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Osteosarcoma is the most common high-grade human primary malignant bone sarcoma with lower survival in the past decades. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been proved to possess potent anti-cancer effects. However, its potential mechanism still remains not fully clear nowadays. In this study, we investigated the anticancer effect of oridonin on human osteosarcoma and illuminated the underlying mechanisms. In vitro, oridonin inhibited the cell viability of various osteosarcoma cells. We demonstrated that oridonin induced mitochondrial-mediated apoptosis by increasing Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), triggering reactive oxygen species (ROS) generation and activating caspase-3 and caspase-9 cleavage in MG-63 and HOS cells. Moreover, we found that oridonin triggered ROS by inhibiting NF-E2-related factor 2 (Nrf2) pathway and induced mitochondrial apoptosis via inhibiting nuclear factor-κB (NF-κB) activation by activating Peroxisome Proliferator-Activated Receptor γ (PPAR-γ) in MG-63 and HOS cells. We further confirmed the results by PPAR-γ inhibitor GW9662, PPAR-γ siRNA as well as overexpression of PPAR-γ and Nrf2 in vitro. Furthermore, our in vivo study showed that oridonin inhibited tumor growth with high safety via inducing apoptosis through activating PPAR-γ and inhibiting Nrf2 activation in xenograft model inoculated HOS tumor. Taken together, oridonin exerted a dramatic pro-apoptotic effect by activating PPAR-γ and inhibiting Nrf2 pathway in vitro and in vivo. Therefore, oridonin may be a promising and effective agent for human osteosarcoma in the future clinical applications.

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We report the bulk self-assembly of diblock copolymer poly(tert-butyl acrylate)-blockpoly(glycidyl methacrylate) (PtBA-b-PGMA) with the PGMA that bears many epoxy groups as a crosslinkable segment and the PtBA as a hydrolyzable segment. The PtBA-b-PGMA block copolymers of a different composition were synthesized by two-step atom transfer radical polymerization (ATRP). After bulk self-assembly, the morphologies of microphase separation of the block copolymers were studied with smallangle X-ray scattering (SAXS) and transmission electron microscopy (TEM). The results showed that with decrease of volume ratio of the PGMA segments the PtBA-b-PGMA self-assembled into lamellae, cylinders, and spheres with the dispersed PGMA domains. The epoxy groups in the PGMA domains were cross-linked by exposing the microphase-separated films into an atmosphere of either ethylenediamine (EDA) or propargylamine (PA). Then the bulk materials were dispersed into the good solvent of PtBA to generate the polymeric nanoobjects of plates, fibers, and spheres, of which the cross-linked PGMAs were the cores and the PtBAs were the coronas. After hydrolysis of the PtBA segments into the poly(acrylic acid)s (PAAs), the cross-linked nanoobjects could be dispersed in basic water and showed reversible pH responsibility. The pendant alkyne groups in the PA cross-linked nanoobjects were applied to anchor anthracenes by click reaction with 9-(azidomethyl)anthracene (9-AMA).

Polyisoprene (PI) with a high content of cis‐1,4 (up to 95%) or cis‐1,4/3,4 binary structures was synthesized using a cobalt system in toluene. The cobalt system, which exhibited high activities (up to 3.50 × 106 g PI (mol Co)−1 h−1), contained a series of 2‐(benzimidazolyl)‐6‐(1‐(arylimino)ethyl)pyridine cobalt(II) dichlorides activated with ethylaluminium sesquichloride. The nature of the ligands and the reaction conditions significantly affected both the catalytic performance of the cobalt complexes as well as the structures of the resultant PI. The stereospecific polymerization of isoprene could be tuned via changing either the co‐catalyst or solvent: for example, increased content of 3,4 PI (up to 36.6%) was achievable in heptane in the presence of diethylaluminium chloride. Sequence distribution analysis by 13C NMR spectroscopy indicated that most 3,4 units occurred randomly in the PI chains. © 2013 Society of Chemical Industry

A multifunctional initiator 1 with chemically labile disulfide and ester groups bearing four bromoisobutyryl groups was prepared by esterification of bis(2-hydroxyethyl)disulfide with 2,2-bis(2-bromoisobutyroyloxymethyl)propionic acid. Then well-defined four-arm star polystyrenes, (S n ) 4 , were synthesized by atom transfer radical polymerization of styrene initiated with 1. Owing to the presence of the -S-Sand the ester linkages in precisely controlled position of the (S n ) 4 core inherited from the initiator, such a star polystyrene demonstrated interesting stepwise cleavage properties dependent upon the applied conditions. When treating samples with tri-n-butylphosphine or dithiothreitol 2,3-dihydroxy-1,4-butanethiol, the disulfide linkage which located in the center of the star polymers was cleaved and, as a result, one star molecule (S n ) 4 was cut into two linear polystyrenes, 2(S n ) 2 , with a -SH group situated in the middle of chains. Then, the resulted (S n ) 2 could be further cleaved into two shorter polystyrenes, 2(S n ) 1 , by hydrolysis to cut two ester groups located in the middle of the PS chains with KOH in a solution of THF/EtOH. Moreover, the (S n ) 4 stars may also be decomposed into the shortest segment, 4(S n ) 1 , directly by applying the hydrolysis condition. Furthermore, a polymer organogel was obtained from the cleavable star polymers (S n ) 4 by subjecting atom transfer radical coupling reaction which occurred between their -Br arm ends that preserved during formation of the star polymers. This gel could be also decomposed into the linear polystyrene segments of different length by breaking disulfide and ester linkages, respectively.

Osteosarcoma, the most common malignant bone tumor with recurring disease or lung metastases, has become one of the leading causes of death in humans. In the current study, we made an investigation on the anticancer effect of glaucocalyxin A, a bioactive ent-kauranoid diterpenoid isolated from Rabdosia japonica var., and unraveled the underlying mechanisms. Here, we found that Glaucocalyxin A inhibited the cell viability of numerous osteosarcoma cells. Our results showed that Glaucocalyxin A exerted the pro-apoptotic effect on human osteosarcoma cells, MG-63 and HOS cells. Glaucocalyxin A induced apoptosis by mitochondrial apoptotic pathway through several steps including increasing the Bax/Bcl-2 ratio, triggering the intracellular reactive oxygen species (ROS) generation, reducing mitochondrial membrane potential (MMP), and inducing cleavage of caspase-9 and caspase-3. We demonstrated that Glaucocalyxin A induced apoptosis via inhibiting Five-zinc finger Glis 1 (GLI1) activation by overexpression and knockdown of GLI1 in vitro. We also found that Glaucocalyxin A inhibited GLI1 activation via regulating phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway. We further confirmed our findings by using PI3K activator and inhibitor to verify the inhibitory effect of Glaucocalyxin A on PI3K/Akt/GLI1 pathway. Moreover, our in vivo study revealed that glaucocalyxin A possessed a remarkable antitumor effect with no toxicity in the xenograft model inoculated with HOS tumor through the same mechanisms as in vitro. In conclusion, our results suggested that Glaucocalyxin A induced apoptosis in osteosarcoma by inhibiting nuclear translocation of GLI1 via regulating PI3K/Akt signaling pathway. Thus, Glaucocalyxin A might be a potential candidate for human osteosarcoma in the future.