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Dis Model Mech ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033107


Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila (A. muc), a gut probiotic, ameliorates systemic inflammation by tightening intestinal barrier. In this study, fractured mice intragastrically administrated with A. muc were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muc at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis and can be stimulated by PDGF-BB. Moreover, A. muc treatment significantly reduced gut permeability and inflammation at early stage. Dextran Sulfate Sodium (DSS) was used to disrupt the gut barrier to determine the role of gut barrier in fracture healing and whether A. muc still can stimulate bone fracture healing. As expected, A. muc evidently improved gut barrier, reduced inflammation, and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muc reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB positive preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidences about the involvement of type H vessels in fracture healing and suggests the potential of A. muc as a promising strategy for bone healing.

Theranostics ; 10(17): 7710-7729, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685015


Osteosarcoma is a common malignant bone cancer easily to metastasize. Much safer and more efficient strategies are still needed to suppress osteosarcoma growth and lung metastasis. We recently presented a pure physical method to fabricate Ångstrom-scale silver particles (AgÅPs) and determined the anti-tumor efficacy of fructose-coated AgÅPs (F-AgÅPs) against lung and pancreatic cancer. Our study utilized an optimized method to obtain smaller F-AgÅPs and aimed to assess whether F-AgÅPs can be used as an efficient and safe agent for osteosarcoma therapy. We also investigated whether the induction of apoptosis by altering glucose metabolic phenotype contributes to the F-AgÅPs-induced anti-osteosarcoma effects. Methods: A modified method was developed to prepare smaller F-AgÅPs. The anti-tumor, anti-metastatic and pro-survival efficacy of F-AgÅPs and their toxicities on healthy tissues were compared with that of cisplatin (a first-line chemotherapeutic drug for osteosarcoma therapy) in subcutaneous or orthotopic osteosarcoma-bearing nude mice. The pharmacokinetics, biodistribution and excretion of F-AgÅPs were evaluated by testing the levels of silver in serum, tissues, urine and feces of mice. A series of assays in vitro were conducted to assess whether the induction of apoptosis mediates the killing effects of F-AgÅPs on osteosarcoma cells and whether the alteration of glucose metabolic phenotype contributes to F-AgÅPs-induced apoptosis. Results: The newly obtained F-AgÅPs (9.38 ± 4.11 nm) had good stability in different biological media or aqueous solutions and were more effective than cisplatin in inhibiting tumor growth, improving survival, attenuating osteolysis and preventing lung metastasis in osteosarcoma-bearing nude mice after intravenous injection, but were well tolerated in normal tissues. One week after injection, about 68% of F-AgÅPs were excreted through feces. F-AgÅPs induced reactive oxygen species (ROS)-dependent apoptosis of osteosarcoma cells but not normal cells, owing to their ability to selectively shift glucose metabolism of osteosarcoma cells from glycolysis to mitochondrial oxidation by inhibiting pyruvate dehydrogenase kinase (PDK). Conclusion: Our study suggests the promising prospect of F-AgÅPs as a powerful selective anticancer agent for osteosarcoma therapy.

Oral Dis ; 26(5): 998-1009, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32144839


OBJECTIVES: We aimed to investigate whether skeletal-specific H-type blood vessels exist in alveolar bone and how they function in alveolar bone remodeling. MATERIALS AND METHODS: H-type vessels with high expression of CD31 and Endomucin (CD31hi Emcnhi ) were immunostained in alveolar bone. Abundance and age-related changes in CD31hi Emcnhi endothelial cells (H-ECs) were detected by flow cytometry. Osteoprogenitors association with H-type vessels and bone mass were detected in tooth extraction model of alveolar bone remodeling by immunohistofluorescence and micro-CT, respectively. Transcription and expression of H-EC feature genes during in vitro Notch inhibition were measured by RT-qPCR and immunocytofluorescence. RESULTS: We verified that H-type vessels existed in alveolar bone, the abundance of which was highest at infancy age, then decreased but maintained a constant level during aging. In tooth extraction model, H-ECs significantly increased with concomitant perivascular accumulation of Runx2+ osteoprogenitors and gradually augmentation of bone mass. Notch inhibition of in vitro cultured H-ECs resulted in decreased expression levels of Emcn and hes1, but not Pecam1 or Kdr genes, with decreased expression levels of H-EC numbers, accordingly. CONCLUSIONS: The present study suggests that H-type vessels promote osteogenesis during alveolar bone remodeling. Notch signaling pathway regulates expression of Emcn and possibly determines fate and functions of alveolar H-ECs.

Remodelação Óssea , Células Endoteliais , Osteogênese , Extração Dentária , Animais , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética
Artigo em Inglês | MEDLINE | ID: mdl-21388863


The aggregation induced emission (AIE) mechanism of the cyano-substituted oligo (p-phenylenevinylene)1,4-bis [1-cyano-2-(4-(diphenylamino) phenyl) vinyl] benzene (TPCNDSB) is investigated by time resolved fluorescence technique. By reconstructing the time resolved emission spectra (TRES), it is found that in solvent of low polarity, the emission is mainly from the local emission (LE) state with high quantum yield, but in high polarity solvent, the emission is mainly from the intramolecular charge transfer (ICT) state, which is a relatively dark state, with low quantum yield. In crystal form, the restriction of transfer from LE state to ICT state results in efficient AIE.

Derivados de Benzeno/química , Polivinil/química , Espectrometria de Fluorescência/métodos , Compostos de Vinila/química , Absorção , Cristalização , Dimetilformamida/química , Soluções , Solventes/química , Fatores de Tempo , Tolueno/química