Effect of calcitriol on regulation of skin barrier function and wound healing in diabetic ulcer patients

• Project/Area Number: 19K17819
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Juntendo University
• Principal Investigator: Trujillo Valentin 順天堂大学, 大学院医学研究科, 博士研究員 (60833605)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ケラチノサイト / カルシトリオール / タイトジャンクション / 糖尿病 / 皮膚バリア機能 / 角化 細胞 / 抗菌ペプチド / 糖尿病性潰瘍 / アトピー 性皮膚炎 / 角化細胞 / アトピー性皮膚炎

Outline of Research at the Start

カルシトリオールは活性型ビタミンD3であり、その欠乏は糖尿病、結核等の多数の疾患と関連している。カルシトリオールが角化細胞において抗菌ペプチドの産生を誘導すること、腸管上皮と眼のタイトジャンクション（TJ）の構造を調節することが報告されている。従って、糖尿病性潰瘍患者等の創傷治癒遅延患者の皮膚にカルシトリオールを使用することは、感染を防御し、創傷治癒を促進することを示唆している。しかし、現在までにカルシトリオールが皮膚のTJ構造を調節しているかは不明である。
本研究ではカルシトリオールが皮膚バリア機能を強化するか否かを検討する。また、糖尿病性潰瘍の治療法として、カルシトリオールの使用を検討する。

Outline of Final Research Achievements

Normal human keratinocytes were stimulated with calcitriol and the expression of tight junction-related proteins was analyzed by qPCR, immunofluorescence, and Western blot. As a result, it was suggested that calcitriol promotes the expression of claudin-4 claudin-7, occludin and ZO-1. The barrier function of tight junctions was measured by transepithelial electrical resistance using CellZscope. Cells stimulated with calcitriol showed a significant increase in transepithelial electrical resistance, suggesting that calcitriol induces tight junction-related proteins and enhances skin barrier function.

Academic Significance and Societal Importance of the Research Achievements

カルシトリオールは活性型ビタミンD3であり、その欠乏は糖尿病、結核、早期破水等の多数の疾患と関連している。最近、カルシトリオールの作用によりケラチノサイトが様々な抗菌ペプチドを産生することが報告されている。従って、糖尿病性潰瘍患者等の創傷治癒遅延患者において、皮膚にカルシトリオールを使用することは、頑固な感染を防御し、創傷治癒を促進する可能性がある。カルシトリオールによるタイトジャンクションの構造や創傷治癒の調節作用を理解することは、糖尿病を含む皮膚バリアを伴う疾患の新たな治療ターゲット探索への貢献となり得る。

Research Products

• [Journal Article] Keratinocytes: innate immune cells in atopic dermatitis (2021)
  • Author(s): Chieosilapatham P.、Kiatsurayanon C.、Umehara Y.、Trujillo‐Paez J. V.、Peng G.、Yue H.、Nguyen L. T. H.、Niyonsaba F.
  • Journal Title: Clinical & Experimental Immunology Volume: In press Issue: 3 Pages: 296-309
  • DOI: 10.1111/cei.13575
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The antimicrobial peptide human β-defensin-3 accelerates wound healing by promoting angiogenesis, cell migration, and proliferation through the FGFR/JAK2/STAT3 signaling pathway. (2021)
  • Author(s): Takahashi M, Umehara Y, Yue H, Trujillo-Paez JV, Peng G, Nguyen HLT, Ikutama R, Okumura K, Ogawa H, Ikeda S, Niyonsaba F.
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 1-17
  • DOI: 10.3389/fimmu.2021.712781
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intractable Itch in Atopic Dermatitis: Causes and Treatments (2021)
  • Author(s): Umehara Yoshie、Kiatsurayanon Chanisa、Trujillo-Paez Juan Valentin、Chieosilapatham Panjit、Peng Ge、Yue Hainan、Nguyen Hai Le Thanh、Song Pu、Okumura Ko、Ogawa Hideoki、Niyonsaba Francois
  • Journal Title: Biomedicines Volume: 9 Issue: 3 Pages: 229-229
  • DOI: 10.3390/biomedicines9030229
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections (2021)
  • Author(s): Yue Hainan、Umehara Yoshie、Trujillo‐Paez Juan Valentin、Peng Ge、Nguyen Hai Le Thanh、Chieosilapatham Panjit、Kiatsurayanon Chanisa、Song Pu、Okumura Ko、Ogawa Hideoki、Ikeda Shigaku、Niyonsaba Francois
  • Journal Title: Clinical & Experimental Allergy Volume: 51 Issue: 3 Pages: 382-392
  • DOI: 10.1111/cea.13820
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis (2020)
  • Author(s): Nguyen Hai Le Thanh、Trujillo-Paez Juan Valentin、Umehara Yoshie、Yue Hainan、Peng Ge、Kiatsurayanon Chanisa、Chieosilapatham Panjit、Song Pu、Okumura Ko、Ogawa Hideoki、Ikeda Shigaku、Niyonsaba Francois
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 20 Pages: 7607-7607
  • DOI: 10.3390/ijms21207607
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Host defense peptide RNase 7 is down-regulated in the skin of diabetic patients with or without chronic ulcers, and its expression is altered with metformin (2020)
  • Author(s): Rodriguez A, Trujillo V, Gonzalez I, Marin S, Torres F, Santos A, Rivas C, Enciso JA, Zaga V, Rivas B
  • Journal Title: Archives of Medical Research Volume: 51 Issue: 4 Pages: 327-335
  • DOI: 10.1016/j.arcmed.2020.03.006
  • Peer Reviewed
• [Presentation] Antimicrobial peptide derived from insulin-like growth factor-binding protein 5 promotes diabetic wound healing by rescuing high-glucose-mediated dysfunction of keratinocytes. (2022)
  • Author(s): Yue H, Umehara Y, Trujillo Paez JV, Peng G, Nguyen HLT, Takahashi M, Ikutama R, Okumura K, Ogawa H, Ikeda S, Niyonsaba F.
  • Organizer: 30th KSID Annual Meeting.
  • Int'l Joint Research
• [Presentation] Effects of the antimicrobial peptide derived from insulin-like growth factor-binding protein 5 on skin barrier function: implication in atopic dermatitis treatment? (2022)
  • Author(s): Nguyen HLT, Trujillo Paez JV, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Okumura K, Ogawa H, Ikeda S, Niyonsaba F.
  • Organizer: 30th KSID Annual Meeting.
  • Int'l Joint Research
• [Presentation] The active form of vitamin D, calcitriol, modulates the epidermal tight junction barrier function in diabetes. (2022)
  • Author(s): 1)Trujillo Paez JV, Nguyen HLT, Umehara Y, Yue H, Ikutama R, Takahashi M, Peng G, Ikeda S, Ogawa H, Okumura K, Niyonsaba F.
  • Organizer: 30th KSID Annual Meeting.
  • Int'l Joint Research
• [Presentation] La catelicidina LL-37 y la vitamina D regulan las uniones estrechas en altas concentraciones de glucosa (Spanish) (2021)
  • Author(s): Trujillo Paez JV, Umehara Y, Ogawa H, Okumura K, Ikeda S, Niyonsaba F.
  • Organizer: XXIV Congreso Nacional de inmunologia
  • Int'l Joint Research
• [Presentation] Effect of the antimicrobial peptide derived from insulin-like growth factor-binding protein 5 on skin barrier regulation. (2021)
  • Author(s): Nguyen HLT, Trujillo Paez JV, Peng G, Yue, H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Ikeda S, Niyonsaba F.
  • Organizer: The 2021 Virtual Meeting of the Society for Investigative Dermatology.
  • Int'l Joint Research
• [Presentation] The antimicrobial peptide AMP-IBP5 enhances the skin barrier function in human keratinocytes. (2021)
  • Author(s): Nguyen HLT, Trujillo Paez JV, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Okumura K, Ikeda S, Niyonsaba F.
  • Organizer: The 120th Annual Meeting of the Japanese Dermatological Association.
  • Int'l Joint Research
• [Presentation] Effect of antimicrobial peptide AMP-IBP5 on the skin barrier function. (2021)
  • Author(s): Nguyen HLT, Trujillo Paez JV, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Okumura K, Ikeda S, Niyonsaba F.
  • Organizer: The 70th Annual Meeting of the Japanese Society of Allergology.
  • Int'l Joint Research
• [Presentation] A skin-derived antimicrobial peptide AMP-IBP5 regulates epidermal barrier function. (2021)
  • Author(s): Nguyen HLT, Trujillo Paez JV, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Okumura K, Ikeda S, Niyonsaba F.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology.
  • Int'l Joint Research
• [Presentation] Calcitriol, the active form of vitamin D, regulates epidermal tight junction barrier function in diabetes. (2021)
  • Author(s): Trujillo Paez JV, Nguyen HLT, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Okumura K, Ikeda S, Niyonsaba F.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology.
  • Int'l Joint Research
• [Presentation] La catelicidina LL-37 y la vitamina D regulan las uniones estrechas en altas concentraciones de glucosa (2021)
  • Author(s): Trujillo V, Umehara Y, Ogawa H, Ikeda S, Okumura K, Niyonsaba F
  • Organizer: XXIV congreso nacional de Inmunologia
  • Int'l Joint Research
• [Presentation] Regulation of skin-tight junction barrier function by calcitriol in diabetic milieu (2020)
  • Author(s): Trujillo V, Nguyen HL, Umehara Y, Yue H, Ikutama R, Takahashi M, Peng G, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Antimicrobial peptide derived from insulin-like growth factor-binding protein 5 improves diabetic wound healing via MAPK pathways (2020)
  • Author(s): Yue H, Umehara Y, Trujillo V, Nguyen HL, Peng G, Takahashi M, Ikutama R, Okumura K, Ikeda S, Ogawa H, Niyonsaba F
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Effects of human beta-defensin-3 on wound healing (2020)
  • Author(s): Takahashi M, Umehara Y, Yue H, Trujillo V, Peng G, Nguyen HL, Ikutama R, Okumura K, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] The effect of antimicrobial peptide AMP-IBP5 on skin barrier regulation (2020)
  • Author(s): Nguyen HL, Trujillo V, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Effect of hBD-3 on Th2 cytokine-mediated modulation of autophagy in human keratinocytes (2020)
  • Author(s): Peng G, Ikutama R, Umehara Y, Trujillo V, Yue H, Nguyen HL, Takahashi M, Kakeyama S, Komatsu M, Okumura K, Ogawa H, Shigaku I, Niyonsaba F
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Both human β-defensin-3 and autophagy are needed for maintenance of skin barrier (2020)
  • Author(s): Peng G, Kageyama S, Ikutama R, Umehara Y, Trujillo V, Nguyen HL, Takahashi M, Yue H, Komatsu M, Okumura O, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 50th Annual Meeting of the Japanese Society for Cutaneous Immunology and Allergy
  • Int'l Joint Research
• [Presentation] The antimicrobial peptide human beta-defensin-3 activates autophagy in human keratinocytes (2020)
  • Author(s): Peng G, Kageyama S, Ikutama R, Umehara Y, Trujillo V, Nguyen HL, Takahashi M, Yue H, Komatsu M, Okumura O, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 78th Annual Meeting of the Society for Investigative Dermatology. 194. Scottsdale
  • Int'l Joint Research
• [Presentation] Acceleration of diabetic wound healing by an antimicrobial peptide AMP-IBP5 (2020)
  • Author(s): Yue H, Umehara Y, Trujillo V, Peng G, Okumura O, Ikeda S, Ogawa H, Niyonsaba F
  • Organizer: The 119th Annual Meeting of the Japanese Dermatological Association
  • Int'l Joint Research
• [Presentation] Effect of the antimicrobial peptide AMP-IBP5 on skin barrier regulation (2020)
  • Author(s): Nguyen HL，Trujillo V, Peng G, Yue H, Ikutama R，Takahashi M, Umehara Y, Ikeda S, Ogawa H, Niyonsaba F
  • Organizer: The 119th Annual Meeting of the Japanese Dermatological Association
  • Int'l Joint Research
• [Presentation] Tight junction barrier regulation by calcitriol and LL-37 in diabetes (2020)
  • Author(s): Trujillo V, Umehara Y, Okumura K, Ogawa H, Niyonsaba F
  • Organizer: 第119回日本皮膚科学会総会
• [Presentation] Acceleration of diabetic wound healing by an antimicrobial peptide AMP-IBP5 (2020)
  • Author(s): Yue H, Umehara Y, Trujillo V, Okumura K, Ikeda S, Ogawa H, Niyonsaba F
  • Organizer: 第119回日本皮膚科学会総会
• [Presentation] Effect of the antimicrobial peptide AMP-IBP5 on skin barrier regulation (2020)
  • Author(s): Nguyen LTH, Trujillo V, Peng G, Yue H, Ikutama R, Takahashi M, Umehara Y, Ikeda S, Ogawa H, Niyonsaba F
  • Organizer: 第119回日本皮膚科学会総会
• [Presentation] Human beta-defensin-3 activates autophagy linked to tight junction barrier in keratinocytes (2020)
  • Author(s): Peng G, Kageyama S, Ikutama R, Umehara Y, Trujillo V, Nguyen HL, Yue H, Komatsu M, Okumura K, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: 第119回日本皮膚科学会総会
• [Presentation] The antimicrobial peptide human beta-defensin-3 activates autophagy in human keratinocytes (2020)
  • Author(s): Peng G, Kageyama S, Ikutama R, Umehara Y, Trujillo V, Nguyen HL, Takahashi M, Yue H, Komatsu M, Okumura K, Ogawa H, Ikeda S, Niyonsaba F
  • Organizer: The 78th Annual Meeting of the Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Regulation of tight junctions and differentiation markers in keratinocytes by calcitriol in diabetes (2019)
  • Author(s): Trujillo V, Umehara Y, Okumura K, Niyonsaba F
  • Organizer: The 44th Annual Meeting of the Japanese Society for Investigative Dermatology