RESUMO
Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research.
Assuntos
Medula Óssea/irrigação sanguínea , Leucemia/fisiopatologia , Neovascularização Patológica , Animais , Humanos , Transdução de SinaisRESUMO
Background: The ovarian blood flow provides oxygen-rich blood and nutrients which are necessary for the growth and secretory activities of follicles and corpora lutea (CL) in cycling and pregnant animals. The blood flow of the ovary is finely regulated by local and systemic mechanisms that integrate nervous, endocrine, and metabolic signals. In the rabbit ovary, administration of prostaglandin F2 (PGF2) to pseudopregnant or pregnant animals affects specific vascular mechanisms regulating luteolytic process, in particular, the regulatory role of progesterone on luteal function through direct and uterine-mediated mechanisms. Thus, the main objective of the present work was to evaluate, at the level of ovarian blood vessels, the immunopresence of the receptors for progesterone (PR-R), PGF2 (FP) and GnRH (GnRH-R), and that of the enzymes endothelial nitric oxide synthase (eNOS), cyclooxygenase 1 (COX1), COX2, and prostaglandin E2-9-ketoreductase (PGE2-9-K).Materials, Methods & Results: Sexually mature New Zealand White female rabbits were used for all experiments. The animals were housed individually, in an indoor facility under controlled conditions of light and temperature, and feed ad libitum. The rabbits were treated with equine chorionic gonadotropin followed 2 days later by an intramuscular injection of a GnRH analogue to induce pseudopregnancy. Five rabbits...
Assuntos
Feminino , Animais , Coelhos , Ciclo-Oxigenase 1 , Dinoprosta , Hormônio Liberador de Gonadotropina , Imuno-Histoquímica/veterinária , Medula Óssea/irrigação sanguínea , Progesterona , Óxido Nítrico Sintase , Ovário , Vasos SanguíneosRESUMO
Background: The ovarian blood flow provides oxygen-rich blood and nutrients which are necessary for the growth and secretory activities of follicles and corpora lutea (CL) in cycling and pregnant animals. The blood flow of the ovary is finely regulated by local and systemic mechanisms that integrate nervous, endocrine, and metabolic signals. In the rabbit ovary, administration of prostaglandin F2 (PGF2) to pseudopregnant or pregnant animals affects specific vascular mechanisms regulating luteolytic process, in particular, the regulatory role of progesterone on luteal function through direct and uterine-mediated mechanisms. Thus, the main objective of the present work was to evaluate, at the level of ovarian blood vessels, the immunopresence of the receptors for progesterone (PR-R), PGF2 (FP) and GnRH (GnRH-R), and that of the enzymes endothelial nitric oxide synthase (eNOS), cyclooxygenase 1 (COX1), COX2, and prostaglandin E2-9-ketoreductase (PGE2-9-K).Materials, Methods & Results: Sexually mature New Zealand White female rabbits were used for all experiments. The animals were housed individually, in an indoor facility under controlled conditions of light and temperature, and feed ad libitum. The rabbits were treated with equine chorionic gonadotropin followed 2 days later by an intramuscular injection of a GnRH analogue to induce pseudopregnancy. Five rabbits...(AU)
Assuntos
Animais , Feminino , Coelhos , Imuno-Histoquímica/veterinária , Medula Óssea/irrigação sanguínea , Progesterona , Dinoprosta , Hormônio Liberador de Gonadotropina , Óxido Nítrico Sintase , Ciclo-Oxigenase 1 , Ovário , Vasos SanguíneosRESUMO
Vascularized bone marrow transplantation (VBMT) appears to promote tolerance for vascularized composite allotransplantation (VCA). However, it is unclear whether VBMT is critical for tolerance induction and, if so, whether there is a finite amount of VCA that VBMT can support. We investigated this with a novel VCA combined flap model incorporating full-thickness hemiabdominal wall and hindlimb osteomyocutaneous (HAW/HLOMC) flaps. Effects of allograft mass (AM) and VBMT on VCA outcome were studied by comparing HAW/HLOMC VCAs with fully MHC-mismatched BN donors and Lewis recipients. Control groups did not receive treatments following transplantation. Treatment groups received a short course of cyclosporine A (CsA), antilymphocyte serum, and three doses of adipocyte-derived stem cells (POD 1, 8, and 15). The results showed that all flaps in control allogeneic groups rejected soon after VCAs. Treatment significantly prolonged allograft survival. Three of eight recipients in HLOMC treatment group had allografts survive long-term and developed donor-specific tolerance. Significantly higher peripheral chimerism was observed in HLOMC than other groups. It is concluded that the relative amount of AM to VBMT is a critical factor influencing long-term allograft survival. Accordingly, VBMT content compared with VCA mass may be an important consideration for VCA in humans.
Assuntos
Parede Abdominal/cirurgia , Transplante de Medula Óssea/métodos , Aloenxertos Compostos , Membro Posterior/cirurgia , Retalhos Cirúrgicos , Alotransplante de Tecidos Compostos Vascularizados/métodos , Animais , Medula Óssea/irrigação sanguínea , Medula Óssea/imunologia , Estudos de Viabilidade , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Tolerância Imunológica , Imunossupressores/uso terapêutico , Teste de Cultura Mista de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Tamanho do Órgão , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Transplante de Pele , Cauda , Quimeras de TransplanteRESUMO
The ability to characterize distribution of neoplastic hematopoietic cells and their progenitors in their native microenvironment is emerging as an important challenge and potential therapeutic target in many disease areas, including multiple myeloma. In multiple myeloma, bone marrow (BM) angiogenesis is typically increased and microvessel density is a known indicator of poor prognosis. However, the difficulty of consistently measuring 3D vessels from 2D cut sections has previously limited the study of spatial distribution of plasma cells (PC) and their interaction with BM microenvironment. The aim of the study is to report a novel method to study myeloma cells spatial distribution within their hematopoietic niche context using readily available tissue sections and standard histology approaches. We utilized a novel whole-tissue image analysis approach to identify vessels, and then applied computational grown regions extended out from each vessel at 15, 35, 55, 75, and 100 µm to identify the spatial distribution of PC on CD34/CD138 double-stained core biopsy slides. Percent PC to total cells (TC) was significantly higher at <15 µm distance compared with those at 16 to 35, 36 to 55, 56 to 75, and 76 to 100 µm distance (P=0.0001). Similarly, PC/TC at <35 µm region was significantly higher compared with 36 to 55 (P=0.0001), 56 to 75 (P≤0.0001), and 76 to 100 (P=0.0002) µm distances. The mean PC/TC differences in the spatial gradient of 36 to 55, 56 to 75, and 76 to 100 µm distance regions were not significant. Our findings suggest possible preferential advantage to neoplastic PC in the proximity of blood vessels compared with other hematopoietic marrow cells. We demonstrate the feasibility of analyzing the spatial distribution of PC, and possibly other hematopoietic/stem cells in their microenvironment, as characterized by the distance to vessels in BM using a novel image analysis approach.
Assuntos
Células da Medula Óssea , Medula Óssea , Processamento de Imagem Assistida por Computador/métodos , Mieloma Múltiplo , Plasmócitos , Adulto , Idoso , Antígenos CD34/biossíntese , Medula Óssea/irrigação sanguínea , Medula Óssea/metabolismo , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Humanos , Processamento de Imagem Assistida por Computador/instrumentação , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/biossíntese , Plasmócitos/metabolismo , Plasmócitos/patologia , Sindecana-1/biossínteseRESUMO
AIM: The aim of this study was to assess and describe the morphological effects of an intra-articular iniection of Mesenchymal Stem Cells (MSCs) and/or Low Intensity Pulsed Ultrasound (LIPUS) stimulation on the mandibular condyles of growing rats, using cone beam computed tomography (CBCT) and histology. METHODS: Twenty-six young (23-day-old) rats were divided into 5 groups identified as LIPUS-stimulated (20 minutes daily using 50 mW/cm2, 1MHz, 0.2 millisecond pulses), MSCs injected (1 x 10(5) cells/kg), LIPUS + MSCs, medium inlected, and untreated controls. All treatments were performed in the left temporomandibular joint of each rat (TMJs). At day 21, CBCTs were obtained for cephalometric analysis and 3D reconstructions. After animal sacrifice, left and right TMJ sections were histologically prepared and examined. The Wilcoxon sign rank test and the Kruskal-Wallis 2 test were applied for statistical comparison. RESULTS: Imaging results showed that left condyles were wider in all LIPUS-treated groups (p < 0.05), while the LIPUS-only group had a greater left sagittal condylar length. LIPUS-treated groups displayed a lower midline shift to the right (p < 0.02). No significant differences were observed in the MSC group. Bone marrow morphology and vascularity differed between the groups as LIPUS-treated groups exhibited increased vascularity in the erosive cartilage zone. CONCLUSION: It was established that LIPUS and MSC application to the TMJ region of growing rats favoured transverse condylar growth, while LIPUS application alone may enhance sagittal condylar development.The MSC injection model had little effect on sagittal condylar growth.
Assuntos
Côndilo Mandibular/crescimento & desenvolvimento , Células-Tronco Mesenquimais/fisiologia , Terapia por Ultrassom , Animais , Medula Óssea/irrigação sanguínea , Medula Óssea/patologia , Cartilagem Articular/irrigação sanguínea , Cartilagem Articular/patologia , Cefalometria/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Injeções Intra-Articulares , Côndilo Mandibular/irrigação sanguínea , Côndilo Mandibular/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Microvasos/patologia , Osteoblastos/patologia , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Articulação Temporomandibular , Fatores de TempoRESUMO
La enfermedad de Huntington (EH) es un trastorno degenerativo hereditario que afecta a personas con predisposición genética. No existe hasta hoy un tratamiento efectivo; la enfermedad avanza lentamente y el paciente termina en incapacidad o muerte después de 15 o 20 años. Los estudios relacionados con el tratamiento de las manifestaciones clínicas que aparecen en la enfermedad, incluyen tratamientos medicamentosos y el uso de trasplante de células. En la actualidad se conoce que es posible reproducir algunas características de la enfermedad en modelos experimentales para ensayar posibles terapéuticas (ej. el modelo de lesión estriatal por inyección de ácido quinolínico; [AQ]). No se conoce el efecto restaurativo de las células de médula ósea (CMO) en este modelo. Objetivos: 1) Caracterizar morfológicamente la lesión por inyección intraestriatal de AQ. 2) Caracterizar inmunocitoquímicamente las CMO. 3) Evaluar la concentración óptima de CMO para el trasplante en el modelo y 4) Evaluar el estado funcional del trasplante de CMO, a través de la conducta motora.
Huntington Disease (HD) is a heritable neurodegenerative disease that affects people with genetic history. Until today, an effective treatment doesn't exist; the illness advances slowly and the patient finishes in inability or death after 15 or 20 years. The studies related with the treatment of the clinical manifestations, include treatments with medications and the use of cells transplant. At the present time it is known that it is possible to reproduce, some characteristics of the disease in experimental models for to use possible therapies [example: estriatal lesion of quinolínico acid; (QA)]. the restorative effect of the bone marrow cells (BMC) is not known in this model. Objectives. 1) characterizationmorphofological of the estriatal lesion whith QA. 2) to characterization immunochemical of BMC. 3) to evaluate the BMC concentration for the transplant and 4) to evaluate the functional state of BMC transplant, through the motor behavior.
Assuntos
Doença de Huntington/induzido quimicamente , Doença de Huntington/radioterapia , Doença de Huntington/sangue , Doença de Huntington , Medula Óssea/anormalidades , Medula Óssea/irrigação sanguíneaRESUMO
Vascular endothelial growth factor (VEGF) is a protein that increases vascular permeability and induces the proliferation, migration and survival of endothelial cells. Bisphosphonates (BPs) are antiresorptive drugs that are widely used in the treatment of bone metabolism diseases and bone metastases. Since 2003, cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have been reported. Few papers explain the mechanisms that induce BRONJ; some authors mention alterations in bone remodelling and a certain antiangiogenic effect of BPs. The aim of this study is to evaluate the expression of VEGF in bone marrow cells and the number of blood vessels and area occupied by them in animals treated with the BP sodium olpadronate (OPD). We used 16 Wistar rats, 60 days old, divided into two groups, experimental (OPD) and control. The OPD group received 0.3 mg/kg/week intraperitoneal OPD for 5 weeks. The control group received an equivalent intraperitoneal volume of physiological saline solution. After euthanasia, hemimandibles were processed and mesio-distal histological sections of the first molar were prepared. Sections were stained with hematoxylin-eosin (HE), immunohistochemical detection of VEGF was performed (sc- 7269) and the following histomorphometric parameters were evaluated: In HE-stained sections - number of blood vessels per sq. mm. and percentage (%) of area occupied by blood vessels in relation to total area evaluated; in sections with immunohistochemical detection of VEGF – number of VEGF+ bone marrow cells per sq. mm. Data underwent statistical analysis. Number of blood vessels/mm2 was significantly lower in the OPD group (OPD: 92 ± 16; Control: 140 ± 31; p<0.05) and % vascular area/ total area evaluated showed no significant difference (OPD: 15.6 ± 6.1; Control: 10.2 ± 4.2). Number of VEGF+ cells/mm2 was lower in the OPD group than in the control group, with statistically significant differences (OPD: 7804.8 ± 597; Control: 13187.6 ± 894; p<0.001). The results of this study suggest that monosodium olpadronate has an antiangiogenic effect. Further studies are needed to reveal its potential as an antitumor agent and its connection with the onset of BRONJ.
El factor de crecimiento vascular (VEGF) es una proteina que incrementa la permeabilidad vascular, induce la proliferacion, migracion y supervivencia de las celulas endoteliales. Los bifosfonatos (BFs) son drogas antirresortivas ampliamente utilizadas en el tratamiento de enfermedades que alteran el metabolismo oseo y de metastasis oseas. Desde el 2003 se han reportado casos de osteonecrosis de maxilar asociada al uso de BFs (ONAB). Escasas publicaciones explican los mecanismos que inducen la ONAB, algunos autores mencionan las alteraciones en la remodelacion osea y un cierto efecto antiangiogenico de los BFs. El objetivo del presente trabajo es evaluar la expresion de VEGF en celulas de la medula osea y el numero y el area ocupada por vasos sanguineos en animales tratados con el BF olpadronato monosodico (OPD). Se utilizaron 16 ratas Wistar de 60 dias divididas en dos grupos, experimental (OPD) y control. El grupo OPD, recibio 0,3 mg/kg/sem de OPD via IP, durante 5 semanas. El grupo control, recibio un volumen equivalente via IP de solucion fisiologica. Luego de practicada la eutanasia se obtuvieron las hemimandibulas y se procesaron para obtener cortes histologicos mesio-distales del primer molar. Se realizo la coloracion hematoxilina-eosina (HE) y la deteccion inmunohistoquimica de VEGF (sc-7269) y se evaluaron los siguientes parametros histomorfometricos: En cortes con H&E: Numero de vasos sanguineos por mm2 y porcentaje (%) de area ocupada por los vasos sanguineos en relacion al area total evaluada; en cortes con la deteccion inmunohistoquimica de VEGF: Numero de celulas medulares VEGF+ por mm2. Los datos fueron estadisticamente analizados. El N° vasos sanguineos/mm2 fue significativamente menor en el grupo OPD (OPD: 92 ± 16; control: 140 ± 31; p<0,05) y el % area vascular/area total evaluada no mostro diferencias significativas (OPD: 15,6 ± 6.1; Control: 10.2 ± 4.2). El N° de celulas VEGF+/mm2 en el grupo OPD fue menor que en el grupo control con diferencias estadisticamente significativas (OPD: 7804,8 ± 597; Control: 13187,6 ± 894; p<0,001). Los resultados de este estudio sugieren que el olpadronato monosodico tiene un efecto antiangiogenico. Futuros estudios revelaran su potencial como agente antitumoral asi como tambien su relacion con la aparicion de ONAB.
Assuntos
Animais , Ratos , Medula Óssea/patologia , Fator A de Crescimento do Endotélio Vascular/análise , Difosfonatos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Mandíbula/patologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/irrigação sanguínea , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Imuno-Histoquímica , Ratos Wistar , Inibidores da Angiogênese/farmacologia , Densitometria , Arco Dental/efeitos dos fármacos , Arco Dental/irrigação sanguínea , Arco Dental/patologia , Difosfonatos/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Injeções Intraperitoneais , Mandíbula/efeitos dos fármacos , Mandíbula/irrigação sanguínea , Dente Molar/patologiaRESUMO
UNLABELLED: Vascular endothelial growth factor (VEGF) is a protein that increases vascular permeability and induces the proliferation, migration and survival of endothelial cells. Bisphosphonates (BPs) are antiresorptive drugs that are widely used in the treatment of bone metabolism diseases and bone metastases. Since 2003, cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have been reported. Few papers explain the mechanisms that induce BRONJ; some authors mention alterations in bone remodelling and a certain antiangiogenic effect of BPs. The aim of this study is to evaluate the expression of VEGF in bone marrow cells and the number of blood vessels and area occupied by them in animals treated with the BP sodium olpadronate (OPD). We used 16 Wistar rats, 60 days old, divided into two groups, experimental (OPD) and control. The OPD group received 0.3 mg/kg/week intraperitoneal OPD for 5 weeks. The control group received an equivalent intraperitoneal volume of physiological saline solution. After euthanasia, hemimandibles were processed and mesio-distal histological sections of the first molar were prepared. Sections were stained with hematoxylin-eosin (HE), immunohistochemical detection of VEGF was performed (sc-7269) and the following histomorphometric parameters were evaluated: In HE-stained sections--number of blood vessels per sq. mm. and percentage (%) of area occupied by blood vessels in relation to total area evaluated; in sections with immunohistochemical detection of VEGF--number of VEGF+ bone marrow cells per sq. mm. Data underwent statistical analysis. Number of blood vessels/mm2 was significantly lower in the OPD group (OPD: 92 +/- 16; CONTROL: 140 +/- 31; p < 0.05) and % vascular area/total area evaluated showed no significant difference (OPD: 15.6 +/- 6.1; CONTROL: 10.2 +/- 4.2). Number of VEGF+ cells/mm2 was lower in the OPD group than in the control group, with statistically significant differences (OPD: 7804.8 +/- 597; CONTROL: 13187.6 +/- 894; p < .001). The results of this study suggest that monosodium olpadronate has an antiangiogenic effect. Further studies are needed to reveal its potential as an antitumor agent and its connection with the onset of BRONJ.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Medula Óssea/patologia , Difosfonatos/farmacologia , Mandíbula/patologia , Fator A de Crescimento do Endotélio Vascular/análise , Inibidores da Angiogênese/farmacologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Conservadores da Densidade Óssea/administração & dosagem , Medula Óssea/irrigação sanguínea , Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Densitometria , Arco Dental/irrigação sanguínea , Arco Dental/efeitos dos fármacos , Arco Dental/patologia , Difosfonatos/administração & dosagem , Imuno-Histoquímica , Injeções Intraperitoneais , Mandíbula/irrigação sanguínea , Mandíbula/efeitos dos fármacos , Dente Molar/patologia , Ratos , Ratos WistarRESUMO
The biologic basis of the negative prognosis of plasmablastic myeloma is not fully understood. To determine whether histologically aggressive multiple myeloma (MM) is associated with a more angiogenic marrow environment, bone marrow samples from 50 recently diagnosed MM patients were evaluated. Twelve percent (6/50) of patients presented plasmablastic MM, and this feature correlated with moderate/strong intensity of vascular endothelial growth factor staining of plasma cells (P = 0.036). Although plasmablastic MM was not associated with increasing of microvessel density, this new evidence of increased expression of vascular endothelial growth factor on plasmablasts suggests that the adverse prognosis conferred by plasmablastic disease may be due, at least in part, to secretion of this angiogenic cytokine, also suggesting that the subset of MM patients with plasmablastic features may derive particular benefit from antiangiogenic therapies.