Bone has a remarkable potential for self-healing and repair, yet several injury types are non-healing even after surgical or non-surgical treatment. Regenerative therapies that induce bone repair or improve the rate of recovery are being intensely investigated. Here, we probed the potential of bone marrow stem cells (BMSCs) engineered with chemically modified mRNAs (modRNA) encoding the hBMP-2 and VEGF-A gene to therapeutically heal bone. Induction of osteogenesis from modRNA-treated BMSCs was confirmed by expression profiles of osteogenic related markers and the presence of mineralization deposits. To test for therapeutic efficacy, a collagen scaffold inoculated with modRNA-treated BMSCs was explored in an in vivo skull defect model. We show that hBMP-2 and VEGF-A modRNAs synergistically drive osteogenic and angiogenic programs resulting in superior healing properties. This study exploits chemically modified mRNAs, together with biomaterials, as a potential approach for the clinical treatment of bone injury and defects.
Bioactivity-directed fractionation of the extract of the mangrove endophytic fungus Talaromyces sp. ZH-154, which was isolated from the stem bark of Kandelia candel (L.) Druce, Rhizophoraceae, afforded two new metabolites, 7-epiaustdiol ( 1) and 8-O-methylepiaustdiol ( 2), together with the known compounds, stemphyperylenol ( 3), skyrin ( 4), secalonic acid A ( 5), emodin ( 6), and norlichexanthone ( 7). Their structures were elucidated on the basis of spectroscopic evidences including CD, MS, and 1D, 2D NMR techniques. The absolute configuration of 1 was unequivocally determined by single-crystal X-ray diffraction. All isolated compounds were evaluated for their antimicrobial and in vitro cytotoxic activities.
Tissue engineering has become a new approach for repairing bone defects. Previous studies indicated that coral scaffolds had been utilized with bone marrow stromal cells (BMSCs) in a variety of approaches for bony reconstruction. In these applications, the degradation rate of the material did not match the rate at which bone was regenerated. In this study, a previously established 30 mm long mandibular segmental defect was repaired with engineered bone using green fluorescent protein-labeled osteogenic BMSCs seeded on porous coral (n = 12). Defects treated with coral alone (n = 12) were used as an experimental control. In the BMSCs/coral group, new bone formation was observed from 4 weeks postoperation, and bony-union was achieved after 32 postoperative weeks. The residual coral volume of the BMSCs/coral grafts at 12 weeks (20-30%) was significantly higher than that at 32 weeks (10-15%, p < 0.05), which was detected by microcomputed tomography and histological examination. The engineered bone with BMSCs/coral achieved satisfactory biomechanical properties at 32 weeks postoperation, which was very close to that of the contralateral edentulous mandible. More importantly, immunostaining demonstrated that the implanted BMSCs differentiated into osteoblast-like cells. In contrast, minimal bone formation with almost solely fibrous connection was observed in the group treated with coral alone. Based on these results, we conclude that engineered bone from osteogenically induced BMSCs and biodegradable coral can successfully repair the critical-sized segmental mandibular defects in canines and the seeding cells could be used for bony restoration.
bOxygenous terpenoids are active components of many medicinal plants. However, current studies that have focused on enzymatic oxidation reactions cannot comprehensively clarify the mechanisms of oxygenous terpenoid synthesis and diversity. This study shows that an endophytic bacterium can trigger the generation of reactive oxygen species (ROS) that directly increase oxygenous sesquiterpenoid content and diversity in Atractylodes lancea. A. lancea is a famous but endangered Chinese medicinal plant that contains abundant oxygenous sesquiterpenoids. Geo-authentic A. lancea produces a wider range and a greater abundance of oxygenous sesquiterpenoids than the cultivated herb. Our previous studies have shown the mechanisms behind endophytic promotion of the production of sesquiterpenoid hydrocarbon scaffolds; however, how endophytes promote the formation of oxygenous sesquiterpenoids and their diversity is unclear. After colonization by Pseudomonas fluorescens ALEB7B, oxidative burst and oxygenous sesquiterpenoid accumulation in A. lancea occur synchronously. Treatment with exogenous hydrogen peroxide (H 2 O 2 ) or singlet oxygen induces oxidative burst and promotes oxygenous sesquiterpenoid accumulation in planta. Conversely, pretreatment of plantlets with the ROS scavenger ascorbic acid significantly inhibits the oxidative burst and oxygenous sesquiterpenoid accumulation induced by P. fluorescens ALEB7B. Further in vitro oxidation experiments show that several oxygenous sesquiterpenoids can be obtained from direct oxidation caused by H 2 O 2 or singlet oxygen. In summary, this study demonstrates that endophytic bacterium-triggered ROS can directly oxidize oxygen-free sesquiterpenoids and increase the oxygenous sesquiterpenoid content and diversity in A. lancea, providing a novel explanation of the mechanisms of oxygenous terpenoid synthesis in planta and an essential complementarity to enzymatic oxidation reactions.A tractylodes lancea is a traditional Chinese medicinal plant and is the main ingredient of many famous Chinese medicines. Oxygenous sesquiterpenoids, such as hinesol, -eudesmol, atractylone, and caryophyllene oxide, are the main active components in A. lancea and have medicinal efficacy against rheumatic diseases, digestive disorders, night blindness, and influenza (1). The quality of A. lancea strongly depends on the area in which the herb is produced, and A. lancea grown in the Maoshan area of the Jiangsu Province is the geo-authentic herb (2), which is characterized by higher oxygenous sesquiterpenoid content and diversity than herbs grown in other areas (3). In recent years, the geoauthentic A. lancea has become endangered due to habitat destruction and overexploitation. Although cultivation ensures the production of medicinal materials, the oxygenous sesquiterpenoid content and diversity in cultivated A. lancea is considerably decreased compared to that of the wild herb. Currently, knowledge on the biosynthesis and diversity of oxygenous sesquiterpenoids is insufficient. Some studies have explained...
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