Publications by authors named "Yongbin Chen"

47 Publications

miR-133b targets NCAPH to promote β-catenin degradation and reduce cancer stem cell maintenance in non-small cell lung cancer.

Signal Transduct Target Ther 2021 Jul 7;6(1):252. Epub 2021 Jul 7.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

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http://dx.doi.org/10.1038/s41392-021-00555-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260594PMC
July 2021

PirB functions as an intrinsic suppressor in hippocampal neural stem cells.

Aging (Albany NY) 2021 06 13;13(12):16062-16071. Epub 2021 Jun 13.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.

Neural stem cells play pivotal roles during prenatal development and throughout life. Here, we report that Paired immunoglobulin-like receptor B (PirB) functions as a suppressor during brain neurogenesis in the adult mouse. PirB expression increased with age during development, and its deficiency promoted neural stem cell proliferation and differentiation and . Furthermore, we detected an increase in Type 1 neural stem cells in PirB-deficient mice compared to their wild-type littermates. PirB deficiency promoted stemness marker gene expression of Sox2 and KLF4 by activating Akt1 phosphorylation. These findings suggest that PirB inhibits the self-renewal and differentiation capacities of neural stem cells. Thus, PirB may have the potential to serve as a therapeutic target for treatment of reduced neurogenesis in adults due to aging or other pathological conditions.
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http://dx.doi.org/10.18632/aging.203134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266311PMC
June 2021

A single mutation underlying phenotypic convergence for hypoxia adaptation on the Qinghai-Tibetan Plateau.

Cell Res 2021 Jun 7. Epub 2021 Jun 7.

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

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http://dx.doi.org/10.1038/s41422-021-00517-6DOI Listing
June 2021

Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression.

Front Cell Dev Biol 2021 11;9:678209. Epub 2021 May 11.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China.

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) not only initiate and sustain uncontrolled cell proliferation but also resistant to conventional clinical therapies including temozolomide (TMZ) dependent chemotherapy and radiotherapy, implying that there is an urgent need to identify new therapeutic strategies especially specific targeting GSCs. Here, we provide evidence showing that ivacaftor commonly applied in cystic fibrosis therapy acts as a potent inhibitor for GSCs maintenance. We found that ivacaftor promotes cellular apoptosis and represses patient-derived xenograft (PDX) tumor growth . In addition, we demonstrate that ivacaftor decreases stemness marker gene expressions of GSCs, including CD133, CD44, and Sox2. In summary, our findings reveal that ivacaftor inhibits glioblastoma progression via specifically eliminating GSCs, which opens a new avenue for GBM clinical therapy in the future.
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http://dx.doi.org/10.3389/fcell.2021.678209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147559PMC
May 2021

The role of m6A modification in the biological functions and diseases.

Signal Transduct Target Ther 2021 Feb 21;6(1):74. Epub 2021 Feb 21.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, 650223, Kunming, Yunnan, China.

N-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.
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http://dx.doi.org/10.1038/s41392-020-00450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897327PMC
February 2021

Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT.

Cell Mol Biol Lett 2020 7;25:45. Epub 2020 Oct 7.

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong 510080 Guangzhou, P. R. China.

Background: Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH). Serotonin (5-hydroxytryptamine, 5-HT) can induce abnormal proliferation of PASMCs. The role of miR-361-3p in serotonin-induced abnormal PASMCs proliferation remains unclear.

Methods: The miR-361-3p level was analyzed in plasma from PAH patients and normal controls and in human PASMCs (hPASMCs) using RT-PCR. The hPASMCs were transfected with an miR-361-3p mimic and then treated with serotonin. Untransfected hPASMCs were used as the control. Cell proliferation was evaluated using an MTS assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. The cell cycle stages were evaluated using flow cytometry. The association between miR-361-3p and serotonin transporter (SERT) was determined using a luciferase reporter assay and anti-AGO2 RNA immunoprecipitation assay. The protein expression was evaluated via western blotting.

Results: The miR-361-3p level was lower in plasma from PAH patients than in plasma from the any of the normal control subjects. The mean pulmonary arterial pressure, pulmonary vascular resistance and pulmonary vascular resistance index were higher in PAH patients whose miR-361-3p level was lower than the median value for patients than in those whose miR-361-3p level was higher than the median. Serotonin treatment reduced miR-361-3p expression in the hPASMCs. MiR-361-3p overexpression suppressed cell proliferation, promoted apoptosis, induced G1 arrest, and decreased the phosphorylation level of ERK1/2 in serotonin-treated hPASMCs. SERT was identified as an miR-361-3p target. Its overexpression alleviated the effect of miR-361-3p overexpression on serotonin-induced hPASMC proliferation and upregulation of phosphorylated ERK1/2.

Conclusions: The miR-361-3p level is lower in the plasma of PAH patients. Upregulation of miR-361-3p suppresses serotonin-induced proliferation of hPASMCs by targeting SERT. Our results suggest that miR-361-3p is a potential therapeutic target in PAH.
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http://dx.doi.org/10.1186/s11658-020-00237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542879PMC
June 2021

Hypoxia and cancer related pathology.

Cancer Lett 2020 08 19;486:1-7. Epub 2020 May 19.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China. Electronic address:

Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.
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http://dx.doi.org/10.1016/j.canlet.2020.05.002DOI Listing
August 2020

PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation.

Theranostics 2020 19;10(8):3767-3778. Epub 2020 Feb 19.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.

Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both and xenograft tumor formation , by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
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http://dx.doi.org/10.7150/thno.43142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069097PMC
May 2021

Elevated serum circ_0068481 levels as a potential diagnostic and prognostic indicator in idiopathic pulmonary arterial hypertension.

Pulm Circ 2019 Oct-Dec;9(4):2045894019888416. Epub 2019 Nov 29.

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.

Circular RNAs have continuous, stable, and covalently closed circular structures and are not easily degraded by nucleases, thus they are ideal serum biomarkers for detecting diseases. However, research is still lacking on circular RNAs as diagnostic and prognostic markers for idiopathic pulmonary arterial hypertension. This study investigated the potential role of serum circ_0068481 levels in idiopathic pulmonary arterial hypertension diagnosis and prognosis. This prospective cohort study enrolled 82 patients with idiopathic pulmonary arterial hypertension between January 2016 and July 2018 at Guangdong Provincial People's Hospital. Serum circ_0068481 levels were measured using quantitative reverse transcription-polymerase chain reaction. Baseline data, including clinical background, hemodynamic variables, and biochemical variables, were collected. Receiver operating characteristic curves were used to investigate diagnostic effect, the Kaplan-Meier method was used to estimate survival rates, and univariate analysis of prognostic factors was performed with a Cox proportional hazard model. We found that serum circ_0068481 expression levels were significantly higher in patients with idiopathic pulmonary arterial hypertension and had higher sensitivity and specificity for predicting idiopathic pulmonary arterial hypertension. Additionally, we found that circ_0068481 expression correlated significantly with heart function, 6-min walk distance, serum N-terminal pro-B-type natriuretic peptide, serum HS, the 6th World Symposium on Pulmonary Hypertension risk stratification, right heart failure, and patient death. Moreover, serum circ_0068481 levels were elevated in patients with idiopathic pulmonary arterial hypertension and right heart failure and were able to predict right heart failure. Serum circ_0068481 levels were also elevated in patients who died with idiopathic pulmonary arterial hypertension and were able to predict poorer clinical outcomes. Circ_0068481 is a novel and noninvasive biomarker for diagnosing idiopathic pulmonary arterial hypertension and predicting poor clinical outcome in patients with idiopathic pulmonary arterial hypertension.
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http://dx.doi.org/10.1177/2045894019888416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886280PMC
November 2019

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Nat Commun 2019 10 25;10(1):4892. Epub 2019 Oct 25.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, mA modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.
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http://dx.doi.org/10.1038/s41467-019-12801-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814821PMC
October 2019

Phosphorylation of Ci/Gli by Fused Family Kinases Promotes Hedgehog Signaling.

Dev Cell 2019 09 3;50(5):610-626.e4. Epub 2019 Jul 3.

Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address:

Hedgehog (Hh) signaling culminates in the conversion of the latent transcription factor Cubitus interruptus (Ci)/Gli into its activator form (Ci/Gli), but the underlying mechanism remains poorly understood. Here, we demonstrate that Hh stimulates the phosphorylation of Ci by the Ser/Thr kinase Fused (Fu) and that Fu-mediated phosphorylation of Ci promotes its activation. We find that Fu directly phosphorylates Ci on Ser218 and Ser1230, which primes its further phosphorylation by CK1 on adjacent sties. These phosphorylation events alter Ci binding to the pathway inhibitor Suppressor of fused (Sufu) and facilitate the recruitment of Transportion and the transcriptional coactivator CBP. Furthermore, we provide evidence that Sonic hedgehog (Shh) activates Gli2 by stimulating its phosphorylation on conserved sites through the Fu-family kinases ULK3 and mFu/STK36 in a manner depending on Gli2 ciliary localization. Hence, Fu-family kinase-mediated phosphorylation of Ci/Gli serves as a conserved mechanism that activates the Hh pathway transcription factor.
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http://dx.doi.org/10.1016/j.devcel.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736714PMC
September 2019

The therapeutic role of inhibition of miR-328 on pulmonary carcinoma induced by chlamydia pneumoniae through targeting histone H2AX.

Cancer Biomark 2018 Dec 27. Epub 2018 Dec 27.

Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.

Lung cancer represents a major healthy concern due to high incidence and morality. Increasing evidences showed critical regulatory role of microRNA (miR) in cell growth, differentiation and apoptosis. It has been indicated that the level of miR-328 is abnormally up regulated in lung cancer cell line, which is correlated with cell apoptosis. An in vitro lung cancer model was established through induction of chlamydia pneumonia. Western blot and real-time quantitative PCR were used to measure miR-328 level and its effects on histone H2AX expression. Bioinformatics analysis and luciferase reporter gene assay were to determine if H2AX was the direct target of miR-328. TUNEL assay, AV-PI staining and Caspase-3 activity assay measured the effect of the decrease of miR-328 on lung cancer cell apoptosis at both in vivo and in vitro level. Bioinformatics analysis predicted histone H2AX as the target of miR-328 during the regulation of lung cancer. Both in vivo and in vitro knockdown of miR-328 up-regulated H2AX expression and elevated TUNEL-positive cell number. In vivo down-regulation of miR-328 decreased incidence of lung cancer induced by chlamydia pneumoniae, suppressed tumor volume, increased caspase 3 activity, and facilitated tumor cell apoptosis. Histone protein H2AX serves as the target of miR-328 and participates in lung cancer regulation. Suppression of miR-328 level promotes lung cancer tissue apoptosis, which provides novel target for lung cancer therapy.
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http://dx.doi.org/10.3233/CBM-181999DOI Listing
December 2018

Author Correction: Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.

Nat Commun 2018 11 16;9(1):4905. Epub 2018 Nov 16.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China.

In the original version of this Article, the affiliation details for Qiushuo Shen incorrectly omitted 'Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China'. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240073PMC
November 2018

Hedgehog signalling in the tumourigenesis and metastasis of osteosarcoma, and its potential value in the clinical therapy of osteosarcoma.

Cell Death Dis 2018 06 13;9(6):701. Epub 2018 Jun 13.

Department of Orthopaedics, Bone and Soft Tissue Tumors Research Center of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China.

The Hedgehog (Hh) signalling pathway is involved in cell differentiation, growth and tissue polarity. This pathway is also involved in the progression and invasion of various human cancers. Osteosarcoma, a subtype of bone cancer, is commonly seen in children and adolescents. Typically, pulmonary osteosarcoma metastases are especially difficult to control. In the present paper, we summarise recent studies on the regulation of osteosarcoma progression and metastasis by downregulating Hh signalling. We also summarise the crosstalk between the Hh pathway and other cancer-related pathways in the tumourigenesis of various cancers. We further summarise and highlight the therapeutic value of potential inhibitors of Hh signalling in the clinical therapy of human cancers.
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http://dx.doi.org/10.1038/s41419-018-0647-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999604PMC
June 2018

Long-Zhi Decoction Medicated Serum Promotes Angiogenesis in Human Umbilical Vein Endothelial Cells Based on Autophagy.

Evid Based Complement Alternat Med 2018 7;2018:6857398. Epub 2018 May 7.

Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Ischemic stroke (IS) is a fatal subtype of stroke that lacks effective treatments. Angiogenesis following IS is an effective response that mediates brain recovery and repair. Our previous study demonstrated that long-zhi decoction (LZD), a Chinese herbal formula, promoted angiogenesis in rats of IS model. To further investigate the association between the proangiogenic mechanism of an LZD-medicated serum and cellular autophagy, we evaluated its promotional effect on angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. We used HUVECs subjected to HO to induce injury and observed the effects of the LZD-medicated serum treatment. Cell-based assays included proliferation, migration, and tube formation. To assess the extent of autophagy, transmission electron microscopy was used to measure the number of autophagosomes. Immunofluorescence and Western blotting were performed to evaluate the autophagy-related protein of LC3-II and Beclin-1. The LZD-medicated serum promoted proliferation, migration, and tube formation in HUVECs. The LZD-medicated serum also increased the autophagosomes and the autophagic protein expressions of LC3-II and Beclin-1. The proangiogenic and autophagic activity of LZD provides new cogitations to its clinical application and may lead to potential drug development for treating various vascular diseases, especially in the elderly, in the future.
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http://dx.doi.org/10.1155/2018/6857398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964498PMC
May 2018

Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.

Nat Commun 2018 02 26;9(1):838. Epub 2018 Feb 26.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.

Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.
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http://dx.doi.org/10.1038/s41467-018-03247-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826945PMC
February 2018

Radio-protective effect and mechanism of 4-Acetamido-2,2,6,6- tetramethylpiperidin-1-oxyl in HUVEC cells.

Environ Health Prev Med 2017 Mar 24;22(1):14. Epub 2017 Mar 24.

School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.

Objectives: To search for more effective radiation protectors with minimal toxicity, a water-soluble nitroxides Acetamido-Tempol (AA-Tempol) was evaluated for potential radioprotective properties in HUVEC cells (Human Umbilical Vein Endothelial cell line).

Methods: To study the anti-radiation effect of AA-Tempol in cell culture, the viability of irradiated HUVEC cells using a clonogenic survival assay was examined. The anti-apoptosis effects of AA-Tempol using Annexin V/propidium iodide staining in a flow cytometry assay was also evaluated. To elucidate the molecular mechanism of the anti-apoptosis effect of AA-Tempol against X-radiation induced HUVEC cell apoptosis, the expression of Bax, Bcl-2 and p53 and caspase-3 were examined. The changes in the level of malondialdehyde (MDA) and glutathione (GSH) in HUVEC cells after X-radiation were also investigated.

Results: Pretreatment of the HUVEC cells colony with AA-Tempol 1 h before X-radiation significantly increased the colony survival (p < 0.05) compared with the cells without pretreatment. This demonstrates that AA-Tempol provides an effective radiation protection in the irradiated HUVEC cells, thus reducing apoptosis from 20.1 ± 1.3% in 8 Gy X-radiated cells to 12.2 ± 0.9% (1.0 mmol/L AA-Tempol) in AA-Tempo pretreated HUVEC cells. This implies that 1.0 mM AA-Tempol treatment significantly block the increase of caspase-3 activity in radiated HUVEC cells (P < 0.01), causing down-regulation in expressions of Bax and P53 and up-regulation in the expression of Bcl-2. Pretreatment with AA-Tempol also decreased the MDA activities (P < 0.01) and increase the GSH level (P < 0.05) in HUVEC cells compared to the 8Gy X-radiated cells without pretreatment.

Conclusions: These observations indicate that AA-Tempol is a potential therapeutic agent against the radiation damage.
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http://dx.doi.org/10.1186/s12199-017-0616-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664570PMC
March 2017

The Effects of Audiovisual Inputs on Solving the Cocktail Party Problem in the Human Brain: An fMRI Study.

Cereb Cortex 2018 10;28(10):3623-3637

Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.

At cocktail parties, our brains often simultaneously receive visual and auditory information. Although the cocktail party problem has been widely investigated under auditory-only settings, the effects of audiovisual inputs have not. This study explored the effects of audiovisual inputs in a simulated cocktail party. In our fMRI experiment, each congruent audiovisual stimulus was a synthesis of 2 facial movie clips, each of which could be classified into 1 of 2 emotion categories (crying and laughing). Visual-only (faces) and auditory-only stimuli (voices) were created by extracting the visual and auditory contents from the synthesized audiovisual stimuli. Subjects were instructed to selectively attend to 1 of the 2 objects contained in each stimulus and to judge its emotion category in the visual-only, auditory-only, and audiovisual conditions. The neural representations of the emotion features were assessed by calculating decoding accuracy and brain pattern-related reproducibility index based on the fMRI data. We compared the audiovisual condition with the visual-only and auditory-only conditions and found that audiovisual inputs enhanced the neural representations of emotion features of the attended objects instead of the unattended objects. This enhancement might partially explain the benefits of audiovisual inputs for the brain to solve the cocktail party problem.
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http://dx.doi.org/10.1093/cercor/bhx235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676955PMC
October 2018

Long noncoding nature brain-derived neurotrophic factor antisense is associated with poor prognosis and functional regulation in non-small cell lung caner.

Tumour Biol 2017 May;39(5):1010428317695948

Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.

In this study, we evaluated the prognostic potential and functional regulation of human nature antisense, brain-derived neurotrophic factor antisense, in non-small cell lung cancer. Non-small cell lung cancer carcinoma and adjacent non-carcinoma lung tissues were extracted from 151 patients. Their endogenous brain-derived neurotrophic factor antisense expression levels were compared by quantitative reverse transcription polymerase chain reaction. Clinical relevance between endogenous brain-derived neurotrophic factor antisense expression level and patients' clinicopathological variances or overall survival was analyzed. The potential of brain-derived neurotrophic factor antisense being an independent prognostic factor in non-small cell lung cancer was also evaluated. In in vitro non-small cell lung cancer cell lines, brain-derived neurotrophic factor antisense was upregulated through forced overexpression. The effects of brain-derived neurotrophic factor antisense upregulation on non-small cell lung cancer in vitro survival, proliferation, and migration were evaluated by viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and transwell assays. Brain-derived neurotrophic factor antisense is lowly expressed in non-small cell lung cancer carcinoma tissues and further downregulated in late-stage carcinomas. Brain-derived neurotrophic factor antisense downregulation was closely associated with non-small cell lung cancer patients' advanced tumor, lymph node, metastasis stage, and positive status of lymph node metastasis, and confirmed to be an independent prognostic factor for patients' poor overall survival. In non-small cell lung cancer A549 and H226 cell lines, forced overexpression of brain-derived neurotrophic factor antisense did not alter cancer cell viability but had significantly tumor suppressive effect in inhibiting in vitro non-small cell lung cancer proliferation and migration. Endogenous brain-derived neurotrophic factor antisense in non-small cell lung cancer carcinoma could be a potential biomarker for predicting patients' prognosis. Overexpressing brain-derived neurotrophic factor antisense may also have a therapeutic potential in inhibiting non-small cell lung cancer tumor growth.
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http://dx.doi.org/10.1177/1010428317695948DOI Listing
May 2017

Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy.

EBioMedicine 2017 May 11;19:49-59. Epub 2017 Apr 11.

Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China.

Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53.
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http://dx.doi.org/10.1016/j.ebiom.2017.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440603PMC
May 2017

The Relationship between Inflammatory Marker Levels and Hepatitis C Virus Severity.

Gastroenterol Res Pract 2016 20;2016:2978479. Epub 2016 Dec 20.

Department of Infection Control, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China.

Red cell distribution width (RDW) and platelet-lymphocyte ratio (PLR) have been studied in a variety of etiological diseases. We aim to investigate the relationship between RDW and PLR and the severity of hepatitis C virus- (HCV-) related liver disease. We included fifty-two chronic HCV and 42 HCV-related cirrhosis patients and 84 healthy controls. Hematological and virological parameters and liver function biomarkers of HCV-related patients at admission were recorded. RDW, RDW-to-platelet (RPR), and 1/PLR values in HCV-related cirrhosis patients were significantly higher than in chronic HCV patients and healthy controls (all < 0.001). The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4) scores in HCV-related cirrhosis patients were significantly higher than in chronic HCV patients (all < 0.001). The areas under the curve of the RDW, RPR, and 1/PLR for predicting cirrhosis were 0.791, 0.960, and 0.713, respectively. Bivariate logistic regression analysis showed that RDW could independently predict the presence of cirrhosis in chronic HCV patients. RDW, RPR, and PLR may be potential markers for estimating HCV severity.
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http://dx.doi.org/10.1155/2016/2978479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206414PMC
December 2016

Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.

PLoS Biol 2016 06 9;14(6):e1002481. Epub 2016 Jun 9.

Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.

Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.
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http://dx.doi.org/10.1371/journal.pbio.1002481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900676PMC
June 2016

MicroRNAs in apoptosis, autophagy and necroptosis.

Oncotarget 2015 Apr;6(11):8474-90

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496162PMC
http://dx.doi.org/10.18632/oncotarget.3523DOI Listing
April 2015

Discriminative analysis of Parkinson's disease based on whole-brain functional connectivity.

PLoS One 2015 17;10(4):e0124153. Epub 2015 Apr 17.

Department of Radiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong, China.

Recently, there has been an increasing emphasis on applications of pattern recognition and neuroimaging techniques in the effective and accurate diagnosis of psychiatric or neurological disorders. In the present study, we investigated the whole-brain resting-state functional connectivity patterns of Parkinson's disease (PD), which are expected to provide additional information for the clinical diagnosis and treatment of this disease. First, we computed the functional connectivity between each pair of 116 regions of interest derived from a prior atlas. The most discriminative features based on Kendall tau correlation coefficient were then selected. A support vector machine classifier was employed to classify 21 PD patients with 26 demographically matched healthy controls. This method achieved a classification accuracy of 93.62% using leave-one-out cross-validation, with a sensitivity of 90.47% and a specificity of 96.15%. The majority of the most discriminative functional connections were located within or across the default mode, cingulo-opercular and frontal-parietal networks and the cerebellum. These disease-related resting-state network alterations might play important roles in the pathophysiology of this disease. Our results suggest that analyses of whole-brain resting-state functional connectivity patterns have the potential to improve the clinical diagnosis and treatment evaluation of PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401568PMC
April 2016

Apoptosis, autophagy, necroptosis, and cancer metastasis.

Mol Cancer 2015 Feb 21;14:48. Epub 2015 Feb 21.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.

Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death to metastasize. This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis, autophagy, and necroptosis involved in the regulation of cancer metastasis.
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http://dx.doi.org/10.1186/s12943-015-0321-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343053PMC
February 2015

Hydrometallurgical recovery of metal values from sulfuric acid leaching liquor of spent lithium-ion batteries.

Waste Manag 2015 Apr 22;38:349-56. Epub 2015 Jan 22.

Key Laboratory of Resources Chemistry of Nonferrous Metals, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.

Environmentally hazardous substances contained in spent Li-ion batteries, such as heavy metals and nocuous organics, will pose a threat to the environment and human health. On the other hand, the sustainable recycling of spent lithium-ion batteries may bring about environmental and economic benefits. In this study, a hydrometallurgical process was adopted for the comprehensive recovery of nickel, manganese, cobalt and lithium from sulfuric acid leaching liquor from waste cathode materials of spent lithium-ion batteries. First, nickel ions were selectively precipitated and recovered using dimethylglyoxime reagent. Recycled dimethylglyoxime could be re-used as precipitant for nickel and revealed similar precipitation performance compared with fresh dimethylglyoxime. Then the separation of manganese and cobalt was conducted by solvent extraction method using cobalt loaded D2EHPA. And McCabe-Thiele isotherm was employed for the prediction of the degree of separation and the number of extraction stages needed at specific experimental conditions. Finally, cobalt and lithium were sequentially precipitated and recovered as CoC2O4 ⋅ 2H2O and Li2CO3 using ammonium oxalate solution and saturated sodium carbonate solution, respectively. Recovery efficiencies could be attained as follows: 98.7% for Ni; 97.1% for Mn, 98.2% for Co and 81.0% for Li under optimized experimental conditions. This hydrometallurgical process may promise a candidate for the effective separation and recovery of metal values from the sulfuric acid leaching liquor.
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http://dx.doi.org/10.1016/j.wasman.2014.12.023DOI Listing
April 2015

Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator.

Proc Natl Acad Sci U S A 2014 Dec 15;111(52):E5651-60. Epub 2014 Dec 15.

Departments of Developmental Biology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235;

Hedgehog (Hh) signaling governs many developmental processes by regulating the balance between the repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms of Cubitus interruptus (Ci)/glioma-associated oncogene homolog (Gli) transcription factors. Although much is known about how Ci(R)/Gli(R) is controlled, the regulation of Ci(A)/Gli(A) remains poorly understood. Here we demonstrate that Casein kinase 1 (CK1) sustains Hh signaling downstream of Costal2 and Suppressor of fused (Sufu) by protecting Ci(A) from premature degradation. We show that Hh stimulates Ci phosphorylation by CK1 at multiple Ser/Thr-rich degrons to inhibit its recognition by the Hh-induced MATH and BTB domain containing protein (HIB), a substrate receptor for the Cullin 3 family of E3 ubiquitin ligases. In Hh-receiving cells, reduction of CK1 activity accelerated HIB-mediated degradation of Ci(A), leading to premature loss of pathway activity. We also provide evidence that Gli(A) is regulated by CK1 in a similar fashion and that CK1 acts downstream of Sufu to promote Sonic hedgehog signaling. Taken together, our study not only reveals an unanticipated and conserved mechanism by which phosphorylation of Ci/Gli positively regulates Hh signaling but also provides the first evidence, to our knowledge, that substrate recognition by the Cullin 3 family of E3 ubiquitin ligases is negatively regulated by a kinase.
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http://dx.doi.org/10.1073/pnas.1416652111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284548PMC
December 2014

Increased levels of β-catenin, LEF-1, and HPA-1 correlate with poor prognosis for acral melanoma with negative BRAF and NRAS mutation in BRAF exons 11 and 15 and NRAS exons 1 and 2.

DNA Cell Biol 2015 Jan;34(1):69-77

1 Department of Orthopedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province , Kunming, People's Republic of China .

To determine the expression of β-catenin, lymphoid enhancer-binding protein-1 (LEF-1), and heparanase-1 (HPA-1) and to evaluate these proteins' potential prognostic values in malignant acral melanoma without mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2, specimens from 90 patients with wild-type BRAF and NRAS were assessed and analyzed by immunohistochemistry and western blotting. The positive expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was observed in 36 (72%), 31 (62%), and 32 (64%) of the detected acral melanomas, respectively. The expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was not correlated with gender, age, or diseased body parts (p>0.05), but was significantly positively correlated with the tumor node metastasis (TNM) stage and metastasis (correlation=0.406 and 0.716, 0.397 and 0.582, 0.353 and 0.579; p=0.040 and 0.0001, 0.0040 and 0.0001, 0.0120 and 0.0001, respectively). We also observed that the increased expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was significantly correlated with decreased survival and poor prognosis (p=0.001, 0.010, and 0.023, respectively). A multifactorial analysis using Cox's regression model revealed that β-catenin, lymphoid enhancer-binding protein-1, heparanase-1, and the TNM stage were all independent factors in malignant melanoma (risk ratios were 7.294, 5.550, 5.622, and 4.794; p-values were 0.007, 0.018, 0.018, and 0.029, respectively). This study may provide the basis for the use of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 as novel targets in the treatment of malignant invasion and metastasis in acral melanoma cancer. The expression of β-catenin, LEF-1, and HPA-1 was assessed and compared in malignant melanoma with that of peritumoral tissue and benign nevus in the patients with negative mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2. The study may provide the basis for β-catenin, LEF-1, and HPA-1 as new targets in the treatment of malignant invasion and metastasis in melanoma cancer.
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http://dx.doi.org/10.1089/dna.2014.2590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281839PMC
January 2015

Meta-analysis of differentially expressed genes in osteosarcoma based on gene expression data.

BMC Med Genet 2014 Jul 14;15:80. Epub 2014 Jul 14.

Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, PR China.

Background: To uncover the genes involved in the development of osteosarcoma (OS), we performed a meta-analysis of OS microarray data to identify differentially expressed genes (DEGs) and biological functions associated with gene expression changes between OS and normal control (NC) tissues.

Methods: We used publicly available GEO datasets of OS to perform a meta-analysis. We performed Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Protein-Protein interaction (PPI) networks analysis.

Results: Eight GEO datasets, including 240 samples of OS and 35 samples of controls, were available for the meta-analysis. We identified 979 DEGs across the studies between OS and NC tissues (472 up-regulated and 507 down-regulated). We found GO terms for molecular functions significantly enriched in protein binding (GO: 0005515, P = 3.83E-60) and calcium ion binding (GO: 0005509, P = 3.79E-13), while for biological processes, the enriched GO terms were cell adhesion (GO:0007155, P = 2.26E-19) and negative regulation of apoptotic process (GO: 0043066, P = 3.24E-15), and for cellular component, the enriched GO terms were cytoplasm (GO: 0005737, P = 9.18E-63) and extracellular region (GO: 0005576, P = 2.28E-47). The most significant pathway in our KEGG analysis was Focal adhesion (P = 5.70E-15). Furthermore, ECM-receptor interaction (P = 1.27E-13) and Cell cycle (P = 4.53E-11) are found to be highly enriched. PPI network analysis indicated that the significant hub proteins containing PTBP2 (Degree = 33), RGS4 (Degree = 15) and FXYD6 (Degree = 13).

Conclusions: Our meta-analysis detected DEGs and biological functions associated with gene expression changes between OS and NC tissues, guiding further identification and treatment for OS.
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http://dx.doi.org/10.1186/1471-2350-15-80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109777PMC
July 2014

[Effects of electromagnetic pulses on apoptosis and TGF-β3 expression of mouse testis tissue].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2014 Apr;32(4):251-5

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Objective: To investigate the effects of electromagnetic pulses (EMP) on the apoptosis and transforming growth factor beta 3 (TGF-β3) expression of mouse testis tissue.

Methods: Thirty-two male BALB/c mice were randomly and equally divided into one control group and three EMP treated groups, which were whole-body exposed to EMP at 200 kV/m with 100, 200, and 400 pulses, respectively. The control group received no treatment. The pathological changes and cell apoptosis in testis tissue were analyzed by TUNEL assay. The mRNA expression of TGF-β3 in testis tissue was determined by RT-PCR, and the protein expression of TGF-β3 was determined by immunohistochemistry and Western blot.

Results: No obvious pathological changes were found in testis tissue after EMP exposure at 200 kV/m with 100 and 200 pulses. However, after EMP exposure with 400 pulses, degeneration and shedding of testis tissue, accompanied by significant increase in apoptosis rate (P < 0.05), was observed. The RT-PCR, immunohistochemistry, and Western blot showed that the expression of TGF-β3 mRNA and protein increased significantly after EMP exposure with 400 pulses as compared with that of the control group (P < 0.05).

Conclusion: EMP exposure at 200 kV/m with 400 pulses increases the incidence of apoptosis and expression of TGF-β3 in mouse testis tissue, which is potentially one of the mechanisms by which EMP increases blood-testis barrier permeability in mice.
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April 2014
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