RESUMEN
Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Manejo del Dolor/métodos , gammaglobulinas/uso terapéutico , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Niño , Método Doble Ciego , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Adulto JovenRESUMEN
We investigated the effects of two antimicrobial peptides (AMPs) isolated from Scolopendra subspinipes mutilans on neutrophil activity. Stimulation of mouse neutrophils with the two AMPs elicited chemotactic migration of the cells in a pertussis toxin-sensitive manner. The two AMPs also stimulated activation of ERK and Akt, which contribute to chemotactic migration of neutrophils. We found that AMP-stimulated neutrophil chemotaxis was blocked by a formyl peptide receptor (FPR) 1 antagonist (cyclosporin H); moreover the two AMPs stimulated the chemotactic migration of FPR1-expressing RBL-2H3 cells but not of vector-expressing RBL-2H3 cells. We also found that the two AMPs stimulate neutrophil migration in vivo, and that this effect is blocked in FPR1-deficient mice. Taken together, our results suggest that the two AMPs stimulate neutrophils, leading to chemotactic migration through FPR1, and the two AMPs will be useful for the study of FPR1 signaling and neutrophil activation. [BMB Reports 2016; 49(9): 520-525].
Asunto(s)
Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Receptores de Formil Péptido/metabolismo , Animales , Western Blotting , Línea Celular , Ciclosporina/farmacología , Alcaloides Diterpénicos , Medicamentos Herbarios Chinos/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Toxina del Pertussis/toxicidad , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores de Formil Péptido/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Sepsis is a serious, life-threatening, infectious disease. In this study, we demonstrate that sucrose methyl 3-formyl-4-methylpentanoate (SMFM), a novel natural compound isolated from garlic (Allium sativum L.), markedly enhances survival rates by inhibiting lung inflammation in a cecal ligation and puncture (CLP) experimental polymicrobial sepsis model. SMFM strongly reduced bacterial colony units from peritoneal fluid in CLP mice by stimulating the generation of reactive oxygen species. Lymphocyte apoptosis in spleens from CLP mice was also markedly decreased by SMFM administration. SMFM also significantly inhibited the production of proinflammatory cytokines, such as TNF-α, interleukin-1ß (IL-1ß) and IL-6, in CLP mice. Lipopolysaccharide-stimulated production of TNF-α and IL-6 were also strongly inhibited by SMFM in mouse bone marrow-derived macrophages. Taken together, our results indicate that SMFM has therapeutic effects against polymicrobial sepsis that are mediated by enhanced microbial killing and blockage of cytokine storm.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Ajo/química , Sepsis/tratamiento farmacológico , Sacarosa/análogos & derivados , Animales , Carga Bacteriana/efectos de los fármacos , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos ICR , Fitoterapia , Sepsis/inmunología , Sepsis/microbiología , Sacarosa/química , Sacarosa/farmacologíaRESUMEN
α-Iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, strongly enhances survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. Mechanistically, α-iso-cubebenol markedly reduces viable bacteria in the peritoneal fluid and peripheral blood, by increasing production of superoxide anion. α-Iso-cubebenol also significantly attenuates widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibits the production of proinflammatory cytokines including interleukin-1ß (IL-1ß) and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. Taken together, the results indicate that α-iso-cubebenol can reverse the progression of septic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival.
Asunto(s)
Productos Biológicos/uso terapéutico , Schisandra/química , Sepsis/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Animales , Bacterias/efectos de los fármacos , Modelos Animales de Enfermedad , Frutas/química , Masculino , Ratones , Ratones Endogámicos ICR , Sesquiterpenos/administración & dosificaciónRESUMEN
α-Iso-cubebene, a natural compound isolated from Schisandra chinensis fruit, strongly enhanced survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. The mechanism involved the marked reduction of viable bacteria in the peritoneal fluid, by virtue of increased phagocytic activity and production of hydrogen peroxide. α-Iso-cubebene also significantly attenuated lung inflammation and widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibited the production of proinflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. The results indicate that α-iso-cubebene can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival.