Yanzhong Hu

Henan University

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Xiukun Cui

Henan University

Hongmei Mu

Kaifeng University

Fengyan Zhang

First Affiliated Hospital of Zhengzhou University

Mingli Wang

Yanshan University

Jing Li

Fourth Affiliated Hospital of China Medical University

Yuanfang Ma

Henan University

Qiang Lou

Peking University

Shulian Li

Henan University

Xuyan Peng

First Affiliated Hospital of Zhengzhou University

Zhengyan Yang

Henan University

Cooperative Institutions

Henan University

First Affiliated Hospital of Zhengzhou University

First Affiliated Hospital of Henan University

Chinese Academy of Sciences

University of Chinese Academy of Sciences

Sun Yat-sen University

China Agricultural University

Sichuan University

Chinese Academy of Medical Sciences & Peking Union Medical College

Shanghai Jiao Tong University

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Expression of mRNAs, miRNAs, and lncRNAs in Human Trabecular Meshwork Cells Upon Mechanical Stretch

Investigative Ophthalmology & Visual Science (2020)

Hannah Youngblood Jingwen Cai Michelle Drewry Inas Helwa Eric Hu

Purpose: Intraocular pressure (IOP), the primary risk factor for primary open-angle glaucoma, is determined by resistance to aqueous outflow through the trabecular meshwork (TM). IOP homeostasis relies on TM responses to mechanical stretch. To model the effects of elevated IOP on the TM, this study sought to identify coding and non-coding RNAs differentially expressed in response to mechanical stretch. Methods: Monolayers of TM cells from non-glaucomatous donors (n = 5) were cultured in the presence or absence of 15% mechanical stretch, 1 cycle/second, for 24 hours using a computer-controlled Flexcell unit. We profiled mRNAs and lncRNAs with stranded total RNA sequencing and microRNA (miRNA) expression with NanoString-based miRNA assays. We used two-tailed paired t-tests for mRNAs and long non-coding RNAs (lncRNAs) and the Bioconductor limma package for miRNAs. Gene ontology and pathway analyses were performed with WebGestalt. miRNA–mRNA interactions were identified using Ingenuity Pathway Analysis Integrative miRNA Target Finder software. Validation of differential expression was conducted using droplet digital PCR. Results: We identified 219 mRNAs, 42 miRNAs, and 387 lncRNAs with differential expression in TM cells upon cyclic mechanical stretch. Pathway analysis indicated significant enrichment of genes involved in steroid biosynthesis, glycerolipid metabolism, and extracellular matrix–receptor interaction. We also identified several miRNA master regulators (miR-125a-5p, miR-30a-5p, and miR-1275) that regulate several mechanoresponsive genes. Conclusions: To our knowledge, this is the first demonstration of the differential expression of coding and non-coding RNAs in a single set of cells subjected to cyclic mechanical stretch. Our results validate previously identified, as well as novel, genes and pathways.

Bioconductor

10.1167/iovs.61.5.2

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Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin‐8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer

Journal of Gastroenterology and Hepatology (2022)

Zhengyan Yang Wenjuan Wan Pai Zhang Shuangfeng Wang Zhi Zhao

Liver cancer stem cells (LCSCs) cause therapeutic refractoriness and relapse in hepatocellular carcinoma. Heat shock factor 1 (HSF1) plays versatile roles in multiple cancers. However, the role of HSF1 in LCSCs is not well understood. This study investigated the function and signal mechanisms of HSF1 in maintaining LCSC phenotypes.We established two LCSC lines, HepG2-R and HuH-7-R. Constitutive activation of HSF1 was observed in these LCSCs. Specific short hairpin RNAs (shRNAs) and chemical inhibitors were used to identify the relationship between HSF1 expression and LCSCs phenotypes.We revealed a concomitant activation modality involving HSF1 and STAT3 in LCSCs and liver cancer tissues. We also found that liver cancer patients whose HSF1 and STAT3 mRNA expression levels were high presented with unfavorable clinicopathological characteristics. Moreover, the secretion of interleukin-8 (IL-8) was elevated in the LCSC medium and was directly regulated by HSF1 at the transcriptional level. In turn, IL-8 activated HSF1 and STAT3 signaling, and a neutralizing IL-8 antibody inhibited HSF1 and STAT3 activity, reduced cancer stem cell marker expression, and decreased LCSC microsphere formation. Simultaneous intervention with HSF1 and STAT3 led to synergistically suppressed stemness acquisition and growth suppression in the LCSCs in vivo and in vitro.Our study indicates that IL-8 mediates the crosstalk between the HSF1 and Stat3 signaling pathways in LCSCs and that the combined targeting of HSF1 and STAT3 is a promising treatment strategy for patients with advanced liver cancer.

HSF1

10.1111/jgh.16040

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RNA interference may suppress stress granule formation by preventing argonaute 2 recruitment

AJP Cell Physiology (2018)

Qiang Lou Yanzhong Hu Yanfang Ma Zheng Dong

RNA-induced silencing complex (RISC) is formed during RNA interference (RNAi), whereas stress granules (SG) are assembled in response to cellular stress. Here, we demonstrate an interesting connection between RISC and SG that may involve argonaute 2 (Ago2), a core component of RISC. We analyzed SG induction by arsenite, the commonly used SG inducer. SG formation was suppressed in heat shock transcription factor 1 (Hsf1) or hypoxia-inducible factor-1α (Hif1α) shRNA-transfected cells but not in Hsf1 or Hif1α-knockout cells, suggesting that RNAi per se (rather than gene deficiency) may account for the suppressive effect on SG. In support, the suppressive effect of RNAi on SG formation was reversed by the RISC-loading inhibitor aurintricarboxylic acid. In non-RNAi cells, arsenite induced the accumulation of Ago2 in SGs as shown by its colocalization and coimmunoprecipitation with SG proteins, but Ago2 was not recruited to SG in the cells with RNAi. Consistently, arsenite induced the dissociation of Ago2 from RISC proteins in non-RNAi cells but not in RNAi cells. CRISPR-Cas9-medicated ablation of Ago2 attenuated SG formation during arsenite treatment, suggesting a critical role of Ago2 in SG assembly. Together, these results indicate that RISC and SG may compete for some key components, such as Ago2. In response to cellular stress, Ago2 is recruited for SG assembly; however, during RNAi, Ago2 is held in RISC, becoming unavailable for SG formation.

Argonaute

Stress granule

RNA-induced silencing complex

10.1152/ajpcell.00251.2018

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Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats

Science Translational Medicine (2020)

Yaohui Wang Hailong Zhang Zhizeng Wang Yinxiang Wei Mingli Wang

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.

10.1126/scitranslmed.aaw3172

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Association and Regulation of Heat Shock Transcription Factor 4b with both Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Dual-Specificity Tyrosine Phosphatase DUSP26

Molecular and Cellular Biology (2006)

Yanzhong Hu Nahid F. Mivechi

The heat shock transcription factors (Hsfs) activate the stress-inducible expression of heat shock proteins (Hsps) and other molecular chaperones in response to stress and, therefore, play an essential role in protein disaggregation and protein folding. In humans, missense mutation in the hsf4 gene causes cataract, and mice bearing a targeted disruption of the hsf4 gene exhibit defects in lens fiber cell differentiation and early cataract formation. Here, we show that Hsf4b is a direct target of the mitogen-activated protein (MAP) kinase extracellular signal-related kinase (ERK) and that phosphorylation of Hsf4b by ERK leads to increased ability of Hsf4b to bind DNA. Surprisingly, Hsf4b also interacts with an ERK-specific dual-specificity tyrosine phosphatase named DUSP26 identified from a yeast two-hybrid screen. While activated ERK phosphorylates Hsf4b, DUSP26 controls the activity of ERK, leading to phosphorylation/dephosphorylation of Hsf4b, altering its ability to bind DNA. Therefore, DUSP26 interaction with Hsf4b places this transcription factor within a regulatory circuit in the MAP kinase signaling pathway.

ASK1

Heat shock factor

10.1128/mcb.26.8.3282-3294.2006

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Citations (67)

[Construction of eukaryotic plasmid expression Hsf4b and phosphorylation of Hsf4b by MAP kinase P38].

PubMed (2010)

Zheng-yi Ma Jun Zhang Xueli Li Zi-ming Xi Yanzhong Hu

Ton construct eukaryotic plasmid expressing Hsf4B and to investigate Hsf4b is phosphorylated by MAP kinase P38:The total RNA of human heart tissues were prepared. Hsf4b cDNA were then synthesized with RT-PCR. The PCR products were digested with Kpn I and EcoR I and subcloned into pcDNA3.0, pcDNA-Flag-Hsf4b was transfected into HEK293T cells. The expression of Hsf4b was testified with Western blotting. The interaction between Hsf4b and P38 was assayed by immunoprecipitation. In vivo pull down GST demonstrated that Hsf4B (196-493) could interact with P38, P38 phosphorylation of Hsf4b were testified with Kinase assay.We subcloned the human cDNA of Hsf4b into eukaryotic expression vectors pcDNA3 and PEBG, and Hsf4b was overexpressed in HEK293T cells. Further studies demonstrated that Hsf4b could interact with and phosphorylated by MAP kinase P38.Hsf4b could interact with and phosphorylated by MAP kinase P38. Our results will provide more evidence for understanding the signal regulation of Hsf4b transcription activity during lens development.

Immunoprecipitation

HEK 293 cells

Cyclin-dependent kinase 9

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Knockout of DNase1l1l abrogates lens denucleation process and causes cataract in zebrafish

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2020)

Jing Zhang Wenwen Cui Chunxiao Du Yu-Wen Huang Xiahui Pi

10.1016/j.bbadis.2020.165724

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The engineered expression of secreted HSPB5-Fc in CHO cells exhibits cytoprotection in vitro

BMC Biotechnology (2021)

Jing Li Jingjing Yu Wenxian Xue Huili Huang Longjun Yan

Abstract Background HSPB5 is an ATP-independent molecular chaperone that is induced by heat shock or other proteotoxic stresses. HSPB5 is cytoprotective against stress both intracellularly and extracellularly. It acts as a potential therapeutic candidate in ischemia-reperfusion and neurodegenerative diseases. Results In this paper, we constructed a recombinant plasmid that expresses and extracellularly secrets a HSPB5-Fc fusion protein (sHSPB5-Fc) at 0.42 μg/ml in CHO-K1 cells. This sHSPB5-Fc protein contains a Fc-tag at the C-terminal extension of HSPB5, facilitating protein-affinity purification. Our study shows that sHSPB5-Fc inhibits heat-induced aggregation of citrate synthase in a time and dose dependent manner in vitro. Administration of sHSPB5-Fc protects lens epithelial cells against cisplatin- or UVB-induced cell apoptosis. It also decreases GFP-Htt ex1 -Q74 insolubility, and reduces the size and cytotoxicity of GFP-Htt ex1 -Q74 aggregates in PC-12 cells. Conclusion This recombinant sHSPB5-Fc exhibits chaperone activity to protect cells against proteotoxicity.

Cytoprotection

Chaperone (clinical)

10.1186/s12896-021-00700-y

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Extracellular HSP90 promotes differentiation of lens epithelial cells to fiber cells by activating LRP1‐YAP‐PROX1 axis

The FASEB Journal (2023)

Jing Li Jingjing Yu Weikang Huang Fan Sang Junmin Li

Abstract Capsular residual lens epithelial cells (CRLEC) undergo differentiation to fiber cells for lens regeneration or tansdifferentiation to myofibroblasts leading to posterior capsular opacification (PCO) after cataract surgery. The underlying regulatory mechanism remains unclear. Using human lens epithelial cell lines and the ex vivo cultured rat lens capsular bag model, we found that the lens epithelial cells secrete HSP90α extracellularly (eHSP90) through an autophagy‐associated pathway. Administration of recombinant GST‐HSP90α protein or its M‐domain induces the elongation of rat CRLEC cells with concomitant upregulation of the crucial fiber cell transcriptional factor PROX1and its downstream targets, β‐ and γ‐crystallins and structure proteins. This regulation is abolished by PROX1 siRNA. GST‐HSP90α upregulates PROX1 by binding to LRP1 and activating LRP1‐AKT mediated YAP degradation. The upregulation of GST‐HSP90α on PROX1 expression and CRLEC cell elongation is inhibited by LRP1 and AKT inhibitors, but activated by YAP‐1 inhibitor (VP). These data demonstrated that the capsular residue epithelial cells upregulate and secrete eHSP90α, which in turn drive the differentiation of lens epithelial cell to fiber cells. The recombinant HSP90α protein is a potential novel differentiation regulator during lens regeneration.

LRP1

Lens Fiber

10.1096/fj.202201187rr

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Citations (2)

Genesis of the Jurassic Dongfengbeishan porphyry Mo deposit in Eastern Yanbian, NE China inferred from molybdenite Re–Os and zircon U–Pb ages, and whole-rock elemental and zircon Hf isotopic compositions

Journal of Asian Earth Sciences (2017)

Weikang Guo Qingdong Zeng Bo Zhang Yanzhong Hu

Molybdenite

Fractional crystallization (geology)

Geochronology

10.1016/j.jseaes.2017.12.035

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Citations (14)