Publications by authors named "Jie Ran"

33 Publications

CYLD deficiency causes auditory neuropathy due to reduced neurite outgrowth.

J Clin Lab Anal 2021 May 2:e23783. Epub 2021 May 2.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

Background: Auditory neuropathy is a cause of hearing loss that has been studied in a number of animal models. Signal transmission from hair cells to spiral ganglion neurons plays an important role in normal hearing. CYLD is a microtubule-binding protein, and deubiquitinase involved in the regulation of various cellular processes. In this study, we used Cyld knockout (KO) mice and nerve cell lines to examine whether CYLD is associated with auditory neuropathy.

Methods: Hearing of Cyld KO mice was studied using the TDT RZ6 auditory physiology workstation. The expression and localization of CYLD in mouse cochlea and cell lines were examined by RT-PCR, immunoblotting, and immunofluorescence. CYLD expression was knocked down in SH-SY5Y cells by shRNAs and in PC12 and N2A cells by siRNAs. Nerve growth factor and retinoic acid were used to induce neurite outgrowth, and the occurrence and length of neurites were statistically analyzed between knockdown and control groups.

Results: Cyld KO mice had mild hearing impairment. Moreover, CYLD was widely expressed in mouse cochlear tissues and different nerve cell lines. Knocking down CYLD significantly reduced the length and proportion of neurites growing from nerve cells.

Conclusions: The abnormal hearing of Cyld KO mice might be caused by a decrease in the length and number of neurites growing from auditory nerve cells in the cochlea, suggesting that CYLD is a key protein affecting hearing.
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http://dx.doi.org/10.1002/jcla.23783DOI Listing
May 2021

Transcriptome Analysis of Needle and Root of in Response to Continuous Drought Stress.

Plants (Basel) 2021 Apr 14;10(4). Epub 2021 Apr 14.

College of Forestry, Guizhou University, Guiyang 550025, China.

Lamb. is an important coniferous tree species in ecological environment construction and sustainable forestry development. The function of gene gradual change and coexpression modules of needle and root parts of under continuous drought stress is unclear. The physiological and transcriptional expression profiles of seedlings from 1a half-sibling progeny during drought stress were measured and analyzed. As a result, under continuous drought conditions, needle peroxidase (POD) activity and proline content continued to increase. The malondialdehyde (MDA) content in roots continuously increased, and the root activity continuously decreased. The needles of seedlings may respond to drought mainly through regulating abscisic acid (ABA) and jasmonic acid (JA) hormone-related pathways. Roots may provide plant growth through fatty acid β-oxidative decomposition, and peroxisomes may contribute to the production of ROS, resulting in the upregulation of the antioxidant defense system. roots and needles may implement the same antioxidant mechanism through the glutathione metabolic pathway. This study provides basic data for identifying the drought response mechanisms of the needles and roots of .
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http://dx.doi.org/10.3390/plants10040769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070838PMC
April 2021

Piccolo is essential for the maintenance of mouse retina but not cochlear hair cell function.

Aging (Albany NY) 2021 Apr 21;13(8):11678-11695. Epub 2021 Apr 21.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

Piccolo is a presynaptic protein with high conservation among different species, and the expression of Piccolo is extensive in vertebrates. Recently, a small fragment of Piccolo (Piccolino), arising due to the incomplete splicing of intron 5/6, was found to be present in the synapses of retinas and cochleae. However, the comprehensive function of Piccolo in the retina and cochlea remains unclear. In this study, we generated knockout mice using CRISPR-Cas9 technology to explore the function of Piccolo. Unexpectedly, whereas no abnormalities were found in the cochlear hair cells of the mutant mice, significant differences were found in the retinas, in which two layers (the outer nuclear layer and the outer plexiform layer) were absent. Additionally, the amplitudes of electroretinograms were significantly reduced and pigmentation was observed in the fundoscopy of the mutant mouse retinas. The expression levels of Bassoon, a homolog of Piccolo, as well as synapse-associated proteins CtBP1, CtBP2, Kif3A, and Rim1 were down-regulated. The numbers of ribbon synapses in the retinas of the mutant mice were also reduced. Altogether, the phenotype of -/- mice resembled the symptoms of retinitis pigmentosa (RP) in humans, suggesting might be a candidate gene of RP and indicates knockout mice are a good model for elucidating the molecular mechanisms of RP.
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http://dx.doi.org/10.18632/aging.202861DOI Listing
April 2021

Nicotinamide Mononucleotide Combined With TKSN041 Reduces the Photoaging Damage in Murine Skin by Activating AMPK Signaling Pathway.

Front Pharmacol 2021 25;12:643089. Epub 2021 Mar 25.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China.

Long-term exposure to UVB (280-320 nm) can cause oxidative skin damage, inflammatory injury, and skin cancer. Research on nicotinamide mononucleotide (NMN) and lactic acid bacteria (LAB) with regard to antioxidation, anti-inflammation, and prevention of other age-related diseases has received increasing attention. In the present study, the antioxidant analysis showed that NMN combined with TKSN041 ( TKSN041) has a high scavenging ability on hydroxyl (OH), 2, 2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt (ABTS) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH), and it also possess a good total antioxidant capacity. The animal experimental results show that NMN combined with LAB maintained normal liver morphology of mice and reduced pathological damage to murine skin. NMN combined with LAB significantly increased the serum levels of total superoxide dismutase (T-SOD), catalase (CAT), and interleukin (IL)-10, but reduced the levels of malondialdehyde, advanced glycation end products, tumor necrosis factor (TNF)-α, and IL-6. NMN combined with LAB increased T-SOD, CAT, IL-10, Na-K-ATPase, and NAD levels in the skin, but reduced TNF-α level in the skin. NMN combined with LAB increased the mRNA expression levels of SOD1, CAT, glutathione (GSH), inhibitor of NF-κB (IκB-α), IL-10, AMP-activated protein kinase (AMPK), adaptor protein, phosphotyros ineinteraction, PH domain and leucine zipper containing 1 (APPL1), peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), and forkhead transcription factor O (FOXO) in the skin and liver, but decreased the mRNA expression levels of nuclear factor (NF)-κBp65, TNF-α, IL-6, and rapamycin target protein (mTOR). NMN combined with LAB increased the protein expression levels of AMPK, IκB-α, SOD1, and CAT in the skin tissues and reduced protein expression of NF-κBp65. NMN combined with TKSN041 improved murine skin damage caused by UVB irradiation, and the protective mechanism may be related to activation of the AMPK signaling pathway. The results of this study are expected to provide a reference for preventing and the treating skin photoaging.
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http://dx.doi.org/10.3389/fphar.2021.643089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027253PMC
March 2021

Enkurin domain containing 1 (ENKD1) regulates the proliferation, migration and invasion of non-small cell lung cancer cells.

Asia Pac J Clin Oncol 2021 Mar 15. Epub 2021 Mar 15.

Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China.

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality worldwide. NSCLC has an aggressive phenotype and poor prognosis, and is quite heterogeneous without effective and specific targeted therapies. Therefore, exploring new tumor markers and drug targets for NSCLC is crucial towards individualized treatment. Here, we demonstrate that enkurin domain containing 1 (ENKD1), a protein with unknown structure and function, is significantly downregulated in NSCLC tumor tissues compared with their non-tumor counterparts. We also show that ENKD1 expression is decreased in NSCLC cells compared to normal human lung epithelial cells. EdU incorporation, wound healing, and transwell invasion assays reveal that ENKD1 regulates the proliferation, migration, and invasion of NSCLC cells. Collectively, these results suggest that ENKD1 plays an important role in NSCLC progression and that ENKD1 is a tumor marker and a potential molecular drug target for the treatment of NSCLC patients.
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http://dx.doi.org/10.1111/ajco.13550DOI Listing
March 2021

Dual Roles of GSNOR1 in Cell Death and Immunity in Tetraploid .

Front Plant Sci 2021 10;12:596234. Epub 2021 Feb 10.

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China.

S-nitrosoglutathione reductase 1 (GSNOR1) is the key enzyme that regulates cellular homeostasis of nitrosylation. Although extensively studied in , the roles of GSNOR1 in tetraploid species have not been investigated previously. To study the function of GSNOR1, we knocked out two genes simultaneously in using clustered regularly interspaced short palindromic repeats (CRISPR)/caspase 9 (Cas9) technology. To our surprise, spontaneous cell death occurred on the leaves of the CRISPR/Cas9 lines but not on those of the wild-type (WT) plants, suggesting that GSNOR1 negatively regulates cell death. The natural cell death on the CRISPR/Cas9 lines could be a result from interactions between overaccumulated nitric oxide (NO) and hydrogen peroxide (HO). This spontaneous cell death phenotype was not affected by knocking out two genes and thus was independent of the salicylic acid (SA) pathway. Unexpectedly, we found that the knockout plants displayed a significantly ( < 0.001) enhanced resistance to paraquat-induced cell death compared to WT plants, suggesting that GSNOR1 functions as a positive regulator of the paraquat-induced cell death. The increased resistance to the paraquat-induced cell death of the knockout plants was correlated with the reduced level of HO accumulation. Interestingly, whereas the gene-mediated resistance to (TMV) was significantly enhanced ( < 0.001), the resistance to pv. DC3000 was significantly reduced ( < 0.01) in the knockout lines. In summary, our results indicate that GSNOR1 functions as both positive and negative regulator of cell death under different conditions and displays distinct effects on resistance against viral and bacterial pathogens.
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http://dx.doi.org/10.3389/fpls.2021.596234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902495PMC
February 2021

USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase-dependent manner.

Asia Pac J Clin Oncol 2020 Oct 13. Epub 2020 Oct 13.

Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.

Ubiquitin-specific protease 21 (USP21) has been implicated in several types of cancer. It promotes or suppresses tumor growth in a cell-context dependent manner. Cholangiocarcinoma is a malignant tumor with a high mortality rate. However, the role of USP21 in cholangiocarcinoma remains unknown. Here, we identify that the level of USP21 is upregulated in cholangiocarcinoma using bioinformatics analysis and confirm this elevation in RBE cell lines. Cell counting and 5-ethynyl-2'-deoxyuridine incorporation assays reveal that USP21 promotes the proliferation of cholangiocarcinoma. Wound healing and transwell assays demonstrate that USP21 accelerates RBE cell migration. In addition, rescue assays reveal that reintroduction of USP21 wildtype other than the deubiquitinase-deficient C221A mutant restores USP21 depletion-induced attenuation in cell proliferation and migration, indicative of the requirement of the deubiquitinase activity. Collectively, these data indicate that USP21 is critically involved in cholangiocarcinoma tumorigenesis and may be an effective target for the treatment of cholangiocarcinoma.
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http://dx.doi.org/10.1111/ajco.13480DOI Listing
October 2020

LncRNA KCNQ1OT1 affects cell proliferation, apoptosis and fibrosis through regulating miR-18b-5p/SORBS2 axis and NF-ĸB pathway in diabetic nephropathy.

Diabetol Metab Syndr 2020 3;12:77. Epub 2020 Sep 3.

Department of Endocrinology, First People's Hospital of Jingzhou, Shashi District, No. 8 Hangkong Road, Jingzhou, 434000 Hubei China.

Background: It has been reported that long non-coding RNAs (lncRNAs) play vital roles in diabetic nephropathy (DN). Our study aims to research the function of lncRNA KCNQ1OT1 in DN cells and the molecular mechanism.

Methods: Human glomerular mesangial cells (HGMCs) and human renal glomerular endothelial cells (HRGECs) were cultured in high glucose (30 mM) condition as models of DN cells. KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) and miR-18b-5p levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mRNA and protein levels of Sorbin and SH3 domain-containing protein 2 (SORBS2), Type IV collagen (Col-4), fibronectin (FN), transcriptional regulatory factor-beta 1 (TGF-β1), Twist, NF-κB and STAT3 were measured by qRT-PCR and western blot. Cell viability was detected by cell counting kit-8 (CCK-8) assay for selecting the proper concentration of glucose treatment. Additionally, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry assay were employed to determine cell proliferation and apoptosis, respectively. The targets of KCNQ1OT1 was predicted by online software and confirmed by dual-luciferase reporter assay.

Results: KCNQ1OT1 and SORBS2 were elevated in DN. Both knockdown of KCNQ1OT1 and silencing of SORBS2 restrained proliferation and fibrosis and induced apoptosis in DN cells. Besides, Overexpression of SORBS2 restored the KCNQ1OT1 knockdown-mediate effects on proliferation, apoptosis and fibrosis in DN cells. In addition, miR-18b-5p served as a target of KCNQ1OT1 as well as targeted SORBS2. KCNQ1OT1 knockdown repressed NF-ĸB pathway.

Conclusion: KCNQ1OT1 regulated DN cells proliferation, apoptosis and fibrosis via KCNQ1OT1/miR-18b-5p/SORBS2 axis and NF-ĸB pathway.
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http://dx.doi.org/10.1186/s13098-020-00585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469295PMC
September 2020

Emerging Roles of the Selective Autophagy in Plant Immunity and Stress Tolerance.

Int J Mol Sci 2020 Aug 31;21(17). Epub 2020 Aug 31.

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China.

Autophagy is a conserved recycling system required for cellular homeostasis. Identifications of diverse selective receptors/adaptors that recruit appropriate autophagic cargoes have revealed critical roles of selective autophagy in different biological processes in plants. In this review, we summarize the emerging roles of selective autophagy in both biotic and abiotic stress tolerance and highlight the new features of selective receptors/adaptors and their interactions with both the cargoes and Autophagy-related gene 8s (ATG8s). In addition, we review how the two major degradation systems, namely the ubiquitin-proteasome system (UPS) and selective autophagy, are coordinated to cope with stress in plants. We especially emphasize how plants develop the selective autophagy as a weapon to fight against pathogens and how adapted pathogens have evolved the strategies to counter and/or subvert the immunity mediated by selective autophagy.
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http://dx.doi.org/10.3390/ijms21176321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503401PMC
August 2020

Targeting the photoreceptor cilium for the treatment of retinal diseases.

Authors:
Jie Ran Jun Zhou

Acta Pharmacol Sin 2020 Nov 4;41(11):1410-1415. Epub 2020 Aug 4.

Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Ji-nan, 250014, China.

Photoreceptors, as polarised sensory neurons, are essential for light sensation and phototransduction, which are highly dependent on the photoreceptor cilium. Structural defects and/or dysfunction of the photoreceptor cilium caused by mutations in photoreceptor-specific genes or common ciliary genes can lead to retinal diseases, including syndromic and nonsyndromic diseases. In this review, we describe the structure and function of the photoreceptor cilium. We also discuss recent findings that underscore the dysregulation of the photoreceptor cilium in various retinal diseases and the therapeutic potential of targeting ciliary genes in these diseases.
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http://dx.doi.org/10.1038/s41401-020-0486-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656575PMC
November 2020

Erratum: Microtubule-Associated Protein Mdp3 Promotes Breast Cancer Growth and Metastasis: Erratum.

Theranostics 2020;10(12):5527. Epub 2020 Apr 12.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

[This corrects the article DOI: 10.7150/thno.9727.].
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http://dx.doi.org/10.7150/thno.45566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196284PMC
April 2020

ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia.

Dev Cell 2020 05 9;53(3):287-299.e5. Epub 2020 Apr 9.

Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China; State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address:

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. However, the pathogenesis and molecular mechanisms underlying ROP remain elusive. Herein, using the oxygen-induced retinopathy (OIR) mouse model of ROP, we demonstrate that disassembly of photoreceptor connecting cilia is an early event in response to oxygen changes. Histone deacetylase 6 (HDAC6) is upregulated in the retina of OIR mice and accumulates in the transition zone of connecting cilia. We also show that in response to oxygen changes, apoptosis signal-regulating kinase 1 (ASK1) is activated and phosphorylates HDAC6, blocking its ubiquitination by von Hippel-Lindau and subsequent degradation by the proteasome. Moreover, depletion of HDAC6 or inhibition of the ASK1/HDAC6 axis protects mice from oxygen-change-induced pathological changes of photoreceptors. These findings reveal a critical role for ASK1/HDAC6-mediated connecting cilium disassembly in the OIR mouse model of ROP and suggest a potential value of ASK1/HDAC6-targeted agents for prevention of this disease.
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http://dx.doi.org/10.1016/j.devcel.2020.03.010DOI Listing
May 2020

Silencing GmFLS2 enhances the susceptibility of soybean to bacterial pathogen through attenuating the activation of GmMAPK signaling pathway.

Plant Sci 2020 Mar 24;292:110386. Epub 2019 Dec 24.

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang Province, 321004, China. Electronic address:

The plasma membrane (PM)-localized receptor-like kinases (RLKs) play important roles in pathogen defense. One of the first cloned RLKs is the Arabidopsis receptor kinase FLAGELLIN SENSING 2 (FLS2), which specifically recognizes a conserved 22 amino acid N-terminal sequence of Pseudomonas syringae pv.tomato DC3000 (Pst) flagellin protein (flg22). Although extensively studied in Arabidopsis, the functions of RLKs in crop plants remain largely uninvestigated. To understand the roles of RLKs in soybean (Glycine max), GmFLS2 was silenced via virus induced gene silencing (VIGS) mediated by Bean pod mottle virus (BPMV). No significant morphological differences were observed between GmFLS2-silenced plants and the vector control plants. However, silencing GmFLS2 significantly enhanced the susceptibility of the soybean plants to Pseudomonas syringae pv.glycinea (Psg). Kinase activity assay showed that silencing GmFLS2 significantly reduced the phosphorylation level of GmMPK6 in response to flg22 treatment. However, reduced phosphorylation level of both GmMPK3 and GmMPK6 in response to Psg infection was observed in GmFLS2-silenced plants, implying that defense response is likely transduced through activation of the downstream GmMAPK signaling pathway upon recognition of bacterial pathogen by GmFLS2. The core peptides of flg22 from Pst and Psg were highly conserved and only 4 amino acid differences were seen at their N-termini. Interestingly, it appeared that the Psg-flg22 was more effective in activating soybean MAPKs than activating Arabidopsis MAPKs, and conversely, Pst-flg22 was more effective in activating Arabidopsis MAPKs than activating soybean MAPKs, suggesting that the cognate recognition is more potent than heterologous recognition in activating downstream signaling. Taken together, our results suggest that the function of FLS2 is conserved in immunity against bacteria pathogens across different plant species.
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http://dx.doi.org/10.1016/j.plantsci.2019.110386DOI Listing
March 2020

Mixed-lineage leukemia protein 2 suppresses ciliary assembly by the modulation of actin dynamics and vesicle transport.

Cell Discov 2019 25;5:33. Epub 2019 Jun 25.

1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of the Ministry of Education, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071 China.

Primary cilia are critically involved in the coordination of diverse signaling pathways and ciliary defects are associated with a variety of human diseases. The past decades have witnessed great progress in the core machinery orchestrating ciliary assembly. However, the upstream epigenetic cues that direct ciliogenesis remain elusive. Herein, we demonstrate that mixed-lineage leukemia protein 2 (MLL2), a histone methyltransferase, plays a negative role in ciliogenesis. RNA-sequencing analysis reveals that the expression of five actin-associated proteins is significantly downregulated in MLL2-depleted cells. Overexpression of these proteins partially rescues ciliary abnormality elicited by MLL2 depletion. Our data also show that actin dynamics is remarkably changed in MLL2-depleted cells, resulting in the impairment of cell adhesion, spreading, and motility. In addition, MLL2 depletion promotes ciliary vesicle trafficking to the basal body in an actin-related manner. Together, these results reveal that MLL2 inhibits ciliogenesis by modulating actin dynamics and vesicle transport, and suggest that alteration of MLL2 may contribute to the pathogenesis of cilium-associated diseases.
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http://dx.doi.org/10.1038/s41421-019-0100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591415PMC
June 2019

Targeted inhibition of histone deacetylase 6 in inflammatory diseases.

Authors:
Jie Ran Jun Zhou

Thorac Cancer 2019 03 21;10(3):405-412. Epub 2019 Jan 21.

Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, China.

Targeting epigenetic modification of gene expression represents a promising new approach under investigation for the treatment of inflammatory diseases. Accumulating evidence suggests that epigenetic mechanisms, such as histone modification, play a crucial role in a number of inflammatory diseases, including rheumatoid arthritis, asthma, and contact hypersensitivity. Consistent with this role, histone deacetylase (HDAC) inhibitors have shown efficacy in the treatment of inflammatory diseases. In particular, selective inhibitors of HDAC6, a cytoplasmic member of the HDAC family that contains two deacetylase domains, are under investigation as a potential treatment strategy for inflammatory diseases due to their ability to regulate inflammatory cells and cytokines. Here, we review recent findings highlighting the critical roles of HDAC6 in a variety of inflammatory diseases, and discuss the therapeutic potential of HDAC6 inhibitors in these settings.
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http://dx.doi.org/10.1111/1759-7714.12974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397899PMC
March 2019

Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications.

Cell Res 2019 02 14;29(2):171-173. Epub 2018 Nov 14.

State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and Pharmacy, Nankai University, 300071, Tianjin, China.

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http://dx.doi.org/10.1038/s41422-018-0114-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355847PMC
February 2019

Response characteristics of the cat somatosensory cortex following the mechanical stimulation to endodontically treated teeth with overextension.

Neurosci Lett 2019 01 5;690:132-137. Epub 2018 Oct 5.

Vision Research Laboratory, School of Life Sciences, The State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200433, China. Electronic address:

The overextension of filling materials may take place accidentally during an endodontic root canal treatment. Previous studies to understand the correlation between overfilling and paresthesia of teeth were inconsistent. In this study, an intrinsic signal optical imaging technique was employed as the objective tool to compare the response characteristics of the cat somatosensory cortex following mechanical stimulation applied to endodontically treated teeth with overextension (ETTWO) and natural teeth. Based on the evoked cortical response, the signal strength of the ETTWO was found to be significantly higher than that of the natural teeth. However, the tactile threshold of the ETTWO was significantly lower than that of the natural teeth. It was concluded that the tactile function of ETTWO is more sensitive than that of natural teeth, and that the overextension of filling materials can cause hyperesthesia of teeth after root canal treatment.
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http://dx.doi.org/10.1016/j.neulet.2018.10.006DOI Listing
January 2019

Non-canonical functions of the mitotic kinesin Eg5.

Thorac Cancer 2018 08 21;9(8):904-910. Epub 2018 Jun 21.

College of Life Sciences, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University, Jinan, China.

Kinesins are widely expressed, microtubule-dependent motors that play vital roles in microtubule-associated cellular activities, such as cell division and intracellular transport. Eg5, also known as kinesin-5 or kinesin spindle protein, is a member of the kinesin family that contributes to the formation and maintenance of the bipolar mitotic spindle during cell division. Small-molecule compounds that inhibit Eg5 activity have been shown to impair spindle assembly, block mitotic progression, and possess anti-cancer activity. Recent studies focusing on the localization and functions of Eg5 in plants have demonstrated that in addition to spindle organization, this motor protein has non-canonical functions, such as chromosome segregation and cytokinesis, that have not been observed in animals. In this review, we discuss the structure, function, and localization of Eg5 in various organisms, highlighting the specific role of this protein in plants. We also propose directions for the future studies of novel Eg5 functions based on the lessons learned from plants.
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http://dx.doi.org/10.1111/1759-7714.12792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068462PMC
August 2018

Response characteristics of the cat somatosensory cortex following the mechanical stimulation to non-vital and vital canine.

Neuroscience 2017 Nov 28;363:34-42. Epub 2017 Jul 28.

Vision Research Laboratory, School of Life Sciences, The State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200433, China. Electronic address:

Patients sometimes complain that non-vital teeth after root canal treatment (RCT) are paresthesia compared with vital teeth, and previous psychological studies on the tactile sensibility of non-vital teeth remained controversial. In the present study, intrinsic signal optical imaging, which served as an objective tool, was employed to compare the cortex response characteristics following forces applied to the cat non-vital and vital canines. Based on the evoked cortical responses, the response threshold, signal strength, spatial pattern, temporal dynamics and the preference of force direction, they were not significantly different between vital and non-vital canines. It seemed that the tactile sensibility of vital and non-vital teeth was comparable at the cortical response level, and pulpal receptors were not concerned in tactile function.
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http://dx.doi.org/10.1016/j.neuroscience.2017.07.041DOI Listing
November 2017

Discovery of Centrosomal Protein 70 as an Important Player in the Development and Progression of Breast Cancer.

Am J Pathol 2017 Mar 5;187(3):679-688. Epub 2017 Jan 5.

Institute of Biomedical Sciences, College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University, Jinan, China. Electronic address:

Centrosome abnormalities have been implicated in the development and progression of breast cancer. However, the molecular players involved in the above processes remain largely uncharacterized. Herein, we identify centrosomal protein 70 (Cep70) as an important factor that mediates breast cancer growth and metastasis. Cep70 is up-regulated in breast cancer tissues and cell lines, and its expression is closely correlated with several clinicopathologic variables associated with breast cancer progression. Mechanistic studies reveal that the up-regulation of Cep70 in breast cancer occurs at the mRNA level and is independent of gene amplification. Cep70 promotes breast cancer cell proliferation and colony formation in vitro and increases tumor growth in mice. In addition, Cep70 stimulates breast cancer cell migration and invasion in vitro. Bioluminescence imaging analysis further shows that Cep70 enhances breast cancer lung metastasis in mice. Together, these results demonstrate a critical role for Cep70 in the development and progression of breast cancer and have important implications in the diagnosis and therapy of this malignancy.
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http://dx.doi.org/10.1016/j.ajpath.2016.11.005DOI Listing
March 2017

Phosphorylation of EB1 regulates the recruitment of CLIP-170 and p150glued to the plus ends of astral microtubules.

Oncotarget 2017 Feb;8(6):9858-9867

Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Shandong Normal University, Jinan, Shandong 250014, China.

Phosphorylation of end-binding protein 1 (EB1), a key member of microtubule plus end-tracking proteins (+TIPs), by apoptosis signal-regulating kinase 1 (ASK1) has been demonstrated to promote the stability of astral microtubules during mitosis by stimulating the binding of EB1 to microtubule plus ends. However, the roles of other members of the +TIPs family in ASK1/EB1-mediated regulation of astral microtubules are unknown. Herein, we show that ASK1-mediated phosphorylation of EB1 enhances the localization of cytoplasmic linker protein 170 (CLIP-170) and p150glued to the plus ends of astral microtubules. Depletion of ASK1 or expression of phospho-deficient or phospho-mimetic EB1 mutants results in changes in the levels of plus-end localized CLIP-170 or p150glued. Mechanistic studies reveal that EB1 phosphorylation promotes its interactions with CLIP-170 and p150glued, thereby recruiting these +TIPs to microtubules. Structural analysis suggests that serine-40 is the primary phosphorylation site on EB1 that exerts these effects. Together, these findings provide novel insight into the molecular mechanisms that regulate the interactions of EB1 with other +TIPs.
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http://dx.doi.org/10.18632/oncotarget.14222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354776PMC
February 2017

ASK1 controls spindle orientation and positioning by phosphorylating EB1 and stabilizing astral microtubules.

Cell Discov 2016 4;2:16033. Epub 2016 Oct 4.

Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Key Laboratory of Molecular and Nano Probes of the Ministry of Education, Shandong Normal University, Jinan, China; State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Protein Science of Tianjin, Key Laboratory of Bioactive Materials of the Ministry of Education, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.

Orientation and positioning of the mitotic spindle are involved in dictating cell division axis and cleavage site, and play important roles in cell fate determination and tissue morphogenesis. However, how spindle movement is controlled to achieve a defined alignment within the dividing cell is not fully understood. Here, we describe an unexpected role for apoptosis signal-regulating kinase 1 (ASK1) in regulating spindle behavior. We find that ASK1 is required for proper mitotic progression and daughter cell adhesion to the substratum. ASK1 interacts with end-binding protein 1 (EB1) and phosphorylates EB1 at serine 40, threonine 154 and threonine 206, enhancing its binding to the plus ends of astral microtubules. Consequently, astral microtubules are stabilized and therefore capable of mediating spindle interaction with the cell cortex, a requirement for spindle movement. These findings reveal a previously undiscovered function of ASK1 in cell division by regulating spindle orientation and positioning, and point to the importance of protein phosphorylation in the regulation of spindle behavior.
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http://dx.doi.org/10.1038/celldisc.2016.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048754PMC
October 2016

Functional interplay between cylindromatosis and histone deacetylase 6 in ciliary homeostasis revealed by phenotypic analysis of double knockout mice.

Oncotarget 2016 May;7(19):27527-37

Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance of Shandong Province, Key Laboratory of Molecular and Nano Probes of The Ministry of Education, Shandong Normal University, Jinan 250014, China.

Cilia are present in most vertebrate tissues with a wide variety of functions, and abnormalities of cilia are linked to numerous human disorders. However, the molecular events underlying ciliary homeostasis are poorly understood. In this study, we generated double knockout (DKO) mice for the deubiquitinase cylindromatosis (CYLD) and histone deacetylase 6 (HDAC6), two critical ciliary regulators. The Cyld/Hdac6 DKO mice were phenotypically normal and showed no obvious variances in weight or behavior compared with their wild-type littermates. Strikingly, Cyld loss-induced ciliary defects in the testis, trachea, and kidney were abrogated in the Cyld/Hdac6 DKO mice. In addition, the diminished α-tubulin acetylation and impaired sonic hedgehog signaling caused by loss of Cyld were largely restored by simultaneous deletion of Hdac6. We further found by immunofluorescence microscopy a colocalization of CYLD and HDAC6 at the centrosome/basal body and, interestingly, loss of Cyld promoted the localization of HDAC6 at the centrosome/basal body. These findings provide physiological insight into the ciliary role of the CYLD/HDAC6 axis and suggest a functional interplay between these two proteins in ciliary homeostasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053669PMC
http://dx.doi.org/10.18632/oncotarget.8374DOI Listing
May 2016

Ciliopathies: Does HDAC6 Represent a New Therapeutic Target?

Trends Pharmacol Sci 2016 Feb 2;37(2):114-119. Epub 2015 Dec 2.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address:

Cilia are cellular appendages with critical roles in sensing and transducing environmental signals and guiding fluid flow. Consistent with these diverse activities, defects in ciliary structure or function have been implicated in a variety of human diseases, collectively known as 'ciliopathies'. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes through its deacetylase and ubiquitin-binding activities. There is accumulating evidence that HDAC6 is a major driver of ciliary disassembly. Small-molecule compounds that inhibit HDAC6 have been demonstrated to restore ciliary structure and function in several different ciliopathies. Here, we discuss recent findings that highlight the important role for HDAC6 in mediating ciliary disassembly and the potential for HDAC6-selective inhibitors as therapeutics for specific ciliopathies.
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http://dx.doi.org/10.1016/j.tips.2015.11.002DOI Listing
February 2016

Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.

Sci Rep 2015 Aug 6;5:12917. Epub 2015 Aug 6.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

Cilia play important roles in sensing extracellular signals and directing fluid flow. Ciliary dysfunction is associated with a variety of diseases known as ciliopathies. Histone deacetylase 6 (HDAC6) has recently emerged as a major driver of ciliary disassembly, but little is known about the downstream players. Here we provide the first evidence that HDAC6-mediated deacetylation of α-tubulin and cortactin is critical for its induction of ciliary disassembly. HDAC6 is localized in the cytoplasm and enriched at the centrosome and basal body. Overexpression of HDAC6 decreases the levels of acetylated α-tubulin and cortactin without affecting the expression or localization of known ciliary regulators. We also find that overexpression of α-tubulin or cortactin or their acetylation-deficient mutants enhances the ability of HDAC6 to induce ciliary disassembly. In addition, acetylation-mimicking mutants of α-tubulin and cortactin counteract HDAC6-induced ciliary disassembly. Furthermore, HDAC6 stimulates actin polymerization, and inhibition of actin polymerization abolishes the activity of HDAC6 to trigger ciliary disassembly. These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis.
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http://dx.doi.org/10.1038/srep12917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526867PMC
August 2015

CYLD Regulates Noscapine Activity in Acute Lymphoblastic Leukemia via a Microtubule-Dependent Mechanism.

Theranostics 2015 2;5(7):656-66. Epub 2015 Mar 2.

1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. ; 2. Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA.

Noscapine is an orally administrable drug used worldwide for cough suppression and has recently been demonstrated to disrupt microtubule dynamics and possess anticancer activity. However, the molecular mechanisms regulating noscapine activity remain poorly defined. Here we demonstrate that cylindromatosis (CYLD), a microtubule-associated tumor suppressor protein, modulates the activity of noscapine both in cell lines and in primary cells of acute lymphoblastic leukemia (ALL). Flow cytometry and immunofluorescence microscopy reveal that CYLD increases the ability of noscapine to induce mitotic arrest and apoptosis. Examination of cellular microtubules as well as in vitro assembled microtubules shows that CYLD enhances the effect of noscapine on microtubule polymerization. Microtubule cosedimentation and fluorescence titration assays further reveal that CYLD interacts with microtubule outer surface and promotes noscapine binding to microtubules. These findings thus demonstrate CYLD as a critical regulator of noscapine activity and have important implications for ALL treatment.
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http://dx.doi.org/10.7150/thno.10844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402491PMC
January 2016

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6.

Cell Res 2014 Nov 24;24(11):1342-53. Epub 2014 Oct 24.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

Cilia are hair-like organelles extending from the cell surface with important sensory and motility functions. Ciliary defects can result in a wide range of human diseases known as ciliopathies. However, the molecular mechanisms controlling ciliogenesis remain poorly defined. Here we show that cylindromatosis (CYLD), a tumor suppressor protein harboring deubiquitinase activity, plays a critical role in the assembly of both primary and motile cilia in multiple organs. CYLD knockout mice exhibit polydactyly and various ciliary defects, such as failure in basal body anchorage and disorganization of basal bodies and axenomes. The ciliary function of CYLD is partially attributed to its deconjugation of the polyubiquitin chain from centrosomal protein of 70 kDa (Cep70), a requirement for Cep70 to interact with γ-tubulin and localize at the centrosome. In addition, CYLD-mediated inhibition of histone deacetylase 6 (HDAC6), which promotes tubulin acetylation, constitutes another mechanism for the ciliary function of CYLD. Small-molecule inhibitors of HDAC6 could partially rescue the ciliary defects in CYLD knockout mice. These findings highlight the importance of protein ubiquitination in the modulation of ciliogenesis, identify CYLD as a crucial regulator of this process, and suggest the involvement of CYLD deficiency in ciliopathies.
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http://dx.doi.org/10.1038/cr.2014.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220159PMC
November 2014

HDAC6 deacetylase activity is critical for lipopolysaccharide-induced activation of macrophages.

PLoS One 2014 16;9(10):e110718. Epub 2014 Oct 16.

Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110718PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199742PMC
December 2015

Microtubule-associated protein Mdp3 promotes breast cancer growth and metastasis.

Theranostics 2014 15;4(10):1052-61. Epub 2014 Aug 15.

1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. ; 2. Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.

Breast cancer is the most prevalent cancer in women worldwide with a high mortality rate, and the identification of new biomarkers and targets for this disease is greatly needed. Here we present evidence that microtubule-associated protein (MAP) 7 domain-containing protein 3 (Mdp3) is highly expressed in clinical samples and cell lines of breast cancer. The expression of Mdp3 correlates with clinicopathological parameters indicating breast cancer malignancy. In addition, Mdp3 promotes breast cancer cell proliferation and motility in vitro and stimulates breast cancer growth and metastasis in mice. Mechanistic studies reveal that γ-tubulin interacts with and recruits Mdp3 to the centrosome and that the centrosomal localization of Mdp3 is required for its activity to promote breast cancer cell proliferation and motility. These findings suggest a critical role for Mdp3 in the growth and metastasis of breast cancer and may have important implications for the management of this disease.
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http://dx.doi.org/10.7150/thno.9727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143944PMC
April 2015

Phosphoregulation of the dimerization and functions of end-binding protein 1.

Protein Cell 2014 Oct;5(10):795-9

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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http://dx.doi.org/10.1007/s13238-014-0081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180461PMC
October 2014