Publications by authors named "Weiwei Guo"

176 Publications

A human antibody of potent efficacy against SARS-CoV-2 in rhesus macaques showed strong blocking activity to B.1.351.

MAbs 2021 Jan-Dec;13(1):1930636

Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai, People's Republic of China.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.
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http://dx.doi.org/10.1080/19420862.2021.1930636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189090PMC
June 2021

CRISPR/Cas9-mediated correction of homozygous point mutation in a Waardenburg syndrome 2A pig model.

Mol Ther Nucleic Acids 2021 Jun 16;24:986-999. Epub 2021 Apr 16.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Gene therapy for curing congenital human diseases is promising, but the feasibility and safety need to be further evaluated. In this study, based on a pig model that carries the c.740T>C (L247S) mutation in with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. By using long donor DNA, precise correction of this point mutation was achieved. The corrected cells were then used as the donor cell for somatic cell nuclear transfer (SCNT) to produce piglets, which exhibited a successfully rescued phenotype of WS2A, including anophthalmia and hearing loss. Furthermore, engineered base editors (BEs) were exploited to make the correction in mutant porcine fibroblast cells and early embryos. The correction efficiency was greatly improved, whereas substantial off-targeting mutations were detected, raising a safety concern for their potential applications in gene therapy. Thus, we explored the possibility of precise correction of WS2A-causing gene mutation by the CRISPR-Cas9 system in a large-animal model, suggesting great prospects for its future applications in treating human genetic diseases.
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http://dx.doi.org/10.1016/j.omtn.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141604PMC
June 2021

Design, synthesis and immunological evaluation of self-assembled antigenic peptides from dual-antigen targets: a broad-spectrum candidate for an effective antibreast cancer therapy.

J Immunother Cancer 2021 Jun;9(6)

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China

Background: Considering the narrow immune response spectrum of a single epitope, and the nanoparticles (NPs) as a novel adjuvant can achieve efficient delivery of antigenic peptides safely, a nano-system (denoted as [email protected]) based on cathepsin B-responsive antigenic peptides was designed and synthesized.

Methods: Highly affinitive antigenic peptides were delivered by self-assembled NPs, and targeted erythrocyte membranes acted as a peptide carrier to improve antigenic peptides presentation and to strengthen cytotoxic T-cells reaction. Cathepsin B coupling could release antigenic peptides rapidly in dendritic cells.

Results: Evaluations showed that [email protected] had obvious inhibitory effects towards both MCF-7 and MDA-MB-231 human breast cancer cell lines.

Conclusion: Overall, this strategy provides a novel strategy for boosting cytotoxic T lymphocytes response, thereby expanding the adaptation range of tumor antigenic peptides and improving the therapeutic effect of tumor immunotherapy with nanomedicine.
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http://dx.doi.org/10.1136/jitc-2021-002523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183215PMC
June 2021

Invited Response on: Comment on: "Oral and Maxillofacial Autologous Fat Transplantation: History, Clinical Application Status and Research Progress".

Aesthetic Plast Surg 2021 May 17. Epub 2021 May 17.

State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xian, 710032, Shaanxi, China.

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http://dx.doi.org/10.1007/s00266-021-02338-9DOI Listing
May 2021

Ebosin Ameliorates Psoriasis-Like Inflammation of Mice miR-155 Targeting on IL-17 Pathway.

Front Immunol 2021 26;12:662362. Epub 2021 Apr 26.

NHC Key Laboratory of Biotechnology of Antibiotics, CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Psoriasis is a recurrent autoimmune skin disease with aberrant regulation of keratinocytes and immunocytes. There is no universally accepted single treatment available for psoriasis, and the establishment of a common treatment option to control its signs and symptoms is urgently needed. Here, we found Ebosin, a novel exopolysaccharide isolated from sp. 139 by our lab, not only could ameliorate inflammation in LPS-induced keratinocytes through IKK/NF-kapaB pathway, but also attenuate psoriatic skin lesions and reduce inflammatory factors expression in imiquimod (IMQ)-mediated psoriatic mice. Except for inhibiting the expression of epidermal differentiation related proteins, Ebosin significantly increased the percentage of CD4Foxp3CD25 Tregs and decreased CD4IL17A Th17 cells in psoriatic mice. Furthermore, we demonstrate that Ebosin significantly suppressed the IL-17 signaling pathway A20 (encoded by ) . As the direct binding of to miR-155 has been demonstrated by luciferase reporter assay, and Ebosin has been demonstrated to inhibit miR-155 level and , our study first indicates that Ebosin reduces inflammation through the miR-155--IL-17 axis and T cell differentiation in a psoriasis-like model. Thus, we conclude that Ebosin can act as a promising therapeutic candidate for the treatment of psoriasis.
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http://dx.doi.org/10.3389/fimmu.2021.662362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107364PMC
April 2021

The endosperm-specific transcription factor TaNAC019 regulates glutenin and starch accumulation and its elite allele improves wheat grain quality.

Plant Cell 2021 May;33(3):603-622

State Key Laboratory for Agrobiotechnology and Key Laboratory of Crop Heterosis and Utilization (MOE) and Beijing Key Laboratory of Crop Genetic Improvement, China Agricultural University, Beijing 100193, China.

In wheat (Triticum aestivum L.), breeding efforts have focused intensively on improving grain yield and quality. For quality, the content and composition of seed storage proteins (SSPs) determine the elasticity of wheat dough and flour processing quality. Moreover, starch levels in seeds are associated with yield. However, little is known about the mechanisms that coordinate SSP and starch accumulation in wheat. In this study, we explored the role of the endosperm-specific NAC transcription factor TaNAC019 in coordinating SSP and starch accumulation. TaNAC019 binds to the promoters of TaGlu-1 loci, encoding high molecular weight glutenin (HMW-GS), and of starch metabolism genes. Triple knock-out mutants of all three TaNAC019 homoeologs exhibited reduced transcript levels for all SSP types and genes involved in starch metabolism, leading to lower gluten and starch contents, and in flour processing quality parameters. TaNAC019 directly activated the expression of HMW-GS genes by binding to a specific motif in their promoters and interacting with the TaGlu-1 regulator TaGAMyb. TaNAC019 also indirectly regulated the expression of TaSPA, an ortholog of maize Opaque2 that activates SSP accumulation. Therefore, TaNAC019 regulation of starch- and SSP-related genes has key roles in wheat grain quality. Finally, we identified an elite allele (TaNAC019-BI) associated with flour processing quality, providing a candidate gene for breeding wheat with improved quality.
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http://dx.doi.org/10.1093/plcell/koaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136912PMC
May 2021

Progranulin Ameliorates Lung Inflammation in an LPS-induced Acute Lung Injury Mouse Model by Modulating Macrophage Polarization and the MAPK Pathway.

Ann Clin Lab Sci 2021 Mar;51(2):220-230

Department of Respiratoryand Critical Care Medicine, Shanghai East Hospital, School of Medicine, To ngji University, Pudong, Shanghai, and Department of Respiratory Medicine, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

Objective: Progranulin (PGRN) has been confirmed to exhibit anti-inflammatory activity. Nevertheless, the mechanisms of PGRN in acute lung injury (ALI) remain uncertain. The aim of this study was to explore the role of PGRN in a lipopolysaccharide (LPS)-induced ALI model and in primary bone marrow-derived macrophages, as well as to investigate the underlying mechanism of PGRN.

Methods: Mice were treated with recombinant PGRN protein to detect the effect of PGRN on mouse ALI. Bronchial alveolar lavage fluid (BALF) was analyzed to quantify the inflammatory cytokines, and the lung wet-to-dry ratio was calculated to assess the degree of pulmonary edema. Histological staining was completed on the lung tissues. CCK-8 assay was used to measure cell viability. Western blotting and quantitative polymerase chain reaction were performed to study the transcriptomic profiles during the MAPK pathway.

Results: Recombinant human PGRN significantly suppressed cellular inflammatory response, increased lung permeability, and reduced the expression of inflammatory proteins in the BALF and serum, which further improved survival time. Also, PGRN inhibited the LPS-induced M1 marker gene expression and enhanced the M2 marker gene expression and . Further analysis revealed that PGRN suppresses the activity of the MAPK pathway in LPS-treated macrophages in a dose-dependent manner.

Conclusion: PGRN exhibited anti-inflammatory activity and regulated macrophage polarization by suppressing the phosphorylation of the MAPK pathway.
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March 2021

Electrophysiological and histomorphological changes of cochlea in miniature pigs after abrasion of round window niches.

Acta Otolaryngol 2021 Jun 21;141(6):557-566. Epub 2021 Apr 21.

Department of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology of PLA, Chinese PLA General Hospital, Beijing, P.R. China.

In operations of cochlea implantation (CI), many surgeons choose to drill a window on the bone wall of cochlea basic rotation, when more and more patients receive CI with residual hearing, what damage this step would result in is unclear. To study the effect to inner ear hair cells which is caused by drilling during CI. 6 miniature pigs are equally divided into two groups, Round window niche of each pig in the experimental group was milled, while the pigs in control group wasn't. After implanting depth of 6.5, 11.5 and 20 mm, round window electrocochleography was recorded to analyze the change of cochlea microphonic (CM) potentials respectively, histomorphological changes was observed. Thresholds of CM in experimental group were higher than that of control group at different depth, amplitudes were smaller. In further group, cilia of inner hair cells (IHC) at bottom rotation were significantly damaged. After operation, ABR hearing threshold of experimental group was higher, differences at low frequency region were more obvious. Damage caused by mulling round window niche may seriously affect the function of the hair cells. Damage of the IHC is greater than OHC. CI through round window may protect residual hearing.
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http://dx.doi.org/10.1080/00016489.2021.1899281DOI Listing
June 2021

Atomic Indium Catalysts for Switching CO Electroreduction Products from Formate to CO.

J Am Chem Soc 2021 May 15;143(18):6877-6885. Epub 2021 Apr 15.

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid and Interface and Thermodynamics, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

Electrochemical reduction of CO to chemicals and fuels is an interesting and attractive way to mitigate greenhouse gas emissions and energy shortages. In this work, we report the use of atomic In catalysts for CO electroreduction to CO. The atomic In catalysts were anchored on N-doped carbon (In/NC) through pyrolysis of In-based metal-organic frameworks (MOFs) and dicyandiamide. It was discovered that In/NC had outstanding performance for selective CO production in the mixed electrolyte of ionic liquid/MeCN. It is different from those common In-based materials, in which formate/formic acid is formed as the main product. The faradaic efficiency (FE) of CO and total current density were 97.2% and 39.4 mA cm, respectively, with a turnover frequency (TOF) of ∼40 000 h. It is one of the highest TOF for CO production to date for all of the catalysts reported. In addition, the catalyst had remarkable stability. Detailed study indicated that In/NC had higher double-layer capacitance, larger CO adsorption capacity, and lower interfacial charge transfer resistance, leading to high activity for CO reduction. Control experiments and theoretical calculations showed that the In-N site of In/NC is not only beneficial for dissociation of COOH* to form CO but also hinders formate formation, leading to high selectivity toward CO instead of formate.
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http://dx.doi.org/10.1021/jacs.1c00151DOI Listing
May 2021

Oral and Maxillofacial Autologous Fat Transplantation: History, Clinical Application Status and Research Progress.

Aesthetic Plast Surg 2021 Mar 29. Epub 2021 Mar 29.

State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xian, 710032, Shaanxi, China.

After more than a century of development, autologous fat transplantation (AFT), a repair method for soft tissue defects and deformities, has the advantages of being simple, rapid, effective and safe, and it is increasingly favoured by plastic surgeons. This article reviews the developmental history of AFT, analyses its clinical application status in the oral and maxillofacial regions, and provides a preliminary summary and discussion of the research progress related to AFT. The hope is that that this technique could be widely applied for oral and maxillofacial diseases as well as facial rejuvenation indications. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-021-02238-yDOI Listing
March 2021

Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 - NEK7 mediated inflammasome activation.

Int Immunopharmacol 2021 Jun 23;95:107576. Epub 2021 Mar 23.

The Institute of Audiology and Balance Science of Xu zhou Medical University, Xuzhou 221004, China. Electronic address:

Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1β, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.
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http://dx.doi.org/10.1016/j.intimp.2021.107576DOI Listing
June 2021

Phenotypic similarities in pigs with SOX10 and SOX10 mutations implied the correlation of SOX10 haploinsufficiency with Waardenburg syndrome.

J Genet Genomics 2020 Dec 17;47(12):770-780. Epub 2021 Feb 17.

Department of Laboratory Animal Science, College of Basic Medical Science, Army Medical University, Chongqing 400038, China. Electronic address:

SOX10 is a causative gene of Waardenburg syndrome (WS) that is a rare genetic disorder characterized by hearing loss and pigment disturbance. More than 100 mutations of SOX10 have been found in patients with Type 2 WS (WS2), Type 4 WS (WS4), and more complex syndromes. However, no mutation hotspot has been detected in SOX10, and most cases are sporadic, making it difficult to establish a correlation between the high phenotypic and genetic variability. In this study, a duplication of the 321th cytosine (c.321dupC) was introduced into SOX10 in pigs, which induced premature termination of the translation of SOX10 (p.K108QfsX45). The premature stop codon in Exon 3 triggered the degradation of mutant mRNA through nonsense-mediated mRNA decay. However, SOX10 induced a highly similar phenotype of WS2 with heterogeneous inner ear malformation compared with its adjacent missense mutation SOX10. In addition, a site-saturation mutation analysis of the SOX10 N-terminal nuclear localization signal (n-NLS), where these two mutations located, revealed the correlation between SOX10 haploinsufficiency and WS by an in vitro reporter assay. The analysis combining the in vitro assay with clinical cases may provide a clue to clinical diagnoses.
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http://dx.doi.org/10.1016/j.jgg.2020.12.003DOI Listing
December 2020

The roles of wavelength in the gaseous toluene removal with OH from UV activated Fenton reagent.

Chemosphere 2021 Jul 18;275:129998. Epub 2021 Feb 18.

School of Ecology and Environment, Zhengzhou University, Zhengzhou, 450001, China.

The UV lights of different wavelengths were performed in boosting hydroxyl radicals (OH) generation from traditional Fenton reagent for the gaseous toluene removal. The Fenton, UV/Fenton and UV/Fenton processes were first adopted to eliminate gaseous toluene through the bubble column reactor, respectively. The stable toluene removal efficiency in 60 min was 85.31% in the UV/Fenton process, which was higher than other processes. The gaseous toluene was mainly oxidized into CO rather than other gaseous intermediates in the UV/Fenton process. For UV/Fenton process, the GC-MS tests were carried out to figure out the aqueous intermediates of gaseous toluene removal. The OH concentration in the UV/Fenton process was the highest among all the parallel tests via the EPR experiments and the quantificational measurements with coumarin as the probe. The iron ion in the aqueous solution was systematically evaluated with the experiments proceeding. The evolution of iron ion in the aqueous solution indicated that the fast reduction of Fe to Fe was assisted with 365 nm UV rather than 254 nm UV, which played a key point in the high gaseous toluene removal efficiency. This study demonstrated that the combination of UV irradiation and Fenton in the wet scrubbing reactor performed a synergistic effect on the gaseous toluene removal.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129998DOI Listing
July 2021

LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.

Sci Adv 2021 Feb 10;7(7). Epub 2021 Feb 10.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including , that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of , , , and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish immune-related oncogenic effect and its suppression of interferon-γ signaling. The -EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.
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http://dx.doi.org/10.1126/sciadv.abb3555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875530PMC
February 2021

Self-Healing Material with Reversible Luminescence Switch Behavior.

ACS Appl Mater Interfaces 2020 Nov 19. Epub 2020 Nov 19.

National-Local Joint Engineering Laboratory for Energy Conservation in Chemical Process Integration and Resources Utilization, Tianjin Key Laboratory of Chemical Process Safety, School of Chemical Engineering and Technology, Hebei University of Technology, Guangrong Dao 8, Hongqiao District, Tianjin 300130, P. R. China.

Luminescent materials with dynamic responsiveness to external stimuli have attracted extensive attention for the development of advanced sensors and smart materials; however, self-healing capability is also of great importance for functional soft materials. An acid/base vapor reversibly triggered luminescence switch with self-healing ability is achieved by incorporating dynamic lanthanide metal-ligand (Ln-L) coordination into the soft polydimethylsiloxane polymer network. The emission color of the resultant luminescent material could be modulated by altering either the Eu/Tb molar ratio or the excitation wavelength. The luminescence "On-Off" reversible switch is realized via direct alternating exposure to acid and base vapor, realizing reversible information encryption and decryption. The dynamic Ln-L cross-link as well as the hydrogen bond in the luminescent material endow it with excellent self-healing capability, high toughness, and stretchability. We believe this acid/base vapor-triggered self-healing switching strategy provides new insights for expanding the application range of luminescent materials.
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http://dx.doi.org/10.1021/acsami.0c13509DOI Listing
November 2020

Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner.

Sci Rep 2020 11 16;10(1):19917. Epub 2020 Nov 16.

Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, No. 92, Wucheng Road, Xiaodian District, TaiyuanShanxi, 030006, China.

Propionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.
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http://dx.doi.org/10.1038/s41598-020-77085-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670463PMC
November 2020

Fluorescent Noble Metal Nanoclusters Loaded Protein Hydrogel Exhibiting Anti-Biofouling and Self-Healing Properties for Electrochemiluminescence Biosensing Applications.

Small 2020 11 20;16(45):e2002621. Epub 2020 Oct 20.

College of Chemistry, Research Centre for Analytical Sciences, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin, 300071, P. R. China.

Electrochemiluminescence (ECL) showed great potential in various analytical applications, especially in the sensing of biotargets, taking advantage of its high sensitivity, selectivity, ease of spatial and temporal control, and simplified optical setup. However, during the sensing of complex biological samples, ECL sensors often suffered severe interferences from unavoidable nonspecific-binding of biomacromolecules and physical damages of ECL sensing interfaces. Herein, a hydrogel based ECL biosensing system exhibiting excellent anti-biofouling and self-healing properties is developed. A protein hydrogel composed of bovine serum albumin (BSA) directed fluorescent Au/Ag alloy nanoclusters (Au/Ag NCs) is applied in building ECL sensing systems. The hydrogel matrix facilitates the immobilization of fluorescent Au/Ag NCs as excellent ECL probes, and the porous hydrophilic structure allows the free diffusion of small molecular biotargets while rejecting macromolecular interferences. Moreover, the hydrogel exhibits excellent self-healing property, with the ECL intensity recovered rapidly in 10 min after cutting. The hydrogel ECL system is successfully applied in sensing glutathione (GSH) in serum, confirming the applicability of the hydrogel based anti-biofouling ECL sensing system in sensing complex biological samples. This research may inspire the development of novel anti-biofouling and self-healing ECL biosensors for biosensing applications.
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http://dx.doi.org/10.1002/smll.202002621DOI Listing
November 2020

KIT gene mutation causes deafness and hypopigmentation in Bama miniature pigs.

Am J Transl Res 2020 15;12(9):5095-5107. Epub 2020 Sep 15.

College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Chinese PLA Medical School No. 28 Fuxing Road, Beijing 100853, China.

Waardenburg syndrome (WS) is a common syndromic hearing loss disease. A large group of patients affected by WS were found no mutations in the existed gene panel, indicating that there are still potential genes responsible for WS yet to be detected. In our previous study, we established an autosomal-dominant (OMIM# 164920) mutation (c.2418T>A, p.Asp806Glu) pig pedigree which presented congenital bilateral severe sensorineural hearing loss and hypopigmentation, exact the same as human WS. Histological analysis showed nearly normal structures of the organ of Corti, stria vascularis (SV) and spiral neuron ganglions at E85. Scanning electron microscopy (SEM) exhibited that hair cells started to degenerate at E100, and totally gone at P1. Transmission electron microscope (TEM) showed disorganization of SV and disappearance of intermediate cells. The absence of endocochlear potentials also demonstrated the dysfunction of stria. Our study demonstrated that mutation (c.2418T>A, p.Asp806Glu) interrupted the development of melanocytes in cochlea, which led to SV malformation and dysfunction, resulting in degeneration of hair cells and finally hearing loss. Therefore, was highly supposed to be a newly found gene associated with WS and be added to the WS related gene screening panel clinically.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540160PMC
September 2020

Smart Bilayer Polyacrylamide/DNA Hybrid Hydrogel Film Actuators Exhibiting Programmable Responsive and Reversible Macroscopic Shape Deformations.

Small 2020 10 28;16(42):e1906998. Epub 2020 Sep 28.

College of Chemistry, Research Centre for Analytical Sciences, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin, 300071, P. R. China.

As a crucial instinct for the survival of organisms, adaptive smart deformation has been well shown via profusely astounding examples within biological morphogenesis in nature, which inspired the construction of biomimetic shape-morphing materials with controlled actuating behaviors. Herein, the construction of nature-inspired bilayer hydrogel film actuators, composed of a polyacrylamide hydrogel passive layer and a polyacrylamide-DNA hybrid hydrogel active layer, which exhibited programmable stimuli-responsive and reversible macroscopic shape deformations directed by the sequence of DNA crosslinking units in the active layer, is reported. As a proof-of-concept, the introduction of DNA i-motif based crosslinking structures into the active layer, which can undergo pH-stimulated formation and dissociation of crosslinking between polymers and therefore change the crosslinking density of the active layer, lead to the redistribution of the internal stresses within the bilayer structure, and result in the pH-stimulated shape deformations. By programming the sequence of DNA units in the active layer, a Ag /Cysteamine-stimulated bilayer DNA hybrid hydrogel film actuator is further constructed and exhibits excellent actuation behaviors. Thanks to the micrometer-scale thickness of the films, these actuators exhibit a high degree of macroscopic and reversible shape deformations at high speed, which may find use in future smart biosensing and biomedical applications.
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http://dx.doi.org/10.1002/smll.201906998DOI Listing
October 2020

Air and bone-conducted vestibular evoked myogenic potentials in children with large vestibular aqueduct syndrome.

Acta Otolaryngol 2021 Jan 23;141(1):50-56. Epub 2020 Sep 23.

College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China.

Background: There are few studies focused on vestibular symptoms and function of the children with LVAS.

Objectives: This study aimed to find the characteristics of air and bone-conducted VEMPs among children with LVAS, and to investigate the relationship between VEMPs and vestibular symptoms.

Material And Methods: A total of 44 children with LVAS and 10 healthy children were recruited as the case group and control group. Air and bone-conducted VEMP were performed to the participants.

Results: For air-conducted measurement, there was elevated amplitude of cVEMP in case group than control group. There was no significant difference at oVEMP parameters between the case group and control group. For bone-conducted measurement, significantly longer P1 latency and shorter P1-N1 latency of cVEMP were observed among the case group; there were a series of changes in oVEMP parameters among the case group. Logistic regression model revealed that air-conducted oVEMP asymmetric ratio was valuable to predict vestibular symptoms' development among the kids with LVAS.

Conclusion: Asymmetric ratio of oVEMP could be used as one predictor of developing vestibular symptoms of the children with LVAS. Applying bone-conducted VEMP as one alternative parameter of vestibular syndrome is novel and will certainly remain an area of continued investigation.
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http://dx.doi.org/10.1080/00016489.2020.1815836DOI Listing
January 2021

The characteristics of vHIT gain and PR score in peripheral vestibular disorders.

Acta Otolaryngol 2021 Jan 15;141(1):43-49. Epub 2020 Sep 15.

College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China.

Background: Clinical application of vHIT is limited due to a lack of interpretation of vHIT gain and saccades.

Objectives: This research focuses on comparing common vertigo diseases on vHIT gain and saccade divergence(PR score).

Material And Methods: We retrospectively reviewed 165 patients who have one definite diagnosis, good data quality, and can be read by MATLAB software. All patients were grouped into unilateral vestibular dysfunction (UVD), Meniere's disease (MD), vestibular migraine (VM), Ramsay Hunt Syndrome (RHS), bilateral vestibular hypofunction (BVH), benign paroxysmal positional vertigo (BPPV), and acoustic neuroma (AN). PR score was calculated by an open-source software HitCal.

Results: The saccade detection rate is higher than the abnormal vHIT gain on UVD, MD, VM, RHS, BVH and BPPV. PR score combined with vHIT gain could separate the affected side in UVD and RHS. In the MD group, both vHIT gain and PR score have inconspicuous performance. We also found that different compensation levels and hearing loss status affect results.

Conclusions And Significance: vHIT gain combined with PR score enables a proper distinction among common vertigo diseases. PR score is more sensitive than the gain value on evaluating the physiological situation, vestibular compensation and disease progression.
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http://dx.doi.org/10.1080/00016489.2020.1812715DOI Listing
January 2021

Involvement of Mitophagy in Aluminum Oxide Nanoparticle-Induced Impairment of Learning and Memory in Mice.

Neurotox Res 2021 Apr 11;39(2):378-391. Epub 2020 Sep 11.

Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, China.

Aluminum oxide nanoparticles (nano-aluminum) have been known to be widespread in the environment for decades. Exposure to nano-aluminum may impair learning and memory, but the potential mechanism has not yet been elucidated. In neurons, efficient clearance of damaged mitochondria through mitophagy plays an important role in mitochondrial energy supply, neuronal survival, and health. However, abnormal mitophagy induces accumulation of damaged mitochondria, which induces cellular dysfunction, contributing to the impairment of learning and memory. It is currently unclear whether nano-aluminum interferes with the function of nerve cells through mitophagy, leading to learning and memory disorders. Institute of Cancer Research (ICR) female mice were randomly divided into four groups, and treated with normal saline (control) and 50 nm nano-aluminum at concentrations of 25, 50, and 75 mg/kg for 30 days. Our results showed that exposure to nano-aluminum impaired the spatial learning and memory of mice. Superoxide dismutase levels decreased, whereas the levels of malondialdehyde increased. Moreover, there were significant pathological changes in the ultra-structure and function of mitochondria. Finally, expression of autophagy-related proteins LC3-II and Beclin-1 was upregulated and p62 expression decreased, but the expression of apoptotic and necrosis-related proteins had no significant difference among groups. Our results suggest that learning and memory impairment induced by nano-aluminum could be related to mitophagy.
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http://dx.doi.org/10.1007/s12640-020-00283-0DOI Listing
April 2021

Live attenuated Salmonella enterica serovar Choleraesuis vector delivering a conserved surface protein enolase induces high and broad protection against Streptococcus suis serotypes 2, 7, and 9 in mice.

Vaccine 2020 10 6;38(44):6904-6913. Epub 2020 Sep 6.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China; Key Laboratory of Animal Infectious Diseases, Ministry of Agriculture, Yangzhou University, China; Jiangsu Key Laboratory of Preventive Veterinary Medicine, Yangzhou University, China. Electronic address:

Streptococcus suis, a major zoonotic pathogen in swine, can be classified into 35 serotypes. However, no universal vaccine against the multiple serotypes of S. suis is available, though some studies have shown homologous protection. Hence, developing an effective universal vaccine to protect pigs against multiple S. suis serotypes is necessary, or at the very least, to protect pigs against diseases caused by the dominant pathogenic serotypes. Enolase, a highly conserved surface protein, is present in all of the described S. suis serotypes. rSC0016 is an improved recombinant attenuated S. Choleraesuis vaccine vector, combining a sopB mutation with regulated delayed systems, achieving an adequate balance between host safety and immunogenicity. In order to develop a universal vaccine against the multiple serotypes of S. suis, a novel recombinant vaccine strain rSC0016 that carries a heterologous antigen enolase was developed in this study. According, it was found that the recombinant vaccine strain rSC0016(pS-Enolase) exhibited better colonization compared to the vaccine control strain rSC0018(pYA3493). In addition, a mouse model immunized with the strain rSC0016(pS-Enolase) elicited significant IgG antibody responses against both enolase and Salmonella antigens, while inducing good mucosal, humoral, and cellular immune responses against enolase. Finally, immunization with rSC0016(pS-Enolase) was shown to confer 100%, 80%, and 100% protection against the serotypes of SS2, SS7, and SS9, respectively, and significantly reduced histopathological lesions in mice. Overall, this study provides a promising universal vaccine candidate for use against the multiple serotypes of S. suis.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.062DOI Listing
October 2020

MYC-binding lncRNA EPIC1 promotes AKT-mTORC1 signaling and rapamycin resistance in breast and ovarian cancer.

Mol Carcinog 2020 10 18;59(10):1188-1198. Epub 2020 Aug 18.

Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania.

AKT-mTORC1 (mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how long noncoding RNA (lncRNAs) regulate the AKT-mTORC1 pathway remains unclear. EPIC1 (epigenetically-induced lncRNA 1) is a Myc-binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression was positively correlated with the AKT-mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancers. RNA-seq analysis of breast and ovarian cancer cells demonstrated that EPIC1-knockdown led to the downregulation of genes in the AKT-mTORC1 signaling pathway. In MCF-7, OVCAR4, and A2780cis cell lines, EPIC1 knockdown and overexpression, respectively, inhibited and activated phosphorylated AKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolished the EPIC1's regulation of AKT-mTORC1 signaling; suggested that the regulation of phosphorylation level of AKT, 4EBP1, and S6K by EPIC1 depended on the expression of Myc. Moreover, EPIC1 overexpressed MCF-7, A2780cis, and OVCAR4 cells treated with rapamycin showed a significant decreasing in rapamycin mediated inhibition of p-S6K and p-S6 comparing with the control group. In addition, Colony Formation assay and MTT assay indicated that EPIC1 overexpression led to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the lncRNA EPIC1 expression activated the AKT-mTORC1 signaling pathway through Myc and led to rapamycin resistance in breast and ovarian cancer.
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http://dx.doi.org/10.1002/mc.23248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882146PMC
October 2020

Proteome and lysine acetylome analysis reveals insights into the molecular mechanism of seed germination in wheat.

Sci Rep 2020 08 10;10(1):13454. Epub 2020 Aug 10.

Shandong Provincial Key Laboratory of Dryland Farming Technology/College of Agronomy, Qingdao Agricultural University, Qingdao Shandong, 266109, China.

Seed germination is the first stage in wheat growth and development, directly affecting grain yield and quality. As an important post-translation modification, lysine acetylation participates in diverse biological functions. However, little is known regarding the quantitative acetylproteome characterization during wheat seed germination. In this study, we generated the first comparative proteomes and lysine acetylomes during wheat seed germination. In total, 5,639 proteins and 1,301 acetylated sites on 722 proteins were identified at 0, 12 and 24 h after imbibitions. Several particularly preferred amino acids were found near acetylation sites, including KS, KT, KK, KR, KH, KF, KN, K*E, FK and K*D, in the embryos during seed germination. Among them, KH, KF, FK and KK were conserved in wheat. Biosynthetic process, transcriptional regulation, ribosome and proteasome pathway related proteins were significantly enriched in both differentially expressed proteins and differentially acetylated proteins through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. We also revealed that histone acetylation was differentially involved in epigenetic regulation during seed germination. Meanwhile, abscisic acid and stress related proteins were found with acetylation changes. In addition, we focused on 8 enzymes involved in carbohydrate metabolism, and found they were differentially acetylated during seed germination. Finally, a putative metabolic pathway was proposed to dissect the roles of protein acetylation during wheat seed germination. These results not only demonstrate that lysine acetylation may play key roles in seed germination of wheat but also reveal insights into the molecular mechanism of seed germination in this crop.
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http://dx.doi.org/10.1038/s41598-020-70230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418024PMC
August 2020

Novel HLA-A2 restricted antigenic peptide derivatives with high affinity for the treatment of breast cancer expressing NY-ESO-1.

Bioorg Chem 2020 10 24;103:104138. Epub 2020 Jul 24.

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Tumor immunotherapy based on specific tumor antigen has become the focus for breast cancer, and research into cancer/testes antigens (CTA) is progressing. As an important member in the CTA, NY-ESO-1 plays a crucial role in the treatment and prognosis of breast cancer. In this study, we aimed to improve the binding ability to MHC by designing and synthesizing stable NY-ESO-1-derived peptides, based on NetMHC 4.0 webserver (http://www.cbs.dtu.dk/services/NetMHC/) and HLP webserver (http://crdd.osdd.net/raghava/hlp/pep_both.htm). Moreover, after modification of the lead compound, affinity of the peptides to human leukocyte antigen-A2 (HLA-A2) was determined by a flow cytometry and an inverted fluorescence microscope in T2 cells that show high expression of HLA-A2. The results demonstrated that the affinity of peptides II-4 and II-10 to HLA-A2 was significantly better when compared to others (II-Lead, II-1 ~ II-3, II-5 ~ II-9, II-11 ~ II-15). Further studies indicated that II-4 and II-10, especially II-4, significantly promoted the maturation of HLA-A2-positive human peripheral blood-derived dendritic cells (DCs) from morphology and surface markers, the activation of CD8 + T lymphocytes, and the type-specific killing effect on HLA-A2/NY-ESO-1 MDA-MB-231 cells. Molecular docking studies suggested a strong interaction between peptide II-4 and HLA-A2, thereby indicating that the II-4 is a promising candidate with antigenic potential in the field of immunotherapy that needs more studies.
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http://dx.doi.org/10.1016/j.bioorg.2020.104138DOI Listing
October 2020

Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors.

Bioorg Med Chem 2020 08 20;28(15):115601. Epub 2020 Jun 20.

Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC value of 0.42 μM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2020.115601DOI Listing
August 2020

Dental injuries at the Xi'an, China Stomatological Hospital: A Retrospective Study.

Dent Traumatol 2020 Oct 12;36(5):505-509. Epub 2020 Jun 12.

State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry and Emergency, School of Stomatology, The Fourth Military Medical University, Xi'an, China.

Background/aim: In order to enrich epidemiological knowledge regarding traumatic dental injuries (TDI) in China, and to further improve the treatment, prevention and education of TDI, the aim of this study was to retrospectively analyze the TDI that presented to the emergency dental department at the Stomatological Hospital in Xi'an, China.

Methods: This retrospective study included all first-visit patients who presented with TDI at the Stomatological Hospital affiliated with the Fourth Military Medical University in Xi'an, China, between January 2013 and June 2019. Data were extracted using the terms of diagnosis of TDI from the hospital database.

Results: Overall, 965 (606 males and 359 females) files were reviewed. The average age was 22.8 ± 13.4 years. Among the 2059 teeth injured (average of 2.1 teeth per patient), the maxillary incisors (1751; 85.0%) were the most prevalent teeth to present with injuries, while the main types of injuries were concussions (14.8%) enamel-dentin-fractures (14.50%) and enamel-dentin-pulp fractures (14.0%). After initial examination and diagnosis, 4.2% patients refused treatment.

Conclusions: The epidemiological statistics of TDI in Xi'an, China show consistency with other studies from around the world, but they also vary in diagnosis proportion and the choice of treatments. This information may further instruct treatment, prevention and emergency resources distribution to target the high-risk groups.
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http://dx.doi.org/10.1111/edt.12572DOI Listing
October 2020

Live-attenuated Salmonella enterica serotype Choleraesuis vaccine with regulated delayed fur mutation confer protection against Streptococcus suis in mice.

BMC Vet Res 2020 May 7;16(1):129. Epub 2020 May 7.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, People's Republic of China.

Background: Recombinant Salmonella enterica serotype Choleraesuis (S. Choleraesuis) vaccine vector could be used to deliver heterologous antigens to prevent and control pig diseases. We have previously shown that a live-attenuated S. Choleraesuis vaccine candidate strain rSC0011 (ΔP::TT araC Pcrp Δpmi-2426 ΔrelA199::araC PlacI TT ΔasdA33, Δ, deletion, TT, terminator) delivering SaoA, a conserved surface protein in most of S. suis serotypes, provided excellent protection against S. suis challenge, but occasionally lead to morbidity (enteritidis) in vaccinated mice (approximately 1 in every 10 mice). Thus, alternated attenuation method was sought to reduce the reactogenicity of strain rSC0011. Herein, we described another recombinant attenuated S. Choleraesuis vector, rSC0012 (ΔP:: TT araC Pfur Δpmi-2426 ΔrelA199:: araC PlacI TT ΔasdA33) with regulated delayed fur mutation to avoid inducing disease symptoms while exhibiting a high degree of immunogenicity.

Results: The strain rSC0012 strain with the ΔP::TT araC Pfur mutation induced less production of inflammatory cytokines than strain rSC0011 with the ΔP::TT araC Pcrp mutation in mice. When delivering the same pS-SaoA plasmid, the intraperitoneal LD of rSC0012 was 18.2 times higher than that of rSC0011 in 3-week-old BALB/C mice. rSC0012 with either pS-SaoA or pYA3493 was cleared from spleen and liver tissues 7 days earlier than rSC0011 with same vectors after oral inoculation. The strain rSC0012 synthesizing SaoA induced high titers of anti-SaoA antibodies in both systemic (IgG in serum) and mucosal (IgA in vaginal washes) sites, as well as increased level of IL-4, the facilitator of Th2-type T cell immune response in mice. The recombinant vaccine rSC0012(pS-SaoA) conferred high percentage of protection against S. suis or S. Choleraesuis challenge in BALB/C mice.

Conclusions: The live-attenuated Salmonella enterica serotype Choleraesuis vaccine rSC0012(pS-SaoA) with regulated delayed fur mutation provides a foundation for the development of a safe and effective vaccine against S. Choleraesuis and S. suis.
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http://dx.doi.org/10.1186/s12917-020-02340-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203871PMC
May 2020

RNA-Seq Revealed a Circular RNA-microRNA-mRNA Regulatory Network in Hantaan Virus Infection.

Front Cell Infect Microbiol 2020 13;10:97. Epub 2020 Mar 13.

State Key Laboratory of Virology, Institute of Medical Virology, School of Basic Medical Sciences and Department of Infectious Diseases, Renmin Hospital, Wuhan University, Wuhan, China.

Hantaan virus (HTNV), a Hantavirus serotype that is prevalent in Asia, causes hemorrhagic fever with renal syndrome (HFRS) with high mortality in human race. However, the pathogenesis of HTNV infection remains elusive. Circular RNAs (circRNAs), a new type of non-coding RNAs, play a crucial role in various pathogenic processes. Nevertheless, circRNA expression profiles and their effects on pathogenesis of HTNV infection are still completely unknown. In the present study, RNA sequencing was performed to analyze the circRNA, microRNA (miRNA), and mRNA expression profiles in HTNV-infected and mock-infected human umbilical vein endothelial cells (HUVECs). A total of 70 circRNAs, 66 miRNAs, and 788 mRNAs were differently expressed. Several differentially expressed RNAs were validated by RT-qPCR. Moreover, we verified that some differentially expressed RNAs, such as circ_0000479, miR-149-5p, miR-330-5p, miR-411-3p, RIG-I, CMPK2, PARP10, and GBP1, promoted or inhibited HTNV replication. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that the host genes of differentially expressed circRNAs were principally involved in the innate immune response, the type I interferon (IFN) signaling pathway, and the cytokine-mediated signaling pathway. Additionally, the circRNA-miRNA-mRNA regulatory network was integrally analyzed. The data showed that there were many circRNA-miRNA-mRNA interactions in HTNV infection. By dual-luciferase reporter assay, we confirmed that circ_0000479 indirectly regulated RIG-I expression by sponging miR-149-5p, hampering viral replication. This study for the first time presents a comprehensive overview of circRNAs induced by HTNV and reveals that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of HTNV infection, thus offering new insight into the mechanisms underlying HTNV-host interaction.
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http://dx.doi.org/10.3389/fcimb.2020.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083127PMC
June 2021