RESUMEN
Glioma is the most common primary central nervous system tumor in adults. Aquaporin-4, as a water channel protein encoded by AQP4 in the brain, is reported to alter its aggregation status to affect plasma membrane dynamics and provide the potential for metastasis of tumor cells and components of the tumor microenvironment. We performed single-cell RNA transcriptome sequencing of 53059 cells from 13 malignant glioma samples and spotted that the expression of AQP4 differed between samples. The same result was observed in the TCGA glioma database, showing poor overall survival and poor response to chemotherapy in AQP4 overexpressed populations. Concomitant with the overexpression of AQP4, genes related to the immune system were also over-expressed, such as CD74, HES1, CALD1, and HEBP2, indicating AQP4 may relate to immune factors of tumor progression. We also found that tumor-associated macrophages tended to polarize toward M2 macrophages in the high AQP4 group. In glioblastoma samples, we examined cell status differences and identified that cell status differs according to AQP4 expression levels. Briefly, our study revealed substantial heterogeneity within malignant gliomas with different AQP4 expression levels, indicating the intricate connection between tumor cells and the tumor immune environment.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , Proteínas Gestacionales , Humanos , Adulto , Glioma/metabolismo , Neoplasias Encefálicas/patología , Macrófagos/metabolismo , Análisis de Secuencia de ARN , Microambiente Tumoral/genética , Proteínas de Unión al Hemo/genética , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/uso terapéuticoRESUMEN
Endometritis is a common inflammatory disease in uterine tissues that leads to animal infertility. Among the causes, Escherichia coli infection is one of the main reasons. Interferon-tau (IFN-τ) is the initial pregnancy signal for ruminant embryos and can induce immune tolerance in humans and other species. However, there are scarce reports on whether IFN-τ has a regulatory effect on endometrial inflammatory damage through HMGB1-NF-κB signalling. The purpose of this study was to investigate the regulatory mechanism of IFN-τ in HMGB1-NF-κB signalling in LPS-induced endometritis. ELISA and qPCR were used to detect the expression of LPS-induced pro-inflammatory cytokines in bovine endometrial epithelial cells (bEECs or BEND) under IFN-τ intervention, and the levels of HMGB1, p-IKK and p-p65 were detected by Western blotting. The nuclear translocation of NF-κB p65 was determined through immunofluorescence. In addition, bEECs were transfected with si-HMGB1 to elucidate the key role of HMGB1 and IFN-τ in the endometrial inflammatory cascade. The results indicated that IFN-τ inhibits the expression of related pro-inflammatory cytokines in an inflammatory injury model of bovine endometrial epithelial cells induced by LPS. Furthermore, experiments have proven that IFN-τ has protective effects on E. coli endotoxin-induced endometritis in mice in vivo. IFN-τ inhibited the HMGB1-NF-κB axis and significantly reduced the secretion of pro-inflammatory cytokines, the expression of HMGB1 protein and the levels of IKK and NF-κB p65 phosphorylation. In summary, our results showed that IFN-τ resists E. coli endotoxin-induced endometritis by attenuating HMGB1/NF-κB signalling.
Asunto(s)
Endometritis/metabolismo , Endometritis/prevención & control , Proteína HMGB1/biosíntesis , Interferón Tipo I/uso terapéutico , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Proteínas Gestacionales/uso terapéutico , Animales , Bovinos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endometritis/inducido químicamente , Endometritis/patología , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Endometrio/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Proteína HMGB1/antagonistas & inhibidores , Interferón Tipo I/farmacología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/antagonistas & inhibidores , Proteínas Gestacionales/farmacologíaRESUMEN
Autoimmune hepatitis (AIH) is an orphan disease characterized by an autoimmune attack against hepatocytes. The exact sequence of events that leads to a breach of tolerance is incompletely understood. Current hypotheses suggest that environmental agents such as toxins or infectious agents like viruses cause a tissue damage that initiates autoimmunity in genetically susceptible individuals. The growing knowledge of the multi-facetted immune dysregulation, which involves Th1/Th17 polarization and the suspected inability of regulatory T cells to revert autoimmunity in the otherwise tolerogenic milieu of the liver, offers multiple new therapeutic approaches and targets. Standard of care (SOC) is treatment with corticosteroids with or without azathioprine, which is sufficient to induce remission in the majority of patients. However, it rarely cures AIH or restores intrahepatic immune tolerance. Hence, life-long therapy is required in the majority of patients. In addition, several studies suggest a weakening of immune regulation mediated by intrahepatic T cells under current therapies. Furthermore, second line therapies for non-responders, intolerant or otherwise difficult to treat patients are urgently needed as this is relevant for at least one fifth of all patients with inefficacy or intolerance to SOC. Current second line therapies are mainly based on single center retrospective experiences and none of them have been approved by regulatory authorities for AIH, yet. This article highlights new therapeutic approaches based on our growing knowledge on the pathophysiology of AIH. It focuses on cell-based therapies that strengthen or restore immune tolerance. An additional focus lies on new therapeutic agents showing promising results in non-hepatic autoimmune diseases that have a potential for treating AIH. The dynamics in the whole field of innovative therapies for non-hepatic autoimmune diseases will hopefully improve the therapeutic armamentarium for AIH patients in the future.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Dieta/métodos , Hepatitis Autoinmune/terapia , Hígado/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Linfocitos T Reguladores/efectos de los fármacos , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos/biosíntesis , Azatioprina/uso terapéutico , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/inmunología , Hepatocitos/patología , Humanos , Tolerancia Inmunológica , Hígado/inmunología , Hígado/patología , Proteínas Gestacionales/uso terapéutico , Nivel de Atención , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/patologíaRESUMEN
Staphylococcus aureus (S. aureus), a significant cause of pneumonia, leads to severe inflammation. Few effective treatments or drugs have been reported for S. aureus infection. Interferon tau (IFN-τ) is a type I interferon with low cellular toxicity even at high doses. Previous studies have reported that IFN-τ could significantly mitigate tissue inflammation; however, IFN-τ treatment in S. aureus-induced pneumonia has not been well reported. Thus, the aim of this study was to identify the anti-inflammatory mechanism of IFN-τ in S. aureus-induced pneumonia in mice. A S. aureus-induced pneumonia model and RAW 264.7 cells were used in this research. The histopathological as well as lung wet to dry ratio (W/D) and myeloperoxidase (MPO) activity results showed that IFN-τ could protect the lung from S. aureus damage. In addition, ELISA and qPCR revealed that IFN-τ treatment led to a decreased expression of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in both the cells and mouse model, but IL-10 was increased. TLR2, which is involved in the response during S. aureus infection, was also down-regulated by IFN-τ treatment and directly affected NF-κB and MAPK pathway activation. Then, we examined the phosphorylation of IκBα, NF-κB p65 and MAPKs by western blotting, and the results displayed that the phosphorylation of IκBα, NF-κB p65 and MAPKs was inhibited upon IFN-τ treatment in both the cells and mouse model. These findings indicate that IFN-τ has anti-inflammatory properties in vitro and in vivo through the inhibition of NF-κB and MAPK activation, suggesting that IFN-τ may have potential as a therapeutic agent against S. aureus-induced inflammatory diseases.
Asunto(s)
Antiinflamatorios/uso terapéutico , Inmunoterapia/métodos , Interferón Tipo I/uso terapéutico , Neumonía/terapia , Proteínas Gestacionales/uso terapéutico , Infecciones Estafilocócicas/terapia , Staphylococcus aureus/inmunología , Animales , Citocinas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Neumonía/inmunología , Neumonía/microbiología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Infecciones Estafilocócicas/inmunologíaRESUMEN
Reduced first-trimester concentrations of placental protein 13 (PP13) are associated with subsequent development of preeclampsia, a major pregnancy disorder. We previously showed that PP13 has a vasodilatory effect, reduces blood pressure and augments expansive remodeling of the uteroplacental vasculature in pregnant rats. In this study, slow-release osmotic pumps were implanted in gravid rats (on day 8) to provide 1 week of PP13 supplementation. Treatment was associated with a reversible blood pressure reduction that returned to normal on day 15. In addition, PP13 caused venous expansion that is larger in the venous branches closer to the placenta. Then, it increased placental and pup weights. Similar administration of a truncated PP13 variant (DelT221) that is unable to bind carbohydrates (a rare spontaneous mutation associated with a high frequency of severe early preeclampsia among Blacks in South Africa) produced a hypotensive effect similar to the full-length molecule, but without venous remodeling and increased placental and pup weights. These results indicate the importance of PP13 carbohydrate binding for inducing vascular remodeling and improving reproductive outcome. Future studies are needed to determine whether beneficial effects would be evident in animal models of preeclampsia or in women predisposed to the development of preeclampsia.
Asunto(s)
Peso al Nacer/efectos de los fármacos , Galectinas/farmacología , Preeclampsia/genética , Proteínas Gestacionales/farmacología , Útero/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Desarrollo Fetal/efectos de los fármacos , Galectinas/genética , Galectinas/uso terapéutico , Tamaño de la Camada/efectos de los fármacos , Placenta/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Embarazo , Proteínas Gestacionales/genética , Proteínas Gestacionales/uso terapéutico , Ratas Sprague-Dawley , Útero/irrigación sanguíneaRESUMEN
OBJECTIVE: To investigate the effect of placental growth factor (PlGF) on revascularization after acute myocardial infarction. METHODS: Myocardial infarction model was established by ligation of left anterior descending coronary artery in Wistar rats. Thirty AMI rats were divided into 3 groups with 10 in each group: PlGF, mouse VEGFR-1/Flt-1 antibody, or saline (control group) was injected in the infarcted border zone for each group, respectively. Two weeks later the hemodynamics parameters were measured with a left ventricular needle catheter and a biological signal analysis system; left ventricular remodeling was observed by HE staining; angiogenesis was examined by immunohistochemistry and cardiomyocyte apoptosis rate was detected by TUNEL. RESULTS: The stroke volume, systolic pressure and left ventricular developed pressure in PlGF group were all higher than those in control group (112±7 vs 65.63±8.50 µl, P<0.01; 131.61±9.26 vs 94.84±8.53 mm Hg, P<0.01 and 175.85±11.36 vs 105.50±15.83 mm Hg, P<0.01; respectively). PlGF animals had less ventricular dilation (left ventricular diameter 8.20±0.14 vs 9.25±0.32 mm, P<0.01) and increased left ventricular wall thickness (1.81±0.10 vs 1.35±0.10 mm, P<0.01) compared to controls. The geometry parameter of anti-VEGFR1 and control animals was almost the same. PlGF animals had increased angiogenesis compared to controls (29.44±5.75 vs 15.88±2.42 endothelial cells/high-powered field, P<0.01); the alpha smooth muscle actin (α-SMA) showed that PlGF animal had a higher density of artery than others (25.14±1.83 vs 19.70±2.52 arteries/mm(2), P<0.01), and the density of artery in anti-VEFGR1 group was less than the controls. The apoptosis rate of cardiomyocytes in PlGF animals was significantly lower than that in controls (9.51%±2.75% vs 37.81%±8.74%, P<0.01). CONCLUSION: Regional delivery of PlGF following acute myocardial infarction can improve cardiac function and left ventricular remodeling, enhance angiogenesis and reduce cardiomyocyte apoptosis rate. PlGF may be a potential agent in adjuvant therapy for acute myocardial infarction.
Asunto(s)
Infarto del Miocardio/fisiopatología , Neovascularización Fisiológica/efectos de los fármacos , Proteínas Gestacionales/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Miocardio/patología , Factor de Crecimiento Placentario , Ratas , Ratas Wistar , Remodelación Ventricular/efectos de los fármacosRESUMEN
Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization.
Asunto(s)
Sistema Nervioso Central/irrigación sanguínea , Revascularización Cerebral , Péptidos y Proteínas de Señalización Intercelular/fisiología , Proteínas Gestacionales/fisiología , Animales , Vasos Sanguíneos/crecimiento & desarrollo , Vasos Sanguíneos/metabolismo , Neoplasias del Sistema Nervioso Central/etiología , Neoplasias del Sistema Nervioso Central/genética , Encefalitis/etiología , Encefalitis/genética , Femenino , Terapia Genética/métodos , Hemangioma/etiología , Hemangioma/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/genética , Factor de Crecimiento Placentario , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/efectos adversos , Factor A de Crecimiento Endotelial Vascular/genética , Factor C de Crecimiento Endotelial Vascular/efectos adversos , Factor C de Crecimiento Endotelial Vascular/genéticaRESUMEN
Placental growth factor (PlGF) has a distinct biological phenotype with a predominant proangiogenic role in disease without affecting quiescent vessels in healthy organs. We tested whether systemic administration of recombinant human (rh)PlGF improves regional myocardial blood flow (MBF) and systolic function recovery in a porcine chronic myocardial ischemia model. We implanted a flow-limiting stent in the proximal left anterior descending coronary artery and measured systemic hemodynamics, regional myocardial function using MRI, and blood flow using colored microspheres 4 wk later. Animals were then randomized in a blinded way to receive an infusion of rhPlGF (15 µg·kg(-1)·day(-1), n = 9) or PBS (control; n = 10) for 2 wk. At 8 wk, myocardial perfusion and function were reassessed. Infusion of rhPlGF transiently increased PlGF serum levels >30-fold (1,153 ± 180 vs. 33 ± 18 pg/ml at baseline, P < 0.001) without affecting systemic hemodynamics. From 4 to 8 wk, rhPlGF increased regional MBF from 0.46 ± 0.11 to 0.85 ± 0.16 ml·min(-1)·g(-1), with a concomitant increase in systolic wall thickening from 11 ± 3% to 26 ± 5% in the ischemic area. In control animals, no significant changes from 4 to 8 wk were observed (MBF: 0.45 ± 0.07 to 0.49 ± 0.08 ml·min(-1)·g(-1) and systolic wall thickening: 14 ± 4% to 18 ± 1%). rhPlGF-induced functional improvement was accompanied by increased myocardial neovascularization, enhanced glycogen utilization, and reduced oxidative stress and cardiomyocyte apoptosis in the ischemic zone. In conclusion, systemic rhPlGF infusion significantly enhances regional blood flow and contractile function of the chronic ischemic myocardium without adverse effects. PlGF protein infusion may represent an attractive therapeutic strategy to increase myocardial perfusion and energetics in chronic ischemic cardiomyopathy.
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Proteínas Gestacionales/uso terapéutico , Animales , Apoptosis , Glucógeno/metabolismo , Ventrículos Cardíacos/patología , Hemodinámica/efectos de los fármacos , Imagen por Resonancia Magnética , Isquemia Miocárdica/fisiopatología , Revascularización Miocárdica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/fisiología , Estrés Oxidativo , Factor de Crecimiento Placentario , Proteínas Gestacionales/sangre , Flujo Sanguíneo Regional/efectos de los fármacos , Sus scrofa , Disfunción Ventricular/tratamiento farmacológicoRESUMEN
I developed a passion for reproductive biology when taking a course in Physiology of Reproduction at Louisiana State University while preparing to apply for Veterinary School at Texas A&M University. My career path changed. I entered graduate school, obtained a Ph.D. and have enjoyed an academic career conducting research in uterine biology and pregnancy in animal science departments at the University of Florida and at Texas A&M University. My contributions to science include: (1) identification of molecules secreted by or transported by uterine epithelia into the uterine lumen that are critical to successful establishment and maintenance of pregnancy, (2) discovery of steroids and proteins required for pregnancy-recognition signalling and their mechanisms of action in pigs and ruminants, (3) patterns of fetal-placental development and placental transport of nutrients, (4) identification of links between nutrients and components of histotroph that affect fetal-placental development, (5) characterising aspects of the endocrinology of pregnancy and (6) contributing to efforts to exploit the therapeutic value of interferon tau, particularly for treatment of autoimmune and inflammatory diseases. Current research focuses on select nutrients in the uterine lumen, specifically amino acids, glucose and fructose, that affect conceptus development, the therapeutic potential for interferon tau, stromal-epithelial cell signalling whereby progesterone and oestrogen act via steroid receptors in uterine stromal cells to stimulate secretion of growth factors (e.g. fibroblast growth factors and hepatocyte growth factor) that regulate uterine epithelial cells and conceptus trophectoderm, and roles of toll-like receptors expressed by uterine epithelia and conceptus trophectoderm in pregnancy.
Asunto(s)
Endocrinología/historia , Desarrollo Fetal , Embarazo/fisiología , Reproducción , Útero/fisiología , Medicina Veterinaria/historia , Ciencias de la Nutrición Animal/historia , Animales , Antivirales/metabolismo , Antivirales/uso terapéutico , Implantación del Embrión , Endometrio/metabolismo , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Interferón Tipo I/metabolismo , Interferón Tipo I/uso terapéutico , Mantenimiento del Embarazo , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/uso terapéutico , Estados UnidosRESUMEN
In this study, the antiviral effects of bovine interferon-tau (boIFN-tau) on bovine viral diarrhea virus (BVDV) were examined in vitro and in vivo. In the in vitro experiments, the replication of cytopathic and non-cytopathic BVDV was inhibited in the bovine cells treated with boIFN-tau. The replication of BVDV was completely suppressed by boIFN-tau at a concentration higher than 10(2) U/ml. In order to examine the effect of boIFN-tau on virus propagation in cattle persistently infected (PI) with non-cytopathic BVDV, boIFN-tau was subcutaneously administered to PI cattle at 10(5) U/kg or 10(6) U/kg body weight 5 times per week for 2 weeks. No physical abnormality such as depression was observed in the cattle during the experiment. The mean BVDV titers in the serum of the PI cattle decreased slightly during the boIFN-tau administration period with the dose of 10(6) U/kg. However, the BVDV titers in the serum returned to the pre-administration level after the final boIFN-tau administration. These results suggest that boIFN-tau demonstrates an anti-BVDV effect, reducing the BVDV level in serum transiently when injected into PI cattle.
Asunto(s)
Antivirales/farmacología , Diarrea Mucosa Bovina Viral/virología , Virus de la Diarrea Viral Bovina/efectos de los fármacos , Interferón Tipo I/farmacología , Proteínas Gestacionales/farmacología , Carga Viral/efectos de los fármacos , Animales , Antivirales/uso terapéutico , Diarrea Mucosa Bovina Viral/tratamiento farmacológico , Bovinos , Virus de la Diarrea Viral Bovina/crecimiento & desarrollo , Virus de la Diarrea Viral Bovina/aislamiento & purificación , Femenino , Interferón Tipo I/uso terapéutico , Proteínas Gestacionales/uso terapéutico , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Placental growth factor (PlGF) is an angiogenic factor that belongs to the vascular endothelial growth factor (VEGF) family. Besides its well known capacity to potentiate the angiogenic action of VEGF, PlGF also participates in inflammatory processes by attracting and activating monocytes; it plays therefore more specifically a role in pathological conditions. PIGF and its two receptors, VEGFR-1 and neuropilins (NRPs), are expressed in the brain and increase after experimental stroke, but their precise functions in the nervous system remain underexplored. In this review article, we summarize present knowledge on the role of PlGF in various nervous system disease processes. Given the available data, P1GF has neuroprotective and neurotrophic properties that make it an actor of considerable interest in the pathophysiology and potentially in the therapy of degenerative and traumatic brain or spinal cord diseases.
Asunto(s)
Enfermedades del Sistema Nervioso/tratamiento farmacológico , Neurología , Neuroprostanos/uso terapéutico , Proteínas Gestacionales/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Modelos Biológicos , Enfermedades del Sistema Nervioso/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Neuroprostanos/metabolismo , Factor de Crecimiento Placentario , Proteínas Gestacionales/química , Proteínas Gestacionales/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
Interferon-tau (IFN-tau) was initially identified as an ovine pregnancy protein. Produced by the trophoblast, it is important in preventing degradation of the corpus luteum and has been used as an early marker for ovine pregnancy. As a member of the family of type I interferons, IFN-tau has demonstrated promising antiviral activity against human viral infections in vitro. Additionally, it displays high species cross-reactivity despite its absence in humans. To date, IFN-tau has shown efficacy in reducing replication of human immunodeficiency virus, feline immunodeficiency virus, and human papillomavirus. While IFN-tau shares similar antiviral activity to IFN-alpha, the current interferon of choice for treatment of viral infections, it lacks the associated toxicity. This may make IFN-tau an attractive alternative to IFN-alpha for the treatment of viral infections.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH/fisiología , Virus de la Inmunodeficiencia Felina/fisiología , Interferón Tipo I/farmacología , Papillomaviridae/fisiología , Animales , Biomarcadores/metabolismo , Gatos , Reacciones Cruzadas/inmunología , Femenino , VIH/efectos de los fármacos , Infecciones por VIH/virología , Humanos , Virus de la Inmunodeficiencia Felina/efectos de los fármacos , Interferón Tipo I/metabolismo , Interferón Tipo I/uso terapéutico , Papillomaviridae/efectos de los fármacos , Embarazo , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/farmacología , Proteínas Gestacionales/uso terapéutico , Ovinos , Trofoblastos/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
In vitro differentiated CD8(+) T cells have been the primary focus of immunotherapy of cancer with little focus on CD4(+) T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4(+) T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8(+), B, natural killer (NK), and NKT cells. Proper activation of CD4(+) T cells in vivo was important for tumor clearance, as naive tumor-specific CD4(+) T cells could not completely treat tumor in lymphopenic common gamma chain (gamma(c))-deficient hosts. gamma(c) signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4(+) T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4(+) T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Melanoma/inmunología , Melanoma/patología , Traslado Adoptivo/métodos , Animales , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diferenciación Celular , Humanos , Inmunoterapia Adoptiva , Interferón Tipo I/inmunología , Interferón Tipo I/uso terapéutico , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Proteínas Gestacionales/inmunología , Proteínas Gestacionales/uso terapéuticoRESUMEN
Hypoxic ischemia (HI) in neonates causes significant neurodevelopmental sequelae. Pharmacological agents designed to target specific transcription factors expressed in neurons and vasculature may provide powerful therapy against HI. Vascular endothelial growth factor-A (VEGF-A) and cAMP response element-binding protein (CREB) both underlie learning and memory, and survival of the nervous system. We examined whether CREB activation is a shared pathway underlying VEGF-A's protection in neurons and cerebral vascular endothelial cells. VEGF-A was used in a HI model of rat pups and in oxygen-glucose-deprivation (OGD) models of immortalized H19-7 neurons and b.End3 cerebral vascular endothelial cells. We found that VEGF-A activated VEGF receptor-2 (VEGFR-2), phosphorylated CREB in neurons and endothelial cells, and protected against HI, and inhibiting VEGFR-2 before VEGF-A reduced the protective effect of VEGF-A in rat pups. VEGF-A also up-regulated VEGFR-2 and phosphorylated CREB, and protected H19-7 neurons and b.End3 endothelial cells against OGD. Inhibiting VEGFR-2 and extracellular signal-regulated kinase (ERK), respectively, reduced VEGF-A-induced CREB phosphorylation and protection of H19-7 and b.End3 cells against OGD. Transfecting H19-7 and b.End3 cells with a serine-133 phosphorylation mutant CREB also inhibited VEGF-A's protection of both types of cells. We conclude that CREB phosphorylation through VEGFR-2/ERK signaling is the shared pathway that underlies VEGF-A's protection of neurons and vascular endothelial cells.
Asunto(s)
Proteína de Unión a CREB/metabolismo , Células Endoteliales/efectos de los fármacos , Hipoxia-Isquemia Encefálica/prevención & control , Neuronas/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Animales Recién Nacidos , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Lesiones Encefálicas/prevención & control , Proteína de Unión a CREB/genética , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Glucosa/deficiencia , Hipoxia/patología , Hipoxia-Isquemia Encefálica/patología , Indoles/farmacología , Indoles/uso terapéutico , Inyecciones Intraventriculares/métodos , Masculino , Morfolinas/farmacología , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Factor de Crecimiento Placentario , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Gestacionales/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Ratas , Ratas Sprague-Dawley , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección/métodos , Regulación hacia Arriba/fisiología , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy.
Asunto(s)
Neoplasias Pulmonares/irrigación sanguínea , Proteínas Gestacionales/uso terapéutico , Animales , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/tratamiento farmacológico , Humanos , Ratones , Neovascularización Patológica/patología , Pericitos/citología , Pericitos/patología , Pericitos/fisiología , Factor de Crecimiento Placentario , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor C de Crecimiento Endotelial Vascular/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
Coronary artery and peripheral vascular disease are global health concerns with limited therapies. Currently available medical and surgical therapies for these disease processes are highly effective for only a fraction of patients. Extensive effort has been devoted to finding molecular therapies to enhance perfusion and function of ischemic myocardial and peripheral skeletal muscle. Angiogenic cytokines (fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], placental growth factor, stromal cell-derived factor-1alpha) have shown theoretical and experimental promise in upregulating endogenous endothelial progenitor cell-mediated angiogenesis. Preliminary clinical trials have suggested improvements in myocardial and peripheral perfusion following therapy with FGF, VEGF, and HGF. Further studies on the efficacy of cytokine-mediated angiogenesis are required before widespread clinical application is possible. Investigation into adjunctive cytokine therapies for myocardial and peripheral muscle ischemia is warranted. Based on experimental evidence, appropriate angiogenic cytokine therapy should provide benefits in both perfusion and hemodynamic function.
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Inductores de la Angiogénesis/uso terapéutico , Enfermedades Cardiovasculares/terapia , Citocinas/uso terapéutico , Animales , Quimiocina CXCL12/uso terapéutico , Factores de Crecimiento de Fibroblastos/uso terapéutico , Factor de Crecimiento de Hepatocito/uso terapéutico , Humanos , Revascularización Miocárdica , Factor de Crecimiento Placentario , Proteínas Gestacionales/uso terapéutico , Trasplante de Células Madre , Ingeniería de Tejidos , Factor A de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
Interferon-alpha (IFN-alpha) inhibits the development of diabetes in animal models of autoimmune diabetes. However, the mechanism of the action is not fully understood and drug toxicity could limit its potential clinical utility. Interferon-tau (IFN-tau) is another type 1 interferon, which has less toxicity but may have different biologic activity than IFN-alpha. This study explores the effect of IFN-tau on the diabetic process in non-obese diabetic (NOD) mice. IFN-tau by intraperitoneal, subcutaneous, or oral routes of administration decreased the development of spontaneous diabetes in NOD mice. Islet inflammation was decreased 50%. IFN-tau administration to recipient mice prevented the development of passively transferred and cyclophosphamide accelerated diabetes. IFN-tau treatment also decreased anti-islet effector activity of NOD splenic cells. Immunoregulatory activity of splenic cells was augmented by IFN-tau administration as was the number of splenic CD25+CD4+ cells. Concanavalin A (Con A)-induced release of IFN-gamma was decreased in spleen cells from IFN-tau treated mice. In conclusion, IFN-tau inhibits spontaneous autoimmune diabetes and passively transferred diabetes in the NOD mouse. This diabetes sparing activity may be due to an induction of regulatory cells, possibly CD25+CD4+ T cells, which in turn inhibit anti-islet effector cell activity and the development of insulitis and diabetes. Due to the lower drug toxicity, IFN-tau could be a better drug candidate than IFN-alpha for experimental clinical trials.
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Células Dendríticas/inmunología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Proteínas Gestacionales/uso terapéutico , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Ciclofosfamida/farmacología , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Modelos Animales de Enfermedad , Femenino , Inmunosupresores/farmacología , Interferón Tipo I/administración & dosificación , Interferón Tipo I/farmacología , Interferón gamma/biosíntesis , Islotes Pancreáticos/inmunología , Ratones , Ratones Endogámicos NOD , Proteínas Gestacionales/administración & dosificación , Proteínas Gestacionales/farmacología , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismoRESUMEN
The antiviral effects of recombinant bovine interferon-tau (rboIFN-tau) on bovine leukemia virus (BLV) were examined in vitro and in vivo. In the in vitro experiments, BLV titers decreased in FLK-BLV cells and in peripheral blood mononuclear cells of BLV-infected cattle treated with rboIFN-tau at a concentration higher than 10(2) U/ml. In order to examine the in vivo effects of rboIFN-tau, 10 BLV-infected cattle were subcutaneously injected with rboIFN-tau. In the first experiment, 6 cows were administrated with 10(5) U/kg body weight of rboIFN-tau 3 times per week for 4 weeks, while in the second experiment 4 cows were administrated with 10(6) U/kg body weight of rboIFN-tau 3 times per week for 3 weeks. No adverse effects were observed after the administration of rboIFN-tau. In experiment No. 1, the mean BLV titers in cattle decreased in the post-rboIFN-tau administration period compared to the pre-rboIFN-tau administration period. In experiment No. 2, the mean BLV titers in cattle decreased in the rboIFN-tau administration period. These results suggest that rboIFN-tau decreases BLV titers in vitro and in vivo and that rboIFN-tau possibly reduces the degree of BLV titer in cattle without severe side effects.
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Antivirales/farmacología , Antivirales/uso terapéutico , Leucosis Bovina Enzoótica/tratamiento farmacológico , Interferón Tipo I/farmacología , Interferón Tipo I/uso terapéutico , Virus de la Leucemia Bovina/efectos de los fármacos , Proteínas Gestacionales/farmacología , Proteínas Gestacionales/uso terapéutico , Animales , Bovinos , Línea Celular , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo/veterinaria , Células Gigantes/efectos de los fármacos , Proteínas RecombinantesRESUMEN
BACKGROUND: Heart failure occurs predominantly due to coronary artery disease and may be amenable to novel revascularization therapies. This study evaluated the effects of placental growth factor (PlGF), a potent angiogenic agent, in a rat model of ischemic cardiomyopathy. METHODS: Wistar rats underwent high proximal ligation of the left anterior descending coronary artery and direct injection of PlGF (n = 10) or saline as a control (n = 10) into the myocardium bordering the ischemic area. After 2 weeks, the following parameters were evaluated: ventricular function with an aortic flow probe and a pressure/volume conductance catheter, left ventricular (LV) geometry by histology, and angiogenesis by immunofluorescence. RESULTS: PlGF animals had increased angiogenesis compared to controls (22.8 +/- 3.5 vs. 12.4 +/- 3.2 endothelial cells/high-powered field, p < 0.03). PlGF animals had less ventricular cavity dilation (LV diameter 8.4 +/- 0.2 vs. 9.2 +/- 0.2 mm, p < 0.03) and increased border zone wall thickness (1.85 +/- 0.1 vs. 1.38 +/- 0.2 mm, p < 0.03). PlGF animals had improved cardiac function as measured by maximum LV pressure (95.7 +/- 4 vs. 73.7 +/- 2 mmHg, p = 0.001), maximum dP/dt (4206 +/- 362 vs. 2978 +/- 236 mmHg/sec, p = 0.007), and ejection fraction (25.7 +/- 2 vs. 18.6 +/- 1%, p = 0.02). CONCLUSIONS: Intramyocardial delivery of PlGF following a large myocardial infarction enhanced border zone angiogenesis, attenuated adverse ventricular remodeling, and preserved cardiac function. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.
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Inductores de la Angiogénesis/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Isquemia Miocárdica/tratamiento farmacológico , Proteínas Gestacionales/uso terapéutico , Inductores de la Angiogénesis/administración & dosificación , Animales , Gasto Cardíaco , Cardiomiopatías/fisiopatología , Inyecciones , Masculino , Isquemia Miocárdica/fisiopatología , Miocardio , Neovascularización Fisiológica/efectos de los fármacos , Factor de Crecimiento Placentario , Proteínas Gestacionales/administración & dosificación , Ratas , Ratas Wistar , Función Ventricular/efectos de los fármacosRESUMEN
Newborn calves received a low dose of bovine interferon-tau (boIFN-tau) orally for 4 weeks and calves that had developed diarrhea received a low dose of boIFN-tau orally for 5 days. No effects of boIFN-tau were seen in the duration of the diarrhea, or in daily weight gain. Calves received a high dose of boIFN-tau subcutaneously 3 times and they were then stimulated with bovine herpesvirus type 1 vaccine. No adverse effects were observed after the administration of boIFN-tau and lymphocyte subsets from calves did not change after the stimulation. Our results suggest that boIFN-tau does not seem protecting for preventing calves from diarrhea, recovering the health of calves with diarrhea or immunomodulation, although the treatment itself is not toxic.