Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
August-2017 Volume 16 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
August-2017 Volume 16 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis

  • Authors:
    • Jiao Li
    • Xue Liang
    • Yuanyuan Wang
    • Zhao Xu
    • Guangping Li
  • View Affiliations / Copyright

    Affiliations: Tianjin Key Laboratory of Ionic‑Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1817-1825
    |
    Published online on: June 19, 2017
       https://doi.org/10.3892/mmr.2017.6803
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The present study aimed to explore the direct toxicity of proprotein convertase subtilisin/kexin type 9 (PCSK9) to atherosclerosis (AS) and its association with apoptotic endothelial cells. Apolipoprotein E‑/‑ mice were randomly divided into two groups, control and experimental. The control group was administered a normal diet and the experimental group was administered a high‑fat diet. After 20 weeks, the aorta was isolated and dissected. Hematoxylin and eosin staining, and immunohistochemical analysis were performed. Human umbilical vein endothelial cells were incubated with varied concentrations of oxidized low‑density lipoprotein (ox‑LDL) for different times. The apoptotic rate was detected by flow cytometry. Western blotting and reverse transcription‑quantitative polymerase chain reaction analysis were conducted to detect the expression of PCSK9, B‑cell lymphoma 2 (Bcl‑2), bcl‑2‑like protein 4 (Bax) and caspase-3. Short hairpin (sh) RNA‑PCSK9 was transfected into endothelial cells using lentiviral transfection. The expression levels of PCSK9, Bax, Bcl‑2, caspase-3 and the mitogen‑activated protein kinase (MAPK) pathway proteins were detected. The high‑fat group was successfully established as an AS model and PCSK9 was highly expressed in the AS plaque. Treatment with ox‑LDL induced apoptosis and increased mRNA and protein levels of PCSK9. PCSK9 mRNA and proteins levels were downregulated by shRNA‑PCSK9. The deficiency of PCSK9 markedly inhibited the expression of pro‑apoptotic proteins and promoted anti‑apoptotic proteins. In addition, phosphorylation of p38 and c‑Jun N‑terminal kinases was altered by shRNA‑PCSK9. Targeting of PCSK9 by shRNA‑PCSK9 may repress endothelial cell apoptosis through MAPK signaling in AS, providing a novel direction for understanding the mechanism and treatment of AS.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Pescetelli I, Zimarino M, Ghirarduzzi A and De Caterina R: Localizing factors in atherosclerosis. J Cardiovasc Med (Hagerstown). 16:824–830. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, et al: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 364:937–952. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Weber C and Noels H: Atherosclerosis: Current pathogenesis and therapeutic options. Nat Med. 17:1410–1422. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Napoli C: Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci. 1010:698–709. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Lu J, Mitra S, Wang X, Khaidakov M and Mehta JL: Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis. Antioxid Redox Signal. 15:2301–2333. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Geng YJ: Biologic effect and molecular regulation of vascular apoptosis in atherosclerosis. Curr Atheroscler Rep. 3:234–242. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Cai H and Harrison DG: Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circ Res. 87:840–844. 2000. View Article : Google Scholar : PubMed/NCBI

8 

Abifadel M, Guerin M, Benjannet S, Rabès JP, Le Goff W, Julia Z, Hamelin J, Carreau V, Varret M, Bruckert E, et al: Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 223:394–400. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Roth EM, McKenney JM, Hanotin C, Asset G and Stein EA: Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 367:1891–1900. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Lee P and Hegele RA: Current Phase II proprotein convertase subtilisin/kexin 9 inhibitor therapies for dyslipidemia. Expert Opin Investig Drugs. 22:1411–1423. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Poirier S and Mayer G: The biology of PCSK9 from the endoplasmic reticulum to lysosomes: New and emerging therapeutics to control low-density lipoprotein cholesterol. Drug Des Devel Ther. 7:1135–1148. 2013.PubMed/NCBI

12 

Leren TP: Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis. 237:76–81. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Constantinides A, Kappelle PJ, Lambert G and Dullaart RP: Plasma lipoprotein-associated phospholipase A2 is inversely correlated with proprotein convertase subtilisin-kexin type 9. Arch Med Res. 43:11–14. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

15 

Libby P, Ridker PM and Maseri A: Inflammation and atherosclerosis. Circulation. 105:1135–1143. 2002. View Article : Google Scholar : PubMed/NCBI

16 

Rioufol G, Finet G, Ginon I, André-Fouët X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF and Tabib A: Multiple atherosclerotic plaque rupture in acute coronary syndrome: A three-vessel intravascular ultrasound study. Circulation. 106:804–808. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Gu HF, Tang CK and Yang YZ: Psychological stress, immune response, and atherosclerosis. Atherosclerosis. 223:69–77. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 352:1685–1695. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Simionescu M and Antohe F: Functional ultrastructure of the vascular endothelium: Changes in various pathologies. Handb Exp Pharmacol. 41–69. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Kwon GP, Schroeder JL, Amar MJ, Remaley AT and Balaban RS: Contribution of macromolecular structure to the retention of low-density lipoprotein at arterial branch points. Circulation. 117:2919–2927. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Benn M, Nordestgaard BG, Grande P, Schnohr P and Tybjaerg-Hansen A: PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol. 55:2833–2842. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Zhang L, Yuan F, Liu P, Fei L, Huang Y, Xu L, Hao L, Qiu X, Le Y, Yang X, et al: Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: Case-control study and meta-analysis. Clin Biochem. 46:727–732. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Wu NQ and Li JJ: PCSK9 gene mutations and low-density lipoprotein cholesterol. Clin Chim Acta. 431:148–153. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Wang Y, Huang Y, Hobbs HH and Cohen JC: Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res. 53:1932–1943. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF and Fazio S: Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: Evidence for a reciprocal regulation. Circulation. 127:2403–2413. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Nguyen MA, Kosenko T and Lagace TA: Internalized PCSK9 dissociates from recycling LDL receptors in PCSK9-resistant SV-589 fibroblasts. J Lipid Res. 55:266–275. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC and Hobbs HH: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 282:18602–18612. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Mousavi SA, Berge KE and Leren TP: The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med. 266:507–519. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Plump AS and Breslow JL: Apolipoprotein E and the apolipoprotein E-deficient mouse. Annu Rev Nutr. 15:495–518. 1995. View Article : Google Scholar : PubMed/NCBI

30 

Getz GS and Reardon CA: Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol. 32:1104–1115. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Jorgensen RA: Cosuppression, flower color patterns, and metastable gene expression states. Science. 268:686–691. 1995. View Article : Google Scholar : PubMed/NCBI

32 

Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE and Mello CC: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391:806–811. 1998. View Article : Google Scholar : PubMed/NCBI

33 

Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W and Tuschl T: Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J. 20:6877–6888. 2001. View Article : Google Scholar : PubMed/NCBI

34 

Onat D, Brillon D, Colombo PC and Schmidt AM: Human vascular endothelial cells: A model system for studying vascular inflammation in diabetes and atherosclerosis. Curr Diab Rep. 11:193–202. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Berens HM and Tyler KL: The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis. J Virol. 85:3858–3871. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Sanz AB, Santamaría B, Ruiz-Ortega M, Egido J and Ortiz A: Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol. 19:1634–1642. 2008. View Article : Google Scholar : PubMed/NCBI

37 

Zhang Y, Chen N, Zhang J and Tong Y: Hsa-let-7g miRNA targets caspase-3 and inhibits the apoptosis induced by ox-LDL in endothelial cells. Int J Mol Sci. 14:22708–22720. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Aplin AE, Hogan BP, Tomeu J and Juliano RL: Cell adhesion differentially regulates the nucleocytoplasmic distribution of active MAP kinases. J Cell Sci. 115:2781–2790. 2002.PubMed/NCBI

39 

Weston CR and Davis RJ: The JNK signal transduction pathway. Curr Opin Genet Dev. 12:14–21. 2002. View Article : Google Scholar : PubMed/NCBI

40 

Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, et al: RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 480:387–390. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Krens SF, Spaink HP and Snaar-Jagalska BE: Functions of the MAPK family in vertebrate-development. FEBS Lett. 580:4984–4990. 2006. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Li J, Liang X, Wang Y, Xu Z and Li G: Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep 16: 1817-1825, 2017.
APA
Li, J., Liang, X., Wang, Y., Xu, Z., & Li, G. (2017). Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Molecular Medicine Reports, 16, 1817-1825. https://doi.org/10.3892/mmr.2017.6803
MLA
Li, J., Liang, X., Wang, Y., Xu, Z., Li, G."Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis". Molecular Medicine Reports 16.2 (2017): 1817-1825.
Chicago
Li, J., Liang, X., Wang, Y., Xu, Z., Li, G."Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis". Molecular Medicine Reports 16, no. 2 (2017): 1817-1825. https://doi.org/10.3892/mmr.2017.6803
Copy and paste a formatted citation
x
Spandidos Publications style
Li J, Liang X, Wang Y, Xu Z and Li G: Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep 16: 1817-1825, 2017.
APA
Li, J., Liang, X., Wang, Y., Xu, Z., & Li, G. (2017). Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Molecular Medicine Reports, 16, 1817-1825. https://doi.org/10.3892/mmr.2017.6803
MLA
Li, J., Liang, X., Wang, Y., Xu, Z., Li, G."Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis". Molecular Medicine Reports 16.2 (2017): 1817-1825.
Chicago
Li, J., Liang, X., Wang, Y., Xu, Z., Li, G."Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis". Molecular Medicine Reports 16, no. 2 (2017): 1817-1825. https://doi.org/10.3892/mmr.2017.6803
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team