Retinoic Acid Receptor Is a Novel Therapeutic Target for Postoperative Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterizing by cognitive impairments in the elderly after surgery. There is limited effective treatment available or clear pathological mechanisms known for this syndrome. In this study, a Connectivity Map (CMap) bioinformatics model of POCD was established by using differently expressed landmark genes in the serum samples of POCD and non-POCD patients from the only human transcriptome study. The predictability and reliability of this model were further supported by the positive CMap scores of known POCD inducers and the negative CMap scores of anti-POCD drug candidates. Most retinoic acid receptor (RAR) agonists were negatively associated with POCD in this CMap model, suggesting that RAR might be a novel target for POCD. Most importantly, acitretin, a clinically used RAR agonist, significantly inhibited surgery-induced cognitive impairments and prevented the reduction in RARα and RARα-target genes in the hippocampal regions of aged mice. The study denotes a reliable CMap bioinformatics model of POCD for future use and establishes that RAR is a novel therapeutic target for treating this clinical syndrome.

Fucoxanthin, a marine derived carotenoid, attenuates surgery-induced cognitive impairments via activating Akt and ERK pathways in aged mice.

BACKGROUND: Fucoxanthin is the most abundant marine carotenoid derived from brown seaweeds, possesses antioxidant, anti-inflammatory, and neuroprotective properties, and might be benefit for the treatment of neurological disorders. Post-operative cognitive dysfunction (POCD) is a neurological symptom with learning and memory impairments, mainly affecting the elderly after surgery. However, there is no effective treatments for this symptom. PURPOSES: In this study, we evaluated the neuroprotective effects of fucoxanthin against POCD in aged mice after surgery. STUDY DESIGN AND METHODS: The animal model of POCD was established in 12 - 14 month aged mice with a laparotomy. Curcumin was used as a positive control. The beneficial effects of fucoxanthin on POCD was analyzed by behavioral tests. Pro-inflammatory cytokines were measured by Enzyme-linked Immunosorbent Assay (ELISA). And the expressions of key proteins in the Akt and ERK signaling pathways were analyzed by Western blotting analysis. The morphology of microglial cells and astrocytes was explored by immunohistochemical staining. The activity of antioxidant superoxide dismutase (SOD) and catalase (CAT) were measured by anti-oxidative enzyme activity assays. RESULTS: Fucoxanthin at 100 - 200 mg/kg significantly attenuated cognitive dysfunction, with a similar potency as curcumin, in aged mice after surgery. In addition, fucoxanthin and curcumin significantly increased the expression of pAkt, prevented the activation of microglial cells and astrocytes, and inhibited the secretion of pro-inflammatory interleukin-1ß (IL - 1ß) and tumor necrosis factor-α (TNF-α). Furthermore, fucoxanthin and curcumin elevated the ERK pathway and potently increased the activity of antioxidant enzymes. Most importantly, U0126, an inhibitor of the ERK pathway, and wortmannin, an inhibitor of the Akt pathway, significantly abolished the cognitive-enhancing effects, as well as the inhibition of neuroinflammation and the reduction of oxidative stress, induced by fucoxanthin in aged mice after surgery. CONCLUSION: Fucoxanthin might be developed as a functional food or drug for the treatment of POCD by inhibiting neuroinflammation and enhancing antioxidant capacity via the activation of the Akt and ERK signaling pathways.

M2 Macrophages-Derived Exosomal miRNA-23a-3p Promotes the Progression of Oral Squamous Cell Carcinoma by Targeting PTEN.

Exosomes from tumor cells and immune cells regulate the tumor microenvironment through the biomolecules or microRNAs (miRNAs) they carry. This research aims to investigate the role of miRNA in exosomes derived from tumor-associated macrophages (TAMs) in the progression of oral squamous cell carcinoma (OSCC). RT-qPCR and Western blotting assays were used to determine the expression of genes and proteins in OSCC cells. CCK-8, Scratch assay and invasion-related proteins were utilized to detect the malignant progression of tumor cells. High-throughput sequencing predicted differentially expressed miRNAs in exosomes secreted by M0 and M2 macrophages. Compared with exosomes from M0 macrophages, exosomes from M2 macrophages led to enhanced proliferation and invasion of OSCC cells and inhibited their apoptosis. High-throughput sequencing results show that miR-23a-3p is differentially expressed in exosomes from M0 and M2 macrophages. MiRNA target gene database predicts that phosphatase and tensin homolog (PTEN) are target genes of miR-23a-3p. Further studies revealed that transfection of miR-23a-3p mimics inhibited PTEN expression in vivo and in vitro and promoted the malignant progression of OSCC cells, which was reversed by miR-23a-3p inhibitors. MiR-23a-3p in exosomes derived from M2 macrophages promotes malignant progression of OSCC. PTEN is a potential intracellular target of miR-23a-3p. MiR-23a-3p, an M2 macrophage-associated exosome, is a promising target for the future treatment of OSCC.

Discrepancy of synaptic and microtubular protein phosphorylation in the hippocampus of APP/PS1 and MAPT×P301S transgenic mice at the early stage of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is caused by multiple pathological factors, such as the overproduction of ß-amyloid (Aß) and the hyperphosphorylation of tau. However, there is limited knowledge of the mechanisms underlying AD pathogenesis and no effective biomarker for the early diagnosis of this disorder. Thus in this study, a quantitative phosphoproteomics analysis was performed to evaluate global protein phosphorylation in the hippocampus of Aß overexpressing APP/PS1 transgenic mice and tau overexpressing MAPT×P301S transgenic mice, two in vivo AD model systems. These animals, up to ten weeks old, do not exhibit cognitive dysfunctions and are widely used to simulate early-stage AD patients. The number of differentially phosphorylated proteins (DPPs) was greater for APP/PS1 transgenic mice than for MAPT×P301S transgenic mice. The function of the DPPs in APP/PS1 transgenic mice was mainly related to synapses, while the function of the DPPs in MAPT×P301S transgenic mice was mainly related to microtubules. In addition, an AD core network was established including seven phosphoproteins differentially expressed in both animal models, and the function of this core network was related to synapses and oxidative stress. The results of this study suggest that Aß and tau induce different protein phosphorylation profiles in the early stage of AD, leading to the dysfunctions in synapses and microtubule, respectively. And the detection of same DPPs in these animal models might be used for early AD diagnosis.

A Study on Drilling of CFRP/Ti Stacks: Temperature Field and Thermal Damage of the Interface Region.

Carbon fiber reinforced plastics (CFRP)/titanium alloy (Ti) stacks have been widely used in aviation field due to the superior mechanical properties. During integrated drilling of CFRP/Ti stacks, serious damage occurs in the CFRP layer because of the disparate properties of two stack components. Heat accumulation and thermal induced damage are typical and critical issue during drilling stacks, especially in the interface region. In this study, in order to deeply analyze the thermal influence of the interface region, a numerical model based on the finite difference method is developed to predict the three-dimensional drilling temperature field. Experiments with accurate measurement point are conducted to valid the rational of temperature prediction model. The results confirm that the temperature distributions predicted by numerical study have good agreements with the experimental results and the maximum error is about 10.3%. Furtherly, based on the drilling experiments, it can be found that thermal damage induced by cutting heat occurs as discoloration rings around the hole which could cause the elastic modulus of resin matrix decrease. An empirical model of thermal damage with maximum drilling temperature of the interface region are developed with the correlation of R2 = 0.97. The findings point out that as the maximum drilling temperature exceeds 410 °C, serious thermal damage could occur in the resin matrix of CFRP layer.

Rose Bengal inhibits ß-amyloid oligomers-induced tau hyperphosphorylation via acting on Akt and CDK5 kinases.

RATIONALE: Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer's disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents. OBJECTIVES: The research aimed to investigate if and how RB could prevent ß-amyloid (Aß) oligomers-induced tau hyperphosphorylation in rodents. METHODS AND RESULTS: RB was tested in vitro (0.3-1 µM) and prevented Aß oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10-30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aß oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3ß (GSK3ß) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3ß and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. CONCLUSIONS: RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3ß and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.

Phloroglucinol, a clinical-used antispasmodic, inhibits amyloid aggregation and degrades the pre-formed amyloid proteins.

Amyloid proteins, such as ß-amyloid (Aß) and α-synuclein (α-syn), could form neurotoxic aggregates during the progression of neurodegenerative disorders. Phloroglucinol, a clinical-used drug for treating spasmodic pain, was predicted to cross the blood brain-barrier and possesses neuroprotective potential. In this study, we have found, for the first time, that phloroglucinol inhibited the formation of amyloid aggregates, and degraded pre-formed amyloid aggregates with the similar efficacy as curcumin, a widely known amyloid aggregation inhibitor. Moreover, phloroglucinol decreased the seeding during aggregation process and inhibited the aggregation of Aß1-42 with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aß1-42/α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aß1-42 + Hcy aggregates-induced cognitive impairments in mice. All these results suggested that phloroglucinol possesses the ability to degrade pre-formed amyloid aggregates, to inhibit the seeding during amyloid aggregation, and to reduce the neurotoxicity, indicating the reposition possibility of phloroglucinol as a novel drug for treating neurodegenerative disorders.

Study on the Cutting Damage Mechanism of Aramid Honeycomb Based on the Progressive Damage Model.

A progressive damage model for aramid honeycomb cutting was proposed to reveal its cutting damage mechanism. It established the relationship between the mesoscale failure modes and the macroscale cutting damage types of the aramid honeycomb. The proposed model addressed the material assignment problem of impregnated honeycomb by developing a material calculation method that simulates the real manufacturing process of the aramid honeycomb. Cutting experiment of aramid honeycomb specimen was conducted concerning on the cutting forces response and cutting damages, which validated that the proposed method was effective for investigating the cutting process and mechanism for the aramid honeycomb. Predicted cutting mechanism results show that: (a) cutting process of the aramid honeycomb can be divided into three stages with four characteristic states-initial state, cut-in state, cut-out state and final state; (b) cell wall bending in the cutting direction relieves the cutting force, and strong plasticity of the aramid fiber makes it hard to break, which lead to uncut fiber and burr damages; (c) using sharp tip cutting tool to reduce cutting force and bonding both top and bottom of the honeycomb to make it stiffer are beneficial to obtain good cutting quality with less damages.

Outdoor Wood Mats-Based Engineering Composite: Influence of Process Parameters on Decay Resistance against Wood-Degrading Fungi Trametes versicolor and Gloeophyllum trabeum.

The process parameters significantly influence the preparation and final properties of outdoor wood mats-based engineering composite (OWMEC). During outdoor use, wood composites are susceptible to destruction by rot fungi. Herein, the role of process parameters such as density and resin content on OWMEC resistance to fungal decay was investigated. The poplar OWMEC samples were exposed to white-rot fungus Trametes versicolor and brown-rot fungus Gloeophyllum trabeum for a period of 12 weeks. The chemical composition, crystallinity, and morphology were evaluated to investigate the effect of process parameters on the chemical composition and microstructure of the decayed OWMEC. With an increase in the density and resin content, the mass loss of the decayed OWMEC decreased. The highest antifungal effect against T. versicolor (12.34% mass loss) and G. trabeum (19.43% mass loss) were observed at a density of 1.15 g/m3 and resin content of 13%. As results of the chemical composition and microstructure measurements, the resistance of OWMEC against T. versicolor and G. trabeum fungi was improved remarkably by increasing the density and resin content. The results of this study will provide a technical basis to improve the decay resistance of OWMEC in outdoor environments.

Flame retardant and visible light-activated Fe-doped TiO2 thin films anchored to wood surfaces for the photocatalytic degradation of gaseous formaldehyde.

Flame retardant and visible light-activated Fe-doped TiO2 thin films were anchored to wood surfaces by a facile precipitation method for the photocatalytic degradation of gaseous formaldehyde. All of the as-prepared TiO2 thin films exhibited the anatase crystal structure and grew on the wood surfaces by the aggregation of nanoparticles with diameters ranging from 11 to 16 nm. The UV-vis diffuse reflectance spectroscopy (UV-vis DRS) results showed that the presence of a small amount of iron ions in the TiO2 matrix could significantly extend the optical responses in the UV to visible region. Compared to the pure TiO2/wood samples, the Fe-doped TiO2/wood samples exhibited higher photocatalytic activities under visible light irradiation. The optimum nFe/nTi molar ratio was 2.0 at. %. The electron spin resonance (ESR) tests further confirmed that the active oxygen species of OH and O2- that were generated on the Fe-doped TiO2/wood samples under visible light irradiation are responsible for the degradation of formaldehyde. The Fe-doped TiO2 samples also exhibited high stability and reusability after 6 cycles. Additionally, the limiting oxygen index of the original wood increased from 24.8% to 33.9% after it was coated with Fe-doped TiO2 thin films, indicating a significant improvement in its flame resistance.