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1.
Nature ; 617(7961): 599-607, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37138086

RESUMEN

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Vías Nerviosas , Humanos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Trombospondina 1/antagonistas & inhibidores , Gabapentina/farmacología , Gabapentina/uso terapéutico , Progresión de la Enfermedad , Cognición , Tasa de Supervivencia , Vigilia , Biopsia , Proliferación Celular/efectos de los fármacos
2.
Am J Transplant ; 22(9): 2246-2253, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35373451

RESUMEN

Thrombospondin-1 (TSP-1) is a key mediator of renal ischemia-reperfusion injury (IRI), a major cause of kidney dysfunction under various disease conditions and a risk factor of renal allograft rejection. In this study, we developed a nanotechnology-based therapy targeting TSP-1 to prevent renal IRI. A biocompatible nanoparticle (NP) capable of specific binding to TSP-1 was prepared by conjugating NPs with TSP-1-binding (LSKL) peptides. LSKL/NPs not only effectively adsorbed recombinant TSP-1 proteins in vitro, but also efficiently neutralized TSP-1 in mice undergoing renal IRI. IRI-induced elevation of TSP-1 in the kidney was significantly inhibited by post-IR treatment with LSKL/NPs, but not free LSKL or NPs. Furthermore, TSP-1 proteins adsorbed on LSKL/NPs were functionally inactive and unable to induce apoptosis in renal tubular epithelial cells. Importantly, LSKL/NPs induced strong protection against renal IRI, as shown by markedly diminished serum creatinine levels and improved histological lesions of the kidney. Thus, LSKL/NPs provide a useful means of depleting and inactivating TSP-1 and a potential therapy for renal IRI.


Asunto(s)
Trasplante de Riñón , Nanopartículas , Daño por Reperfusión , Animales , Apoptosis , Riñón/patología , Trasplante de Riñón/efectos adversos , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/metabolismo , Trombospondina 1/farmacología
3.
Int Immunopharmacol ; 96: 107618, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34015597

RESUMEN

An important factor in periodontitis pathogenesis relates to a network of interactions of various cytokines. Thrombospondin-1 (TSP-1) is upregulated in several inflammatory diseases. We previously found that Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS)-induced TSP-1 production, and that TSP-1 simultaneously and effectively elevated inflammatory cytokines in THP-1 macrophages. This suggests that TSP-1 plays an important role in the pathology of periodontitis. However, the function of TSP-1 on oral cells is largely unknown. This study aimed to elucidate the underlying molecular mechanisms of TSP-1 in human periodontal fibroblasts (hPDLFs). We demonstrated that TSP-1 is highly expressed in the gingival crevicular fluid of patients with chronic periodontitis and in the inflammatory gingival tissues of rats. TSP-1 overexpression or treatment with recombinant human TSP-1(rTSP-1) promoted the expression of MMP-2, MMP-9 and RANKL/OPG in hPDLFs, while anti-TSP-1 inhibited cytokines production from P. gingivalis LPS-treated hPDLFs. Additional experiments showed that SB203580 (a special p38MAPK inhibitor) inhibited MMP-2, MMP-9 and RANKL/OPG expression induced by rTSP-1. Thus, TSP-1 effectively promoted P. gingivalis LPS-induced periodontal tissue (extracellular matrix (ECM) and alveolar bone) destruction by the p38MAPK signalling pathway, indicating that it may be a potential therapeutic target against periodontitis.


Asunto(s)
Pérdida de Hueso Alveolar/tratamiento farmacológico , Pérdida de Hueso Alveolar/metabolismo , Matriz Extracelular/metabolismo , Periodontitis/tratamiento farmacológico , Trombospondina 1/metabolismo , Pérdida de Hueso Alveolar/patología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Encía/metabolismo , Encía/patología , Líquido del Surco Gingival/química , Líquido del Surco Gingival/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Osteoprotegerina/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Cultivo Primario de Células , Ligando RANK/metabolismo , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/genética , Regulación hacia Arriba
4.
Arterioscler Thromb Vasc Biol ; 41(1): e1-e17, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33232198

RESUMEN

OBJECTIVE: TSP-1 (thrombospondin 1) is one of the most expressed proteins in platelet α-granules and plays an important role in the regulation of hemostasis and thrombosis. Interaction of released TSP-1 with CD47 membrane receptor has been shown to regulate major events leading to thrombus formation, such as, platelet adhesion to vascular endothelium, nitric oxide/cGMP (cyclic guanosine monophosphate) signaling, platelet activation as well as aggregation. Therefore, targeting TSP-1:CD47 axis may represent a promising antithrombotic strategy. Approach and Results: A CD47-derived cyclic peptide was engineered, namely TAX2, that targets TSP-1 and selectively prevents TSP-1:CD47 interaction. Here, we demonstrate for the first time that TAX2 peptide strongly decreases platelet aggregation and interaction with collagen under arterial shear conditions. TAX2 also delays time for complete thrombotic occlusion in 2 mouse models of arterial thrombosis following chemical injury, while Thbs1-/- mice recapitulate TAX2 effects. Importantly, TAX2 administration is not associated with increased bleeding risk or modification of hematologic parameters. CONCLUSIONS: Overall, this study sheds light on the major contribution of TSP-1:CD47 interaction in platelet activation and thrombus formation while putting forward TAX2 as an innovative antithrombotic agent with high added-value.


Asunto(s)
Arteriopatías Oclusivas/prevención & control , Antígeno CD47/antagonistas & inhibidores , Fibrinolíticos/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Trombosis/prevención & control , Trombospondina 1/antagonistas & inhibidores , Animales , Arteriopatías Oclusivas/sangre , Arteriopatías Oclusivas/metabolismo , Antígeno CD47/metabolismo , Colágeno/metabolismo , Modelos Animales de Enfermedad , Fibrinolíticos/toxicidad , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Péptidos Cíclicos/toxicidad , Inhibidores de Agregación Plaquetaria/toxicidad , Ratas Sprague-Dawley , Transducción de Señal , Trombosis/sangre , Trombosis/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Factores de Tiempo
5.
Toxicol Appl Pharmacol ; 409: 115323, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33176120

RESUMEN

Acetaminophen (N-Acetyl-p-Aminophenol or APAP)-induced hepatotoxicity is the most common cause of acute liver failure in the United States and Western Europe. Previous studies have shown that TGFß1 is elevated during APAP-induced hepatotoxicity and promotes liver injury by reducing liver regeneration while inducing hepatocyte senescence. At this time, little is known about the role of proteins that activate latent TGFß1 and their effects during APAP-induced hepatotoxicity. Thrombospondin-1 (TSP1) is a homotrimeric protein that can not only activate latent TGFß1 but can also interact with other proteins including Nrf2 to induce antioxidant signaling. The aim of the current study was to assess the role of thrombospondin-1 (TSP1) in both TGFß1 activation and its contribution to APAP-induced liver injury. C57Bl/6 mice or TSP1 null mice (TSP1-/-) were administered 300 mg/kg or 600 mg/kg of APAP. TGFß1 signaling, TSP1 expression, measures of hepatic injury, Nrf2 expression, measures of oxidative/nitrosative stress and GSH metabolism were assessed. The expression of TGFß1, TSP1 and phosphorylation of SMAD proteins increased in APAP-treated mice compared to controls. TSP1-/- mice had reduced TGFß1 expression and phosphorylation of SMAD proteins but increased liver injury. Hepatocyte cell death was increased in TSP1-/- mice and this was associated with decreased Nrf2 activity, decreased GSH levels and increased oxidative stress in comparison to wild-type C57Bl/6 mice. Together, these data demonstrate that elimination of TSP1 protein in APAP-treated mice reduces TGFß1 signaling but leads to increased liver injury by reducing Nrf2 expression and GSH activity, ultimately resulting in increased cell death.


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Glutatión/metabolismo , Fallo Hepático Agudo/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Trombospondina 1/antagonistas & inhibidores , Animales , Antioxidantes/metabolismo , Muerte Celular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Fallo Hepático Agudo/inducido químicamente , Regeneración Hepática/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
6.
Am J Physiol Cell Physiol ; 319(1): C45-C63, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32374675

RESUMEN

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.


Asunto(s)
Envejecimiento/genética , Envejecimiento/metabolismo , Trombospondina 1/biosíntesis , Trombospondina 1/genética , Animales , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Daño del ADN/fisiología , Humanos , Enfermedades Musculoesqueléticas/genética , Enfermedades Musculoesqueléticas/metabolismo , Enfermedades Musculoesqueléticas/terapia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Transducción de Señal/fisiología , Trombospondina 1/antagonistas & inhibidores , Cicatrización de Heridas/fisiología
7.
J Cell Physiol ; 235(1): 364-379, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31236971

RESUMEN

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) is a profibrotic cytokine which induces mesothelial cell mesothelial-to-mesenchymal transition (MMT) and peritoneal fibrosis in patients receiving treatment of peritoneal dialysis. Because thrombospondin-1 (TSP-1) is able to activate latent TGF-ß1 in vivo, we investigated whether blockade of TSP-1 could modulate mesothelial cell MMT and ameliorate peritoneal fibrosis. METHODS: Human pleural mesothelial cells (Met-5A cells) were treated with TSP-1 and addition of TGF-ß1 neutralizing antibody to assess the effect of TSP-1 on MMT. Furthermore, TSP-1 blocking peptide Leu-Ser-Lys-Leu (LSKL) was applied to Met-5A cells treated with 4.25% d-glucose to determine its function in high glucose-induced MMT. Consequently, a uremic dialysate injection rat model was set up to confirm the results in vivo. RESULTS: Exposure of Met-5A cells to TSP-1 increased TGF-ß1 secretion, expression and bioactivity, triggered Smad3 phosphorylation, upregulated the expression of mesenchymal molecules including fibronectin, collagen type III, α-smooth muscle actin, Snail, and decreased calretinin expression. The effect was partially attenuated by TGF-ß1 neutralizing antibody. TSP-1 expression in Met-5A cells was increased by 4.25% d-glucose, followed by increased secretion and bioactivity of TGF-ß1, the onset of Smad3 phosphorylation and induction of MMT. LSKL significantly attenuated high glucose-mediated mesothelial cell MMT and ameliorated peritoneal fibrosis in uremic rats receiving dextrose dialysate injection. CONCLUSIONS: Taken together, these data demonstrated that TSP-1 contributes to mesothelial cell MMT by activating TGF-ß1/Smad3 signaling pathway and blockade of TSP-1 attenuates high glucose-mediated mesothelial cell MMT and peritoneal fibrosis.


Asunto(s)
Fibrosis Peritoneal/patología , Proteína smad3/metabolismo , Trombospondina 1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Anticuerpos Neutralizantes/farmacología , Diferenciación Celular/fisiología , Línea Celular , Regulación hacia Abajo/genética , Células Epiteliales/citología , Glucosa , Humanos , Masculino , Diálisis Peritoneal/efectos adversos , Fibrosis Peritoneal/inducido químicamente , Fibrosis Peritoneal/genética , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología
8.
Carcinogenesis ; 41(7): 950-960, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-31587040

RESUMEN

Previous research suggests that far upstream element-binding protein 1 (FUBP1) plays an important role in various tumors including epatocellular carcinoma (HCC). However, the role of FUBP1 in liver cancer remains controversial, and the regulatory pathway by FUBP1 awaits to be determined. This study aims to identify the role of FUBP1 in HCC progression. Our result shows that the high level of FUBP1 expression in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion, and metastasis by activating transforming growth factor-ß (TGF-ß)/Smad pathway and enhancing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Inhibitor of Thrombospondin-1 (LSKL) could inhibit HCC proliferation and invasion in vitro and in vivo by blocking the activation of TGF-ß/Smad pathway mediated by thrombospondin-1 (THBS1). Our study identified the critical role of FUBP1-THBS1-TGF-ß signaling axis in HCC and provides potentially new therapeutic modalities in HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Proteínas de Unión al ADN/genética , Neoplasias Hepáticas/genética , Proteínas de Unión al ARN/genética , Trombospondina 1/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Péptidos/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Smad/genética , Trombospondina 1/antagonistas & inhibidores , Análisis de Matrices Tisulares
9.
Pharmacol Res ; 149: 104475, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31593755

RESUMEN

Selenium, at high-dose levels approaching its toxicity, protects tissues from dose-limiting toxicities of many cancer chemotherapeutics without compromising their therapeutic effects on tumors, there by allowing the delivery of higher chemotherapeutic doses to achieve increased cure rate. In this regard, selenium nanoparticles (SeNPs), which show the lowest toxicity among extensively investigated selenium compounds including methylselenocysteine and selenomethionine, are more promising for application. The key issue remains to be resolved is whether low-toxicity SeNPs possess a selective protective mechanism. p53 or p53-regulated thrombospondin-1 has each been confirmed to be an appropriate target for therapeutic suppression to reduce side effects of anticancer therapy. The present study demonstrated that SeNPs transiently suppressed the expression of many intestinal p53-associated genes in healthy mice. SeNPs did not interfere with tumor-suppressive effect of nedaplatin, a cisplatin analogue; however, effectively reduced nedaplatin-evoked diarrhea. Nedaplatin-induced diarrhea was associated with activation of intestinal p53 and high expression of intestinal thrombospondin-1. The preventive effect of SeNPs on nedaplatin-induced diarrhea was correlated with a powerful concomitant suppression of p53 and thrombospondin-1. Moreover, the high-dose SeNPs used in the present study did not suppress growth nor caused liver and kidney injuries as well as alterations of hematological parameters in healthy mice. Overall, the present study reveals that chemotherapeutic selectivity conferred by SeNPs involves a dual suppression of two well-documented targets, the p53 and thrombospondin-1, providing mechanistic and pharmacologic insights on low-toxicity SeNPs as a potential chemoprotectant for mitigating chemotherapy-induced diarrhea.


Asunto(s)
Antineoplásicos/efectos adversos , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Compuestos Organoplatinos/efectos adversos , Sustancias Protectoras/uso terapéutico , Selenio/uso terapéutico , Animales , Diarrea/patología , Masculino , Ratones , Nanopartículas/uso terapéutico , Trombospondina 1/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
10.
Nat Commun ; 10(1): 1146, 2019 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-30850588

RESUMEN

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFß canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFß1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.


Asunto(s)
Neoplasias Encefálicas/genética , Antígeno CD47/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Proteína smad3/genética , Trombospondina 1/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Antígeno CD47/antagonistas & inhibidores , Antígeno CD47/metabolismo , Línea Celular Tumoral , Corteza Cerebral , Glioblastoma/irrigación sanguínea , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Captura por Microdisección con Láser , Masculino , Ratones , Ratones Noqueados , Invasividad Neoplásica , Péptidos/farmacología , Regiones Promotoras Genéticas , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína smad3/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Análisis de Supervivencia , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Mol Vis ; 24: 459-470, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30078983

RESUMEN

Purpose: Preservative-free cationic emulsion-based artificial tears (ATs) or drug vehicles are innovative eye drop formulations with tear film stabilization and drug delivery properties, and valuable in vivo anti-inflammatory and wound healing properties. These ATs have recently reached the market as ATs for the management of dry eye disease (DED) symptoms (i.e., Cationorm) or as a drug vehicle for cyclosporine (Ikervis). The aim of the present study was to explore the mechanism of action underlying the intrinsic anti-inflammatory and wound-healing efficacies harbored by the cationic emulsions of cetalkonium chloride (CE-CKC). Methods: The anti-inflammatory activity of two CE-CKC (0.002% and 0.005% CKC) emulsions was evaluated by assessing the expression of proinflammatory genes and the secretion of various markers in the following human cell types stressed by different agents: peripheral blood mononuclear cells (PBMCs; stimulation with anti-CD3/anti-CD28 or lipopolysaccharide (LPS)), CD4+ T lymphocytes (TCD4; stimulation with anti-CD3/anti-CD28), and a human corneal epithelial cell line (HCE-2; stimulation with LPS). The cells were incubated for 30 min with a 10% dilution of CE-CKC emulsions and then cultured without the emulsions for 24 h or 72 h in the presence of the various challenging agents. The supernatant was collected, and the secreted markers quantitated with flow cytometry or an enzyme-linked immunosorbent assay (ELISA). Gene expression of inflammatory markers was evaluated only in the PBMCs and HCE-2 cells stimulated with LPS. The in vitro protein kinase C (PKC) binding assay for IC50 determination was performed using standard procedures. Results: The CE-CKC emulsions decreased inflammatory gene expression in LPS-stimulated PBMCs (IFN-γ, IL-17A, CXCL-9, and TNFα) and LPS-stimulated HCE-2 cells (THBS1 and CCL2). Both CE-CKC emulsions inhibited the secretion of IL-17 (from anti-CD3/anti-CD28-stimulated TCD4), TNFα, IFN-γ, and IL-2 (from anti-CD3-/anti-CD28-stimulated PBMCs), and IL-6 and IL-8 (from LPS-stimulated HCE-2). The in vitro PKC binding assay revealed that CKC, the cationic agent, is a specific PKCα inhibitor. In addition, tyloxapol, another excipient, showed some anti-inflammatory activity on IL-6 and IL-8 in the LPS-stimulated HCE-2 cells. Conclusions: This study indicates that the CE-CKC emulsions are able to directly modulate the secretion and expression of proinflammatory cytokines and chemokines. The results also suggest that CKC and tyloxapol are pharmacologically active excipients with potentially beneficial effects in vivo. These data shed new light on the efficacy observed on the DED signs of these CE-CKC emulsions in clinical trials.


Asunto(s)
Antiinflamatorios/farmacología , Células Epiteliales/efectos de los fármacos , Alcoholes Grasos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Gotas Lubricantes para Ojos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Línea Celular , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CXCL9/antagonistas & inhibidores , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Córnea/citología , Córnea/efectos de los fármacos , Córnea/inmunología , Emulsiones , Células Epiteliales/citología , Células Epiteliales/inmunología , Humanos , Interferón gamma/antagonistas & inhibidores , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/antagonistas & inhibidores , Interleucina-8/genética , Interleucina-8/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Transducción de Señal , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/genética , Trombospondina 1/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
12.
Matrix Biol ; 68-69: 28-43, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29288716

RESUMEN

Transforming growth factor-ß (TGF-ß) is a central player in fibrotic disease. Clinical trials with global inhibitors of TGF-ß have been disappointing, suggesting that a more targeted approach is warranted. Conversion of the latent precursor to the biologically active form of TGF-ß represents a novel approach to selectively modulating TGF-ß in disease, as mechanisms employed to activate latent TGF-ß are typically cell, tissue, and/or disease specific. In this review, we will discuss the role of the matricellular protein, thrombospondin 1 (TSP-1), in regulation of latent TGF-ß activation and the use of an antagonist of TSP-1 mediated TGF-ß activation in a number of diverse fibrotic diseases. In particular, we will discuss the TSP-1/TGF-ß pathway in fibrotic complications of diabetes, liver fibrosis, and in multiple myeloma. We will also discuss emerging evidence for a role for TSP-1 in arterial remodeling, biomechanical modulation of TGF-ß activity, and in immune dysfunction. As TSP-1 expression is upregulated by factors induced in fibrotic disease, targeting the TSP-1/TGF-ß pathway potentially represents a more selective approach to controlling TGF-ß activity in disease.


Asunto(s)
Fibrosis/tratamiento farmacológico , Trombospondina 1/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Fibrosis/metabolismo , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Mieloma Múltiple/complicaciones , Mieloma Múltiple/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Trombospondina 1/antagonistas & inhibidores
13.
Clin Exp Metastasis ; 33(7): 637-49, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27349907

RESUMEN

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.


Asunto(s)
Antígeno CD47/genética , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Trombospondina 1/genética , Animales , Antígeno CD47/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Melanoma/genética , Melanoma/patología , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Metástasis de la Neoplasia , Neovascularización Patológica , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Trombospondina 1/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Melanoma Cutáneo Maligno
14.
Biol Reprod ; 94(1): 25, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26658711

RESUMEN

Thrombospondin-1 (THBS1) and transforming growth factor-beta1 (TGFB1) are specifically up-regulated by prostaglandin F2alpha in mature corpus luteum (CL). This study examined the relationship between the expression of THBS1 and TGFB1 and the underlying mechanisms of their actions in luteal endothelial cells (ECs). TGFB1 stimulated SMAD2 phosphorylation and SERPINE1 levels in dose- and time-dependent manners in luteal EC. THBS1 also elevated SERPINE1; this effect was abolished by TGFB1 receptor-1 kinase inhibitor (SB431542). The findings here further imply that THBS1 activates TGFB1 in luteal ECs: THBS1 increased the effects of latent TGFB1 on phosphorylated SMAD (phospho-SMAD) 2 and SERPINE1. THBS1 silencing significantly decreased SERPINE1 and levels of phospho-SMAD2. Lastly, THBS1 actions on SERPINE1 were inhibited by LSKL peptide (TGFB1 activation inhibitor); LSKL also counteracted latent TGFB1-induced phospho-SMAD2. We found that TGFB1 up-regulated its own mRNA levels and those of THBS1. Both compounds generated apoptosis, but THBS1 was significantly more effective (2.5-fold). Notably, this effect of THBS1 was not mediated by TGFB1. THBS1 and TGFB1 also differed in their activation of p38 mitogen-activated protein kinase. Whereas TGFB1 rapidly induced phospho-p38, THBS1 had a delayed effect. Inhibition of p38 pathway by SB203580 did not modulate TGFB1 effect on cell viability, but it amplified THBS1 actions. THBS1-stimulated caspase-3 activation coincided with p38 phosphorylation, suggesting that caspase-induced DNA damage initiated p38 phosphorylation. The in vitro data suggest that a feed-forward loop exists between THBS1, TGFB1, and SERPINE1. Indeed all these three genes were similarly induced in the regressing CL. Their gene products can promote vascular instability, apoptosis, and matrix remodeling during luteolysis.


Asunto(s)
Células Lúteas/efectos de los fármacos , Trombospondina 1/farmacología , Factor de Crecimiento Transformador beta1/fisiología , Animales , Apoptosis/efectos de los fármacos , Bovinos , Dinoprost/metabolismo , Células Endoteliales/efectos de los fármacos , Femenino , Luteólisis/efectos de los fármacos , Péptidos/farmacología , Fosforilación , Inhibidor 1 de Activador Plasminogénico/biosíntesis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteína Smad2/metabolismo , Trombospondina 1/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
15.
Oncogene ; 34(22): 2823-35, 2015 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-25109329

RESUMEN

Tumor-associated angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate here that the critical step in establishing the angiogenic capability of human tumor cells is the repression of a key secreted anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. In transformed epithelial cells, a signaling pathway leading from Ras to Tsp-1 repression induces the sequential activation of PI3 kinase, Rho and ROCK, leading to activation of Myc through phosphorylation, thereby enabling Myc to repress Tsp-1 transcription. In transformed fibroblasts, however, the repression of Tsp-1 can be achieved by an alternative mechanism involving inactivation of both p53 and pRb. We thus describe novel mechanisms by which the activation of oncogenes in epithelial cells and the inactivation of tumor suppressors in fibroblasts permits angiogenesis and, in turn, tumor formation.


Asunto(s)
Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Células Cultivadas , Regulación hacia Abajo/genética , Factor de Transcripción E2F1/fisiología , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína de Retinoblastoma/fisiología , Transducción de Señal/genética , Trombospondina 1/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/fisiología , Proteínas ras/fisiología
16.
Am J Physiol Cell Physiol ; 308(2): C111-22, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25354527

RESUMEN

Trivalent chromium (Cr(3+)) is a mineral nutrient reported to have beneficial effects in glycemic and cardiovascular health. In vitro and in vivo studies suggest that Cr(3+) supplementation reduces the atherogenic potential and lowers the risk of vascular inflammation in diabetes. However, effects of Cr(3+) in vascular cells under conditions of hyperglycemia, characteristic of diabetes, remain unknown. In the present study we show that a therapeutically relevant concentration of Cr(3+) (100 nM) significantly downregulates a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in human aortic smooth muscle cells (HASMC) stimulated with high glucose in vitro. Promoter-reporter assays reveal that this downregulation of TSP-1 expression by Cr(3+) occurs at the level of transcription. The inhibitory effects of Cr(3+) on TSP-1 were accompanied by significant reductions in O-glycosylation of cytoplasmic and nuclear proteins. Using Western blotting and immunofluorescence studies, we demonstrate that reduced protein O-glycosylation by Cr(3+) is mediated via inhibition of glutamine: fructose 6-phosphate amidotransferase, a rate-limiting enzyme of the hexosamine pathway, and O-linked N-acetylglucosamine (O-GlcNAc) transferase, a distal enzyme in the pathway that controls intracellular protein O-glycosylation. Additionally, we found that Cr(3+) attenuates reactive oxygen species formation in glucose-stimulated HASMC, suggesting an antioxidant effect. Finally, we report an antiproliferative effect of Cr(3+) that is specific for high glucose and conditions triggering elevated protein O-glycosylation. Taken together, these findings provide the first cellular evidence for a novel role of Cr(3+) to modulate aberrant vascular smooth muscle cell function associated with hyperglycemia-induced vascular complications.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Cromo/farmacología , Glucosa/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Trombospondina 1/antagonistas & inhibidores , Aorta/efectos de los fármacos , Aorta/metabolismo , Proliferación Celular/genética , Células Cultivadas , Fructosafosfatos/metabolismo , Glutamina/genética , Glicosilación/efectos de los fármacos , Hexosaminas/metabolismo , Humanos , Hiperglucemia/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , N-Acetilglucosaminiltransferasas/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/genética , Trombospondina 1/genética , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética
17.
Arterioscler Thromb Vasc Biol ; 35(2): 389-98, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25524772

RESUMEN

OBJECTIVE: Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serine-lysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-ß complex is important in regulating TGF-ß1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE(-/-)) mice. APPROACH AND RESULTS: Abdominal aortic aneurysm was established in 3-month-old male ApoE(-/-) mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucine-lysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-ß1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-ß receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-ß1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-ß1-target gene lysyl oxidase like 1 (LOXL1). CONCLUSIONS: Attenuation of thrombospondin-1-directed activation of TGF-ß1 promotes abdominal aortic aneurysm and atherosclerosis progression in the angiotensin II-infused ApoE(-/-) mouse model.


Asunto(s)
Angiotensina II , Aorta/efectos de los fármacos , Aneurisma de la Aorta Abdominal/inducido químicamente , Apolipoproteínas E/deficiencia , Aterosclerosis/inducido químicamente , Péptidos/toxicidad , Trombospondina 1/antagonistas & inhibidores , Aminoácido Oxidorreductasas/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Elastina/metabolismo , Mediadores de Inflamación/sangre , Inyecciones Intraperitoneales , Masculino , Ratones Noqueados , Péptidos/administración & dosificación , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Trombospondina 1/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/sangre
18.
Biol Reprod ; 91(3): 58, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25061096

RESUMEN

Previously, we showed luteal stage-specific regulation of angiogenesis-modulating factors by prostaglandin F2 alpha (PGF2alpha). Fibroblast growth factor 2 (FGF2) and thrombospondins (THBSs) exhibited the most divergent profile of induction by PGF2alpha. We therefore examined the transcriptional regulation and roles of THBSs in luteal cells and studied their interaction with FGF2. THBSs and their receptors exhibited cell-specific expression: THBS1 was the predominant form in luteal endothelial cells (LEC), whereas luteinized granulosa cells (LGC) expressed mostly THBS2. CD36 was confined to LGC, but CD47 did not exhibit preferential expression between LEC and LGC. THBS1 and THBS2 were both stimulated in vitro by PGF2a and its analog in LGC. In contrast, luteinizing signals (LH and insulin) decreased the expression of THBS1, THBS2, and CD36. Importantly, LH increased FGF2 expression, suggesting that THBSs and FGF2 are conversely regulated. We found that FGF2 inhibited THBS1 and vice versa, and that THBS1 treatment decreased FGF2 expression, suggesting reciprocal inhibition. In agreement, ablation of THBS1 by specific small interference RNAs elevated FGF2 levels. THBS1 reduced LEC numbers and promoted apoptosis by activation of caspase-3. In contrast, FGF2 reduced basal and THBS1-induced caspase-3 levels. Consistent with these findings, small interference RNA silencing of THBS1 in luteal cells reduced the levels of active caspase-3 and improved the survival of cells when challenged with staurosporine. Taken together, these studies suggest that THBSs are suppressed during luteinization but are induced by PGF2alpha in luteolysis. THBS1 has antiangiogenic, proapoptotic properties; these, together with its ability to inhibit FGF2 expression and activity, can promote luteolysis.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Lúteas/metabolismo , Trombospondina 1/metabolismo , Trombospondinas/metabolismo , Mataderos , Animales , Apoptosis , Biomarcadores/metabolismo , Antígenos CD36/metabolismo , Bovinos , Células Cultivadas , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Endotelina-1/metabolismo , Femenino , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factor 2 de Crecimiento de Fibroblastos/genética , Silenciador del Gen , Células de la Granulosa/citología , Células de la Granulosa/metabolismo , Insulina/metabolismo , Células Lúteas/citología , Luteinización , Hormona Luteinizante/metabolismo , Trombospondina 1/agonistas , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/genética , Trombospondinas/agonistas , Trombospondinas/genética
19.
Med Sci (Paris) ; 29(12): 1131-7, 2013 Dec.
Artículo en Francés | MEDLINE | ID: mdl-24356144

RESUMEN

Thrombospondin-1 (TSP-1) is a 450-kDa matricellar glycoprotein. By its various domains, it can interact with various partners and exhibit anti-angiogenic, pro-apoptotic and immunomodulatory activities. TSP-1 is also a major endogenous activator of the pro-fibrotic growth factor TGF-ß. In healthy adult renal parenchyma, TSP-1 expression is very scarce and limited to Bowman's capsule and interstitium. During nephropathies, many cell types can express or secrete TSP-1 (mesangial, endothelial, smooth muscle, tubular cells, podocytes and fibroblasts) depending on the nature of injury and the evolutive stage of the disease. Inhibition of the different domains of TSP-1 using specific antibodies or peptides, blockade of TSP-1 expression by antisense oligonucleotides and use of knock-out mice, allowed to identify the role of TSP-1 in various models of experimental nephropathy. All these studies demonstrated a deleterious effect of TSP-1 on renal repair by inducing TGF-ß and fibrosis, decreasing VEGF and capillary density, and enhancing inflammatory cells recruitment. Thus, TSP-1 represents a potential therapeutic target for the management of chronic kidney diseases.


Asunto(s)
Enfermedades Renales , Trombospondina 1/fisiología , Inhibidores de la Angiogénesis , Animales , Apoptosis , Modelos Animales de Enfermedad , Humanos , Inmunomodulación/fisiología , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ratones , Ratones Noqueados , Trombospondina 1/antagonistas & inhibidores , Trombospondina 1/química , Factor de Crecimiento Transformador beta/metabolismo
20.
Sci Rep ; 3: 1038, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23301159

RESUMEN

Accidental or therapeutic total body exposure to ionizing radiation has profound pathophysiological consequences including acute radiation syndrome. Currently only investigational drugs are available in case of radiological or nuclear accidents or terrorism. Lack of selective radioprotectants for normal tissues also limits the therapeutic doses that can be delivered to treat cancers. CD47 is a receptor for the secreted protein thrombospondin-1. Blockade of thrombospondin-1 or CD47 provides local radioprotection of soft tissues and bone marrow. We now report that suppression of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation. Increased survival is associated with increased peripheral circulating blood cell counts and increased proliferative capacity of bone marrow derived cells. Moreover, CD47 blockade decreased cell death while inducing a protective autophagy response in radiosensitive gastrointestinal tissues. Thus, CD47 is a new target for radiomitigation that prevents both hematopoietic and gastrointestinal radiation syndromes.


Asunto(s)
Síndrome de Radiación Aguda/tratamiento farmacológico , Síndrome de Radiación Aguda/prevención & control , Antígeno CD47/genética , Morfolinos/farmacología , Protectores contra Radiación/farmacología , Animales , Recuento de Células Sanguíneas , Médula Ósea/efectos de la radiación , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Antígeno CD47/metabolismo , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Esófago/efectos de los fármacos , Esófago/efectos de la radiación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Morfolinos/administración & dosificación , Morfolinos/uso terapéutico , Tolerancia a Radiación/efectos de los fármacos , Protectores contra Radiación/administración & dosificación , Protectores contra Radiación/uso terapéutico , Sobrevida , Trombospondina 1/antagonistas & inhibidores , Factor de Transcripción TFIIH , Factores de Transcripción/biosíntesis , Irradiación Corporal Total
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