Publications by authors named "Huafeng Zhang"

146 Publications

Associations of Copper Intake with Bone Mineral Density and Osteoporosis in Adults: Data from the National Health and Nutrition Examination Survey.

Biol Trace Elem Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Orthopaedic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.

Some studies have suggested an association between serum copper and bone density. Few studies have explored the association between copper intake and osteoporosis and bone mineral density (BMD). Our research aims to assess the associations of copper intake with the risk of osteoporosis in United States adults using the National Health and Nutritional Examination Surveys (NHANES). A total of 8224 individuals were included in our study. Osteoporosis was defined that BMD values surpass 2.5 standard deviations (SD) below the mean of the young adult reference group. Copper intake from diets and supplements was estimated by using two 24-h recall surveys. After adjustment for all the covariates of interest, the odds ratios (ORs) (95% confidence interval (CI)) between the risk of osteoporosis and total copper intake across quartiles 3 and 4 compared with quartile 1 were 0.48 (0.31-0.74) (P < 0.01) and 0.41 (0.26-0.65) (P < 0.01), respectively. The mean total femur BMD and total spine BMD of the highest dietary copper intake quartile (Cu 1.51 mg/d) was 0.03 g/cm and 0.02 g/cm greater than the lowest quartile. Our results indicate that dietary and total copper intake was positively associated with increasing BMD in US adults and negatively associated with the risk of osteoporosis in US adults.
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http://dx.doi.org/10.1007/s12011-021-02845-5DOI Listing
July 2021

Symmetrical superfission of optical solitons in a well-type nonlocal system.

Appl Opt 2021 Jul;60(20):5854-5859

The dynamical properties of fundamental and dipolar mode solitons, in the process of propagating in the well-type nonlocal system, are provided. During propagating in a deep well-type nonlocal system with a moderate width, a fundamental mode soliton splits into a pair of symmetrical sub-beams, and a dipolar mode soliton can divide into two pairs of symmetrical sub-beams. Furthermore, the propagation directions of these sub-beams can be effectively controlled by adjusting system parameters that include the well depth and well width. These properties could be applied to optical routing, all-optical switching, signal processing, and ultrafast optical communications.
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http://dx.doi.org/10.1364/AO.423993DOI Listing
July 2021

KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.

Cancer Commun (Lond) 2021 Jun 19. Epub 2021 Jun 19.

Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.

Background: Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.

Methods: Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth.

Results: KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.

Conclusion: Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.
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http://dx.doi.org/10.1002/cac2.12180DOI Listing
June 2021

EZH2 Mediates miR-146a-5p/HIF-1 to Alleviate Inflammation and Glycolysis after Acute Spinal Cord Injury.

Mediators Inflamm 2021 19;2021:5591582. Epub 2021 May 19.

Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China.

Acute spinal cord injury (ASCI) is a severe traumatic disease of the central nervous system, the underlying mechanism of which is unclear. This study was intended to study the role of EZH2 and miR-146a-5p/HIF-1 in inflammation and glycolysis after ASCI, providing reference and basis for the clinical treatment and prognosis of ASCI injury. We used lipopolysaccharide (LPS) to induce inflammation of microglia, and we constructed the ASCI animal model. qRT-PCR detected the relative expression levels of EZH2, HIF-1, miR-146a-5p, IL-6, TNF-, IL-17, PKM2, GLUT1, and HK2 in cells and tissues. Western blot was performed to detect the expression levels of EZH2, HIF-1, H3K27me3, IL-6, TNF-, IL-17, PKM2, GLUT1, and HK2. ChIP verified the enrichment of H3K27me3 in the miR-146a-5p promoter region. Bioinformatics predicted the binding sites of HIF-1 and miR-146a-5p, and dual-luciferase reporter assay verified the binding of HIF-1 and miR-146a-5p. ELISA detects the levels of inflammatory factors IL-6, TNF-, and IL-17 in the cerebrospinal fluid of rats. The GC-TOFMS was used to detect the changes of glycolytic metabolites in the cerebrospinal fluid of rats. EZH2 could mediate inflammation and glycolysis of microglia. EZH2 regulates inflammation and glycolysis through HIF-1. EZH2 indirectly regulated the HIF-1 expression by mediating miR-146a-5p. EZH2 mediates miR-146a-5p/HIF-1 to alleviate inflammation and glycolysis in ASCI rats. In the present study, our results demonstrated that EZH2 could mediate miR-146a-5p/HIF-1 to alleviate the inflammation and glycolysis after ASCI. Therefore, EZH2/miR-146a-5p/HIF-1 might be a novel potential target for treating ASCI.
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http://dx.doi.org/10.1155/2021/5591582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159642PMC
May 2021

Characterization and Functional Analysis of Tumor-Derived Microparticles.

Curr Protoc 2021 Jun;1(6):e144

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.

Microparticles (MPs) are heterogeneous populations of cell-derived vesicles that play an important role in intercellular communications. The release of MPs by tumor cells is a very common event in tumor microenvironments (TMEs). Tumor cell-derived MPs (T-MPs) contain a variety of bioactive molecules, thus modulating various biological processes, including the regulation of immune cell phenotype and function, as well as immune responses. Moreover, T-MPs can be used as natural carriers to deliver therapeutic drugs into tumor cells and immune cells, thus remodeling TMEs and modifying anti-tumor immune responses. These features allow T-MPs to function as potential biomaterials to be applied in tumor immunotherapies and vaccines. This article describes protocols for the isolation of T-MPs from supernatants of cultured tumor cells by multi-step centrifugations. Tools and protocols are also provided in order to characterize and validate the isolated MPs and to analyze the interaction between T-MPs and different target cells. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Isolation of tumor cell-derived microparticles by multi-step centrifugations Basic Protocol 2: Characterization and validation of tumor cell-derived microparticles Basic Protocol 3: Functional analysis of the uptake of tumor cell-derived microparticles by different cell types.
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http://dx.doi.org/10.1002/cpz1.144DOI Listing
June 2021

Metabolic reprogramming and epigenetic modifications on the path to cancer.

Protein Cell 2021 May 29. Epub 2021 May 29.

Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
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http://dx.doi.org/10.1007/s13238-021-00846-7DOI Listing
May 2021

An Entire Process Optimization Strategy for Comprehensive In Vivo Metabolite Profiling of Prucalopride in Rats Based on Ultra-Performance Liquid Chromatography With Q-Exactive Hybrid Quadrupole-Orbitrap High-Resolution Mass Spectrometry.

Front Pharmacol 2021 7;12:610226. Epub 2021 May 7.

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Prucalopride was widely used for chronic constipation, which is difficult to be adequately relieved by laxatives in adult patients in clinic. Due to the difficulty in metabolite identification, metabolic process of prucalopride had not been investigated in vivo. In this study, an efficient strategy was proposed for comprehensive metabolite profiling of prucalopride after oral administration in rat plasma, urine, and feces samples. This strategy was composed of five steps. First, the samples at multiple time points after oral administration were collected to increase the representativeness of the samples. Second, different sample preparation methods were investigated to obtain superior extraction efficiency. Third, the raw data of test sample and blank sample were acquired using ultra-performance liquid chromatography with Q-Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry under the positive and negative full-scan/dd MS mode. Fourth, combined mass defect filter with background subtraction model in soft of compound discovery, all peaks were constructed to filter potential metabolites after retention time alignment and ion filtration, which could remove large amounts of interference ions. Besides, it can predict potential biotransformation, promoting to understand how to metabolize the drug. This provides multiple possibilities and prevents us conjecturing the potential metabolites blindly. Finally, the verification procedure was implemented through exporting the structure and MS spectrum to the analytical tool of Mass Frontier. The proposed strategy significantly improved the targeted detection and identification for metabolites in vivo. A total of 47 metabolites were tentatively characterized in the plasma, urine, and feces samples after oral administration of prucalopride. This study could provide a valuable reference for systematic metabolite profile of drug in vivo.
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http://dx.doi.org/10.3389/fphar.2021.610226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138455PMC
May 2021

Author Correction: Soft fibrin gels promote selection and growth of tumorigenic cells.

Nat Mater 2021 Jun;20(6):905

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.

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http://dx.doi.org/10.1038/s41563-021-01032-0DOI Listing
June 2021

LncRNA MIAT activates vascular endothelial growth factor A through RAD21 to promote nerve injury repair in acute spinal cord injury.

Mol Cell Endocrinol 2021 05 17;528:111244. Epub 2021 Mar 17.

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address:

Background: The main pathological feature of acute spinal cord injury (ASCI) is neuronal apoptosis and Long non-coding RNA (lncRNA) myocardial infarction-related transcript (MIAT) is involved in the regulation of neuronal apoptosis. This study aimed to investigate the role and potential mechanism of LncRNA MIAT in neuronal apoptosis induced by ASCI.

Methods: After Lenti-MIAT lentivirus was microinjected into ASCI rats, Basso, Beattie and Bresnahan Score, Hematoxylin-eosin staining, TUNEL staining, immunohistochemical, immunofluorescence, quantitative real-time PCR and Western blot were used to observe the effect of LncRNA MIAT on the nerve function of ASCI rats. MTT and flow cytometry assays were used to identify the in vitro function of LncRNA MIAT. RNA immunoprecipitation, RNA pull-down, Cycloheximide chase and Chromatin immunoprecipitation combined with qPCR experiments were used to study the mechanism.

Results: The overexpression of LncRNA MIAT was conducive to the recovery of motor function in ASCI rats and repressed neuronal cell apoptosis and increased neuronal cell viability. Furthermore, the overexpression of LncRNA MIAT in PC12 cells upregulated RAD21 expression by repressing RAD21 protein degradation and further promoted VEGFA transcription to inhibit neuronal cell apoptosis, ultimately improved ASCI.

Conclusion: Our data indicated that the overexpression of LncRNA MIAT activated VEGFA through RAD21 to inhibit neuronal cell apoptosis in ASCI.
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http://dx.doi.org/10.1016/j.mce.2021.111244DOI Listing
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Efficiency of Double Plasma Molecular Absorption System on the Acute Severe Cholestatic Hepatitis.

Blood Purif 2021 Jan 28:1-7. Epub 2021 Jan 28.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,

Background: Cholestasis may lead to hepatic cirrhosis and a longer hospital stay. A part of the patients with cholestasis requires liver transplantation. However, most of the treatment efficiency of cholestatic hepatitis (CH) is not satisfactory. For the patients with severe CH after artificial liver support, there was a lack of systemic evaluation on the treatment efficiency of double plasma molecular absorption system (DPMAS) for acute severe CH.

Objective: We aim to investigate the treatment efficiency of DPMAS on acute severe CH.

Methods: This retrospective study involved 309 cases diagnosed with acute severe CH admitted to the First Affiliated Hospital, Zhejiang University. We compared the prognosis of patients received standard medical therapy (SMT) and SMT + DPMAS. Besides, the effects of DPMAS on total bilirubin (TBIL) and prothrombin time (PT) were investigated.

Results: DPMAS could significantly reduce the requirements for liver transplantation in the CH patients. After DPMAS therapy, significant decline was noticed in the TBIL, direct bilirubin (DBIL), total bile acid, and cholesterol. The baseline ratio of neutrophil showed significant elevation in the patients received 4 or more DPMAS compared with those received less DPMAS.

Conclusions: DPMAS could significantly eliminate the necessity of liver transplantation. The artificial liver support system should be conducted to bring down the bilirubin level and the ratio of cases with severe conditions. In general, DPMAS should be preferred as an artificial liver support therapy for the patients with acute severe CH.
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http://dx.doi.org/10.1159/000513161DOI Listing
January 2021

Design of planar distributed three beam electron gun with narrow beam separation for W band staggered double vane TWT.

Sci Rep 2021 Jan 13;11(1):940. Epub 2021 Jan 13.

School of Electronics and Information Engineering, Beihang University, Beijing, 100191, China.

A novel planar distributed three-beam electron gun with narrow beam separations is designed based on grids loaded sheet beam method. The dimensions of the three-beam gun in the y-O-z plane are determined using our basic theoretical design method developed for sheet beam gun. The results show that the profile of focusing electrode in the y-O-z plane is related to the beam width in the x-O-z plane. Then, the characteristics and parameters of three-beam array formation with their stability are analyzed thoroughly by adjustment of control grids in the x-O-z plane. Each of the beamlet obtained is with a small axial deviation of the two transverse waists. Based on the theoretical analysis and simulations, the planar three-beam electron gun is constructed with the beam voltage of 22 kV and the current of 3 [Formula: see text] 0.15 A. The average radius of 0.08 mm at each beam waist is obtained with the compression factor of 4 for the 0.18 mm beam tunnel radius. The beam waist can be achieved at about 4.4 mm away from the cathode with the axis separation about 0.46 mm for each of beamlet. Thus, the design method can be generally used to construct such type of narrow beam separation and planar distributed multiple beam electron gun for the miniaturization and integrated vacuum electron devices in millimeter wave and terahertz band.
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http://dx.doi.org/10.1038/s41598-020-80276-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806985PMC
January 2021

IL-2 regulates tumor-reactive CD8 T cell exhaustion by activating the aryl hydrocarbon receptor.

Nat Immunol 2021 03 11;22(3):358-369. Epub 2021 Jan 11.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.

CD8 T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8 T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8 T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8 T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.
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http://dx.doi.org/10.1038/s41590-020-00850-9DOI Listing
March 2021

MYC promotes cancer progression by modulating m A modifications to suppress target gene translation.

EMBO Rep 2021 03 11;22(3):e51519. Epub 2021 Jan 11.

Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China.

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m A controls the translation of MRG mRNA via the specific m A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m A modifications in selected MRG transcripts promotes cancer progression.
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http://dx.doi.org/10.15252/embr.202051519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926262PMC
March 2021

Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1.

Cancer Res 2021 03 5;81(5):1265-1278. Epub 2021 Jan 5.

Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.

Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. SIGNIFICANCE: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2876DOI Listing
March 2021

Corrigendum to "Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy" [Biomaterials 89C (2016) 56-66].

Biomaterials 2021 Feb 30;269:120619. Epub 2020 Dec 30.

National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China. Electronic address:

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http://dx.doi.org/10.1016/j.biomaterials.2020.120619DOI Listing
February 2021

Cell softness regulates tumorigenicity and stemness of cancer cells.

EMBO J 2021 01 4;40(2):e106123. Epub 2020 Dec 4.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.

Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133 , ALDH , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
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http://dx.doi.org/10.15252/embj.2020106123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809788PMC
January 2021

Beyond energy storage: roles of glycogen metabolism in health and disease.

FEBS J 2021 06 26;288(12):3772-3783. Epub 2020 Dec 26.

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Beyond storing and supplying energy in the liver and muscles, glycogen also plays critical roles in cell differentiation, signaling, redox regulation, and stemness under various physiological and pathophysiological conditions. Such versatile functions have been revealed by various forms of glycogen storage diseases. Here, we outline the source of carbon flux in glycogen metabolism and discuss how glycogen metabolism guides CD8 T-cell memory formation and maintenance. Likewise, we review how this affects macrophage polarization and inflammatory responses. Furthermore, we dissect how glycogen metabolism supports tumor development by promoting tumor-repopulating cell growth in hypoxic tumor microenvironments. This review highlights the essential role of the gluconeogenesis-glycogenesis-glycogenolysis-PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer.
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http://dx.doi.org/10.1111/febs.15648DOI Listing
June 2021

Silencing SGK1 alleviates osteoarthritis through epigenetic regulation of CREB1 and ABCA1 expression.

Life Sci 2021 Mar 7;268:118733. Epub 2020 Nov 7.

Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, No. 1, Eastern Jianshe Road, Zhengzhou 450000, Henan Province, PR China. Electronic address:

Aim: Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. While early proactive management is crucial in alleviating symptoms in OA patients, currently available therapeutic approaches are yet to achieve an ideal level of efficacy. The path to the development of a potent treatment begins with the thorough understanding of the pathophysiology of OA. The present study aims to explore the mechanism by which SGK1 is involved in OA progression.

Methods: Firstly, the potential target gene of SGK1 was screened and SGK1 expression was determined in OA through bioinformatics analysis. Mouse OA model was then established and chondrocytes were extracted, after which inflammation was induced with lipopolysaccharide (LPS). Following LPS treatment, the chondrocytes were transfected with synthesized plasmids to explore the impact of SGK1, CREB1, and ABCA1 on apoptosis, proliferation and inflammation in OA. ChIP-PCR and dual-luciferase reporter gene assay were conducted to determine the binding relation between SGK1 and CREB1 as well as between CREB1 and ABCA1.

Results: OA mice presented with high expression of SGK1. Interestingly, we found that SGK1 inhibited CREB1 expression in chondrocytes, thereby inducing inflammation and suppressing chondrocyte proliferation. CREB1 was found to have a positive correlation with ABCA1 expression, while down-regulation of CREB1 resulted in the inhibition of cell proliferation and aggravated inflammation, which could be reversed by overexpressed ABCA1.

Conclusion: Taken altogether, silencing of SGK1 alleviated OA through epigenetic regulation of CREB1 and ABCA1 expression. These findings may provide novel insight into SGK1-based strategy for OA treatment.
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http://dx.doi.org/10.1016/j.lfs.2020.118733DOI Listing
March 2021

Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells.

Cancer Res 2021 01 9;81(2):476-488. Epub 2020 Nov 9.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, China.

Biomechanics is a fundamental feature of a cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused by CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces to less F-actins in soft TRC, thus generating an inadequate contractile force for perforin pore formation. Stiffening TRC allowed perforin the ability to drill through the membrane, leading to CTL-mediated killing of TRC. Importantly, overcoming mechanical softness in human TRC also enhanced TRC cell death caused by human CTL, potentiating a mechanics-based immunotherapeutic strategy. These findings reveal a mechanics-mediated tumor immune evasion, thus potentially providing an alternative approach for tumor immunotherapy. SIGNIFICANCE: Tumor-repopulating cells evade CD8 cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2569DOI Listing
January 2021

Tumor-derived microparticles in tumor immunology and immunotherapy.

Eur J Immunol 2020 11 28;50(11):1653-1662. Epub 2020 Oct 28.

Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P. R. China.

Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus, remodeling tumor microenvironments and resetting antitumor immune responses, thus, conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy.
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http://dx.doi.org/10.1002/eji.202048548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702100PMC
November 2020

Corrigendum to "Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy" [Biomaterials 89 (2016) 56-66].

Biomaterials 2020 Dec 16;263:120372. Epub 2020 Sep 16.

National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China. Electronic address:

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http://dx.doi.org/10.1016/j.biomaterials.2020.120372DOI Listing
December 2020

Corni Fructus as a Natural Resource Can Treat Type 2 Diabetes by Regulating Gut Microbiota.

Am J Chin Med 2020 9;48(6):1385-1407. Epub 2020 Sep 9.

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource, Development of Endangered Crude, Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P. R. China.

Accumulating evidence suggests that gut microbiota plays a crucial role in the development of metabolic diseases, especially type 2 diabetes mellitus (T2DM). The nutrient-rich resource Cornus Fructus (CF) showed curative effects on diabetes mellitus. However, the mechanism underlying its hyperglycemic activity remains obscure. Herein, the antidiabetic potential of four extracts from CF, including saponin (CTS), iridoid glycoside (CIG), tannin (CT), and alcohol extract (CCA) was evaluated . The results showed that all four extracts could increase the body weight, decrease the blood glucose levels, and elevate the glucose tolerance. Moreover, insulin sensitivity and lipid profile were significantly improved in fed mice. In the [Formula: see text]-diversity index of samples, compared to the DM group, the diversity and richness of gut microbiota in mice to a certain extent were reduced in both CF extracts and Metformin (PC). Among them, there was statistical significance in PC (ACE, [Formula: see text]) and CCA (ACE, [Formula: see text]; chao1: [Formula: see text]). Beta diversity showed the same trend as the UPGMA clustering trees, which revealed that CF extracts could improve intestinal homeostasis in T2DM mice. Also, CF extracts could elevate the production of short-chain fatty acids, as well as regulate the composition of gut microbiota. The key bacteria related to T2DM including Firmicutes, Bacteroides, Lactobacillus, and Clostridium were modulated by metformin and CF. Altogether, CF is a potential nutrient-rich candidate that can be used in functional foods for the treatment of T2DM, and the change of gut microbiota might be a novel mechanism underlying its hyperglycemic activity.
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http://dx.doi.org/10.1142/S0192415X20500688DOI Listing
October 2020

Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis.

Nat Metab 2020 03 16;2(3):256-269. Epub 2020 Mar 16.

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.

The transcriptional role of cMyc (or Myc) in tumorigenesis is well appreciated; however, it remains to be fully established how extensively Myc is involved in the epigenetic regulation of gene expression. Here, we show that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to H3K4me3 activation and gene expression. We find that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase. We further demonstrate that Myc inhibition of SDH-complex activity leads to cellular succinate accumulation, which triggers H3K4me3 activation and tumour-specific gene expression. We demonstrate that acetylated SDHA at Lys 335 contributes to tumour growth in vitro and in vivo, and we confirm increased tumorigenesis in clinical samples. This study illustrates a link between acetylation-dependent SDHA deactivation and Myc-driven epigenetic regulation of gene expression, which is critical for cancer progression.
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http://dx.doi.org/10.1038/s42255-020-0179-8DOI Listing
March 2020

Chemotherapeutic Tumor Microparticles Elicit a Neutrophil Response Targeting Malignant Pleural Effusions.

Cancer Immunol Res 2020 09 13;8(9):1193-1205. Epub 2020 Jul 13.

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Malignant pleural effusion (MPE) is a frequent complication of various cancers and often leads to a poor quality of life, prognosis, and life expectancy, and its management remains palliative. New approaches that can effectively treat MPE are highly desirable. Here, we show that methotrexate (MTX)-packaging tumor cell-derived microparticles (MTX-MP) act as an effective immunotherapeutic agent to treat patients with MPE by mobilizing and activating neutrophils. We find that MTX-MP perfusion via a pleural catheter elicits the recruitment of neutrophils in patients through macrophage-released CXCL1 and CXCL2. By performing experiments, we find that the recruited neutrophils are activated and release reactive oxygen species (ROS) and neutrophil extracellular trap (NET) to kill tumor cells. Neutrophil-released NETs were also able to seal off the damaged endothelium, facilitating MPE resolution and in tumor-bearing mice. These findings reveal the potential for use of cell-derived materials to package drugs as an immunotherapeutic agent against MPE.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0789DOI Listing
September 2020

Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma.

Nat Biomed Eng 2020 07 6;4(7):743-753. Epub 2020 Jul 6.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients' overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.
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http://dx.doi.org/10.1038/s41551-020-0583-0DOI Listing
July 2020

Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity.

Nat Cell Biol 2020 06 4;22(6):716-727. Epub 2020 May 4.

Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.
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http://dx.doi.org/10.1038/s41556-020-0510-3DOI Listing
June 2020

Glycogen metabolism regulates macrophage-mediated acute inflammatory responses.

Nat Commun 2020 04 14;11(1):1769. Epub 2020 Apr 14.

Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.

Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls macrophage-mediated inflammatory responses. IFN-γ/LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y in macrophages. The UDPG/P2Y signaling pathway not only upregulates the expression of STAT1 via activating RARβ but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases.
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http://dx.doi.org/10.1038/s41467-020-15636-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156451PMC
April 2020

Molecular and Functional Characterization of , an NAC Transcription Factor From Pepper ( L.).

Front Plant Sci 2020 4;11:14. Epub 2020 Feb 4.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Horticulture, Northwest A&F University, Yangling, China.

NAC (NAM, ATAF1/2, and CUC2) proteins are the plant-specific transcription factors (TFs) which are important in plant response to abiotic stresses. However, knowledge about the functional role that NACs play in pepper abiotic stress tolerance is limited. In this study, we isolated a NAC TF gene, , from pepper ( L.), where the protein is localized in the nucleus and functions as a transcriptional activator. expression is induced by low and high temperatures, osmotic stress, salt, gibberellic acid (GA), methyl-jasmonic acid (MeJA), salicylic acid (SA), and abscisic acid (ABA). To understand the function of in the abiotic stress responsep, we used virus-induced gene silencing in pepper to knockdown the and overexpressed the in . The results showed that pepper seedlings in which was silenced, showed more damage than the control pepper plants after cold, NaCl, and mannitol treatments. Correspondingly increased electrolyte leakage, a higher level of malondialdehyde (MDA), HO, and superoxide radicals were found after cold treatments. -silenced seedlings exhibited lower chlorophyll content while -overexpressed s plants had higher germination rate and fresh weight after mannitol and NaCl treatments. We also reported 18 proteins that potentially interact with CaNAC035 and may participate in processes such as the stress response, resistance, and photosynthesis. Our results suggest that is a positive regulator of abiotic stress tolerance in pepper which acts through multiple signaling pathways.
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http://dx.doi.org/10.3389/fpls.2020.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011960PMC
February 2020

Enhanced Glycogen Metabolism Supports the Survival and Proliferation of HPV-Infected Keratinocytes in Condylomata Acuminata.

J Invest Dermatol 2020 08 29;140(8):1513-1523.e5. Epub 2020 Jan 29.

Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Condylomata acuminata (CA) is caused by human papillomavirus (HPV) infections of keratinocytes and is a common sexually transmitted disease. The main clinical feature and risk of CA is the high recurrence of genital warts formed by infected keratinocytes. Metabolic reprogramming of most types of mammalian cells including keratinocytes can provide energy and intermediates essential for their survival. Here, we report that HPV infection develops a hypoxic microenvironment in CA warts by inducing the accumulation of glycogen and increased glycogen metabolism in the infected keratinocytes in a hypoxia-inducible factor 1α (HIF-1α) -dependent pathway. Our in vitro studies show that the increased glycogen metabolism is essential for the survival and proliferation of keratinocytes. Regarding its mechanism of action, glycogenolysis generates glucose-1-phosphate that fluxes into the pentose phosphate pathway and, then, generates abundant nicotinamide adenine dinucleotide phosphate, thereby ensuring high levels of glutathione in keratinocytes under hypoxia. The abrogation of glycogen synthesis and glycogenolysis decreases the ratio of glutathione and glutathione disulfide and increases the level of ROS, further resulting in the impairment of keratinocyte survival. Collectively, our work offers an insight into the metabolic reprogramming in the development of CA and implies that the intervention of glycogen metabolism would be a promising therapeutic target for CA.
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http://dx.doi.org/10.1016/j.jid.2020.01.010DOI Listing
August 2020
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