A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO.

N 6-Methyladenosine (m6A) is the most prevalent mRNA modification and is required for gene regulation in eukaryotes. ALKBH5, an m6A demethylase, is a promising target, particularly for anticancer drug discovery. However, the development of selective and potent inhibitors of ALKBH5 rather than FTO remains challenging. Herein, we used a targeted covalent inhibition strategy and identified a covalent inhibitor, TD19, which selectively inhibits ALKBH5 compared with FTO demethylase in protein-based and tumor cell-based assays. TD19 irreversibly modifies the residues C100 and C267, preventing ALKBH5 from binding to m6A-containing RNA. Moreover, TD19 displays good anticancer efficacy in acute myeloid leukemia and glioblastoma multiforme cell lines. Thus, the ALKBH5 inhibitor developed in this study, which selectively targets ALKBH5 compared with FTO, can potentially be used as a probe for investigating the biological functions of RNA demethylase and as a lead compound in anticancer research.

Development of Sustainable and Active Food Packaging Materials Composed by Chitosan, Polyvinyl Alcohol and Quercetin Functionalized Layered Clay.

In order to solve the problems of insufficient active functions (antibacterial and antioxidant activities) and the poor degradability of traditional plastic packaging materials, biodegradable chitosan (CS)/polyvinyl alcohol (PVA) nanocomposite active films reinforced with natural plant polyphenol-quercetin functionalized layered clay nanosheets (QUE-LDHs) were prepared by a solution casting method. In this study, QUE-LDHs realizes a combination of the active functions of QUE and the enhancement effect of LDHs nanosheets through the deposition and complexation of QUE and copper ions on the LDHs. Infrared and thermal analysis results revealed that there was a strong interface interaction between QUE-LDHs and CS/PVA matrix, resulting in the limited movement of PVA molecules and the increase in glass transition temperature and melting temperature. With the addition of QUE-LDHs, the active films showed excellent UV barrier, antibacterial, antioxidant properties and tensile strength, and still had certain transparency in the range of visible light. As QUE-LDHs content was 3 wt%, the active films exhibited a maximum tensile strength of 58.9 MPa, representing a significant increase of 40.9% compared with CS/PVA matrix. Notably, the UV barrier (280 nm), antibacterial (E. coli) and antioxidant activities (DPPH method) of the active films achieved 100.0%, 95.5% and 58.9%, respectively. Therefore, CS/PVA matrix reinforced with QUE-LDHs has good potential to act as an environmentally and friendly active packaging film or coating.

Golgi-protein 73 facilitates vimentin polymerization in hepatocellular carcinoma.

Golgi-protein 73 (GP73) is highly expressed in hepatocellular carcinoma (HCC) and, as a secretory protein, it has been proposed as a serum biomarker indicating progression of HCC. The underlying mechanism by which GP73 may promote HCC metastasis is still poorly understood. In this study, we discovered that GP73 interacted with vimentin to facilitate Serine/Threonine-protein phosphatase PP1-alpha (PP1A)-mediated dephosphorylation of vimentin at S56 and facilitated vimentin polymerization, which blocked vimentin degradation via TRIM56-mediated ubiquitin/proteasome-dependent pathway. Strikingly, Clomipramine, a 5-hydroxytryptamine receptor (5-HTR) agonist approved for the treatment of depression, impaired GP73-mediated vimentin polymerization to effectively inhibit metastasis of HCC with high GP73 expression, which provided a new strategy against HCC metastasis. Lastly, it was found that serum GP73 (sGP73) correlated positively with vimentin in primary tissues of HCC, suggesting that sGP73 might serve as a potential serum biomarker for companion diagnosis of HCC with highly expressed vimentin. In summary, this study reveals the process of GP73-mediated vimentin polymerization and proves that Clomipramine serves as a potential drug targeting vimentin for metastatic HCC patients with high sGP73 level.

Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents.

Glioblastoma (GBM) is an aggressive brain tumor with extremely limited clinical treatment options. Because of the blood-brain barrier (BBB), it is difficult for anti-GBM drug candidates to enter the brain to exert their therapeutic effects. The spirocyclic skeleton structure exhibits good lipophilicity and permeability, enabling small-molecule compounds to cross the BBB. Herein, we designed and synthesized novel 3-oxetanone-derived spirocyclic compounds containing a spiro[3.4]octane ring and determined their structure-activity relationship for antiproliferation in GBM cells. Among these, the chalcone-spirocycle hybrid 10m/ZS44 exhibited high antiproliferative activity in U251 cells and permeability in vitro. Furthermore, 10m/ZS44 activated the SIRT1/p53-mediated apoptosis pathway to inhibit proliferation in U251 cells, whereas it minimally impaired other cell-death pathways, such as pyroptosis or necroptosis. In a mouse xenograft model, 10m/ZS44 exhibited a substantial inhibitory effect on GBM tumor growth without showing obvious toxicity. Overall, 10m/ZS44 represents a promising spirocyclic compound for the treatment of GBM.

The Key to Solving Plastic Packaging Wastes: Design for Recycling and Recycling Technology.

Confronted with serious environmental problems caused by the growing mountains of plastic packaging waste, the prevention and control of plastic waste has become a major concern for most countries. In addition to the recycling of plastic wastes, design for recycling can effectively prevent plastic packaging from turning into solid waste at the source. The reasons are that the design for recycling can extend the life cycle of plastic packaging and increase the recycling values of plastic waste; moreover, recycling technologies are helpful for improving the properties of recycled plastics and expanding the application market for recycled materials. This review systematically discussed the present theory, practice, strategies, and methods of design for recycling plastic packaging and extracted valuable advanced design ideas and successful cases. Furthermore, the development status of automatic sorting methods, mechanical recycling of individual and mixed plastic waste, as well as chemical recycling of thermoplastic and thermosetting plastic waste, were comprehensively summarized. The combination of the front-end design for recycling and the back-end recycling technologies can accelerate the transformation of the plastic packaging industry from an unsustainable model to an economic cycle model and then achieve the unity of economic, ecological, and social benefits.

Effects of electrode materials and dimensions of an electrostatic spray scrubber on water droplet charging for dust removal.

Droplet charging is an effective method to enhance dust removal efficiency using an electrostatic spray scrubber (ESS). However, effects of the materials and dimensions of different electrodes on droplet charging efficiency have not been studied systematically. In this study, ring-shaped electrodes were selected to test effects of three types of electrode materials (copper, stainless steel, and graphite) with various dimensions on droplet charging efficiency. A Faraday pail charge measurement device was used to measure the droplet charge generated by the electrodes. A reduced factorial design with four factors was used in this study to investigate the charging efficiency affected by the factors. The four factors tested were electrode material, electrode diameter, nozzle height, and applied voltage. A 304L stainless steel electrode was found to achieve higher droplet charge-to-mass ratio (CMR) values than identically shaped electrodes made from either copper or graphite. The optimal stainless steel electrode inner diameter was 100 mm. The 304L stainless-steel electrode with this optimal diameter and a height of 45 mm achieved the highest mean CMR of 0.435 ± 0.002 mC kg-1 at an applied voltage of -11 kV with the bottom of the nozzle tip positioned 15 mm below the top of the electrode.Implications Currently, the low removal efficiency of submicron particles cannot meet the environmental control requirements of industrial applications that may have significant concentrations of particulate matter (PM) in this size range. As stricter environmental regulations are increasingly enforced, there is an urgent need to efficiently remove submicron dust particles from the air. Experiments show that the dust capture process is improved by charging droplets in the spray separator and reducing the secondary escape of dust particles in the electrostatic precipitatorAlthough high-voltage charging of droplets has been investigated in many studies, the effect of electrode material and size on droplet CMR is still not fully understood. The purpose of this study was to (1) quantify the performance of 304L stainless steel (304L SS), copper, and high-purity graphite electrodes for spray droplet CMR, (2) evaluate effects of the applied voltage, nozzle height, electrode material and dimension on CMR, and (3) optimize the specific values of key design factors and operating parameters that lead to the highest CMR. The results of this study aim to optimize electrostatic spray scrubbers to achieve high droplet CMR values.

An Electrochemical Way to Generate Amphiphiles from Hydrazones for the Synthesis of 1,2,4-Triazole Scaffold Cyclic Compounds.

An electro-oxidative cyclization pathway in which hydrazones are selected as starting materials to generate amphiphiles by reacting with benzylamines and benzamides was reported. This strategy successfully prepared a series of 1,2,4-triazoles in satisfactory yields. Moreover, the use of cheap stainless steel as the anode, the feasibility to conduct the transformation as a one-pot reaction and the proof that scaling-up these reactions is possible make this transformation attractive for potential application in industry.

Ambient electric arc ionization for versatile sample analysis using mass spectrometry.

A novel, convenient ambient electric arc ionization (AEAI) device was developed as a mass spectrometry ion source for versatile sample analysis. AEAI could be considered as a soft ionization technique in which the protonated ion ([M + H]+) is the main ion species with little or no in-source fragmentation for most analytes. Coupled with a high-resolution Orbitrap mass spectrometer, AEAI could be applied to the analysis of a variety of organic compounds having a wide range of polarities, ranging from non-polar species such as polybenzenoid aromatic hydrocarbons (PAHs) to highly polar species such as amino acids. With its versatile capabilities in the mass spectrometric analysis of small molecules, AEAI has the potential to be an alternative to traditional ionization methods such as electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and electron impact (EI) ionization. The limitations of AEAI are also discussed.

The Crosstalk Between Cancer Cells and Neutrophils Enhances Hepatocellular Carcinoma Metastasis via Neutrophil Extracellular Traps-Associated Cathepsin G Component: A Potential Therapeutic Target.

BACKGROUND: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigated the roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer. METHODS: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays. RESULTS: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by co-culture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidase-dependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients. CONCLUSION: Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer-host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression.

Improved mechanical, antibacterial and UV barrier properties of catechol-functionalized chitosan/polyvinyl alcohol biodegradable composites for active food packaging.

Bioinspired from adhesion behaviors of mussels, we first reported a new strategy to prepare catechol-functionalized chitosan (C-CS)/polyvinyl alcohol (PVA) composite films via a solution blending method in neutral aqueous solution for active food packaging. Compared with pure PVA film, the UV transmittance (at 280 nm) of C-CS/PVA composite films decreases by 67.6 % when C-CS content reaches 10 wt%. Still, all the C-CS/PVA composite films are transparent in the visible range. The maximal tensile strength and elongation at break of C-CS/PVA composite films can reach 45.2 MPa and 153 % respectively, which are 46.3 % and 25.4 % higher than those of pure PVA film. The incorporation of C-CS into PVA matrix increases the antibacterial properties significantly. The water resistance of C-CS/PVA composite films can not be significantly deteriorated by the appropriate amount of C-CS. Therefore, C-CS/PVA composite films show great potential in the field of active packaging due to its good mechanical, antibacterial and UV barrier properties.

Design, synthesis, and evaluation of novel coumarin-dithiocarbamate derivatives (IDs) as anti-colorectal cancer agents.

Colorectal cancer (CRC) is a common malignant tumour of human digestive tract. The high mortality rate of CRC is closely related to the limitations of existing treatments. Thus, there is an urgent need to search for new anti-CRC agents. In this work, twenty novel coumarin-dithiocarbamate derivatives (IDs) were designed, synthesized and evaluated in vitro. The results suggest that the most active compound ID-11 effectively inhibited the proliferation of CRC cell lines while shown little impact on normal colon epithelial cells. Mechanism studies revealed that ID-11 displayed bromodomain-containing protein 4 inhibitory activity, and induced G2/M phase arrest, apoptosis as well as decreased the expression levels of the key genes such as c-Myc and Bcl-2 in CRC cell lines. Moreover, the ADMET properties prediction results shown that ID-11 possess well metabolic characteristics without obvious toxicities. Our data demonstrated that compound ID-11 may be a promising anti-CRC agent and deserved for further development.

Discovery of novel 2-aryl-3-sulfonamido-pyridines (HoAns) as microtubule polymerization inhibitors with potent antitumor activities.

Microtubules play a vital role in cell mitosis. Drugs targeting taxol or vinca binding site of tubulin have been proved an effective way to against cancer. However, drug resistance and cancer recurrence are inevitable, there is an urgent need to search for new microtubule-targeting agents (MTAs). In our study, a series of novel 2-aryl-3-sulfonamido-pyridines (HoAns) had been designed, synthesized, and evaluated for their antiproliferative activities in vitro and in vivo. Among them, compound HoAn32 exhibited the most potent activity with IC50 values ranging from 0.170 to 1.193 µM in a panel of cancer cell lines. Mechanism studies indicated that compound HoAn32 bound to the colchicine site of ß-tubulin, resulting in colony formation inhibition, G2/M phase cell cycle arrest, cell apoptosis as well as increased the generation of ROS in both RKO and SW620 cells. In addition, compound HoAn32 showed potent anti-vascular activity in vitro. Furthermore, compound HoAn32 also exhibited outstanding antitumor activity in SW620 xenograft tumor models without observable toxic effects, which was more potent than that of ABT-751. In conclusion, our findings suggest that compound HoAn32 may be a promising microtubule destabilizing agent and deserves for further development in cancer therapy.

Canopy spray application technology in specialty crops: a slowly evolving landscape.

Many specialty crops are susceptible to insects and diseases, and as such are reliant on regular canopy pesticide applications to achieve quality attributes required for salability. The majority of specialty crop producers continue to use antiquated pesticide application technologies for directed canopy spraying such as the radial air blast sprayer that has been associated with chemical wastage and off-target drift of around 40% and 15% of total applied spray volume, respectively. However, precision sprayers are available that result in remarkable improvements to these parameters. The wide-scale adoption of precision sprayers by specialty crop producers remains low. Reasons for the continued dominance of old technologies include risk averseness of farmers and regulatory bottlenecks. However, as farm labor becomes more expensive, less available, and consumers and regulations favor sustainably produced products, motivations to improve spray application efficiency are increasing. While there are many opportunities and future directions application technology may take, sensor-controlled sprayer technology that applies a proportionate amount of spray will likely be the primary technology of precision sprayers going into the future. © 2020 Society of Chemical Industry.

Copper/Palladium Bimetallic System for the Synthesis of Isobenzofuranones through [4 + 1] Annulation between Propiophenones and Benzoic Acids.

A copper/palladium-catalyzed annulation from benzoic acids and propiophenones for the synthesis of isobenzofuranones was reported. The Cu-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl system showed a great ability to activate the C-H bond on the α- and ß-carbons of a carbonyl group, and the in situ-generated enone intermediate in this reaction could be further transformed to construct isobenzofuranones with the catalysis of Pd(dba)2 (dba = dibenzylideneacetone). Various isobenzofuranones could be obtained in moderate to good yields, and a great atom economy was highlighted by utilizing this method.

Evaluation of the Intelligent Sprayer System in Peach Production.

Air-blast sprayers are routinely used to apply pesticides in commercial peach orchards, with growers using both conventional air-blast and ultrasonic sensor-driven models. Even with advanced spray technologies, there are still concerns with the amount of chemicals used and lost to drift. Our study evaluated a laser sensor-based variable-rate sprayer system in three experimental peach orchards for pest and brown rot disease control, spray volume output, spray coverage, and spray drift. A single 378-liter air-blast sprayer was used for both the conventional air-blast and the Intelligent Sprayer (iSprayer) treatments. Treatments were started at the phenological stage of bloom and continued through final swell. The iSprayer treatment was as effective in controlling pests and brown rot disease as the conventional air-blast treatment. Compared with the conventional air-blast treatment, the iSprayer treatment reduced the spray volume (liters/hectare) in cultivar PF23 by 71% at bloom, 62% at pit hardening, and 55% at final swell. For Juneprince, the spray volume reduction was 50% at bloom, 40% at pit hardening, and 13% at final swell. Spray drift was significantly (P < 0.05) reduced only at bloom in the iSprayer treatment. Spray coverage was increased by 50.13 and 26.67% in the iSprayer treatment at bloom and pit hardening, respectively, but not at final swell. Our results show that the iSprayer maintained pest and disease control efficacy in peach orchards while reducing spray volume and drift compared with the conventional air-blast treatment.

Synthesis of unsymmetrical disulfides via PPh3-mediated reductive coupling of thiophenols with sulfonyl chlorides.

A facile and rapid synthesis of unsymmetrical aryl disulfides using PPh3-mediated reductive coupling of thiophenols with aryl sulfonyl chlorides was described. Good functional group tolerance and scalability were achieved in this strategy. More importantly, the approach enables the introduction of sulfonyl chlorides into the synthesis of asymmetric organic disulfides under catalyst- and base-free conditions. Using this method, unsymmetrical aromatic disulfides could be prepared from inexpensive and readily available starting materials in moderate to excellent isolated yields, through a nucleophilic substitution pathway.

Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a.

BACKGROUND: Gastric cancer is one of the leading causes of cancer-related deaths. Allylated monocarbonyl analogs of curcumin (MACs) have been reported to selectively inhibit a broad range of human cancers including gastric cancer. However, the precise molecular mechanisms underlying the inhibitory activities of MACs are not fully known. METHODS: In this study, we examined the anti-tumor activities of an allylated MAC, CA6, on gastric cancer cells and gastric cancer xenograft mouse model. The potential molecular anti-tumor mechanisms of CA6 were also elucidated. RESULTS: Our data show that CA6 exhibited significant cytotoxicity in gastric cancer cells, which was seen as an induction of G2/M cell cycle arrest and apoptosis. These activities were mediated through an elaboration of ROS levels in gastric cancer cells and induction of endoplasmic reticulum stress. CA6 increased ROS levels through directly binding to and inhibiting thioredoxin reductase R1 (TrxR1). Also, CA6-generated ROS inhibited Akt and activated forkhead O3A (FoxO3a), causing cytotoxicity in gastric cancer cells. Finally, CA6 treatment dose-dependently reduced the growth of gastric cancer xenografts in tumor-bearing mice, which was associated with reduced TrxR1 activity and increased ROS in the tumor. CONCLUSION: In summary, our studies demonstrate that CA6 inhibited gastric cancer growth by inhibiting TrxR1 and increasing ROS, which in turn activated FoxO3a through suppressing Akt. CA6 is a potential candidate for the treatment of gastric cancer.

Development of Fast E-nose System for Early-Stage Diagnosis of Aphid-Stressed Tomato Plants.

An electronic nose (E-nose) system equipped with a sensitive sensor array was developed for fast diagnosis of aphid infestation on greenhouse tomato plants at early stages. Volatile organic compounds (VOCs) emitted by tomato plants with and without aphid attacks were detected using both the developed E-nose system and gas chromatography mass spectrometry (GC-MS), respectively. Sensor performance, with fast sensor responses and high sensitivity, were observed using the E-nose system. A principle component analysis (PCA) indicated accurate diagnosis of aphid-stressed plants compared to healthy ones, with the first two PCs accounting for 86.7% of the classification. The changes in VOCs profiles of the healthy and infested tomato plants were quantitatively determined by GC-MS. Results indicated that a group of new VOCs biomarkers (linalool, carveol, and nonane (2,2,4,4,6,8,8-heptamethyl-)) played a role in providing information on the infestation on the tomato plants. More importantly, the variation in the concentration of sesquiterpene VOCs (e.g., caryophyllene) and new terpene alcohol compounds was closely associated with the sensor responses during E-nose testing, which verified the reliability and accuracy of the developed E-nose system. Tomato plants growing in spring had similar VOCs profiles as those of winter plants, except several terpenes released from spring plants that had a slightly higher intensity.

Aerobic Copper-Catalyzed Synthesis of (E)-Vinyl Sulfones by Direct C-S Bond Oxidative Coupling.

Copper-catalyzed aerobic oxidative C-S bond coupling reaction between thiophenols and aryl-substituted alkenes for (E)-vinyl sulfones synthesis is reported here. With air utilized as a green oxidant, this transformation not only produces various vinyl sulfones in moderate to good yields but also possesses a simple and ecofriendly system. To clarify the mechanism, kinetic experiments has been investigated.

Printing the Ultra-Long Ag Nanowires Inks onto the Flexible Textile Substrate for Stretchable Electronics.

: Printing technology offers a simple and cost-effective opportunity to develop all-printed stretchable circuits and electronic devices, possibly providing ubiquitous, low-cost, and flexible devices. To successfully prepare high-aspect-ratio Ag nanowires (NWs), we used water and anhydrous ethanol as the solvent and polyvinylpyrrolidone (PVP) as the viscosity regulator to obtain a water-soluble Ag NWs conductive ink with good printability. Flexible and stretchable fabric electrodes were directly fabricated through screen printing. After curing at room temperature, the sheet resistance of the Ag NW fabric electrode was 1.5 Ω/sq. Under a tensile strain of 0-80% and with 20% strains applied for 200 cycles, good conductivity was maintained, which was attributed to the inherent flexibility of the Ag NWs and the intrinsic structure of the interlocked texture.