No abstract

Most cancer chemotherapy regimens rely on the use of two or more chemotherapeutic agents. A supramolecular approach that may allow co-delivery of two drugs is described here.

Scope: Dietary advanced glycation products (dAGEs) have been reported to induce cognitive impairment while quercetin possesses potential neuroprotective effects. The aim is to explore whether dAGEs would induce similar cognitive impairment from both young and aged ICR mice, and the protective effects of quercetin. Methods and results: A total of 32 aged ICR mice (15-month-old) and 16 young ICR mice (3-month-old) are randomly assigned into the following six groups: Young mice control group, young mice fed with AGEs diet group, old mice control group, old mice fed with AGEs diet group, old mice with quercetin supplemented diet group, old mice fed with AGE diet supplemented with quercetin group. Dietary AGEs induced cognitive impairment only in aged, but not in young, ICR mice, while quercetin intervention is capable of reversing dAGEs-induced cognitive dysfunction. This may be since quercetin 1) increased miR-219, miR-15a, and miR-132 expression, inhibited p-ERK1/2, and tau phosphorylation; and 2) improved gut microbiota richness and diversity, inhibited phylum Tenericutes and Proteobacteria, and elevated butyric acid from cecum. Conclusion: Prolonged application of quercetin may be beneficial in the elderly, especially for those with high consumption of dAGEs.

Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats. Methods: Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126. Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze. Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.

Developing a meniscal replacement with reliable long-term mechanical and functional support has faced a grand challenge due to difficulty in recapitulating the anisotropic microarchitecture and modulus. Herein, a high-strength supramolecular polymer hydrogel-cushioned biomimetic structured meniscus replacement is reported for the first time. The radially and circumferentially oriented poly(e-caprolactone) (PCL) fiber framework is 3D printed to imitate collagen fibers in the native meniscus to provide circumferential tensile supports. Then, hydrogen bonding strengthened anti-swelling poly(N-acryloyl glycinamide) (PNAGA) hydrogel that replicates the function of proteoglycan in resisting axial compressive loads is infused into the 3D printed PCL framework, thus fulfilling a durable energy absorbing and cushion function, which far outperforms the performance of conventional polyacrylamide hydrogel. The PNAGA-cushioned PCL construct can achieve Young's moduli of 20.15 ± 1.37 MPa in the circumferential direction and 10.43 ± 1.54 MPa in the radial direction, a compressive modulus of 1.11 ± 0.14 MPa as well as a tearing energy of 17.00 ± 2.07 kJ m −2 . This 3D printed PCL-PNAGA meniscus scaffold is implanted into rabbit knee joints for 12 weeks and in vivo outcome demonstrates the structural stability and efficient protection against wearing of the cartilage, meanwhile ameliorating the development of osteoarthritis.