Publications by authors named "Wenqing Xu"

126 Publications

Different Crystal Forms of ZnS Nanomaterials for the Adsorption of Elemental Mercury.

Environ Sci Technol 2021 Feb 6. Epub 2021 Feb 6.

CAS Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Innovation Academy for Green Manufacture, Chinese Academy of Sciences, Beijing 100190, P. R. China.

ZnS is a promising sorbent in recovering Hg from industrial flue gas due to its excellent Hg adsorption capacity. However, the internal structure-activity relationship still needs to be further clarified. In this work, ZnS sorbents with different structures were synthesized with the hydrothermal method by tuning the temperature. The samples had significant differences in the crystallinity, morphology, particle size, and sulfur (S) active sites. The results indicated that Hg removal performance was determined by the specific surface area and S active sites. ZnS synthesized at low temperatures (80-ZnS and 120-ZnS) had a larger surface area, while the S sites on the high-temperature-synthesized sample (160-ZnS) were more active for Hg adsorption. The 160-ZnS sample exhibited a much higher Hg adsorption amount per unit surface area. Further characterization revealed that S and S were the main active sites for Hg adsorption. S existed in the form of long-chain polysulfur (L-S) on 80-ZnS and 120-ZnS, while it exhibited in the form of short-chain polysulfur (S-S) on 160-ZnS. L-S had negligible adsorption ability, while S-S had a high affinity for Hg. Hg can react with S and S-S, forming α-HgS and β-HgS, respectively. The new insight in this work can provide theoretical guidance for the design and structure optimization of ZnS, facilitating its practical industrial application.
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http://dx.doi.org/10.1021/acs.est.0c05878DOI Listing
February 2021

Structural insights into SARS-CoV-2 infection and therapeutics development.

Stem Cell Res 2021 04 2;52:102219. Epub 2021 Feb 2.

School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address:

The current COVID-19 pandemic is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). By late October 2020, more than 43 million cases of infections, including over 1.15 million deaths, have been confirmed worldwide. This review focuses on our current understanding of SARS-CoV-2 from the perspective of the three-dimensional (3D) structures of SARS-CoV-2 viral proteins and their implications on therapeutics development against COVID-19.
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http://dx.doi.org/10.1016/j.scr.2021.102219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985237PMC
April 2021

Exploring Food Safety Messages in an Era of COVID-19: Analysis of YouTube Video Content.

J Food Prot 2021 Jan 11. Epub 2021 Jan 11.

Purdue University Assistant Professor Food Science 745 Agriculture Mall Dr. UNITED STATES West Lafayette In 47907 +15305742267.

Although SARS-CoV-2 is not a proven foodborne pathogen, the COVID-19 pandemic has put the food system on alert. Food safety is identified as an important pillar in mitigating the crisis. Therefore, understanding how popular media are used as a vital disseminator of food safety and health information for public use is more important than ever. YouTube deserves particular attention as one of the most highly trafficked websites on the internet, especially as it has been blamed for spreading misleading or untrustworthy information during the pandemic that contradicts validated information. This study evaluates the food safety information and practices circulated on YouTube during the COVID-19 pandemic and their alignment with government agencies' recommendations. A search for videos on YouTube was conducted using the keywords "Food and COVID-19," "Food safety and COVID-19," and "Groceries and COVID-19." After applying a series of inclusive and exclusive criteria, a total of 85 different videos from the United States and Canada were evaluated. More than half (59%) of the videos presented handwashing procedures, less than a third (22%) showed kitchen disinfection, and most (69%) showed concern for "take-out" or "grocery store" practices. Multiple and different produce washing procedures were also shown throughout videos. Food was not considered hazardous by 33% of the videos, but 20% mentioned that food packaging is potentially hazardous. Most videos cited government agencies and had a host or guest who was a healthcare professional or professor/expert. Of the overall citations, three videos were not aligned with a government agency's guideline or information cited; two were presented by a healthcare professional. These findings demonstrate the need to develop educational interventions that increase YouTube video hosts and guests' awareness of social media use as a tool for food safety dissemination and the need to provide trustworthy sources.
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http://dx.doi.org/10.4315/JFP-20-463DOI Listing
January 2021

β-Naphthoflavone Activation of the Ah Receptor Alleviates Irradiation-Induced Intestinal Injury in Mice.

Antioxidants (Basel) 2020 Dec 12;9(12). Epub 2020 Dec 12.

Department of Veterinary and Biomedical Sciences, The Center for Molecular Toxicology and Carcinogenesis, 309 LSB, The Pennsylvania State University, University Park, PA 16802, USA.

Radiotherapy induced gastrointestinal syndrome results from the acute damage of intestinal stem cells, impaired crypts reconstruction, and subsequent breakdown of the mucosal barrier. The toxicity of ionizing radiation is associated with oxidative stress in the intestinal epithelial cells (IECs). Moreover, the rapid proliferation of IECs is a risk factor for radiation damage. β-naphthoflavone (BNF) is an agonist of the aryl hydrocarbon receptor (AhR) and possesses potential antioxidative activity. We investigated BNF radioprotection in IECs experiencing γ-ray exposure, contributed to mitigation of radiation enteritis. BNF significantly enhanced cell viability and suppressed cell apoptosis in an AhR activation-dependent manner. The mechanism of BNF reducing the IECs radiosensitivity was associated with cell cycle arrest and suppression of cell proliferation. In contrast, AhR antagonist CH-223191 significantly blocked BNF-induced cell cycle arrest. mRNA levels are induced after irradiation in a dose-dependent manner, and CYP1A1 protein expression increased in the irradiated intestinal tract as well. BNF also reduces DNA strand breaks induced by irradiation. These studies demonstrate that BNF pretreatment prolonged median survival time of mice upon exposure to a lethal dose of radiation and alleviated irradiation-induced toxicity within the bowel.
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http://dx.doi.org/10.3390/antiox9121264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763649PMC
December 2020

Structural basis of trehalose recycling by the ABC transporter LpqY-SugABC.

Sci Adv 2020 Oct 30;6(44). Epub 2020 Oct 30.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.

In bacteria, adenosine 5'-triphosphate (ATP)-binding cassette (ABC) importers are essential for the uptake of nutrients including the nonreducing disaccharide trehalose, a metabolite that is crucial for the survival and virulence of several human pathogens including SugABC is an ABC transporter that translocates trehalose from the periplasmic lipoprotein LpqY into the cytoplasm of mycobacteria. Here, we report four high-resolution cryo-electron microscopy structures of the mycobacterial LpqY-SugABC complex to reveal how it binds and passes trehalose through the membrane to the cytoplasm. A unique feature observed in this system is the initial mode of capture of the trehalose at the LpqY interface. Uptake is achieved by a pivotal rotation of LpqY relative to SugABC, moving from an open and accessible conformation to a clamped conformation upon trehalose binding. These findings enrich our understanding as to how ABC transporters facilitate substrate transport across the membrane in Gram-positive bacteria.
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http://dx.doi.org/10.1126/sciadv.abb9833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608808PMC
October 2020

Survival and inactivation of human norovirus GII.4 Sydney on commonly touched airplane cabin surfaces.

AIMS Public Health 2020 29;7(3):574-586. Epub 2020 Jul 29.

School of Nutrition and Food Sciences, Louisiana State University Agricultural Center, Baton Rouge, LA, USA.

Human norovirus (HuNoV) is one of the leading causes of acute gastroenteritis globally. HuNoV outbreaks have been recently reported during air travels. Contaminated surfaces are known as a critical transmission route at various settings. The aim of this study was to provide key information about the survival and the decontamination of HuNoV on three commonly touched airplane cabin surfaces. In this study, we monitored the survival of HuNoV on seat leather, plastic tray table, and seatbelt for 30 days, with and without additional organic load (simulated gastric fluid). The efficacy of two EPA registered anti-norovirus disinfectants were also evaluated. Results showed that HuNoV was detected at high titers (>4 log genomic copy number) for up to 30 days when additional organic load was present. Both tested disinfectants were found highly ineffective against HuNoV when the surface was soiled. The study showed that when the organic load was present, HuNoV was highly stable and resistant against disinfectants. Findings from this study indicated that appropriate procedures should be developed by airline companies with the help of public health authorities to decrease passengers' exposure risk to HuNoV.
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http://dx.doi.org/10.3934/publichealth.2020046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505796PMC
July 2020

What is the Impact of Bisphenol A on Sperm Function and Related Signaling Pathways: A Mini-review?

Curr Pharm Des 2020 ;26(37):4822-4828

Institute of Life Science and School of Life Science, Nanchang University, No. 999, Xuefu Road, Honggutan New District, Nanchang, Jiangxi 330031, China.

Bisphenol A (BPA) is an organic synthetic compound that is ubiquitously present in daily life. It is a typical environmental endocrine disruptor that affects the functions of endogenous hormones. There is a significant negative correlation between BPA and male reproduction. This mini-review describes current research data on the negative effects of BPA on sperm functions in humans and animal models, as well as on its supposed mechanisms of action, such as CATSPER-Ca2+ signaling, cAMP-protein kinase A signaling, and epigenetic changes. The published evidence showed an adverse impact of BPA on sperm tail morphology, counts, motility, and acrosome reaction action. Sperm function related signaling pathways, such as CATSPER-Ca2+ signaling, cAMP-protein kinase A signaling, and phosphorylation signaling, as well as epigenetic changes and sperm aging, are associated with BPA exposure in human and animal models. The clear risks of BPA exposure can provide greater awareness of the potential threat of environmental contaminants on male fertility.
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http://dx.doi.org/10.2174/1381612826666200821113126DOI Listing
March 2021

Black carbon-enhanced transformation of dichloroacetamide safeners: Role of reduced sulfur species.

Sci Total Environ 2020 Oct 2;738:139908. Epub 2020 Jun 2.

Department of Civil and Environmental Engineering, Villanova University, Villanova, PA 19085, USA. Electronic address:

Dichloroacetamide safeners are commonly included in herbicide formulations to protect crops from unintended herbicide toxicity, but knowledge of their environmental fate is scarce. Hydrogen sulfide, a naturally-occurring nucleophile and reductant, often coexists with black carbon (e.g., biochar, soot) in subsurface environments and could influence the fate of these safeners. In this study, we demonstrated that graphite powder, a model black carbon, significantly accelerated the transformation of three dichloroacetamide safeners (AD-67, benoxacor, and dichlormid) and two chloroacetamide herbicides (metolachlor and acetochlor) by hydrogen sulfide. Chloride was formed together with an array of sulfur-substituted products, suggesting a nucleophilic substitution pathway. Our results suggest that the electron-accepting capacity of black carbon can oxidize hydrogen sulfide species to elemental sulfur, which can further react with bisulfide to form polysulfide, likely accounting for the observed accelerated transformation of (di)chloroacetamides in systems containing black carbon and hydrogen sulfide. Moreover, our product analyses indicate that dimerization and/or trimerization of (di)chloroacetamides is possible in the presence of hydrogen sulfide and graphite, which is anticipated to decrease the mobility of these products in aquatic environments relative to the parent compounds. Herein, we also discuss how the structure and concentration of (di)chloroacetamides can influence their reactivity in the presence of black carbon and reduced sulfur species.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139908DOI Listing
October 2020

Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.

Cell 2020 07 22;182(2):417-428.e13. Epub 2020 May 22.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China. Electronic address:

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
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http://dx.doi.org/10.1016/j.cell.2020.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242921PMC
July 2020

Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO.

J Mol Biol 2020 07 6;432(16):4426-4434. Epub 2020 Jun 6.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300353, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China.

Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.
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http://dx.doi.org/10.1016/j.jmb.2020.05.019DOI Listing
July 2020

Effects of MoO and CeO doping on the decomposition and reactivity of NHHSO on VO/TiO catalysts.

Environ Sci Pollut Res Int 2020 Aug 25;27(24):30243-30253. Epub 2020 May 25.

Shanxi Provincial Key Laboratory Higee-Oriented Chemical Engineering, North University of China, Taiyuan, 030051, Shanxi, China.

The deposition of NHHSO on catalysts is one of the key issues for selective catalytic reduction of NO. In this study, NHHSO was preloaded on catalysts, and the effects of MoO and CeO doping on the decomposition and reactivity of NHHSO on VO/TiO catalysts are studied. The results show that the introduction of MoO and CeO significantly promoted NO conversion on the VO/TiO catalysts. Doping with MoO could effectively enhance the S and HO resistance of the catalysts. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis indicate that it is the strong chemical interactions between NHHSO and the catalysts that are adverse to the decomposition of NHHSO. However, doping with MoO apparently inhibits these interactions, which significantly decrease the decomposition temperature of NHHSO. In situ FTIR experiments show that the NH in preloaded NHHSO could react with gaseous NO on catalysts, and doping with MoO could facilitate the reaction rate.
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http://dx.doi.org/10.1007/s11356-020-09343-6DOI Listing
August 2020

Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB-AcpM.

Protein Cell 2020 07 3;11(7):505-517. Epub 2020 May 3.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, 300353, China.

Inhibition of Mycobacterium tuberculosis (Mtb) cell wall assembly is an established strategy for anti-TB chemotherapy. Arabinosyltransferase EmbB, which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis. Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug, ethambutol. Herein, we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its "resting state" and DPA-bound "active state". EmbB is a fifteen-transmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrier-protein (AcpM) on their cytoplasmic surface. Conformational changes upon DPA binding indicate an asymmetric movement within the EmbB dimer during catalysis. Functional studies have identified critical residues in substrate recognition and catalysis, and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA. The structures represent the first step directed towards a rational approach for anti-TB drug discovery.
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http://dx.doi.org/10.1007/s13238-020-00726-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305291PMC
July 2020

Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol.

Science 2020 06 23;368(6496):1211-1219. Epub 2020 Apr 23.

Shanghai Institute for Advanced Immunochemical Studies, iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo-electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.
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http://dx.doi.org/10.1126/science.aba9102DOI Listing
June 2020

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Cell 2020 04 20;181(3):688-701.e16. Epub 2020 Apr 20.

Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.
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http://dx.doi.org/10.1016/j.cell.2020.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243596PMC
April 2020

Structure of the RNA-dependent RNA polymerase from COVID-19 virus.

Science 2020 05 10;368(6492):779-782. Epub 2020 Apr 10.

Laboratory of Structural Biology, School of Life Sciences, and School of Medicine, Tsinghua University, Beijing, China.

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.
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http://dx.doi.org/10.1126/science.abb7498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164392PMC
May 2020

Structure of M from SARS-CoV-2 and discovery of its inhibitors.

Nature 2020 06 9;582(7811):289-293. Epub 2020 Apr 9.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M) of SARS-CoV-2: M is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M. Six of these compounds inhibited M, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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http://dx.doi.org/10.1038/s41586-020-2223-yDOI Listing
June 2020

Effect of AlO doping on the structure and performance of an AlO/FeO catalyst for mercury oxidation.

J Environ Sci (China) 2020 Apr 9;90:138-145. Epub 2019 Dec 9.

Research Center for Process Pollution Control, National Engineering Laboratory for Hydrometallurgical Cleaner Production Technology, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China. Electronic address:

In this study, the thermal stability of a FeO catalyst for mercury oxidation was significantly improved by doping with AlO. After 1 hr, the catalyst doped with 10 wt.% AlO still exhibited a mercury conversion efficiency of 70.9%, while the undoped sample even lost its catalytic activity. Doping with AlO retarded the collapse of the catalyst mesoporous structure during high-temperature calcination, and the doped samples maintained a higher specific surface area, smaller pore size, and narrower pore size distribution. Transmission electron microscope images revealed that after calcination at 350°C, the average size of the catalyst grains in FeO was 23.4 nm; however, the corresponding values for 1%AlO/FeO, 3%AlO/FeO, and 10%AlO/FeO were only 13.3, 7.1, and 4.7 nm, respectively. Results obtained from X-ray diffraction and thermogravimetry coupled with differential scanning calorimetry confirmed that doping with AlO also retards the crystallization of the catalysts at high temperature, constraining catalyst grains to a smaller size.
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http://dx.doi.org/10.1016/j.jes.2019.11.003DOI Listing
April 2020

The effects of an enteral nutrition feeding protocol on critically ill patients: A prospective multi-center, before-after study.

J Crit Care 2020 04 17;56:249-256. Epub 2020 Jan 17.

Department of Emergency Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88, Jiefang Rd, Hangzhou, China. Electronic address:

Purpose: The aim of this study was to explore the effects of an enteral nutrition (EN) feeding protocol in critically ill patients.

Methods: This was a prospective multi-center before-after study. We compared energy related and prognostic indicators between the control group (pre-implementation stage) and intervention group (post-implementation stage). The primary endpoint was the percentage of patients receiving EN within 7 days after ICU admission.

Results: 209 patients in the control group and 230 patients in the intervention group were enrolled. The implementation of the EN protocol increased the percentage of target energy reached from day 3 to day 7, and the difference between two groups reached statistical significance in day 6 (P = .01) and day 7 (P = .002). But it had no effects on proportion of patient receiving EN (P = .65) and start time of EN (P = .90). The protocol application might be associated with better hospital survival (89.1% vs 82.8%, P = .055) and reduce the incidence of EN related adverse (P = .004). There was no difference in ICU length of stay, duration of mechanical ventilation and ICU cost.

Conclusion: The implementation of the enteral feeding protocol is associated with improved energy intake and a decreased incidence of enteral nutrition related adverse events for critically ill patients, but it had no statistically beneficial effects on reducing the hospital mortality rate. Trial registration ClinicalTrials.gov, NCT02976155. Registered November 29, 2016- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02976155.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.018DOI Listing
April 2020

Facial expression recognition in patients with type 2 diabetes mellitus.

Ann Transl Med 2019 Nov;7(22):654

Department of Senile Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.

Background: Facial expression recognition is an important social cognitive skill. Type 2 diabetes mellitus (T2DM) affects cognitive function. Whether facial expression recognition deficits and attention bias exist in T2DM is unknown. Facial expression search task is a commonly used paradigm to measure emotional processing. In this study, facial expression recognition features of T2DM patients were studied by facial expression search task.

Methods: Thirty outpatients with T2DM and 30 normal controls matched by sex, age and education etc. were selected. Standardized stick drawings with happy, neutral and sad emotion expressions were selected as stimulus materials, and facial expression search task was used to Search for expression targets in neutral interferers to compare the response time between the two groups.

Results: The reaction time of identifying the positive expression (happy) in the diabetic group and the control group was greater than that of the negative expression (sad). The response time of the diabetic group to identify positive expressions and negative expressions was greater than that of the control group. The slope of the search for positive expressions in the diabetic group was 419.14 ms, and the search slope for negative expressions in the diabetic group was 237.97 ms. The slope of the search for positive expressions in the control group was 300.4 ms, and that of the control group for negative expressions was 119.07 ms.

Conclusions: In the diabetic group and the control group, the reaction time of identifying the positive expression was positively delayed compared with the negative expression, which showed a negative attention bias; Patients with type 2 diabetes significantly prolonged the response time of recognizing positive expression and negative expression without obvious clinical cognitive impairment.
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http://dx.doi.org/10.21037/atm.2019.10.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944595PMC
November 2019

Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients.

Front Oncol 2019 17;9:1422. Epub 2019 Dec 17.

Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Ministry of Education, Guangxi Medical University, Nanning, China.

Kidney is an important organ for ketone body metabolism. However, the role of abnormal ketone metabolism and its possible function in tumorigenesis of clear cell renal cell carcinoma (ccRCC) have not yet been elucidated. Three differentially expressed key enzymes involved in ketone body metabolism, ACAT1, BDH2, and HMGCL, were screened out between ccRCC and normal kidney tissues using the GEO and TCGA databases.We confirmed that the transcription and protein expression of ACAT1, BDH2, and HMGCL were significantly lower in ccRCC by real-time RT-PCR and IHC assays. Those patients with lower expression of these three genes have a worse outcome. In addition, we demonstrated that ectopic expression of each of these genes inhibited the proliferation of ccRCC cells. The overexpressed and genes remarkably impeded the migratory and invasive capacity of ccRCC cells. Furthermore, exogenous β-hydroxybutyrate suppressed the growth of ccRCC cells in a dose-dependent manner. Our findings suggest that , and are potential tumor suppressor genes, and constitute effective prognostic biomarkers for ccRCC. Ketone body metabolism might thus be a promising target in a process for developing novel therapeutic approaches to treat ccRCC.
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http://dx.doi.org/10.3389/fonc.2019.01422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928137PMC
December 2019

Crystal structure of human LDB1 in complex with SSBP2.

Proc Natl Acad Sci U S A 2020 01 31;117(2):1042-1048. Epub 2019 Dec 31.

National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China;

The Lim domain binding proteins (LDB1 and LDB2 in human and Chip in ) play critical roles in cell fate decisions through partnership with multiple Lim-homeobox and Lim-only proteins in diverse developmental systems including cardiogenesis, neurogenesis, and hematopoiesis. In mammalian erythroid cells, LDB1 dimerization supports long-range connections between enhancers and genes involved in erythropoiesis, including the β-globin genes. Single-stranded DNA binding proteins (SSBPs) interact specifically with the LDB/Chip conserved domain (LCCD) of LDB proteins and stabilize LDBs by preventing their proteasomal degradation, thus promoting their functions in gene regulation. The structural basis for LDB1 self-interaction and interface with SSBPs is unclear. Here we report a crystal structure of the human LDB1/SSBP2 complex at 2.8-Å resolution. The LDB1 dimerization domain (DD) contains an N-terminal nuclear transport factor 2 (NTF2)-like subdomain and a small helix 4-helix 5 subdomain, which together form the LDB1 dimerization interface. The 2 LCCDs in the symmetric LDB1 dimer flank the core DDs, with each LCCD forming extensive interactions with an SSBP2 dimer. The conserved linker between LDB1 DD and LCCD covers a potential ligand-binding pocket of the LDB1 NTF2-like subdomain and may serve as a regulatory site for LDB1 structure and function. Our structural and biochemical data provide a much-anticipated structural basis for understanding how LDB1 and the LDB1/SSBP interactions form the structural core of diverse complexes mediating cell choice decisions and long-range enhancer-promoter interactions.
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http://dx.doi.org/10.1073/pnas.1914181117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969494PMC
January 2020

Mechanistic Investigation of Haloacetic Acid Reduction Using Carbon-TiO Composite Reactive Electrochemical Membranes.

Environ Sci Technol 2020 02 13;54(3):1982-1991. Epub 2020 Jan 13.

Department of Chemical Engineering , University of Illinois at Chicago , 945 West Taylor Street , Chicago , Illinois 60607 , United States.

Carbon-TiO composite reactive electrochemical membranes (REMs) were studied for adsorption and electrochemical reduction of haloacetic acids (HAAs). Powder activated carbon (PAC) or multiwalled carbon nanotubes (MWCNTs) were used in these composites. Results from flow-through adsorption experiments with dibromoacetic acid (DBAA) as a model HAA were interpreted with a transport model. It was estimated that ∼46% of C in the MWCNT-REM and ∼10% of C in the PAC-REM participated in adsorption reactions. Electrochemical reduction of 1 mg L DBAA in 10 mM KHPO/KHPO at -1.5 V/SHE (hydraulic residence time, ∼11 s) resulted in 73, 94, and 96% DBAA reduction for TiO, PAC-TiO, and MWCNT-TiO REMs, respectively. The reactive-transport model yielded values between 9.16 and 33.3 min, which were 2 to 4 orders of magnitude higher than previously reported. PAC-TiO REM was tested with tap water spiked with 0.11 mg L of nine different HAAs in a similar reduction experiment. The results indicated that all HAAs were reduced to <20 μg L. Moreover, the total combined concentration of five regulated HAAs was lower than the regulatory limit (60 μg L). Density functional theory simulations suggest that a direct electron transfer reaction was the probable rate-determining step for HAA reduction.
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http://dx.doi.org/10.1021/acs.est.9b06744DOI Listing
February 2020

Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions.

J Enzyme Inhib Med Chem 2020 Dec;35(1):344-353

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-Ras protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.
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http://dx.doi.org/10.1080/14756366.2019.1702653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968486PMC
December 2020

Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors.

Oncogene 2020 01 20;39(3):703-717. Epub 2019 Sep 20.

Department of Internal Medicine: Genetic Medicine, University of Michigan, Ann Arbor, MI, USA.

The serine/threonine Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways. The canonical PP2A holoenzyme comprises a scaffolding subunit (PP2A Aα/β), which serves as the platform for binding of both the catalytic C subunit and one regulatory B subunit. Somatic heterozygous missense mutations in PPP2R1A, the gene encoding the PP2A Aα scaffolding subunit, have been identified across multiple cancer types, but the effects of the most commonly mutated residue, Arg-183, on PP2A function have yet to be fully elucidated. In this study, we used a series of cellular and in vivo models and discovered that the most frequent Aα R183W mutation formed alternative holoenzymes by binding of different PP2A regulatory subunits compared with wild-type Aα, suggesting a rededication of PP2A functions. Unlike wild-type Aα, which suppressed tumorigenesis, the R183W mutant failed to suppress tumor growth in vivo through activation of the MAPK pathway in RAS-mutant transformed cells. Furthermore, cells expressing R183W were less sensitive to MEK inhibitors. Taken together, our results demonstrate that the R183W mutation in PP2A Aα scaffold abrogates the tumor suppressive actions of PP2A, thereby potentiating oncogenic signaling and reducing drug sensitivity of RAS-mutant cells.
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http://dx.doi.org/10.1038/s41388-019-1012-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980487PMC
January 2020

Survival and inactivation of Salmonella enterica serovar Typhimurium on food contact surfaces during log, stationary and long-term stationary phases.

Food Microbiol 2019 Dec 16;84:103272. Epub 2019 Jul 16.

School of Nutrition and Food Sciences, Louisiana State University Agricultural Center, Baton Rouge, LA, United States.

One of the most important transmission routes of foodborne pathogens is through contaminated food contact surfaces. In this study, we investigated the survival and inactivation of Salmonella enterica serovar Typhimurium on frequently used food contact surfaces in household settings, including plastic cutting board (CB), formica laminate (LA), and stainless steel (SS) surfaces. S. Typhimurium at log (6 h), stationary (24 h), or long-term stationary (LTS) (14 days) phases were evaluated. Results showed that, at medium and high microbial loads, LTS phase cells had significantly higher survivor population compared to log and stationary phase cells at 24 h after inoculation (p < 0.05). Disinfection study showed that LTS phase cells were very resilient to sodium hypochlorite when the initial microbial load was high with disinfection efficacy ranging from 26 to 35%. Scanning electron microscopy of these surfaces at 24 h after inoculation with a high microbial load revealed an early biofilm structure.
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http://dx.doi.org/10.1016/j.fm.2019.103272DOI Listing
December 2019

Probing the Surface Reactivity of Pyrogenic Carbonaceous Material (PCM) through Synthesis of PCM-Like Conjugated Microporous Polymers.

Environ Sci Technol 2019 Jul 20;53(13):7673-7682. Epub 2019 Jun 20.

Department of Civil and Environmental Engineering , Villanova University , Villanova , Pennsylvania 19085 , United States.

Pyrogenic carbonaceous matter (PCM) is redox-active and promotes both abiotic and biotic reactions in the environment, possibly as a result of its conductivity and phenolic/quinone functional groups. However, due to the complexity of PCM, the contribution of conductivity or phenolic/quinone functional groups to its redox activity is poorly understood, which hinders its potential engineering applications. Here, we synthesized tunable conjugated microporous polymers (CMPs) that possess key properties of PCM, which can be used as PCM analogues to provide insights to PCM reactivity. Specifically, controlled incorporation of phenolic moieties into CMPs during polymer synthesis affected electron-donating capacity, while carbonization of CMPs at various temperatures altered conductivity. Both properties were then correlated with PCM reactivity measured by the decay kinetics of a model pollutant trichloronitromethane. We demonstrate that some of the prepared CMPs enabled transformation of trichloronitromethane, while no decay was observed in the absence of CMPs. Results of further investigation suggest that trichloronitromethane decay occurs by reductive dechlorination, suggesting that CMPs are electron donors and the first dissociative electron transfer from CMPs was likely to be the rate-limiting step. Conductivity but not electron-donating capacity was positively correlated with CMP-mediated trichloronitromethane decay kinetics, suggesting an important role of the electron transfer kinetics at the interface for PCM-mediated transformation of environmental pollutants.
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http://dx.doi.org/10.1021/acs.est.9b01772DOI Listing
July 2019

The synergistic interaction between sulfate-reducing bacteria and pyrogenic carbonaceous matter in DDT decay.

Chemosphere 2019 Oct 28;233:252-260. Epub 2019 May 28.

Department of Civil and Environmental Engineering, Villanova University, Villanova, PA, 19085, USA. Electronic address:

Although 1,1,1-trichloro-2,2-di(4-chlorophenyl)ethane (DDT) was banned in the United States in 1972, it is still often detected in sediments where pyrogenic carbonaceous matter (PCM) and sulfate-reducing bacteria (SRB) co-exist. In this study, we found that 70.2 ± 0.2% of DDT disappeared in the presence of SRB and graphite powder, a model PCM, after 21 days at pH 7. Our results suggest that the observed DDT decay was due to the reaction between graphite powder and the reduced sulfur species that were produced by SRB. No biofilm formation was observed on the surface of graphite powder. Rather, the activity of SRB was inhibited by the presence of graphite powder. To understand the involvement of PCM in DDT decay, electrochemical cells and batch reactor experiments with sulfur-pretreated PCM as well as direct electrochemical reduction by a potentiostat were employed. Our results suggest that polysulfide, sulfide, sulfite, and thiosulfate could all react with PCM, forming surface-bound intermediates that subsequently led to DDT decay. The reactivity of reduced sulfur species was the highest for polysulfide, followed by sulfide, sulfite, and thiosulfate.
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http://dx.doi.org/10.1016/j.chemosphere.2019.05.208DOI Listing
October 2019

The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.

Cancer Res 2019 Aug 29;79(16):4242-4257. Epub 2019 May 29.

Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis . Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity . These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R mutations. SIGNIFICANCE: This study characterizes a highly recurrent, disease-specific PP2A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724736PMC
August 2019

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties.

Psychopharmacology (Berl) 2019 May 22;236(5):1653-1670. Epub 2019 May 22.

Department of Integrative Physiology, Center for Neuroscience, and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA.

Rationale: Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known.

Objectives: Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659.

Methods: We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages.

Results: The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.

Conclusion: Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.
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http://dx.doi.org/10.1007/s00213-019-05253-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626661PMC
May 2019

Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway.

Drug Des Devel Ther 2019 26;13:1335-1345. Epub 2019 Apr 26.

Key laboratory of High-Incidence-Tumor Prevention & Treatment, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China.

Caffeic acid phenethyl ester (CAPE) is the main polyphenol extracted from honeybee propolis, which inhibits the growth of several kinds of tumor. This study aimed to assess the inhibitory effect of CAPE in nasopharyngeal carcinoma (NPC), evaluate the synergistic action of CAPE in radiotherapy sensitivity of NPC cell lines and further elucidate the possible molecular mechanism involved. CCK-8 assay was used to analyze cell proliferation ability. Colony formation assay was used to evaluate the clonogenic ability and radio-sensitiveness of NPC cells by CAPE treatment. Wound-healing and transwell assay were used to assess the motility of cells. The expression of key molecules of the epithelial-mesenchymal transition (EMT) was determined by western blot analysis and changes in radiation sensitivity were measured by colony-formation assay. cDNA microarray analysis was used to determine differentially expressed genes with and without CAPE treatment, with Gene Ontology enrichment of gene function and KEGG pathways determined. Cell cycle and apoptosis were detected by flow cytometry and western blot analysis. CAPE suppressed the viability of NPC cell lines time- and dose-dependently. It induced apoptosis in NPC cells along with decreased expression of Bcl-XL and increased cleavage of PARP and expression of Bax. G1 phase arrest was induced by CAPE with ower expression of CDK4, CDK6, Rb and p-Rb. The migratory and invasive ability of NPC cells was decreased by the EMT pathway. The irradiation sensitivity of NPC cells was enhanced with CAPE treatment. CAPE specifically inhibited nuclear factor κB (NF-κB) signaling pathway by suppressing p65 subunit translocation from cytoplasm to nucleus. CAPE treatment was synergistic with chemotherapy and radiotherapy. CAPE may inhibit the proliferation and metastasis of NPC cells but enhance radiosensitivity in NPC therapy by inhibiting the NF-κB pathway. CAPE could be a potential therapeutic compound for NPC therapy.
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http://dx.doi.org/10.2147/DDDT.S199182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499142PMC
February 2020