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
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
April-2019 Volume 43 Issue 4

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
April-2019 Volume 43 Issue 4

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

  • Supplementary Files
    • Supplementary_Data.pdf
Article Open Access

Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways

  • Authors:
    • Zheng‑Luan Liao
    • Heng Su
    • Yun‑Fei Tan
    • Ya‑Ju Qiu
    • Jun‑Peng Zhu
    • Yan Chen
    • Si‑Si Lin
    • Ming‑Hao Wu
    • Yan‑Ping Mao
    • Jiao‑Jiao Hu
    • En‑Yan Yu
  • View Affiliations / Copyright

    Affiliations: Department of Psychiatry, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China, Psychiatry and Mental Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, Psychiatry and Mental Health, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
    Copyright: © Liao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1769-1777
    |
    Published online on: February 1, 2019
       https://doi.org/10.3892/ijmm.2019.4088
  • 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

Alzheimer's disease (AD) is one of the most frequent diseases in elderly people and causes high mortality. Its incidence is increasing annually and no effective therapeutic treatment currently exists. In the present study, salidroside, a major active ingredient of Rhodiola rosea, was able to protect PC‑12 cells from the toxicity and apoptosis induced by AD inducer amyloid (A)β1‑42. Salidroside significantly protected PC‑12 cells by inhibiting Aβ1‑42‑induced cytotoxicity and mitochondria‑mediated endogenous caspase apoptotic pathways. Mechanistic studies demonstrated that salidroside significantly activated the extracellular signal regulated kinase (ERK)1/2 and protein kinase B (AKT) signaling pathways. This observation was further confirmed using the ERK1/2 inhibitor PD98059 and the AKT inhibitor LY294002, which demonstrated that salidroside promoted PC‑12 cell survival and proliferation by activating the ERK1/2 and AKT signaling pathways. Salidroside is a therapeutic candidate for the treatment of AD and provides a basis for further drug development.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Jarrett JT and Lansbury PT Jr: Seeding ‘one-dimensional crystallization’ of amyloid: A pathogenic mechanism in Alzheimer’s disease and scrapie? Cell. 73:1055–1058. 1993. View Article : Google Scholar : PubMed/NCBI

2 

Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, et al: Mild cognitive impairment-beyond controversies, towards a consensus: Report of the international working group on mild cognitive impairment. J Intern Med. 256:240–246. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Coyle JT, Price DL and DeLong MR: Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science. 219:1184–1190. 1983. View Article : Google Scholar : PubMed/NCBI

4 

Alzheimer’s A: 2011 Alzheimer’s disease facts and figures. W V Med J. 107:82–83. 2011.

5 

Colucci L, Bosco M, Fasanaro AM, Gaeta GL, Ricci G and Amenta F: Alzheimer’s disease costs: What we know and what we should take into account. J Alzheimers Dis. 42:1311–1324. 2014. View Article : Google Scholar

6 

Ittner LM and Gotz J: Amyloid-β and tau - a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci. 12:65–72. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, et al: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 41:1088–1093. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Bertram L and Tanzi RE: Alzheimer disease: New light on an old CLU. Nat Rev Neurol. 6:11–13. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Selkoe DJ: The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol. 8:447–453. 1998. View Article : Google Scholar : PubMed/NCBI

10 

Love S and Kehoe PG: Clearance of Abeta from the brain in Alzheimer’s disease. Foreword. Brain Pathol. 18:2392008. View Article : Google Scholar

11 

Akwa Y, Allain H, Bentue-Ferrer D, Berr C, Bordet R, Geerts H, Nieoullon A, Onteniente B and Vercelletto M: Neuroprotection and neurodegenerative diseases: From biology to clinical practice. Alzheimer Dis Assoc Disord. 19:226–239. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT and Brinton RD: Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 106:14670–14675. 2009. View Article : Google Scholar

13 

Zeng Z, Xu J and Zheng W: Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol. 12:625–633. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Godyn J, Jonczyk J, Panek D and Malawska B: Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep. 68:127–138. 2016. View Article : Google Scholar

15 

Cummings JL, Morstorf T and Zhong K: Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res Ther. 6:372014. View Article : Google Scholar

16 

Selkoe DJ and Hardy J: The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 8:595–608. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Abidov M, Crendal F, Grachev S, Seifulla R and Ziegenfuss T: Effect of extracts from Rhodiola rosea and Rhodiola crenulata (Crassulaceae) roots on ATP content in mitochondria of skeletal muscles. Bull Exp Biol Med. 136:585–587. 2003. View Article : Google Scholar

18 

Zhang J, Zhen YF, Pu-Bu-Ci-Ren, Song LG, Kong WN, Shao TM, Li X and Chai XQ: Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res. 244:70–81. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Liu Z, Li X, Simoneau AR, Jafari M and Zi X: Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog. 51:257–267. 2012. View Article : Google Scholar

20 

Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G and Wang Z: Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int. 57:547–555. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Hu M, Waring JF, Gopalakrishnan M and Li J: Role of GSK-3beta activation and alpha7 nAChRs in Abeta(1–42)-induced tau phosphorylation in PC12 cells. J Neurochem. 106:1371–1377. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Mahbub AA, Le Maitre CL, Haywood-Small SL, McDougall GJ, Cross NA and Jordan-Mahy N: Differential effects of poly-phenols on proliferation and apoptosis in human myeloid and lymphoid leukemia cell lines. Anticancer Agents Med Chem. 13:1601–1613. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar

24 

Ly JD, Grubb DR and Lawen A: The mitochondrial membrane potential (deltapsi(m)) in apoptosis. An update Apoptosis. 8:115–128. 2003. View Article : Google Scholar

25 

Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI

26 

Bufill E, Bartes A, Moral A, Casadevall T, Codinachs M, Zapater E, Carles Rovira J, Roura P, Oliva R and Blesa R: Genetic and environmental factors that may influence in the senile form of Alzheimer’s disease: Nested case control studies. Neurologia. 24:108–112. 2009.In Spanish. PubMed/NCBI

27 

Di Paolo G and Kim TW: Linking lipids to Alzheimer’s disease: Cholesterol and beyond. Nat Rev Neurosci. 12:284–296. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Butterfield DA and Boyd-Kimball D: Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease. J Alzheimers Dis. 62:1345–1367. 2018. View Article : Google Scholar :

29 

Knezevic D and Mizrahi R: Molecular imaging of neuroinflammation in Alzheimer’s disease and mild cognitive impairment. Prog Neuropsychopharmacol Biol Psychiatry. 80:123–131. 2018. View Article : Google Scholar

30 

Ma YG, Wang JW, Zhang YB, Wang BF, Dai ZJ, Xie MJ and Kang HF: Salidroside improved cerebrovascular vasodilation in streptozotocin-induced diabetic rats through restoring the function of BKCa channel in smooth muscle cells. Cell Tissue Res. 370:365–377. 2017. View Article : Google Scholar : PubMed/NCBI

31 

Liu X, Bai Y, Liang L, Feng J and Deng F: Salidroside improves pulmonary fibrosis by down-regulation of cathepsin B and NF-κBp65 in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 42:128–133. 2017.In Chinese. PubMed/NCBI

32 

Richter L, Munter LM, Ness J, Hildebrand PW, Dasari M, Unterreitmeier S, Bulic B, Beyermann M, Gust R, Reif B, et al: Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc Natl Acad Sci USA. 107:14597–14602. 2010. View Article : Google Scholar

33 

Postu PA, Noumedem JAK, Cioanca O, Hancianu M, Mihasan M, Ciorpac M, Gorgan DL, Petre BA and Hritcu L: Lactuca capensis reverses memory deficits in Aβ1–42-induced an animal model of Alzheimer’s disease. J Cell Mol Med. 22:111–122. 2018. View Article : Google Scholar

34 

Lu Z and Xu S: ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life. 58:621–631. 2006. View Article : Google Scholar : PubMed/NCBI

35 

Franke TF, Hornik CP, Segev L, Shostak GA and Sugimoto C: PI3K/Akt and apoptosis: Size matters. Oncogene. 22:8983–8998. 2003. View Article : Google Scholar : PubMed/NCBI

36 

Imai Y, Yamagishi H, Ono Y and Ueda Y: Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells. Clin Transl Med. 1:242012. View Article : Google Scholar

37 

Zhu C, Qi X, Chen Y, Sun B, Dai Y and Gu Y: PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer. J Cancer Res Clin Oncol. 137:1587–1594. 2011. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liao ZL, Su H, Tan YF, Qiu YJ, Zhu JP, Chen Y, Lin SS, Wu MH, Mao YP, Hu JJ, Hu JJ, et al: Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways. Int J Mol Med 43: 1769-1777, 2019.
APA
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y. ... Yu, E. (2019). Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways. International Journal of Molecular Medicine, 43, 1769-1777. https://doi.org/10.3892/ijmm.2019.4088
MLA
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y., Lin, S., Wu, M., Mao, Y., Hu, J., Yu, E."Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways". International Journal of Molecular Medicine 43.4 (2019): 1769-1777.
Chicago
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y., Lin, S., Wu, M., Mao, Y., Hu, J., Yu, E."Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways". International Journal of Molecular Medicine 43, no. 4 (2019): 1769-1777. https://doi.org/10.3892/ijmm.2019.4088
Copy and paste a formatted citation
x
Spandidos Publications style
Liao ZL, Su H, Tan YF, Qiu YJ, Zhu JP, Chen Y, Lin SS, Wu MH, Mao YP, Hu JJ, Hu JJ, et al: Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways. Int J Mol Med 43: 1769-1777, 2019.
APA
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y. ... Yu, E. (2019). Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways. International Journal of Molecular Medicine, 43, 1769-1777. https://doi.org/10.3892/ijmm.2019.4088
MLA
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y., Lin, S., Wu, M., Mao, Y., Hu, J., Yu, E."Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways". International Journal of Molecular Medicine 43.4 (2019): 1769-1777.
Chicago
Liao, Z., Su, H., Tan, Y., Qiu, Y., Zhu, J., Chen, Y., Lin, S., Wu, M., Mao, Y., Hu, J., Yu, E."Salidroside protects PC-12 cells against amyloid β-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways". International Journal of Molecular Medicine 43, no. 4 (2019): 1769-1777. https://doi.org/10.3892/ijmm.2019.4088
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