RESUMEN
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli-evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-ß levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ-/-) when compared to WT. In addition, GILZ-/- showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli-evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli.
Asunto(s)
Infecciones por Escherichia coli , Peritonitis , Factores de Transcripción , Animales , Ratones , Escherichia coli/metabolismo , Infecciones por Escherichia coli/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Peritonitis/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Using a rat model of peritonitis, we herein report the inflammatory effect induced by the lectin isolated from Vatairea guianensis (VGL) seeds in the context of interactions between VGL and both toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1). Peritoneal macrophages were stimulated with VGL for dose-dependent gene expression and release of TNF-α. In vivo results showed that VGL (1 mg/kg; intraperitoneal) induced peritonitis in female Wistar rats. Leukocyte migration, macrophage activation, and protein leakage were measured 3 and 6 hours after induction. In vitro, peritoneal macrophages were stimulated with VGL for gene expression and TNF-α dosage (mean ± SEM (n = 6), analysis of variance, and Bonferroni's test (P < .05)). In silico, VGL structure was applied in molecular docking with representative glycans. It was found that (a) VGL increases vascular permeability and stimulates leukocyte migration, both rolling and adhesion; (b) lectin-induced neutrophil migration occurs via macrophage stimulation, both in vitro and in vivo; (c) lectin interacts with TLR4 and TNFR1; and (d) stimulates TNF-α gene expression (RT-PCR) and release from peritoneal macrophages. Thus, upon lectin-glycan binding on the cell surface, our results suggest that VGL induces an acute inflammatory response, in turn activating the release of peritoneal macrophages via TNF-α and TLR and/or TNFR receptor pathways.
Asunto(s)
Fabaceae/química , Glicoconjugados/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Lectinas de Plantas/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glicoconjugados/química , Leucocitos/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Peritonitis/patología , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Ratas Wistar , Receptores Tipo I de Factores de Necrosis Tumoral/química , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Seaweed lectins are very promising biotechnological tools that also gain prominence when applied to the pharmacology field. The purpose of the present work was to isolate and characterize lectin from the red algae Amansia multifida and subsequently test it in general inflammation models. The lectin was purified by ion exchange chromatography, characterized with two-dimensional electrophoresis, automated analysis of amino acid sequences and circular dichroism spectroscopy. The pharmacological tests performed were paw edema induced by carrageenan or rapid inflammatory mediators, peritonitis induced by carrageenan and myeloperoxidase leukocyte count assays, glutathione and cytokine concentration. Our results have identified a 30 KDa molecular weight protein that presents a major secondary structure arranged in ß-strand elements (~43%). A fragment of 20 amino acid residues was sequenced and presented low identity to the known classes of lectins from marine alga. This lectin was able to modulate inflammatory parameters such as paw edema, leukocyte migration, oxidative stress and proinflammatory cytokines. Thus, the lectin from the seaweed Amansia multifida has evident anti-inflammatory properties because it acts by reducing the formation of edema by modulating the effect of vascular mediators, migration of neutrophils, proinflammatory cytokines and oxidative stress control.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Lectinas/química , Lectinas/farmacología , Rhodophyta/química , Animales , Carragenina/farmacología , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Edema/tratamiento farmacológico , Edema/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/química , Mediadores de Inflamación/farmacología , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Peroxidasa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Stem barks of Caesalpinia ferrea Mart. Ex Tul. (Caesalpiniaceae), also known as pau-ferro jucá or jucaína, are popularly used to treat contusions, diabetes, rheumatism and other inflammatory conditions in the form of tea, lick or decoction. OBJECTIVE: To evaluate the effect of the polysaccharide-rich extract obtained from C. ferrea stem barks (PE-Cf) in mice models of acute inflammation induced by zymosan and the involvement of oxidative stress biomarkers. MATERIALS AND METHODS: Mice were treated with PE-Cf (0.001, 0.01, 0.1, 1 mg/kg) by endovenous route (i.v.) or per oral (p.o.) 30 or 60 min before injection of the inflammatory stimuli zymosan (0.5 mg; intraperitoneal or subcutaneous intraplantar). The inflammatory parameters (edema, nociception, leukocyte migration) and oxidative stress markers (myeloperoxidase-MPO, malondialdehyde-MDA, nitrite, reduced glutathione-GSH, glutathione peroxidase-GPx) were evaluated in the models of paw edema (hidropletysmometry/expressed as ml or area under curve-AUC) and peritonitis (optical microscopy/expressed as n° of cells/mm3 of peritoneal fluid). Statistical analysis was performed by ANOVA, followed by Bonferroni test. RESULTS: PE-Cf (0.1, 0.01 and 1 mg/kg) dose-dependently inhibited paw edema, showing maximal effect (74%) at 1 mg/kg in the 5th (52 ± 9.6 µl vs. zymosan: 204 ± 3.6 µl). PE-Cf (1 mg/kg) also inhibited by 43% MPO activity in the paw tissues (17 ± 1 vs. zymosan: 30 ± 2.6 U/mg). Besides, 4 h after peritonitis induction, PE-Cf (1 mg/kg) reduced neutrophil migration by 84% (432 ± 45 vs. zymosan: 2651 ± 643 cells/mm3); visceral nociception by 76% (3 ± 0.6 vs. zymosan: 16 ± 4 writhes); nitric oxide by 73% (0.131 ± 0.033 vs. zymosan: 0.578 ± 0.185 NO2-/NO3-ml); MDA (98 ± 10 vs. zymosan:156 ± 21 U/ml), and increased GSH by 65% (736 ± 65 vs. zymosan: 259 ± 58 µmol/ml) and GPx by 72% (0.037 ± 0.007 vs. zymosan: 0.010 ± 0.005 U/mg protein). CONCLUSION: The polysaccharide-rich extract of Caesalpinia ferrea stem barks present anti-inflammatory and antioxidant effects in mice models of acute inflammation induced by zymosan.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Caesalpinia , Edema/prevención & control , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Peritonitis/prevención & control , Corteza de la Planta , Tallos de la Planta , Polisacáridos/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Biomarcadores/metabolismo , Caesalpinia/química , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/metabolismo , Edema/patología , Femenino , Ratones , Infiltración Neutrófila , Dolor Nociceptivo/inducido químicamente , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/prevención & control , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Peritonitis/patología , Corteza de la Planta/química , Tallos de la Planta/química , Polisacáridos/aislamiento & purificación , Transducción de Señal , ZimosanRESUMEN
Morita-Baylis-Hillman adducts (MBHA) are synthetic molecules with several biological actions already described in the literature. It has been previously described that adduct 2-(3-hydroxy-2-oxoindolin-3-yl)acrylonitrile (ISACN) has anticancer potential in leukemic cells. Inflammation is often associated with the development and progression of cancer. Therefore, to better understand the effect of ISACN, this study aimed to evaluate the anti-inflammatory potential of ISACN both in vitro and in vivo. Results demonstrated that ISACN negatively modulated the production of inflammatory cytokines IL-1ß, TNF-α, and IL-6 by cultured macrophages. In vivo, ISACN 6 and 24 mg/kg treatment promoted reduced leukocyte migration, especially neutrophils, to the peritoneal cavity of zymosan-challenged animals. ISACN displays no anti-edematogenic activity, but it was able to promote a significant reduction in the production of inflammatory cytokines in the peritoneal cavity. These data show, for the first time, that MBHA ISACN negatively modulates several aspects of the inflammatory response, such as cell migration and cytokine production in vivo and in vitro, thus having an anti-inflammatory potential.
Asunto(s)
Acrilonitrilo/farmacología , Antiinflamatorios/farmacología , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Peritonitis/prevención & control , Acrilonitrilo/análogos & derivados , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Ratones , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Peritonitis/inducido químicamente , Peritonitis/inmunología , Peritonitis/metabolismo , ZimosanRESUMEN
Bitis arietans is a snake of medical importance, as it is responsible for more accidents in humans and domestic animals than all other African snakes put together. The accidents are characterized by local and systemic alterations, such as inflammation, cardiovascular and hemostatic disturbances, which can lead victims to death or permanent disability. However, little is known about the envenomation mechanism, especially regarding the inflammatory response, which is related to severe clinical conditions triggered by the venom. Therefore, the aim of the present study was to evaluate the inflammatory response related to the B. arietans envenomation using a peritonitis mice model. By pharmacological interventions and use of mice genetically deficient of the 5-lipoxygenase enzyme (5-LO-/-) or platelet-activating factor (PAF) receptor (PAFR-/- the participation of eicosanoids and PAF in this response was also investigated. The obtained results demonstrated that the venom induces an in vivo inflammatory response, characterized by an early increased vascular permeability, followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity, accompanied by the production of the eicosanoids LTB4, LTC4, TXB2 and PGE2, as well as the local and systemic production of IL-6 and MCP-1. These inflammatory events were attenuated by the pre-treatment with anti-inflammatory drugs that interfere in lipid mediators' functions. However, 5-LO-/- mice did not show a reduction of inflammatory response induced by the venom, while PAFR-/- mice showed a reduction in both the PMN leukocytes number and the local and systemic production of IL-6 and MCP-1. This study demonstrated that the Bitis arietans venom contains toxins that trigger an inflammatory process, which is partially dependent on lipid mediators, and may contribute to the envenomation pathology.
Asunto(s)
Mediadores de Inflamación/metabolismo , Leucotrienos/metabolismo , Neutrófilos/metabolismo , Peritonitis/metabolismo , Prostaglandinas/metabolismo , Mordeduras de Serpientes/metabolismo , Venenos de Víboras/metabolismo , Viperidae/metabolismo , Animales , Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/genética , Araquidonato 5-Lipooxigenasa/metabolismo , Permeabilidad Capilar , Modelos Animales de Enfermedad , Femenino , Metabolismo de los Lípidos , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Peritonitis/tratamiento farmacológico , Peritonitis/inmunología , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Mordeduras de Serpientes/tratamiento farmacológico , Mordeduras de Serpientes/inmunologíaRESUMEN
We aim to investigate the role of A2A receptor in peritonitis-related sepsis by injection of a fecal solution (FS) as a model of polymicrobial infection. C57/black J6 wild-type (WT) and A2A-deficient mice (A2AKO) were exposed to sepsis induced by intraperitoneal injection of a FS (FS-induced peritonitis) or instead was injected with saline buffer (Sham). Survival rate and sepsis score were measured up to 48 h. The presence of bacteria in tissue homogenates was analyzed. Telemetry and speckle laser Doppler were used for systemic blood pressure and peripheral blood perfusion analysis, respectively. Histological analysis and identification of active caspase 3 were performed in selected organs, including the liver. The survival rate of A2AKO mice exposed to FS-induced peritonitis was significantly higher, and the sepsis score was lower than their respective WT counterpart. Injection of FS increases (50 to 150 folds) the number of colonies forming units in the liver, kidney, blood, and lung in WT mice, while these effects were significantly attenuated in A2AKO mice exposed to FS-induced peritonitis. A significant reduction in both systolic and diastolic blood pressure, as well as in the peripheral perfusion was observed in WT and A2AKO mice exposed to FS-induced peritonitis. Although, these last effects were significantly attenuated in A2AKO mice. Histological analysis showed a large perivascular infiltration of polymorphonuclear in the liver of WT and A2AKO mice exposed to FS-induced peritonitis, but again, this effect was attenuated in A2AKO mice. Finally, high expression of active caspase 3 was found only in the liver of WT mice exposed to FS-induced peritonitis. The absence of the A2A receptor increases the survival rate in mice exposed to polymicrobial sepsis. This outcome was associated with both hemodynamic compensation and enhanced anti-bacterial response.
Asunto(s)
Peritonitis/metabolismo , Receptor de Adenosina A2A/metabolismo , Sepsis/metabolismo , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Peritonitis/genética , Peritonitis/microbiología , Peritonitis/mortalidad , Receptor de Adenosina A2A/genética , Sepsis/genética , Sepsis/mortalidad , Tasa de SupervivenciaRESUMEN
Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-ß, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-ß and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.
Asunto(s)
Antiinflamatorios/farmacología , Edema/tratamiento farmacológico , Granuloma/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Sesquiterpenos Policíclicos/farmacología , Reacción de Fase Aguda/tratamiento farmacológico , Reacción de Fase Aguda/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Permeabilidad Capilar/efectos de los fármacos , Carragenina/toxicidad , Fibra de Algodón/toxicidad , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Femenino , Granuloma/inducido químicamente , Histamina/química , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Peroxidasa/antagonistas & inhibidores , Peroxidasa/metabolismo , Pleuresia/tratamiento farmacológico , Pleuresia/metabolismo , Sesquiterpenos Policíclicos/administración & dosificación , Receptores Histamínicos/química , Receptores Histamínicos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background and aims: Lipopolysaccharide (LPS), an endotoxin, is a component of the outer membrane of Gram-negative bacteria that is able to activate the peripheral immune system, leading to changes in signalling pathways that act locally and systemically to achieve adaptive responses. Sickness behaviour is a motivational state in response to endotoxin exposure and includes depressed activity and a reduction of exploratory behaviour, potentially reorganising organism priorities to cope with infectious diseases. We hypothesised that 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) modulates the leukocyte response to endotoxins and decreases LPS-induced sickness behaviour in mice.Methods: The effects of Tempol on LPS-induced peritonitis and the respiratory burst of neutrophils primed with LPS and triggered by phorbol 12-myristate-13-acetate (PMA) were evaluated. To evaluate the effects of Tempol on sickness behaviour, the mice were submitted to an open field and forced swim tests.Results: Tempol (50-100 µM/106 cells) decreased the respiratory burst of LPS-primed and PMA-stimulated neutrophils in vitro. In vivo, this nitroxide (30 and 100 mg/kg body weight) inhibited leukocyte migration to the peritoneal cavity after LPS administration in mice. Moreover, Tempol pretreatment (30 and 100 mg/kg body weight) before LPS administration also attenuated sickness behavioural changes.Conclusions: Together, these findings shed light on the mechanisms underlying the anti-inflammatory potential and confirm the therapeutic potential of nitroxides.
Asunto(s)
Conducta Animal/efectos de los fármacos , Óxidos N-Cíclicos/farmacología , Endotoxinas/farmacología , Leucocitos/efectos de los fármacos , Animales , Óxidos N-Cíclicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Inflamación/inmunología , Leucocitos/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Marcadores de Spin , Superóxidos/metabolismoRESUMEN
Species of the Vernonia genius are widely distributed across the world. In traditional communities, they are commonly used in popular medicine for the treatment of inflammatory diseases. The objective of the present study was to evaluate the anti-inflammatory activity of Vernonia polysphaera Baker hydroalcoholic extract. A λ-carrageenan-induced paw edema and peritonitis model was established in BALB/c mice. The in vitro activity of the extract was measured on LPS-stimulated RAW 264.7 cells. There was no toxic effect on mice or on the cells treated with the extract. Animals treated with V. polysphaera extract demonstrated inhibition of paw edema in comparison with the untreated animals at all the analyzed doses. In peritonitis, treatment with the extract at a dose of 500 mg/kg resulted in a lower total leukocyte count in the peritoneal fluid and blood and lower levels of IL-1ß, IL-6, TNF-α and PGE-2 than the control group. Cells treated with 50 and 100 µg/mL of the extract exhibited lower levels of nitrite and pro-inflammatory cytokine production and lower COX-2, NF-κB expression. The V. polysphaera extract demonstrated an anti-inflammatory effect, interfering with cell migration, reducing pro-inflammatory cytokine levels and COX-2 expression and consequent interference with PGE-2, as well as inhibiting NF-κB transcription.
Asunto(s)
Antiinflamatorios/uso terapéutico , Edema/tratamiento farmacológico , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Peritonitis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Vernonia , Animales , Antiinflamatorios/farmacología , Líquido Ascítico/efectos de los fármacos , Líquido Ascítico/metabolismo , Carragenina , Citocinas/metabolismo , Edema/inducido químicamente , Edema/metabolismo , Femenino , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Extractos Vegetales/farmacología , Células RAW 264.7RESUMEN
2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico, in vitro, and in vivo. At 30 min prior to the start of in vivo pharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-α and IL-1ß. In vitro antioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals. In silico docking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-α and IL-1ß reduction activity, corroborating its antinociceptive effect.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Interleucina-1beta/metabolismo , Fenoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Masculino , Ratones , Simulación del Acoplamiento Molecular , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Peritonitis/patología , Fenoles/química , Receptor de Adenosina A2A/química , Receptor de Adenosina A2A/metabolismoRESUMEN
Hemodynamic collapse and myocardial dysfunction are among the major causes of death in severe sepsis. The purpose of this study was to assess the role played by toll-like receptor 4 and by the NLRP3 inflammasome in the cardiac dysfunction that occurs after high-grade polymicrobial sepsis. We performed the colon ascendens stent peritonitis (CASP) surgery in Tlr4, Nlrp3, and caspase-1 mice. We also assessed for the first time the electrical heart function in the colon ascendens stent peritonitis (CASP) model. The QJ interval was increased in wild-type C57BL/6J mice after CASP when compared with sham controls, a result paralleled by an increase in the cardiac action potential (AP) duration (APD). The decreases in ejection fraction (EF), left ventricle end diastolic volume, stroke volume, and cardiac output found after CASP were similar among all groups of mice. Similar heart response was found when Nlrp3 mice were submitted to high-grade cecal ligation and puncture. Despite developing cardiac dysfunction similar to wild types after CASP, Nlrp3 mice had reduced circulating levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α. Our results demonstrate that the genetic ablation of Tlr4, Nlrp3, and caspase-1 does not prevent the cardiac dysfunction, despite preventing the increase in pro-inflammatory cytokines, indicating that these are not feasible targets to therapy in high-grade sepsis.
Asunto(s)
Caspasa 1/metabolismo , Colon/metabolismo , Cardiopatías/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Peritonitis/complicaciones , Peritonitis/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Ecocardiografía , Masculino , Ratones , Ratones Endogámicos C57BL , Función Ventricular Izquierda/fisiologíaRESUMEN
Acute kidney injury (AKI) and metabolic dysfunction are critical complications in sepsis syndrome; however, their pathophysiological mechanisms remain poorly understood. Therefore, we evaluated whether the pharmacological properties of 6-gingerol (6G) and 10-gingerol (10G) could modulate AKI and metabolic disruption in a rat model of sepsis (faecal peritonitis). Animals from the sham and AKI groups were intraperitoneally injected with 6G or 10G (25 mg/kg). Septic AKI decreased creatinine clearance and renal antioxidant activity, but enhanced oxidative stress and the renal mRNA levels of tumour necrosis factor-α, interleukin-1ß, and transforming growth factor-ß. Both phenol compounds repaired kidney function through antioxidant activity related to decreased oxidative/nitrosative stress and proinflammatory cytokines. Metabolomics analysis indicated different metabolic profiles for the sham surgery group, caecal ligation and puncture model alone group, and sepsis groups treated with gingerols. 1H nuclear magnetic resonance analysis detected important increases in urinary creatine, allantoin, and dimethylglycine levels in septic rats. However, dimethylamine and methylsulfonylmethane metabolites were more frequently detected in septic animals treated with 6G or 10G, and were associated with increased survival of septic animals. Gingerols attenuated septic AKI by decreasing renal disturbances, oxidative stress, and inflammatory response through a mechanism possibly correlated with increased production of dimethylamine and methylsulfonylmethane.
Asunto(s)
Lesión Renal Aguda/prevención & control , Catecoles/administración & dosificación , Alcoholes Grasos/administración & dosificación , Peritonitis/complicaciones , Sepsis/complicaciones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/mortalidad , Animales , Dimetilsulfóxido/metabolismo , Dimetilaminas/metabolismo , Modelos Animales de Enfermedad , Heces/microbiología , Humanos , Inyecciones Intraperitoneales , Masculino , Metaboloma/efectos de los fármacos , Metabolómica , Estrés Oxidativo/efectos de los fármacos , Peritonitis/metabolismo , Peritonitis/microbiología , Peritonitis/mortalidad , Ratas , Ratas Wistar , Sepsis/metabolismo , Sepsis/microbiología , Sepsis/mortalidad , Sulfonas/metabolismo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
This study investigated the anti-inflammatory activity of the extract (LEG) and purified (LPG) lycopene from guava (Psidium guajava L.), as well as some mechanisms possibly involved in this effect. The anti-inflammatory activity was initially assessed using paw edema induced by Carrageenan, Dextran, Compound 48/80, Histamine and Prostaglandin E2 in Swiss mice. A peritonitis model was used to evaluate neutrophil migration, the activity of myeloperoxidase (MPO) and reduced glutathione (GSH) concentration; while the effect on the expression of iNOS, COX-2 and NF-κB, was assessed by immunohistochemistry analysis. Results showed that oral and intraperitoneal administration of LEG and LPG inhibited inflammation caused by carrageenan. LPG (12.5mg/kg p.o.) significantly inhibited the edema formation induced by different phlogistic agents and immunostaining for iNOS, COX-2 and NF-κB. Leukocytes migration in paw tissue and peritoneal cavity was reduced, as well as MPO concentration, whereas GSH levels increased. Thus, lycopene-rich extract from red guava has beneficial effect on acute inflammation, offering protection against the consequences of oxidative stress by downregulating inflammatory mediators and inhibiting gene expression involved in inflammation.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Edema/prevención & control , Inflamación/prevención & control , Leucocitos/efectos de los fármacos , Peritonitis/prevención & control , Extractos Vegetales/farmacología , Psidium , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Edema/inmunología , Edema/metabolismo , Femenino , Frutas , Glutatión/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Peritonitis/inmunología , Peritonitis/metabolismo , Peroxidasa/metabolismo , Extractos Vegetales/aislamiento & purificación , Psidium/químicaRESUMEN
Previous reports have demonstrated that a thermostable lipid transfer protein isolated from noni seeds (McLTP1; 9.4kDa) displays anti-nociceptive and anti-inflammatory activities. This work aimed to investigate the underlying mechanisms of the anti-inflammatory activity of McLTP1 in mice. The protein was solubilised in sterile saline (0.9% NaCl) immediately before the treatment of mice by oral or intraperitoneal routes at doses of 8mg/kg. Given orally or intraperitoneally, McLTP1 significantly inhibited (p<0.05) cell migration in experimental models of carrageenan-induced peritonitis and the formation of paw oedema induced by carrageenan and dextran. Additionally, McLTP1 demonstrated the ability to significantly inhibit the production of the cytokines IL-1ß, IL-6, and TNF-α (p<0.05) and to promote an increase in the production of the anti-inflammatory cytokine IL-10. The treatment of mice with McLTP1 by the oral or i.p route reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury. This study suggested that the observed anti-inflammatory effects of McLTP1 can be related to modulation of pro- and anti-inflammatory cytokine levels.
Asunto(s)
Antiinflamatorios/farmacología , Proteínas Portadoras/farmacología , Citocinas/metabolismo , Morinda/química , Proteínas de Plantas/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Proteínas Portadoras/química , Proteínas Portadoras/uso terapéutico , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Peritonitis/tratamiento farmacológico , Peritonitis/metabolismo , Peritonitis/patología , Proteínas de Plantas/química , Proteínas de Plantas/uso terapéutico , SolubilidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ipomoea asarifolia (Desr.) Roem. and Schult.(Convolvulaceae), popularly known as salsa or salsa-brava, is a plant of which the decoction of leaves is used in folk medicine to treat various inflammatory disorders such of dermatitis, scabies, symptoms of syphilis, skin ulcers and external wounds. However, little is known about possible compounds and mechanisms of action of the plant to support the activities reported by popular use. AIM OF THE STUDY: The study aimed to identify bioactive molecules present in the crude extract of I. asarifolia leaves and investigate the anti-inflammatory potential of this extract in different experimental in vivo models to improve the understanding on that activity. MATERIAL AND METHODS: Aqueous extract of I. asarifolia leaves was prepared by decoction (1:10 m/v) and its chromatographic profile was obtained by high performance liquid chromatography coupled with diode array detector (HPLC-DAD) and liquid chromatography diode array detector coupled with mass spectrometry (LC-DAD-MS). The potential anti-inflammatory activity of the extract was assessed using the following in vivo models: xylene-induced ear edema (20, 30 and 40mg/kg), evaluating the degree of edema formation; carrageenan-induced peritonitis (10, 20 and 30mg/kg), evaluating leukocyte migration and cytokine levels (IL-1ß, IL-6, IL-12 and TNF-α) at 4h; zymosan-induced air pouch inflammation (20, 30 and 40mg/kg), evaluating the kinetics of leukocyte migration by total and differential counts at 6, 24 and 48h. The same tests were conducted using pure compounds identified in the aqueous extract from I. asarifolia leaves in different doses for each experimental model. RESULTS: The compounds identified in the aqueous extract of I. asarifolia leaves by HPLC-DAD and LC-DAD-MS were rutin, chlorogenic acid and caffeic acid. The extract significantly reduced ear edema induced by xylene (81%, 85% and 86% for doses of 20, 30 and 40mg/kg, respectively, p<0.001), as well as cell migration in experimental models of peritonitis (70%, 78% and 83% for doses of 10, 20 and 30mg/kg, respectively, p<0.001) and air pouch inflammation (58%, 67% and 53% for doses of 20, 30 and 40mg/kg, respectively, p<0.001). In addition, the extract demonstrated the ability to significantly inhibit the production of cytokines IL-1ß, IL-6, IL-12 and TNF-α (p<0.001). The secondary metabolites tested (rutin, chlorogenic acid and caffeic acid) also showed the ability to significantly (p<0.001) decrease the parameters analyzed above. CONCLUSION: This is the first study to identify and confirm these phenolic compounds in I. asarifolia leaves extract and to suggest that these compounds contribute to the anti-inflammatory activity in vivo, as reported by ethnomedicinal use of this plant. Through the different experimental models performed, we can conclude that the results obtained with the aqueous extract from I. asarifolia leaves support its popular use for the treatment of inflammatory disorders.
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Antiinflamatorios/farmacología , Edema/prevención & control , Inflamación/prevención & control , Ipomoea/química , Peritonitis/prevención & control , Fenoles/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/química , Animales , Antiinflamatorios/aislamiento & purificación , Carragenina , Quimiotaxis de Leucocito/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/metabolismo , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Recuento de Leucocitos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Espectrometría de Masas , Ratones Endogámicos BALB C , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Fenoles/aislamiento & purificación , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Factores de Tiempo , Xilenos , ZimosanRESUMEN
Folk medicine suggests that pomegranate (peels, seeds and leaves) has anti-inflammatory properties; however, the precise mechanisms by which this plant affects the inflammatory process remain unclear. Herein, we analyzed the anti-inflammatory properties of a hydroalcoholic extract prepared from pomegranate leaves using a rat model of lipopolysaccharide-induced acute peritonitis. Male Wistar rats were treated with either the hydroalcoholic extract, sodium diclofenac, or saline, and 1 h later received an intraperitoneal injection of lipopolysaccharides. Saline-injected animals (i.âp.) were used as controls. Animals were culled 4 h after peritonitis induction, and peritoneal lavage and peripheral blood samples were collected. Serum and peritoneal lavage levels of TNF-α as well as TNF-α mRNA expression in peritoneal lavage leukocytes were quantified. Total and differential leukocyte populations were analyzed in peritoneal lavage samples. Lipopolysaccharide-induced increases of both TNF-α mRNA and protein levels were diminished by treatment with either pomegranate leaf hydroalcoholic extract (57â% and 48â% mean reduction, respectively) or sodium diclofenac (41â% and 33â% reduction, respectively). Additionally, the numbers of peritoneal leukocytes, especially neutrophils, were markedly reduced in hydroalcoholic extract-treated rats with acute peritonitis. These results demonstrate that pomegranate leaf extract may be used as an anti-inflammatory drug which suppresses the levels of TNF-α in acute inflammation.
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Antiinflamatorios no Esteroideos/farmacología , Lythraceae/química , Peritonitis/tratamiento farmacológico , Extractos Vegetales/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Modelos Animales de Enfermedad , Lipopolisacáridos/toxicidad , Masculino , Neutrófilos/efectos de los fármacos , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Hojas de la Planta/química , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: To evaluate the effects of platelet rich plasma (PRP) on the healing of fascia wherein peritonitis has been created. METHODS: Twenty eight Wistar Albino rats were divided into four groups. Only a primary fascial repair following laparotomy was performed on Group 1, a primary fascial repair performed and PRP treatment applied following laparotomy on Group 2, and a fecal peritonitis created following laparotomy and a primary fascial repair carried out on Group 3. A fecal peritonitis was created following laparotomy and primary fascial repair and PRP treatment on the fascia was carried out on Group 4. RESULTS: TNF-α was found to be significantly lower in the control group (Group 1). It was detected at the highest level in the group in which fecal peritonitis was created and PRP applied (Group 4). TGF-ß was determined as being significantly higher only in Group 4. Histopathologically, the differences between the groups in terms of cell infiltration and collagen deposition were not found to be significant. CONCLUSION: When platelet rich plasma was given histologically and biochemicaly as wound healing parameters cellular infiltration, collagen accumulation, and tissue hydroxyiproline levels were not increased but neovascularization, fibroblast activation and TNF Alfa levels were increased and PRP accelerated wound healing.
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Fascia/fisiología , Peritonitis/complicaciones , Plasma Rico en Plaquetas , Cicatrización de Heridas , Animales , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Endopeptidasas , Fascia/irrigación sanguínea , Gelatinasas/metabolismo , Hidroxiprolina/análisis , Hidroxiprolina/metabolismo , Proteínas de la Membrana/metabolismo , Modelos Animales , Neovascularización Fisiológica , Peritonitis/metabolismo , Distribución Aleatoria , Ratas Wistar , Serina Endopeptidasas/metabolismo , Factor de Crecimiento Transformador beta/análisis , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ABSTRACT PURPOSE : To evaluate the effects of platelet rich plasma (PRP) on the healing of fascia wherein peritonitis has been created. METHODS: Twenty eight Wistar Albino rats were divided into four groups. Only a primary fascial repair following laparotomy was performed on Group 1, a primary fascial repair performed and PRP treatment applied following laparotomy on Group 2, and a fecal peritonitis created following laparotomy and a primary fascial repair carried out on Group 3. A fecal peritonitis was created following laparotomy and primary fascial repair and PRP treatment on the fascia was carried out on Group 4. RESULTS: TNF-α was found to be significantly lower in the control group (Group 1). It was detected at the highest level in the group in which fecal peritonitis was created and PRP applied (Group 4). TGF-β was determined as being significantly higher only in Group 4. Histopathologically, the differences between the groups in terms of cell infiltration and collagen deposition were not found to be significant. CONCLUSION: When platelet rich plasma was given histologically and biochemicaly as wound healing parameters cellular infiltration, collagen accumulation, and tissue hydroxyiproline levels were not increased but neovascularization, fibroblast activation and TNF Alfa levels were increased and PRP accelerated wound healing.
Asunto(s)
Animales , Peritonitis/complicaciones , Cicatrización de Heridas , Plasma Rico en Plaquetas , Fascia/fisiología , Peritonitis/metabolismo , Serina Endopeptidasas/metabolismo , Distribución Aleatoria , Factor de Crecimiento Transformador beta/análisis , Factor de Crecimiento Transformador beta/metabolismo , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Wistar , Gelatinasas/metabolismo , Neovascularización Fisiológica , Modelos Animales , Fascia/irrigación sanguínea , Hidroxiprolina/análisis , Hidroxiprolina/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1ß), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.