RESUMEN
Antibody repertoires of healthy humans and animals contain a fraction of antibodies able to acquire additional polyspecificity following exposure to several biologically relevant redox molecules (free heme, reactive oxygen species, ferrous ions, HOCl, etc.). The physiological role of these "hidden" polyspecific antibodies is poorly understood. Similar to inherently polyspecific antibodies, those with induced polyspecificicty may also have immunoregulatory properties. We have previously shown that a pooled human IgG preparation, modified by the exposure to ferrous ions, acquires the ability to significantly improve survival of animals with polymicrobial sepsis or aseptic systemic inflammation induced by bacterial lipopolysaccharide or zymosan administration. In the present study, we have analyzed the effects of administration of heme-exposed pooled human IgG in the same models of sepsis and aseptic systemic inflammation. The administration of a single dose of heme-exposed pooled IgG has resulted in a significant increase in the survival of mice with endotoxinemia, but not in those with polymicrobial sepsis and zymosan-induced severe generalized inflammation. Finally, we have provided evidence that the anti-inflammatory effect of heme-exposed IgG can be explained by scavenging of pro-inflammatory mediators.
Asunto(s)
Endotoxemia/tratamiento farmacológico , Hemo/farmacología , Inmunoglobulina G/uso terapéutico , Inflamación/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Especificidad de Anticuerpos , Endotoxemia/mortalidad , Humanos , Inmunoglobulina G/efectos de los fármacos , Inmunoglobulina G/inmunología , Mediadores de Inflamación , Lipopolisacáridos , Ratones , Tasa de SupervivenciaRESUMEN
Tyrphostin AG490 is a Janus kinase (JAK) 2 inhibitor that is clinically used as an anticancer agent and is also effective in various models of inflammatory and autoimmune diseases. In this study, we examined the effects of tyrphostin AG490 on the development of collagenase-induced osteoarthritis (CIOA). Our results showed that tyrphostin-ameliorated cartilage and bone destructions. This effect was associated with decreased expression of signal transducers and activators of transcription 3 (STAT3), phosphorylated JAK2, Dickkopf homolog 1, and receptor activator of nuclear factor κB ligand (RANKL) in the joints of arthritic mice. Tyrphostin AG490 suppressed STAT3 phosphorylation and the expression of tumor necrosis factor-related apoptosis-inducing ligand and RANKL by synovial fluid cells. The drug inhibited RANKL-induced osteoclast differentiation in vitro. Molecules, such as tyrphostin AG490 that limit bone erosion and influence osteoclast generation, might have therapeutic utility in joint degenerative disorders.
Asunto(s)
Inflamación/tratamiento farmacológico , Articulaciones/efectos de los fármacos , Tirfostinos/farmacología , Animales , Animales Recién Nacidos , Remodelación Ósea , Huesos/metabolismo , Diferenciación Celular , Citocinas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-17/sangre , Interleucina-6/sangre , Janus Quinasa 2/metabolismo , Ratones , Ratones Endogámicos ICR , Osteoclastos/citología , Osteoclastos/metabolismo , Fosforilación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ligando RANK/metabolismo , Factor de Transcripción STAT3/metabolismo , Líquido Sinovial/metabolismoRESUMEN
Despite the intensive research in the past decade on the microbial bioaccumulation of heavy metals, the significance of redox state for oxidative stress induction is not completely clarified. In the present study, we examined the effect of redox-active (copper and chromium) and redox-inactive (cadmium) metals on the changes in levels of oxidative stress biomarkers and antioxidant enzyme defence in Trichosporon cutaneum R57 cells. This filamentous yeast strain showed significant tolerance and bioaccumulation capability of heavy metals. Our findings indicated that the treatment by both redox-active and redox-inactive heavy metal induced oxidative stress events. Enhanced concentrations of Cu2+, Cr6+ and Cd2+ caused acceleration in the production of reactive oxygen species (ROS), increase in the level of oxidatively damaged proteins and accumulation of reserve carbohydrates (glycogen and trehalose). Cell response against heavy metal exposure also includes elevation in the activities of antioxidant enzymes, superoxide dismutase and catalase, which are key enzymes for directly scavenging of ROS. Despite the mentioned changes in the stress biomarkers, T. cutaneum did not show a significant growth diminution. Probably, activated antioxidant defence contributes to the yeast survival under conditions of heavy metal stress.
RESUMEN
Coumarin and its derivatives have potent immunomodulatory activities. Here we describe the parameters of the protective effect of 7-hydroxycoumarin (7-OHC) in experimental Salmonella enterica Serovar Typhimurium infection in mice. The protective effect depended on the duration of treatment reaching its maximum after 10 days of pretreatment and lasted for at least 15 days after its end. Electron microscopy studies revealed that 7-OHC induced ultrastructural changes in macrophages consistent with their activation as well as faster destruction of ingested salmonellae. Superoxide and hydrogen peroxide secretion by macrophages was decreased in both healthy and Salmonella-infected 7-OHC treated animals, which is in line with the current view that some coumarins possess antioxidant and radical scavenging activity. Thus, 7-OHC pretreatment also appears beneficial to the host by limiting the harmful tissue damaging and immunosuppressive effects of the oxidative stress during a Salmonella infection but still activates the microbicidal capacity of exposed phagocytes.
Asunto(s)
Macrófagos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Salmonelosis Animal/tratamiento farmacológico , Salmonella enterica/inmunología , Umbeliferonas/administración & dosificación , Animales , Células Cultivadas , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Inmunomodulación , Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Macrófagos/ultraestructura , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica , Fagocitosis/inmunología , Salmonelosis Animal/inmunología , Salmonella enterica/patogenicidad , Umbeliferonas/efectos adversos , Umbeliferonas/químicaRESUMEN
The combined protective effect of a polyphenol-rich extract, isolated from Geranium sanguineum L. (PC), and a novel naturally glycosylated Cu/Zn-containing superoxide dismutase, produced from the fungal strain Humicula lutea 103 (HL-SOD), in the experimental influenza A virus infection (EIVI) in mice, induced with the virus A/Aichi/2/68 (H3N2), was investigated. The combined application of HL-SOD and PC in doses, which by themselves do not defend significantly mice in EIVI, resulted in a synergistically increased protection, determined on the basis of protective indices and amelioration of lung injury. Lung weights and consolidation as well as infectious lung virus titers were all decreased significantly parallel to the reduction of the mortality rates; lung indices were raised. The excessive production of reactive oxygen species (ROS) by alveolar macrophages (aMphi) as well as the elevated levels of the lung antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), induced by EIVI, were brought to normal. For comparative reasons the combined protective effect of PC and vitamin C was investigated. The obtained results support the combined use of antioxidants for the treatment of influenza virus infection and in general indicate the beneficial protective role of combinations of viral inhibitors of natural origin with diverse modes of action.
Asunto(s)
Flavonoides/uso terapéutico , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Fenoles/uso terapéutico , Extractos Vegetales/uso terapéutico , Plantas Medicinales , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Superóxido Dismutasa/farmacología , Animales , Femenino , Geranium , Peróxido de Hidrógeno/metabolismo , Virus de la Influenza A , Masculino , Ratones , Ratones Endogámicos ICR , PolifenolesRESUMEN
* Author for correspondence and reprint requests Z. Naturforsch. 65c, 141-147 (2010); received June 17/July 21, 2009 The superoxide radical (O2-), hydrogen peroxide (H2O2) and nitric oxide (NO) are pleiotropic inflammatory mediators which play an important role in inflammatory joint diseases. They are overproduced during rheumatoid arthritis and its experimental model - adjuvant-induced arthritis in rodents--and may be detected both systemically and intra-articularly. Their secretion is up-regulated by proinflammatory cytokines such as IFN-gamma, IL-12, IL-6 and TNF-alpha, and they are responsible for the destruction of joint tissue. In this work, the effect of superoxide dismutase (SOD) from a thermotolerant yeast strain, Kluyveromyces marxianus, on the production of proinflammatory cytokines, reactive oxygen and nitrogen species was studied. Mice received three intraperitoneal injections of yeast SOD at a dose of 10 mg/ kg body weight (30,000 U/kg) on consecutive days starting on the day after arthritic induction. On days 3, 8 and 14 post induction peritoneal macrophages were isolated and both spontaneous and stimulated production of reactive oxygen and nitrogen metabolites were measured. Early in arthritic development yeast SOD treatment did not influence the O2- production, but on day 14 both spontaneous and PMA-induced secretion were dramatically reduced. Spontaneous H2O2 release was inhibited on day 14, while PMA-stimulated production was decreased from the beginning of the arthritic development. Yeast SOD treatment effectively suppressed the spontaneous and recombinant mouse IFN-gamma + LPS induced release of NO as well. Serum levels of proinflammatory cytokines, IL-12, IFN-gamma, IL-6 and TNF-alpha, were also significantly reduced. The obtained results show some of the mechanisms of action of SOD in reducing the severity of arthritic inflammation. Besides direct inhibition of joint tissue destruction exogenous SOD substantially limits the existing positive feedback between secretion of reactive oxygen species and inflammatory cytokine production.
Asunto(s)
Artritis Experimental/fisiopatología , Inflamación/tratamiento farmacológico , Inflamación/etiología , Kluyveromyces/enzimología , Superóxido Dismutasa/uso terapéutico , Animales , Artritis Experimental/sangre , Artritis Experimental/tratamiento farmacológico , Citocinas/sangre , Edema/etiología , Inflamación/sangre , Inyecciones , Ratones , Ratones Endogámicos ICR , Superóxido Dismutasa/administración & dosificación , Superóxido Dismutasa/aislamiento & purificación , Superóxidos/metabolismoRESUMEN
New La(III) and Dy(III) complexes of deprotonated 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (Acenocoumarol) were synthesized and characterized using FT-IR, FT-Raman, (1)H NMR spectra, and elemental analyses. The ligand and its lanthanide(III) complexes were tested for their cytotoxic/cytostatic activity against two tumor cell lines and peritoneal mouse macrophages. The La(III) and Dy(III) complexes exhibit good activity against melanoma B16 and fibrosarcoma L929 and they are stronger inhibitors of tumor cell proliferation compared to the ligand without influencing normal cell viability and NO release by mouse peritoneal macrophages.
Asunto(s)
Acenocumarol/química , Acenocumarol/toxicidad , Antineoplásicos/química , Antineoplásicos/toxicidad , Citostáticos/química , Disprosio/química , Lantano/química , Acenocumarol/síntesis química , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Citostáticos/toxicidad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Disprosio/toxicidad , Humanos , Lantano/toxicidad , Ligandos , Espectroscopía de Resonancia Magnética , Ratones , Espectrometría Raman , Relación Estructura-ActividadRESUMEN
Influenza infection was induced in white mice by intranasal inoculation of the virus A/Aichi/2/68 (H3N2). The lung protease and the protease-inhibitory activities were followed for 9 days after infection. The intranasal application of a polyphenol-rich extract (PC) isolated from Geranium sanguineum L. induced a continuous rise in the anti-protease activity but did not cause substantial changes in the lung protease activity of healthy mice. Influenza virus infection triggered a slight reduction in protease activity in the lungs at 5 and 48 h post infection (p.i.) and a marked increase at 24 h and 6 day p.i.. Protease inhibition in the lungs was reduced at 24 and 48 h p.i. and an increase was observed at 5 h and 6 and 9 days p.i.. PC treatment brought both activities to normal levels. The restoration of the examined parameters was consistent with a prolongation of mean survival time and reduction of mortality rate, infectious virus titre and lung consolidation. PC reinstated superoxide production by alveolar macrophages and increased their number in virus-infected mice. The favourable effect on the protease and the protease-inhibitory activities in the lungs of influenza-virus-infected mice apparently contributes to the overall protective effect of PC in the murine experimental influenza A/Aichi infection. The antiviral effect of the individual constituents was evaluated.
Asunto(s)
Antivirales/farmacología , Flavonoides/farmacología , Geranium , Subtipo H3N2 del Virus de la Influenza A , Pulmón/enzimología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Fenoles/farmacología , Extractos Vegetales/farmacología , Inhibidores de Proteasas/farmacología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Infecciones por Orthomyxoviridae/enzimología , Polifenoles , Superóxidos/metabolismoRESUMEN
The antitumor effect of peroral treatment with coumarin and its main metabolite in humans 7-hydroxycoumarin (7-OHC) against Sarcoma 180 in mice was studied. Both agents inhibited tumor growth and increased survival time of tumor-bearing animals. The antitumor effect was better when coumarins were administered prior to tumor inoculation suggesting that the immunomodulatory potential of coumarins might exceed their well-known direct cytostatic activity. The additive effect of coumarins in combination with a suboptimal LPS dose in tumor growth inhibition was demonstrated. Coumarin treatment enhanced the macrophage migration activity in the presence and absence of LPS and increased nitric oxide release. In vitro, coumarins induced IL-12 in murine macrophages and additively increased the LPS-induced IL-12 release. These data indicate that the immunomodulatory activity of coumarins contributes to their direct cytostatic effect and demonstrate their potential to combine as immunostimulators with other antitumor agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Cumarinas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Umbeliferonas/uso terapéutico , Animales , Movimiento Celular/efectos de los fármacos , Cumarinas/administración & dosificación , Cumarinas/farmacología , Interleucina-12/biosíntesis , Lipopolisacáridos/administración & dosificación , Activación de Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos ICR , Óxido Nítrico/biosíntesis , Umbeliferonas/administración & dosificación , Umbeliferonas/farmacologíaRESUMEN
Coumarin and its derivatives are naturally occurring substances with multiple biological activities. Here we demonstrate that prophylactic peroral administration of coumarin or 7-hydroxycoumarin (7-OHC) enhances resistance to subsequent lethal Salmonella enterica Serovar Typhimurium infection in mice. 7-OHC decreased bacterial load in liver and spleen, and enhanced phagocytosis and bacterial killing by macrophages when applied in vitro and in vivo. 7-OHC treatment induced significant NO release in peritoneal macrophage cultures. The observed protective effect correlated with the induction of Th1-associated cytokines, such as IL-12, IFN-gamma, and TNF-alpha. These data demonstrate a clear immunomodulatory potential of coumarins which might have important therapeutic implications to enhance resistance to infection.