RESUMO
microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were isolated from BMMSCs overexpressed with miR-126 (Exo-miR-126) by ultracentrifugation. In vitro study, Exo-miR-126 treatment promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the gene/protein expression of angiogenesis-related vascular endothelial growth factor (VEGF) and angiotensin-1 (Ang-1) were up-regulated after incubation with Exo-miR-126. Additionally, the expression level of phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) showed an inverse correlation with miR-126 in HUVECs. Particularly, the Exo-miR-126 treatment contributed to enhanced angiogenesis of HUVECs by targeting PIK3R2 to activate the PI3K/Akt signalling pathway. Similarly, Exo-miR-126 administration profoundly increased the number of newly formed capillaries in wound sites and accelerated the wound healing in vivo. The results demonstrate that exosomes derived from BMMSCs combined with miR-126 may be a promising strategy to promote angiogenesis.
Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Neovascularização Fisiológica/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/genética , Cicatrização/genéticaRESUMO
The present study was undertaken to explore the therapeutic potential of hydrogen sulfide against bone loss induced by modeled microgravity. Hindlimb suspension (HLS) and rotary wall vessel bioreactor were applied to model microgravity in vivo and in vitro, respectively. Treatment of rats with GYY4137 (a water soluble donor of hydrogen sulfide, 25 mg/kg per day, i.p.) attenuated HLS-induced reduction of bone mineral density in tibiae, and preserved bone structure in tibiae and mechanical strength in femurs. In HLS group, GYY4137 treatment significantly increased levels of osteocalcin in sera. Interestingly, treatment of HLS rats with GYY4137 enhanced osteoblast surface, but had no significant effect on osteoclast surface of proximal tibiae. In MC3T3-E1 cells exposed to modeled microgravity, GYY4137 stimulated transcriptional levels of runt-related transcription factor 2 and enhanced osteoblastic differentiation, as evidenced by increased mRNA expression and activity of alkaline phosphatase. HLS in rats led to enhanced levels of interleukin 6 in sera, skeletal muscle, and tibiae, which could be attenuated by GYY4137 treatment. Our study showed that GYY4137 preserved bone structure in rats exposed to HLS and promoted osteoblastic differentiation in MC3T3-E1 cells under modeled microgravity.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Sulfeto de Hidrogênio/metabolismo , Simulação de Ausência de Peso/efeitos adversos , Células 3T3 , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/sangue , Interleucina-6/metabolismo , Masculino , Camundongos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Compostos Organotiofosforados/farmacologia , Compostos Organotiofosforados/uso terapêutico , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Differentiation from RAW264.7 cells to osteoclasts rely on many signaling pathways, such as NF-κB, MAPK, Akt and others. However, the specific underlying mechanisms are not clear. Recently, much works have focused on the inhibitory effects of plant derived compounds in the differentiation from RAW264.7 to osteoclasts. However, the specific mechanisms remain unclear. In this paper, we summarize a lot of plant derived compounds which exert blocking effect on the progression of differentiation via signaling pathways.
Assuntos
Produtos Biológicos/farmacologia , Linhagem da Célula , Macrófagos/citologia , Osteogênese , Animais , Linhagem da Célula/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Plantas/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacosRESUMO
Diabetic neuropathic pain (DNP) plays a major role in decreased life quality of diabetes patients, however, the neural mechanisms underlying DNP remain unclear. Endomorphins are the endogenous ligands for mu-opioid receptor. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, using a streptozotocin induced diabetic rat model that displayed obvious mechanical allodynia, it was found that the expression of spinal EM2 was significantly decreased in DNP rats. While intrathecal administration of exogenous EM2 attenuated mechanical allodynia in DNP rats, the mu-opioid receptor antagonist ß-funaltrexamine facilitated these events. It was found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of diabetes-induced oxidative stress. Taken together, our results provide the first evidence that the reduction in the level of an endogenous opioid in primary afferents was significantly associated with DNP. This indicates that the chronic pain associated with DNP might be due to the loss of an inhibitory effect on pain signal transmission.