The acid sphingomyelinase inhibitor imipramine enhances the release of UV photoproduct-containing DNA in small extracellular vesicles in UVB-irradiated human skin.

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  • Additional Information
    • Source:
      Publisher: American Society for Photobiology Country of Publication: United States NLM ID: 0376425 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1751-1097 (Electronic) Linking ISSN: 00318655 NLM ISO Abbreviation: Photochem Photobiol Subsets: MEDLINE
    • Publication Information:
      Publication: <2004->: Lawrence KS : American Society for Photobiology
      Original Publication: Augusta, GA: American Society for Photobiology, <1996->
    • Subject Terms:
      Imipramine*/pharmacology ; Ultraviolet Rays* ; Sphingomyelin Phosphodiesterase*/metabolism ; Sphingomyelin Phosphodiesterase*/antagonists & inhibitors ; Extracellular Vesicles*/metabolism ; Skin*/radiation effects ; Skin*/drug effects ; Skin*/metabolism ; Skin*/cytology ; Keratinocytes*/drug effects ; Keratinocytes*/radiation effects ; Keratinocytes*/metabolism ; DNA*; Humans ; Enzyme Inhibitors/pharmacology ; DNA Damage
    • Abstract:
      Nucleic acids, lipids, and other cell components can be found within different types of extracellular vesicles (EVs), which include apoptotic bodies (ABs), large extracellular vesicles (LEVs), and small extracellular vesicles (SEVs). Release of LEVs from cells can be reduced by genetic or pharmacological inhibition of the enzyme acid sphinogomyelinase (aSMase), and indeed several studies have demonstrated a role for the clinically approved aSMase inhibitor imipramine in blocking LEV release, including in response to UVB exposure. Given that exposure of keratinocytes to UVB radiation results in the generation of UVR photoproducts in DNA that can subsequently be found in association with ABs and SEVs, we examined how imipramine impacts the release of extracellular DNA containing UVR photoproducts at an early time point after UVR exposure. Using several different model systems, including cultured keratinocytes in vitro, discarded human surgical skin ex vivo, and skin biopsies obtained from treated human subjects, these pilot studies suggest that imipramine treatment stimulates the release of CPD-containing, SEV-associated DNA. These surprising findings indicate that LEV and SEV generation pathways could be linked in UVB-irradiated cells and that imipramine may exacerbate the systemic effects of extracellular UVR-damaged DNA throughout the body.
      (© 2024 The Authors. Photochemistry and Photobiology published by Wiley Periodicals LLC on behalf of American Society for Photobiology.)
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    • Grant Information:
      R01HL062996 United States HL NHLBI NIH HHS; R01GM230583 United States GM NIGMS NIH HHS; R01ES031087 United States ES NIEHS NIH HHS; R01HL062996 United States HL NHLBI NIH HHS; R01GM230583 United States GM NIGMS NIH HHS; R01ES031087 United States ES NIEHS NIH HHS; I01BX00853 U.S. Department of Veterans Affairs; I01CX002241 U.S. Department of Veterans Affairs
    • Contributed Indexing:
      Keywords: DNA damage; UV radiation; apoptosis; cell biology; exosome; extracellular vesicles; pharmacology; skin biology
    • Accession Number:
      OGG85SX4E4 (Imipramine)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
      9007-49-2 (DNA)
      0 (Enzyme Inhibitors)
    • Publication Date:
      Date Created: 20240304 Date Completed: 20241116 Latest Revision: 20241116
    • Publication Date:
      20241118
    • Accession Number:
      10.1111/php.13932
    • Accession Number:
      38433456