title: Multitargeted effects of hangeshashinto for treatment of chemotherapy-induced oral mucositis on inducible prostaglandin E2 production in human oral keratinocytes.
abstract: OBJECTIVE
  Chemotherapy-induced oral mucositis (COM) is characterized by painful inflammation with prolonged damage that involves the pathological pain-evoking prostaglandin E2 (PGE2). We previously found that gargling with hangeshashinto (HST), a traditional Japanese medicine, was effective for the treatment of COM. However, little is known regarding the mechanisms. Our aim was to identify the active ingredients and clarify the characteristic effects of HST on the PGE2 system.
  
  
  METHODS
  Prostanoids produced by human oral keratinocytes (HOK) stimulated with IL-1β were measured by enzyme immunoassay. Active ingredients that regulate PGE2 production were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and a culture system of HOK cells.
  
  
  RESULTS
  Inducible PGE2, PGD2, and PGF2α, metabolites of cyclooxygenase (COX) pathways, were reduced by HST (10-300 µg/mL) without inducing cytotoxicity. The active ingredients of HST were quantified by LC-MS/MS, and [6]-shogaol, [6]-gingerol, wogonin, baicalein, baicalin, and berberine were shown to reduce PGE2 production. A mixture of these 6 ingredients at concentrations equal to 300 µg/mL of HST strongly suppressed PGE2 production to the same level as HST. [6]-Shogaol and [6]-gingerol did not decrease COX-2 mRNA expression and mostly inhibited PGE2 metabolic activity in an assay using intact HOK cells, suggesting that they regulate PGE2 synthesis at the posttranscriptional level. Wogonin, baicalin, and berberine inhibited expression of COX-2 mRNA without affecting PGE2 metabolic activity. Moreover, wogonin, but not [6]-shogaol, suppressed phosphorylation of mitogen-activated protein kinases (p38s and JNKs).
  
  
  CONCLUSIONS
  These lines show that HST includes several PGE2-regulating ingredients that have different mechanisms and can function as a multicomponent and multitarget agent for treatment of COM, indicating that HST may be beneficial in a new medical strategy for COM treatment.
authors: Hokkaido University, Sapporo, Japan Sapporo Higashi Tokushukai Hospital, Sapporo, Japan kono@toru-kono.com.
authors: Toru
authors: T
authors: Kono
authors: Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan.
authors: Atsushi
authors: A
authors: Kaneko
authors: Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan.
authors: Chinami
authors: C
authors: Matsumoto
authors: Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan.
authors: Chika
authors: C
authors: Miyagi
authors: Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan.
authors: Katsuya
authors: K
authors: Ohbuchi
authors: Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan.
authors: Yasuharu
authors: Y
authors: Mizuhara
authors: National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors: Kanako
authors: K
authors: Miyano
authors: National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors: Yasuhito
authors: Y
authors: Uezono
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D002478:Cells, Cultured; D002853:Chromatography, Liquid / Q000379:methods; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000008:administration & dosage; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D013280:Stomatitis / Q000139:chemically induced / Q000188:drug therapy; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D053583:Interleukin-1beta; C088236:hange-shashinto; D015232:Dinoprostone
keywords: [6]-shogaol; baicalin; hangeshashinto; oral mucositis; prostaglandin E2; wogonin