Publications by authors named "Yingli Wang"

132 Publications

RNA-seq bulked segregant analysis combined with KASP genotyping rapidly identified PmCH7087 as responsible for powdery mildew resistance in wheat.

Plant Genome 2021 Jul 26:e20120. Epub 2021 Jul 26.

Institute of Pharmaceutical & Food Engineering, Shanxi Univ. of Chinese Medicine, Jingzhong, 030619, China.

Powdery mildew causes considerable yield losses in common wheat (Triticum aestivum L.) production. Mapping and cloning powdery mildew-resistant quantitative trait loci can benefit stable yield production by facilitating the breeding of resistant varieties. In this study, we used the powdery mildew resistance introgression line 'CH7087' (harboring the resistance gene PmCH7087) and developed a large F population and a corresponding F segregation population containing 2,000 family lines for molecular mapping of PmCH7087. Genetic analysis demonstrated that the resistance phenotype was controlled by a single dominant gene. According to the performance exhibited by the F lines, 50 resistant lines and 50 susceptible lines without phenotype segregation were chosen for pooling and bulked segregant RNA sequencing (BSR-Seq) analysis. A region spanning 42.77 Mb was identified, and genotyping of an additional 183 F lines with extreme phenotypes using 20 kompetitive allele-specific polymerase chain reaction (KASP) markers in the BSR-Seq mapping regions confirmed this region and narrowed it to 9.68 Mb, in which 45 genes were identified and annotated. Five of these transcripts harbored nonsynonymous single nucleotide polymorphisms between the two parents, with the transcripts of TraesCS2B01G302800 being involved in signal transduction. Furthermore, TraesCS2B01G302800.2 was annotated as the closest homologue of serine/threonine-protein kinase PBS1, a typical participant in the plant disease immune response, indicating that TraesCS2B01G302800 was the candidate gene of PmCH7087. Our results may facilitate future research attempting to improve powdery mildew resistance in wheat and to identify candidate genes for further verification and gene cloning.
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http://dx.doi.org/10.1002/tpg2.20120DOI Listing
July 2021

Immunogenicity study of engineered ferritins with C- and N-terminus insertion of Epstein-Barr nuclear antigen 1 epitope.

Vaccine 2021 Aug 18;39(34):4830-4841. Epub 2021 Jul 18.

School of Chemical Engineering and Advanced Materials, Faculty of Engineering, Computer and Mathematical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address:

Human ferritin heavy chain, an example of a protein nanoparticle, has recently been used as a vaccine delivery platform. Human ferritin has advantages of uniform architecture, robust thermal and chemical stabilities, and good biocompatibility and biodegradation. There is however a lack of understanding about the relationship between insertion sites in ferritin (N-terminus and C-terminus) and the corresponding humoral and cell-mediated immune responses. To bridge this gap, we utilized an Epstein-Barr Nuclear Antigen 1 (EBNA1) epitope as a model to produce engineered ferritin-based vaccines E1F1 (N-terminus insertion) and F1E1 (C-terminus insertion) for the prevention of Epstein-Barr virus (EBV) infections. X-ray crystallography confirmed the relative positions of the N-terminus insertion and C-terminus insertion. For N-terminus insertion, the epitopes were located on the exterior surface of ferritin, while for C-terminus insertion, the epitopes were inside the ferritin cage. Based on the results of antigen-specific antibody titers from in-vivo tests, we found that there was no obvious difference on humoral immune responses between N-terminus and C-terminus insertion. We also evaluated splenocyte proliferation and memory lymphocyte T cell differentiation. Both results suggested C-terminus insertion produced a stronger proliferative response and cell-mediated immune response than N-terminus insertion. C-terminus insertion of EBNA1 epitope was also processed more efficiently by dendritic cells (DCs) than N-terminus insertion. This provides new insight into the relationship between the insertion site and immunogenicity of ferritin nanoparticle vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2021.07.021DOI Listing
August 2021

Cost-effective purification process development for chimeric hepatitis B core (HBc) virus-like particles assisted by molecular dynamic simulation.

Eng Life Sci 2021 Jun 3;21(6):438-452. Epub 2021 May 3.

School of Chemical Engineering & Advanced Materials, Faculty of Engineering, Computer and Mathematical Sciences University of Adelaide Adelaide SA Australia.

Inserting foreign epitopes to hepatitis B core (HBc) virus-like particles (VLPs) could influence the molecular conformation and therefore vary the purification process. In this study, a cost-effective purification process was developed for two chimeric HBc VLPs displaying Epstein-Barr nuclear antigens 1 (EBNA1), and hepatitis C virus (HCV) core. Both chimeric VLPs were expressed in soluble form with high production yields in . Molecular dynamic (MD) simulation was employed to predict the stability of chimeric VLPs. HCV core-HBc was found to be less stable in water environment compared with EBNA1-HBc, indicating its higher hydrophobicity. Assisting with MD simulation, ammonium sulfate precipitation was optimized to remove host cell proteins with high target protein recovery yields. Moreover, 99% DNA impurities were removed using POROS 50 HQ chromatography. In characterization measurement, we found that inserting HCV core epitope would reduce the ratio of α-helix of HCV core-HBc. This could be another reason on the top of its higher hydrophobicity predicted by MD simulation, causing its less stability. Tertiary structure, transmission electron microscopy, and immunogenicity results indicate that two chimeric VLPs maintained correct VLP structure ensuring its bioactivity after being processed by the developed cost-effective purification approach.
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http://dx.doi.org/10.1002/elsc.202000104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182290PMC
June 2021

The Feasibility and Efficacy of Self-help Relaxation Exercise in Symptom Distress in Patients With Adult Acute Leukemia: A Pilot Randomized Controlled Trial.

Pain Manag Nurs 2021 May 26. Epub 2021 May 26.

Department of Hematology, West China Hospital, Sichuan University, China. Electronic address:

Aims: To examine the feasibility and efficacy of self-help relaxation exercises in alleviating symptom distress in adult patients with acute leukemia (AL).

Methods: A pilot randomized controlled trial was used. Thirty adult patients with AL who were hospitalized in a teaching hospital were enrolled and randomly divided into a wait-list control group or an intervention group. The intervention group received self-help relaxation exercise twice per day for 4 weeks. The feasibility indicators, patients' symptom distress were assessed by a blinded data collector.

Results: Twenty-nine patients completed the study. The recruitment rate, retention rate, and adherence rate was 65.2%, 93.3%, and 98.2%, respectively. The intervention group had a significantly decreased distress score for pain symptoms (F = 6.594, P = .016, the partial η = 0.20, 90% confidence interval = 0.02-0.39).

Conclusions: Self-help relaxation exercises were feasible for the AL patients and significantly reduced their pain symptoms. Minor revision of the protocol for future definitive trials is needed.
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http://dx.doi.org/10.1016/j.pmn.2021.04.009DOI Listing
May 2021

Label-free terahertz microfluidic biosensor for sensitive DNA detection using graphene-metasurface hybrid structures.

Biosens Bioelectron 2021 Sep 14;188:113336. Epub 2021 May 14.

College of Biosystems Engineering and Food Science, Zhejiang University, 866 Yuhangtang Rd., 310058, Hangzhou, Zhejiang Province, PR China.

Metasurface assisted terahertz (THz) real-time and label-free biosensors have attracted intense attention. However, it is still challenging for specific detection of highly absorptive liquid samples with high sensitivity in the THz range. Here, we incorporated graphene with THz metasurface into a microfluidic cell for sensitive biosensing. The proposed THz graphene-metasurface microfluidic platform can effectively reduce the volume of the sample solution and boost the interaction between biomolecules and THz waves, thus enhancing the sensitivity. As a proof of concept, comparative experiments using other three kinds of microfluidic cells (pure microfluidic cell, metasurface-based microfluidic cell and graphene-based microfluidic cell) were conducted to explore and verify the sensing mechanism, which evidences the high sensitivity of delicate sensing based on the hybrid graphene-metasurface THz microfluidic device. Furthermore, to perform biosensing applications on that basis, specific aptamers were modified on the graphene-metasurface, enabling DNA sequences of foodborne pathogen Escherichia coli O157:H7 to be recognized. Based on the THz microfluidic biosensor, 100 nM DNA short sequences can be successfully detected. The sensing results of antibiotics and DNA based on the graphene-metasurface microfluidic biosensor confirm the superiority of the proposed design and considerable promise in THz biosensing. The novel sensing platform provides the merits of enabling highly sensitive, label-free, low-cost, easy to use, reusable, and real-time biosensing, which opens an exciting prospect for nanomaterial-metasurface hybrid structure assisted THz label-free biosensing in liquid environment.
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http://dx.doi.org/10.1016/j.bios.2021.113336DOI Listing
September 2021

Revealing the developmental dynamics in male strobilus transcriptome of Gnetum luofuense using nanopore sequencing technology.

Sci Rep 2021 May 18;11(1):10516. Epub 2021 May 18.

Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangdong Academy of Forestry, Guangzhou, 510520, China.

Gnetum is a pantropical distributed gymnosperm genus. As being dioecious, Gnetum species apply female and male strobili to attract and provide nutrition to insect pollinators. Due to its unique gross morphology, a Gnetum male strobilus receives much attention in previous taxonomic and evolutionary studies. However, underlying molecular mechanisms that control male strobilus development and pollination adaptation have not been well studied. In the present study, nine full-length transcriptomes were sequenced from three developmental stages of the G. luofuense male strobili using Oxford Nanopore Technologies. In addition, weighted gene co-expression network analysis (WGCNA), and RT-qPCR analysis were performed. Our results show that a total of 3138 transcription factors and 466 long non-coding RNAs (lncRNAs) were identified, and differentially expressed lncRNAs and TFs reveal a dynamic pattern during the male strobilus development. Our results show that MADS-box and Aux/IAA TFs were differentially expressed at the three developmental stages, suggesting their important roles in the regulation of male strobilus development of G. luofuense. Results of WGCNA analysis and annotation of differentially expressed transcripts corroborate that the male strobilus development of G. luofuense is closely linked to plant hormone changes, photosynthesis, pollination drop secretion and reproductive organ defense. Our results provide a valuable resource for understanding the molecular mechanisms that drive organ evolution and pollination biology in Gnetum.
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http://dx.doi.org/10.1038/s41598-021-90082-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131605PMC
May 2021

Simultaneous determination of both kavalactone and flavokawain constituents by different single-marker methods in kava.

J Sep Sci 2021 Jul 25;44(14):2705-2716. Epub 2021 May 25.

Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, P. R. China.

Kava, the rhizomes and roots of Piper methysticum Forst, is a popular edible medicinal herb traditionally used to prepare beverages for anxiety reduction. Since the German kava ban has been lifted by the court, the quality evaluation is particularly important for its application, especially the flavokawains which were believed to be responsible for hepatotoxicity. Now, by employing two different standard references and four different methods to calculate the relative correction factors, eight different quantitative analyses of multicomponents by single-marker methods have been developed for the simultaneous determination of eight major kavalactones and flavokawains in kava. The low standard method difference on quantitative measurement of the compounds among the external standard method and ours confirmed the reliability of the mentioned methods. A radar plot clearly illustrated that the contents of dihydrokavain and kavain were higher, whereas flavokawains A and B were lower in different kava samples. Only one of eight samples did not detect flavokawains that may be related to hepatotoxicity. In summary, by using different agents as an internal standard reference, the developed methods were believed as a powerful analytical tool not only for the qualitative and quantitative of kava constituents but also for the other multicomponents when authentic standard substances were unavailable.
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http://dx.doi.org/10.1002/jssc.202100198DOI Listing
July 2021

Engineered Human Heavy-Chain Ferritin with Half-Life Extension and Tumor Targeting by PAS and RGDK Peptide Functionalization.

Pharmaceutics 2021 Apr 9;13(4). Epub 2021 Apr 9.

School of Chemical Engineering and Advanced Materials, The University of Adelaide, Adelaide SA5005, Australia.

Ferritin, one of the most investigated protein nanocages, is considered as a promising drug carrier because of its advantageous stability and safety. However, its short half-life and undesirable tumor targeting ability has limited its usage in tumor treatment. In this work, two types of functional peptides, half-life extension peptide PAS, and tumor targeting peptide RGDK (Arg-Gly-Asp-Lys), are inserted to human heavy-chain ferritin (HFn) at C-terminal through flexible linkers with two distinct enzyme cleavable sites. Structural characterizations show both HFn and engineered HFns can assemble into nanoparticles but with different apparent hydrodynamic volumes and molecular weights. RGDK peptide enhanced the internalization efficiency of HFn and showed a significant increase of growth inhibition against 4T1 cell line in vitro. Pharmacokinetic study in vivo demonstrates PAS peptides extended ferritin half-life about 4.9 times in Sprague Dawley rats. RGDK peptides greatly enhanced drug accumulation in the tumor site rather than in other organs in biodistribution analysis. Drug loaded PAS-RGDK functionalized HFns curbed tumor growth with significantly greater efficacies in comparison with drug loaded HFn.
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http://dx.doi.org/10.3390/pharmaceutics13040521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070472PMC
April 2021

Immunomodulatory Effect of a New Ingredients Group Extracted from Through Membrane Separation Technique.

Drug Des Devel Ther 2021 15;15:1595-1607. Epub 2021 Apr 15.

Department of Traditional Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong, People's Republic of China.

Introduction: is a commonly used traditional Chinese medicine in China, which has been widely applied to enhance the immunomodulatory function of the body. The main bioactive components are complicated. To explore the role of the components, various techniques have been applied in extraction. Membrane separation technique featured with green processing condition and high efficiency is of signification interest in the application of treatment.

Methods: In this study, a new ingredients group A4 was separated from using membrane separation technique. The quantification and identification of A4 were achieved by UV-vis spectrometry and UPLC-MS measurements. Pathological approaches along with serum metabolomics were utilized to study the immunoprotective effects of the extracts and explore the underlying mechanisms on metabolic activity.

Results: It was observed that A4 could promote the secretion of IL-2 and IFN-γ, stimulate the activated CD4CD25 and CD8 CD25 T lymphocytes in splenocytes and protect rat spleen to some extent. Seven crucial biomarkers that related to immunity regulations were screened out and identified through serum metabonomic analysis coupled with nuclear magnetic resonance. The enrichment analysis revealed that A4 alleviated the immune dysfunction by modulating amino acid metabolism and energy metabolism for the first time.

Conclusion: The new ingredients group A4 isolated from the membrane can reduce the immune dysfunction by regulating the amino acid metabolism and energy metabolism of rats.
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http://dx.doi.org/10.2147/DDDT.S309422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055285PMC
April 2021

Comparative Analyses of Full-Length Transcriptomes Reveal e Stem Developmental Dynamics.

Front Genet 2021 25;12:615284. Epub 2021 Mar 25.

Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangdong Academy of Forestry, Guangzhou, China.

Genus , of which the majority species are pantropical liana, have broad industrial uses including for string, nets, and paper production. Although numerous studies have investigated anatomical structures during stem development, the underlying molecular mechanisms that regulate this developmental trajectory in species remain poorly understood. A total of 12 full-length transcriptomes were generated from four stem developmental stages of an arborescent representative of this genus, , using Oxford Nanopore Technologies. The results of this analysis reveal a total of 24,151 alternative splicing (AS) and 134,391 alternative polyadenylation events. A remarkably dynamic pattern of AS events, especially in the case of intron retentions, was found across the four developmental stages while no dynamic pattern was found among transcript numbers with varied poly(A) sites. A total of 728 long non-coding RNAs were also detected; the number of -regulated target genes dramatically increased while no changes were found among -regulated target genes. In addition, a K-means clustering analysis of all full-length transcripts revealed that primary growth is associated with carbohydrate metabolism and fungi defense, while secondary growth is closely linked with photosynthesis, nitrogen transportation, and leaf ontogenesis. The use of weighted gene co-expression network analysis as well as differentially expressed transcripts reveals that bHLH, GRF, and MYB-related transcription factors are involved in primary growth, while AP2/ERF, MYB, NAC, PLAZ, and bZIP participate in stem secondary growth. The results of this study provide further evidence that Nanopore sequencing technology provides a cost-effective method for generating full-length transcriptome data as well as for investigating seed plant organ development.
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http://dx.doi.org/10.3389/fgene.2021.615284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027257PMC
March 2021

Changes of Mineralogical Properties and Biological Activities of Gypsum and Its Calcined Products with Different Phase Structures.

Evid Based Complement Alternat Med 2021 9;2021:6676797. Epub 2021 Mar 9.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.

Raw gypsum (RG) and calcined gypsum (CG) are widely used in traditional Chinese medicine (TCM). RG is usually taken orally to resolve heat and diminish inflammation, while CG is only used externally to treat ulcerations and empyrosis. Calcination at different temperatures, three phase CG structures, namely, bassanite, anhydrite III, and anhydrite II, may be generated. We herein investigated the relationship between the phase structure and the efficacy of CG and the optimum phase structure for CG. RG has a compact structure, small pore size, weak anti-inflammatory effect, but no antibacterial effect, and has almost no effect on the repair of scalds. CG150 (bassanite) has a loose texture, large pore size and specific surface area, and certain antibacterial and anti-inflammatory effects, but it has a poor repair effect on scalds. CG750 (anhydrite II) has a compact structure, small pore size and specific surface area, and low antibacterial and anti-inflammatory effects, but it has a certain repair effect on scalds. Only CG350 (anhydrite III) has good performance in texture, pore size, specific surface area, antibacterial, anti-inflammatory, and scald repair. Our research has proved that the mineral properties and biological activities of CG are different due to different phase structures. CG350, namely, anhydrite III, is considered by our research to be the optimal phase structure as CG.
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http://dx.doi.org/10.1155/2021/6676797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969087PMC
March 2021

Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation.

Nat Commun 2021 03 10;12(1):1570. Epub 2021 Mar 10.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

The ULK complex initiates the autophagosome formation, and has recently been implicated in selective autophagy by interacting with autophagy receptors through its FIP200 subunit. However, the structural mechanism underlying the interactions of autophagy receptors with FIP200 and the relevant regulatory mechanism remain elusive. Here, we discover that the interactions of FIP200 Claw domain with autophagy receptors CCPG1 and Optineurin can be regulated by the phosphorylation in their respective FIP200-binding regions. We determine the crystal structures of FIP200 Claw in complex with the phosphorylated CCPG1 and Optineurin, and elucidate the detailed molecular mechanism governing the interactions of FIP200 Claw with CCPG1 and Optineurin as well as their potential regulations by kinase-mediated phosphorylation. In addition, we define the consensus FIP200 Claw-binding motif, and find other autophagy receptors that contain this motif within their conventional LC3-interacting regions. In all, our findings uncover a general and phosphoregulatable binding mode shared by many autophagy receptors to interact with FIP200 Claw for autophagosome biogenesis, and are valuable for further understanding the molecular mechanism of selective autophagy.
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http://dx.doi.org/10.1038/s41467-021-21874-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946963PMC
March 2021

Electroless Formation of a Fluorinated Li/Na Hybrid Interphase for Robust Lithium Anodes.

J Am Chem Soc 2021 Feb 15;143(7):2829-2837. Epub 2021 Feb 15.

Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Research Center of High-Efficiency Energy Storage (Ministry of Education), College of Chemistry, Nankai University, Tianjin 300071, P. R. China.

Engineering a stable solid electrolyte interphase (SEI) is one of the critical maneuvers in improving the performance of a lithium anode for high-energy-density rechargeable lithium batteries. Herein, we build a fluorinated lithium/sodium hybrid interphase via a facile electroless electrolyte-soaking approach to stabilize the repeated plating/stripping of lithium metal. Jointed experimental and computational characterizations reveal that the fluorinated hybrid SEI mainly consisting of NaF, LiF, LiPOF, and organic components features a mosaic polycrystalline structure with enriched grain boundaries and superior interfacial properties toward Li. This LiF/NaF hybrid SEI exhibits improved ionic conductivity and mechanical strength in comparison to the SEI without NaF. Remarkably, the fluorinated hybrid SEI enables an extended dendrite-free cycling of metallic Li over 1300 h at a high areal capacity of 10 mAh cm in symmetrical cells. Furthermore, full cells based on the LiFePO cathode and hybrid SEI-protected Li anode sustain long-term stability and good capacity retention (96.70% after 200 cycles) at 0.5 C. This work could provide a new avenue for designing robust multifunctional SEI to upgrade the metallic lithium anode.
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http://dx.doi.org/10.1021/jacs.0c12051DOI Listing
February 2021

A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect.

Acta Pharm Sin B 2021 Jan 13;11(1):258-270. Epub 2020 Aug 13.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
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http://dx.doi.org/10.1016/j.apsb.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838024PMC
January 2021

Wearable plasmonic-metasurface sensor for noninvasive and universal molecular fingerprint detection on biointerfaces.

Sci Adv 2021 Jan 22;7(4). Epub 2021 Jan 22.

College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China.

Wearable sensing technology is an essential link to future personalized medicine. However, to obtain a complete picture of human health, it is necessary but challenging to track multiple analytes inside the body simultaneously. Here, we present a wearable plasmonic-electronic sensor with "universal" molecular recognition ability. Flexible plasmonic metasurface with surface-enhanced Raman scattering (SERS)-activity is introduced as the fundamental sensing component in a wearable sensor since we solved the technical challenge of maintaining the plasmonic activities of their brittle nanostructures under various deformations. Together with a flexible electronic sweat extraction system, our sensor can noninvasively extract and "fingerprint" analytes inside the body based on their unique SERS spectra. As a proof-of-concept example, we successfully monitored the variation of trace-amounts drugs inside the body and obtained an individual's drug metabolic profile. Our sensor bridges the existing gap in wearable sensing technology by providing a universal, sensitive molecular tracking means to assess human health.
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http://dx.doi.org/10.1126/sciadv.abe4553DOI Listing
January 2021

Growing Nanostructured CuO on Copper Foil via Chemical Etching to Upgrade Metallic Lithium Anode.

ACS Appl Mater Interfaces 2021 Feb 26;13(5):6367-6374. Epub 2021 Jan 26.

Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Engineering Research Center of High-efficiency Energy Storage (Ministry of Education), Renewable Energy Conversion and Storage Center, College of Chemistry, Nankai University, Tianjin 300071, China.

Metallic lithium is one of the most promising anode materials to build next generation electrochemical power sources such as Li-air, Li-sulfur, and solid-state lithium batteries. The implementation of rechargeable Li-based batteries is plagued by issues including dendrites, pulverization, and an unstable solid electrolyte interface (SEI). Herein, we report the use of nanostructured CuO grown on commercial copper foil ([email protected]) via chemical etching as a Li-reservoir substrate to stabilize SEI formation and Li stripping/plating. The lithiophilic interconnected CuO layer enhances electrolyte wettability. Besides, a mechanically stable LiO- and LiF-rich SEI is generated on [email protected] during initial discharge, which permits dense and uniform lithium deposition upon subsequent cycling. Compared with bare Cu, the [email protected] electrode exhibits superior performance in terms of Coulombic efficiency, discharge/charge overpotentials, and cyclability. By pairing with the [email protected] anodes, full cells with LiFePO and LiNiMnCoO cathodes sustain 300 cycles with 98.8% capacity retention at 1 C and deliver a specific capacity of 80 mAh g at 10 C, respectively. This work would shed light on the design of advanced current collectors with SEI modulation to upgrade lithium anodes.
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http://dx.doi.org/10.1021/acsami.0c22046DOI Listing
February 2021

Remote loading paclitaxel-doxorubicin prodrug into liposomes for cancer combination therapy.

Acta Pharm Sin B 2020 Sep 26;10(9):1730-1740. Epub 2020 Apr 26.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX--DOX (PSD). The prodrug displayed comparable cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.
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http://dx.doi.org/10.1016/j.apsb.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564015PMC
September 2020

Stimuli-responsive phospholipid-drug conjugates (PDCs)-based nanovesicles for drug delivery and theranostics.

Int J Pharm 2020 Nov 28;590:119920. Epub 2020 Sep 28.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address:

Liposomes represent one of the most successful nano-drug delivery systems among enormous nano-carriers. Although great progress has been made in conventional liposomes, the emerging shortcomings still impair the therapeutic index. The proposal of stimuli-responsive phospholipid-drug conjugates (PDCs)-based nanovesicles solves the challenges that conventional liposomes are faced with, showing great potential for cancer diagnosis and therapy. Herein, we intend to overview the current progress and unique advantages of stimuli-responsive PDCs-based nanovesicles. First, the challenges of conventional liposomes and the development of PDCs-based nanovesicles are summarized. Next, the stimuli-responsive elements used in current stimuli-responsive PDCs-based nanovesicles are outlined. Then, the unique superiorities of stimuli-responsive PDCs-based nanovesicles for drug delivery and theranostics are highlighted in detail. Finally, the future opportunities and challenges of stimuli-responsive PDCs-based nanovesicles for clinical translation are put forward.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119920DOI Listing
November 2020

Decoding three distinct states of the Syntaxin17 SNARE motif in mediating autophagosome-lysosome fusion.

Proc Natl Acad Sci U S A 2020 09 19;117(35):21391-21402. Epub 2020 Aug 19.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 200032 Shanghai, China;

Syntaxin17, a key autophagosomal -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, can associate with ATG8 family proteins SNAP29 and VAMP8 to facilitate the membrane fusion process between the double-membraned autophagosome and single-membraned lysosome in mammalian macroautophagy. However, the inherent properties of Syntaxin17 and the mechanistic basis underlying the interactions of Syntaxin17 with its binding proteins remain largely unknown. Here, using biochemical, NMR, and structural approaches, we systemically characterized Syntaxin17 as well as its interactions with ATG8 family proteins, SNAP29 and VAMP8. We discovered that Syntaxin17 alone adopts an autoinhibited conformation mediated by a direct interaction between its Habc domain and the Qa-SNARE motif. In addition, we revealed that the Qa-SNARE region of Syntaxin17 contains one LC3-interacting region (LIR) motif, which preferentially binds to GABARAP subfamily members. Importantly, the GABARAP binding of Syntaxin17 can release its autoinhibited state. The determined crystal structure of the Syntaxin17 LIR-GABARAP complex not only provides mechanistic insights into the interaction between Syntaxin17 and GABARAP but also reveals an unconventional LIR motif with a C-terminally extended 3 helix for selectively binding to ATG8 family proteins. Finally, we also elucidated structural arrangements of the autophagic Syntaxin17-SNAP29-VAMP8 SNARE core complex, and uncovered its conserved biochemical and structural characteristics common to all other SNAREs. In all, our findings reveal three distinct states of Syntaxin17, and provide mechanistic insights into the Syntaxin17-mediated autophagosome-lysosome fusion process.
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http://dx.doi.org/10.1073/pnas.2006997117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474698PMC
September 2020

Clinical Validation of Two Recombinase-Based Isothermal Amplification Assays (RPA/RAA) for the Rapid Detection of African Swine Fever Virus.

Front Microbiol 2020 21;11:1696. Epub 2020 Jul 21.

National Reference Laboratory for African Swine Fever, National Surveillance and Research Center for Exotic Animal Diseases, National Surveillance and Research Center for Exotic Animal Diseases, China Animal Health and Epidemiology Center, Qingdao, China.

African swine fever (ASF), caused by African swine fever virus (ASFV), is a devastating infectious disease of domestic pigs and wild boars, and has tremendous negative socioeconomic impact on the swine industry and food security worldwide. It is characterized as a notifiable disease by World Organisation for Animal Health (OIE). No effective vaccine or treatment against ASF has so far been available. Early detection and rapid diagnosis are of potential significance to control the spread of ASF. Recombinase-based isothermal amplification assay, recombinase polymerase amplification (RPA) developed by TwistDx (Cambridge, United Kingdom) or recombinase-aided amplification (RAA) by Qitian (Wuxi, China), is becoming a molecular tool for the rapid, specific, and cost-effective identification of multiple pathogens. In this study, we aim to investigate if RPA/RAA can be a potential candidate for on-site, rapid and primary detection of ASFV. A panel of 152 clinical samples previously well-characterized by OIE-recommended qPCR was enrolled in this study, including 20 weak positive (Ct value ≥ 30) samples. This panel was consisted of different types, such as EDTA-blood, spleen, lung, lymph node, kidney, tonsil, liver, brain. We evaluated two recombinase-based isothermal amplification assays, RPA or RAA, by targeting the ASFV gene (p72), and validated the clinical performance in comparison with OIE real-time PCR. Our result showed that the analytical sensitivity of RPA and RAA was as 93.4 and 53.6 copies per reaction, respectively at 95% probability in 16 min, at 39°C. They were universally specific for all 24 genotypes of ASFV and no cross reaction to other pathogens including Classical swine fever virus (CSV), Foot-and-mouth disease virus (FMDV), Pseudorabies virus, Porcine circovirus 2 (PCV2), Porcine Reproductive and respiratory syndrome virus (PPRSV). The results on detection of various kinds of clinical samples indicated an excellent diagnostic agreement between RPA, RAA and OIE real-time PCR method, with the kappa value of 0.960 and 0.973, respectively. Compared to real-time PCR, the specificity of both RPA and RAA was 100% (94.40% ∼ 100%, 95% CI), while the sensitivity was 96.59% (90.36% ∼ 99.29%, 95% CI) and 97.73% (92.03% ∼ 99.72%, 95% CI), respectively. Our data demonstrate that the developed recombinase-based amplification assay (RPA/RAA), promisingly equipped with field-deployable instruments, offers a sensitive and specific platform for the rapid and reliable detection of ASFV, especially in the resource-limited settings for the purpose of screening and surveillance of ASF.
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http://dx.doi.org/10.3389/fmicb.2020.01696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385304PMC
July 2020

Prevalence of MRI abnormalities in people with epilepsy in rural China.

Neurology 2020 09 1;95(9):e1236-e1243. Epub 2020 Jul 1.

From the Academic Department of Neuroradiology (I.D.), Department of Brain Repair and Rehabilitation, and NIHR University College London Hospitals (J.S.D., J.W.S.), Biomedical Research Centre, UCL Queen Square Institute of Neurology, London, UK; Clinical Epidemiology (Z.C.), School of Public Health and Preventive Medicine, and Department of Neuroscience (Z.C., P.K.), Central Clinical School, Monash University, Melbourne; Department of Medicine (Z.C., P.K.), Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Lysholm Department of Neuroradiology (C.H.), National Hospital for Neurology & Neurosurgery, Queen Square, London, UK; Institute of Neurology (D.D.), Huashan Hospital, Fudan University, Shanghai; Beijing Neurosurgical Institute (W.W.); Jiaozuo People's Hospital (B.Y.), Henan Province; Ningxia Medical University (Y.W.); Jincheng Emergency Medical Rescue Center (T.W.), Shanxi Province; Affiliated Second Hospital (W.L.), Hebei Medical University, China; Chalfont Centre for Epilepsy (J.S.D., J.W.S.), Chalfont St. Peter, UK; and Stichting Epilepsie Instellingen Nederland (J.W.S.), Heemstede, Netherlands

Objective: To assess the prevalence of brain MRI abnormalities in people with epilepsy in rural China and to compare it with that of individuals in the United Kingdom.

Methods: Brain MRI scans were obtained in people with epilepsy who participated in a rural community-based program in China between July 2010 and December 2012. Individual epileptogenic lesion types were reviewed and their associations with seizure control examined. The MRI findings were compared with 2 previous similar studies in the United Kingdom.

Results: Among the 597 individuals (58% male, median age 38 years) with MRI scans analyzed, 488 (82%) had active epilepsy. The MRI was abnormal in 389 individuals (65%), with potentially epileptogenic lesion in 224 (38%) and nonspecific abnormalities in 165 (28%), and 108 (18%) were potentially resectable. The potentially epileptogenic lesions were less frequently detected in children (<18 years old, 12 of 68, 18%) than in adults (212 of 529, 40%; < 0.001). In people with potentially epileptogenic lesions, 67% (150 of 224) had failed ≥2 antiseizure medications. They had higher risk of uncontrolled epilepsy than those with normal MRI (risk ratio [RR] 1.25; < 0.001) and those with nonspecific abnormality (RR 1.15; = 0.002) after adjustment for age and sex. The diagnostic yield of MRI was similar to that reported in community- and hospital-based studies in the United Kingdom.

Conclusions: More than one-third of people with chronic epilepsy in rural China have potentially epileptogenic lesions identifiable on brain MRI, with two-thirds fulfilling the definition of pharmacoresistance. These findings highlight the magnitude of the unmet needs for epilepsy surgery in China.
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http://dx.doi.org/10.1212/WNL.0000000000010171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538231PMC
September 2020

The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles.

Artif Cells Nanomed Biotechnol 2020 Dec;48(1):983-996

Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Chinese Medicine, Jinzhong, China.

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) and targeting assessment, including the role of penetrating BBB and targeting glioma; (II) regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion ; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma inhibiting invasive and VM channels.
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http://dx.doi.org/10.1080/21691401.2020.1773489DOI Listing
December 2020

Evolution of the Chinese guarantee network under financial crisis and stimulus program.

Nat Commun 2020 06 1;11(1):2693. Epub 2020 Jun 1.

The Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China.

Our knowledge about the evolution of guarantee network in downturn period is limited due to the lack of comprehensive data of the whole credit system. Here we analyze the dynamic Chinese guarantee network constructed from a comprehensive bank loan dataset that accounts for nearly 80% total loans in China, during 01/2007-03/2012. The results show that, first, during the 2007-2008 global financial crisis, the guarantee network became smaller, less connected and more stable because of many bankruptcies; second, the stimulus program encouraged mutual guarantee behaviors, resulting in highly reciprocal and fragile network structure; third, the following monetary policy adjustment enhanced the resilience of the guarantee network by reducing mutual guarantees. Interestingly, our work reveals that the financial crisis made the network more resilient, and conversely, the government bailout degenerated network resilience. These counterintuitive findings can provide new insight into the resilience of real-world credit system under external shocks or rescues.
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http://dx.doi.org/10.1038/s41467-020-16535-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264362PMC
June 2020

Triphenylphosphonium-modified mitochondria-targeted paclitaxel nanocrystals for overcoming multidrug resistance.

Asian J Pharm Sci 2019 Sep 18;14(5):569-580. Epub 2018 Sep 18.

Shenyang Pharmaceutical University, Shenyang 110016, China.

Mitochondria are currently known as novel targets for treating cancer, especially for tumors displaying multidrug resistance (MDR). This present study aimed to develop a mitochondria-targeted delivery system by using triphenylphosphonium cation (TPP)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel (PTX) nanocrystals (NCs) against drug-resistant cancer cells. Evaluations were performed on 2D monolayer and 3D multicellular spheroids (MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs, the targeted PTX NCs showed the strongest cytotoxicity against both 2D MCF-7 and MCF-7/ADR cells, which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.
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http://dx.doi.org/10.1016/j.ajps.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032231PMC
September 2019

assessment of praziquantel nanocrystals: Formulation, characterization, and pharmacokinetics in beagle dogs.

Asian J Pharm Sci 2019 May 17;14(3):321-328. Epub 2018 Aug 17.

Wuya College of Innovation, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China.

To investigate the impact of particle size on performance of praziquantel (PZQ), nanocrystals (NCs) and microcrystals (MCs) of PZQ were prepared using the methods of wet milling and jet milling, respectively. PZQ NCs and MCs were characterized with dynamic light scattering, laser particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray powder diffraction and fourier transform infrared spectroscopy. The average diameters of PZQ NCs and MCs were 364.4 nm and 3.7 µm, respectively. No change in crystalline form was observed. Dissolution tests were performed in two different media, where the cumulative dissolution and dissolution rate of NCs were significantly improved in comparison with those of MCs and KANGQING in non-sink condition. Similarly, oral bioavailability of PZQ NCs in beagle dogs was 1.68 ( < 0.05) and 1.83 fold ( < 0.01) higher than that of MCs and KANGQING. Considering the advantages of performance and facile preparation, PZQ NCs may have a great application in the treatment of schistosomiasis.
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http://dx.doi.org/10.1016/j.ajps.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032129PMC
May 2019

Comparison between local infiltration analgesia with combined femoral and sciatic nerve block for pain management after total knee arthroplasty.

J Orthop Surg Res 2020 Feb 7;15(1):41. Epub 2020 Feb 7.

Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China.

Background: Total knee arthroplasty (TKA) is usually associated with moderate to severe postoperative pain. Peripheral nerve block (PNB) and local infiltration analgesia (LIA) are two major methods for postoperative analgesia. Femoral nerve block (FNB) leads to residual posterior knee pain; thus, currently sciatic nerve block (SNB) and LIA are two major options for supplementing FNB. However, the efficacy and safety of LIA compared with combined femoral and sciatic nerve block still remain controversial. Here, we conducted a study to analyze the postoperative analgesic efficacy of these two methods.

Method: Two hundred six patients undergoing TKA were enrolled in a retrospective cohort study. The patients received either PNB or LIA. All patients in PNB group were conducted combined femoral and sciatic nerve block. All patients were encouraged to use patient-controlled analgesia (PCA) after surgery. The postoperative visual analog scale (VAS) at rest or with movement during the first 24 h and 48 h was recorded. We analyzed the VAS of 24 h, VAS of 48 h, opioid consumption, and adverse effects between PNB group and LIA group. Chi-square test and nonparametric test were used in this study.

Results: There were 82 patients in the PNB group and 124 patients in the LIA group. The patients' characteristics such as age, height, weight, and ASA showed no significant difference (P > 0.05). No significant differences were found (P > 0.05) between the two groups regarding VAS score at rest or with movement. The LIA group had less opioid consumption than the PNB group but without significant difference (P > 0.05). In both groups, the most common side effect was nausea, and the side effects showed no significant differences between groups (P > 0.05).

Conclusion: Local infiltration analgesia provided a similar analgesic effect and complications compared with combined femoral and sciatic nerve block in the short term. Considering less opioid consumption with local infiltration analgesia though without significant difference and its convenience, local infiltration analgesia provided better postoperative analgesia.
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http://dx.doi.org/10.1186/s13018-020-1577-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006123PMC
February 2020

Shape-dependent significant physical mutilation and antibacterial mechanisms of gold nanoparticles against foodborne bacterial pathogens (Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus) at lower concentrations.

Mater Sci Eng C Mater Biol Appl 2020 Mar 30;108:110338. Epub 2019 Oct 30.

College of Biosystems Engineering and Food Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China; Key Laboratory of on Site Processing Equipment for Agricultural Products, Ministry of Agriculture and Rural Affairs, Zhejiang University, Hangzhou, China; Zhejiang A&F University, Hangzhou, Zhejiang, 311300, China. Electronic address:

Gold nanoparticles (AuNPs) have been reported for their most desirable properties as compared to any other noble metal-based nanoparticles, which wider their applications in various fields including catalysis, bio-imaging, biosensors, medicine, biology, and material chemistry. In this study, the shape-dependent antibacterial activity of AuNPs: nanospheres (AuNSps), nanostars (AuNSts), and nanocubes (AuNCs) were investigated against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus at lower concentrations. The optical, crystallographic and morphological characterization of AuNPs was analyzed by UV-visible spectroscopy, X-ray diffraction spectroscopy, and transmission electron microscopy (TEM). Shape-dependent antibacterial qualitative and quantitative analyses revealed an effective bactericidal activity of AuNCs against the tested bacteria, followed by AuNSps and AuNSts. The study revealed that the AuNCs are effective bactericidal agents with 100% inactivation rate. The visual analysis confirmed the antibacterial activity of AuNCs and AuNSps by showing physical mutilated bacterial cells which involved cell loss, loosening of the cell wall, loss of flagella and cellular matrix. Finally, released nucleic acid was measured for the treated bacterial cells which support the physical mutilation by releasing 38 μg/mL (Pseudomonas aeruginosa) of cellular material after treating with AuNCs. It is concluded from this study that AuNPs showed the significant antibacterial property at lower concentrations. More applications can be explored including anti-infections, decontamination, and food safety.
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http://dx.doi.org/10.1016/j.msec.2019.110338DOI Listing
March 2020

Tyrosine modified irinotecan-loaded liposomes capable of simultaneously targeting LAT1 and ATB for efficient tumor therapy.

J Control Release 2019 12 30;316:22-33. Epub 2019 Oct 30.

Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China. Electronic address:

As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B (ATB) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes, and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB, and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB. The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB. Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB-mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.
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http://dx.doi.org/10.1016/j.jconrel.2019.10.037DOI Listing
December 2019

Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis.

Mol Pharm 2019 09 22;16(9):3780-3790. Epub 2019 Aug 22.

Department of Pharmaceutical Analysis, Wuya College of Innovation , Shenyang Pharmaceutical University , No. 103, Wenhua Road , Shenyang 110016 , PR China.

A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a -factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 μm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00350DOI Listing
September 2019

Structure of Myosin VI/Tom1 complex reveals a cargo recognition mode of Myosin VI for tethering.

Nat Commun 2019 08 1;10(1):3459. Epub 2019 Aug 1.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200032, Shanghai, China.

Myosin VI plays crucial roles in diverse cellular processes. In autophagy, Myosin VI can facilitate the maturation of autophagosomes through interactions with Tom1 and the autophagy receptors, Optineurin, NDP52 and TAX1BP1. Here, we report the high-resolution crystal structure of the C-terminal cargo-binding domain (CBD) of Myosin VI in complex with Tom1, which elucidates the mechanistic basis underpinning the specific interaction between Myosin VI and Tom1, and uncovers that the C-terminal CBD of Myosin VI adopts a unique cargo recognition mode to interact with Tom1 for tethering. Furthermore, we show that Myosin VI can serve as a bridging adaptor to simultaneously interact with Tom1 and autophagy receptors through two distinct interfaces. In all, our findings provide mechanistic insights into the interactions of Myosin VI with Tom1 and relevant autophagy receptors, and are valuable for further understanding the functions of these proteins in autophagy and the cargo recognition modes of Myosin VI.
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http://dx.doi.org/10.1038/s41467-019-11481-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673701PMC
August 2019
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