Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin.

BACKGROUND: Current antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. PURPOSE: The objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. RESULTS: We found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. CONCLUSION: Our study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.

Structure Design of GFRP Composite Leaf Spring: An Experimental and Finite Element Analysis.

Due to the high load-bearing capacity and light weight, composite leaf spring with variable width and variable thickness has been increasingly used in the automobile industry to replace the conventional steel leaf spring with a heavy weight. The optimum structural design of composite leaf spring is particularly favorable for the weight reduction. In this study, an effective algorithm is developed for structural optimization of composite leaf spring. The mechanical performance of composite leaf spring with designed dimensions is characterized using a combined experimental and computational approach. Specifically, the composite leaf spring with variable width and variable thickness was prepared using the filament winding process, and the three-dimensional finite element (FE) model of the designed composite leaf spring is developed. The experimental sample and FE model of composite leaf spring are tested under the three-point bending method. From experimental and simulation results, it is shown that the bending stiffness of the designed leaf spring meets the design requirement in the automotive industry, while the results of stress calculation along all directions meet the requirements of material strength requirement. The developed algorithm contributes to the design method for optimizing the stiffness and strength performance of the composite leaf spring.

Rational and wide-range tuning of CNT aerogel conductors with multifunctionalities.

Different from conventional conductors, elastic 3D nanoarchitectured conductors have shown promise in developing various flexible devices. However, rational design and control of their microstructures to achieve desired physicochemical properties is challenging and lacks comprehensive and profound investigation. In this study, we report an interesting quantitative correlation between density and physical properties when highly porous CNT aerogels are densified, enabling a wide-range tuning of CNT 3D networked structures with different functions. Upon densification by compressing the original thickness of a CNT aerogel by 100 fold, a linear double-logarithmic structure-property relationship in terms of both thickness and density is witnessed, with the resultant density increased by a factor of 100 from 3 to 286 mg cm-3, Young's modulus by 20 times (5.0-105 kPa), electrical conductivity by 400 times (0.4-163 s cm-1), and thermal conductivity by 140 times (0.048-6.7 W m-1 K-1). It can be thus inferred that the CNT aerogel can be regulated with desired mechanical, electrical and thermal properties in a quantitative manner over a wide range, making it promising as a multifunctional aerogel conductor. As a proof, two pieces of CNT aerogel conductors tailored with high conductivity and low thermal conductivity are employed to fabricate a flexible TE device using a simple all-carbon design, which yields a typical power density of 27.5 µW cm-2 and stable outputs under various deformations, demonstrating a potential strategy for design and fabrication of low-cost, flexible and portable power-generation devices.

Mechanical and electrical enhancement of super-aligned carbon nanotube film by organic and inorganic doping.

Inspired by the chemical and physical doping methods on traditional composites, bismaleimide (BMI) resin and graphene oxide (GO) are selected for doping modification of carbon nanotube (CNT) film in this paper. Based on the diverse enhancement effects of CNT film, the mechanisms and characteristics of resin crosslink and inorganic doping are compared. Due to the crosslinking network of resin, BMI is more beneficial for cooperative deformation and mechanical enhancement, while GO doping shows more advantages in improving electrical performance because of the numerous functional groups on the surface, and good intrinsic properties. With the appropriate doping method and optimized process conditions, the tensile property and electrical conductivity of CNT film can be improved by over 150% and 200% (e.g., tensile strength and modulus of 2990 MPa and 149 GPa, and electrical conductivity of 38 700 S m-1).

Millisecond tension-annealing for enhancing carbon nanotube fibers.

Mechanically strong carbon nanotube (CNT) fibers have increasingly become the focus of the present research in the fiber industry. However, the weak or even a lack of interconnections between adjacent CNTs induces much inter-tube slippages during fiber failure, and thus results in their low mechanical strength. Moreover, achieving fast cross-linking between neighbouring CNTs on a large scale to prevent the failure by slip is still a big challenge. Herein we report an ultrafast and continuous tension-annealing process to achieve the considerably improved tube alignment and strong covalent cross-linking of neighbouring CNTs in milliseconds, resulting in great improvement of the fiber performance. The CNT fibers were heated to high temperature (∼2450 °C) by Joule heating under the applied tension and subsequently annealed for just 12 ms. Due to the rapid electromechanical response of the fibers, instant nanotube rearrangements coupled by the formation of cross-links robustly bonding the adjacent CNTs occurred at power-on, which could be attributed to the considerable increases of strength and modulus by factors of 2.9 (up to 3.2 GPa) and 4.8 (up to 123 GPa), respectively. The resultant fibers showed high specific strength (2.2 N per tex), comparable with that of PAN-based carbon fibers, and high specific electrical conductivity higher than that of PAN-based carbon fibers. Moreover, the obtained strongly crosslinked and highly dense structures also endowed the fibers with the significantly improved thermal stability under a high-temperature oxidation atmosphere. Moreover, a continuous tension-annealing process was designed to achieve the large scale production of high performance fibers with the average strength of 2.2 GPa. The high-toughness, lightweight and continuous features together with their outstanding mechanical and electrical properties would certainly boost the large-scale applications of CNT fibers.

Next-generation Metabolomics in the Development of New Antidepressants: Using Albiflorin as an Example.

Depression is a highly prevalent disorder that affects more than 300 million adults worldwide in 2015. Depression also frequently coexists with many other conditions such as osteoporosis and one-third of the Intensive Care Unit (ICU) survivors had depressive symptoms. Antidepressants have become the most commonly prescribed drugs in the United States. In addition to the regular process, drug discovery and development (R&D) for depression presents extra challenges because of the heterogeneity of the symptoms and various co-occurring disorders. Botanical medicine with multi-functional nature has been proposed to be more effective, providing rapid control of core and comorbid conditions of depression. With the technical advances in analytical instruments, metabolomics is entering into a "new generation". Next-generation metabolomics (NGM) has the capability to comprehensively characterize drug-induced metabolic changes in the biological systems. NGM has demonstrated great potential in all the stages of pharmaceutical R&D in the last 10 years. Albiflorin isolated from Peony roots is a promising drug candidate with multi-target for depression and is currently under development by Beijing Wonner Biotech. In this work, we summarized the common analytical platforms for NGM and its main applications in drug R&D. We used albiflorin as an example to illustrate how NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation. Future directions on how to expand the use of NGM for new antidepressant development in pharmaceutical industry were also discussed.

Piezoresistivity of resin-impregnated carbon nanotube film at high temperatures.

This paper presents the development of a continuous carbon nanotube (CNT) composite film sensor with a strain detecting range of 0%-2% for structural composites. The strain-dependent resistance responses of continuous CNT film and its resin-impregnated composite films were investigated at temperatures as high as 200 °C. The results manifest that impregnation with resin leads to a much larger gauge factor than pristine film. Both the pristine and composite films show an increase in resistivity with increasing temperature. For different composite films, the ordering of gauge factors is consistent with that of the matrix moduli. This indicates that a resin matrix with higher modulus and strong interactions between CNTs/CNT bundles and the resin matrix are beneficial for enhancing the piezoresistive effect. The CNT/PAA composite film has a gauge factor of 4.3 at 150 °C, an order of magnitude higher than the metal foil sensor. Therefore, the CNT composite films have great potential for simultaneous application for reinforcement and as strain sensor to realise a multifunctional composite.

Hierarchical carbon nanotube composite yarn muscles.

Hybrid smart actuators fabricated using composites of carbon fibers and shape memory polymers have been extensively studied in recent years. However, relatively slow shape recovery has combined with the reset of shape deformation during cycles to restrict their practical use. An electrothermally reversible actuator based on carbon nanotube (CNT) composite yarn containing CNT fiber and thermoplastic polyurethane (TPU) resin with excellent shape memory was investigated in this paper. The combination of CNT yarn and TPU resin considerably amplified the contraction and stability. Large tensile stroke was obtained within 5 s (∼13.8%) while lifting a load that was ∼1905 times as heavy as the actuator. The generated contractive stress reached more than 33 MPa (corresponding to 120 g of the load) at a weight-to-yarn mass ratio of 28 400, which was about 30 times more than the shape recovery stress of shape memory polymer. In terms of the stability study, the process of annealing and contraction training was introduced. In addition, the quantitative relationship between temperature and contraction was also rigorously explored, which facilitated a more accurate and controllable contractile stroke. Great potential applications ranging from soft robots, wearable intelligent devices, and biomimetic devices to self-deployable structures in the aerospace field are likely to benefit from the advantages of low density, fast response without hysteresis, super flexible structure, as well as stitchability and large-scale production.

Densification of chlorine-doped continuous CNT sheet/polyvinylidene fluoride sandwich film and improvement of the mechanical and dielectric properties.

The compact structure of a chlorine-doped continuous CNT sheet/polyvinylidene fluoride (Cl-CNT sheet/PVDF) was successfully optimized by means of a hot-press treatment to improve the mechanical and dielectric properties with a high densification degree. Then, the densified Cl-CNT sheet/PVDF dielectric layer was inserted between two PVDF insulating layers to fabricate a sandwich composite. It was found that the dielectric and mechanical properties were effectively enhanced, with a dielectric permittivity of 40.4 (@102 Hz), a dielectric loss of 0.16 (@102 Hz), a tensile strength of 139 MPa, and a tensile modulus of 4.4 GPa under a hot-pressing pressure of 20 MPa. Furthermore, the densified Cl-CNT sheet/PVDF was used as an electrode in a multilayer sandwich composite film, and good performance was obtained. The improvement mechanism was discussed and the studied CNT composite and other dielectric composites were compared. It demonstrates great potential for applications in dielectric and electrode materials to achieve structural and functional integration.

Gut-brain axis metabolic pathway regulates antidepressant efficacy of albiflorin.

The gut microbiota is increasingly recognized to influence brain function through the gut-brain axis. Albiflorin, an antidepressant natural drug in China with a good safety profile, is difficult to absorb and cannot be detected in the brain after oral administration. Accordingly, the antidepressant mechanism of albiflorin in vivo has not been elucidated clearly. Methods: We identified benzoic acid as the characteristic metabolite of albiflorin in vivo and in vitro, then discovered the roles of gut microbiota in the conversion of albiflorin by carboxylesterase. Pharmacodynamic and pharmacokinetic studies were performed for the antidepressant activities of albiflorin in animals, and the efficacy of benzoic acid in inhibiting D-amino acid oxidase (DAAO) in brain was further investigated. Results: We validated that gut microbiota transformed albiflorin to benzoic acid, a key metabolite in the intestine that could cross the blood-brain barrier and, as an inhibitor of DAAO in the brain, improved brain function and exerted antidepressant activity in vivo. Intestinal carboxylesterase was the crucial enzyme that generated benzoic acid from albiflorin. Additionally, the regulatory effect of albiflorin on the gut microbiota composition was beneficial to alleviate depression. Conclusion: Our findings suggest a novel gut-brain dialogue through intestinal benzoic acid for the treatment of depression and reveal that the gut microbiota may play a causal role in the pathogenesis and treatment of the central nervous system disease.

Tuning carbon nanotube assembly for flexible, strong and conductive films.

Carbon nanotubes are ideal scaffolds for designing and architecting flexible graphite films with tunable mechanical, electrical and thermal properties. Herein, we demonstrate that the assembly of aligned carbon nanotubes with different aggregation density and morphology leads to different mechanical properties and anisotropic electrical conduction along the films. Using drying evaporation under tension treatment, the carbon nanotubes can be assembled into strong films with tensile strength and Young's modulus as high as 3.2 GPa and 124 GPa, respectively, leading to a remarkable toughness of 54.38 J g(-1), greatly outperforming conventional graphite films, spider webs and even Kevlar fiber films. Different types of solvents may result in the assembly of CNTs with different aggregation morphology and therefore different modulus. In addition, we reveal that the high density assembly of aligned CNTs correlates with better electric conduction along the axial direction, enabling these flexible graphite films to be both strong and conductive.

Highly aligned dense carbon nanotube sheets induced by multiple stretching and pressing.

The CNT sheet fabricated by the floating catalyst chemical vapor deposition (CVD) method has attracted great attention due to its easy fabrication process and promising mass production at low cost. However, the randomly oriented CNT sheet with a loose stacking density shows relatively poor mechanical properties. In this work, a highly aligned dense CNT sheet was successfully fabricated by a simple process of two-time stretching and pressing of a multilayered CVD-grown CNT sheet. Drastic nanotube rearrangements occurred during stretching and pressing processes. A polymer-like tensile necking behavior was observed during the stretching process, accompanied by inter-tube junction breakage due to long-distance slippage. Simultaneously the CNT sheet was thickened after the stretching process due to the increase of the inter-layer space, which could be effectively eliminated by the following pressing treatment. After two-time stretching and pressing, a highly aligned dense CNT sheet was fabricated with the volume density increasing to 0.98 g cm(-3) (by 109%) and the tensile strength increasing to 598 MPa (by 221%) compared to the as-prepared CNT sheet.