Publications by authors named "Lu Han"

850 Publications

Associations of Circulating microRNA-221 and 222 With the Severity of Coronary Artery Lesions in Acute Coronary Syndrome Patients.

Angiology 2021 Jul 30:33197211034286. Epub 2021 Jul 30.

Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China.

Circulating levels of microRNA-221 and 222 (miR-221/222) in patients with coronary artery disease (CAD) are elevated, yet the relationship between circulating miR-221/222 and the severity of coronary lesions in patients with acute coronary syndrome (ACS) remains unknown. In this study, the relative expression levels of circulating miR-221/222 in patients with ACS (n = 267) and controls (n = 71) were compared by real-time fluorescence quantitative-polymerase chain reaction (RT-qPCR). The ACS group was further divided into unstable angina pectoris (UA) group (n = 191) and acute myocardial infarction (AMI) group (n = 76). Significant upregulation of circulating miR-221/222 was observed in ACS. A positive linear correlation between circulating miR-221/222 and Gensini scores was demonstrated. The area under the curve (AUC) of circulating miR-221/222 in the diagnosis of coronary artery stenosis ≥50% was 0.605 and 0.643, respectively. The circulating miRNA-221/222 expression levels in ACS patients were elevated and positively associated with the severity of the coronary artery lesions. Circulating miR-221/222 may be novel biomarkers for the diagnosis of coronary artery stenosis ≥50% and the occurrence of ACS.
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http://dx.doi.org/10.1177/00033197211034286DOI Listing
July 2021

CT-MRI Image Fusion-Based Computer-Assisted Navigation Management of Communicative Tumors Involved the Infratemporal-Middle Cranial Fossa.

J Neurol Surg B Skull Base 2021 Jul 7;82(Suppl 3):e321-e329. Epub 2020 Feb 7.

National Clinical Research Center for Oral Diseases, Beijing, P.R. China.

 Computed tomography (CT) and magnetic resonance imaging (MRI) are crucial for preoperative assessment of the three-dimensional (3D) spatial position relationships of tumor, vital vessels, brain tissue, and craniomaxillofacial bones precisely. The value of CT-MRI-based image fusion was explored for the preoperative assessment, virtual planning, and navigation surgery application during the treatment of communicative tumors involved the infratemporal fossa (ITF) and middle cranial fossa.  Eight patients with infratemporal-middle cranial fossa communicative tumors (ICFCTs) were enrolled in this retrospective study. Plain CT, contrast CT, and MRI image data were imported into a workstation for image fusion, which were used for 3D image reconstruction, virtual surgical planning, and intraoperative navigation sequentially. Therapeutic effect was evaluated through the clinical data analysis of ICFCT patients after CT-MRI image fusion-based navigation-guided biopsy or surgery.  High-quality CT-MRI image fusion and 3D reconstruction were obtained in all eight cases. Image fusion combined with 3D image reconstruction enhanced the preoperative assessment of ICFCT, and improved the surgical performance via virtual planning. Definite pathological diagnosis was obtained in all four navigation-guided core needle biopsies. Complete removal of the tumor was achieved with one exception among the seven navigation-guided operations. Postoperative cerebrospinal fluid leakage occurred in one patient with recurrent meningioma.  CT-MRI image fusion combined with computer-assisted navigation management, optimized the accuracy, safety, and surgical results for core needle biopsy and surgery of ICFCTs.
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http://dx.doi.org/10.1055/s-0040-1701603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289544PMC
July 2021

A Stable Cell Line Expressing Clustered AChR: A Novel Cell-Based Assay for Anti-AChR Antibody Detection in Myasthenia Gravis.

Front Immunol 2021 8;12:666046. Epub 2021 Jul 8.

Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Cell-based assays (CBAs) and radioimmunoprecipitation assay (RIPA) are the most sensitive methods for identifying anti-acetylcholine receptor (AChR) antibody in myasthenia gravis (MG). But CBAs are limited in clinical practice by transient transfection. We established a stable cell line (KL525) expressing clustered AChR by infecting HEK 293T cells with dual lentiviral vectors expressing the genes encoding the human AChR α1, β1, δ, ϵ and the clustering protein rapsyn. We verified the stable expression of human clustered AChR by immunofluorescence, immunoblotting, and real-time PCR. Fluorescence-activated cell sorting (FACS) was used to detect anti-AChR antibodies in 103 MG patients and 58 healthy individuals. The positive results of MG patients reported by the KL525 was 80.6% (83/103), 29.1% higher than the 51.4% (53/103) of RIPA. 58 healthy individuals tested by both the KL525 CBA and RIPA were all negative. In summary, the stable expression of clustered AChR in our cell line makes it highly sensitive and advantageous for broad clinical application in CBAs.
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http://dx.doi.org/10.3389/fimmu.2021.666046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297518PMC
July 2021

Endothelial microparticle-associated protein disulfide isomerase increases platelet activation in diabetic coronary heart disease.

Aging (Albany NY) 2021 Jul 20;13(undefined). Epub 2021 Jul 20.

Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong key Laboratory of Cardiovascular Proteomics, Jinan 250012, Shandong, China.

Background: Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD.

Methods: Patients with CHD (n=223) were divided as non-diabetic CHD (n=121) and diabetic CHD (n=102). Platelet activation biomarkers, circulating microparticles (MPs), the concentration of protein disulfide isomerase (PDI), and MP-PDI activity were determined. The effect of EMPs on platelet activation was investigated . Allosteric GIIb/IIIa receptors that bind to PDI were detected by a proximity ligation assay (PLA).

Results: Platelet activation, platelet-leukocyte aggregates, circulating MPs, EMPs, PDI, and MP-PDI activity in the diabetic CHD group were significantly higher than in the non-diabetic CHD group (<0.05). Diabetes (=0.006) and heart rate <60 bpm (=0.047) were associated with elevated EMPs. EMPs from diabetes increased CD62p on the surface of the platelets compared with the controls (0.01), which could be inhibited by the PDI inhibitor RL90 (0.05). PLA detected the allosteric GIIb/IIIa receptors caused by EMP-PDI, which was also inhibited by RL90.

Conclusions: In diabetic patients with CHD, platelet activation was significantly high. Diabetes and heart rate <60 bpm were associated with elevated EMPs and simultaneously increased PDI activity on EMP, activating platelets through the allosteric GPIIb/IIIa receptors.
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http://dx.doi.org/10.18632/aging.203316DOI Listing
July 2021

Dialdehyde Nanocrystalline Cellulose as Antibiotic Substitutes against Multidrug-Resistant Bacteria.

ACS Appl Mater Interfaces 2021 Jul 20;13(29):33802-33811. Epub 2021 Jul 20.

Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Road, Nanshan District, Shenzhen, Guangdong 518055, P. R. China.

Antibiotic abuse resulted in the emergence of multidrug-resistant Gram-positive pathogens, which pose a severe threat to public health. It is urgent to develop antibiotic substitutes to kill multidrug-resistant Gram-positive pathogens effectively. Herein, the antibacterial dialdehyde nanocrystalline cellulose (DNC) was prepared and characterized. The antibacterial activity and biosafety of DNC were studied. With the increasing content of aldehyde groups, DNC exhibited high antibacterial activity against Gram-positive pathogens in vitro. DNC3 significantly reduced the amounts of methicillin-resistant (MRSA) on the skin of infected mice models, which showed low cytotoxicity, excellent skin compatibility, and no acute oral toxicity. DNC exhibited potentials as antibiotic substitutes to fight against multidrug-resistant bacteria, such as ingredients in salves to treat skin infection and other on-skin applications.
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http://dx.doi.org/10.1021/acsami.1c06308DOI Listing
July 2021

Near-Infrared Fluorescent Agent for Screening of Endometrial Cancer and Precancerous Lesions.

Front Oncol 2021 1;11:713583. Epub 2021 Jul 1.

Department of Obstetrics and Gynecology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.

The lack of cytopathologists delays the advancement of screening for endometrial cancer. It was urgent to develop a new dye for rapid diagnosis. Our study aimed to synthesize a targeted folate receptor-α near-infrared (NIR) fluorescent agent, folic acid-zwitterionic NIR fluorophore (ZW-FA), and explore the feasibility for screening of endometrial cancer and precancerous change. Folic acid was conjugated with zwitterionic NIR fluorophore. The preparation of ZW-FA was validated by H NMR, mass spectrometric, ultraviolet spectra and fluorescence spectra. ZW-FA was incubated with endometrial cytology samples obtained from patients who underwent dilation and curettage or total hysterectomy. Diagnostic utility was calculated by applying laser confocal microscope, Image-J and statistical models, such as enumeration, receiver operating characteristic curve, logistic regression, support vector machine and decision tree were used. The purity of ZW-FA was > 95% determined by H NMR. ZW-FA had the strongest absorption peak at 633 nm in ultraviolet spectra. Photostability of ZW-FA was over 8 hours. In clinical validation, a total of 92 patients were enrolled. The cut-off value of ZW-FA was 49 in enumeration, which was used to distinguish the type of samples. Indicators about diagnostic utility are as follows: sensitivity 90.77%, specificity 62.96%, false-positive rate 37.04%, false-negative rate 9.23%, positive predictive value 85.51% and negative predictive value 73.91%. The samples processed by ZW-FA did not affect further Hematoxylin-Eosin staining and pathological diagnosis. It was an effective cytologic strategy for diagnosis of endometrial cancer and precancerous change by using ZW-FA.

Clinical Trial Registration: http://www.chictr.org.cn/index.aspx, identifier ChiCTR1800020123.
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http://dx.doi.org/10.3389/fonc.2021.713583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281888PMC
July 2021

In-situ fabrication of few-layered MoS wrapped on TiO-decorated MXene as anode material for durable lithium-ion storage.

J Colloid Interface Sci 2021 Jul 6;604:30-38. Epub 2021 Jul 6.

Shanghai Key Laboratory of Magnetic Resonance, School of Physics and Electronic Science, East China Normal University, Shanghai 200241, PR China. Electronic address:

Rational construction of hybrid materials integrating the collective virtues of individual building blocks has spurred significant interest in electrode materials for energy storage. Herein, a smart hybrid was fabricated via in-situ assembling of the few-layered MoS (f-MoS) coated on the multi-layered TiC MXene decorated with the TiO nanoparticles by the scalable hydrothermal and annealing approaches. In the unique architecture, the multi-layered TiC with the expanded interspaces as the conductive backbone can facilitate the electron transport, provide adequate space to facilitate the infiltration of organic electrolyte into the interior of electrode, and inhibit the aggregation of MoS nanosheets, while the f-MoS with enlarged interlayer can be beneficial for the lithium-ion diffusion and prevent the multi-layered TiCfrom restacking. Moreover, the TiO decorated on the TiC can effectively inhibit the instability of long-chain lithium polysulfides dissolved in organic electrolyte to improve the cycling stability. Thanks to the synergistic effect of the building blocks, the TiC/[email protected] hybrid employed as lithium storage anode delivers an extraordinary endurable ability with a high storage capacity of 403.1 mA h g after 1200 cycles at 2 A g. Importantly, the smart hybridization strategy in this work paves an efficient way to explore the high-performance MXene-based hybrid materials in energy storage fields.
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http://dx.doi.org/10.1016/j.jcis.2021.07.013DOI Listing
July 2021

Activation of autophagy reverses gemcitabine-induced immune inhibition of RAW264.7 macrophages by promoting TNF-α, IL-6 and MHC-II expression.

Immunol Res 2021 Jul 14. Epub 2021 Jul 14.

Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.

This research aims to investigate the effect of gemcitabine (GEM) on various activities and functions of macrophages. Phagocytosis, cell autophagy and reactive oxygen species (ROS) were analysed by laser scanning confocal microscope. The cell cycle status and major histocompatibility complex II (MHC-II) expression were examined by flow cytometry. Inflammatory cytokine secretion such as tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6) was detected by Elisa assay. The expression of proteins was analysed by western blot method. The results revealed that GEM-induced immune inhibition of M1-type RAW264.7 macrophages activated by interferon-γ (IFN-γ) and lipopolysaccharide (LPS). We also found that GEM inhibited autophagy, as evidenced by the reduced formation of autophagosome-like vacuoles and autophagosomes. Further study showed that incubation of activated macrophages with the autophagy inhibitor 3-MA induced immune suppression. In contrast, treatment with the autophagy inducer trehalose (Tre) restored phagocytosis, TNF-α and IL-6 secretion, and MHC-II expression in GEM-induced immune-inhibited macrophages. GEM reduced immune effect of M1-type RAW264.7 macrophages via inhibiting TNF-α, IL-6 and MHC-II expression. Furthermore, activation of autophagy by Tre reversed GEM-induced immune inhibition of RAW264.7 macrophages.
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http://dx.doi.org/10.1007/s12026-021-09210-7DOI Listing
July 2021

Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer.

Sci China Life Sci 2021 Jul 2. Epub 2021 Jul 2.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.

Colorectal cancer has one of the highest mortality rates among malignant tumors, and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint inhibitors. Identification of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer immunotherapy. Here, we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumor-specific cytotoxic T cell responses. Three HLA-A2-restricted neoepitopes (P31, P50, and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer patients. Cytotoxic T lymphocytes induced in HLA-A2.1/K transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2 cancer cells. Adoptive transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 antibody. These results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal cancer. The combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors, such as anti-PD-1, could provide a promising treatment strategy for non-MSI-H colorectal cancer.
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http://dx.doi.org/10.1007/s11427-021-1944-5DOI Listing
July 2021

Role of SIRT1 in Neuropathic Pain from the Viewpoint of Neuroimmunity.

Curr Pharm Des 2021 Jul 5. Epub 2021 Jul 5.

Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

The current clinical first-line treatment of neuropathic pain still considers only the nervous system as the target, and its therapeutic effect is limited. An increasing number of studies support the opinion that neuropathic pain is a result of the combined action of the sensory nervous system and the related immune system. Under physiological conditions, both the nervous system and the immune system can maintain homeostasis by adjusting the mitochondrial function when sensing noxious stimulation. However, in the case of neuropathic pain, mitochondrial regulatory dysfunction occurs, which may result from the decreased expression of SIRT1. In this study, we review the role of SIRT1 in neuropathic pain from the viewpoint of neuroimmunity.
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http://dx.doi.org/10.2174/1381612827666210705162610DOI Listing
July 2021

Resistance-Chiral Anisotropy of Chiral Mesostructured Half-metallic Fe O Films.

Angew Chem Int Ed Engl 2021 Jul 5. Epub 2021 Jul 5.

School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.

Half-metallic materials are theoretically predicted to be metallic and insulating, which have not been confirmed experimentally, and the predictions are still in doubt. We report the resistance-chiral anisotropy (R-ChA), i.e., chirality-dependent electrical conductivity, in chiral mesostructured Fe O films (CMFFs) grown on the substrates via a hydrothermal method using amino acids as symmetry-breaking agents. Two levels of chirality exist in the CMFFs: primary distortion of the crystal lattice forms twisted nanoflakes, and secondary helical stacking of nanoflakes forms fan-shaped nanoplates. At temperatures below 30 K, the CMFFs exhibited metallic conductivity and insulation for one handedness and the other, respectively. The chirality-dependent effective magnetic fields were speculated to stabilize the opposite spin in the antipodal chiral frame, which led to the free transport of electrons in one handedness of the chiral structure and immobility for the other handedness.
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http://dx.doi.org/10.1002/anie.202108142DOI Listing
July 2021

[Determination of gastrodin activity inhibition on acetylcholinesterase by capillary electrophoresis].

Se Pu 2020 Sep;38(9):1102-1106

School of Pharmacy, Xi'an Medical University, Shaanxi Province, Xi'an 710021, China.

Alzheimer's disease (AD) is the most common cause of dementia in elderly individuals. Currently, acetylcholinesterase inhibitors (AChEI) are the most effective clinical treatment for AD. AChEIs in natural products may have therapeutic potential and should be screened for use in AD treatment. The authors describe a simple and reliable method for AChEI screening by capillary electrophoresis (CE). A hexadimethrine bromide (HDB) solution was pushed into a capillary (0.015 MPa×10 s) and incubated for 5 min. The capillary was flushed with deionized water for 5 min to remove free HDB, followed by plugging with an acetylcholinesterase (AChE) solution. After a 5 min incubation, the AChE was immobilized on the positively charged coating by ion binding, and the micro-reactor was created. The substrate solution, acetylthiocholine iodide (AThC), was injected into the capillary and incubated in the micro-reactor for 1 min. The unreacted substrate and the enzymolysis product were separated by CE. Gastrodin, an important component of , can inhibit AChE activity. After a certain amount of gastrodin was spiked into the substance solution, the peak area of the product decreased. Greater peak area reduction indicated stronger inhibition of AChEI. We observed good reproducibility of the product peak, with relative standard deviation (RSD) values less than 5.3%. The micro-reactor can be reused up to 300 times, which greatly improves efficiency. When the concentration of gastrodin was 5.24 μmol/L, the inhibition rate of AChE reached 64.8%. The IC of gastrodin was (2.26±0.14) μmol/L (=0.9983), which was consistent with the result of traditional UV method (2.09±0.18 μmol/L). If the function of the micro-reactor deteriorates, it can be conveniently renewed by flushing the column to remove the enzyme and repeating the AChE immobilization protocol. The proposed method is simple, efficient, and low cost, and can be used to screen AChEI from natural products, thus contributing to the improvement of AD treatment.
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http://dx.doi.org/10.3724/SP.J.1123.2020.02015DOI Listing
September 2020

Molecular Epidemiology of Fosfomycin Resistant from a Pigeon Farm in China.

Antibiotics (Basel) 2021 Jun 25;10(7). Epub 2021 Jun 25.

National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.

We determined the prevalence and molecular characteristics of fosfomycin-resistant from a domestic pigeon farm. A total of 79 samples collected from pigeons and their surrounding environments were screened for the presence of fosfomycin resistant isolates and these included 49 isolates that displayed high-level resistance (MIC ≥ 256 mg L) and carried the gene on plasmids with sizes ranging from 80 to 370 kb. MLST analysis of these -positive isolates indicated the presence of nine sequence types (ST6856, ST8804, ST457, ST746, ST533, ST165, ST2614, ST362 and ST8805) of which ST6856 was the most prevalent (24.5%, 12/49). PFGE combined with genomic context comparative analyses indicated that the gene was spread by horizontal transfer as well as via clonal transmission between in the pigeon farm, and IS played an important role in transmission. The high prevalence of in the pigeon farm and the high similarity of the genomic environment between isolates from humans and pigeons indicated that the pigeon farm served as a potential reservoir for human infections. The pigeon farm was found to be an important reservoir for the gene and this should be further monitored.
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http://dx.doi.org/10.3390/antibiotics10070777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300711PMC
June 2021

Chiral Mesostructured BiOBr Films with Circularly Polarized Colour Response.

Angew Chem Int Ed Engl 2021 Jul 1. Epub 2021 Jul 1.

School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.

Achieving strong and broadband circularly polarized colour responses in chiral inorganic materials is challenging. Here, we fabricated chiral mesostructured bismuth oxybromide (BiOBr) films (CMBFs) via hydrothermal growth using chiral sugar alcohols as symmetry-breaking agents. The layered slabs of BiOBr crystals with weak van-der-Waals interactions are prone to mismatching due to the chiral driving force, resulting in hierarchically chiral arrangements of fine size. Three levels of chirality exist in the CMBFs: primary, helical distortion crystal lattices of a nanoflake, secondary, helical stacking of nanoflakes to form nanoplates, and tertiary, chiral vortexes arranged by nanoplates. The CMBFs displayed optical activities (OAs) over a wide wavelength range of 350-2500 nm with an anisotropic factor of up to 0.99, which led to a significant chirality-dependent colour response to circularly polarized light. The high selectivity can be considered as the result of enhanced resonance due to structural-handedness matching and the synergistic effect of multiple OAs.
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http://dx.doi.org/10.1002/anie.202105496DOI Listing
July 2021

Electron Crystallographic Investigation of Crystals on the Mesostructural Scale.

Microsc Microanal 2021 Jun 30:1-11. Epub 2021 Jun 30.

School of Chemical Science and Engineering, Tongji University, Shanghai200092, China.

The precise structural solution of crystals on a mesostructural scale is challenging due to the difficulties in obtaining electron diffraction and the complicated relationship between the crystal structure factors (CSFs) and the conventional underfocus phase-contrast transmission electron microscopy (TEM) images due to the large unit cell and the complex structures. Here, we present the structural investigation of mesostructured crystals via the combination of electron crystallographic Fourier synthesis and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) that only relies on the mass-thickness contrast. The three-dimensional electrostatic potential is reconstructed from the amplitudes and phases extracted from the Fourier transforms of the corresponding HAADF-STEM images and merged into a set of CSFs. This method is verified on silica scaffolds following a shifted double-diamond surface network with space group I41/amd. The results indicate that electron crystallography reconstruction by HAADF-STEM images is more suitable and accurate in determining the structure in comparison with conventional TEM electron crystallography reconstruction. This approach transfers the contrast of mesostructured crystals to images more accurately and the relationship between the Fourier transforms of HAADF-STEM images and the CSFs is more intuitive. It shows great advantages for the structural solution of crystals on the mesostructural scale.
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http://dx.doi.org/10.1017/S1431927621012149DOI Listing
June 2021

Alternative splicing of GluN1 gates glycine site-dependent nonionotropic signaling by NMDAR receptors.

Proc Natl Acad Sci U S A 2021 Jul;118(27)

Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada;

-methyl-D-aspartate (NMDA) receptors (NMDARs), a principal subtype of excitatory neurotransmitter receptor, are composed as tetrameric assemblies of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. NMDARs can signal nonionotropically through binding of glycine alone to its cognate site on GluN1. A consequence of this signaling by glycine is that NMDARs are primed such that subsequent gating, produced by glycine and glutamate, drives receptor internalization. The GluN1 subunit contains eight alternatively spliced isoforms produced by including or excluding the N1 and the C1, C2, or C2' polypeptide cassettes. Whether GluN1 alternative splicing affects nonionotropic signaling by NMDARs is a major outstanding question. Here, we discovered that glycine priming of recombinant NMDARs critically depends on GluN1 isoforms lacking the N1 cassette; glycine priming is blocked in splice variants containing N1. On the other hand, the C-terminal cassettes-C1, C2, or C2'-each permit glycine signaling. In wild-type mice, we found glycine-induced nonionotropic signaling at synaptic NMDARs in CA1 hippocampal pyramidal neurons. This nonionotropic signaling by glycine to synaptic NMDARs was prevented in mice we engineered, such that GluN1 obligatorily contained N1. We discovered in wild-type mice that, in contrast to pyramidal neurons, synaptic NMDARs in CA1 inhibitory interneurons were resistant to glycine priming. But we recapitulated glycine priming in inhibitory interneurons in mice engineered such that GluN1 obligatorily lacked the N1 cassette. Our findings reveal a previously unsuspected molecular function for alternative splicing of GluN1 in controlling nonionotropic signaling of NMDARs by activating the glycine site.
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http://dx.doi.org/10.1073/pnas.2026411118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271567PMC
July 2021

Computational study on new natural compound agonists of dopamine receptor.

Aging (Albany NY) 2021 06 25;13(12):16620-16636. Epub 2021 Jun 25.

Department of Neurology, The First Hospital of Jilin University, Changchun, China.

Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.
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http://dx.doi.org/10.18632/aging.203180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266345PMC
June 2021

Pair Sites on Nodes of Metal-Organic Framework hcp UiO-66 Catalyze -Butyl Alcohol Dehydration.

J Phys Chem Lett 2021 Jul 25;12(26):6085-6089. Epub 2021 Jun 25.

College of Chemical Engineering, State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, Jiangsu 21000, China.

On metal oxide cluster nodes of metal-organic frameworks (MOFs), sites not bonded to linkers (e.g., defects and structural vacancies) control reactivity and catalysis. Attention has been focused on isolated, individual sites, but pair sites have been largely overlooked. We now show that the MOF UiO-66, which incorporates dimeric ZrO nodes bridged by μ-OH groups, is an excellent platform for identifying and controlling adjacent sites consisting of OH groups and Zr sites, which catalyze -butyl alcohol dehydration much more rapidly than isolated single sites.
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http://dx.doi.org/10.1021/acs.jpclett.1c01574DOI Listing
July 2021

Functional Calsequestrin-1 Is Expressed in the Heart and Its Deficiency Is Causally Related to Malignant Hyperthermia-Like Arrhythmia.

Circulation 2021 Jun 24. Epub 2021 Jun 24.

Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Capital Medical University, Beijing 100069, P. R. China.

Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca and regulate its release in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in or include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often suffer from arrhythmia for which the underlying mechanism remains unknown. Working hearts from conventional (-KO) and cardiac-specific (-CKO) knockout mice were monitored and by electrocardiogram and electrical mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes (NRVMs) with knockdown, over-expression or truncation of the gene. Conformational change in both Casqs was determined by crosslinking Western blot analysis. Like MH/EHS patients, -KO and -CKO mice had faster basal heart rate, and ventricular tachycardia upon exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electrical triggering also occurred in -KO hearts . Accordingly, the ventricular cardiomyocytes from -CKO mice displayed dantrolene-sensitive increased Ca waves and diastole premature Ca transients/oscillations upon isoflurane. NRVMs with Casq1-knockdown had enhanced spontaneous Ca2+ sparks/transients upon isoflurane, while cells over-expressing Casq1 exhibited decreased Ca2+ sparks/transients that were absent in cells with truncation of 9 amino acids at the C-terminus of Casq1. Structural evaluation showed that most of the Casq1 protein was present as a polymer and physically interacted with RyR2 in the ventricular SR. The Casq1 isoform was also expressed in human myocardium. Mechanistically, exposure to 2% isoflurane or heating at 41ºC induced Casq1 oligomerization in mouse ventricular and skeletal muscle tissues, leading to a reduced Casq1/RyR2 interaction and increased RyR2 activity in the ventricle. Casq1 is expressed in the heart, where it regulates SR Ca release and heart rate. Casq1 deficiency independently causes MH/EHS-like ventricular arrhythmia by trigger-induced Casq1 oligomerization and a relief of its inhibitory effect on RyR2-mediated Ca release, thus revealing a new inherited arrhythmia and a novel mechanism for MH/EHS arrhythmogenesis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053255DOI Listing
June 2021

Benchmarked approaches for reconstruction of in vitro cell lineages and in silico models of C. elegans and M. musculus developmental trees.

Cell Syst 2021 Jun 15. Epub 2021 Jun 15.

Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.

The recent advent of CRISPR and other molecular tools enabled the reconstruction of cell lineages based on induced DNA mutations and promises to solve the ones of more complex organisms. To date, no lineage reconstruction algorithms have been rigorously examined for their performance and robustness across dataset types and number of cells. To benchmark such methods, we decided to organize a DREAM challenge using in vitro experimental intMEMOIR recordings and in silico data for a C. elegans lineage tree of about 1,000 cells and a Mus musculus tree of 10,000 cells. Some of the 22 approaches submitted had excellent performance, but structural features of the trees prevented optimal reconstructions. Using smaller sub-trees as training sets proved to be a good approach for tuning algorithms to reconstruct larger trees. The simulation and reconstruction methods here generated delineate a potential way forward for solving larger cell lineage trees such as in mouse.
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http://dx.doi.org/10.1016/j.cels.2021.05.008DOI Listing
June 2021

Wiggling Mesopores Kinetically Amplify the Adsorptive Separation of Propylene/Propane.

Angew Chem Int Ed Engl 2021 Jun 18. Epub 2021 Jun 18.

State Key Laboratory of Fine Chemicals, Liaoning Key Laboratory for Catalytic Conversion of Carbon Resources, and School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, P. R. China.

Adsorptive separation is an appealing technology for propylene and propane separation; however, the challenge lies in the design of efficient adsorbents which can distinguish the two molecules having very similar properties. Here we report a kinetically amplified separation by creating wiggling mesopores in structurally robust carbon monoliths. The wiggling mesopores with alternating wide and narrow segments afford a surface area of 413 m  g and a tri-modal pore size distribution centered at 1.5, 4.2 and 6.6 nm, respectively. The synergistically kinetic and equilibrium effects were observed and quantitatively assessed, which together ensured a remarkable propylene/propane selectivity up to 39. This selectivity outperformed not only the available carbon adsorbents but also highly competitive among the dominated crystalline porous adsorbents. In addition, the wiggling mesoporous carbon adsorbent showed excellent dynamical separation stability, which ensured its great potential in practical molecular separations.
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http://dx.doi.org/10.1002/anie.202106523DOI Listing
June 2021

Adsorption and wettability of extended anionic surfactants with different PO numbers on a polymethylmethacrylate surface.

Soft Matter 2021 Jul;17(26):6426-6434

Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.

To investigate the effect of the number of propylene oxide (PO) units on the wettability of surfactants, the wettability of isomeric dodecyl(polyoxyisopropyl)7 sulfate (S-C12PO7S) and isomeric dodecyl(polyoxyisopropyl)13 sulfate (S-C12PO13S) on the surface of polymethylmethacrylate (PMMA) was investigated. The adsorption behavior on the PMMA surface was analyzed by measuring the surface tension and the contact angle. It is found that the PO group may form hydrogen bonds with the PMMA surface, thus facilitating the hydrophobic tails pointing to the aqueous phase. Moreover, the steric effect of the PO group benefits the formation of semi-micelles above the critical micelle concentration (CMC). Surfactant molecules adsorb on the PMMA surface by polar adsorption below the CMC with hydrophobic tails towards the water. Therefore, the PMMA surface is modified to be more hydrophobic. However, the sodium dodecyl sulfate (SDS) surfactant with no PO unit does not have hydrophobic modification ability on the PMMA surface. Below the CMC, the adsorption amounts of the S-C12PO7S and S-C12PO13S surfactants at the solid-liquid interface were approximately 1/3 of those at the air-liquid interface. Interestingly, the adsorption behavior changes when the concentration of the surfactants is around the CMC. The hydrophilic heads of the surfactant molecules will point to water, and the surfactant molecules will form semi-micellar aggregates on the PMMA surface. Therefore, the PMMA surface is modified to be hydrophilic above the CMC. What's more, both the hydrophilic modification ability and hydrophobic modification ability of the S-C12PO13S surfactant are stronger than those of the S-C12PO7S surfactant. This means that the number of PO units will affect the wettability ability of the surfactants. Therefore, the S-C12PO13S surfactant possesses smaller contact angles than the S-C12PO7S surfactant at high concentrations.
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http://dx.doi.org/10.1039/d1sm00557jDOI Listing
July 2021

Advanced Renal-Cell Carcinoma Pseudoprogression After Combined Immunotherapy: Case Report and Literature Review.

Front Oncol 2021 28;11:640447. Epub 2021 May 28.

Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.

Treatment with a combination of programmed cell death-1 (PD-1) blocker and cytokine-induced killer (CIK) cells has improved outcome in cancer patients but is also associated with various patterns of responses. Pseudoprogression is a unique and uncommon phenomenon with no clear criteria for rapid diagnosis. Although some reports of pseudoprogression during immunotherapy exist, there are few reports of pseudoprogression occurring twice in the same patient. Here, we report the case of 51-year-old female patient with advanced renal cell carcinoma, who received a combination treatment of PD-1 blocker and CIK cells, and where pseudoprogression of lung and brain tumors occurred successively during treatment.
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http://dx.doi.org/10.3389/fonc.2021.640447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194346PMC
May 2021

Monascus ruber fermented Panax ginseng ameliorates lipid metabolism disorders and modulate gut microbiota in rats fed a high-fat diet.

J Ethnopharmacol 2021 Oct 15;278:114300. Epub 2021 Jun 15.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yangguang South Street, Fangshan, 102488, Beijing, China; Key Laboratory for Production Process Control and Quality Evaluation of Traditional Chinese Medicine, Beijing Municipal Science & Technology Commission, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Ginseng (Panax ginseng Meyer) is rich in a variety of biologically active ingredients, which shows good effect in the treatment of metabolic diseases. Monascus has lipid-lowering activity and one of its metabolites, lovastatin, is widely used in clinical practice.

Aim Of The Study: The main purpose of this study was to clarify the effects of fermented Panax ginseng by Monascus ruber (PM) on lipid metabolism and gut microbiota in rats fed a high-fat diet.

Materials And Methods: SPF Sprague-Dawley rats were randomly divided into 5 groups, the therapeutic effect of PM on HFD-induced obesity, hyperlipidemia, hepatic steatosis, and disordered gut microbiota were determined in rats.

Results: PM could attenuate features of obesity in rats, decrease serum TC, LDL-C and IgA levels, increase excretion of bile acids in feces. Hepatic histopathologic analysis revealed that PM decrease lipid accumulation in hepatocytes. Consistently, mRNA expression levels of cholesterol metabolism-related genes were regulated in the livers of HFD-fed rats administered with PM. In addition, PM could enhance the diversity and relative abundance of gut microbiota, reduce the Firmicutes/Bacteroidetes (F/B) ratio, increase significantly the relative abundance of Prevotella_9, and decrease these of Muribaculaceae.

Conclusions: PM could regulate lipid metabolism and the structure of the gut microbiota in the HFD rats. Our findings provide valuable experience for the development of ginseng. PM could be a potentially effective strategy to prevent and treat metabolic diseases and alleviate the gut microbiota disturbance caused by it.
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http://dx.doi.org/10.1016/j.jep.2021.114300DOI Listing
October 2021

N-Heterocyclic Carbene-Stabilized Ultrasmall Gold Nanoclusters in a Metal-Organic Framework for Photocatalytic CO Reduction.

Angew Chem Int Ed Engl 2021 Aug 30;60(32):17388-17393. Epub 2021 Jun 30.

Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Rd., Shanghai, 200092, China.

Ultrafine gold nanoclusters (Au-NCs) are susceptible to migrate and aggregate, even in the porosity of many crystalline solids. N-heterocyclic carbenes (NHCs) are a class of structurally diverse ligands for the stabilization of Au-NCs in homogeneous chemistry, showing catalytic reactivity in CO activation. Herein, for the first time, we demonstrate a heterogeneous nucleation approach to stabilize ultrasmall and highly dispersed gold nanoclusters in an NHC-functionalized porous matrix. The sizes of gold nanoclusters are tunable from 1.3 nm to 1.8 nm based on the interpenetration of the metal-organic framework (MOF) topology. Control experiments using amine or imidazolium-functionalized MOFs afforded the aggregation of Au species. The resultant [email protected] composite exhibits a steady and excellent activity in photocatalytic CO reduction, superior to control mixtures without NHC-ligand stabilization. Mechanistic studies reveal the synergistic catalytic effect of MOFs and Au-NCs through the MOF-NHC-Au covalent-bonding bridges.
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http://dx.doi.org/10.1002/anie.202105420DOI Listing
August 2021

Molecular Dockings and Molecular Dynamics Simulations Reveal the Potency of Different Inhibitors against Xanthine Oxidase.

ACS Omega 2021 May 22;6(17):11639-11649. Epub 2021 Apr 22.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China.

Xanthine oxidase (XO), which can catalyze the formation of xanthine or hypoxanthine to uric acid, is the most important target of gout. To explore the conformational changes for inhibitor binding, molecular dockings and molecular dynamics simulations were performed. Docking results indicated that three inhibitors had similar pose binding to XO. Molecular dynamics simulations showed that the binding of three inhibitors influenced the secondary structure changes in XO. After binding to the inhibitor, the peptide Phe798-Leu814 formed different degrees of unhelix, while for the peptide Glu1065-Ser1075, only a partial helix region was formed when allopurinol was bound. Through the protein structure analysis in the simulation process, we found that the distance between the active residues Arg880 and Thr1010 was reduced and the distance between Glu802 and Thr1010 was increased after the addition of inhibitors. The above simulation results showed the similarities and differences of the interaction between the three inhibitors binding to the protein. MM-PBSA calculations suggested that, among three inhibitors, allopurinol had the best binding effect with XO followed by daidzin and puerarin. This finding was consistent with previous experimental data. Our results can provide some useful clues for further gout treatment research.
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http://dx.doi.org/10.1021/acsomega.1c00968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154014PMC
May 2021

Aryne-mediated [2,3]-sigmatropic rearrangement of tertiary 2,3-allenylamines bearing an electron-withdrawing group at the α-position.

Org Biomol Chem 2021 Jun 28;19(24):5353-5357. Epub 2021 May 28.

Hefei National Laboratory for Physical Sciences at the Microscale, Center for Excellence in Molecular Synthesis (CAS), and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China.

An unprecedented [2,3]-sigmatropic rearrangement reaction of quaternary 2,3-allenylammonium ylides, generated in situ from tertiary 2,3-allenylamines and arynes, has been established. With 2-(trimethylsilyl)aryl triflates as aryne precursors, a range of tertiary 2,3-allenylamines bearing an electron-withdrawing group at the α-position smoothly participated in the aryne-mediated [2,3]-sigmatropic rearrangement at room temperature, delivering structurally diverse 2-vinylallyamines or 1-amino-1,3-dienes in moderate to excellent yields. The reaction proceeds in the absence of strong bases and transition metals, is compatible with moisture and air, and tolerates a wide variety of functional groups.
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http://dx.doi.org/10.1039/d1ob00887kDOI Listing
June 2021

Determinants of Self-Rated Health Among Middle-Aged and Elderly Patients with COPD: The China Health and Retirement Longitudinal Study.

Clin Nurs Res 2021 May 28:10547738211018818. Epub 2021 May 28.

Peking University School of Nursing, Beijing, China.

This study aimed to assess self-rated health (SRH) status and its determinants in patients with chronic obstructive pulmonary disease (COPD). Participants aged at least 45 years were included from a nationally representative investigation in 2015. The SRH assessment was divided into two groups: "good" and "not good." Independent samples -tests, chi-square tests, and Fisher's exact tests were used to determine differences in patient characteristics between the two groups. Multiple logistic models were used to determine factors influencing SRH. A total of 1,215 patients with COPD were included in the final analysis, of whom 21.2% reported favorable SRH status. The results indicated that female gender, non-smoking, and elevated peak expiratory flow correlated with better SRH, while nighttime sleep duration less than 7 hours, asthma, and disability, negatively impacted SRH. Our findings provide new evidence for the development of effective health promotion programs for the well-being of patients with COPD.
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http://dx.doi.org/10.1177/10547738211018818DOI Listing
May 2021

Hitchhiking on Controlled-Release Drug Delivery Systems: Opportunities and Challenges for Cancer Vaccines.

Front Pharmacol 2021 10;12:679602. Epub 2021 May 10.

College of Pharmacy, Southwest Minzu University, Chengdu, China.

Cancer vaccines represent among the most promising strategies in the battle against cancers. However, the clinical efficacy of current cancer vaccines is largely limited by the lack of optimized delivery systems to generate strong and persistent antitumor immune responses. Moreover, most cancer vaccines require multiple injections to boost the immune responses, leading to poor patient compliance. Controlled-release drug delivery systems are able to address these issues by presenting drugs in a controlled spatiotemporal manner, which allows co-delivery of multiple drugs, reduction of dosing frequency and avoidance of significant systemic toxicities. In this review, we outline the recent progress in cancer vaccines including subunit vaccines, genetic vaccines, dendritic cell-based vaccines, tumor cell-based vaccines and vaccines. Furthermore, we highlight the efforts and challenges of controlled or sustained release drug delivery systems (e.g., microparticles, scaffolds, injectable gels, and microneedles) in ameliorating the safety, effectiveness and operability of cancer vaccines. Finally, we briefly discuss the correlations of vaccine release kinetics and the immune responses to enlighten the rational design of the next-generation platforms for cancer therapy.
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http://dx.doi.org/10.3389/fphar.2021.679602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141731PMC
May 2021

miR-20a suppresses Treg differentiation by targeting Map3k9 in experimental autoimmune encephalomyelitis.

J Transl Med 2021 05 26;19(1):223. Epub 2021 May 26.

Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China.

Background: Experimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; however, the function of miR-20a remains unclear. In this study, we intended to explore the role of miR-20a in EAE.

Methods: The expression of miR-20a was detected by quantitative real-time PCR (qRT-PCR) in EAE mice and patients with MOG antibody-associated demyelinating diseases. CD4 T cells of EAE mice were sorted, stimulated, and polarized with miR-20a knockdown. Activation and differentiation of CD4 T cells were analyzed by flow cytometry. The expression of target gene Map3k9 was detected by qRT-PCR and western blot experiments. The binding of miR-20a to the 3' UTR of Map3k9 was tested by luciferase assays. The feasibility of miR-20a as a therapeutic target to alleviate the severity of EAE was explored by intravenous administration of miR-20a antagomirs to EAE mice.

Results: miR-20a was upregulated in splenocytes and lymph node cells, CD4 T cells, and spinal cords of EAE mice. Moreover, miR-20a knockdown did not influence the activation of antigen-specific CD4 T cells but promoted their differentiation into Treg cells. Map3k9 was predicted to be a target gene of miR-20a. The expressions of Map3k9 and miR-20a were negatively correlated, and miR-20a knockdown increased the expression of Map3k9. In addition, miR-20a binded to the 3' UTR of Map3k9, and simultaneous knockdown of miR-20a and Map3k9 counteracted the enhanced differentiation of Tregs observed when miR-20a was knocked down alone. Furthermore, injection of miR-20a antagomirs to EAE mice reduced the severity of the disease and increased the proportion of Treg cells in peripheral immune organs.

Conclusions: miR-20a suppresses the differentiation of antigen-specific CD4 T cells into Tregs in EAE by decreasing the expression of Map3k9. miR-20a antagomirs alleviate EAE, suggesting a new therapy for EAE and CNS inflammatory demyelinating diseases.
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http://dx.doi.org/10.1186/s12967-021-02893-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157414PMC
May 2021
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