Publications by authors named "Xiaoxiao Zhu"

73 Publications

Combined therapy of adenovirus vector mediated IGF-1 gene with anti-CD20 mAbs exerts potential beneficial role on type 1 diabetes in nonobese diabetic mice.

Life Sci 2021 Jul 28:119853. Epub 2021 Jul 28.

Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China. Electronic address:

Aims: To assess the protective effects of combined treatment with anti-CD20 monoclonal antibody (mAb) and adenovirus mediated mouse insulin-like growth factor 1 (Adv-mIGF-1) gene on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice at early stage.

Methods: To simultaneously restore the proportion of Th cells and block the interaction of B cells, NOD model mice were assigned to four groups which received PBS, Adv-mIGF-1 gene and anti-CD20 mAbs alone or combination, respectively. After 16 weeks of therapeutic intervention, blood samples and pancreatic tissues of mice were measured via the methods of ELISA, RT-PCR, western blotting, H&E staining, TUNEL and immunohistochemistry assays.

Key Findings: Chronic combination intervention with Adv-mIGF-1 gene and anti-CD20 mAbs reduced the T1D-related morbidity, promoted the secretion of insulin, controlled the blood glucose levels (BGLs) and alleviated insulitis of experimental mice. In addition, current combination intervention also protected the pancreatic β cells via suppressing the expression of Fas and TNF-α, inhibiting Caspase-3/8 related apoptotic pathway, and activating the Bcl-2-related antiapoptotic pathway. Furthermore, current combination therapy also increased the expression levels of PDX-1 and CK-19 genes, and finally accelerated the proliferation and differentiation of pancreatic β-cells. In addition, combination therapy could also ameliorate the pathological characteristics of diabetic nephropathy in NOD mice.

Conclusion: Combination treatment with Adv-mIGF-1 gene and anti-CD20 mAbs may exert a potential beneficial role on T1D in NOD mice.
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http://dx.doi.org/10.1016/j.lfs.2021.119853DOI Listing
July 2021

Polyhexamethylene guanidine aerosol triggers pulmonary fibrosis concomitant with elevated surface tension via inhibiting pulmonary surfactant.

J Hazard Mater 2021 Jul 13;420:126642. Epub 2021 Jul 13.

Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China. Electronic address:

Environmental chemicals inhalation exposure could induce pulmonary fibrosis, which is characterized by the excessive proliferation of fibroblasts and accumulation of extracellular matrix components, in which surface tension usually plays vital roles. Polyhexamethylene guanidine (PHMG) was first recognized as a potential hazard ingredient in humidifier disinfectants, which caused an outbreak of pulmonary fibrosis in South Korea. However, the underlying mechanisms involved in PHMG-induced pulmonary fibrosis have not yet been fully elucidated. Therefore, this study mainly focuses on the effect of PHMG on surface tension to unveil the influence and involved mechanisms in PHMG-induced pulmonary fibrosis. C57BL/6J mice were exposed to sub-acute PHMG aerosol for 8 weeks. The results indicated that PHMG induced pulmonary fibrosis combined with elevated surface tension. Results from in vitro study further confirmed PHMG elevated surface tension by inhibited pulmonary surfactant. Mechanistically, PHMG suppressed the key surfactant protein SP-B and SP-C by inhibiting protein expression and block their active sites. The present study, for the first time, revealed the molecular mechanism of PHMG-induced pulmonary fibrosis based on pulmonary surfactant inhibition mediated surface tension elevated. And pulmonary surfactant may be a potential target for further intervention to prevent PHMG-induced fibrosis or alleviate the symptom of relevant patients.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126642DOI Listing
July 2021

Global profiling of RNA-binding protein target sites by LACE-seq.

Nat Cell Biol 2021 06 9;23(6):664-675. Epub 2021 Jun 9.

Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

RNA-binding proteins (RBPs) have essential functions during germline and early embryo development. However, current methods are unable to identify the in vivo targets of a RBP in these low-abundance cells. Here, by coupling RBP-mediated reverse transcription termination with linear amplification of complementary DNA ends and sequencing, we present the LACE-seq method for identifying RBP-regulated RNA networks at or near the single-oocyte level. We determined the binding sites and regulatory mechanisms for several RBPs, including Argonaute 2 (Ago2), Mili, Ddx4 and Ptbp1, in mature mouse oocytes. Unexpectedly, transcriptomics and proteomics analysis of Ago2 oocytes revealed that Ago2 interacts with endogenous small interfering RNAs (endo-siRNAs) to repress mRNA translation globally. Furthermore, the Ago2 and endo-siRNA complexes fine-tune the transcriptome by slicing long terminal repeat retrotransposon-derived chimeric transcripts. The precise mapping of RBP-binding sites in low-input cells opens the door to studying the roles of RBPs in embryonic development and reproductive diseases.
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http://dx.doi.org/10.1038/s41556-021-00696-9DOI Listing
June 2021

The state-dependent impulsive control for a general predator-prey model.

J Biol Dyn 2021 Jun 5:1-19. Epub 2021 Jun 5.

School of Mathematics and Physics, University of South China, Hengyang, People's Republic of China.

In this paper, a general predator-prey model with state-dependent impulse is considered. Based on the geometric analysis and Poincaré map or successor function, we construct three typical types of Bendixson domains to obtain some sufficient conditions for the existence of order-1 periodic solutions. At the same time, the existing domains are discussed with respect to the system parameters. Moreover, the Analogue of Poincaré Criterion is used to obtain the asymptotic stability of the periodic solutions. Finally, to illustrate the results, an example is presented and some numerical simulations are carried out.
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http://dx.doi.org/10.1080/17513758.2021.1937721DOI Listing
June 2021

Blockade of platelet glycoprotein receptor Ib ameliorates blood-brain barrier disruption following ischemic stroke via Epac pathway.

Biomed Pharmacother 2021 Aug 22;140:111698. Epub 2021 May 22.

Department of Pharmacology, School of Basic Medical Science, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China; Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, PR China. Electronic address:

Glycoprotein (GP) Ib is a platelet membrane receptor complex exposed to vascular injury, proposed as an effective target for stroke therapy. Previously, we have observed that the GPIb antagonist anfibatide (ANF) could mitigate blood-brain barrier (BBB) disruption following cerebral ischemia/reperfusion (CI/R) injury. The current study was designed to investigate whether the amelioration of the BBB by ANF is mediated via the Epac signaling pathway. A murine model of CI/R injury was induced following 90 min of transient middle cerebral artery occlusion (MCAO). ANF (4 μg/kg) was intravenously injected 1 h after reperfusion. Herein, ANF ameliorated BBB disruption, increased the expression of tight junction proteins, suppressed F-actin cytoskeleton rearrangement, decreased the permeability of the ischemic brain tissue, and relieved brain edema. ANF-treated mice had smaller infarct volumes and less severe neurological deficits than the MCAO mice. Moreover, the effects of ANF and Epac1 agonists were very similar in the MCAO mice. Epac activation with a cAMP analog, 8-CPT-2'-O-Me-cAMP, mitigated the breakdown of BBB function and CI/R injury. The Epac specific antagonist, ESI-09, worsened barrier damage and cerebral impairment, antagonizing the protective effects afforded by ANF. In addition, ANF upregulated the expression of Epac1 protein in the ischemic cerebral cortex. Collectively, our results indicate that the protective effect of ANF on the BBB after CI/R could be attributed to the activation of the Epac pathway.
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http://dx.doi.org/10.1016/j.biopha.2021.111698DOI Listing
August 2021

MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway.

Front Pharmacol 2021 4;12:614044. Epub 2021 May 4.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.

Macrophages, an important type of immune cells, are generally polarized to classically activated macrophage (M1) or alternatively activated macrophage (M2) to respond to environmental stimuli. Signal transducer and activator of transcription 1 (STAT1), a very important transcription factor, can promote M1 macrophage polarization. However, the mechanisms of regulating STAT1 in macrophage polarization remain unclear. In the present study, STAT1 was markedly elevated, however, miR-19a-3p was down-regulated in interferon (IFN)-γ and lipopolysaccharide (LPS) treated RAW264.7 cells, and dual-luciferase reporter assay identified that miR-19a-3p directly targeted STAT1 by binding to its 3'UTR. Up-regulated miR-19a-3p inhibited M1 polarization by targeting STAT1/interferon regulatory factor 1 (IRF1) and vice versa . Consistently, overexpression of miR-19a-3p in LPS treated mice by systemically administering agomiR-19a-3p effectively reduced the inflammation in mouse lung tissues, and inhibited M1 macrophage polarization via suppressing STAT1/IRF1 pathway. In summary, our study confirmed that miR-19a-3p, as a direct regulator of STAT1, inhibited M1 macrophages polarization. The miR-19a-3p/STAT1/IRF1 pathway can potentially be used to design novel immunotherapy for modulating macrophage polarization.
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http://dx.doi.org/10.3389/fphar.2021.614044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129022PMC
May 2021

Fiber-Shaped Triboiontronic Electrochemical Transistor.

Research (Wash D C) 2021 26;2021:9840918. Epub 2021 Apr 26.

Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing 101400, China.

Contact electrification-activated triboelectric potential offers an efficient route to tuning the transport properties in semiconductor devices through electrolyte dielectrics, i.e., triboiontronics. Organic electrochemical transistors (OECTs) make more effective use of ion injection in the electrolyte dielectrics by changing the doping state of the semiconductor channel. However, the mainstream flexible/wearable electronics and OECT-based devices are usually modulated by electrical signals and constructed in conventional geometry, which lack direct and efficient interaction between the external environment and functional electronic devices. Here, we demonstrate a fiber-shaped triboiontronic electrochemical transistor with good electrical performances, including a current on/off ratio as high as ≈1286 with off-current at ~nA level, the average threshold displacements ( ) of 0.3 mm, the subthreshold swing corresponding to displacement (SS) at 1.6 mm/dec, and excellent flexibility and durability. The proposed triboiontronic electrochemical transistor has great potential to be used in flexible, functional, and smart self-powered electronic textile.
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http://dx.doi.org/10.34133/2021/9840918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098052PMC
April 2021

Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent mA demethylation of Nr4a1 mRNA.

Cell Mol Immunol 2021 Jun 28;18(6):1412-1424. Epub 2021 Apr 28.

Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Group 3 innate lymphoid cells (ILC3s) play critical roles in innate immunity and gut homeostasis. However, how ILC3 homeostasis is regulated remains elusive. Here, we identified a novel circular RNA, circZbtb20, that is highly expressed in ILC3s and required for their maintenance and function. CircZbtb20 deletion causes reduced ILC3 numbers, increasing susceptibility to C. rodentium infection. Mechanistically, circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA, leading to ablation of the mA modification of Nr4a1 mRNA to promote its stability. Nr4a1 initiates Notch2 signaling activation, which contributes to the maintenance of ILC3 homeostasis. Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection. Thus, our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.
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http://dx.doi.org/10.1038/s41423-021-00680-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166869PMC
June 2021

Correction to: A cable-driven distal end-effector mechanism for single-port robotic surgery.

Int J Comput Assist Radiol Surg 2021 Apr;16(4):705

School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.

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http://dx.doi.org/10.1007/s11548-021-02331-2DOI Listing
April 2021

A cable-driven distal end-effector mechanism for single-port robotic surgery.

Int J Comput Assist Radiol Surg 2021 Feb 3;16(2):301-309. Epub 2021 Jan 3.

School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.

Purpose: The development of surgery is to be minimally invasive and collaborative with robot systems, which has caught increasing attention in recent years. However, the narrow access routes and confined working spaces in vivo usually make distal end-effectors of surgical systems not easy to operate. To overcome this problem, a novel cable-driven distal end-effector mechanism designed for single-port robotic surgery was proposed.

Methods: A cable-driven joint structure and the corresponding methods of threading cables were proposed which can maintain the length and even the tension force of cables constant during operation. Based on the proposed joint structure, the cable-driven distal end-effector mechanism consists of a parallelogram mechanism and a snake mechanism. The parallelogram mechanism is used to enlarge its reachable workspace through establishing the triangulation of operation. The snake mechanism is used to achieve the expected pose through providing sufficient bending degrees of freedom. All of the degrees of freedom can be decoupled at the expense of a slightly more tedious process of threading cables.

Results: The primary prototype and its miniature assembled and threaded manually performed as expected regardless of bend, translation and their combination. But the inadequate tension force of cables and assembly errors affect the load capacity and accuracy, which need to be improved by automatic assembly.

Conclusion: A cable-driven distal end-effector mechanism composed of a parallelogram mechanism, and a snake mechanism used for single-port robotic surgery was proposed. The mechanism adopts a novel cable-driven joint structure and corresponding methods of threading cables to keep the length and even the tension force of cables constant during surgery.
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http://dx.doi.org/10.1007/s11548-020-02290-0DOI Listing
February 2021

Dendritic cells in pregnancy and pregnancy-associated diseases.

Biomed Pharmacother 2021 Jan 28;133:110921. Epub 2020 Nov 28.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China. Electronic address:

Dendritic cells (DCs) play a critical immuno-modulating role in pregnancy, which requires the maternal immune system to tolerate semiallogeneic fetus and at the same time to maintain adequate defense against pathogens. DCs interact closely with other immune components such as T cells, natural killer cells and macrophages, as well as the endocrine system to keep a pregnancy-friendly environment. Aberrant DC activities have been related to various pregnancy-associated diseases such as recurrent spontaneous abortion, preterm birth, pre-eclampsia, peripartum cardiomyopathy and infectious pregnancy complications. These findings make DCs an attractive candidate for prevention or therapy on the pregnancy-associated diseases. Here, we review recent findings that provide new insights into the roles of DCs in pregnancy and the related diseases. We also discuss the medical potentials to manipulate DCs in clinics. Whereas this is an emerging area with much work remaining, we anticipate that a better understanding of the role of DCs in maternal-fetal immunotolerance and a therapeutic manipulation of DCs will help women suffering from the pregnancy-associated diseases.
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http://dx.doi.org/10.1016/j.biopha.2020.110921DOI Listing
January 2021

TGFβ/Smad mediated the polyhexamethyleneguanide areosol-induced irreversible pulmonary fibrosis in subchronic inhalation exposure.

Inhal Toxicol 2020 Sep - Oct;32(11-12):419-430. Epub 2020 Nov 4.

Department of Occupational and Environmental Health, School of Public Health, Qingdao University, Qingdao, China.

Aim: Polyhexamethylene guanidine (PHMG) is widely used as a disinfectant with broad spectra of bactericidal activity and low oral toxicity. However, inhalation of PHMG can cause pulmonary injury and severe pulmonary fibrosis. The mechanism underlying PHMG aerosol induced pulmonary fibrosis remains unclear. In this study, we aimed to examine the subchronic lung injury and determine potential cytokines involved in PHMG aerosol induced fibrosis.

Methods: C57BL/6N mice were exposed to 1.03 mg/m PHMG through aerosol inhalation for 3 weeks, or 3 weeks followed by other 3 weeks recovery.

Results: The results indicated that the expression of transforming growth factor-beta1 (TGF-β1) and extracellular matrix remodeling markers were up-regulated in the PHMG-treated mice and these parameters were aggravated after 3 weeks recovery. Bronchoalveolar lavage fluids (BALFs) analysis showed that the number of total cells was significantly decreased in exposure group. The percentage of macrophages in BALFs decreased significantly whereas the percentage of neutrophils and lymphocytes increased. Extensive collagen deposition was observed in the peribronchiolar and interstitial areas in the PHMG exposed lungs.

Conclusion: In conclusion, even low-does PHMG aerosol exposure could induce mice pulmonary local inflammation and irreversible fibrosis. In addition, TGF-β/Smad signaling pathway mediated the extracellular matrix remodeling involved in the development of pulmonary fibrosis.
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http://dx.doi.org/10.1080/08958378.2020.1836091DOI Listing
March 2021

Meta-analysis based gene expression profiling reveals functional genes in ovarian cancer.

Biosci Rep 2020 11;40(11)

Department of Oncology, Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, No. 18877 Jingshi Road, Jinan 250062, China.

Background: Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray-based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets.

Methods: In the present study, the data of gene expression in ovarian cancer were downloaded from Gene Expression Omnibus (GEO) and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation.

Results: A total of 972 DEGs with P-value < 0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up- and down-regulated genes were selected for the validation of gene expression profiling. Among these genes, up-regulated CD24 molecule (CD24), SRY (sex determining region Y)-box transcription factor 17 (SOX17), WFDC2, epithelial cell adhesion molecule (EPCAM), innate immunity activator (INAVA), and down-regulated aldehyde oxidase 1 (AOX1) were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFDC2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer.

Conclusion: Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.
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http://dx.doi.org/10.1042/BSR20202911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677829PMC
November 2020

Potential treatment with Chinese and Western medicine targeting NSP14 of SARS-CoV-2.

J Pharm Anal 2021 Jun 7;11(3):272-277. Epub 2020 Sep 7.

School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, 610500, China.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious global health threat. This raises an urgent need for the development of effective drugs against the deadly disease. SARS-CoV-2 non-structural protein 14 (NSP14) carrying RNA cap guanine N7-methyltransferase and 3'-5' exoribonuclease activities could be a potential drug target for intervention. NSP14 of SARS-CoV-2 shares 98.7% of similarity with the one (PDB 5NFY) of acute respiratory syndrome (SARS) by ClustalW. Then, the SARS-CoV-2 NSP14 structures were modelled by Modeller 9.18 using SARS NSP14 (PDB 5NFY) as template for virtual screening. Based on the docking score from AutoDock Vina1.1.2, 18 small molecule drugs were selected for further evaluation. Based on the 5 ns MD simulation trajectory, binding free energy (ΔG) was calculated by MM/GBSA method. The calculated binding free energies of Saquinavir, Hypericin, Baicalein and Bromocriptine for the -terminus of the homology model were -37.2711 ± 3.2160, -30.1746 ± 3.1914, -23.8953 ± 4.4800, and -34.1350 ± 4.3683 kcal/mol, respectively, while the calculated binding free energies were -60.2757 ± 4.7708, -30.9955 ± 2.9975, -46.3099 ± 3.5689, and -59.8104 ± 3.5389 kcal/mol, respectively, when binding to the C-terminus. Thus, the compounds including Saquinavir, Hypericin, Baicalein and Bromocriptine could bind to the -terminus and C-terminus of the homology model of the SARS-CoV-2 NSP14, providing a candidate drug against SARS-CoV-2 for further study.
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http://dx.doi.org/10.1016/j.jpha.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476502PMC
June 2021

miR-130b-3p regulates M1 macrophage polarization via targeting IRF1.

J Cell Physiol 2021 03 27;236(3):2008-2022. Epub 2020 Aug 27.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Polarized macrophages can be broadly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2) in response to the microenvironment signals. Interferon regulatory factor 1 (IRF1) has been demonstrated to play a critical role in macrophage polarization. However, the mechanisms underlying the regulation of IRF1 expression in macrophage polarization still remain unclear. In this study, IRF1 expression was significantly increased in interferon-γ (IFN-γ) and lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, miR-130b-3p was decreased and negatively associated with Irf1 in M1 macrophages. miR-130b-3p repressed M1 polarization by inhibiting IRF1 and subsequently reducing the levels of the targets of IRF1, C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), inducible NO synthase (iNOS), and tumor necrosis factor (TNF). Consistent with these data, overexpressed miR-130b-3p in LPS-treated mice suppressed M1 macrophage polarization in lung macrophages and peritoneal macrophages by inhibiting Irf1 expression and alleviated the inflammation in mouse lung tissues. Furthermore, the predicted binding site between the Irf1 messenger RNA 3'-untranslated region (3'-UTR) and miR-130b-3p was confirmed by the dual-luciferase reporter assay. In conclusion, our research gave the first evidence that miR-130b-3p affected the polarization of M1 macrophages by directly inhibiting Irf1. The miR-130b-3p/IRF1 pathway may be a potential target for regulating macrophage polarization.
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http://dx.doi.org/10.1002/jcp.29987DOI Listing
March 2021

An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution.

Nat Commun 2020 08 14;11(1):4076. Epub 2020 Aug 14.

Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3Rag1 and circKcnt2Rag1 mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.
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http://dx.doi.org/10.1038/s41467-020-17944-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427797PMC
August 2020

MiR-103 protects from recurrent spontaneous abortion via inhibiting STAT1 mediated M1 macrophage polarization.

Int J Biol Sci 2020 25;16(12):2248-2264. Epub 2020 May 25.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 18877 Jingshi Road, Jinan 250062, Shandong, China.

Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Excessive M1 macrophage was found to be involved in RSA, but the underlying mechanisms remains unclear. MicroRNAs play critical roles in RSA as well as the polarization of macrophages; however, the regulatory effect of miRNAs on M1 differentiation in RSA has not been fully investigated. In this study, miRNA microarray assay revealed that miR-103 was significantly decreased in RAW264.7-derived M1 macrophages upon IFNγ and LPS stimulation. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that in RSA patients, miR-103 expression was decreased substantially, and negatively correlated with that of STAT1. Moreover, down-regulation of miR-103 could sensitively discriminate RSA patients from normal pregnancies (NP) subjects. Experiments showed that overexpression of miR-103 suppressed M1 polarization by inhibiting STAT1/IRF1 signaling pathway and vice versa. miR-103 regulated STAT1 expression by direct binding to its 3'-UTR. Moreover, our study demonstrated that overexpressed miR-103 could reduce mice embryo resorption and M1 polarization effectively. Overall, the results suggested that decreased miR-103 was involved in RSA by increasing M1 macrophage polarization via promoting STAT1/IRF1 signaling pathway. miR-103 may be explored as a promising diagnostic marker and therapeutic target for RSA.
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http://dx.doi.org/10.7150/ijbs.46144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294935PMC
May 2020

Correction: Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer.

Cell Res 2020 Jul;30(7):630

CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41422-020-0352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414023PMC
July 2020

The chromatin remodeler SRCAP promotes self-renewal of intestinal stem cells.

EMBO J 2020 07 25;39(13):e103786. Epub 2020 May 25.

Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Lgr5 intestinal stem cells (ISCs) exhibit self-renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self-renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISCs. Srcap deletion impairs both self-renewal of ISCs and intestinal epithelial regeneration. Mechanistically, SRCAP recruits the transcriptional regulator REST to the Prdm16 promoter and induces expression of this transcription factor. By activating PPARδ expression, Prdm16 in turn initiates PPARδ signaling, which sustains ISC stemness. Rest or Prdm16 deficiency abrogates the self-renewal capacity of ISCs as well as intestinal epithelial regeneration. Collectively, these data show that the SRCAP-REST-Prdm16-PPARδ axis is required for self-renewal maintenance of Lgr5 + ISCs.
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http://dx.doi.org/10.15252/embj.2019103786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327502PMC
July 2020

miR-374b-5p is increased in deep vein thrombosis and negatively targets IL-10.

J Mol Cell Cardiol 2020 07 21;144:97-108. Epub 2020 May 21.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 18877 Jingshi Road, Jinan 250062, Shandong, China. Electronic address:

Background: Deep venous thrombosis (DVT) is one of the most common venous thromboembolic (VTE) disorders and the third leading cardiovascular complication. Accumulating evidence has shown that decreased interleukin-10 (IL-10) was involved in DVT. However, the underlying molecular mechanisms are still largely unknown. Here, we proposed that the epigenetic modification of IL-10 at the post-transcriptional level may be a crucial trigger for IL-10 down-regulation in DVT.

Methods: miRNA expression in DVT was profiled by miRNA microarray analysis. The upstream miRNA regulators of IL-10 were predicted by in silico target prediction tools. The expression of IL-10 mRNA and miR-374b-5p were examined by quantitative real-time PCR (qRT-PCR) and the protein expression of IL-10 was detected by enzyme-linked immunoassay. Dual luciferase reporter assay was used to identify the interaction between miR-374b-5p and IL10. A murine model of DVT was developed and the localization of miR-374b-5p was visualized in vitro by fluorescence in situ hybridization. The biological effects of miR-374b-5p on IL-10 was examined both in vitro and in vivo.

Results: Microarray and qRT-PCR results showed that the IL-10 expression was decreased while miR-374b-5p level was increased substantially in peripheral blood mononuclear cells of DVT patients, and there was significant negative correlation between miR-374b-5p and IL-10. Experiments in vitro showed that overexpressed miR-374b-5p reduced IL-10 expression, while miR-374b-5p knockdown increased IL-10 expression. Moreover, in vivo studies revealed that DVT mice with anti-IL-10 antibody or agomiR-374b-5p delivery resulted in decreased IL-10 expression and aggravated DVT formation, whereas antagomiR-374b-5p acted inversely. Dual luciferase reporter assay identified direct binding between miR-374b-5p and IL10.

Conclusions: These findings suggest that increased miR-374b-5p promotes DVT formation by downregulating IL-10 expression. miR-374b-5p may be explored as a promising diagnostic marker and therapeutic target for DVT.
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http://dx.doi.org/10.1016/j.yjmcc.2020.05.011DOI Listing
July 2020

Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer.

Cell Res 2020 07 4;30(7):610-622. Epub 2020 May 4.

CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.

Innate lymphoid cells (ILCs) reside in mucosal surfaces to potentiate immune responses, sustain mucosal integrity and maintain tissue homeostasis. However, how tumor infiltrating ILCs modulate tumor development and progression is unclear. Here we profiled tumor infiltrating ILCs during colorectal cancer (CRC) progression by single-cell RNA sequencing. We identified six clusters of tumor infiltrating ILCs with unique features. ILC1s expressed inhibitory receptors and underwent inhibitory functional conversion at the late stage of CRC. ILC2s were classified into three subsets (called ILC2-A, -B, -C), of which ILC2-C subset could facilitate tumor progression. HS3ST1 and PD1 were highly expressed in ILC2s of late stage CRC tumors and deficiency of HS3ST1 or PD1 in ILC2s suppressed tumor growth. Moreover, ILC3s transdifferentiated into ILCregs during CRC progression and ILCregs promoted tumor growth. Of note, TGF-β signaling initiated the conversion of ILC3s to ILCregs and blockade of TGF-β signaling could disrupt the ILCreg transdifferentiation and inhibited tumor growth. Thus, intervention of ILC conversions might be a potential strategy for CRC immunotherapy.
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http://dx.doi.org/10.1038/s41422-020-0312-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343789PMC
July 2020

Ground elevation accuracy verification of ICESat-2 data: a case study in Alaska, USA.

Opt Express 2019 Dec;27(26):38168-38179

Accurate estimation of ground elevation on a large scale is essential and worthwhile in topography, geomorphology, and ecology. The Ice, Cloud and Land Elevation Satellite-2 (ICESat-2) mission, launched in September 2018, offers an opportunity to obtain global elevation data over the earth's surface. This paper aimed to evaluate the performance of ICESat-2 data for ground elevation retrieval. To fulfill this objective, our study first tested the availability of existing noise removal and ground photon identification algorithms on ICESat-2 data. Second, the accuracy of ground elevation data retrieved from ICESat-2 data was validated using airborne LiDAR data. Finally, we explored the influence of various factors (e.g., the signal-to-noise ratio (SNR), slope, vegetation height and vegetation cover) on the estimation accuracy of ground elevation over forest, tundra and bare land areas in interior Alaska. The results indicate that the existing noise removal and ground photon identification algorithms for simulated ICESat-2 data also work well for ICESat-2 data. The overall mean difference and RMSE values between the ground elevations retrieved from the ICESat-2 data and the airborne LiDAR-derived ground elevations are -0.61 m and 1.96 m, respectively. In forest, tundra and bare land scenarios, the mean differences are -0.64 m, -0.61 m and -0.59 m, with RMSE values of 1.89 m, 2.05 m, and 1.76 m, respectively. By analyzing the influence of four error factors on the elevation accuracy, we found that the slope is the most important factor affecting the accuracy of ICESat-2 elevation data. The elevation errors increase rapidly with increasing slope, especially when the slope is greater than 20°. The elevation errors decrease with increasing SNR, but this decrease varies little once the SNR is greater than 10. In forest and tundra areas, the errors in the ground elevation also increase with increasing vegetation height and the amount of vegetation cover.
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http://dx.doi.org/10.1364/OE.27.038168DOI Listing
December 2019

IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p.

Arterioscler Thromb Vasc Biol 2020 02 19;40(2):323-334. Epub 2019 Dec 19.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China (Y.Z., Z.Z., R.W., S.S., C.C., L.Z., X.Z., Q.G., X.L.).

Objective: Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6-an important inflammatory cytokine-has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT. Approach and Results: To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti-IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and .

Conclusions: Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression.
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http://dx.doi.org/10.1161/ATVBAHA.119.313137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975520PMC
February 2020

How did the bacterial community respond to the level of urbanization along the Yangtze River?

Environ Sci Process Impacts 2020 Jan 5;22(1):161-172. Epub 2019 Dec 5.

Key Laboratory of Integrated Regulation and Resource Development on Shallow Lake of Ministry of Education, College of Environment, Hohai University, Nanjing 210098, China.

Bacterial communities in the sediment of the Yangtze River influenced by rapid urbanization have thus far been under-investigated despite the importance of microorganisms as mass transporters. Here, the response patterns of the bacterial community along the Yangtze River to different levels of urbanization were generated using 16S rRNA Miseq sequencing. The results reveal that economic aspects have made the largest contribution (41.8%) to the urbanization along the Yangtze River. A clear declining tendency in the abundance of Chloroflexi and Acidobacteria and a significant increase in the abundance of Bacteroidetes were observed with an elevated urbanization level gradient. Bacterial diversity showed a negative relevance (P < 0.01) to the demographic, economic and social urbanization index. Per capita gross domestic product (GDP) (PCGDP) and the GDP of tertiary industry (GDP3) exhibited significantly (P < 0.05) negative correlations with the bacterial diversity, while a positive relationship between the pH and α-diversity (P < 0.05) was observed. Redundancy analysis revealed that PCGDP was significantly correlated (13.9%, P < 0.01) with the overall bacterial compositions, followed by temperature (10.8%, P < 0.01) and GDP3 (8.4%, P < 0.05). Meanwhile, the GDP3 (35.9%), the ratio of total nitrogen and total phosphorus (N/P) (12.9%) and the PCGDP (8.8%) were revealed to be most significantly related to the metabolic bacteria (P < 0.05). The metabolic functions of the bacteria related to the N-cycle and S-cycle were significant in the sediment of the Yangtze River. The variations of the bacterial community and metabolic function responding to the rapid urbanization were related to the economic development via the influence of the 'mass effect'. In brief, the tertiary industry was significantly correlated with the variations in the composition of the metabolic community and the variations in the overall bacteria were both related to the tertiary and secondary industry.
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http://dx.doi.org/10.1039/c9em00399aDOI Listing
January 2020

AcrIIA5 Inhibits a Broad Range of Cas9 Orthologs by Preventing DNA Target Cleavage.

Cell Rep 2019 11;29(9):2579-2589.e4

CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

CRISPR-Cas9 is an adaptive immune system for prokaryotes to defend against invasive genetic elements such as phages and has been used as a powerful tool for genome editing and modulation. To overcome CRISPR immunity, phages encode anti-CRISPR proteins (Acrs) to inhibit Cas9, providing an efficient "off-switch" tool for Cas9-based applications. Here, we characterized AcrIIA5, which is a Cas9 inhibitor discovered in a virulent phage of Streptococcus thermophilus. We found that AcrIIA5 is a potent and broad-spectrum inhibitor of CRISPR-Cas9, which can inhibit diverse Cas9 orthologs of type II-A, type II-B, and type II-C. AcrIIA5 inhibits Cas9 by preventing DNA target cleavage, but DNA target binding of Cas9 is unaffected. Importantly, it can affect the activity of the RuvC nuclease domain of Cas9 independent of the HNH nuclease domain. Our work expands the diversity of the inhibitory mechanisms used by Acrs and provides the guidance for developing controlling tools in Cas9-based applications.
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http://dx.doi.org/10.1016/j.celrep.2019.10.078DOI Listing
November 2019

RMP/URI inhibits both intrinsic and extrinsic apoptosis through different signaling pathways.

Int J Biol Sci 2019 15;15(12):2692-2706. Epub 2019 Oct 15.

Department of Cell Biology, Institute of Bioengineering, School of Medicine, Soochow University, Suzhou 215123, China.

The evading apoptosis of tumor cells may result in chemotherapy resistance. Therefore, investigating what molecular events contribute to drug-induced apoptosis, and how tumors evade apoptotic death, provides a paradigm to explain the relationship between cancer genetics and treatment sensitivity. In this study, we focused on the role of RMP/URI both in cisplatin-induced endogenous apoptosis and in TRAIL-induced exogenous apoptosis in HCC cells. Although flow cytometric analysis indicated that RMP overexpression reduced the apoptosis rate of HCC cells treated with both cisplatin and TRAIL, there was a difference in mechanism between the two treatments. Western blot showed that in intrinsic apoptosis induced by cisplatin, the overexpression of RMP promoted the Bcl-xl expression both and . Besides, RMP activated NF-κB/p65(rel) through the phosphorylation of ATM. However, in TRAIL-induced extrinsic apoptosis, RMP significantly suppressed the transcription and expression of P53. Moreover, the forced expression of P53 could offset this inhibitory effect. In conclusion, we presumed that RMP inhibited both intrinsic and extrinsic apoptosis through different signaling pathways. NF-κB was distinctively involved in the RMP circumvention of intrinsic apoptosis, but not in the extrinsic apoptosis of HCC cells. RMP might play an important role in defects of apoptosis, hence the chemotherapeutic resistance in hepatocellular carcinoma. These studies are promising to shed light on a more rational approach to clinical anticancer drug design and therapy.
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http://dx.doi.org/10.7150/ijbs.36829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854365PMC
June 2020

Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis.

J Exp Med 2020 02;217(2)

Key Laboratory of Infection and Immunity of Chinese Academy of Sciences, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression, leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.
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http://dx.doi.org/10.1084/jem.20190974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041701PMC
February 2020

MiR-337-3p suppresses proliferation of epithelial ovarian cancer by targeting PIK3CA and PIK3CB.

Cancer Lett 2020 01 17;469:54-67. Epub 2019 Oct 17.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address:

Epithelial ovarian cancer (EOC) is responsible for nearly 140,000 deaths worldwide each year. MicroRNAs play critical roles in cancer development and progression. The function of microRNA miR-337-3p has been described in various cancers. However, the biological role of miR-337-3p and its molecular mechanisms underlying EOC initiation and progression have not been reported. Here, we reported that the expression of miR-337-3p is down-regulated in EOC tissues and low expression of miR-337-3p is correlated with advanced pathological grade for patients. Ectopic expression of miR-337-3p inhibited proliferation and induced apoptosis and cell cycle arrest in G0/G1 phase of EOC cells. PIK3CA and PIK3CB were revealed to be direct targets of miR-337-3p for reducing the activation of PI3K/AKT signaling pathway. PIK3CA and PIK3CB were discovered to affect cell proliferation of EOC cells in combination, and only when overexpressed simultaneously in miR-337-3p-expressing cells, could fully restore cell proliferation. In vivo investigation confirmed that miR-337-3p is a tumor suppressor that control expression of PIK3CA and PIK3CB encoded protein: p110α and p110β. Altogether, our results demonstrate that miR-337-3p is a tumor suppressor in EOC that inhibits the expression of PIK3CA and PIK3CB.
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http://dx.doi.org/10.1016/j.canlet.2019.10.021DOI Listing
January 2020

The profiling and identification of the absorbed constituents and metabolites of Naoshuantong capsule in mice biofluids and brain by ultra- fast liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Oct 9;1129:121791. Epub 2019 Sep 9.

Guangzhou Quality R&D Center of Traditional Chinese Medicine, Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, PR China. Electronic address:

Naoshuantong capsule (NSTC) is an oral traditional Chinese medicine formula used widely in the clinic for ischemic stroke. The absorbed ingredients and metabolites of NSTC have never been reported before. In this study, a method incorporating rapid resolution liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to identify absorbed ingredients and metabolites after oral administration of NSTC. A total of 15 constituents were detected and identified as prototypes of NSTC. 109 metabolites related to catechin, gallic acid, paeoniflorin, chlorogenic acid, protocatechuate, typhaneoside, β-elemene, calycosin were identified in serum, urine and brain. 19 metabolites of typhaneoside, 3 metabolites of β-elemene, 12 metabolites of calycosin were reported for the first time. This is the first time to explore the absorption and metabolism of NSTC. The work will provide helpful information for further research of the mechanism and application of NSTC.
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http://dx.doi.org/10.1016/j.jchromb.2019.121791DOI Listing
October 2019

Specific DNA identification of Pheretima in the Naoxintong capsule.

Chin Med 2019 30;14:41. Epub 2019 Sep 30.

1Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China.

Background: Pheretima is a minister drug in Naoxintong capsule (NXTC), a well-known traditional Chinese medicine (TCM) formula for the treatment of cardiovascular and cerebrovascular diseases. Owing to the loss of morphological and microscopic characteristics and the lack of recognized chemical marker, it is difficult to identify Pheretima in NXTC. This study aims to evaluate the feasibility of using DNA techniques to authenticate Pheretima, especially when it is processed into NXTC.

Methods: DNA was extracted from crude drugs of the genuine and adulterant species, as well as nine batches of NXTCs. Based on mitochondrial cytochrome oxidase subunit I (COI) gene, specific primers were designed for two genera of genuine species, and , respectively. PCR amplification was performed with the designed primers on crude drugs of Pheretima and NXTCs. The purified PCR products were sequenced and the obtained sequences were identified to species level with top hit of similarity with BLAST against GenBank nucleotide database.

Results: Primers MF2R2 and AF3R1 could amplify specific DNA fragments with sizes around 230-250 bp, both in crude drugs and NXTC. With sequencing and the BLAST search, identities of the tested samples were found.

Conclusion: This study indicated that the molecular approach is effective for identifying Pheretima in NXTC. Therefore, DNA identification may contribute to the quality control and assurance of NXTC.
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http://dx.doi.org/10.1186/s13020-019-0264-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767644PMC
September 2019
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