Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition

Rational

Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction.

Objective

The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory.

Methods

Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine.

Result

Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories.

Conclusions

These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.     

Structure and bioactivity of triterpenoids from the stems of Schisandra sphenanthera

Two new triterpenoids, schisphendilactone A and B (1 and 2), together with three known triterpenoids, were isolated from the stems of Schisandra sphenanthera. Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 was determined by single-crystal X-ray diffraction. Compound 2 showed moderate inhibitory activity against SW480 cancer cell line, and compound 5 exhibited promising anti-HIV-1 activity with EC₅₀ value of 0.52 μg ml^?1 and therapeutic index value of 117.12.     

维和二级医院药房管理体会

目的 以健全的制度和完善的管理经验,促进维和二级医院药房管理工作的开展,提高维和二级医院的服务质量.方法 对中国驻刚果（金）维和二级医院药房的管理工作特点进行分析,总结有效可行的药房工作的做法,即制订合理的管理制度,严抓制度落实并不断完善;加强药品质量管理;提高药师自身素质和管理水平.结果 药房各项制度更加健全和完善,药师的专业知识和综合能力得到明显提高,患者用药安全、经济、有效,为圆满完成联合国赋予的医疗卫生保健任务提供了强有力的保障.结论 结合维和任务区特点,建立健全制度并严抓落实、提高药师综合素质是管理好维和二级医院药房的重要措施.     

Structural Analysis of Composite Conical Convex-Concave Plate (CCCP) Using VAM-Based Equivalent Model

Compared with the ordinary foundation plate, the composite conical convex-concave plate (CCCP) has obvious anisotropic characteristics, and there is less research on the relationship between its mechanical properties and structural parameters. In this article, a numerical model for the equivalent stiffness of a typical unit cell with conical convex is established by using the variational asymptotic method. Then, the 3D finite element model (3D-FEM) of CCCP is transformed into 2D equivalent plate model (2D-EPM) with the effective plate properties obtained from the constitutive analysis of unit cell. The accuracy of 2D-EPM is verified by comparing with the displacement, natural frequencies, and buckling results from 3D-FEM under different boundary conditions. Then, the influence of geometric parameters and layup configurations on the effective performances of CCCP are investigated. Finally, the buckling loads and natural frequencies of bidirectional CCCP are compared with those of CCCP by using the present model. The present model is particularly useful in the early design stage of CCCP where many design trade-offs need to be made over a vast design space in terms of material selection, ply angles, and geometric parameters.     

Palladium nanoparticles loaded on nitrogen and boron dual-doped single-wall carbon nanohorns with high electrocatalytic activity in the oxygen reduction reaction

Palladium nanoparticles with a diameter of 2–4 nm supported on nitrogen and boron dual-doped single-wall carbon nanohorns (Pd-NBCNHs) are synthesized via a one-step method and their electrocatalytic activities are investigated for the oxygen reduction reaction (ORR) in alkaline media. The electrochemical results demonstrate that the oxygen reduction peak potential of Pd-NBCNHs is similar to that of commercial 20% Pt–C. Furthermore, Pd-NBCNHs show a more positive half-wave potential than 20% Pt–C and display better long-term stability and resistance to methanol than 20% Pt–C, which is attributed to the synergetic effect of the Pd nanoparticles and NBCNHs. As NBCNHs have abundant pyrrolic nitrogen, charged sites and defective structures, they not only act as a carrier, but also provide the active sites for oxygen adsorption during the oxygen reduction reaction process. The outstanding electrochemical performance makes Pd-NBCNHs promising to be applied in fuel cells.

Palladium nanoparticles with a diameter of 2–4 nm loaded on nitrogen and boron dual-doped single-wall carbon nanohorns (Pd-NBCNHs) are prepared via one-step method and their electrocatalytic activities are studied for the oxygen reduction reaction.     

Quantification and cytoprotection by vanillin, 4-methylguaiacol and 4-ethylguaiacol against AAPH-induced abnormal oxidative stress in HepG2 cells

Vanillin, 4-methylguaiacol, and 4-ethylguaiacol, three phenolic compounds in Gujinggong (GJG) Chinese baijiu (Chinese liquor), were quantified by liquid–liquid extraction (LLE) combined with gas chromatography-mass spectrometry (GC-MS) and evaluated for their possible cytoprotective effects by AAPH-induced HepG2 cell model. To confirm whether vanillin, 4-methylguaiacol, and 4-ethylguaiacol protected HepG2 cells against AAPH-induced abnormal oxidative stress via motivating the Keap1–Nrf2 pathway, the gene and protein expression of Nrf2, Keap1, SOD, CAT, and GPx from the Keap1–Nrf2 pathway were measured with real-time PCR and western blot. Three levels of treatment doses (1000, 500, and 100 mg L⁻¹) were applied. Results showed that vanillin, 4-methylguaiacol, and 4-ethylguaiacol exhibited potent cytoprotective effect in a dose-dependent manner, greatly alleviating or reversing the increased oxidative stress induced by AAPH through up-regulating the mRNA and protein expression levels of Nrf2, SOD, CAT, and GPx, and thereby, significantly improving the intracellular antioxidant defense system in HepG2 cells (p < 0.05). Based on these findings, it was confirmed that vanillin, 4-methylguaiacol, and 4-ethylguaiacol, natural components of Chinese baijiu, were able to modulate the expression of Nrf2 and its downstream antioxidative enzymes (i.e., SOD, CAT, and GPx) against AAPH-induced abnormal oxidative stress. Further, this study lays the foundation for better illustrating the health benefits of Chinese baijiu.

Vanillin, 4-methylguaiacol, and 4-ethylguaiacol widely exist in Gujinggong Chinese baijiu and could protect HepG2 cells against oxidative stress via activating the Nrf2 pathway.     

Synthesis,characterization and osteogenesis of phosphorylated methacrylamide chitosan hydrogels

Phosphorylated biopolymers can induce mineralization, mimic the process of natural bone formation, and have the potential as scaffolds for bone tissue engineering. 2-Methacryloyloxyethyl phosphorylcholine (MPC), a low cytotoxicity phosphorus source, is mainly applied in vascularization and promoting blood compatibility and has been less researched for bone repair. In this study, phosphorylated methacrylamide chitosan (PMAC) hydrogel was prepared by mixing methacrylamide chitosan (MAC) and different mass of MPC with photoinitiator under UV irradiation. A series characterization tests showed that PMAC hydrogels were successful prepared and had a pretty good mineralization ability. Moreover, human fetal osteoblastic (hFOB) cells cultured on PMAC hydrogels exhibited not only highly viability but also the enhanced ALP activity and calcium deposition. The PMAC hydrogels have great potential in bone tissue engineering applications.

Phosphorylated biopolymers can induce mineralization, mimic the process of natural bone formation, and have the potential as scaffolds for bone tissue engineering.