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1.
Mol Pharm ; 12(3): 991-6, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25588055

RESUMO

To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic chemically modified mRNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in an in vivo murine model of MI. Delivery of IGF1 modRNA, with a polyethylenimine-based nanoparticle, augmented secreted and cell-associated IGF1, promoting cardiomyocyte survival and abrogating cell apoptosis under hypoxia-induced apoptosis conditions. Translation of modRNA-IGF1 was sufficient to induce downstream increases in the levels of Akt and Erk phosphorylation. Downregulation of IGF1 specific miRNA-1 and -133 but not miR-145 expression was also confirmed. As a proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased the level of TUNEL positive cells, augmented Akt phosphorylation, and decreased caspase-9 activity within the infarct border zone 24 h post-MI. These findings demonstrate the potential for an extended cytoprotective effect of transient IGF1 driven by synthetic modRNA delivery.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Animais , Biofarmácia , Linhagem Celular , Sobrevivência Celular , Citoproteção/genética , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Proteínas de Fluorescência Verde/genética , Fator de Crescimento Insulin-Like I/genética , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , Nanopartículas/química , Polietilenoimina/química , Transfecção
2.
J Am Geriatr Soc ; 71(8): 2640-2652, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37224415

RESUMO

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is clinically defined as a non-healing jawbone ulcerative-necrotic lesion appearing after dental therapy or minor trauma in patients treated previously with anti-resorptive, anti-angiogenic or immunomodulators. Older patients with osteoporosis and cancer receive these pharmacological agents regularly. As these patients are long-term survivors, efficient treatment is of paramount importance for their quality of life. METHODS: Literature searches via PubMed were conducted to identify relevant MRONJ studies. Basic information on MRONJ classification, clinical features, and pathosphysiology is presented herein as well as various clinical studies dealing with MRONJ in patients with osteoporosis and cancer. Lastly, we discuss current managment of patients and new trends in treatment of MRONJ. RESULTS: Although close follow-up and local hygiene have been advocated by some authors, severe forms of MRONJ are not responsive to conservative therapy. At present, there is no "gold standard" therapy for this condition. However, as the physiopathological basis of MRONJ is represented by the anti-angiogenic action of various pharmacological agents, new methods to increase and promote local angiogenesis and vascularization have recently been successfully tested in vitro, limited preclinical studies, and in a pilot clinical study. CONCLUSIONS: It appears that the best method implies application on the lesion of endothelial progenitor cells as well as pro-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and other related molecules. More recently, scaffolds in which these factors have been incorporated have shown positive results in limited trials. However, these studies must be replicated to include a large number of cases before any official therapeutic protocol is adopted.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias , Osteoporose , Humanos , Difosfonatos/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Qualidade de Vida , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Osteoporose/tratamento farmacológico , Neoplasias/tratamento farmacológico
3.
Biomaterials ; 69: 22-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26275859

RESUMO

We evaluated the therapeutic efficacy of a novel drug eluting stent (DES) inhibiting inflammation and smooth muscle cell (SMC) proliferation. We identified CX3CR1 as a targetable receptor for prevention of monocyte adhesion and inflammation and in-stent neointimal hyperplasia without interfering with stent re-endothelization. Efficacy of AZ12201182 (AZ1220), a CX3CR1 antagonist was evaluated in inhibition of monocyte attachment in vitro. A prototype AZ1220 eluting PLGA-based polymer coated stent developed with an optimal elution profile and dose of 1 µM/stent was tested over 4 weeks in a porcine model of coronary artery stenting. Polymer coated stents without AZ1220 and bare metal stents were used as controls. AZ1220 inhibited monocyte attachment to CX3CL1 in a dose dependent manner. AZ1220 eluted from polymer coated stents in an ex vivo flow system retained bioactivity in inhibiting monocyte attachment to CX3CL1. At 4 weeks following deployment, AZ1220 eluting stents significantly reduced (∼60%) in-stent stenosis compared to both bare metal and polymer only coated stents and markedly reduced peri-stent inflammation and monocyte/macrophage accumulation without affecting re-endothelization. Anti-CX3CR1 drug eluting stents potently inhibited in-stent stenosis and may offer an alternative to mTOR targeting by current DES, specifically inhibiting polymer-induced inflammatory response and SMC proliferation, while retaining an equivalent re-endothelization response to bare metal stents.


Assuntos
Anti-Inflamatórios/administração & dosagem , Estenose Coronária/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Stents Farmacológicos/efeitos adversos , Inflamação/prevenção & controle , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Anti-Inflamatórios/uso terapêutico , Receptor 1 de Quimiocina CX3C , Proliferação de Células/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/química , Estenose Coronária/etiologia , Estenose Coronária/patologia , Vasos Coronários/patologia , Vasos Coronários/cirurgia , Feminino , Inflamação/etiologia , Inflamação/patologia , Ácido Láctico/química , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Suínos
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