Publications by authors named "Luyao Wang"

164 Publications

Low-Temperature Aging Provides 22% Efficient Bromine-Free and Passivation Layer-Free Planar Perovskite Solar Cells.

Nanomicro Lett 2020 Apr 3;12(1):84. Epub 2020 Apr 3.

School of Material Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.

Previous reports of formamidinium/methylamine (FAMA)-mixed halide perovskite solar cells have focused mainly on controlling the morphology of the perovskite film and its interface-for example, through the inclusion of bromine and surface passivation. In this paper, we describe a new processing pathway for the growth of a high-quality bromine-free FAMAPbI halide perovskites via the control of intermediate phase. Through low-temperature aging growth (LTAG) of a freshly deposited perovskite film, α-phase perovskites can be seeded in the intermediate phase and, at the same time, prevent beta-phase perovskite to nucleate. After postannealing, large grain-size perovskites with significantly reduced PbI presence on the surface can be obtained, thereby eliminating the need of additional surface passivation step. Our pristine LTAG-treated solar cells could provide PCEs of greater than 22% without elaborate use of bromine or an additional passivation layer. More importantly, when using this LTAG process, the growth of the pure alpha-phase FAMAPbI was highly reproducible.
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http://dx.doi.org/10.1007/s40820-020-00418-0DOI Listing
April 2020

Integrin αβ Targeting DGEA-Modified Liposomal Doxorubicin Enhances Antitumor Efficacy against Breast Cancer.

Mol Pharm 2021 Jun 16. Epub 2021 Jun 16.

Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R. China.

Breast cancer was the leading cause of newly diagnosed cases of tumors in 2020, ranking as the second highest cause of female death. Chemotherapy remains the conventional treatment of choice for breast tumors in most clinical cases. However, it is often accompanied by a poor prognosis and severe side effects, resulting from an insufficient accumulation of the drug at tumor sites and an unsystematic distribution of the drug across the body. Inspired by the fact that breast tumor cells overexpress integrin αβ on the surface, we designed and constructed an integrin αβ targeting DGEA-modified liposomal doxorubicin (DGEA-Lipo-DOX) platform for application in breast cancer therapy. The DGEA-Lipo-DOX was stable with a uniform particle size of 121.1 ± 3.8 nm and satisfactory drug encapsulation. Demonstrated and , the constructed platform exhibited improved antitumor ability. The DGEA-Lipo-DOX showed 4-fold enhanced blood circulation and 6-fold increased accumulation of DOX at the tumor sites compared to those of free DOX, resulting in a significantly enhanced antitumor efficacy in tumor-bearing mice. A preliminary safety evaluation suggested that the systemic toxicity of DOX was relieved by DGEA-Lipo delivery. Collectively, binding integrin αβ by DGEA may represent an alternative therapeutic strategy for potentially safer breast cancer treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00132DOI Listing
June 2021

Functional examination of lncRNAs in allotetraploid Gossypium hirsutum.

BMC Genomics 2021 Jun 13;22(1):443. Epub 2021 Jun 13.

College of Agriculture and Biotechnology, Zhejiang University, 210058, Hangzhou, Zhejiang, China.

Background: An evolutionary model using diploid and allotetraploid cotton species identified 80 % of non-coding transcripts in allotetraploid cotton as being uniquely activated in comparison with its diploid ancestors. The function of the lncRNAs activated in allotetraploid cotton remain largely unknown.

Results: We employed transcriptome analysis to examine the relationship between the lncRNAs and mRNAs of protein coding genes (PCGs) in cotton leaf tissue under abiotic stresses. LncRNA expression was preferentially associated with that of the flanking PCGs. Selected highly-expressed lncRNA candidates (n = 111) were subjected to a functional screening pilot test in which virus-induced gene silencing was integrated with abiotic stress treatment. From this low-throughput screen, we obtained candidate lncRNAs relating to plant height and tolerance to drought and other abiotic stresses.

Conclusions: Low-throughput screen is an effective method to find functional lncRNA for further study. LncRNAs were more active in abiotic stresses than PCG expression, especially temperature stress. LncRNA XLOC107738 may take a cis-regulatory role in response to environmental stimuli. The degree to which lncRNAs are constitutively expressed may impact expression patterns and functions on the individual gene level rather than in genome-wide aggregate.
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http://dx.doi.org/10.1186/s12864-021-07771-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201905PMC
June 2021

Dickkopf-1: A Promising Target for Cancer Immunotherapy.

Front Immunol 2021 20;12:658097. Epub 2021 May 20.

Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both cell models and animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8 T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.658097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174842PMC
May 2021

Rational Design for Broadened Substrate Specificity and Enhanced Activity of a Novel Acetyl Xylan Esterase from .

J Agric Food Chem 2021 Jun 2;69(23):6665-6675. Epub 2021 Jun 2.

Laboratory of Biomanufacturing and Food Engineering, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Gut bacteria-derived enzymes play important roles in the metabolism of dietary fiber through enabling the hydrolysis of polysaccharides. In this study, we identified and characterized a 29 kDa novel acetyl xylan esterase, Axe1, from VPI5482. Then, we solved the structure of Axe1 and performed the rational design. Mutants N65S and N65A increased the activities toward short-chain (NPA, NPB) to near four-fold, and gained the activities toward longer-chain substrate (NPO). Molecular docking analysis showed that the mutant N65S had a larger substrate binding pocket than the wild type. Hydrolysis studies using natural substrates showed that either N65S or N65A showed higher activity of that of wild-type, yielding 131.31 and 136.09 mM of acetic acid from xylan. This is the first study on the rational design of gut bacteria-derived Axes with broadened substrate specificity and enhanced activity, which can be referenced by other acetyl esterases or gut-derived enzymes.
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http://dx.doi.org/10.1021/acs.jafc.1c00750DOI Listing
June 2021

Identification and characterization of a novel carboxylesterase EstQ7 from a soil metagenomic library.

Arch Microbiol 2021 May 31. Epub 2021 May 31.

Key Laboratory of Food Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, People's Republic of China.

A novel lipolytic gene, estq7, was identified from a fosmid metagenomic library. The recombinant enzyme EstQ7 consists of 370 amino acids with an anticipated molecular mass of 42 kDa. Multiple sequence alignments showed that EstQ7 contained a pentapeptide motif GHSMG, and a putative catalytic triad Ser174-Asp306-His344. Interestingly, EstQ7 was found to have very little similarity to the characterized lipolytic enzymes. Phylogenetic analysis revealed that EstQ7 may be a member of a novel family of lipolytic enzymes. Biochemical characterization of the recombinant enzyme revealed that it constitutes a slightly alkalophilic, moderate thermophilic and highly active carboxylesterase against short-chain fatty acid esters with optimum temperature 50 ℃ and pH 8.2. The Km and kcat values toward p-nitrophenyl acetate were determined to be 0.17 mM and 1910s, respectively. Moreover, EstQ7 was demonstrated to have acyltransferase activity by GC-MS analysis. Structural modeling of the three-dimensional structure of this new enzyme showed that it exhibits a typical α/β hydrolase fold, and the catalytic triad residues are spatially close. Molecular docking revealed the interactions between the enzyme and the ligand. The high levels of lipolytic activity of EstQ7, combined with its moderate thermophilic property and acyltransferase activity, render this novel enzyme a promising candidate biocatalyst for food, pharmaceutical and biotechnological applications.
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http://dx.doi.org/10.1007/s00203-021-02398-0DOI Listing
May 2021

Functional Lignin Nanoparticles with Tunable Size and Surface Properties: Fabrication, Characterization, and Use in Layer-by-Layer Assembly.

ACS Appl Mater Interfaces 2021 Jun 27;13(22):26308-26317. Epub 2021 May 27.

Department of Chemical Engineering, Lakehead University, Thunder Bay, ON, Canada.

Lignin is the richest source of renewable aromatics and has immense potential for replacing synthetic chemicals. The limited functionality of lignin is, however, challenging for its potential use, which motivates research for creating advanced functional lignin-derived materials. Here, we present an aqueous-based acid precipitation method for preparing functional lignin nanoparticles (LNPs) from carboxymethylated or carboxypentylated lignin. We observe that the longer grafted side chains of carboxypentylated lignin allow for the formation of larger LNPs. The functional nanoparticles have high tolerance against salt and aging time and well-controlled size distribution with ≤ 60 nm over a pH range of 5-11. We further investigate the layer-by-layer (LbL) assembly of the LNPs and poly(allylamine hydrochloride) (PAH) using a stagnation point adsorption reflectometry (SPAR) and quartz crystal microbalance with dissipation (QCM-D). Results demonstrate that LNPs made of carboxypentylated lignin (i.e., PLNPs with the adsorbed mass of 3.02 mg/m) form a more packed and thicker adlayer onto the PAH surface compared to those made of carboxymethylated lignin (i.e., CLNPs with the adsorbed mass of 2.51 mg/m). The theoretical flux, , and initial rate of adsorption, (dΓ/d), analyses confirm that 22% of PLNPs and 20% of CLNPs arriving at the PAH surface are adsorbed. The present study provides a feasible platform for engineering LNPs with a tunable size and adsorption behavior, which can be adapted in bionanomaterial production.
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http://dx.doi.org/10.1021/acsami.1c03496DOI Listing
June 2021

Electrochemically reduced phytic acid-doped TiO nanotubes for the efficient electrochemical degradation of toxic pollutants.

J Hazard Mater 2021 07 6;414:125600. Epub 2021 Mar 6.

School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China; State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, PR China; Nanjing University & Yancheng Academy of Environmental Protection Technology and Engineering, Yancheng 210009, PR China. Electronic address:

Element-doped TiO nanotube arrays (TNAs) with optimized active sites provide an effective approach for significantly improving electrocatalytic performance. The challenges in such construction mainly include selection of green dopant and control of active sites. Herein, we present phytic acid as a phosphorus source for P-doped TNAs. An oxygen vacancy (Ov) and P co-doped TNAs (P-TiO) was prepared as an electrochemical oxidation anode. P-TiO exhibits excellent degradation activity due to the formation of Ti-O-P bonds and generation of Ov. P-doping was beneficial in improving the oxygen evolution potential of the electrode, which would be benefit for electrocatalytic degradation of pollutants. Using the P-TiO anode with a current density of 10 mA/cm for tetracycline degradation, after a 3 h treatment, the removal rate, chemical oxygen demand and total organic carbon removal rates were 100%, 90.32% and 76.60%, respectively. The P-TiO also has excellent degradation performance for phenol, hydroquinone, p-nitrophenol and metronidazole.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125600DOI Listing
July 2021

Characteristics of the Microbial Community in the Production of Chinese Rice-Flavor Baijiu and Comparisons With the Microflora of Other Flavors of Baijiu.

Front Microbiol 2021 29;12:673670. Epub 2021 Apr 29.

State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.

Rice-flavor baijiu is one of the four basic flavor types of Chinese baijiu. Microbial composition plays a key role in the classification of baijiu flavor types and the formation of flavor substances. In this study, we used high-throughput sequencing technology to study the changes of microbial community in the production of rice-flavor baijiu, and compared the microbial community characteristics during production of rice-, light-, and strong-flavor baijiu. The results showed that the species diversity of bacteria was much higher than that of fungi during the brewing of rice-flavor baijiu. The bacterial diversity index first increased and then decreased, while the diversity of fungi showed an increasing trend. A variety of major microorganisms came from the environment and raw rice materials; the core bacteria were , , , , , etc., among which was dominant (62.88-99.23%). The core fungi were (7.06-83.50%) and (15.21-90.89%). Temperature and total acid content were the main physicochemical factors affecting the microbial composition. Non-metric multidimensional scaling analysis showed that during the fermentation of rice-, light-, and strong-flavor baijiu, their microbial communities formed their own distinct systems, with considerable differences among different flavor types. Compared with the other two flavor types of baijiu, in the brewing process of rice-flavor baijiu, microbial species were fewer and dominant microorganisms were prominent, which may be the main reason for the small variety of flavor substances in rice-flavor baijiu. This study provides a theoretical basis for the production of rice-flavor baijiu, and lays a foundation for studying the link between baijiu flavor formation and microorganisms.
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http://dx.doi.org/10.3389/fmicb.2021.673670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116502PMC
April 2021

The α-Helical Cap Domain of a Novel Esterase from Gut Shaping the Substrate-Binding Pocket.

J Agric Food Chem 2021 Jun 12;69(21):6064-6072. Epub 2021 May 12.

Laboratory of Biomanufacturing and Food Engineering, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

The human gut microbiota regulates nutritional metabolism, especially by encoding specific ferulic acid esterases (FAEs) to release functional ferulic acid (FA) from dietary fiber. In our previous study, we observed seven upregulated FAE genes during fecal slurry fermentation using wheat bran. Here, a 29 kDa FAE (FAE) from of was characterized and identified as the type-A FAE. The X-ray structure of FAE has been determined, revealing a unique α-helical domain comprising five α-helices, which was first characterized in FAEs from the gut microbiota. Further molecular docking analysis and biochemical studies revealed that Tyr100, Thr122, Tyr219, and Ile220 are essential for substrate binding and catalytic efficiency. Additionally, Glu129 and Lys130 in the cap domain shaped the substrate-binding pocket and affected the substrate preference. This is the first report on FAE, providing a theoretical basis for the dietary metabolism in the human gut.
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http://dx.doi.org/10.1021/acs.jafc.1c00940DOI Listing
June 2021

Slit diaphragm maintenance requires dynamic clathrin-mediated endocytosis facilitated by AP-2, Lap, Aux and Hsc70-4 in nephrocytes.

Cell Biosci 2021 May 11;11(1):83. Epub 2021 May 11.

Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD, 21201, USA.

Background: The Slit diaphragm (SD) is the key filtration structure in human glomerular kidney that is affected in many types of renal diseases. SD proteins are known to undergo endocytosis and recycling to maintain the integrity of the filtration structure. However, the key components of this pathway remain unclear.

Methods: Using the Drosophila nephrocyte as a genetic screen platform, we screened most genes involved in endocytosis and cell trafficking, and identified the key components of the cell trafficking pathway required for SD protein endocytosis and recycling.

Results: We discovered that the SD protein endocytosis and recycling pathway contains clathrin, dynamin, AP-2 complex, like-AP180 (Lap), auxilin and Hsc70-4 (the endocytosis part) followed by Rab11 and the exocyst complex (the recycling part). Disrupting any component in this pathway led to disrupted SD on the cell surface and intracellular accumulation of mislocalized SD proteins. We also showed the first in vivo evidence of trapped SD proteins in clathrin-coated pits at the plasma membrane when this pathway is disrupted.

Conclusions: All genes in this SD protein endocytosis and recycling pathway, as well as SD proteins themselves, are highly conserved from flies to humans. Thus, our results suggest that the SD proteins in human kidney undergo the same endocytosis and recycling pathway to maintain the filtration structure, and mutations in any genes in this pathway could lead to abnormal SD and renal diseases.
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http://dx.doi.org/10.1186/s13578-021-00595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111712PMC
May 2021

[CRISPR/Cas9 technology in disease research and therapy: a review].

Sheng Wu Gong Cheng Xue Bao 2021 Apr;37(4):1205-1228

College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.

Genome editing is a genetic manipulation technique that can modify DNA sequences at the genome level, including insertion, knockout, replacement and point mutation of specific DNA fragments. The ultimate principle of genome editing technology relying on engineered nucleases is to generate double-stranded DNA breaks at specific locations in genome and then repair them through non-homologous end joining or homologous recombination. With the intensive study of these nucleases, genome editing technology develops rapidly. The most used nucleases include meganucleases, zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats associated Cas proteins. Based on introducing the development and principles of above mentioned genome editing technologies, we review the research progress of CRISPR/Cas9 system in the application fields of identification of gene function, establishment of disease model, gene therapy, immunotherapy and its prospect.
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http://dx.doi.org/10.13345/j.cjb.200401DOI Listing
April 2021

Population Receptive Field Characteristics in the between- and Within-Digit Dimensions of the Undominant Hand in the Primary Somatosensory Cortex.

Cereb Cortex 2021 May 10. Epub 2021 May 10.

School of Life Science, Beijing Institute of Technology, Beijing 100081, China.

Somatotopy is an important guiding principle for sensory fiber organization in the primary somatosensory cortex (S1), which reflects tactile information processing and is associated with disease-related reorganization. However, it is difficult to measure the neuronal encoding scheme in S1 in vivo in normal participants. Here, we investigated the somatotopic map of the undominant hand using a Bayesian population receptive field (pRF) model. The model was established in hand space with between- and within-digit dimensions. In the between-digit dimension, orderly representation was found, which had low variability across participants. The pRF shape tended to be elliptical for digits with high spatial acuity, for which the long axis was along the within-digit dimension. In addition, the pRF width showed different change trends in the 2 dimensions across digits. These results provide new insights into the neural mechanisms in S1, allowing for in-depth investigation of somatosensory information processing and disease-related reorganization.
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http://dx.doi.org/10.1093/cercor/bhab097DOI Listing
May 2021

Absence of CG methylation alters the long noncoding transcriptome landscape in multiple species.

FEBS Lett 2021 May 5. Epub 2021 May 5.

Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.

The noncoding regions throughout the genome are in large part comprised of transposable elements (TEs), some of which are functionalized with long intergenic noncoding RNAs (lincRNAs). DNA methylation is predominantly associated with TEs, but little is known about its contribution to the transcription of lincRNAs. Here, we examine the lincRNA profiles of DNA methylation-related mutants of five species, Arabidopsis, rice, tomato, maize, and mouse, to elucidate patterns in lincRNA regulation under altered DNA methylation status. Significant activation of lincRNAs was observed in the absence of CG DNA methylation rather than non-CG. Our study establishes a working model of the contribution of DNA methylation to regulation of the dynamic activity of lincRNA transcription.
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http://dx.doi.org/10.1002/1873-3468.14100DOI Listing
May 2021

Neofunctionalization of a Polyploidization-Activated Cotton Long intergenic non-coding RNA DAN1 During Drought Stress Regulation.

Plant Physiol 2021 Apr 19. Epub 2021 Apr 19.

College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310058, China.

The genomic shock of whole-genome duplication and hybridization introduces great variation into transcriptomes, for both coding and non-coding genes. An altered transcriptome provides a molecular basis for improving adaptation during the evolution of new species. The allotetraploid cotton, together with the putative diploid ancestor species compose a fine model for study the rapid gene neofunctionalization over the genome shock. Here we report on Drought-Associated Non-coding gene 1 (DAN1), a long intergenic non-coding RNA (lincRNA) that arose from the cotton progenitor A-diploid genome after hybridization and whole-genome duplication events during cotton evolution. DAN1 in allotetraploid upland cotton (Gossypium hirsutum, Gh) is a drought-responsive lincRNA predominantly expressed in nucleoplasm. A chromatin isolation by RNA purification (ChIRP) profiling and electrophoretic mobility shift assay (EMSA) analysis demonstrated that GhDAN1 RNA can bind with DNA fragments containing AAAG motifs, similar to DNA-binding one zinc finger (Dof) transcription factor binding sequences. The suppression of GhDAN1 mainly regulates genes with AAAG motifs in auxin-response pathways, which are associated with drought stress regulation. As a result, GhDAN1-silenced plants exhibit improved tolerance to drought stress. This phenotype resembles the drought-tolerant phenotype of the A-diploid cotton ancestor species, which has an undetectable expression of DAN1. The role of DAN1 in cotton evolution and drought tolerance regulation suggests that the genomic shock of interspecific hybridization and whole-genome duplication (WGD) stimulated neofunctionalization of non-coding genes during the natural evolutionary process.
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http://dx.doi.org/10.1093/plphys/kiab179DOI Listing
April 2021

Synergy and allostery in ligand binding by HIV-1 Nef.

Biochem J 2021 Apr;478(8):1525-1545

King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Biological and Environmental Science and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.

The Nef protein of human and simian immunodeficiency viruses boosts viral pathogenicity through its interactions with host cell proteins. By combining the polyvalency of its large unstructured regions with the binding selectivity and strength of its folded core domain, Nef can associate with many different host cell proteins, thereby disrupting their functions. For example, the combination of a linear proline-rich motif and hydrophobic core domain surface allows Nef to bind tightly and specifically to SH3 domains of Src family kinases. We investigated whether the interplay between Nef's flexible regions and its core domain could allosterically influence ligand selection. We found that the flexible regions can associate with the core domain in different ways, producing distinct conformational states that alter the way in which Nef selects for SH3 domains and exposes some of its binding motifs. The ensuing crosstalk between ligands might promote functionally coherent Nef-bound protein ensembles by synergizing certain subsets of ligands while excluding others. We also combined proteomic and bioinformatics analyses to identify human proteins that select SH3 domains in the same way as Nef. We found that only 3% of clones from a whole-human fetal library displayed Nef-like SH3 selectivity. However, in most cases, this selectivity appears to be achieved by a canonical linear interaction rather than by a Nef-like 'tertiary' interaction. Our analysis supports the contention that Nef's mode of hijacking SH3 domains is a virus-specific adaptation with no or very few cellular counterparts. Thus, the Nef tertiary binding surface is a promising virus-specific drug target.
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http://dx.doi.org/10.1042/BCJ20201002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079166PMC
April 2021

The Roles of Sclerostin in Immune System and the Applications of Aptamers in Immune-Related Research.

Front Immunol 2021 25;12:602330. Epub 2021 Feb 25.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.

Wnt signaling is one of the fundamental pathways that play a major role in almost every aspect of biological systems. In addition to the well-known influence of Wnt signaling on bone formation, its essential role in the immune system also attracted increasing attention. Sclerostin, a confirmed Wnt antagonist, is also proven to modulate the development and differentiation of normal immune cells, particularly B cells. Aptamers, single-stranded (ss) oligonucleotides, are capable of specifically binding to a variety of target molecules by virtue of their unique three-dimensional structures. With in-depth study of those functional nucleic acids, they have been gradually applied to diagnostic and therapeutic area in immune diseases due to their various advantages over antibodies. In this review, we focus on several issues including the roles of Wnt signaling and Wnt antagonist sclerostin in the immune system. For the sake of understanding, current examples of aptamers applications for the immune diseases are also discussed. At the end of this review, we propose our ideas for the future research directions.
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http://dx.doi.org/10.3389/fimmu.2021.602330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946814PMC
February 2021

[Bispecific antibodies in clinical tumor therapy].

Sheng Wu Gong Cheng Xue Bao 2021 Feb;37(2):513-529

College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.

Bispecific antibody (BsAb) has two different antigen-binding sites, divided into the "IgG-like" format and the "non-IgG-like" format. Different formats have different characteristics and applications. BsAb has higher sensitivity and specificity than conventional antibodies, with special functions such as recruitment of immune cells and blocking of dual signaling pathways, playing an important role in immune-diagnosis and therapy. With the deterioration of the global environment and the irregular living habits of people, the incidence of tumor is becoming higher and higher. Tumor becomes the most serious fatal disease threatening human health after cardiovascular disease. There are 12 million estimated new tumor cases each year worldwide. The major clinical treatments of tumor are surgical resection, chemoradiotherapy, target therapy. Tumor immunotherapy is a novel approach for tumor treatment in recent years, and activates human immune system to control and kill tumor cells. Although the traditional monoclonal antibodies have already acquired some therapeutic effects in tumor targeted therapy and immunotherapy, they induce drug resistance resulted from the heterogeneity and plasticity of tumors. Binding to two target antigens at the same time, BsAb has been used in the clinical treatment of tumors and obtained promising outcomes. This review elaborates the research progress and applications of bispecific antibody in clinical tumor therapy.
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http://dx.doi.org/10.13345/j.cjb.200327DOI Listing
February 2021

[Research progresses in the biosynthesis of curcuminoids].

Sheng Wu Gong Cheng Xue Bao 2021 Feb;37(2):404-417

Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Curcuminoids are rare diketone compounds in plants and can be found in the rhizome of Curcuma longa as well as other Zingiberaceae and Araceae. Curcuminoids have been widely used in food and medical area owing to the yellow colors, as well as the antioxidant and many other pharmacological activities. Curcuminoids are a mixture of compounds containing curcumin, demethoxycurcumin and bisdemethoxycurcumin, which have distinct benzene ring substituents. Currently, curcuminoids are exclusively produced through plant extraction, which do not satisfy the meeting of the market demand. Empowered with new synthetic biology tools and metabolic engineering strategies, there is renewed interest in production of curcuminoids using microorganisms. Heterologous production of curcuminoids has been achieved using Escherichia coli, Yarrowia lipolytica, Pseudomonas putida and Aspergillus oryzae via engineering of curcuminoids biosynthesis pathway. In this review, we first describe the biological activities and various applications of curcuminoids. Next, we summarize the biosynthetic pathway of curcuminoids in Curcuma longa and discuss the catalytic mechanisms of curcumin synthases. Then, we thoroughly explore recent advances in the use of distinct microorganisms for the production of curcuminoids with a special focus on metabolic engineering strategies. Finally, we prospect the microbial production of curcuminoids by highlighting some promising techniques and approaches.
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http://dx.doi.org/10.13345/j.cjb.200286DOI Listing
February 2021

Active Modulation of an All-Dielectric Metasurface Analogue of Electromagnetically Induced Transparency in Terahertz.

ACS Omega 2021 Feb 4;6(6):4480-4484. Epub 2021 Feb 4.

School of Microelectronics, Shandong University, Jinan 250100, China.

In this work, an analogue of electromagnetically induced transparency (EIT) is excited by a periodic unit consisting of a silicon rectangular bar resonator and a silicon ring resonator in terahertz (THz). The analogue of the EIT effect can be well excited by coupling of the "bright mode" and the "dark mode" supported by the bar and the ring, respectively. Using the semimetallic properties of graphene, active control of the EIT-like effect can be realized by integrating a monolayer graphene into THz metamaterials. By adjusting the Fermi energy of graphene, the resonating electron distribution changes in the dielectric structures, resulting in the varying of the EIT-like effect. The transmission can be modulated from 0.9 to 0.3 with the Fermi energy of graphene placed under the ring resonator mold varying from 0 to 0.6 eV, while a modulation range of 0.9-0.3 corresponds to Fermi energy from 0 to 0.3 eV when graphene is placed under the rectangular bar resonator. Our results may provide potential applications in slow light devices and an ultrafast optical signal.
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http://dx.doi.org/10.1021/acsomega.0c06082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906593PMC
February 2021

Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor.

Genes Cancer 2020 Dec 22;11(3-4):106-121. Epub 2020 Jul 22.

Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development.
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http://dx.doi.org/10.18632/genesandcancer.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805538PMC
December 2020

Intramolecular Electric Field Construction in Metal Phthalocyanine as Dopant-Free Hole Transporting Material for Stable Perovskite Solar Cells with >21 % Efficiency.

Angew Chem Int Ed Engl 2021 Mar 12;60(12):6294-6299. Epub 2021 Feb 12.

State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China.

Low conductivity and hole mobility in the pristine metal phthalocyanines greatly limit their application in perovskite solar cells (PSCs) as the hole-transporting materials (HTMs). Here, we prepare a Ni phthalocyanine (NiPc) decorated by four methoxyethoxy units as HTMs. In NiPc, the two oxygen atoms in peripheral substituent have a modified effect on the dipole direction, while the central Ni atom contributes more electron to phthalocyanine ring, thus efficiently increasing the intramolecular dipole. Calculation analyses reveal the extracted holes within NiPc are mainly concentrated on the phthalocyanine core induced by the intramolecular electric field, and further to be transferred by π-π stacking space channel between NiPc molecules. Finally, the best efficiency of PSCs with NiPc as dopant-free HTMs realizes a record value of 21.23 % (certified 21.03 %). The PSCs also exhibit the good moisture, heating and light stabilities. This work provides a novel way to improve the performance of PSCs with free-doped metal phthalocyanines as HTMs.
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http://dx.doi.org/10.1002/anie.202016087DOI Listing
March 2021

Optimal combination treatment regimens of vaccine and radiotherapy augment tumor-bearing host immunity.

Commun Biol 2021 01 19;4(1):78. Epub 2021 Jan 19.

Protein & Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.

A major obstacle to immunotherapy is insufficient infiltration of effector immune cells into the tumor microenvironment. Radiotherapy greatly reduces tumor burden but relapses often occur. Here we show that the immunosuppressive tumor microenvironment was gradually established by recruiting Tregs after radiation. Despite tumors being controlled after depletion of Tregs in the irradiated area, improvement of mice survival remained poor. A much better antitumor effect was achieved with vaccination followed by radiation than other treatments. Vaccination followed by radiation recruited more effector T cells in tumor regions, which responded to high levels of chemokines. Sequential combination of vaccination and radiotherapy could elicit distinct host immune responses. Our study demonstrated that optimal combination of irradiation and vaccination is required to achieve effective antitumor immune responses. We propose a combination regimen that could be easily translated into the clinic and offer an opportunity for rational combination therapies design in cancer treatment.
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http://dx.doi.org/10.1038/s42003-020-01598-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815836PMC
January 2021

Divergent improvement of two cultivated allotetraploid cotton species.

Plant Biotechnol J 2021 Jan 14. Epub 2021 Jan 14.

Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.

Interspecific genomic variation can provide a genetic basis for local adaptation and domestication. A series of studies have presented its role of interspecific haplotypes and introgressions in adaptive traits, but few studies have addressed their role in improving agronomic character. Two allotetraploid Gossypium species, Gossypium barbadense (Gb) and G. hirsutum (Gh) originating from the Americas, are cultivated independently. Here, through sequencing and the comparison of one GWAS panel in 229 Gb accessions and two GWAS panels in 491 Gh accessions, we found that most associated loci or functional haplotypes for agronomic traits were highly divergent, representing the strong divergent improvement between Gb and Gh. Using a comprehensive interspecific haplotype map, we revealed that six interspecific introgressions from Gh to Gb were significantly associated with the phenotypic performance of Gb, which could explain 5%-40% of phenotypic variation in yield and fibre qualities. In addition, three introgressions overlapped with six associated loci in Gb, indicating that these introgression regions were under further selection and stabilized during improvement. A single interspecific introgression often possessed yield-increasing potential but decreased fibre qualities, or the opposite, making it difficult to simultaneously improve yield and fibre qualities. Our study not only has proved the importance of interspecific functional haplotypes or introgressions in the divergent improvement of Gb and Gh, but also supports their potential value in further human-mediated hybridization or precision breeding.
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http://dx.doi.org/10.1111/pbi.13547DOI Listing
January 2021

Quercetin promotes osteogenic differentiation and antioxidant responses of mouse bone mesenchymal stem cells through activation of the AMPK/SIRT1 signaling pathway.

Phytother Res 2021 Jan 9. Epub 2021 Jan 9.

Research Office, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Decrepitude and apoptosis of bone mesenchymal stem cells (BMSCs) induced by reactive oxygen species (ROS) lead to inhibited osteogenic differentiation, causing decreased bone density and osteoporosis. Quercetin, a bioactive component of Solanum muricatum extracts, promotes the osteogenic differentiation of BMSCs and ameliorates the symptoms of osteoporosis in vivo. However, the detailed mechanism underlying this process remains unclear. The study aims to reveal the regulatory mechanism of quercetin in BMSCs. Mouse BMSCs (mBMSCs) were isolated from the bone marrow and characterized by flow cytometry. QRT-PCR and western blot assays were performed to evaluate the expression levels of related genes and proteins. Alkaline phosphatase (ALP) staining and Oil Red O staining of lipids were used to estimate the osteogenesis and adipogenesis levels of mBMSCs, respectively. Quercetin treatment (2 and 5 μM) induced significant upregulation of antioxidant enzymes, SOD1 and SOD2, in mBMSCs. Quercetin promoted osteogenic differentiation and inhibited adipogenic differentiation of mBMSCs. Quercetin treatment enhanced the phosphorylation of AMPK protein and upregulated the expression of SIRT1, thus activating the AMPK/SIRT1 signaling pathway in mBMSCs. Quercetin promoted osteogenic differentiation and antioxidant responses of mBMSCs by activating the AMPK/SIRT1 signaling pathway.
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http://dx.doi.org/10.1002/ptr.7010DOI Listing
January 2021

Defect Engineering for Tuning the Photoresponse of Ceria-Based Solid Oxide Photoelectrochemical Cells.

ACS Appl Mater Interfaces 2021 Jan 29;13(1):541-551. Epub 2020 Dec 29.

Electrochemical Thin Film Group, School of Physical Science and Technology, ShanghaiTech University, Shanghai, P.R. China.

Solid oxide photoelectrochemical cells (SOPECs) with inorganic ion-conducting electrolytes provide an alternative solution for light harvesting and conversion. Exploring potential photoelectrodes for SOPECs and understanding their operation mechanisms are crucial for continuously developing this technology. Here, ceria-based thin films were newly explored as photoelectrodes for SOPEC applications. It was found that the photoresponse of ceria-based thin films can be tuned both by Sm-doping-induced defects and by the heating temperature of SOPECs. The whole process was found to depend on the surface electrochemical redox reactions synergistically with the bulk photoelectric effect. Samarium doping level can selectively switch the open-circuit voltages polarity of SOPECs under illumination, thus shifting the potential of photoelectrodes and changing their photoresponse. The role of defect chemistry engineering in determining such a photoelectrochemical process was discussed. Transient absorption and X-ray photoemission spectroscopies, together with the state-of-the-art X-ray absorption spectroscopy, allowed us to provide a compelling explanation of the experimentally observed switching behavior on the basis of the surface reactions and successive charge balance in the bulk.
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http://dx.doi.org/10.1021/acsami.0c17921DOI Listing
January 2021

The Significance of Platelet-Albumin-Bilirubin (PALBI) Grade in Hepatocellular Carcinoma Patients Stratified According to Platelet Count.

Cancer Manag Res 2020 14;12:12811-12822. Epub 2020 Dec 14.

Department of Hepatobiliary Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province 233000, People's Republic of China.

Background: Platelet-albumin-bilirubin (PALBI) has been demonstrated to be superior to conventional Child-Pugh (C-P) grade in evaluating liver function and prognosis of HCC patients. However, both thrombocytosis and thrombocytopenia are unfavorable for HCC survival. The aim of this study was to preliminarily investigate the prognostic value of PALBI in HCC patients with thrombocytopenia and excluding thrombocytopenia.

Methods: In this retrospective cohort study, we reviewed 465 cases of HCC patients who underwent radical surgery. PALBI grade was calculated based on preoperative serological examinations. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS), which were assessed by Kaplan-Meier method and Cox regression. The prognostic performances of PALBI and other models were estimated by using the concordance index (C-index).

Results: During a median follow-up time of 28 months, 31.6% (147/465) of patients died and 33.5% (156/465) experienced recurrence. Multivariate analyses revealed that both thrombocytosis and thrombocytopenia were independently associated with poor OS and RFS compared with normal platelet count (PLT) in HCC patients. Stratified analysis further revealed that PALBI was a significant predictor for HCC survival in patients excluding thrombocytopenia but not in patients with thrombocytopenia. In particular, in HCC patients excluding thrombocytopenia, the combination of tumor size with PALBI (C-index = 0.730, 95% CI: 0.674-0.786) may be superior to the classical Barcelona Clinic Liver Cancer (BCLC) and Cancer of Liver Italian Program (CLIP) staging systems in predicting survival.

Conclusion: In conclusion, PALBI grade, in particular the combination with tumor size, is an effective model for discriminating survival in HCC patients excluding thrombocytopenia but not in thrombocytopenic HCC patients.
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http://dx.doi.org/10.2147/CMAR.S277013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751793PMC
December 2020

Enhancing the activity and thermal stability of a phthalate-degrading hydrolase by random mutagenesis.

Ecotoxicol Environ Saf 2021 Feb 17;209:111795. Epub 2020 Dec 17.

Key Laboratory of Food Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address:

Our previous work has reported that EstJ6 was a phthalate-degrading hydrolase. In the study, a random mutant library was constructed by two rounds of error-prone PCR, three mutants (ET1.1, ET2.1, and ET2.2) with enhanced hydrolytic activity against dibutyl phthalate (DBP) were obtained. The best mutant ET2.2, accumulated three amino acid substitutions (Thr91Met, Ala67Val, and Val249Ile) and exhibited 2.8-fold increase enzyme activity and 2.3-fold higher expression level. Meanwhile, compared with EstJ6, ET2.2 showed over 50% improvement in thermostability (at 50 °C for 1 h) and 1.2-fold increase in 50% methanol tolerance. Kinetic parameters analysis revealed that the Km value for ET2.2 decreased by 60% and the kcat/Km value increased by 166%. The molecular docking indicated that the shortening of hydrogen bond between Ser146-OH and DBP-CO, which may led to an increase in enzyme activity and catalytic efficiency, the enhancement of hydrophobicity of hydrophobic pocket was related to the improvement of organic solvents tolerance, and three hydrophobic amino acid substitutions Thr91Met, Ala67Val, and Val249Ile facilitated to improve the thermal stability and organic solvents tolerance. These results confirmed that random mutagenesis was an effective tool for improving enzyme properties and lay a foundation for practical applications of phthalate-degrading hydrolase in biotechnology and industrial fields.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111795DOI Listing
February 2021

Silencing of miR-138-5p sensitizes bone anabolic action to mechanical stimuli.

Theranostics 2020 30;10(26):12263-12278. Epub 2020 Oct 30.

Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.

Emerging evidence is revealing that microRNAs (miRNAs) play essential roles in mechanosensing for regulating osteogenesis. However, no mechanoresponsive miRNAs have been identified in human bone specimens. Bedridden and aged patients, hindlimb unloaded and aged mice, and Random Positioning Machine and primary aged osteoblasts were adopted to simulate mechanical unloading conditions at the human, animal and cellular levels, respectively. Treadmill exercise and Flexcell cyclic mechanical stretching were used to simulate mechanical loading and , respectively. Here, we found increased miR-138-5p levels with a lower degree of bone formation in bone specimens from bedridden and aged patients. Loss- and gain-of-function studies showed that miR-138-5p directly targeted microtubule actin crosslinking factor 1 (MACF1) to inhibit osteoblast differentiation under different mechanical conditions. Regarding translational medicine, bone-targeted inhibition of miR-138-5p attenuated the decrease in the mechanical bone anabolic response in hindlimb unloaded mice. Moreover, bone-targeted inhibition of miR-138-5p sensitized the bone anabolic response to mechanical loading in both miR-138-5p transgenic mice and aged mice to promote bone formation. These data suggest that miR-138-5p as a mechanoresponsive miRNA accounts for the mechanosensitivity of the bone anabolic response and that inhibition of miR-138-5p in osteoblasts may be a novel bone anabolic sensitization strategy for ameliorating disuse or senile osteoporosis.
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http://dx.doi.org/10.7150/thno.53009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667683PMC
May 2021

Virus-induced p38 MAPK activation facilitates viral infection.

Theranostics 2020 30;10(26):12223-12240. Epub 2020 Oct 30.

State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.

Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.
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http://dx.doi.org/10.7150/thno.50992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667676PMC
December 2020