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Background: Fracture nonunion is a major concern among an orthopaedic patient population, especially in those who have sustained traumatic fractures involving the tibia. Strong risk factors for nonunion include age, smoking history, and a poor diet. The incidence of nonunion also increases with each additional failed surgical intervention. Methods: Our retrospective case study involved 56-year-old woman with a history of chronic low back pain, osteopenia, malnutrition, smoking, marijuana use, and alcohol use, who presented with a proximal tibia fracture after a fall, initial treatment included temporization with multiplanar external fixation and subsequent internal fixation. Five weeks later, she presented with atrophic nonunion. She subsequently underwent multiple unsuccessful surgeries to address her nonunion, including open repair with bone grafting and multiplanar external fixation for bone transport. Ultimately, the nonunion was addressed by proximal tibia replacement with megaprosthesis with excellent clinical results. Results and conclusion: Replacement of a proximal tibia with megaprosthesis is a viable option for limb salvage, especially when all alternative treatments have been unsuccessful.
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CASE: We present a case of a female athlete who sustained a nonunion of a tibial stress fracture and was treated with intramedullary nailing (IMN). The patient developed osteomyelitis likely secondary to a thermal osteonecrosis during the index procedure and required resection of the necrotic tibia and bone transport using the Ilizarov technique. CONCLUSIONS: The authors believe that all actions should be taken to avoid thermal osteonecrosis during reaming for tibial IMN, especially in patients with a small medullary canal. We believe that bone transport with the Ilizarov technique is an effective treatment method for patients who develop tibial osteomyelitis after treatment of tibial shaft fractures.
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Fijación Intramedular de Fracturas , Fracturas por Estrés , Fracturas no Consolidadas , Osteonecrosis , Fracturas de la Tibia , Humanos , Femenino , TibiaRESUMEN
INTRODUCTION: Geriatric patients represent 14% of acetabular fractures and are the fastest growing subset of patients affected by this injury in the US. Treatment outcomes have been reported as inferior to those achieved in younger patients after high-energy (HE) acetabular trauma. This study aimed to compare detailed demographic characteristics and clinical outcomes in elderly patients (≥65 years of age) treated in a tertiary North American trauma center for acetabular fractures after both high- and low-energy mechanisms of injury. METHODS: Patients (≥65 years of age) diagnosed with an acetabular fracture were identified over a 7-year period. Patient and injury characteristics were extracted from our institutional trauma database. Length of stay, intervention, operative details, disposition, complications, readmissions, and mortality were analyzed. RESULTS: One hundred nine patients were identified for inclusion. Low-energy mechanisms (simple falls) were found in 64 (58.7%) and HE mechanisms in 45 (41.3%) patients. The HE cohort was younger (74.6 vs 80.7 years; P < .001), had a higher male predominance (76% vs 56%; P = .10), a lower Charlson comorbidity index (1.29 ± 1.49 vs 2.16 ± 1.76; P = .01), and a higher injury severity score (19.90 ± 15.33 vs 6.46 ± 3.57; P < .001). Fracture patterns, described according to the Letournel-Judet classification, were similar between the 2 groups. Thirty-day mortality was significantly higher in the HE group (26.7% vs 3.1%; P < .001); however, the 1-year mortality rates were not statistically different (31.1% vs 25.0%; P = .20). DISCUSSION: Patients with acetabular fractures sustained due to HE accidents demonstrate significantly higher 30-day mortality rate than patients with low-energy fractures, but similar mortality 1 year after the injury, despite having a much lower mean age and fewer comorbidities. CONCLUSION: Medical efforts made during initial hospital admission may have the biggest impact on survivorship following acetabular fracture.
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Open reduction and internal fixation has become a reliable technique to treat complex middle-third clavicle fractures (AO/OTA B-15). Nonoperative treatment of these fractures may result in higher rates of symptomatic malunion, nonunion, dissatisfaction with cosmetic appearance, and even dysfunction and muscular weakness. Risk factors such as substantial displacement or comminution, far lateral fractures, fractures in the elderly, open fractures, or those occurring in polytrauma scenarios are appropriate indications for surgery. The aim of the procedure is to reconstitute the initial curvature and length of the clavicle, restore a normal connection from the arm to the axial skeleton, and provide stable fixation of the proximal and distal fragments, to allow an immediate full range of motion during rehabilitation. The procedure includes the following steps. Step 1: Place the patient in a beach-chair, semi-sitting position.Step 2: Make a transverse skin incision along the anteroinferior aspect of the clavicle.Step 3: Expose the fracture site, identify and prepare the fragments unless they are comminuted, and preserve soft-tissue attachments to the extent possible.Step 4: Reduce the fragments by direct or indirect manipulation, and maintain the reduction with clamps, Kirschner wires, or mini-fragment plates. Consider bridging comminuted zones to allow secondary fracture-healing.Step 5: Apply a contoured plate to the superior or anterior surface of the clavicle, and obtain at least 6 cortices of fixation on each side with strategic nonlocking and locking screws. The working length of the plate is more important than the number of screws or cortices.Step 6: Obtain a single intraoperative anteroposterior radiograph of the clavicle.Step 7: Separately close the wound in layers (deltotrapezial fascia, platysma, and skin). Apply sterile dressings and a sling. The patient is discharged home on the same day if the injury is isolated, and a full range of motion of the affected shoulder is allowed immediately. The patient is expected to regain full function and strength of the arm once healing occurs.
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INTRODUCTION: An alternative method to external fixation for the treatment of unstable anterior pelvic ring injuries, termed the pelvic bridge technique, provides equivalent results with fewer complications and is performed using occipital cervical rods subcutaneously, with fixation into the iliac wings and parasymphyseal bone. STEP 1 PREOPERATIVE PLANNING: For preoperative planning, review the appropriate imaging, including radiographs and computed tomography (CT) scans, to mesh the findings on imaging to the clinical picture of the patient and ensure that the patient meets operative criteria and that none of the contraindications are present. STEP 2 PATIENT POSITIONING: Position the patient to facilitate anterior and posterior fixation. STEP 3 APPROACH: Make the incisions necessary to expose the osseous contour where fixation will be utilized. STEP 4 CONTOURING THE PLATE-ROD CONSTRUCT: Carefully contour the plate-rod construct, which is necessary to minimize postoperative complications. STEP 5 PASSING THE PLATE-ROD CONSTRUCT: Use care when inserting the rod as doing so will help to avoid neurovascular complications. STEP 6 ACHIEVING ADEQUATE REDUCTION: To recreate pelvic stability, the pelvic ring needs to heal in as close to anatomic position as possible and there are multiple methods that help to obtain an adequate reduction. STEP 7 FRACTURE FIXATION: Multiple constructs may be used to stabilize the anterior pelvic ring, but the fundamental principle is to attach the 2 hemipelves to achieve stability, and the location where fixation can be achieved depends on the fracture pattern. STEP 8 WOUND CLOSURE: Ensure meticulous closure to reduce the chance of infection and achieve appropriate soft-tissue coverage over hardware. STEP 9 REHABILITATION: Early mobilization is a fundamental goal of this procedure, but the time to full weight-bearing is dependent on fracture characteristics and healing. RESULTS: Anterior pelvic internal fixation (APIF) using the pelvic bridge technique has been demonstrated to have significantly fewer complications than APEF2.
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Pelvic fractures are usually the result of high-energy trauma. In addition to the underlying disruption of the pelvic ring extensive damage to the surrounding soft tissue envelope might be present. Different fixation techniques have been developed including open plating, external fixation and transramus intraosseous screw fixation. Recently another method has been reported the so called pelvic Bridge or Infix technique. In this short review article the different techniques of pelvic fixation are described.
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Fijación Interna de Fracturas/métodos , Fracturas Óseas/cirugía , Huesos Pélvicos/lesiones , Huesos Pélvicos/cirugía , Fenómenos Biomecánicos , Placas Óseas , Tornillos Óseos , Fijación Interna de Fracturas/instrumentación , Curación de Fractura , Fracturas Óseas/patología , Humanos , Procedimientos Quirúrgicos Mínimamente Invasivos , Satisfacción del Paciente , Huesos Pélvicos/patología , Resultado del Tratamiento , Soporte de PesoRESUMEN
PURPOSE: This study was conducted to assess whether a single-row suture anchor repair of a bony Bankart lesion comprising 19% of the glenoid length restores peak translational force and glenoid depth compared with the intact shoulder. METHODS: Nine thawed adult cadaveric shoulders were dissected and mounted in 45° of abduction and 30° of external rotation. A bony Bankart lesion was simulated with an anterior longitudinal osteotomy, parallel to the superoinferior axis of the glenoid, equivalent to 19% of the glenoid length. The humeral head was displaced 10 mm anteriorly at a speed of 2 mm/s with a 50-N compressive load applied. Testing was performed with the glenoid intact, a simulated lesion, and the lesion repaired with 3 single-row suture anchors. Median (interquartile range [IQR]) peak translational force and glenoid depth were reported. The Friedman test and post hoc comparisons with the Wilcoxon signed rank test were used for between-group analyses. RESULTS: Peak translational force decreased after osteotomy (13.7 N; IQR, 9.6 to 15.5 N; P = .01) and increased after the repair (18.3 N; IQR, 18.3 to 20.6 N; P = .01) compared with the intact shoulder (23.7 N; IQR, 16.4 to 29.9 N). Glenoid depth significantly decreased after the osteotomy (0.2 mm; IQR, -0.6 to 0.7 mm) compared with baseline (1.7 mm; IQR, 1.3 to 2.0 mm; P = .01) and increased after repair (0.8 mm; IQR, 0.1 to 1.0 mm; P = .03) compared with the osteotomized shoulder. The glenoid depth of the repair was less than the baseline value (P = .01). CONCLUSIONS: Repair of an anterior bony Bankart lesion equivalent to 19% of the glenoid length with 3 suture anchors restored the peak translational force needed to anteriorly displace the humerus relative to the glenoid; however, this technique failed to restore the natural glenoid depth in a laboratory setting. CLINICAL RELEVANCE: Our findings describe the inability of a single-row suture anchor repair to provide anatomic fixation of the bony Bankart lesion equivalent to 19% of the glenoid length.
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Fracturas del Hombro/cirugía , Lesiones del Hombro , Anclas para Sutura , Anciano , Anciano de 80 o más Años , Fenómenos Biomecánicos , Cadáver , Femenino , Humanos , Cabeza Humeral , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/cirugía , Masculino , Persona de Mediana Edad , Osteotomía/métodos , Rotación , Luxación del Hombro/cirugía , Fracturas del Hombro/fisiopatología , Articulación del Hombro/cirugíaRESUMEN
CONTEXT: Inhibition of pathological angiogenesis. OBJECTIVE: Obtaining new transactivator, bifunctional, thyroid antagonist, non-toxic anti-angiogenic compounds. MATERIALS AND METHODS: In silico drug design, synthesis in bulk and biological evaluation in chick chorioallantoic membrane (CAM) model. RESULTS: Significant inhibition (range 65-73%) at 0.25-2.0 µg/ml doses. DISCUSSION AND CONCLUSION: The synthesis of compounds (9), (10), and (11) incorporating long-chain moieties guanidine, urea, methyl amine and, propyl amine substitutions, respectively, into the core molecular framework of tetrac (tetraiodothyroacetic acid) were undertaken. The evaluation of the anti-angiogenic bioactivity of these compounds in the CAM model revealed no loss of activity in comparison with tetrac and XT199, which showed nearly 86% inhibition at dose levels of 1 and 0.5 µg/ml, respectively, and validated the concept.
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Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Integrina alfaVbeta3/antagonistas & inhibidores , Glándula Tiroides/efectos de los fármacos , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Pollos , Relación Dosis-Respuesta a Droga , Huevos , Modelos Moleculares , Estructura MolecularRESUMEN
Novel thyroxine analogs with hindered phenol, amino and carboxylic acid groups have been synthesized and the effects of the synthesized compounds on angiogenesis using the chick chorioallantoic membrane and mouse matrigel models have been tested. Pharmacological profiles revealed that thyroxine tolerates numerous modifications on the amino group and remains active. These results provide the rationale for the selection of a novel thyroxine nanoparticle precursor.
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Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Tiroxina/síntesis química , Tiroxina/farmacología , Animales , Embrión de Pollo , Ratones , Modelos Moleculares , Tiroxina/análogos & derivadosRESUMEN
BACKGROUND: Tetraiodothyroacetic acid (tetrac) is a deaminated analogue of L-thyroxine that blocks the actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine at the cell surface receptor for thyroid hormone on integrin alpha v beta 3. Tetrac blocks the proliferative effects of thyroid hormone on tumor cells and the proangiogenesis actions of the hormone. In the absence of thyroid hormone, tetrac also blocks angiogenesis induced by various growth factors. Covalently linked to poly(lactide-co-glycolide), tetrac nanoparticles (tetrac NP) do not gain access to the cell interior and act exclusively at the integrin receptor. Here, the activity of tetrac and tetrac NP against follicular thyroid carcinoma (FTC)-236 cells was studied in two models: (1) tumor cell implants in the chick chorioallantoic membrane (CAM) system and (2) xenografts in the nude mouse. METHODS: FTC-236 cells (10(6)) were implanted in the CAM (n = 8 each for control, and for tetrac and tetrac NP, both at 1 microg/CAM) and the actions of tetrac and tetrac NP were determined after 8 days on tumor-related angiogenesis and tumor growth. Xenografts of 10(7) FTC-236 cells were implanted in nude mice (n = 8 per group). Tetrac or tetrac NP was administered intraperitoneal (1 mg/kg and 1 mg tetrac equivalent/kg, respectively) every other day for 32 days beginning on day 10, when tumor volume was 200-250 mm(3). Animals were monitored after discontinuation of treatment up to day 40. RESULTS: In the CAM paradigm, tetrac and tetrac NP arrested tumor-related angiogenesis and tumor growth. In the xenograft model, tetrac and tetrac NP promptly and progressively reduced tumor volume (p < 0.01) over 32 days. There was some regrowth of tumor after interruption of tetrac treatment, but at day 40, tumor volume and tumor weight at sacrifice were 45-55% below those of controls (p < 0.01). Animal weight gain was comparable in the control and treatment groups of animals. CONCLUSIONS: Tetrac and tetrac NP effectively arrest FTC-236 cell tumor growth in the CAM and xenograft models, suggesting its potential utility against FTC.
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Adenocarcinoma Folicular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Nanopartículas , Glándula Tiroides/efectos de los fármacos , Tiroxina/análogos & derivados , Adenocarcinoma Folicular/patología , Análisis de Varianza , Animales , Línea Celular Tumoral , Células Cultivadas , Embrión de Pollo , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/patología , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Ratones Desnudos , Glándula Tiroides/patología , Tiroxina/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
UNLABELLED: Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported. MATERIALS AND METHODS: In vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601. RESULTS: TM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight pro-angiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice. CONCLUSION: TM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.
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Inhibidores de la Angiogénesis/farmacología , Neurotoxinas/farmacología , Venenos de Escorpión/farmacología , Inhibidores de la Angiogénesis/farmacocinética , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Bevacizumab , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Sinergismo Farmacológico , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Neurotoxinas/farmacocinética , Venenos de Escorpión/farmacocinéticaRESUMEN
Cancer stem cells are known for their inherent resistance to therapy. Here we investigated whether normal stem cells with acquired resistance to stress can be used to identify novel markers of cancer stem cells. For this, we generated a human embryonic stem cell line resistant to Trichostatin A and analyzed changes in its gene expression. The resistant cells over-expressed various genes associated with tumor aggressiveness, many of which are also expressed in the CD133+ glioma cancer stem cells. These findings suggest that stress-resistant stem cells generated in vitro may be useful for the discovery of novel markers of cancer stem cells.
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Antígenos CD/metabolismo , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos , Células Madre Embrionarias/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glicoproteínas/metabolismo , Ácidos Hidroxámicos/farmacología , Células Madre Neoplásicas/metabolismo , Péptidos/metabolismo , Antígeno AC133 , Western Blotting , Diferenciación Celular , Células Cultivadas , Células Madre Embrionarias/patología , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Células Madre Neoplásicas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G(0)/G(1) phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule alphaVbeta3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.
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Inhibidores de la Angiogénesis/farmacología , Catepsina L/antagonistas & inhibidores , Dipéptidos/farmacología , Células Endoteliales/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Animales , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Embrión de Pollo , Células Endoteliales/citología , Células Endoteliales/enzimología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
Silver and gold nanoparticles display unique physical and biological properties that have been extensively studied for biological and medical applications. Typically, gold and silver nanoparticles are prepared by chemical reductants that utilize excess toxic reactants, which need to be removed for biological purposes. We utilized a clean method involving a single synthetic step to prepare metal nanoparticles for evaluating potential effects on angiogenesis modulation. These nanoparticles were prepared by reducing silver nitrate and gold chloride with diaminopyridinyl (DAP)-derivatized heparin (HP) polysaccharides. Both gold and silver nanoparticles reduced with DAPHP exhibited effective inhibition of basic fibroblast growth factor (FGF-2)-induced angiogenesis, with an enhanced anti-angiogenesis efficacy with the conjugation to DAPHP (P<0.01) as compared to glucose conjugation. These results suggest that DAPHP-reduced silver nanoparticles and gold nanoparticles have potential in pathological angiogenesis accelerated disorders such as cancer and inflammatory diseases.
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Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Oro/química , Heparina/farmacología , Nanopartículas del Metal , Neovascularización Fisiológica/efectos de los fármacos , Plata/química , Animales , Embrión de Pollo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Compuestos de Oro/química , Heparina/química , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/ultraestructura , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Nitrato de Plata/químicaRESUMEN
Novel Tetrac analogs were synthesized and then tested. Anti-angiogenesis efficacy was carried out using the Chick Chorioallantoic Membrane (CAM) model and the mouse matrigel model for angiogenesis. Pharmacological activities showed Tetrac can accommodate numerous modifications and maintain anti-angiogenesis activity.
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Inhibidores de la Angiogénesis/química , Tiroxina/análogos & derivados , Inhibidores de la Angiogénesis/farmacología , Animales , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Factores de Crecimiento de Fibroblastos/farmacología , Hemoglobinas/análisis , Ratones , Relación Estructura-Actividad , Tiroxina/síntesis química , Tiroxina/química , Tiroxina/farmacologíaRESUMEN
The organism's ability to regulate oxidative stress and metabolism is well recognized as a major determinant of longevity. While much research interest in this area is directed towards the study of genes that inhibit oxidative stress and/or improve metabolism, contribution to the aging process of genes with antagonistic effects on these two pathways is still less understood. The present study investigated the respective roles of the histone deacetylase Sirt1 and the thioredoxin binding protein TXNIP, two genes with opposite effects on oxidative stress and metabolism, in mediating the action of putative anti-aging interventions. Experiments were carried out in vitro and in vivo to determine the effect of proven, limited calorie availability, and unproven, resveratrol and dehydroepiandrosterone (DHEA), on the expression of Sirt1 and TXNIP. The results indicated that limited calorie availability consistently inhibited TXNIP in cancer and in normal cells including stem cells, however, it only slightly induced Sirt1expression in cancer cells. In contrast, resveratrol had a biphasic effect, and DHEA inhibited the expression of these two genes in a tissue specific manner, both in vitro and in vivo. Whereas all the three approaches tested inhibited TXNIP through the glycolytic pathway, DHEA acted by inhibiting G6PD and resveratrol through the activation of AMPK. In light of previous reports that Sirt1 induces AMPK-mediated signaling pathway, our findings point to the possibility of a negative relationship between Sirt1 and TXNIP that, if validated, can be exploited to improve the efficacy of putative anti-aging interventions.
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Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Tiorredoxinas/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Proteínas Portadoras/genética , Células Cultivadas , Deshidroepiandrosterona/farmacología , Glucosa/farmacología , Humanos , Ratones , Ratas , Resveratrol , Sirtuina 1 , Estilbenos/farmacología , Tiorredoxinas/genéticaRESUMEN
Thyroid hormone has been recently shown to induce tumor growth and angiogenesis via a plasma-membrane hormone receptor on integrin alphaVbeta3. The receptor is at or near the Arg-Gly-Asp (RGD) recognition site on the integrin that is important to extracellular matrix (ECM) protein and vascular growth factor interactions with the integrin. In the present study, we examined the possibility that tetraiodothyroacetic acid (tetrac), a deaminated, non-agonist thyroid hormone analog that binds to the integrin receptor, may modulate vascular growth factor-induced angiogenesis in the absence of thyroid hormone. Angiogenesis models were studied in which VEGF or FGF2 (1-2 microg/ml) induced tube formation in human dermal microvascular endothelial cells (HDMEC), stimulated new blood vessel branch formation in the chick chorioallantoic membrane (CAM) and induced angiogenesis in the mouse matrigel model. In all models, tetrac (1-10 microM) and at 10 microg in mouse matrigel inhibited the pro-angiogenesis activity of VEGF and FGF2 by more than 50%. RT-PCR revealed that tetrac (1-3 microM) decreased abundance of angiopoietin-2 mRNA, but not angiopoietin-1 mRNA, in VEGF-exposed endothelial cells, suggesting that specific angiogenic pathways are targeted by tetrac. Tetrac is a novel, inexpensive small molecule whose anti-angiogenic activity in the present studies is proposed to reflect inhibition, via the integrin RGD recognition/thyroid hormone receptor site, of crosstalk between plasma-membrane vascular growth factor receptors and integrin alphaVbeta3.