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
November-2017 Volume 16 Issue 5

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
November-2017 Volume 16 Issue 5

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

Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway

  • Authors:
    • Xiaodan Wu
    • Li Long
    • Jian Liu
    • Jin Zhang
    • Tong Wu
    • Xixi Chen
    • Bing Zhou
    • Ting‑Zhuo Lv
  • View Affiliations / Copyright

    Affiliations: Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, Department of Orthopedics, Baodi People's Hospital of Tianjin, Tianjin 301800, P.R. China
  • Pages: 7112-7118
    |
    Published online on: September 11, 2017
       https://doi.org/10.3892/mmr.2017.7459
  • 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

Gamboge is the dried resin secreted by the Garcinia maingayi gambogic tree and is a substance that may be used to treat a variety of diseases, exhibits anti‑tumor and detoxification effects and prevents bleeding. The primary active constituent is gambogic acid. The present study aimed to investigate the anti‑inflammatory effects of gambogic acid in rheumatoid arthritis (RA) rats and to elucidate the mechanisms by which these effects occur. The swelling degree, the clinical arthritic scoring and pain threshold measurements were used to evaluate the effects of gambogic acid on RA. ELISA kits and western blot analysis were used to investigate inflammatory processes and the expression of RA‑associated proteins, respectively. The present results demonstrated that gambogic acid significantly inhibited the degree of right foot swelling, increased pain thresholds and reduced clinical arthritic scores of RA rats. Treatment with gambogic acid suppressed the activities of interleukin (IL)‑1β and IL‑6, promoted the protein expression of phosphorylated (p)‑Akt serine/threonine kinase (Akt), p‑mammalian target protein of rapamycin (mTOR) and inhibited hypoxia‑inducible factor‑1α and vascular endothelial growth factor expression in RA rats. The results of the present study therefore suggest that the anti‑inflammatory effects of gambogic acid in RA rats occur via regulation of the phosphoinositide 3‑kinase/Akt/mTOR signaling pathway.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

View References

1 

Meyfroidt S, Stevens J, De Lepeleire J, Westhovens R, De Cock D, Van Der Elst K, Vanhaecht K and Verschueren P: A general practice perspective on early rheumatoid arthritis management: A qualitative study from Flanders. Eur J Gen Pract. 21:231–237. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Abram SG, Nicol F, Hullin MG and Spencer SJ: The long-term outcome of uncemented low contact stress total knee replacement in patients with rheumatoid arthritis: Results at a mean of 22 years. Bone Joint J. 95-B:1–1499. 2013. View Article : Google Scholar

3 

Avina-Zubieta JA, Abrahamowicz M, De Vera MA, Choi HK, Sayre EC, Rahman MM, Sylvestre MP, Wynant W, Esdaile JM and Lacaille D: Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: A population-based study. Rheumatology (Oxford). 52:68–75. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Halabi H, Alarfaj A, Alawneh K, Alballa S, Alsaeid K, Badsha H, Benitha R, Bouajina E, Al Emadi S, El Garf A, et al: Challenges and opportunities in the early diagnosis and optimal management of rheumatoid arthritis in Africa and the Middle East. Int J Rheum Dis. 18:268–275. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Andersson U and Tracey KJ: HMGB1 as a mediator of necrosis-induced inflammation and a therapeutic target in arthritis. Rheum Dis Clin North Am. 30:627–637, xi. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Szabo-Taylor KE, Eggleton P, Turner CA, Faro ML, Tarr JM, Tóth S, Whiteman M, Haigh RC, Littlechild JA and Winyard PG: Lymphocytes from rheumatoid arthritis patients have elevated levels of intracellular peroxiredoxin 2 and a greater frequency of cells with exofacial peroxiredoxin 2, compared with healthy human lymphocytes. Int J Biochem Cell Biol. 44:1223–1231. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Calmon-Hamaty F, Combe B, Hahne M and Morel J: Lymphotoxin alpha stimulates proliferation and pro-inflammatory cytokine secretion of rheumatoid arthritis synovial fibroblasts. Cytokine. 53:207–214. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Hsiao HB, Hsieh CC, Wu JB, Lin H and Lin WC: Kinsenoside inhibits the inflammatory mediator release in a type-II collagen induced arthritis mouse model by regulating the T cells responses. BMC Complement Altern Med. 16:802016. View Article : Google Scholar : PubMed/NCBI

9 

Pavelka K, Kavanaugh AF, Rubbert-Roth A and Ferraccioli G: Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease-modifying anti-rheumatic drugs. Rheumatology (Oxford). 51 Suppl 5:v12–v21. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Yuan H, Yang P, Zhou D, Gao W, Qiu Z, Fang F, Ding S and Xiao W: Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro. Mol Biol Rep. 41:5157–5165. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Mitra A, Raychaudhuri SK and Raychaudhuri SP: IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine. 60:38–42. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Chiu YC, Lin CY, Chen CP, Huang KC, Tong KM, Tzeng CY, Lee TS, Hsu HC and Tang CH: Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1-dependent pathway. J Immunol. 183:2785–2792. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Li GQ, Zhang Y, Liu D, Qian YY, Zhang H, Guo SY, Sunagawa M, Hisamitsu T and Liu YQ: PI3 Kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol Cell Biochem. 372:221–231. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Liu Y, Li W, Ye C, Lin Y, Cheang TY, Wang M, Zhang H and Wang S, Zhang L and Wang S: Gambogic acid induces G0/G1 cell cycle arrest and cell migration inhibition via suppressing PDGF receptor β tyrosine phosphorylation and Rac1 activity in rat aortic smooth muscle cells. J Atheroscler Thromb. 17:901–913. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Jang SW, Okada M, Sayeed I, Xiao G, Stein D, Jin P and Ye K: Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death. Proc Natl Acad Sci USA. 104:16329–16334. 2007; View Article : Google Scholar : PubMed/NCBI

16 

Lu N, Yang Y, You QD, Ling Y, Gao Y, Gu HY, Zhao L, Wang XT and Guo QL: Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor-induced tyrosine phosphorylation of KDR/Flk-1. Cancer Lett. 258:80–89. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Jia Z and He J: Paeoniflorin ameliorates rheumatoid arthritis in rat models through oxidative stress, inflammation and cyclooxygenase 2. Exp Ther Med. 11:655–659. 2016. View Article : Google Scholar : PubMed/NCBI

18 

de la Torre I, Leandro MJ, Edwards JC and Cambridge G: Baseline serum immunoglobulin levels in patients with rheumatoid arthritis: Relationships with clinical parameters and with B-cell dynamics following rituximab. Clin Exp Rheumatol. 30:554–560. 2012.PubMed/NCBI

19 

Roberts CA, Dickinson AK and Taams LS: The interplay between monocytes/macrophages and CD4(+) T cell subsets in rheumatoid arthritis. Front Immunol. 6:5712015. View Article : Google Scholar : PubMed/NCBI

20 

El-Kady IM and El-Masry SA: Pro-inflammatory and anti-inflammatory cytokines profile in rheumatoid arthritis patients. Egypt J Immunol. 15:109–114. 2008.PubMed/NCBI

21 

Ferraccioli G and Gremese E: Thrombogenicity of TNF alpha in rheumatoid arthritis defined through biological probes: TNF alpha blockers. Autoimmun Rev. 3:261–266. 2004. View Article : Google Scholar : PubMed/NCBI

22 

Liu D, Guo M, Hu Y, Liu T, Yan J, Luo Y, Yun M, Yang M, Zhang J and Guo L: Effect of sanhuangwuji powder, anti-rheumatic drugs, and ginger-partitioned acupoint stimulation on the treatment of rheumatoid arthritis with peptic ulcer: A randomized controlled study. J Tradit Chin Med. 35:273–280. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Cobo-Ibáñez T, Descalzo MÁ, Loza-Santamaría E, Carmona L and Munoz-Fernandez S: Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: Data from the Spanish registry BIOBADASER 2.0. Rheumatol Int. 34:953–961. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Xu Y, Zhu Q, Song J, Liu H, Miao Y, Yang F, Wang F, Cheng W, Xi Y, Niu X, et al: Regulatory effect of iguratimod on the balance of Th subsets and inhibition of inflammatory cytokines in patients with rheumatoid arthritis. Mediators Inflamm. 2015:3560402015. View Article : Google Scholar : PubMed/NCBI

25 

Wu T and Mohan C: The AKT axis as a therapeutic target in autoimmune diseases. Endocr Metab Immune Disord Drug Targets. 9:145–150. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Oranskiy SP, Yeliseyeva LN, Tsanaeva AV and Zaytseva NV: Body composition and serum levels of adiponectin, vascular endothelial growth factor, and interleukin-6 in patients with rheumatoid arthritis. Croat Med J. 53:350–356. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Hetland ML, Christensen IJ, Lottenburger T, Johansen JS, Svendsen MN, Hørslev-Petersen K, Nielsen L and Nielsen HJ: Circulating VEGF as a biological marker in patients with rheumatoid arthritis? Preanalytical and biological variability in healthy persons and in patients. Dis Markers. 24:1–10. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Hah YS, Koh YJ, Lim HS, Kim HO, Cheon YH, Noh HS, Jang KY, Lee SY, Lee GM, Koh GY and Lee SI: Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis. Arthritis Res Ther. 15:R852013. View Article : Google Scholar : PubMed/NCBI

29 

Li GF, Qin YH and Du PQ: Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling. Life Sci. 136:67–72. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Brouwer E, Gouw AS, Posthumus MD, van Leeuwen MA, Boerboom AL, Bijzet J, Bos R, Limburg PC, Kallenberg CG and Westra J: Hypoxia inducible factor-1-alpha (HIF-1alpha) is related to both angiogenesis and inflammation in rheumatoid arthritis. Clin Exp Rheumatol. 27:945–951. 2009.PubMed/NCBI

31 

Seo Y, Ji YW, Lee SM, Shim J, Noh H, Yeo A, Park C, Park MS, Chang EJ and Lee HK: Activation of HIF-1α (hypoxia inducible factor-1α) prevents dry eye-induced acinar cell death in the lacrimal gland. Cell Death Dis. 5:e13092014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wu X, Long L, Liu J, Zhang J, Wu T, Chen X, Zhou B and Lv TZ: Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. Mol Med Rep 16: 7112-7118, 2017.
APA
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X. ... Lv, T. (2017). Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. Molecular Medicine Reports, 16, 7112-7118. https://doi.org/10.3892/mmr.2017.7459
MLA
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X., Zhou, B., Lv, T."Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway". Molecular Medicine Reports 16.5 (2017): 7112-7118.
Chicago
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X., Zhou, B., Lv, T."Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway". Molecular Medicine Reports 16, no. 5 (2017): 7112-7118. https://doi.org/10.3892/mmr.2017.7459
Copy and paste a formatted citation
x
Spandidos Publications style
Wu X, Long L, Liu J, Zhang J, Wu T, Chen X, Zhou B and Lv TZ: Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. Mol Med Rep 16: 7112-7118, 2017.
APA
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X. ... Lv, T. (2017). Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. Molecular Medicine Reports, 16, 7112-7118. https://doi.org/10.3892/mmr.2017.7459
MLA
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X., Zhou, B., Lv, T."Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway". Molecular Medicine Reports 16.5 (2017): 7112-7118.
Chicago
Wu, X., Long, L., Liu, J., Zhang, J., Wu, T., Chen, X., Zhou, B., Lv, T."Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway". Molecular Medicine Reports 16, no. 5 (2017): 7112-7118. https://doi.org/10.3892/mmr.2017.7459
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