Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible μ opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K i = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the δ receptor (DOR) and more than 150-fold selectivity over the κ receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.

A double-network polymer hydrogel composed of chemically cross-linked poly(ethylene glycol) (PEG) and physically cross-linked poly(vinyl alcohol) (PVA) was prepared. When the hydrogel (70 wt % of water) is subjected to freezing/thawing treatment under strain, the enhanced physical network as a result of crystallization of PVA chains can stabilize the hydrogel deformation after removal of the external force at room temperature. Subsequent disruption of the physical network of PVA by heating allows for the recovery of the initial shape of the hydrogel. Moreover, the double-network hydrogel exhibits self-healing capability stemming from the physical network of PVA by virtue of the extensive interchain hydrogen bonding between the hydroxyl side groups. This study thus demonstrates a general approach to imparting both the shape memory and self-healing properties to chemically cross-linked hydrogels that otherwise do not have such functionalities. Moreover, by making use of the fixed hydrogel elongation, the effect of anisotropy arising from chain orientation on the self-healing was also observed.

Therapeutic-ultrasound-triggered shape memory was demonstrated for the first time with a melamine-enhanced poly(vinyl alcohol) (PVA) physical hydrogel. The addition of a small amount of melamine (up to 1.5 wt %) in PVA results in a strong hydrogel due to the multiple H-bonding between the two constituents. A temporary shape of the hydrogel can be obtained by deformation of the hydrogel (∼65 wt % water) at room temperature, followed by fixation of the deformation by freezing/thawing the hydrogel under strain, which induces crystallization of PVA. We show that the ultrasound delivered by a commercially available device designed for the patient's pain relief could trigger the shape recovery process as a result of ultrasound-induced local heating in the hydrogel that melts the crystallized PVA cross-linking. This hydrogel is thus interesting for potential applications because it combines many desirable properties, being mechanically strong, biocompatible, and self-healable and displaying the shape memory capability triggered by a physiological stimulus.

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Bone tissue engineering emerges as an advantageous technique to achieve tissue regeneration. Its scaffolds must present excellent biomechanical properties, where bare polymers poorly perform. Development of new biomaterials with high osteogenic capacity is urgently pursued. In this study, an electrospun poly­(3-hydroxybutyrate-co-4-hydroxybutyrate)/graphene oxide (P34HB/GO) nanofibrous scaffold is successfully fabricated and characterized. The effects of GO amount on scaffold morphology, biomechanical properties, and cellular behaviors are investigated. GO reduces the fiber diameter and enhances porosity, hydrophilicity, mechanical properties, cellular performance, and osteogenic differentiation of scaffolds. P34HB/GO triumphs over P34HB in in vivo bone regeneration in critical-sized calvarial defect of rats. We believe that this study is the first to evaluate the capability of in vivo bone repair of electrospun P34HB/GO scaffold. With facile fabrication process, favorable porous structures, enhanced biomechanical properties, and fast osteogenic capability, P34HB/GO scaffold holds practical potentials for bone tissue engineering application.

O pioid receptor selective antagonists are important pharmacological probes to study the structureÀfunction relationship of each opioid receptor. 1À3 It has been demonstrated that, for many clinically available opiates, not only their analgesic function but also their side effects (such as addiction and abuse liability, respiratory depression, and tolerance) are primarily due to their interaction with the mu opioid receptor (MOR). 4À6 Yet the lack of a nonpeptidyl, highly selective, and potent MOR antagonist limits our understanding of the structureÀfunction relationship of MOR. Currently available antagonists for the MOR carry certain characteristics that limit their application (Figure 1). For example, cyprodime 7 only possesses a moderate selectivity for the MOR over the delta opioid receptor (DOR) and kappa opioid receptor (KOR) (K i value ratios are kappa/mu ≈ 45, delta/mu ≈ 40) with much lower affinity for the MOR than naloxone and naltrexone.8 β-FNA, clocinnamox, and other irreversible antagonists for the MOR 9À11 bind covalently with the receptor, which largely limits their utility. Some currently available conformation-constrained peptides, for example, CTOP and CTAP, are highly selective and reversible MOR antagonists. They are relatively metabolically stable and have been used to target the MOR in in vitro and in vivo studies, while their limited bioavailability when administered peripherally hindered their potential medical applications. 12À19 Because the utility of antagonists as pharmacological tools requires both in vitro and in vivo activity, nonpeptide ligands are still preferred due to their ability to penetrate the central nervous system (CNS) and lesser vulnerability to metabolic inactivation compared to the peptide agents. Therefore, the development of a nonpeptidyl, potent, selective, and reversible antagonist for the MOR is highly desirable.Recently, based on the "message-address concept" and molecular modeling studies, a series of 6R-and 6β-N-heterocyclic substituted naltrexamine derivatives were designed, synthesized, and characterized. 20 Among them, NAP and NAQ (Figure 1) seemed to be promising leads as MOR selective antagonists. NAP displayed high binding affinity for the MOR at K i = 0.37 nM with over 700-fold selectivity for the MOR over the DOR and more than 150-fold selectivity over the KOR. The binding affinity of NAQ to MOR was 0.55 nM with over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Meanwhile they were both low efficacy MOR agonists compared with DAMGO in the ABSTRACT: As important pharmacological probes, highly selective opioid receptor antagonists are essential in opioid receptor structural characterization and opioid agonist functional studies. At present, a nonpeptidyl, highly selective, and reversible mu opioid receptor antagonist is still not available. Among a series of novel naltrexamine derivatives that have been designed and synthesized following molecular modeling studies, two compounds, NAP and NAQ, were ...

Adipose-derived stem cells (ASCs) and mesenchymal stem cells are promising for tissue repair because of their multilineage differentiation capacity. Our previous data confirmed that the implantation of mixed ASCs and chondrocytes into cartilage defects induced desirable in vivo healing outcomes. However, the paracrine action of ASCs on chondrocytes needs to be further elucidated. In this study, we established a co-culture system to achieve cell-to-cell and cell-to-tissue crosstalk and explored the soluble growth factors in both ASCs and chondrocytes supplemented with 1% fetal bovine serum to mimic the physiological microenvironment. In ASCs, we screened for growth factors by semi-quantitative PCR and quantitative real-time PCR and found that the expression of bone morphogenetic protein 2 (BMP-2), vascular endothelial growth factor B (VEGFB), hypoxia inducible factor-1α (HIF-1α), fibroblast growth factor-2 (FGF-2), and transforming growth factor-β1 significantly increased after co-culture in comparison with mono-culture. In chondrocytes, VEGFA was significantly enhanced after co-culture. Unexpectedly, the expression of collagen II and aggrecan was significantly down-regulated in the co-culture group compared with the mono-culture group. Meanwhile, among all the growth factors screened, we found that the BMP family members BMP-2, BMP-4, and BMP-5 were down-regulated and that VEGFB, HIF-1α, FGF-2, and PDGF were significantly decreased after co-culture. These results suggest that crosstalk between ASCs and chondrocytes is a pathway through the regulated growth factors that might have potential in cartilage repair and regeneration and could be useful for tissue engineering.

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