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
Oncology Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
April-2024 Volume 27 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-2024 Volume 27 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
Article Open Access

Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway

  • Authors:
    • Tingting Jiang
    • Yan Liang
    • Yenan Ji
    • Yin Xue
  • View Affiliations / Copyright

    Affiliations: Department of Traditional Chinese Medicine, Changzhou Wujin People's Hospital, Changzhou, Jiangsu 213100, P.R. China, Department of Emergency Center, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, Shandong 266042, P.R. China, Department of Colorectal Anal Surgery, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, Shandong 266042, P.R. China, Department of Traditional Chinese Medicine, Changzhou Wujin People's Hospital, Changzhou, Jiangsu 213100, P.R. China
    Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 165
    |
    Published online on: February 20, 2024
       https://doi.org/10.3892/ol.2024.14298
  • 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

Cisplatin resistance is ubiquitous among patients with renal cell carcinoma (RCC). The present study assessed the role of fisetin in regulating cisplatin sensitivity and increasing the efficacy of chemotherapy for patients with RCC. Cell Counting Kit‑8 and colony formation assays were used to assess the proliferation of RCC cells after fisetin and cisplatin treatment. The mRNA expression levels of cyclin‑dependent kinase (CDK)6 were evaluated using reverse transcription‑quantitative PCR. The expression levels of CDK6 and key proteins of the PI3K/Akt/mTOR signaling pathway were assessed using western blotting. The present study demonstrated that fisetin inhibited the proliferation and colony‑forming ability of RCC cells, and induced apoptosis and cell cycle arrest in a dose‑dependent manner. Additionally, fisetin enhanced the antineoplastic effects of cisplatin, as demonstrated by the increase in proliferation inhibition and apoptosis promotion after fisetin and cisplatin combination treatment. Furthermore, fisetin regulated the PI3K/Akt/mTOR signaling pathway through CDK6 inhibition, which enhanced cisplatin sensitivity. Overexpression of CDK6 neutralized the positive effects of fisetin on the improvement of cisplatin sensitivity in RCC cells. In conclusion, fisetin may enhance the sensitivity of RCC cells to cisplatin via the CDK6/PI3K/Akt/mTOR signaling pathway.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Jonasch E, Gao J and Rathmell WK: Renal cell carcinoma. BMJ. 349:g47972014. View Article : Google Scholar : PubMed/NCBI

2 

Van Poppel H, Becker F, Cadeddu JA, Gill IS, Janetschek G, Jewett MA, Laguna MP, Marberger M, Montorsi F, Polascik TJ, et al: Treatment of localised renal cell carcinoma. Eur Urol. 60:662–672. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Tanji N and Yokoyama M: Treatment of metastatic renal cell carcinoma and renal pelvic cancer. Clin Exp Nephrol. 15:331–338. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Sousa C, Duarte D, Silva-Lima B and Videira M: Repurposing natural dietary flavonoids in the modulation of cancer tumorigenesis: Decrypting the molecular targets of naringenin, hesperetin and myricetin. Nutr Cancer. 74:1188–1202. 2022. View Article : Google Scholar : PubMed/NCBI

5 

Manisha DS, Ratheesh AK, Benny S and Presanna AT: Heterocyclic and non-heterocyclic arena of monocarboxylate transporter inhibitors to battle tumorigenesis. Chem Biol Drug Des. 102:1604–1617. 2023. View Article : Google Scholar : PubMed/NCBI

6 

Duan N, Hu X, Zhou R, Li Y, Wu W and Liu N: A Review on Dietary Flavonoids as Modulators of the Tumor Microenvironment. Mol Nutr Food Res. 67:e22004352023. View Article : Google Scholar : PubMed/NCBI

7 

Felice MR, Maugeri A, De Sarro G, Navarra M and Barreca D: Molecular pathways involved in the anti-cancer activity of flavonols: A focus on myricetin and kaempferol. Int J Mol Sci. 23:44112022. View Article : Google Scholar : PubMed/NCBI

8 

Lu X, Jung Ji, Cho HJ, Lim DY, Lee HS, Chun HS, Kwon DY and Park JH: Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr. 135:2884–2890. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE and Klotz LH: Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 9:68–76. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Kashyap D, Garg VK, Tuli HS, Yerer MB, Sak K, Sharma AK, Kumar M, Aggarwal V and Sandhu SS: Fisetin and quercetin: Promising flavonoids with chemopreventive potential. Biomolecules. 9:1742019. View Article : Google Scholar : PubMed/NCBI

11 

Hsieh MH, Tsai JP, Yang SF, Chiou HL, Lin CL, Hsieh YH and Chang HR: Fisetin suppresses the proliferation and metastasis of renal cell carcinoma through Upregulation of MEK/ERK-Targeting CTSS and ADAM9. Cells. 8:9682019. View Article : Google Scholar

12 

Si Y, Liu J, Shen H, Zhang C, Wu Y, Huang Y, Gong Z, Xue J and Liu T: Fisetin decreases TET1 activity and CCNY/CDK16 promoter 5hmC levels to inhibit the proliferation and invasion of renal cancer stem cell. J Cell Mol Med. 23:1095–1105. 2019. View Article : Google Scholar : PubMed/NCBI

13 

Jafarzadeh S, Baharara J and Tehranipour M: Apoptosis induction with combined use of cisplatin and fisetin in cisplatin-resistant ovarian cancer cells (A2780). Avicenna J Med Biotechnol. 13:176–182. 2021.PubMed/NCBI

14 

Zhuo W, Zhang L, Zhu Y, Zhu B and Chen Z: Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway. Am J Transl Res. 7:2045–2052. 2015.PubMed/NCBI

15 

Nebenfuehr S, Kollmann K and Sexl V: The role of CDK6 in cancer. Int J Cancer. 147:2988–2995. 2020. View Article : Google Scholar : PubMed/NCBI

16 

Jiang J, Han P, Qian J, Zhang S, Wang S, Cao Q and Shao P: Knockdown of ALPK2 blocks development and progression of renal cell carcinoma. Exp Cell Res. 392:1120292020. View Article : Google Scholar : PubMed/NCBI

17 

Guo Z, Jia H and Ge J: MiR-206 suppresses proliferation and epithelial-mesenchymal transition of renal cell carcinoma by inhibiting CDK6 expression. Hum Cell. 33:750–758. 2020. View Article : Google Scholar : PubMed/NCBI

18 

Guo L, Wang D and Zhang Z: MiR-384 represses tumorigenesis by regulating CDK6 and predicts prognosis of clear cell renal cell carcinoma. J BUON. 23:787–794. 2018.PubMed/NCBI

19 

Pan H, Hong Y, Yu B, Li L and Zhang X: miR-4429 Inhibits Tumor Progression and Epithelial-Mesenchymal Transition Via Targeting CDK6 in Clear Cell Renal Cell Carcinoma. Cancer Biother Radiopharm. 34:334–341. 2019.PubMed/NCBI

20 

Sundarraj K, Raghunath A, Panneerselvam L and Perumal E: Fisetin inhibits autophagy in HepG2 Cells via PI3K/Akt/mTOR and AMPK Pathway. Nutr Cancer. 73:2502–2514. 2021. View Article : Google Scholar : PubMed/NCBI

21 

Farooqi AA, Naureen H, Zahid R, Youssef L, Attar R and Xu B: Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers. Pharmacol Res. 172:1057842021. View Article : Google Scholar : PubMed/NCBI

22 

Zhang Y, Fang L, Zang Y, Ren J and Xu Z: CIP2A promotes proliferation, invasion and chemoresistance to cisplatin in renal cell carcinoma. J Cancer. 9:4029–4038. 2018. View Article : Google Scholar : PubMed/NCBI

23 

Seo SH and Jeong GS: Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression. Int Immunopharmacol. 29:246–253. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Chang PR, Liou JW, Chen PY, Gao WY, Wu CL, Wu MJ and Yen JH: The neuroprotective effects of flavonoid fisetin against corticosterone-induced cell death through modulation of ERK, p38, and PI3K/Akt/FOXO3a-dependent pathways in PC12 cells. Pharmaceutics. 15:23762023. View Article : Google Scholar : PubMed/NCBI

25 

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

26 

Lloyd A, Reeves F, Abu-Ghanem Y and Challacombe B: Metastasectomy in renal cell carcinoma: Where are we now? Curr Opin Urol. 32:627–633. 2022. View Article : Google Scholar : PubMed/NCBI

27 

Cayetano-Salazar L, Nava-Tapia DA, Astudillo-Justo KD, Arizmendi-Izazaga A, Sotelo-Leyva C, Herrera-Martinez M, Villegas-Comonfort S and Navarro-Tito N: Flavonoids as regulators of TIMPs expression in cancer: Consequences, opportunities, and challenges. Life Sci. 308:1209322022. View Article : Google Scholar : PubMed/NCBI

28 

Alhaj-Suliman SO, Wafa EI and Salem AK: Engineering nanosystems to overcome barriers to cancer diagnosis and treatment. Adv Drug Deliv Rev. 189:1144822022. View Article : Google Scholar : PubMed/NCBI

29 

Jafarzadeh E, Montazeri V, Aliebrahimi S, Sezavar AH, Ghahremani MH and Ostad SN: Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis. Life Sci. 304:1206802022. View Article : Google Scholar : PubMed/NCBI

30 

Han Y, Wen P, Li J and Kataoka K: Targeted nanomedicine in cisplatin-based cancer therapeutics. J Control Release. 345:709–720. 2022. View Article : Google Scholar : PubMed/NCBI

31 

Ravula AR, Teegala SB, Kalakotla S, Pasangulapati JP, Perumal V and Boyina HK: Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. Eur J Pharmacol. 910:1744922021. View Article : Google Scholar : PubMed/NCBI

32 

Simunkova M, Alwasel SH, Alhazza IM, Jomova K, Kollar V, Rusko M and Valko M: Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 93:2491–2513. 2019. View Article : Google Scholar : PubMed/NCBI

33 

Kubina R, Krzykawski K, Kabała-Dzik A, Wojtyczka RD, Chodurek E and Dziedzic A: Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients. 14:26042022. View Article : Google Scholar : PubMed/NCBI

34 

Maher P: Preventing and treating neurological disorders with the flavonol fisetin. Brain Plast. 6:155–166. 2021. View Article : Google Scholar : PubMed/NCBI

35 

Wang J and Huang S: Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway. Exp Ther Med. 15:2667–2673. 2018.PubMed/NCBI

36 

Ho CS, Grange RW and Joho RH: Pleiotropic effects of a disrupted K+ channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures. Proc Natl Acad Sci USA. 94:1533–1538. 1997. View Article : Google Scholar : PubMed/NCBI

37 

Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT and Hsieh YH: Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 86:263–273. 2012. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Jiang T, Liang Y, Ji Y and Xue Y: Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway. Oncol Lett 27: 165, 2024.
APA
Jiang, T., Liang, Y., Ji, Y., & Xue, Y. (2024). Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway. Oncology Letters, 27, 165. https://doi.org/10.3892/ol.2024.14298
MLA
Jiang, T., Liang, Y., Ji, Y., Xue, Y."Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway". Oncology Letters 27.4 (2024): 165.
Chicago
Jiang, T., Liang, Y., Ji, Y., Xue, Y."Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway". Oncology Letters 27, no. 4 (2024): 165. https://doi.org/10.3892/ol.2024.14298
Copy and paste a formatted citation
x
Spandidos Publications style
Jiang T, Liang Y, Ji Y and Xue Y: Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway. Oncol Lett 27: 165, 2024.
APA
Jiang, T., Liang, Y., Ji, Y., & Xue, Y. (2024). Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway. Oncology Letters, 27, 165. https://doi.org/10.3892/ol.2024.14298
MLA
Jiang, T., Liang, Y., Ji, Y., Xue, Y."Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway". Oncology Letters 27.4 (2024): 165.
Chicago
Jiang, T., Liang, Y., Ji, Y., Xue, Y."Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway". Oncology Letters 27, no. 4 (2024): 165. https://doi.org/10.3892/ol.2024.14298
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