RESUMEN
Methyl gallate (MG) is a plant-derived phenolic compound known to present remarkable anti-inflammatory effect in different experimental models, such as paw oedema, pleurisy, zymosan-induced arthritis and colitis. Herein we investigated the effect of MG in the mice model of antigen-induced arthritis (AIA), a model with complex inflammatory response, driven primally by immune process and that cause bone and cartilage erosion similarly found in rheumatoid arthritis. Arthritis was induced by intra-articular injection of albumin methylated from bovine serum (mBSA) in C57BL/6 male mice previously immunized. The dose-response analysis of MG (0.7-70 mg/kg; p.o) showed that maximum inhibition was reached with the dose of 7 mg/kg on paw oedema and cell infiltration induced by AIA at 7 h. Treatment with MG (7 mg/kg; p.o) or with the positive control, dexamethasone (Dexa, 10 mg/kg, ip) reduced AIA oedema formation, leukocyte infiltration, release of extracellular DNA and cytokine production 7 and 24 h (acute response). Mice treated daily with MG for 7 days showed no significant weight loss or liver and kidney toxicity contrary to dexamethasone that induced some degree of toxicity. Prolonged treatment with MG inhibited the late inflammatory response (28 days) reducing oedema formation, cell infiltration, synovial hyperplasia, pannus formation and cartilage degradation as observed in histopathological analyses. Ultimately, MG reduced bone resorption as evidenced by a decrease in tartrate-resistant acid phosphate (TRAP)-positive cells number in femur histology. Altogether, we demonstrate that MG ameliorates the inflammatory reaction driven primarily by the immune process, suggesting a potential therapeutic application in arthritis treatment.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Animales , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Ácido Gálico/análogos & derivados , Ácido Gálico/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE AND DESIGN: Methyl gallate (MG) is a prevalent polyphenol in the plant kingdom, which may be related to the effects of several medicinal plants. Although it is widely reported that polyphenols have therapeutic effects, there are few studies demonstrating that MG has anti-inflammatory action. This study aimed to investigate the molecular mechanism behind the anti-inflammatory activity of MG and its effect on hyperalgesia. METHODS: Swiss mice were pretreated orally with different doses of MG and subjected to i.pl. injection of zymosan to induce paw edema. RAW264.7 macrophages and BMDMs stimulated with different TLR agonists such as zymosan, LPS, or Pam3CSK4 were used to investigate the molecular mechanisms of MG RESULTS: MG inhibits zymosan-induced paw edema and hyperalgesia and modulates molecular pathways crucial for inflammation development. Pretreatment with MG inhibited cytokines production and NF-κB activity by RAW 264.7 cells stimulated with zymosan, Pam3CSK4 or LPS, but not with PMA. Moreover, pretreatment with MG decreased IκB degradation, nuclear translocation of NF-κBp65, c-jun and c-fos and ERK1/2, p38 and JNK phosphorylation. CONCLUSION: Thus, the results of this study demonstrate that MG has a promising anti-inflammatory effect and suggests an explanation of its mechanism of action through the inhibition of NF-κB signaling and the MAPK pathway.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ácido Gálico/análogos & derivados , Inflamación/tratamiento farmacológico , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Receptores Toll-Like/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Citocinas/metabolismo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Células RAW 264.7 , ZimosanRESUMEN
High salt diet (HSD), considered a public health problem worldwide, is associated with chronic degenerative diseases including renal diseases. However, little is known about the effects of HSD on renal function independently of the development of hypertension. To address the hypothesis that HSD induces renal injuries even without changes in blood pressure, BALB/c mice were fed for 7 days with chow with a high salt content (0.3-8%). Blood pressure did not change and there was a decrease in cortical (Na+ + K+)ATPase and NHE3 exchanger and an increase in renal fractional excretion of sodium. Positive correlations between Na+ intake or urinary sodium excretion with proteinuria were found. HSD did not change glomerular function and structure, but induced tubule-interstitial injury measured by an increase in collagen deposition, interstitial space and γ-GT activity, a marker of tubular injury. These effects were associated with a decrease in cortical albumin reabsorption and megalin expression. Similarly, the addition of NaCl 20 mM to the incubation medium of LLC-PK1 cells reduced megalin expression and albumin endocytosis indicating that HSD could have a direct effect on proximal tubule cells. Furthermore, tubule-interstitial injury was associated with pro-inflammatory and pro-fibrotic phenotypes with an increase in Th1 and Th17 phenotypes and a decrease in Tregs followed by increases in IL-6, -17, -10, TNF-α, IFN-γ and TGF-ß. Our results reveal a complex network involved in renal injuries induced by HSD independently of changes in blood pressure. These findings strengthen the importance of restriction of salt intake for the general population even for salt-resistant individuals.
Asunto(s)
Hipertensión/metabolismo , Inflamación/metabolismo , Cloruro de Sodio Dietético/efectos adversos , Animales , Presión Sanguínea/efectos de los fármacos , Endocitosis/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Hipertensión/inducido químicamente , Immunoblotting , Inmunohistoquímica , Inflamación/inducido químicamente , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Porcinos , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Nuclear factor kappa B (NF-κB) plays critical roles in the regulation of many pathophysiological processes, including inflammation and immune responses, cell growth and apoptosis. This DNA-binding protein receptor is considered an important molecular target to treat many diseases through host-directed therapy. In this line, several drugs containing thiophene cores have been extensively evaluated due to their ability to interfere on NF-κB translocation to the nucleus. In this work, assays using drug affinity responsive target stability (DARTS) revealed that the parent compound N-(Aryl)-2-thiophen-2-ylacetamide referred to as thiophenacetamide (TAA) specifically binds to the p65 subunit of the NF-κB. Since no experimental binding mode of TAA with p65 is available, we explored TAA within putative sites in silico to gain insights into its possible binding mode and behavior. The binding mode of TAA found in Site 1 formed hydrogen bonds with Lys37 and Asp125 on p65, important residues near DNA-binding region. Molecular dynamics simulations showed the stability of this mode of binding in contrast to the other also tested modes. Our results suggest that TAA binding could occur in regions close to residues responsible for DNA binding, increasing NF-κB protein rigidity and affecting the association between DNA and NF-κB. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Acetamidas/química , Sistemas de Liberación de Medicamentos , FN-kappa B/genética , Factor de Transcripción ReIA/genética , Acetamidas/uso terapéutico , Apoptosis/genética , Sitios de Unión/genética , Núcleo Celular/genética , Proliferación Celular/genética , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Humanos , Simulación de Dinámica Molecular , FN-kappa B/química , Unión Proteica/genética , Transducción de Señal/genética , Factor de Transcripción ReIA/químicaRESUMEN
Malaria-induced acute kidney injury (MAKI) is a life-threatening complication of severe malaria. Here, we investigated the potential role of the angiotensin II (Ang II)/AT1 receptor pathway in the development of MAKI. We used C57BL/6 mice infected by Plasmodium berghei ANKA (PbA-infected mice), a well-known murine model of severe malaria. The animals were treated with 20 mg/kg/day losartan, an antagonist of AT1 receptor, or captopril, an angiotensin-converting enzyme inhibitor. We observed an increase in the levels of plasma creatinine and blood urea nitrogen associated with a significant decrease in creatinine clearance, a marker of glomerular flow rate, and glomerular hypercellularity, indicating glomerular injury. PbA-infected mice also presented proteinuria and a high level of urinary γ-glutamyltransferase activity associated with an increase in collagen deposition and interstitial space, showing tubule-interstitial injury. PbA-infected mice were also found to have increased fractional excretion of sodium (FENa+) coupled with decreased cortical (Na++K+)ATPase activity. These injuries were associated with an increase in pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, interleukin-17, and interferon gamma, in the renal cortex of PbA-infected mice. All modifications of these structural, biochemical, and functional parameters observed in PbA-infected mice were avoided with simultaneous treatment with losartan or captopril. Our data allow us to postulate that the Ang II/AT1 receptor pathway mediates an increase in renal pro-inflammatory cytokines, which in turn leads to the glomerular and tubular injuries observed in MAKI.
Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Angiotensina II/metabolismo , Malaria/complicaciones , Malaria/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Lesión Renal Aguda/patología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Captopril/farmacología , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Losartán/farmacología , Malaria/patología , Masculino , Ratones Endogámicos C57BL , Plasmodium berghei , Distribución AleatoriaRESUMEN
Acute lung injury (ALI) models are characterized by neutrophil accumulation, tissue damage, alteration of the alveolar capillary membrane, and physiological dysfunction. Lipoxin A4 (LXA4 ) is an anti-inflammatory eicosanoid that was demonstrated to attenuate lipopolysaccharide-induced ALI. Experimental models of severe malaria can be associated with lung injury. However, to date, a putative effect of LXA4 on malaria (M)-induced ALI has not been addressed. In this study, we evaluated whether LXA4 exerts an effect on M-ALI. Male C57BL/6 mice were randomly assigned to the following five groups: noninfected; saline-treated Plasmodium berghei-infected; LXA4 -pretreated P. berghei-infected (LXA4 administered 1 h before infection and daily, from days 0 to 5 postinfection), LXA4 - and LXA4 receptor antagonist BOC-2-pretreated P. berghei-infected; and LXA4 -posttreated P. berghei-infected (LXA4 administered from days 3 to 5 postinfection). By day 6, pretreatment or posttreatment with LXA4 ameliorate lung mechanic dysfunction reduced alveolar collapse, thickening and interstitial edema; impaired neutrophil accumulation in the pulmonary tissue and blood; and reduced the systemic production of CXCL1. Additionally, in vitro treatment with LXA4 prevented neutrophils from migrating toward plasma collected from P. berghei-infected mice. LXA4 also impaired neutrophil cytoskeleton remodeling by inhibiting F-actin polarization. Ex vivo analysis showed that neutrophils from pretreated and posttreated mice were unable to migrate. In conclusion, we demonstrated that LXA4 exerted therapeutic effects in malaria-induced ALI by inhibiting lung dysfunction, tissue injury, and neutrophil accumulation in lung as well as in peripheral blood. Furthermore, LXA4 impaired the migratory ability of P. berghei-infected mice neutrophils.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Movimiento Celular , Lipoxinas/uso terapéutico , Malaria/complicaciones , Neutrófilos/inmunología , Plasmodium berghei/patogenicidad , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/parasitología , Animales , Células Cultivadas , Malaria/parasitología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.
RESUMEN
OBJECTIVE AND DESIGN: ß-Caryophyllene (BCP) is a sesquiterpene that binds to the cannabinoid 2 (CB2) receptor and exerts anti-inflammatory effects. In this study, we investigated the anti-inflammatory effect of BCP and another CB2 agonist, GP1a in inflammatory experimental model induced by Mycobacterium bovis (BCG). METHODS: C57Bl/6 mice were pretreated orally with BCP (0.5-50 mg/kg) or intraperitonealy with GP1a (10 mg/kg) 1 h before the induction of pleurisy or pulmonary inflammation by BCG. The direct action of CB2 agonists on neutrophils function was evaluated in vitro. RESULTS: ß-Caryophyllene (50 mg/kg) impaired BCG-induced neutrophil accumulation in pleurisy without affecting mononuclear cells or the production of TNF-α and CCL2/MCP-1. However, BCP inhibited CXCL1/KC, leukotriene B4 (LTB4), IL-12, and nitric oxide production. GP1a had a similar effect to BCP. Preincubation of neutrophils with BCP (10 µM) impaired chemotaxis toward LTB4 and adhesion to endothelial cells stimulated with TNF-α, and both, BCP and GP1a, impaired LTB4-induced actin polymerization. CONCLUSION: These results suggest that the CB2 receptor may represent a new target for modulating the inflammatory reaction induced by mycobacteria.
Asunto(s)
Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Receptor Cannabinoide CB2/agonistas , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Actinas/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Citocinas/inmunología , Dinoprostona/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Mycobacterium bovis , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/fisiología , Óxido Nítrico/metabolismo , Pleuresia/tratamiento farmacológico , Pleuresia/inmunología , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Sesquiterpenos Policíclicos , Tuberculosis Pulmonar/inmunologíaRESUMEN
Methyl gallate (MG) is a prevalent phenolic acid in the plant kingdom, and its presence in herbal medicines might be related to its remarkable biological effects, such as its antioxidant, antitumor, and antimicrobial activities. Although some indirect evidence suggests anti-inflammatory activity for MG, there are no studies demonstrating this effect in animal models. Herein, we demonstrated that MG (0.7-70 mg/kg) inhibited zymosan-induced experimental arthritis in a dose-dependent manner. The oral administration of MG (7 mg/kg) attenuates arthritis induced by zymosan, affecting edema formation, leukocyte migration, and the production of inflammatory mediators (IL-1ß, IL-6, TNF-α, CXCL-1, LTB4, and PGE2). Pretreatment with MG inhibited in vitro neutrophil chemotaxis elicited by CXCL-1, as well as the adhesion of these cells to TNF-α-primed endothelial cells. MG also impaired zymosan-stimulated macrophages by inhibiting IL-6 and NO production, COX-2 and iNOS expression, and intracellular calcium mobilization. Thus, MG is likely to present an anti-inflammatory effect by targeting multiple cellular events such as the production of various inflammatory mediators, as well as leukocyte activation and migration.
Asunto(s)
Ácido Gálico/análogos & derivados , Mediadores de Inflamación/farmacología , Macrófagos/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Plantas Medicinales/química , Administración Oral , Animales , Artritis Experimental , Brasil , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ácido Gálico/química , Ácido Gálico/farmacología , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Estructura Molecular , Óxido Nítrico Sintasa de Tipo II , Factor de Necrosis Tumoral alfa/farmacología , Zimosan/farmacologíaRESUMEN
Malaria is the most important parasitic disease worldwide, accounting for 1 million deaths each year. Severe malaria is a systemic illness characterized by dysfunction of brain tissue and of one or more peripheral organs as lungs and kidney. The most severe and most studied form of malaria is associated with cerebral complications due to capillary congestion and the adhesion of infected erythrocytes, platelets, and leukocytes to brain vasculature. Thus, leukocyte rolling and adhesion in the brain vascular bed during severe malaria is singular and distinct from other models of inflammation. The leukocyte/endothelium interaction and neutrophil accumulation are also observed in the lungs. However, lung interactions differ from brain interactions, likely due to differences in the blood-brain barrier and blood-air barrier tight junction composition of the brain and lung endothelium. Here, we review the importance of endothelial dysfunction and the mechanism of leukocyte/endothelium interaction during severe malaria. Furthermore, we hypothesize a possible use of adjunctive therapies to antimalarial drugs that target the interaction between the leukocytes and the endothelium.
Asunto(s)
Endotelio/metabolismo , Leucocitos/metabolismo , Malaria/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo , Endotelio/citología , Humanos , Leucocitos/citología , Malaria/sangreRESUMEN
INTRODUCTION: Malaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year. Since current antimalarial drugs are unable to prevent death in severe cases, new therapeutic strategies have been developed. Mesenchymal stromal cells (MSC) confer host resistance against malaria; however, thus far, no study has evaluated the therapeutic effects of MSC therapy on brain and distal organ damage in experimental cerebral malaria. METHODS: Forty C57BL/6 mice were injected intraperitoneally with 5 × 10(6) Plasmodium berghei-infected erythrocytes or saline. After 24 h, mice received saline or bone marrow (BM)-derived MSC (1x10(5)) intravenously and were housed individually in metabolic cages. After 4 days, lung and kidney morphofunction; cerebrum, spleen, and liver histology; and markers associated with inflammation, fibrogenesis, and epithelial and endothelial cell damage in lung tissue were analyzed. RESULTS: In P. berghei-infected mice, BM-MSCs: 1) reduced parasitemia and mortality; 2) increased phagocytic neutrophil content in brain, even though BM-MSCs did not affect the inflammatory process; 3) decreased malaria pigment detection in spleen, liver, and kidney; 4) reduced hepatocyte derangement, with an increased number of Kupffer cells; 5) decreased kidney damage, without effecting significant changes in serum creatinine levels or urinary flow; and 6) reduced neutrophil infiltration, interstitial edema, number of myofibroblasts within interstitial tissue, and collagen deposition in lungs, resulting in decreased lung static elastance. These morphological and functional changes were not associated with changes in levels of tumor necrosis factor-α, keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8), or interferon-γ, which remained increased and similar to those of P. berghei animals treated with saline. BM-MSCs increased hepatocyte growth factor but decreased VEGF in the P. berghei group. CONCLUSIONS: BM-MSC treatment increased survival and reduced parasitemia and malaria pigment accumulation in spleen, liver, kidney, and lung, but not in brain. The two main organs associated with worse prognosis in malaria, lung and kidney, sustained less histological damage after BM-MSC therapy, with a more pronounced improvement in lung function.
Asunto(s)
Lesión Renal Aguda/terapia , Lesión Pulmonar/terapia , Trasplante de Células Madre Mesenquimatosas , Animales , Células de la Médula Ósea/citología , Células Cultivadas , Modelos Animales de Enfermedad , Riñón/patología , Riñón/fisiología , Macrófagos del Hígado/citología , Pulmón/patología , Pulmón/fisiología , Malaria Cerebral/mortalidad , Malaria Cerebral/patología , Malaria Cerebral/terapia , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos C57BL , Plasmodium berghei/patogenicidad , Tasa de SupervivenciaRESUMEN
Gedunin, a natural limonoid from Meliaceae species, has been previously described as an antiinflammatory compound in experimental models of allergic inflammation. Here, we report the antiinflammatory and antinociceptive effects of gedunin in an acute model of articular inflammation induced by zymosan (500 µg/cavity; intra-articular) in C57BL/6 mice. Intraperitoneal (i.p.) pretreatment with gedunin (0.005-5 mg/kg) impaired zymosan-induced edema formation, neutrophil accumulation and hypernociception in mouse knee joints, due to decreased expression of preproET-1 mRNA and production of LTB4, PGE2, TNF-α and IL-6. Mouse post-treatment with gedunin (0.05 mg/kg; i.p.) 1 and 6 h after stimulation also impaired articular inflammation, by reverting edema formation, neutrophil accumulation and the production of lipid mediators, cytokines and endothelin. In addition, gedunin directly modulated the functions of neutrophils and macrophages in vitro. The pre-incubation of neutrophil with gedunin (100 µM) impaired shape change, adhesion to endothelial cells, chemotaxis and lipid body formation triggered by different stimuli. Macrophage pretreatment with gedunin impaired intracellular calcium mobilization, nitric oxide production, inducible nitric oxide synthase expression and induced the expression of the antiinflammatory chaperone heat shock protein 70. Our results demonstrate that gedunin presents remarkable antiinflammatory and anti-nociceptive effects on zymosan-induced inflamed knee joints, modulating different cell populations.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cartílago Articular/efectos de los fármacos , Limoninas/farmacología , Nocicepción/efectos de los fármacos , Osteocondritis/tratamiento farmacológico , Animales , Cartílago Articular/inmunología , Cartílago Articular/patología , Supervivencia Celular , Endotelina-1/metabolismo , Mediadores de Inflamación/metabolismo , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/inmunología , Articulación de la Rodilla/patología , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Infiltración Neutrófila , Osteocondritis/inmunologíaRESUMEN
Malaria is a worldwide disease that leads to 1 million deaths per year. Plasmodium falciparum is the species responsible for the most severe form of malaria leading to different complications. Beyond the development of cerebral malaria, impairment of renal function is a mortality indicator in infected patients. Treatment with antimalarial drugs can increase survival, however the long-term effects of malaria on renal disease, even after treatment with antimalarials, are unknown. The aim of this study was to evaluate the effect of antimalarial drug treatment on renal function in a murine model of severe malaria and then evaluate kidney susceptibility to a second renal insult. Initially, mice infected with Plasmodium berghei ANKA achieved 20% parasitemia on day 5 post infection, which was completely abolished after treatment with 25 mg/kg artesunate and 40 mg/kg mefloquine. The treatment also decreased plasma creatinine levels by 43% and partially reversed the reduction in the glomerular filtration rate induced by infection. The urinary protein/creatinine ratio, collagen deposition, and size of the interstitial space decreased by 75%, 40%, and 20%, respectively, with drugs compared with untreated infected animals. In infected-treated mice that underwent a second renal insult, the plasma creatinine level decreased by 60% and the glomerular filtration rate increased compared with infected animals treated only with antimalarials. The number of glomerular cells, collagen deposition and the size of the interstitial space decreased by 20%, 39.4%, and 41.3%, respectively, in the infected group that underwent a second renal insult compared with the infected-treated groups. These functional and structural data show that renal injury observed in a murine model of severe malaria is partially reversed after antimalarial drug treatment, making the kidney less susceptible to a second renal insult.
Asunto(s)
Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/parasitología , Antimaláricos/farmacología , Malaria/complicaciones , Malaria/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Antimaláricos/administración & dosificación , Colágeno/metabolismo , Modelos Animales de Enfermedad , Corteza Renal/metabolismo , Corteza Renal/patología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Ratones , Parasitemia/tratamiento farmacológico , Parasitemia/patología , Plasmodium berghei/efectos de los fármacos , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacologíaRESUMEN
CONTEXT: Despite the many biological activities reported for essential oils, their anti-inflammatory ability is relatively underexplored considering the wide variation in plant sources and in their volatile composition. Oils from Syzygium cumini Skells (SC) and Psidium guajava L. (PG) (Myrtaceae) have been described as having diverse pharmacological activities. OBJECTIVE: The current study seeks to evaluate the anti-inflammatory activity of the essential oils from the leaves of SC and PG, as well as some of their terpene-enriched fractions (+V = more volatile and -V = less volatile) obtained by vacuum distillation. Both the pharmacological responses and chemical compositions were correlated. MATERIALS AND METHODS: The relative contents of the oils and their fractions were evaluated by gas chromatography. Individual constituents in the oils were characterized by gas chromatography coupled to mass spectrometry. Anti-inflammatory activity was accessed in the lipopolysaccharide-induced pleurisy model, by measuring the inhibition of total leukocyte, neutrophil and eosinophil migration in the mice pleural lavage, after oil treatment with the oils at 100 mg/kg. RESULTS: Eosinophil migration was inhibited by SC (67%), SC (+V) (63%), PG (76%), PG (+V) (67%) and PG (-V) (74%). This efficacy was correlated with the presence of ß-pinene and ß-caryophyllene in the oils, a result that was reinforced by evaluating both these pure components (38 and 50% inhibition, respectively). Synergistic effects associated with the presence of α-pinene were speculated. DISCUSSION AND CONCLUSION: Essential oils from SC and PG may be useful to treat inflammatory diseases by mechanisms that include the inhibition of eosinophil migration.
Asunto(s)
Antiinflamatorios/farmacología , Aceites Volátiles/farmacología , Psidium/química , Syzygium/química , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Aceites Volátiles/química , Aceites Volátiles/aislamiento & purificación , Hojas de la Planta , Pleuresia/tratamiento farmacológico , Pleuresia/patologíaRESUMEN
OBJECTIVE: It is well known that sepsis causes damage in different organs, including kidneys. However, few studies have been conducted on the magnitude of the long-term effects of sepsis on the surviving population, in particular, in relation to kidney disease. In this study, we examined the impact of long-term effects of sepsis on a second kidney insult. DESIGN: Prospective experimental study. SETTING: University research laboratory. INTERVENTIONS: Wild-type mice were subjected to the cecal ligation and puncture sepsis model. Control animals underwent identical laparotomy but without ligation and cecum puncture. On days 0, 7, and 14 after surgery, the ratio between urinary protein and creatinine was measured. Fifteen days after surgery, surviving mice were subjected to a second kidney insult through intraperitoneal injections of bovine serum albumin for 7 days. On day 22 after surgery, urinary protein and creatinine, γ-glutamyl transpeptidase, lactate dehydrogenase, histologic parameters, macrophage infiltration, apoptotic cell, renal and plasmatic cytokines were determined. MEASUREMENTS AND MAIN RESULTS: On days 7 and 14 after surgery, the urinary protein and creatinine observed in the septic animal group were higher than those observed in the control group. On day 22 after surgery, sepsis-surviving animals that were subjected to a second kidney insult showed more severe tubular injury compared with controls. This process seems to involve an immunosuppressive state because the concentrations of some renal cytokines, such as tumor necrosis factor-α, interleukin 6, interferon-γ and chemokine ligand 2, were decreased and leukocyte numbers were increased. CONCLUSIONS: These results suggest that sepsis induces long-term effects in kidney structure aggravating tubule damage in a second kidney insult.
Asunto(s)
Lesión Renal Aguda/patología , Lesión Renal Aguda/orina , Choque Séptico/patología , Choque Séptico/orina , Lesión Renal Aguda/diagnóstico , Animales , Biomarcadores/orina , Ciego , Modelos Animales de Enfermedad , Ratones , Estudios Prospectivos , Punciones , Distribución Aleatoria , Valores de ReferenciaRESUMEN
We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action.
Asunto(s)
Cinamatos/química , Diseño de Fármacos , Hidrazonas/síntesis química , Hidrazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Cisteína Endopeptidasas , Hidrazonas/química , Hidrazonas/toxicidad , Concentración 50 Inhibidora , Ratones , Proteínas Protozoarias/antagonistas & inhibidores , Tripanocidas/química , Tripanocidas/toxicidad , Trypanosoma cruzi/enzimologíaRESUMEN
Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17(+) γδ T cells mediated by α(4) ß(7) integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α(4) ß(7) integrin in the pleura, but failed to attract αß T lymphocytes. CCL25 attracted CCR6(+) γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9(+) , α(4) ß(7) (+) , and CCR6(+) /IL-17(+) γδ T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of α(4) ß(7) integrin also inhibited the migration of IL-17(+) γδ T lymphocytes (but not of αß T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α(4) ß(7) integrin pathway is selective for γδ T cells. In addition, α(4) ß(7) integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α(4) ß(7) ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17(+) γδ T-cell mobilization to inflamed tissue via α(4) ß(7) integrin and modulates IL-17 levels.
Asunto(s)
Quimiocinas CC/inmunología , Quimiotaxis de Leucocito/inmunología , Hipersensibilidad/inmunología , Integrinas/inmunología , Interleucina-17/inmunología , Linfocitos T/inmunología , Animales , Moléculas de Adhesión Celular/inmunología , Ratones , Ratones Endogámicos C57BL , Mucoproteínas , Pleuresia/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores CCR/inmunología , Receptores CCR6/inmunología , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
The antimalarial acitivity of hydroxyethylamines, synthesized from the reaction of intermediated hydroxyethypiperazines with benzenesulfonyl chlorides or benzoyl chlorides, has been evaluated in vitro against a W2 Plasmodium falciparum clone. Some of the nineteen tested derivatives showed a significant activity in vitro, thus turning into a promising new class of antimalarials. In addition, a molecular modeling study of the most active derivative (5l) was performed and its most probable binding modes within plasmepsin II enzyme were identified.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Etanolaminas/síntesis química , Etanolaminas/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/toxicidad , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular , Eritrocitos/parasitología , Etanolaminas/química , Etanolaminas/toxicidad , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Modelos Moleculares , Monocitos/citología , Monocitos/efectos de los fármacos , Murinae , Plasmodium falciparum/enzimología , Unión Proteica , Proteínas Protozoarias/metabolismoRESUMEN
The antimalarial activity of hydroxyethylpiperazine derivatives, synthesized from the reaction of (2S,3S)Boc-phenylalanine epoxide with benzylpiperazines in good yields (76-96%), has been evaluated in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant). The results show that some compounds have moderate activity against this parasite and none of the active compounds showed cytotoxicity at high concentration (100 microg/ml).
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Cromatografía Liquida , Evaluación Preclínica de Medicamentos , Eritrocitos/parasitología , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y=p-NO2, pIC(50)=4.55 M) and 6l (X=F, Y=p-CN, pIC(50)=4.27 M) as the most potent derivatives compared to crystal violet (pIC(50)=3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it.