RESUMO
We investigate the nonlinear propagation of an ultra-short, 150 fs, optical pulse along the waveguide of a quantum dot (QD) laser operating above threshold. We demonstrate that among the various nonlinear processes experienced by the propagating pulse, four-wave mixing (FWM) between the pulse and the two oscillating counter-propagating cw fields of the laser is the dominant one. FWM has two important consequences. One is the creation of a spectral hole located in the vicinity of the cw oscillating frequency. The width of the spectral hole is determined by an effective carrier and gain relaxation time. The second is a modification of the shape of the trailing edge of the pulse. The wave mixing involves first and second order processes which result in a complicated interaction among several fields inside the cavity, some of which are cw while the others are time varying, all propagating in both directions. The nonlinear pulse propagation is analyzed using two complementary theoretical approaches. One is a semi-analytical model which considers only the wave mixing interaction between six field components, three of which propagate in each direction (two cw fields and four time-varying signals). This model predicts the deformation of the tail of the output signal by a secondary idler wave, produced in a cascaded FWM process, which co-propagates with the original injected pulse. The second approach is a finite-difference time-domain simulation, which considers also additional nonlinear effects, such as gain saturation and self-phase modulation. The theoretical results are confirmed by a series of experiments in which the time dependent amplitude and phase of the pulse after propagation are measured using the cross-frequency-resolved optical gating technique.
RESUMO
The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
Assuntos
Imunidade/genética , Proteínas de Membrana Transportadoras , Proteínas Mitocondriais , Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Sequência de Bases , Primers do DNA/genética , Expressão Gênica , Marcação de Genes , Canais Iônicos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas/imunologia , Proteínas/metabolismo , Toxoplasmose Animal/genética , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/metabolismo , Desacopladores/metabolismo , Proteína Desacopladora 2RESUMO
A complete characterization of pulse shape and phase of a 1.3 microm, monolithic-two-section, quantum-dot mode-locked laser (QD-MLL) at a repetition rate of 40 GHz is presented, based on frequency resolved optical gating. We show that the pulse broadening of the QD-MLL is caused by linear chirp for all values of current and voltage investigated here. The chirp increases with the current at the gain section, whereas larger bias at the absorber section leads to less chirp and therefore to shorter pulses. Pulse broadening is observed at very high bias, likely due to the quantum confined stark effect. Passive- and hybrid-QD-MLL pulses are directly compared. Improved pulse intensity profiles are found for hybrid mode locking. Via linear chirp compensation pulse widths down to 700 fs can be achieved independent of current and bias, resulting in a significantly increased overall mode-locking range of 101 MHz. The suitability of QD-MLL chirp compensated pulse combs for optical communication up to 160 Gbit/s using optical-time-division multiplexing are demonstrated by eye diagrams and autocorrelation measurements.
Assuntos
Lasers , Pontos Quânticos , Processamento de Sinais Assistido por Computador/instrumentação , Telecomunicações/instrumentação , Desenho de Equipamento , Análise de Falha de Equipamento , Micro-OndasRESUMO
OBJECTIVE: To investigate the impact of beta-adrenoceptor deficiency on the metabolic effects of leptin. MEASUREMENTS: Leptin was infused subcutaneously through an osmotic minipump in wild-type (WT) and beta(1)/beta(2)/beta(3)-adrenoceptor knockout (beta-less) mice and its effects on food intake, energy expenditure, carbohydrate and lipid utilization as well as on the levels of expression of the brown adipose tissue (BAT), thermogenic marker uncoupling protein-1 (UCP1) and type II deiodinase (D2) mRNAs were compared. RESULTS: Leptin treatment decreased food intake by 23% in both the WT and the beta-less mice. In pair-fed animals being used as controls, leptin treatment was found to increase energy expenditure in WT, but not in beta-less mice. No difference was observed in carbohydrate or fat utilization between leptin-treated WT and beta-less mice. Leptin increased UCP1 and D2 mRNA levels in WT mouse BAT 1.7- and 3-fold, respectively, but had no effect on the expression of these genes in beta-less mouse BAT. CONCLUSION: The stimulatory effects of leptin on oxygen consumption, BAT UCP1 and D2 expression require functional beta-adrenoceptors, but its inhibitory effect on food intake and its stimulatory effect on fat utilization is independent of the beta-adrenoceptor signalling.
Assuntos
Tecido Adiposo Marrom/metabolismo , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Leptina/farmacologia , Receptores Adrenérgicos beta/deficiência , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Calorimetria Indireta/métodos , Métodos de Alimentação , Iodeto Peroxidase/metabolismo , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Receptores Adrenérgicos beta/fisiologia , Proteína Desacopladora 1 , Iodotironina Desiodinase Tipo IIRESUMO
To determine whether Toxoplasma gondii infection could modify biological phenomena associated with brain ischemia, we investigated the effect of permanent middle cerebral artery occlusion (MCAO) on neuronal survival, inflammation and redox state in chronically infected mice. Infected animals showed a 40% to 50% decrease of infarct size compared with non-infected littermates 1, 4 and 14 days after MCAO. The resistance of infected mice may be associated with increased basal levels of anti-inflammatory cytokines and/or a marked reduction of the MCAO-related brain induction of two pro-inflammatory cytokines, tumor necrosis factor-alpha and interferon-gamma (IFNgamma). In addition, potential anti-inflammatory/neuroprotective factors such as nerve growth factor, suppressor of cytokine signaling-3, superoxide dismutase activity, uncoupling protein-2 and glutathione (GSH) were upregulated in the brain of infected mice. Consistent with a role of GSH in central cytokine regulation, GSH depletion by diethyl maleate inhibited Toxoplasma gondii lesion resistance by increasing the proinflammatory cytokine IFNgamma brain levels. Overall, these findings indicate that chronic toxoplasmosis decisively influences both the inflammatory molecular events and outcome of cerebral ischemia.
Assuntos
Isquemia Encefálica , Infarto da Artéria Cerebral Média , Toxoplasma , Toxoplasmose/imunologia , Toxoplasmose/patologia , Animais , Encéfalo/imunologia , Encéfalo/parasitologia , Encéfalo/patologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/parasitologia , Isquemia Encefálica/patologia , Doença Crônica , Citocinas/metabolismo , Glutationa/metabolismo , Hiperfagia/imunologia , Hiperfagia/parasitologia , Hiperfagia/patologia , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/parasitologia , Infarto da Artéria Cerebral Média/patologia , Canais Iônicos/genética , Masculino , Camundongos , Proteínas Mitocondriais/genética , Degeneração Neural/imunologia , Degeneração Neural/parasitologia , Degeneração Neural/patologia , RNA Mensageiro/metabolismo , Superóxido Dismutase/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteína Desacopladora 2 , Regulação para CimaRESUMO
The role of neutrophils (PMNs) and leukocyte integrins was investigated in two models of lipopolysaccharide (LPS)-induced toxicity: the systemic lethality assay in D-galactosamine-sensitized mice and the local reaction elicited by intradermal injection of LPS and tumor necrosis factor (TNF) at 24-h intervals. In the local reaction, depletion of PMNs with an anti-PMN monoclonal antibody (mAb) and mAbs against CD-11a (or LFA1) and CD-11b (or CR3) completely prevented the hemorrhagic necrosis. Evaluation of histological sections and myeloperoxidase levels suggested different mechanism of protection because PMNs were abundant in anti-CD-11- and absent in anti-PMN-treated mice. In the systemic assay, depletion of PMNs ensured 100% survival, whereas after administration of anti-CD-11a or b mAb, the percentages of survivors were 6 and 59%, respectively. One hour after LPS injection, the serum TNF-alpha level was higher in PMN-depleted mice than in controls. These studies provide evidence that neutrophils are essential for the expression of local or systemic LPS-induced injury, whereas the requirement for their leukocytic integrins is obvious only in the local reaction.
Assuntos
Lipopolissacarídeos/toxicidade , Antígeno-1 Associado à Função Linfocitária/fisiologia , Antígeno de Macrófago 1/fisiologia , Neutrófilos/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Studies reported here investigate the influence of dietary fat types on cytokine production in response to endotoxin (LPS) challenge. Tumor necrosis factor (TNF) serum levels were markedly higher (by 10-fold) in mice fed chronically a diet rich in fish oil rather than either a diet rich in corn or coconut oil or a low fat diet. This in vivo hyper-responsiveness in LPS-induced TNF production following fish oil consumption concorded with similar exaggerated in vitro TNF release from macrophages exposed to LPS. These data suggest that high consumption of fish oils, by virtue of their high content of omega-3 polyunsaturated fatty acids, can lead to an exaggerated production of mediators of inflammation with potentially adverse consequences on the outcome and severity of infectious diseases.
Assuntos
Gorduras na Dieta/farmacologia , Óleos de Peixe/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Óleo de Coco , Óleo de Milho/farmacologia , Feminino , Técnicas In Vitro , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Óleos de Plantas/farmacologia , Fatores de TempoRESUMO
Dietary supplementation with fish oil has previously been shown to enhance in vivo and in vitro (macrophage) synthesis of tumor necrosis factor-alpha (TNF-alpha) in response to bacterial lipopolysaccharide (LPS) stimulation. The studies reported here were conducted to gain insight into the molecular mechanisms of this nutrient-immune interaction by comparing the concentration, rate of synthesis, and rate of decay of TNF-alpha mRNA upon LPS stimulation of macrophages obtained from mice fed high-fat diets, rich in either fish oil, corn oil, or coconut oil, or a low-fat diet for a period of 4 weeks. The results indicate that compared with the other diet groups, LPS stimulation of macrophages from mice fed fish oil resulted in (1) enhanced levels of mRNA and protein for TNF-alpha, and (2) increased transcription of TNF-alpha mRNA as assessed by nuclear run-on assays. Posttranscriptional studies showed that the rate of decay of TNF-alpha mRNA did not vary significantly for macrophages from mice fed with fish oil as compared with corn oil. Further studies using actinomycin D and cycloheximide suggested that RNA synthesis, but not protein synthesis, was necessary for TNF-alpha mRNA accumulation. Taken together, the present studies suggest that fish oil enhances macrophage TNF-alpha mRNA expression at the transcriptional level. Although such TNF-alpha upregulation may provide a mechanism for the beneficial effects of fish oil in certain inflammatory and immune disorders, it can also underlie its potential deleterious effects if the degree of upregulation leads to exaggerated TNF-alpha production that exceeds the limits of benefit to reach toxic levels.
Assuntos
Óleos de Peixe/farmacologia , Macrófagos Peritoneais/metabolismo , RNA Mensageiro/metabolismo , Transcrição Gênica , Fator de Necrose Tumoral alfa/genética , Animais , Sequência de Bases , Peso Corporal/efeitos dos fármacos , Feminino , Immunoblotting , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Sondas de Oligonucleotídeos/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Mortality rate in mice fed fish oil for 4 weeks was remarkably higher after a very low peroral (PO) challenge with Salmonella typhimurium, as compared with those fed diets rich in either corn oil or hydrogenated coconut oil, or a low fat (chow) diet. None of the surviving mice fed the fish oil diet showed bacterial counts in their spleens, unlike 45.4% to 66.6% of surviving mice fed high fat or low fat diets. The spleens of mice fed fish oil presented the highest number of bacteria 7 days after intraperitoneal infection with the same bacterial strain. Thus, the current studies demonstrate that a diet rich in fish oil decreases host resistance to infection.
Assuntos
Óleos de Peixe/farmacologia , Salmonelose Animal/imunologia , Salmonella typhimurium , Tecido Adiposo/anatomia & histologia , Animais , Peso Corporal , Gorduras na Dieta/farmacologia , Feminino , Imunidade Inata/efeitos dos fármacos , Camundongos , Salmonelose Animal/mortalidadeRESUMO
Toxoplasma gondii (Me49 strain) infection into Swiss Webster mice is followed by hypermetabolism and weight loss in the acute phase lasting 14 days. In the subsequent chronic phase of infection, mice showed either a resolution of hypermetabolism and partial weight recovery (Gainers) or persistent hypermetabolism, with stable weight loss (Non-Gainers). The hypermetabolic response was not associated with an augmentation in the thermogenic uncoupling protein 1 (UCP1) mRNA expression in interscapular brown adipose tissue (BAT), but rather UCP1 expression was reduced. Hypermetabolism is associated with high lipid oxidation as attested by a low respiratory quotient (RQ). Neither BAT nor sympathetic nervous system appear to be involved in the increased lipid utilization, since propranolol did not increase the lower RQ in infected mice. The mitochondrial lipid oxidation blocker mercaptoacetate did not reestablish the respiratory quotient RQ in acute infection (on day 4) and in chronically infected Non-Gainer mice. This suggests an important extra-mitochondrial mechanism of lipid oxidation. Increased lipid peroxidation was detected especially in serum, lung, spleen and liver, which are rich in macrophage-type cells. Following infection peritoneal macrophages exhibited an enhanced capacity to produce reactive oxygen species (ROS). Using IFN-gamma knockout mice we observed that not only the hypermetabolic response was ablated in these mice but there was not a marked increase in ROS production or preferential oxidation/peroxidation of lipids in the acute phase of infection prior to the cachectic phase. The present study described a novel hypermetabolic mechanism involving enhanced lipid peroxidation dependent on IFN-gamma, especially associated with tissues rich in macrophages.
Assuntos
Proteínas de Transporte/metabolismo , Citocinas/biossíntese , Interferon gama/metabolismo , Peroxidação de Lipídeos , Proteínas de Membrana/metabolismo , Toxoplasmose Animal/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Citocinas/sangue , Ingestão de Alimentos/fisiologia , Metabolismo Energético , Interferon gama/genética , Canais Iônicos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Respiração , Baço/metabolismo , Toxoplasma , Proteína Desacopladora 1RESUMO
Lipopolysaccharide (LPS)-induced effects on energy balance are characterized by alterations in energy expenditure (hypermetabolism) and food intake (anorexia). To study the role of tumour necrosis factor alpha (TNF-alpha) on some of these metabolic responses to endotoxin, we have used transgenic mice expressing soluble tumour necrosis factor receptor-1 IgG fusion protein (TNFR1-IgG) as well as TNF-alpha knockout (KO), lymphotoxin-alpha (LT-alpha) KO, and interferon-gamma receptor (IFN-gamma R) KO mice. The results from TNFR1-IgG transgenic mice suggest that the hypermetabolic and anorectic responses induced by LPS are independently regulated since, in the absence of TNF-alpha or LT-alpha, the LPS-induced hypermetabolism is almost prevented but not the anorexia. The anorectic response shows the strongest association with IFN-gamma since both IFN-gamma R KO mice and mice treated with anti-IFN-gamma antibody showed marked reduction in the LPS-induced anorexia compared to other mice. IFN-gamma R KO mice also have an attenuated thermogenic response to endotoxin. Anti-Asialo GM1 antibody treatment attenuated both the hypermetabolic and anorectic responses to LPS, to an extent comparable to that observed in IFN-gamma R KO mice. This finding suggests that natural killer cells (lymphocytic subsets) may be involved in IFN-gamma production and play an important role in the metabolic alterations induced by LPS. We also showed that the hypermetabolic response of control mice is associated with an upregulation of cytokine expression within the brain and an increase in permeability of the blood brain barrier. LPS-induced anorexia appears to involve peripheral cytokine expression.
Assuntos
Ingestão de Alimentos , Metabolismo Energético , Interferon gama/imunologia , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Antígenos CD/genética , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Citocinas/biossíntese , Citocinas/sangue , Citocinas/genética , Metabolismo Energético/efeitos dos fármacos , Azul Evans/metabolismo , Feminino , Interferon gama/biossíntese , Linfotoxina-alfa/genética , Linfotoxina-alfa/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , RNA Mensageiro/biossíntese , Receptores de Interferon/genética , Receptores do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Baço/efeitos dos fármacos , Baço/imunologia , Ativação Transcricional , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Receptor de Interferon gamaRESUMO
The temporal pattern of changes in energy balance and cytokine mRNA expression in spleen and brain were examined in a mouse model of infection with Toxoplasma gondii. During days 1-7 postinfection, food intake was unaltered, but energy expenditure was significantly increased, and this was associated with elevated tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-5, and interferon (IFN)-gamma. The hypermetabolic state persisted during subsequent anorexia, whose onset coincided with elevated IL-2, and at the end of the acute phase of cachexia, the dual anorexic and hypermetabolic states were associated with the cytokines examined: TNF-alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, and IFN-gamma. In the chronic phase of the infection, the mice showed either partial weight recovery (gainers) or no weight regain (nongainers). The infected gainers, though still hypophagic, were no longer hypermetabolic, and their cytokine mRNA was no longer elevated, except for TNF-alpha and IL-10. In contrast, the infected nongainers continued to show both anoroxia and hypermetabolism, which were associated with elevations in all cytokines examined and particularly those of the TH2 profile (IL-4 and IL-5) and IL-6. Taken together, these studies reveal a distinct pattern of cytokine mRNA expression underlying 1) hypermetabolism vs. anorexia, 2) acute vs. chronic cachexia, and 3) stable weight loss vs. partial weight recovery.
Assuntos
Citocinas/genética , Metabolismo Energético , Expressão Gênica , Toxoplasma , Toxoplasmose Animal/genética , Toxoplasmose Animal/metabolismo , Doença Aguda , Animais , Composição Corporal , Peso Corporal , Doença Crônica , Citocinas/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Feminino , Imunidade , Camundongos , Toxoplasmose Animal/patologiaRESUMO
The cell surface component CD14 and the toll-like receptors 2 and 4 (TLR2 and TLR4) are important in mediating the immune responses to bacterial products in mammals. Using mice genetically deficient in CD14, TLR2, or TLR4, we studied the role of these molecules in the anorectic effects of LPS and muramyl dipeptide (MDP). CD14 or TLR2 knockout (KO) and TLR4-deficient (TLR4-DEF) mice as well as corresponding wild-type (WT) colittermates were injected intraperitoneally at dark onset with LPS (2 microg/mouse), MDP (10 mg/kg), interleukin-1 beta (IL-1 beta, 150 ng/mouse), or vehicle, and food intake was recorded. LPS and MDP reduced food intake in WT mice of all genotypes tested. The anorectic effect of LPS was attenuated (P < 0.04) in CD14-KO and TLR4-DEF mice but not in TLR2-KO (P > 0.05). The anorectic effect of MDP was blunted in CD14-KO and TLR2-KO (P < 0.02) mice but not in TLR4-DEF mice. IL-1 beta reduced food intake similarly in all genotypes tested. These results indicate that CD14 is involved in mediating the anorectic effects of both LPS and MDP. Furthermore, TLR4 and TLR2 are specifically involved in mediating the anorectic effects of LPS and MDP, respectively. The results are consistent with the hypothesis that TLR4 functions as the true LPS receptor and that TLR2 is involved in recognition of gram-positive bacterial products.
Assuntos
Anorexia/induzido quimicamente , Anorexia/fisiopatologia , Receptores de Lipopolissacarídeos/genética , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/genética , Receptores de Superfície Celular/genética , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adjuvantes Imunológicos/farmacologia , Animais , Anorexia/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Injeções Intraperitoneais , Interleucina-1/farmacologia , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/metabolismo , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 10(4) parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0% of the mice, respectively. When these drugs were administered simultaneously, a 100% survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kg/day, respectively) protected 100% of the mice. A 3-week therapy of chronically infected mice with either epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine (15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.
Assuntos
Dapsona/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Toxoplasma/efeitos dos fármacos , Trimetoprima/análogos & derivados , Animais , Dapsona/administração & dosagem , Sinergismo Farmacológico , Feminino , Camundongos , Toxoplasmose Animal/tratamento farmacológico , Trimetoprima/administração & dosagem , Trimetoprima/sangue , Trimetoprima/farmacologia , Uracila/metabolismoRESUMO
Lipoprotein and endothelial lipases are members of the triglyceride lipase gene family. These genes are expressed in the brain, where the encoded proteins are fulfilling functions that have yet to be elucidated. In this study, we examined the distribution of their respective mRNAs in the C57BL/6 mouse brain by in situ hybridization. In control mice, we observed widespread expression of lipoprotein lipase (LPL) mRNA mainly in pyramidal cells of the hippocampus (CA1, CA2 and CA3 areas), in the striatum and in several cortical areas. Endothelial lipase (EL) mRNA expression was restricted to CA3 pyramidal cells of the hippocampus, to ependymal cells in the ventral part of the third ventricle and to some cortical cell layers. To gain insight into the role played by lipases in the brain, neurodegeneration was induced by intraperitoneal injection of kainic acid (KA) or by occlusion of the middle cerebral artery (MCA). Upon injection of KA, a rapid increase in EL mRNA expression was observed in the piriform cortex, hippocampus, thalamus and neocortex. However, the levels of LPL mRNA were unaffected by KA injection. Remarkably, after focal cerebral ischemia, the expression of EL was unaffected whereas a dramatic increase in LPL expression was observed in neocortical areas of the lesioned side of the brain. These results show that LPL and EL transcripts are selectively upregulated in function of the type of brain injury. LPL and EL could thus fulfill a function in the pathophysiological response of the brain to injury.
Assuntos
Isquemia Encefálica/enzimologia , Encéfalo/enzimologia , Regulação Enzimológica da Expressão Gênica/genética , Lipase/genética , Lipase Lipoproteica/genética , Degeneração Neural/enzimologia , Animais , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/enzimologia , Córtex Cerebral/fisiopatologia , Infarto Cerebral/enzimologia , Infarto Cerebral/fisiopatologia , Corpo Estriado/enzimologia , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/fisiopatologia , Ácido Caínico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Neurotoxinas/farmacologia , Células Piramidais/enzimologia , RNA Mensageiro/metabolismo , Tempo de Reação/fisiologia , Regulação para Cima/fisiologiaRESUMO
Injection of 10 cysts of Toxoplasma gondii (Me49 strain) into Swiss Webster mice results in 1) an acute phase of infection lasting for 2-3 wk, characterized by weight loss, and 2) a chronic phase in which surviving mice show either partial weight recovery (Gainers) or persistent, although stable, cachexia (Nongainers). In response to a second immunological stimulation with lipopolysaccharide (LPS) in the chronic phase of the infection, it is shown that 1) the increase in energy expenditure was more prolonged in both groups of infected mice than in controls, 2) the intensity and duration of hypophagia were also differently affected with Nongainers > Gainers > controls, and 3) the infected mice had higher serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10 and a lower ratio of IL-10 to TNF-alpha than controls. In contrast, serum IL-4 increased to the same level in all three groups. Evaluation of the permeability of the blood-brain barrier by intravenous injection of Evans blue revealed a marked staining in the brain of only the infected Nongainers. Taken together, these results indicate that, in mice with chronic toxoplasmosis, a second nonspecific challenge (with LPS) exacerbates the hypophagic and hypermetabolic states, the latter being associated with hyperresponsiveness in TNF-alpha and IL-10 production. Furthermore, the greater exacerbation of the hypophagic state in mice showing persistent cachexia may be due to a preexisting higher permeability of the blood-brain barrier, which would allow a greater access of plasma-borne cytokines and/or other neuroimmunologically active substances to the central nervous system.