title: Hyperforin/HP-β-Cyclodextrin Enhances Mechanosensitive Ca2+Signaling in HaCaT Keratinocytes and in Atopic Skin Ex Vivo Which Accelerates Wound Healing.
abstract: Cutaneous wound healing is accelerated by mechanical stretching, and treatment with hyperforin, a major component of a traditional herbal medicine and a known TRPC6 activator, further enhances the acceleration. We recently revealed that this was due to the enhancement of ATP-Ca2+signaling in keratinocytes by hyperforin treatment. However, the low aqueous solubility and easy photodegradation impede the topical application of hyperforin for therapeutic purposes. We designed a compound hydroxypropyl-β-cyclodextrin- (HP-β-CD-) tetracapped hyperforin, which had increased aqueous solubility and improved photoprotection. We assessed the physiological effects of hyperforin/HP-β-CD on wound healing in HaCaT keratinocytes using live imaging to observe the ATP release and the intracellular Ca2+increase. In response to stretching (20%), ATP was released only from the foremost cells at the wound edge; it then diffused to the cells behind the wound edge and activated the P2Y receptors, which caused propagating Ca2+waves via TRPC6. This process might facilitate wound closure, because the Ca2+response and wound healing were inhibited in parallel by various inhibitors of ATP-Ca2+signaling. We also applied hyperforin/HP-β-CD on an ex vivo skin model of atopic dermatitis and found that hyperforin/HP-β-CD treatment for 24 h improved the stretch-induced Ca2+responses and oscillations which failed in atopic skin.
authors.affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya 466-8550, Japan; Pixy Central Research Institute, 3-7-1 Kamitsuchidananaka, Ayase, Kanagawa 252-1113, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya 466-8550, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yonekawa
authors.affiliation: Pixy Central Research Institute, 3-7-1 Kamitsuchidananaka, Ayase, Kanagawa 252-1113, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya 466-8550, Japan.
authors.forename: Kishio
authors.identifier: 0000-0003-4714-8689
authors.initials: K
authors.lastname: Furuya
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya 466-8550, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D003505:Cyclodextrins / Q000008:administration & dosage; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D010696:Phloroglucinol / Q000008:administration & dosage / Q000031:analogs & derivatives; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D013314:Stress, Mechanical; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D000074287:TRPC6 Cation Channel; D013729:Terpenes / Q000008:administration & dosage; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D003505:Cyclodextrins; D058470:Receptors, Purinergic P2Y; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D013729:Terpenes; D000255:Adenosine Triphosphate; D010696:Phloroglucinol; C001654:hyperforin