Qing Xia

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Organization: Peking University

Department: 1 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering

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Chemicals
References

A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase

Co-reporter:Jiaqi Lu, Hua Zhang, Xian Chen, Yong Zou, ... Jiangyun Wang

Free Radical Biology and Medicine 2017 Volume 112(Volume 112) pp:

Publication Date(Web):1 November 2017

DOI:10.1016/j.freeradbiomed.2017.07.012

The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4′-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome.Download high-res image (200KB)Download full-size image

Re-exploration of the Codon Context Effect on Amber Codon-Guided Incorporation of Noncanonical Amino Acids in Escherichia coli by the BlueWhite Screening Assay

Co-reporter:Dr. Huan Xu;Dr. Yan Wang;Dr. Jiaqi Lu;Dr. Bo Zhang;Ziwei Zhang;Dr. Longlong Si;Ling Wu;Tianzhuo Yao;Dr. Chuanling Zhang; Sulong Xiao; Lihe Zhang; Qing Xia; Demin Zhou

ChemBioChem 2016 Volume 17( Issue 13) pp:1250-1256

Publication Date(Web):

DOI:10.1002/cbic.201600117

Abstract

The effect of codon context on amber codon-guided incorporation of noncanonical amino acids (NAAs) has been previously examined by antibiotic selection. Here, we re-explored this effect by screening a library in which three nucleotides upstream and downstream of the amber codon were randomised, and inserted within the lacZ-α gene. Thousands of clones were obtained and distinguished by the depth of blue colour upon exposure to X-gal. Large-scale sequencing revealed remarkable preferences in nucleotides downstream of the amber codon, and moderate preferences for upstream nucleotides. Nucleotide preference was quantified by a dual-luciferase assay, which verified that the optimum context for NAA incorporation, AATTAGACT, was applicable to different proteins. Our work provides a general guide for engineering amber codons into genes of interest in bacteria.

γ-Cyclodextrin–folate complex-functionalized quantum dots for tumor-targeting and site-specific labeling

Co-reporter:Mei-Xia Zhao, Hai-Feng Huang, Qing Xia, Liang-Nian Ji and Zong-Wan Mao

Journal of Materials Chemistry A 2011 vol. 21(Issue 28) pp:10290-10297

Publication Date(Web):02 Jun 2011

DOI:10.1039/C1JM11066G

Quantum dots (QDs) encapsulated with high affinity ligands, specifically binding organic ligands, such as antibodies, peptides or small molecules, have been used in intracellular imaging and targeting. In this work, a series of folate-receptor targeted QDs, in which tumor-targeting folic acid (FA) was conjugated to the surface of QDs through cell-penetrated γ-cyclodextrin (γ-CD), was synthesized. The QDs showed good optical properties and biocompatibility, such as strong optical emission, long luminescent lifetime, appropriate size (4–5 nm in diameter), and lower toxicity. In particular, the γ-CD–FA-coated CdSe–ZnSe QDs presented lower cytotoxicity to these cells at higher IC50 concentrations of above 200 μg mL−1 for 48 h. Folate-receptor overexpressed FR(+) and folate-receptor deficient FR(−) cells were incubated with folate-receptor targeted γ-CD–FA-coated QDs and non-targeted L-Cys-β-CD-coated QDs in vitro. It was found that folate-receptor targeted QDs could more effectively recognize cancer cells with folate receptor (FR) over-expression compared to non-targeted QDs by flow cytometry and confocal laser scanning microscopy (CLSM). Confirming the specificity of folate-receptor targeted QDs, binding and internalization were inhibited by free folate, and hardly any uptake was found in FR(+) cells. Inside the cells, the γ-CD–FA-functionalized QDs are mostly distributed within lysosomes. These properties not only offer insights into the mechanism of the functionalized QDs delivery but also will guide the design and development of nanoparticle probes for intracellular imaging and targeting applications.

Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons

Co-reporter:Qing Xia;Xudong Feng;Haifeng Huang;Lingyan Du;Xiaoda Yang ;Kui Wang

Journal of Neurochemistry 2011 Volume 117( Issue 1) pp:38-47

Publication Date(Web):

DOI:10.1111/j.1471-4159.2010.07162.x

J. Neurochem. (2011) 117, 38–47.

Abstract

Introduction of Gadolinium (Gd) to the nervous system is linked to the development of neurotoxicity involving both oxidative and endoplasmic reticulum (ER) stress. Gd levels (0.2–20 μm) in the form of gadolinium trichloride (GdCl₃) cause neurotoxicity in vitro. We investigated the signaling pathways in primary cultured rat cortical neurons and tested whether GdCl₃ induced oxidative and ER stress. Results showed that Gd-induced neural cell death followed a rapid accumulation of intracellular reactive oxygen species. In addition, Gd exposure resulted in spliced X-box binding protein 1 mRNA and increased expression of binding immunoglobulin protein, thus activating transcription factor 4 (ATF4), ATF6, and C/EBP homologous protein mRNA. Up-regulated expression of binding immunoglobulin protein is a hallmark of ER stress and C/EBP homologous protein is an ER stress-related pro-apoptotic transcription factor. Activation of ER stress downstream substrates, inositol-requiring kinase 1 and ATF6, was also observed in Gd-treated cells. The neurotoxic effects of Gd were blocked by the antioxidant N-acetylcysteine. Results demonstrated that Gd-induced cytotoxicity in neurons occurs via oxidative injury and ER stress-related signal transduction, thus offering new insight into the neurotoxicology of gadolinium.

Gadolinium triggers unfolded protein responses (UPRs) in primary cultured rat cortical astrocytes via promotion of an influx of extracellular Ca2+

Co-reporter:Xu-Dong Feng;Lan Yuan;Hai-Feng Huang

Cell Biology and Toxicology 2011 Volume 27( Issue 1) pp:1-12

Publication Date(Web):2011 February

DOI:10.1007/s10565-010-9166-2

Gadolinium (Gd) and its complexes are utilized widely in industrial and clinical diagnoses. As a rare earth metal ion, free gadolinium (Gd3+) in the human body poses neurotoxic risks during its in vivo release and retention. In the central nervous system, astrocytes play a pivotal role in processing toxic metal ions. The present study evaluates the effects of Gd on cellular calcium homeostasis, a common mechanism that causes cell death, and on unfolded protein responses (UPRs), a mechanism for cell survival in response to toxic stimuli in mammalian cells. The experimental results indicate that the influx of extracellular Ca2+ increases greatly after the exposure of astrocytes to Gd; however, no cell deaths were observed. Further evidence suggests the up-regulated expression of the endoplasmic reticulum (ER)-resident chaperone protein GRP78 by ER stress-mediated signal transductions, specifically the activation of ATF6, eIF2a, and IRE1. These results suggest that Gd promotes Ca2+ influx, thus triggering UPRs, which can be closely associated to the resistance of astrocytes to Gd-induced cytotoxicity.

Cover Picture: Targeted Cellular Uptake and siRNA Silencing by Quantum-Dot Nanoparticles Coated with -Cyclodextrin Coupled to Amino Acids (Chem. Eur. J. 18/2011)

Co-reporter:Mei-Xia Zhao;Jin-Ming Li;Lingyan Du;Dr. Cai-Ping Tan;Dr. Qing Xia; Zong-Wan Mao; Liang-Nian Ji

Chemistry - A European Journal 2011 Volume 17( Issue 18) pp:

Publication Date(Web):

DOI:10.1002/chem.201190087

Targeted Cellular Uptake and siRNA Silencing by Quantum-Dot Nanoparticles Coated with -Cyclodextrin Coupled to Amino Acids

Co-reporter:Mei-Xia Zhao;Jin-Ming Li;Lingyan Du;Dr. Cai-Ping Tan;Dr. Qing Xia; Zong-Wan Mao; Liang-Nian Ji

Chemistry - A European Journal 2011 Volume 17( Issue 18) pp:5171-5179

Publication Date(Web):

DOI:10.1002/chem.201003523

Abstract

Quantum dots (QDs) have the potential to serve as photostable beacons to track siRNA delivery, which is fast becoming an attractive approach to probe gene function in cells. In this paper, we synthesized QD nanoparticles coated with β-cyclodextrin (β-CD) coupled to amino acids with different surface charges (positive, negative, and neutral) through direct ligand-exchange reactions and used them to deliver siRNA. We found that these QDs are diffluent in biological buffer with high colloidal stability and have strong optical emission properties similar to those of tri-n-octylphosphine oxide (TOPO)-coated QDs and also have a long fluorescence lifetime (12.5 ns for L-His-β-CD-coated CdSe/ZnSe QDs). The results of in vitro cytotoxicity and internalization of these modified QDs in normal and cancer cells showed that the β-CD coupled to amino acid outlayers greatly improved the biocompatibility of QDs, and conferred with lower cytotoxicity even at very high concentration. In particular, the L-His-β-CD-coated CdSe/ZnSe QDs presented lower cytotoxicity to these cells (CC₅₀ value is 180.6±3.4 μg mL⁻¹ in ECV-304 cells for 48 h). Transmission electron microscope (TEM) images showed that the QDs were localized in vesicles in the cytoplasm of the cells. Furthermore, compared with existing transfection agents, gene-silencing efficiency of the modified QDs was slightly improved for HPV18 E6 gene in HeLa cells by gel electrophoresis analysis. Finally, the unique optical properties of QDs allow visible imaging of siRNA delivery in live cells. Taken together, our study not only provides new insights into the mechanisms of amino acid mediated delivery, but also greatly facilities the monitoring of gene-silencing studies.

Brain-derived neurotrophic factor protects neurons from GdCl3-induced impairment in neuron-astrocyte co-cultures

Co-reporter:Qing Xia;XuDong Feng;Lan Yuan;Kui Wang;XiaoDa Yang

Science China Chemistry 2010 Volume 53( Issue 10) pp:2193-2199

Publication Date(Web):2010 October

DOI:10.1007/s11426-010-4105-x

Gadolinium (Gd3+) complexes are important contrast agents in medical magnetic resonance imaging (MRI) and of great potential value in brain research. In order to better understand the mechanisms of the action of Gd3+ on neurons in the complex central nervous system (CNS), the neurotoxic actions of GdCl3 have been investigated in both neuron monoculture and astrocyte-neuron co-culture systems. Measurements of lactate dehydrogenase release showed that GdCl3 causes significant cell death of monocultured neurons as a result of reactive oxygen species (ROS) generation and down-regulation of brain-derived neurotrophic factor (BDNF). However, GdCl3 does not affect the viability and BDNF expression of astrocytes. Both co-culturing of neurons with astrocytes and addition of BDNF ameliorated GdCl3-induced neurotoxicity by decreasing ROS generation and facilitating recovery of BDNF levels. The results obtained suggest that astrocytes in the CNS may protect neurons from GdCl3-induced impairment through secreting BDNF and thus up-regulating BDNF expression and interfering with Gd3+-induced cell signaling in neurons. A possible molecular mechanism is suggested which should be helpful in understanding the neurotoxic actions of gadolinium probes.

Synthesis, biocompatibility and cell labeling of l-arginine-functional β-cyclodextrin-modified quantum dot probes

Co-reporter:Mei-Xia Zhao, Qing Xia, Xu-Dong Feng, Xu-Hui Zhu, Zong-Wan Mao, Liang-Nian Ji, Kui Wang

Biomaterials 2010 31(15) pp: 4401-4408

Publication Date(Web):

DOI:10.1016/j.biomaterials.2010.01.114

Impaired mitochondrial function and oxidative stress in rat cortical neurons: Implications for gadolinium-induced neurotoxicity

Co-reporter:Xudong Feng, Qing Xia, Lan Yuan, Xiaoda Yang, Kui Wang

NeuroToxicology (August 2010) Volume 31(Issue 4) pp:391-398

Publication Date(Web):1 August 2010

DOI:10.1016/j.neuro.2010.04.003

Gadolinium (Gd), a rare-earth lanthanides metal, is widely utilized for various industrial and medical purposes, particularly in brain magnetic resonance imaging. However, its potential effects on the impairment of the central nervous system remain uncertain, especially with regard to the mitochondria, the potential primary target in metal-induced neural injury. This study investigates the effects of gadolinium on mitochondrial energy metabolism, ROS accumulation, and cell death toward cortical neurons. Results show that the metabolic activity of the mitochondria significantly decreased as early as 3 h after exposure of cells to gadolinium chloride. Subsequently, significant elevation of intracellular ROS, decrease in ATP synthesis, depolarization of mitochondrial membrane potential, release of cytochrome c and activation of caspase-3 were observed. Following these changes, increased release of LDH into culture medium and DNA fragmentation were detected. Inhibition of both cytochrome c release and caspase-3 activation could significantly reduce Gd-induced neuron cell death. All these results suggest that gadolinium cause neuron cell apoptosis primarily by inhibiting mitochondrial function and inducing oxidative stress. The present work provides new insight into the toxicological mechanism of gadolinium in neurons.

γ-Cyclodextrin–folate complex-functionalized quantum dots for tumor-targeting and site-specific labeling

Co-reporter:Mei-Xia Zhao, Hai-Feng Huang, Qing Xia, Liang-Nian Ji and Zong-Wan Mao

Journal of Materials Chemistry A 2011 - vol. 21(Issue 28) pp:NaN10297-10297

Publication Date(Web):2011/06/02

DOI:10.1039/C1JM11066G