein protected from AOM/DSS-induced CRC by improving clinical symptoms, disease activity index score as well as suppressed the growth and multiplicity of colonic tumors. Treatment with oleuropein reduced intestinal IL-6, IFN-γ, TNF-α, and IL-17A concentration, and decreased cyclooxygenase-2, Bax and proliferating cell nuclear antigen protein expression. Western blot analysis also showed a markedly downregulation of CRC-related pathways as nuclear factor-κB (NF-κB), Wnt/ß-catenin, phosphatidylinositol-3-kinase (P3IK)/Akt, and signal transducer and activators of transcription (STAT)3. In DSS acute model, oleuropein inhibited Th17 response, by decreasing CD4(+) Rorγt(+) IL-17(+) IFN-γ(+) T-cell subsets in the lamina propria, as well as IL-17A and IFN-γ expression. CONCLUSION: Oleuropein as a dietary supplementation could be a promising protective agent against colitis-associated CRC.
Assuntos
Anticarcinógenos/farmacologia , Colite/tratamento farmacológico , Colo/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Iridoides/farmacologia , Animais , Azoximetano/toxicidade , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Feminino , Glucosídeos Iridoides , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/prevenção & controle , Células Th17/efeitos dos fármacosRESUMO
BACKGROUND: Cigarette smoking is an important risk factor for the development of cardiovascular disease, yet the pathways through which this may operate are poorly understood. Therefore, the mechanism underlying cigarette smoke (CS)-induced arterial endothelial dysfunction and the potential link with fractalkine/CX(3)CL1 upregulation were investigated. METHODS AND RESULTS: Stimulation of human arterial umbilical endothelial cells (HUAECs) with pathophysiological concentrations of CS extract (1% CSE) increased CX(3)CL1 expression. Neutralisation of CX(3)CL1 activity under dynamic flow conditions significantly inhibited CSE-induced mononuclear cell adhesion to HUAECs (67%). The use of small interfering RNA (siRNA) revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (Nox5) but not Nox2 or Nox4 is the main NADPH isoform involved in CSE-induced CX(3)CL1 upregulation and mononuclear cell arrest. Knock down of HUAEC tumour necrosis factor α expression with siRNA or pharmacological inhibition of p38 mitogen-activated protein kinase and nuclear factor κB also abolished these responses. Interestingly, circulating monocytes and lymphocytes from patients with chronic obstructive pulmonary disease (COPD) (n=29) versus age-matched controls (n=23) showed CX(3)CR1overexpression. Furthermore, CX(3)CL1 neutralisation dramatically diminished their enhanced adhesiveness to CSE-stimulated HUAECs. Finally, when animals were exposed for 3 days to CS, a mild inflammatory response in the lung was observed which was accompanied by enhanced CX(3)CL1 expression in the cremasteric arterioles, an organ distant from the lung. CS exposure resulted in increased leukocyte-arteriolar endothelial cell adhesion which was significantly reduced (51%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). CONCLUSIONS: These results suggest that CS induces functional CX(3)CL1 expression in arterial endothelium and leukocytes from patients with COPD show increased CX(3)CL1-dependent adhesiveness. Therefore, targeting the CX(3)CL1/CX(3)CR1 axis might prevent COPD-associated cardiovascular disorders.
Assuntos
Quimiocina CX3CL1/fisiologia , Endotélio Vascular/citologia , Fumar/fisiopatologia , Animais , Adesão Celular , Endotélio Vascular/fisiologia , Humanos , Proteínas de Membrana/fisiologia , Camundongos , Microcirculação/fisiologia , NADPH Oxidase 5 , NADPH Oxidases/fisiologia , RNA Interferente Pequeno/fisiologia , Regulação para Cima/fisiologiaRESUMO
Oleuropein, the major secoiridoid in olive tree leaves, possesses a wide range of health promoting properties. It has recently been shown to exhibit anti-inflammatory activity. We have evaluated the effect of oleuropein on dextran sulfate sodium (DSS)-induced experimental colitis in mice in order to provide insight into its mechanisms of action. Oral administration of oleuropein notably attenuated the extent and severity of acute colitis while reducing neutrophil infiltration; production of NO, IL-1ß, IL-6, and TNF-α; expression of iNOS, COX-2, and MMP-9; and the translocation of the NF-κB p65 subunit to the nucleus in colon tissue. In LPS-stimulated peritoneal macrophages, the oleuropein metabolite, hydroxytyrosol, was shown to inhibit NO production, iNOS expression, NF-κB p65 subunit translocation, mRNA expression, and the release of IL-1ß, IL-6, and TNF-α. These results suggest that the effect of oleuropein on DSS-induced colitis is associated with a decrease in the production of interleukins and expression of proteins, principally through reduction of NF-κB activation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Piranos/uso terapêutico , Doença Aguda , Animais , Colite/induzido quimicamente , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Feminino , Glucosídeos Iridoides , Iridoides , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologiaRESUMO
Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II-induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.
Assuntos
Angiotensina II/antagonistas & inibidores , Endotélio Vascular/patologia , Mediadores da Inflamação/farmacologia , NF-kappa B/antagonistas & inibidores , PPAR gama/biossíntese , Estilbenos/farmacologia , Regulação para Cima/imunologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Angiotensina II/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Feminino , Humanos , Mediadores da Inflamação/administração & dosagem , Mediadores da Inflamação/química , Masculino , NF-kappa B/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Resveratrol , Estereoisomerismo , Estilbenos/administração & dosagem , Estilbenos/química , Regulação para Cima/efeitos dos fármacosRESUMO
The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-beta-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1alpha and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1alpha in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-beta-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.
Assuntos
Estrogênios/administração & dosagem , Inflamação/prevenção & controle , Losartan/administração & dosagem , Menopausa , Ovariectomia/efeitos adversos , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Benzazepinas/administração & dosagem , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/antagonistas & inibidores , Células Cultivadas , Quimiocinas/sangue , Células Endoteliais , Endotélio Vascular , Feminino , Humanos , Inflamação/etiologia , Leucócitos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-DawleyRESUMO
Angiotensin II (Ang-II) exerts inflammatory activity and is involved in different cardiovascular disorders. This study has evaluated the involvement of tumor necrosis factor alpha (TNFalpha) in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nM intraperitoneally in rats) induced TNFalpha release at 1 hour followed by neutrophil and mononuclear cell recruitment. The administration of an antirat TNFalpha antiserum had no effect on Ang-IIinduced neutrophil accumulation but inhibited the infiltration of mononuclear cells and reduced CC chemokine content in the peritoneal exudate. Pretreatment with either an anti-TNFalpha or an anti-IL-4 antiserum decreased Ang-II-induced arteriolar mononuclear leukocyte adhesion by 68% and 60%, respectively, in the rat mesenteric microcirculation. While no expression of TNFalpha was found in the postcapillary venules of Ang-II-injected animals, this cytokine was clearly up-regulated in the arterioles. Stimulation of human umbilical arterial endothelial cells (HUAECs) or isolated human mononuclear cells with 1 microM Ang-II caused increased TNFalpha mRNA expression and protein. Neutralization of TNFalpha activity reduced Ang-II-induced MCP-1, MCP-3, and RANTES release from HUAECs and MIP-1alpha from blood cells. In conclusion, the selective mononuclear leukocyte adhesion to Ang-II-stimulated arterioles is largely mediated by TNFalpha in cooperation with constitutive IL-4. Therefore, neutralization of TNFalpha activity may help to prevent mononuclear cell infiltration and the progression of the atherogenic process.