研究活動情報

• Clinical trial on the efficacy and safety of NPC-15 for patients with xeroderma pigmentosum exaggerated sunburn reaction type: XP-1 study protocol for a multicentre, double-blinded, placebo-controlled, two-group crossover study followed by a long-term open study in Japan.

  Mariko Tsujimoto, Yasumasa Kakei, Nozomi Yamano, Takeshi Fujita, Takehiro Ueda, Ryusuke Ono, Sae Murakami, Shinichi Moriwaki, Chikako Nishigori

  INTRODUCTION: Xeroderma pigmentosum (XP) is a rare intractable disease without a fundamental treatment, presenting with severe photosensitivity, freckle-like pigmented and depigmented maculae and numerous skin cancers before the age of 10 years without strict sun protection. About 70% of the patients exhibit extremely severe sunburn reactions and most of them develop neurological symptoms, including sensorineural hearing impairment and progressive peripheral and central nervous disorders beginning from childhood ages. In the preclinical study, we found that N-acetyl-5-methoxytryptamine was effective in suppressing skin tumour development in addition to improvement of auditory brainstem response in chronically ultraviolet-irradiated XP-A model mice. METHODS AND ANALYSIS: On the bases of the preclinical study, we conduct a clinical trial on the efficacy of NPC-15 for patients with XP with exaggerated sunburn reaction type by a multicentre, double-blinded placebo-controlled, two-group crossover study followed by a 52 weeks open study. ETHICS AND DISSEMINATION: Ethics approval is overseen by the Kobe University Institutional Review Board and Osaka Medical and Pharmaceutical University Institutional Review Board, and the study is conducted in accordance with the approved protocol. All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The data sets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs051210181.

  2023年03月, BMJ open, 13(3) (3), e068112, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Biological Impact of Shorter Wavelength Ultraviolet Radiation-C†.

  Chikako Nishigori, Nozomi Yamano, Makoto Kunisada, Aiko Nishiaki-Sawada, Hiroyuki Ohashi, Tatsushi Igarashi

  Life on earth has constantly coped with the impact of solar radiation, especially solar ultraviolet radiation (solar UV). Various biological mechanisms protect us from solar UV. New devices emitting shorter wavelengths UV-C, i.e. <254 nm emitted by conventional UV germicidal lamps, have emerged. These shorter wavelength UV-C emitting devices are useful for various purposes, including microorganism inactivation. However, as solar UV-C does not reach the earth surface, biological impacts of UV-C has been studied using 254 nm germicidal lamps, and those using shorter wavelength UV-C is rarely known. To balance the utility and risk of UV-C, the biological effect of these new UV-C emitting devices must be investigated. In addition, our knowledge of biological impacts of the wavelength-dependent entire UV (100-400 nm) must be enhanced. In this review, we briefly summarize the biological impacts of shorter wavelength UV-C. Mechanisms of UV-C-induced cellular damage and factors affecting the microorganism inactivation efficiency of UV-C have been discussed. In addition, we theoretically estimate the probable photocarcinogenic action spectrum of shorter wavelength UV-C. We propose that increasing the knowledge on UV-C will facilitate the adoption of shorter wavelength UV-C emitting new devices in an optimal and appropriate manner.

  2023年03月, Photochemistry and photobiology, 99(2) (2), 335 - 343, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• 遠紫外線Far-UVC領域における皮膚への影響

  国定 充, 山野 希, 錦織 千佳子, 西明 愛子, 大橋 広行, 五十嵐 龍志

  (公社)日本皮膚科学会, 2021年07月, 日本皮膚科学会雑誌, 131(8) (8), 1892 - 1892, 日本語


• Evaluation of Acute Reactions on Mouse Skin Irradiated with 222 and 235 nm UV-C.

  Nozomi Yamano, Makoto Kunisada, Aiko Nishiaki-Sawada, Hiroyuki Ohashi, Tatsushi Igarashi, Chikako Nishigori

  Biological response and DNA damage following irradiation with shorter wavelengths in the UV-C range were evaluated to investigate the safety at three wavelengths because of the recent emergence of germicidal equipment emitting short-wavelength UV-C for various purposes, including medical uses. To estimate an acceptable safety dose for human skin in the UV-C range, especially short UV-C, we studied the biological effects of 207, 222 and 235 nm UV-C using albino hairless mice and evaluated the inflammatory reactions in the skin. To explore an appropriate indicator to evaluate the biological response, we employed determination of the minimal perceptible response dose (MPRD), by which any subtle cutaneous response; erythema, edema and scale could be observed by visual inspection. Erythema was rarely observed, but edema and scale formation were evident for short UV-C wavelengths. The MPRD at 207, 222 and 235 nm was determined to be > 15, 15 and 2.0 kJ m-2 , respectively. These values could be thresholds and indicators for possible safety assessments. Our data suggest that the current human exposure limits for short UV-C wavelengths below 254 nm are overly restrictive and should be reconsidered for future disinfection lamps with short UV-C wavelengths.

  2021年07月, Photochemistry and photobiology, 97(4) (4), 770 - 777, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Long-term Effects of 222-nm ultraviolet radiation C Sterilizing Lamps on Mice Susceptible to Ultraviolet Radiation.

  Nozomi Yamano, Makoto Kunisada, Sachiko Kaidzu, Kazunobu Sugihara, Aiko Nishiaki-Sawada, Hiroyuki Ohashi, Ai Yoshioka, Tatsushi Igarashi, Akihiro Ohira, Masaki Tanito, Chikako Nishigori

  Germicidal lamps that emit primarily 254 nm ultraviolet radiation (UV) are routinely utilized for surface sterilization but cannot be used for human skin because they cause genotoxicity. As an alternative, 222-nm UVC has been reported to exert sterilizing ability comparable to that of 254-nm UVC without producing cyclobutane pyrimidine dimers (CPDs), the major DNA lesions caused by UV. However, there has been no clear evidence for safety in chronic exposure to skin, particularly with respect to carcinogenesis. We therefore investigated the long-term effects of 222-nm UVC on skin using a highly photocarcinogenic phenotype mice that lack xeroderma pigmentosum complementation group A (Xpa-) gene, which is involved in repairing of CPDs. CPDs formation was recognized only uppermost layer of epidermis even with high dose of 222-nm UVC exposure. No tumors were observed in Xpa-knockout mice and wild-type mice by repetitive irradiation with 222-nm UVC, using a protocol which had shown to produce tumor in Xpa-knockout mice irradiated with broad-band UVB. Furthermore, erythema and ear swelling were not observed in both genotype mice following 222-nm UVC exposure. Our data suggest that 222-nm UVC lamps can be safely used for sterilizing human skin as far as the perspective of skin cancer development.

  2020年07月, Photochemistry and photobiology, 96(4) (4), 853 - 862, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Exploratory clinical trial on the safety and bactericidal effect of 222-nm ultraviolet C irradiation in healthy humans.

  Tomoaki Fukui, Takahiro Niikura, Takahiro Oda, Yohei Kumabe, Hiroyuki Ohashi, Masahiro Sasaki, Tatsushi Igarashi, Makoto Kunisada, Nozomi Yamano, Keisuke Oe, Tomoyuki Matsumoto, Takehiko Matsushita, Shinya Hayashi, Chikako Nishigori, Ryosuke Kuroda

  INTRODUCTION: Surgical site infection is one of the most severe complications of surgical treatments. However, the optimal procedure to prevent such infections remains uninvestigated. Ultraviolet radiation C (UVC) with a short wavelength has a high bactericidal effect; however, it is cytotoxic. Nonetheless, given that UVC with a wavelength of 222 nm reaches only the stratum corneum, it does not affect the skin cells. This study aimed to investigate the safety of 222-nm UVC irradiation and to examine its skin sterilization effect in healthy volunteers. METHODS: This trial was conducted on 20 healthy volunteers. The back of the subject was irradiated with 222-nm UVC at 50-500 mJ/cm2, and the induced erythema (redness of skin) was evaluated. Subsequently, the back was irradiated with a maximum amount of UVC not causing erythema, and the skin swabs before and after the irradiation were cultured. The number of colonies formed after 24 hours was measured. In addition, cyclobutene pyrimidine dimer (CPD) as an indicator of DNA damage was measured using skin tissues of the nonirradiated and irradiated regions. RESULTS: All subjects experienced no erythema at all doses. The back of the subject was irradiated at 500 mJ/cm2, and the number of bacterial colonies in the skin swab culture was significantly decreased by 222-nm UVC irradiation. The CPD amount produced in the irradiated region was slightly but significantly higher than that of the non-irradiated region. CONCLUSION: A 222-nm UVC at 500 mJ/cm2 was a safe irradiation dose and possessed bactericidal effects. In the future, 222-nm UVC irradiation is expected to contribute to the prevention of perioperative infection.

  2020年, PloS one, 15(8) (8), e0235948, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Agminated fibroblastic connective tissue nevus in a 1-year-old boy.

  Marie Ohata, Susumu Fujiwara, Ai Yoshioka, Hiroshi Nagai, Shintaro Sugita, Nozomi Yamano, Yusuke Inoue, Chikako Nishigori

  Fibroblastic connective tissue nevus (FCTN) is a benign cutaneous mesenchymal lesion characterized by proliferation of CD34-positive fibroblastic/myofibroblastic spindle-shaped cells. We report a case of agminated FCTN on the right lower abdomen of a 1-year-old boy.

  2019年11月, Pediatric dermatology, 36(6) (6), 997 - 998, 英語, 国際誌

  研究論文（学術雑誌）


• 222nm殺菌ランプは紫外線皮膚発癌を起こさない 色素性乾皮症A群モデルマウスでの検討

  山野 希, 国定 充, 海津 幸子, 杉原 一暢, 西明 愛子, 大橋 広行, 吉岡 愛育, 五十嵐 龍志, 谷戸 正樹, 錦織 千佳子

  (公社)日本皮膚科学会, 2019年05月, 日本皮膚科学会雑誌, 129(5) (5), 1170 - 1170, 日本語


• Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice.

  Makoto Kunisada, Nozomi Yamano, Chieko Hosaka, Chihiro Takemori, Chikako Nishigori

  Voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis, we utilized Xpa-knockout mice, which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice. Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. Voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8-dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole-metabolite during UV exposure. The data suggest that voriconazole plus UVB-induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis.

  2018年09月, Photochemistry and photobiology, 94(5) (5), 1077 - 1081, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Reduced size of sebaceous gland and altered sebum lipid composition in mice lacking fatty acid binding protein 5 gene.

  Tomoko Sugawara, Kei Nemoto, Yasuhiro Adachi, Nozomi Yamano, Nobuko Tokuda, Masahiko Muto, Ryuhei Okuyama, Shingo Sakai, Yuji Owada

  Fatty acid binding proteins (FABPs) are capable of binding long-chain FA and are involved in intracellular FA transport and signal transduction. In sebaceous glands, FABP5 is highly expressed in differentiated sebocytes; though, its function remains unclear. In this study, we examined the role of FABP5 in sebocytes using FABP5-deficient mice. The size of sebaceous glands was significantly reduced, while the sebum volume was increased with altered lipid composition in FABP5-deficient mice. However, no significant differences were discerned in the expression of proliferation or differentiation markers including Blimp1, c-myc, Ki67 and peroxisome proliferator-activated receptors (PPAR)γ between wild-type and FABP5-deficient sebaceous glands. The expression of cellular retinoic acid binding protein-2 (CRABP2) that is a competitor of FABP5 for RA signalling was increased in FABP5-deficient mice. These results suggest that FABP5 is involved in the regulation of sebaceous gland activity through modulation of cellular lipid signalling and/or metabolism in the sebocytes.

  2012年07月, Experimental dermatology, 21(7) (7), 543 - 6, 英語, 国際誌

• 254nm以下の短波長UVCにおいて生体に安全に照射可能な線量の検討

  山野希, 国定充, 西明愛子, 大橋広行, 五十嵐龍志, 錦織千佳子

  2021年, 日本光医学・光生物学会, 42nd

• 色素性乾皮症患者の紫外線発癌予防を目的とした日用品の遮光評価基準確立と有用性検証

  山野 希

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2023年04月01日 - 2026年03月31日

  本研究は、紫外線曝露によるDNA損傷の修復機能が欠損した遺伝性疾患である色素性乾皮症(XP)患者の日常生活を支援することを目的とし、UVB・UVA領域で波長ごとに患者の日用品のUV透過率を測定したところ、380-400nmのUVA領域の透過線量に製品ごとの大きなばらつきが生じていることの問題提起を行い、紫外線による非メラノーマ皮膚癌形成は紫外線による紅斑形成とは異なり、UVBだけでなく380nm付近のUVA領域からも影響を受けるため、一般に使用される紫外線対策の基準であるUVprotection factor(UPF)に代わる新たな遮光基準の確立と有用性の検証を行うことを最終目標としている。2023年度の研究計画では、UVB・UVA領域の透過率の実測を、XP患者の使用製品を中心に購入し、紫外線可視分光光度計により測定する予定であった。 まずが使用物品の購入を施行した。しかしながら、XP患者の生活支援を考えた際に、UPFに代わる新たな遮光基準の確立に先行して、科研費作成時には想定していなかった、測定時の検出感度について検討する必要があると考えた。 XP患者は遮光対策指導において、日の出～日没までの日中は紫外線防護服の着用が必須であり、夜間であれば、防護服を脱いでの生活は問題ないとされている。しかしながら、その結果、紫外線曝露強度がどの程度低下しているかを、具体的に製品ごとに区別可能な検出限界をもつ紫外線強度計が存在せず、測定不可能な現状を把握したためである。 そのため、透過率測定機器、また、遮光環境下の体表面の紫外線曝露強度を測定する機器の開発を現在先行して取り組んでいる。