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Valbenazine (VBZ) is a selective synaptic vesicle monoamine transporter 2 (VMAT2) inhibitor that counteracts the increased activity of the dopamine system by inhibiting VMAT2 activity, reducing the uptake and storage of monoamines from the cytoplasm into presynaptic vesicles, and decreasing the concentration of monoamines released into the synapse. VBZ is the first drug approved by the US FDA for using in adult patients with tardive dyskinesia. Compound P109 is a structural modification product of VBZ, which is substituted by cyclopropane methyl at position 9. It has similar pharmacological activity and pharmacological mechanism as VBZ. In order to study its metabolites in the human liver microsome incubation system, a Waters Eclipse Plus C18 column (150 mm×2.1 mm×3.5 μm) was used for separation, and 0.1% formic acid water (A)-0.1% formic acid acetonitrile (B) as the mobile phase for gradient elution. The high performance liquid chromatography coupled with four stage electrostatic field Orbitrap mass spectrometry (UHPLC-Q ExactiveTM-Orbitrap MS) was used to analyze samples in positive ion mode. Nine compounds (including P109 and its 8 metabolites) were screened, and retention time, accurate mass measurement results and fragmentation patterns were all characterized. By using the Xcaliber4.2 workstation, the accurate molecular mass was used to infer the possible element composition, and then combined with the mass spectrometry fragment information for data processing. The molecular formula prediction module was used to predict the molecular formula of the parent ion and the fragment ion, and to identify the structure of in vitro metabolites of P109. The results showed that P109 undergoes three main metabolic pathways via human liver microsomes: 1) Oxidation reaction occurs to produce compounds 2, 4 and 9; 2) Hydrolysis reaction occurs to produce metabolites 1, 3, 7 and 8; 3) Decyclopropanemethyl reaction occurs to produce metabolite 5. The reaction phenotypes of seven cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4) were studied using specific chemical inhibitor inhibition method. The content of P109 metabolites was determined by HPLC-MS/MS, and the data was analyzed by Excel software. The results showed that oxidative metabolites and dehydrogenation metabolite were mainly metabolized by CYP3A4, and the secondary metabolic subtype was CYP2C8. The decyclopropane-methyl metabolites were mainly metabolized by CYP2C8, and the secondary metabolites were CYP3A4 and CYP2D6. Hydrolysis of metabolites involved multiple subtypes of enzymes. This study can help to clarify the metabolic pathways of drugs in vivo, which is of great significance to the research of pharmacokinetics, pharmacodynamics, and drug safety evaluation. At the same time, it provides theoretical support for extrapolating the results of in vitro experiments to in vivo experiments.

Aqueous zinc ion batteries (ZIBs) are considered as promising energy storage devices in the post-lithium-ion era, due to their high energy density, low cost, high safety, and environmental benignity, however their commercialization is hindered by the sluggish diffusion kinetics of cathode materials due to the large hydrate Zn2+ radius. In this work, we propose a unique structure inheritance strategy for preparing Bi2S3 micro-straws in which a metal–organic framework (MOF) denoted as Bi-PYDC (PYDC2− = 3,5-pyridinedicarboxylate) with a string of [Bi2O2]2+ chains is judiciously selected as the structure-directing template to induce the formation of micro-straws based on a topochemical reaction. The distinctive hollow structure significantly enhances the ionic storage kinetics. Impressively, the obtained battery exhibits an ultra-long cycle life of more than 10 000 cycles at a current density of 1 A g−1 while maintaining a capacity of more than 153.4 mA h g−1. In addition, the Zn2+ insertion/extraction mechanism of Bi2S3 micro-straws is also investigated by multiple analytical methods, revealing the involvement of Zn2+ rather than H+ in the electrochemical storage process. This work may lead a new direction for constructing high performance cathodes of Zn-ion batteries through a MOF-based structure-directing template. [ABSTRACT FROM AUTHOR]

3D Bi2S3 materials were prepared by the trisodium citrate (Na3Cit)-assisted solvothermal method and applied to aqueous zinc ion batteries (AZIBs) to explore the effect of the electrode material morphology on the electrochemical performance. As the concentration of Na3Cit increases, the 3D assembly morphology evolves from coral-like to sphere-like to snowflake-like structures. The electrochemical test results show that the electrode materials of various morphologies possess excellent cycle life, but the specific capacity varies greatly depending on the morphology. Impressively, the Bi2S3-1.2 electrode has the best electrochemical performance, with a capacity of 203.5 mA h g−1 after 4000 charge/discharge cycles at 0.5 A g−1. Furthermore, the Bi2S3-1.2 electrode delivers an ultralong lifetime of over 10 000 cycles with a capacity of 150.2 mA h g−1 at 1 A g−1. This work demonstrates a feasible route to prepare ultra-long cycle life AZIBs. [ABSTRACT FROM AUTHOR]

Recently, the skyrocketing interest in smart wearable devices has led to innovations in energy-harvesting materials. Flexible thermoelectric (TE) materials have thus developed rapidly, but in this process TE performances have been over pursued, leaving the research of more practical TE self-supporting films at a less advanced level. In this work, Ag2Se/nylon self-supporting composite films with both excellent flexibility and leading TE performances (874.3 and 1825.1 μW m−1 K−2 with 80 and 90 wt% Ag2Se contents) were prepared by sequential chemical silver plating, selenization reaction and vacuum hot-pressing processes using nylon mesh as the flexible backbone, and the excellent photothermal (PT) effect of Ag2Se was introduced into the TE field for the first time to build a homogeneous synchronous photo-thermoelectric generator (PTEG). The PTEG can produce a high output voltage and power of 8.8 mV and 8.36 μW with low power NIR light irradiation of 100 mW cm−2 without a cooling source, and considerable output characteristics under visible light irradiation of different intensities can also be acquired. The superior output power can be attributed to the outstanding TE and PT characteristics of the sample, as well as the thickness optimization due to the self-supporting film. This work provides a new idea for preparing high performance flexible TE self-supporting films and developing PTEGs with high output characteristics, and the PTEGs are expected to be applied to self-powered systems for wearable devices. [ABSTRACT FROM AUTHOR]

Aims: The NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5 (NLRC5) was dysregulated in endometrial cancer (EC). However, the potential regulatory mechanisms of NLRC5 in EC remained unclear. We aimed to explore whether NLRC5 could regulate the programmed cell death protein ligand 1 (PD-L1) in EC. We also investigated the related molecular which led to the inactivation of NLRC5 in EC. Methods: The expressions of NLRC5 and PD-L1 in endometrium tissue microarray were detected by immunohistochemistry. Pearson's correlation analysis was performed to detect the expression correlation between NLRC5 and PD-L1. Immunofluorescence staining, western blotting, and quantitative real-time PCR (qRT-PCR) were used to detect the role of NLRC5 in PD-L1 in EC cell lines. The somatic mutation in EC patients was detected by whole-exome sequencing (WGS). Results: NLRC5 was downregulated in the endometrium of EC patients when compared to those in the normal endometrium. The level of PD-L1 in the endometrium of EC patients was higher when compared to those in the normal endometrium. There was a negative expression correlation between NLRC5 and PD-L1. NLRC5 could promote the expression of PD-L1 in EC cell lines. The mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Conclusion: NLRC5 could inhibit the activation of PD-L1 in EC. Mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Future study should investigate the mechanism of NLRC5 in PD-L1, as well as the mechanism of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK in NLRC5. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a noninfectious inflammatory disease seriously affecting the quality of life. This study aimed to assess the efficacy of the Tuomin Zhiti decoction in allergic rhinitis and to provide a reference for clinical treatment. One hundred patients with AR treated in the Department of Otolaryngology of our hospital from January 2019 to December 2020 were recruited and assigned via a random number table method (1 : 1) to receive either oral loratadine and mometasone nasal spray (control group) or the Tuomin Zhiti decoction plus oral loratadine and mometasone nasal spray (study group). The total clinical efficacy was 86% (43/50) in the study group, which was significantly higher than that of 64% (32/50) in the control group. After treatment, the Total Nasal Symptoms Scores (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores between the two groups were similar, but 12 weeks after treatment, the study group had significantly lower TNSS and RQLQ scores than the control group. After treatment, the study group obtained lower levels of interleukin (IL)-4 and higher levels of interferon-γ (IFN-γ) than the control group. Significantly lower post-treatment peripheral blood eosinophil count (EOS) and eosinophil cationic protein (ECP) levels were observed in the study group in contrast to those of the control group. The Tuomin Zhiti decoction for the treatment of AR patients alleviates their clinical symptoms, reduces the inflammatory responses, enhances the immune function of patients by regulating IL-4 and IFN-γ, and lowers the long-term recurrence rate. [ABSTRACT FROM AUTHOR]

Sugars are involved in plant growth, fruit quality, and signaling perception. Therefore, understanding the mechanisms involved in soluble sugar accumulation is essential to understand fruit development. Here, we report that MdPFPβ, a pyrophosphate‐dependent phosphofructokinase gene, regulates soluble sugar accumulation by enhancing the photosynthetic performance and sugar‐metabolizing enzyme activities in apple (Malus domestica Borkh.). Biochemical analysis revealed that a basic helix‐loop‐helix (bHLH) transcription factor, MdbHLH3, binds to the MdPFPβ promoter and activates its expression, thus promoting soluble sugar accumulation in apple fruit. In addition, MdPFPβ overexpression in tomato influenced photosynthesis and carbon metabolism in the plant. Furthermore, we determined that MdbHLH3 increases photosynthetic rates and soluble sugar accumulation in apple by activating MdPFPβ expression. Our results thus shed light on the mechanism of soluble sugar accumulation in apple leaves and fruit: MdbHLH3 regulates soluble sugar accumulation by activating MdPFPβ gene expression and coordinating carbohydrate allocation. [ABSTRACT FROM AUTHOR]

A series of novel 2-amino-4-aryl-pyrimidine derivatives of ursolic acid were designed, synthesized, and evaluated for their anticancer activities against four cancer cell lines (MCF-7, HeLa, HepG2, and A549) and a human hepatocyte cell line (LO2) via MTT assay. Among these derivatives, compound 7b exhibited potent cytotoxic activity against MCF-7 and HeLa cells with IC50 values of 0.48 ± 0.11 and 0.74 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. Further cellular mechanism studies in MCF-7 cells elucidated that compound 7b could inhibit cell migration, induce cell cycle arrest at S phase and trigger mitochondrial-related apoptosis by increasing the generation of intracellular ROS and decreasing the mitochondrial membrane potential (MMP), which was associated with upregulation of the protein expression level of Bax and downregulation the level of Bcl-2 and the activation of caspase cascade. Western blot analyses also revealed that compound 7b could simultaneously suppress RAS/Raf/MEK/ERK and PI3K/AKT/mTOR signaling pathways, which could be responsible for the induction of apoptosis. Molecular docking study revealed that MEK1 kinase could be one of the possible targets of the title compounds. These results offered a promising scaffold for the investigation of novel targeted anticancer agents. [ABSTRACT FROM AUTHOR]

The mechanical properties of thermally conductive composites are the key to realize their applications. Strength of materials is of significance, furthermore the toughness of materials also should attract more concern. Actually, few researchers have reported the simultaneous improvement of strength and toughness of anisotropic thermally and electrically conductive composites. Therefore, this study aims to obviously improve the in-plane thermal and electrical conductivities of nylon composites, which display superior tensile strength and toughness, compared to other thermally conductive composites. The nylon composite papers, prepared through a facile method involving vacuum-assisted filtration and compression molding processes, present a laminate structure and compact graphene nanoplatelet (GNP) stacks inside composites. On account of the special structure, the nylon composite papers show a super-high in-plane thermal conductivity of 16.0 W m−1 K−1 and electrical conductivity of 18.0 S cm−1 at a filler loading of 14.6 wt%. Surprisingly, the composite papers still exhibit a high strength of 48.3 MPa, which is comparable to that of a pure nylon film. In addition, the elongation at break of the composite paper with 14.6 wt% GNPs is as high as 34.2%, ultimately endowing the composite papers with a good toughness of 13.15 MJ m−3. The nylon composite papers successfully achieve the integration of excellent thermal and electrical conductivities, and superior strength and toughness, showing huge application values in the field of intelligent electronic device. [ABSTRACT FROM AUTHOR]

In this paper, a turn-on fluorescent probe (DBE) was designed and synthesized for probing bisulfite (HSO3−) by coupling dehydroabietic acid-based benzimidazole derivatives with ethyl cyanoacetate moiety. The structure of the compound was characterized using its UV-Vis, 1H-NMR, 13C-NMR and HRMS spectra. The probe showed significant selectivity and sensitivity towards HSO3− compared to other analytes in DMF/PBS buffer (3/7, v/v, 10 mM, pH = 7.4), and exhibited a detection limit at the nanomolar level (3.2 nM), fast response time (140 s) and good pH stability (6–10) in living systems. Furthermore, this probe was successfully utilized for the fluorescence imaging of HSO3− in living zebrafish and MCF-7 cells with remarkable lysosome-targeting properties. [ABSTRACT FROM AUTHOR]

Composites with high thermal conductivity and excellent electromagnetic interference (EMI) shielding performance are in urgent demand in the fields of wireless communication technologies and portable intelligent electronic devices. However, it remains a great challenge to simultaneously improve thermal conductivity and EMI shielding effectiveness (SE) for polymer composites. This work reports a feasible and scaled method relating to vacuum-assisted filtration and compression-molding to fabricate nylon/graphene nanoplatelet (GNP) composite papers using commercial nylon gauze and GNPs. The results show that the composite papers exhibit good flexibility and multifunctional performances. At 11.8 wt% GNPs, the three-layered composite nylon/GNP paper, which had a thickness of about 180 μm, showed high thermal and electrical conductivities of 15.8 W m−1 K−1 and 24.3 S cm−1, respectively, and an outstanding EMI SE of 58.1 dB at the X-band (8.2–12.4 GHz). The compromise of thermal conductivity and EMI SE of the composite paper is much greater than that of other multifunctional composites reported in the literature. Specifically, the composite papers also show greatly enhanced hydrophobicity and flame resistance and satisfactory mechanical properties. To sum up, this work paves the way for the real engineering application of nylon-based composite papers in next-generation electronic devices. [ABSTRACT FROM AUTHOR]

With the expectation of finding new and effective antitumor drugs, a series of novel N‐(1H‐benzo[d]imidazole‐2‐yl)‐benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF‐7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC50 values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF‐7 cells at S phase and induce the apoptosis of MCF‐7 cells in ROS‐mediated mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Tuning the magnetic anisotropy of metal ions remains highly interesting in the design of improved single‐molecule magnets (SMMs). We herein report synthetic, structural, magnetic, and computational studies of four mononuclear CoII complexes, namely [Co(hfac)2(MeCN)2] (1), [Co(hfac)2(Spy)2] (2), [Co(hfac)2(MBIm)2] (3), and [Co(hfac)2(DMF)2] (4) (MeCN=acetonitrile, hfac=hexafluoroacetylacetone, Spy=4‐styrylpyridine, MbIm=5,6‐dimethylbenzimidazole, DMF=N,N‐dimethylformamide), with distorted octahedral geometry constructed from hexafluoroacetylacetone (hfac) and various axial ligands. By a building block approach, complexes 2–4 were synthesized by recrystallization of the starting material of 1 from various ligands containing solution. Magnetic and theoretical studies reveal that 1–4 possess large positive D values and relative small E parameters, indicating easy‐plane magnetic anisotropy with significant rhombic anisotropy in 1–4. Dynamic alternative current (ac) magnetic susceptibility measurements indicate that these complexes exhibit slow magnetic relaxation under external fields, suggesting field‐induced single‐ion magnets (SIMs) of 1–4. These results provide a promising platform to achieve fine tuning of magnetic anisotropy through varying the axial ligands based on Co(II) bis(hexafluoroacetylacetonate) complexes. [ABSTRACT FROM AUTHOR]

In this paper, a series of novel 1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid bearing different N-(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their in vitro anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound 10g exhibited the most potent activity against three cancer cell lines with IC50 values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound 10g could significantly inhibit MEK1 kinase activity with IC50 of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound 10g could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound 10g could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations. [ABSTRACT FROM AUTHOR]

In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation. [ABSTRACT FROM AUTHOR]

Using dicyanamides, three two-dimensional coordination polymers (CPs) [CuII(valdmpn)LnIII(μ-1,5-dca)3]n (LnIII = Gd (1), Tb (2) and Dy (3)) were synthesized and characterized. Compounds 1–3 are two-dimensional coordination polymers bridged with μ-1,5-dca connecting the [CuII(valdmpn)LnIII]3+ units. In compounds 1–3, the Cu atom was pentacoordinated with an elongated square pyramidal (C4v) geometry, while the Ln (Gd, Tb and Dy) atom was nine-coordinated with a muffin (Cs) geometry. Detailed direct current (dc) magnetic measurements and simulated data demonstrated the existence of a ferromagnetic CuII–GdIII interaction for compound 1. Alternating current (ac) magnetic measurements revealed that compound 2 exhibited a slow magnetic relaxation behavior under a zero dc field. A hysteresis loop at 1.8 K was observed in compound 2, characteristic of typical single-molecule magnets (SMMs). However, compound 3 showed a slow magnetic relaxation behavior under a dc field. This system provides a good opportunity to determine the character of the Ln(III) ions incorporated and/or the origin of the slow magnetic relaxation behavior. [ABSTRACT FROM AUTHOR]