Publications by authors named "Xiaoyu Zhao"

138 Publications

An integrated microfluidic detection system for the automated and rapid diagnosis of high-risk human papillomavirus.

Analyst 2021 Jul 15. Epub 2021 Jul 15.

Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.

Human papillomavirus (HPV) causes the prevalent sexually transmitted infection that accounts for the majority of cervical cancer incidences. Therefore, the development of a rapid, accurate, automatic and affordable nucleic acid detection strategy is urgently required for HPV tests, among which microfluidic chip is a promising diagnostic method. In this work, we developed a microfluidic detection system consisting of a microfluidic chip and the corresponding detection equipment to diagnose high-risk HPV. The proposed method integrates nucleic acid purification, isothermal amplification and real-time fluorescence detection into one device. Moreover, it demonstrates good detection performance such as high specificity of primer sets (100%) and exceptional stability (coefficient of variation <6%) among five HPV genotypes. Besides, the microfluidic loop-mediated isothermal amplification (LAMP) assay is accurate (specificity of 91.7% and sensitivity of 100%) and fast (average time threshold = 10.56 minutes) when considering the conventional qPCR assay as the gold standard. The integrated microfluidic detection system offers automated and rapid diagnosis within 40 minutes and shows broad potential to deliver point-of-care detection in resource-limited circumstances owing to its simplicity and affordability.
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http://dx.doi.org/10.1039/d1an00623aDOI Listing
July 2021

Cyanobacteria blooms potentially enhance volatile organic compound (VOC) emissions from a eutrophic lake: Field and experimental evidence.

Environ Res 2021 Jul 10;202:111664. Epub 2021 Jul 10.

School of Ecology and Environment, Anhui Normal University, Wuhu, 241000, China.

Eutrophication promotes massive cyanobacteria blooms (CBBs), leading to the release of volatile organic compounds (VOCs). To investigate the effects of cyanobacteria on VOC emissions, field campaigns were carried out in eutrophic Chaohu Lake at six sites with different microalgae densities during CBBs in summer 2019, and incubation experiments were performed in the laboratory. The results showed that the lake water was the primary source of VOCs at six sampling sites in Chaohu Lake during CBBs, with an average total VOC flux of 81.2 ± 20.6 μg m h. Alkanes were the most abundantly emitted VOCs, with a share of 23.1-63.7% of total emitted VOCs, followed by aromatics (16.6-46.3%). The fluxes of total VOCs were significantly greater at sites B and/or C than at site A in July, and at site B' and/or C' than at site A' in August in Chaohu Lake. The fluxes of total VOCs from living and decayed cyanobacteria in the experimental treatments were two orders of magnitude higher than the corresponding values in the control treatments in the laboratory incubation. Taken together, these results suggested that CBBs potentially enhanced VOC emissions from the eutrophic lake, and that cyanobacteria acted as an important source of VOCs. Additionally, non-methane hydrocarbons (i.e., alkanes, alkenes, and aromatics) predominated among the released VOCs during the stabilization and senescence stages, while oxygenated volatile organic compounds (i.e. alcohols, aldehydes, ketones, esters, and furans) prevailed during the apoptosis stage and aromatics and volatile organic sulfur compounds predominated during the decomposition stage, suggesting that VOC emissions varied markedly at different life stages.
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http://dx.doi.org/10.1016/j.envres.2021.111664DOI Listing
July 2021

Associations Between Sleep Quality and Health Span: A Prospective Cohort Study Based on 328,850 UK Biobank Participants.

Front Genet 2021 15;12:663449. Epub 2021 Jun 15.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Objective: To examine the associations between sleep quality and health span using a prospective cohort design based on the UK Biobank (UKB).

Materials And Methods: This longitudinal cohort study enrolled 328,850 participants aged between 37 and 73 years from UKB to examine the associations between sleep quality and risk of terminated health span. End of health span was defined by eight events strongly associated with longevity (cancer, death, congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, and diabetes), and a sleep score was generated according to five sleep behavioral factors (sleep duration, chronotype, sleeplessness, daytime sleepiness, and snoring) to characterize sleep quality. The hazard ratio (HR) and 95% confidence intervals (CIs) were calculated by multivariate-adjusted Cox proportional hazards model. Moreover, we calculated population attributable risk percentage (PAR%) to reflect the public health significance of healthy sleep quality.

Results: Compared with poor sleep quality, participants with healthy sleep quality had a 15% (HR: 0.85, 95% CI: 0.81-0.88) reduced risk of terminated health span, and those of less-healthy sleep quality had a 12% (HR: 0.88, 95% CI: 0.85-0.92) reduced risk. Linear trend results indicated that the risk of terminated health span decreased by 4% for every additional sleep score. Nearly 15% health span termination events in this cohort would have been prevented if a healthy sleep behavior pattern was adhered to (PAR%: 15.30, 95% CI: 12.58-17.93).

Conclusion: Healthy sleep quality was associated with a reduced risk of premature end of health span, suggesting healthy sleep behavior may extend health span. However, further studies are suggested for confirmation of causality and potential mechanism.
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http://dx.doi.org/10.3389/fgene.2021.663449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239359PMC
June 2021

Development and application of an efficient recombineering system for Burkholderia glumae and Burkholderia plantarii.

Microb Biotechnol 2021 Jul 30;14(4):1809-1826. Epub 2021 Jun 30.

Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, People's Republic of China.

The lambda phage Red proteins Redα/Redβ/Redγ and Rac prophage RecE/RecT proteins are powerful tools for precise and efficient genetic manipulation but have been limited to only a few prokaryotes. Here, we report the development and application of a new recombineering system for Burkholderia glumae and Burkholderia plantarii based on three Rac bacteriophage RecET-like operons, RecEThe , RecETh and RecETh1h2e , which were obtained from three different Burkholderia species. Recombineering experiments indicated that RecETh and RecETh1h2e showed higher recombination efficiency compared to RecEThe in Burkholderia glumae PG1. Furthermore, all of the proteins currently categorized as hypothetical proteins in RecETh1h2e RecETh and RecEThe may have a positive effect on recombination in B. glumae PG1 except for the h2 protein in RecETh1h2e . Additionally, RecET combined with exonuclease inhibitors Pluγ or Redγ exhibited equivalent recombination efficiency compared to Redγβα in Escherichia coli, providing potential opportunity of recombineering in other Gram-negative bacteria for its loose host specificity. Using recombinase-assisted in situ insertion of promoters, we successfully activated three cryptic non-ribosomal peptide synthetase biosynthetic gene clusters in Burkholderia strains, resulting in the generation of a series of lipopeptides that were further purified and characterized. Compound 7 exhibited significant potential anti-inflammatory activity by inhibiting lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 macrophages. This recombineering system may greatly enhance functional genome research and the mining of novel natural products in the other species of the genus Burkholderia after optimization of a protocol.
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http://dx.doi.org/10.1111/1751-7915.13840DOI Listing
July 2021

PEG/Sodium Tripolyphosphate-Modified Chitosan/Activated Carbon Membrane for Rhodamine B Removal.

ACS Omega 2021 Jun 11;6(24):15885-15891. Epub 2021 Jun 11.

Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan 250061, People's Republic of China.

Textile dyes from wastewater effluent are highly toxic to both living species and aqueous environments. An environmentally friendly method to remove hazardous dyes from wastewater in the textile industry has been a challenge. Chitosan (CS) and activated carbon (AC) are widely used as adsorbents for dye removal. However, the poor porosity and unsatisfactory stability of CS and the unfriendly cost of AC limited their applications to be used alone as a single adsorbent. Here, we report a novel method to prepare a CS/AC membrane using PEG as a porogen and sodium tripolyphosphate (TPP) as a cross-linking agent. The adsorption efficiency and reusability of the PEG/TPP-modified CS/AC membrane to remove RhB were investigated based on dynamic and static adsorption models. The results reveal that the adsorption performance of CS/AC membranes was significantly improved after the PEG/TPP modification based on the abundance macroporous structure. The modified CS/AC membrane with a 30% AC doping ratio exhibited an excellent adsorption efficiency of 91.29 and 73.91% in the dynamic and static adsorption processes, respectively. These results provide new insights into designing membranes to remove dyes from wastewater efficiently.
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http://dx.doi.org/10.1021/acsomega.1c01444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223414PMC
June 2021

An Integrin-αβ/αβ-Bitargeted Probe for the SPECT Imaging of Pancreatic Adenocarcinoma in Preclinical and Primary Clinical Studies.

Bioconjug Chem 2021 Jul 17;32(7):1298-1305. Epub 2021 Jun 17.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Pancreatic adenocarcinoma (PA) is one of the deadliest human malignancies. However, early detection, prediction of surgical resectability, and prognosis of PA are challenging with current conventional imaging technologies in the clinic. Molecular imaging technologies combined with novel imaging probes could be useful for early detection and accurate staging of PA. Integrin αβ and αβ are found to be overexpressed in PA. In this study, integrin αβ/αβ-bitargeted probes Tc-HYNIC-isoDGR (Tc-isoDGR) and Tc-HYNIC-PEG-PisoDGR2 (Tc-3PisoDGR2) were prepared and evaluated in the BxPC-3 human pancreatic tumor model. Both subcutaneous and BxPC-3 tumors could be clearly visualized by Tc-isoDGR nanoScan SPECT/CT imaging with a high ratio of tumor to background. The blocking study with excess nonradioactive peptide showed a significantly reduced tumor uptake, which confirmed the specificity of Tc-isoDGR. Biodistribution results confirmed the imaging results. The dimer tracer Tc-3PisoDGR2 significantly enhanced tumor uptake compared with Tc-isoDGR, and the spontaneous PA lesion in the mouse model could be clearly visualized by Tc-3PisoDGR2. The primary clinical study also verified the ability of Tc-3PisoDGR2 for detection of PA. Therefore, SPECT/CT imaging using the integrin αβ/αβ-bitargeted Tc-3PisoDGR2 provided a potential approach for the noninvasive detection of PA.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00296DOI Listing
July 2021

Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity.

Sci Adv 2021 06 16;7(25). Epub 2021 Jun 16.

State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.
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http://dx.doi.org/10.1126/sciadv.abf8577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208716PMC
June 2021

Wheat TaPUB1 protein mediates ABA response and seed development through ubiquitination.

Plant Sci 2021 Aug 5;309:110913. Epub 2021 May 5.

State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, College of Life Science, Shandong Agricultural University, Tai'an, Shandong, 271018, PR China. Electronic address:

Abscisic acid (ABA) is an important regulator of plant growth, development, and biotic and abiotic stress responses. Ubiquitination plays important roles in regulating ABA signaling. E3 ligase, a key member in ubiquitination, actively participates in the regulation of biosynthesis, de-repression, and activation of ABA response and degradation of signaling components. In this study, we found that that overexpression of wheat E3 ligase TaPUB1 decreased the sensitivity of wheat seedlings to ABA, whereas TaPUB1-RNA interference (TaPUB1-RNAi) lines increased wheat sensitivity to ABA during germination, root growth, and stomatal opening. TaPUB1 influenced the expression of several ABA-responsive genes, and also interacted with TaPYL4 and TaABI5, which are involved in ABA signal transduction, and promoted their degradation. Additionally, we observed that TaPUB1-OE lines resulted in lower single-split grain numbers, larger seed size, and higher thousand kernel weight, when compared with the WT lines. Contrasting results were obtained for TaPUB1-RNAi lines. It suggests that TaPUB1 acts as a negative regulator in the ABA signaling pathway by interacting with TaPYL4 and TaABI5, subsequently affecting seed development in wheat. In addition, the enhanced abiotic tolerance of overexpression lines due to enhanced photosynthesis and root development may be related to the degradation of TaABI5 by TaPUB1.
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http://dx.doi.org/10.1016/j.plantsci.2021.110913DOI Listing
August 2021

Identification of zinc pollution in rice plants based on two characteristic variables.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 4;261:120043. Epub 2021 Jun 4.

Communication and Electronic Engineering Institute, Qiqihar University, Qiqihar 161006, People's Republic of China.

Traditional chemical methods used to measure the zinc content in rice plants are time-consuming, laborious, requires reagents, and have a limited monitoring range, while the Raman spectroscopy method has the advantage of being fast, non-destructive, and requires no reagents. Unfortunately, the identification accuracy of the Raman partial least squares (PLS) model based on principal components is only 53.33%. To boost this, a One-Way ANOVA method was used to extract the characteristic variables in the Raman spectra. Based on these Raman variables, a model for identifying zinc stressed samples was established. The identification accuracy was improved to 70% but still fell short of the measurement requirements. To further enhance these results, the Raman spectrum was decomposed into components based on the Hilbert Vibration Decomposition (HVD) method. Using characteristic variables of the Raman spectrum and its HVD components to establish a PLS model, the identification accuracy of the test set is raised to 90.25%. These results are a significant improvement from those obtained using a model solely based on the Raman spectral characteristic variables, revealing that HVD components provide highly effective identification information. A Raman modeling method based on the characteristic variables of the HVD component is an innovative way for improving the accuracy of Raman detection, especially for the measurement of trace substances.
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http://dx.doi.org/10.1016/j.saa.2021.120043DOI Listing
November 2021

Stretch-driven microfluidic chip for nucleic acid detection.

Biotechnol Bioeng 2021 May 27. Epub 2021 May 27.

Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Guangdong, Shenzhen, China.

Molecular diagnosis is an essential means to detect pathogens. The portable nucleic acid detection chip has excellent prospects in places where medical resources are scarce, and it is also of research interest in the field of microfluidic chips. Here, the article developed a new type of microfluidic chip for nucleic acid detection where stretching acts as the driving force. The sample entered the chip by applying capillary force. The strain valve was opened under the action of tensile force, and the spring pump generated the power to drive the fluid to flow to the detection chamber in a specific direction. The detection of coronavirus disease 2019 (COVID-19) was realized on the chip. The RT-LAMP amplification system was adopted to observe the liquid color in the detection chamber to decide whether the sample tested positive or negative qualitatively.
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http://dx.doi.org/10.1002/bit.27839DOI Listing
May 2021

Removal of antibiotic resistance genes and inactivation of antibiotic-resistant bacteria by oxidative treatments.

Sci Total Environ 2021 Jul 11;778:146348. Epub 2021 Mar 11.

Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, P.R.China; South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510300, China; Shenzhen Base South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen 518121, China. Electronic address:

The persistence of antibiotics in the environment because of human activities, such as seafood cultivation, has attracted great attention as they can give rise to antibiotic resistance genes (ARGs) and antibiotic-resistant bacteria (ARB). In this study, we explored the inactivation and removal efficiencies of Escherichia coli SR1 and sul1 (plasmid-encoded ARGs), respectively, in their extracellular and intracellular forms (eARGs and iARGs) by three commonly used fishery oxidants, namely chlorine, bromine, and potassium permanganate (KMnO), at the practical effective concentration range (0.5, 5, and 15 mg/L). Kinetics data were obtained using laboratory phosphate-buffered saline (PBS). Following the same fishery oxidation methods, the determined kinetics models were tested by studying the SR1 and sul1 disinfection efficiencies in (sterilized) pond water matrix. At concentrations of 5 and 15 mg/L, all three oxidants achieved sufficient cumulative integrated exposure (CT values) to completely inactivate SR1 and efficiently remove sul1 (up to 4.0-log). The oxidation methods were then applied to an unsterilized pond water matrix in order to study and evaluate the indigenous ARB and ARGs disinfection efficiencies in aquaculture, which reached 1.4-log and 1.0-log during treatment with fishery oxidants used in pond preparation at high concentrations before stocking (5-15 mg/L), respectively. A high chlorine concentration (15 mg/L) could efficiently remove ARGs (or iARGs) from pond water, and the iARG removal efficiency was higher than that of eARGs in pond water. The method and results of this study could aid in guiding future research and practical disinfection to control the spread of ARGs and ARB in aquaculture.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146348DOI Listing
July 2021

Wheat TaPUB1 Regulates Cd Uptake and Tolerance by Promoting the Degradation of TaIRT1 and TaIAA17.

J Agric Food Chem 2021 Jun 21;69(21):5818-5829. Epub 2021 May 21.

State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, College of Life Science, Shandong Agricultural University, Tai'an, Shandong 271018, P. R. China.

Cadmium (Cd) accumulation in agricultural soils is an increasingly serious problem, as plants absorb Cd, which inhibits their growth and development. Nonetheless, the molecular mechanisms underlying Cd detoxification and accumulation in wheat ( L.) are unclear. Here, we isolated the U-box E3 ligase TaPUB1 from wheat and reported the functional characterization of 1 in Cd uptake and tolerance in wheat. Under Cd stress, 1 overexpression lines displayed higher photosynthetic rates than the wild type; opposite results were observed in the -RNAi lines. In addition, 1 overexpression lines showed reduced Cd uptake and accumulation, whereas RNAi plants exhibited a significant increase in Cd accumulation after Cd treatment. We further found that 1 enhanced the resistance of wheat to Cd stress in three ways. First, TaPUB1 interacts with and ubiquitinates TaIRT1, resulting in the inhibition of Cd uptake. Second, TaPUB1 interacts directly with and ubiquitinates TaIAA17, facilitates its degradation, and results in primary root elongation by activating the Aux signaling pathway under Cd stress. Moreover, 1 decreases ROS accumulation by regulating antioxidant-related gene expression and antioxidant enzyme activity under Cd stress. Thus, a molecular mechanism by which 1 regulates Cd uptake and tolerance by modulating the stability of TaIRT1 and TaIAA17 proteins was revealed.
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http://dx.doi.org/10.1021/acs.jafc.0c08042DOI Listing
June 2021

Novel Fe(III)-Polybasic acid coordination polymer nanoparticles with targeted retention for photothermal and chemodynamic therapy of tumor.

Eur J Pharm Biopharm 2021 Aug 18;165:174-184. Epub 2021 May 18.

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Targeted Therapy and Diagnosis of Tumor and Major Diseases, Henan Province, Zhengzhou 450001, China. Electronic address:

The development of Fe-coordination polymer-based nanoparticles, with safe and high anti-tumor effects, for the treatment of tumor is facing challenges such as limited resources and poor targeting. In this study, we prepared Fe-polyhydroxy coordination polymer nanoparticles ([email protected]), based on tartaric acid (TA)-Fe(III) coordination polymer as the new photothermal agent, mannose (M) as the target, and bovine serum albumin (BSA) and polyethyleneimine (PEI) as the carrier materials, and investigated them for targeting the multifunctional therapy of tumors. The [email protected] synthesized via a simple coordination of Fe with TA, bovine serum albumin, and polyethyleneimine under ambient conditions exhibited an appropriate size (~125 nm), electrically neutral surfaces, good biocompatibility, and low normal cell toxicity. The [email protected] are the first to exhibit a remarkable photothermal performance. They also showed a pH-sensitive Fenton-like response that was further enhanced via glutathione response. Interestingly, after a single injection, the [email protected] could be retained at the tumor site for 36 h with an effective photothermal dose, which was attributed to the reduced protein adsorption and slow elimination in tumor cells with the aid of M modification and carrier materials, while that for the [email protected] did so for only 2 h. Tumor ablation was demonstrated by in vivo photothermal and chemokinetic therapy using [email protected], and their safety was evident from the weight changes and blood parameters. These results indicated that the [email protected], as new photothermal and CDT agents, have the potential to be used in clinical tumor therapy nanoplatforms.
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http://dx.doi.org/10.1016/j.ejpb.2021.05.012DOI Listing
August 2021

Efficient 3D printing via photooxidation of ketocoumarin based photopolymerization.

Nat Commun 2021 May 17;12(1):2873. Epub 2021 May 17.

Key Lab for Material Chemistry of Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), Wuhan, China.

Photopolymerization-based three-dimensional (3D) printing can enable customized manufacturing that is difficult to achieve through other traditional means. Nevertheless, it remains challenging to achieve efficient 3D printing due to the compromise between print speed and resolution. Herein, we report an efficient 3D printing approach based on the photooxidation of ketocoumarin that functions as the photosensitizer during photopolymerization, which can simultaneously deliver high print speed (5.1 cm h) and high print resolution (23 μm) on a common 3D printer. Mechanistically, the initiating radical and deethylated ketocoumarin are both generated upon visible light exposure, with the former giving rise to rapid photopolymerization and high print speed while the latter ensuring high print resolution by confining the light penetration. By comparison, the printed feature is hard to identify when the ketocoumarin encounters photoreduction due to the increased lateral photopolymerization. The proposed approach here provides a viable solution towards efficient additive manufacturing by controlling the photoreaction of photosensitizers during photopolymerization.
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http://dx.doi.org/10.1038/s41467-021-23170-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129151PMC
May 2021

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells.

Emerg Microbes Infect 2021 Dec;10(1):1024-1037

State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, The University of Hong Kong, Pokfulam, People's Republic of China.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.
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http://dx.doi.org/10.1080/22221751.2021.1929503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205058PMC
December 2021

Investigation of the relationships between sleep behaviors and risk of healthspan termination: a prospective cohort study based on 323,373 UK-Biobank participants.

Sleep Breath 2021 May 6. Epub 2021 May 6.

Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, China.

Objectives: To examine the associations between four sleep behaviors and the risk of healthspan termination.

Methods: This study included 323,373 participants, free of terminated healthspan at baseline, from the UK-Biobank (UKB). We applied multivariable-adjusted Cox regression models to estimate the risk of terminated healthspan based on four sleep behaviors (insomnia/sleeplessness, napping, daytime sleepiness, and difficulty getting up from bed), which were self-reported and measured on Likert scales from "usually" to "never/rarely" experiences. In this study, healthspan was defined based on eight events that are strongly associated with longevity (congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, diabetes, cancer, and death).

Results: Participants who reported the following unhealthy sleep behaviors had a significantly higher risk of terminated healthspan: "usually experience sleeplessness/insomnia" (HR = 1.05, 95% CI: 1.03-1.07; P < 0.001); "usually nap" (HR = 1.22, 95% CI: 1.18-1.26; P < 0.01); "excessive daytime sleepiness" (HR = 1.25, 95% CI: 1.19-1.32; P < 0.001); and "difficult getting up from bed" (HR = 1.08, 95% CI: 1.05-1.10; P < 0.001). The corresponding population attributable risk percentage (PAR%) indicated that about 7% of healthspan termination in this cohort would have been eliminated if all participants had healthy sleep behaviors.

Conclusion: Participants who reported "usually experience sleeplessness/insomnia," "usually nap," "excessive daytime sleepiness," and "difficult getting up from bed" had increased risk of shortened healthspan. Therefore, adherence to healthy sleep behavior is significant for the extension of healthspan.
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http://dx.doi.org/10.1007/s11325-021-02394-0DOI Listing
May 2021

HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma.

PLoS Biol 2021 Apr 27;19(4):e3001197. Epub 2021 Apr 27.

Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China.

Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.
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http://dx.doi.org/10.1371/journal.pbio.3001197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104400PMC
April 2021

Inhibition mechanism and hot-spot prediction of nine potential drugs for SARS-CoV-2 M by large-scale molecular dynamic simulations combined with accurate binding free energy calculations.

Nanoscale 2021 May 26;13(17):8313-8332. Epub 2021 Apr 26.

School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China.

Coronavirus disease 2019 (COVID-19), which is caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading around the world. However, a universally effective treatment regimen has not been developed to date. The main protease (M), a key enzyme of SARS-CoV-2, plays a crucial role in the replication and transcription of this virus in cells and has become the ideal target for rational antiviral drug design. In this study, we performed molecular dynamics simulations three times for these complexes of M (monomeric and dimeric) and nine potential drugs that have a certain effect on the treatment of COVID-19 to explore their binding mechanism. In addition, a total of 12 methods for calculating binding free energy were employed to determine the optimal drug. Ritonavir, Arbidol, and Chloroquine consistently showed an outstanding binding ability to monomeric M under various methods. Ritonavir, Arbidol, and Saquinavir presented the best performance when binding to a dimer, which was independent of the protonated state of Hie41 (protonated at N) and Hid41 (protonated at N), and these findings suggest that Chloroquine may not effectively inhibit the activity of dimeric Min vivo. Furthermore, three common hot-spot residues of Met165, Hie41, and Gln189 of monomeric M systems dominated the binding of Ritonavir, Arbidol, and Chloroquine. In dimeric M, Gln189, Met165, and Met49 contributed significantly to binding with Ritonavir, Arbidol, and Saquinavir; therefore, Gln189 and Met165 might serve as the focus in the discovery and development of anti-COVID-19 drugs. In addition, the van der Waals interaction played a significant role in the binding process, and the benzene ring of the drugs showed an apparent inhibitory effect on the normal function of M. The binding cavity had great flexibility to accommodate these different drugs. The results would be notably helpful for enabling a detailed understanding of the binding mechanisms for these important drug-M interactions and provide valuable guidance for the design of potent inhibitors.
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http://dx.doi.org/10.1039/d0nr07833fDOI Listing
May 2021

Bibliometric Analysis of Research Articles on Pain in the Elderly Published from 2000 to 2019.

J Pain Res 2021 16;14:1007-1025. Epub 2021 Apr 16.

Department of Rehabilitation Medicine, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.

Background: Given the rapid growth of the global aging population, pain has become an unneglectable concern amongst the elderly. The quantity of scientific research outputs on pain in the elderly has increased over time, but only a small number of studies have used bibliometric methods to analyze scientific research in this field. This paper aimed to analyze scientific research on pain in the elderly published from 2000 to 2019 in a systematic manner using bibliometric methods.

Methods: Articles on pain in the elderly published from 2000 to 2019 were retrieved from the Web of Science (WoS). Abstracts were coded on the basis of predetermined items (eg, type of article, topic, type of subjects, pain characteristics), and relevant information on the first author, citation scores, and article keywords were collected.

Results: A total of 2105 articles were included in this study. Statistical analysis revealed that the publication of articles on pain in the elderly increased in frequency over time (P<0.001). Most of the publications were original articles. Amongst the countries identified, the United States published the largest number of papers on this topic. Pain characteristics (50.21%), pain intervention (35.68%), and pain assessment (9.69%) were the main topics of research on geriatric pain. Back pain (12.30%) appeared to be the most popular pain type described in the included papers.

Conclusion: This work provides researchers with an in-depth understanding of pain in the elderly by evaluating relevant publications in the past two decades. Researchers in this field are warranted to explore future directions on geriatric pain such as the transition from acute pain to chronic pain and the underlying mechanisms of pain in the elderly.
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http://dx.doi.org/10.2147/JPR.S283732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058449PMC
April 2021

MoS Nanocomposite Films with High Irradiation Tolerance and Self-Adaptive Lubrication.

ACS Appl Mater Interfaces 2021 May 22;13(17):20435-20447. Epub 2021 Apr 22.

State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China.

Although nanostructures and oxide dispersion can reduce radiation-induced damage in materials and enhance radiation tolerance, previous studies prove that MoS nanocomposite films subjected to several dpa heavy ion irradiation show significant degradation of tribological properties. Even in YSZ-doped MoS nanocomposite films, irradiation leads to obvious disordering and damage such as vacancy accumulation to form lamellar voids in the amorphous matrix, which accelerates the failure of lubrication. However, after thermal annealing in vacuum, YSZ-doped MoS nanocomposite films exhibit high irradiation tolerance, and their wear duration remains unchanged and the wear rate was nearly three orders of magnitude lower than that of the as-deposited films after 7 dpa irradiation. This successful combination of anti-irradiation and self-adaptive lubrication mainly results from the manipulation of the nanosize and the change of composition by annealing. Compared with the smaller nanograins in as-deposited MoS/YSZ nanocomposite films, the thermally annealed MoS nanocrystals (7-15 nm) with fewer intrinsic defects exhibited remarkable stabilization upon irradiation. Abundant amorphous nanocrystal phases in ion-irradiated thermally annealed films, where each has advantages of their own, greatly inhibit accumulation of voids and crack growth in irradiation; meanwhile, they can be easily self-assembled under induction of friction and achieve self-adaptive lubrication.
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http://dx.doi.org/10.1021/acsami.0c18864DOI Listing
May 2021

Highly Lithiophilic Copper-Reinforced Scaffold Enables Stable Li Metal Anode.

ACS Appl Mater Interfaces 2021 May 20;13(17):20240-20250. Epub 2021 Apr 20.

School of Materials Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.

Lithium (Li) metal is regarded as one of the most prospective electrodes for next-generation rechargeable batteries. However, its widespread usage has been fettered by low coulombic efficiency (CE), poor cycling stability, and serious safety concerns, mainly arising from huge volumetric variation, inhomogeneous Li deposition, and dendrite growth during repeated Li plating/stripping cycles. Herein, we propose a facile one-pot electrospinning-derived highly lithiophilic nanocopper-reinforced three-dimensional-structured carbon nanofiber (Cu-CNF) as functional scaffold to stabilize the Li metal. The Cu-CNF scaffolded Li metal demonstrates homogeneous nanoplate-like Li deposition, enhanced CE, and ultrastable long lifespan cycling. As coupled with LiNiCoMnO (NCM811), the cell possesses a remarkably stable high capacity retention of 93% over 300 cycles at 0.2 C. Furthermore, the cells paired with a thick LiFePO (LFP) electrode (∼12 mg cm) still can deliver a superior cycling performance even under the harsh conditions of an extremely low negative/positive electrode capacity (N/P) ratio (∼1.5) and lean electrolyte. Density functional theory calculations are performed to disclose the mechanism of the enhanced electrochemical performance of Cu-CNF scaffolded Li. This work provides a handy and cost-effective method to design superior performance Li metal anodes for practical applications.
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http://dx.doi.org/10.1021/acsami.1c04735DOI Listing
May 2021

MassARRAY multigene screening combined with LDL-C and sdLDL-C detection for more favorable outcomes in type 2 diabetes mellitus therapy.

BMC Med Genomics 2021 03 17;14(1):83. Epub 2021 Mar 17.

Shanghai Biotecan Pharmaceuticals Co., Ltd, Shanghai Zhangjiang Institute of Medical Innovation, 180 Zhangheng Road, Shanghai, 200120, China.

Background: To determine the clinical value of multigene polymorphisms, LDL-C and sdLDL-C on T2DM therapy.

Methods: In total, 352 T2DM patients before and after treatment and 48 healthy individuals were enrolled in this study. LDL-C and sdLDL-C were detected in 352 T2DM patients and 48 healthy individuals by Quantimetrix Lipoprint System. The 11 gene polymorphisms-HTR3B (rs2276307, A > G), APOE (rs7412, c.526C > T), APOE (rs429358, c.388 T > C), CYP2C9*3 (rs1057910, c.1075A > C), KIF6 (rs20455, c.2155 T > C), HMGCR (rs17238540, T > G), HMGCR (rs17244841, A > T), ABCB1 (rs2032582, A > C/T), HTR7 (rs1935349, C > T), SLCO1B1 (rs4149056, c.521 T > C), and CETP (rs708272, G > A)-were screened in these 352 T2DM patients by the Agena Bioscience MassARRAY system before therapy.

Results: Genetic polymorphisms associated with T2DM and statin effects in pretreatment patients were detected, then results showed that all 11 genes had heterozygous mutation, and 7 genes had homozygous mutation in 352 T2DM patients, more specifically reflected that these gene polymorphisms were common in Chinese T2DM patients. LDL-C and sdLDL-C were detected before and after treatment, sdLDL mainly existed in T2DM patients, and T2DM patients had higher mean levels of sdLDL-C than healthy people. After pharmacotherapy, the coincidence rates of decreases in LDL-C and sdLDL-C levels were 88.35% (311/352) and 84.09% (296/352), consistent with patients in remission.

Conclusions: Gene polymorphisms related to pharmacotherapy were common in Chinese T2DM patients. And the expression of LDL-C and sdLDL-C was consistent with the T2DM disease course. Combined multigene screening before therapy and LDL-C and sdLDL-C detection before and after therapy could better assist T2DM treatment.
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http://dx.doi.org/10.1186/s12920-021-00937-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972339PMC
March 2021

Corrigendum to "Globular CTRP9 protects cardiomyocytes from palmitic acid-induced oxidative stress by enhancing autophagic flux" Epub 2020 Apr 10.

Chem Biol Interact 2021 Apr 12;339:109391. Epub 2021 Mar 12.

Department of General Medicine, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China; Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.cbi.2021.109391DOI Listing
April 2021

Sunflower-Like Nanostructure with Built-In Hotspots for Alpha-Fetoprotein Detection.

Molecules 2021 Feb 23;26(4). Epub 2021 Feb 23.

College of Physics, Jilin Normal University, Changchun 130103, China.

In the present study, a sunflower-like nanostructure array composed of a series of synaptic nanoparticles and nanospheres was manufactured through an efficient and low-cost colloidal lithography technique. The primary electromagnetic field contribution generated by the synaptic nanoparticles of the surface array structures was also determined by a finite-difference time-domain software to simulate the hotspots. This structure exhibited high repeatability and excellent sensitivity; hence, it was used as a surface-enhanced Raman spectroscopy (SERS) active substrate to achieve a rapid detection of ultra-low concentrations of Alpha-fetoprotein (AFP). This study demonstrates the design of a plasmonic structure with strong electromagnetic coupling, which can be used for the rapid detection of AFP concentration in clinical medicine.
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http://dx.doi.org/10.3390/molecules26041197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926938PMC
February 2021

Human Intestinal Organoids Recapitulate Enteric Infections of Enterovirus and Coronavirus.

Stem Cell Reports 2021 03 12;16(3):493-504. Epub 2021 Feb 12.

State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong, China. Electronic address:

Enteroviruses, such as EV-A71 and CVA16, mainly infect the human gastrointestinal tract. Human coronaviruses, including SARS-CoV and SARS-CoV-2, have been variably associated with gastrointestinal symptoms. We aimed to optimize the human intestinal organoids and hypothesize that these optimized intestinal organoids can recapitulate enteric infections of enterovirus and coronavirus. We demonstrate that the optimized human intestinal organoids enable better simulation of the native human intestinal epithelium, and that they are significantly more susceptible to EV-A71 than CVA16. Higher replication of EV-A71 than CVA16 in the intestinal organoids triggers a more vigorous cellular response. However, SARS-CoV and SARS-CoV-2 exhibit distinct dynamics of virus-host interaction; more robust propagation of SARS-CoV triggers minimal cellular response, whereas, SARS-CoV-2 exhibits lower replication capacity but elicits a moderate cellular response. Taken together, the disparate profile of the virus-host interaction of enteroviruses and coronaviruses in human intestinal organoids may unravel the cellular basis of the distinct pathogenicity of these viral pathogens.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940440PMC
March 2021

EEG power spectral analysis reveals tandospirone improves anxiety symptoms in patients with Alzheimer's disease: a prospective cohort study.

Ann Transl Med 2021 Jan;9(1):64

Bengbu Medical College, Bengbu, China.

Background: To study the efficacy of tandospirone citrate in treating Alzheimer's disease (AD) patients with anxiety.

Methods: Thirty mild-to-moderate AD patients with anxiety symptoms were randomly divided into a monotherapy group (donepezil) and a combination therapy group (donepezil and tandospirone). The treatment lasted for 12 weeks. Drug efficacy was regularly assessed using psychological assessment scales and quantitative pharmaco-electroencephalogram (QPEEG) power spectral analysis.

Results: After 12 weeks of treatment, the mean Hamilton Anxiety Scale (HAMA) score and mean Neuropsychiatric Inventory (NPI) score of the combination therapy group were 5.13±4.18 and 4.2±5.0, respectively, which was significantly lower compared to baseline and the monotherapy group (all P<0.05). The mean attention score on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) was 0.07±0.26 for the combination group, which was significantly lower than that of the monotherapy group (P<0.05). QPEEG revealed that the power values of the δ wave in the right prefrontal lobe, left middle temporal lobe and right posterior temporal lobe decreased in the combination therapy group but not in the monotherapy group. Similarly, the power values of the α2 wave in the right parietal, right posterior temporal and left middle temporal lobes, and the β1 wave power values of left middle temporal and left posterior temporal lobes were also significantly decreased in the combination therapy group, but not in the monotherapy group.

Conclusions: Tandospirone citrate can significantly improve anxiety symptoms and attention in patients with mild to moderate AD. QPEEG examination might provide a objective way for the efficacy of the tandospirone in anxiety symptoms of the patients with Alzheimer's disease.
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http://dx.doi.org/10.21037/atm-20-6647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859764PMC
January 2021

Modulation of the HMGB1/TLR4/NF-κB signaling pathway in the CNS by matrine in experimental autoimmune encephalomyelitis.

J Neuroimmunol 2021 03 16;352:577480. Epub 2021 Jan 16.

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address:

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens, has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1β in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577480DOI Listing
March 2021

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses.

Biomedicines 2021 Jan 18;9(1). Epub 2021 Jan 18.

State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses.
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http://dx.doi.org/10.3390/biomedicines9010088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831294PMC
January 2021

Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target.

Emerg Microbes Infect 2020 Dec;9(1):2663-2672

State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, People's Republic of China.

Rapid accumulation of viral proteins in host cells render viruses highly dependent on cellular chaperones including heat shock protein 90 (Hsp90). Three highly pathogenic human coronaviruses, including MERS-CoV, SARS-CoV and SARS-CoV-2, have emerged in the past 2 decades. However, there is no approved antiviral agent against these coronaviruses. We inspected the role of Hsp90 for coronavirus propagation. First, an Hsp90 inhibitor, 17-AAG, significantly suppressed MERS-CoV propagation in cell lines and physiological-relevant human intestinal organoids. Second, siRNA depletion of Hsp90β, but not Hsp90α, significantly restricted MERS-CoV replication and abolished virus spread. Third, Hsp90β interaction with MERS-CoV nucleoprotein (NP) was revealed in a co-immunoprecipitation assay. Hsp90β is required to maintain NP stability. Fourth, 17-AAG substantially inhibited the propagation of SARS-CoV and SARS-CoV-2. Collectively, Hsp90 is a host dependency factor for human coronavirus MERS-CoV, SARS-CoV and SARS-COV-2. Hsp90 inhibitors can be repurposed as a potent and broad-spectrum antiviral against human coronaviruses.
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http://dx.doi.org/10.1080/22221751.2020.1850183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751432PMC
December 2020

Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton.

Eur J Med Chem 2021 Jan 2;209:112896. Epub 2020 Oct 2.

Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address:

Covalent drugs play corresponding bioactivities by forming covalent bonds with the target, which possess many significant pharmacological advantages including high potency, ligand efficiency, and long-lasting effects. However, development of covalent inhibitors is a challenge due to their presumed indiscriminate reactivity. Here, we report the discovery of series of lysosome-targeting covalent anticancer agents by introducing nitrogenous bases to the modified isosteviol skeleton in order to minimize the toxicity and increase the selectivity. By introducing the electrophilic α, β-unsaturated ketones into the A- and D-rings of isosteviol, the cytotoxicity of the obtained compounds were greatly increased. Further nitrogen-containing modifications to the D-ring led to the discovery of novel molecules that targeted lysosomes, and of which, compound 30 was the most potent and selective antiproliferative one to kill A549 cells in vitro and in vivo. Mechanism investigation revealed that compound 30 was trapped into lysosomes and damaged lysosomes to cause cell death.
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http://dx.doi.org/10.1016/j.ejmech.2020.112896DOI Listing
January 2021
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