Search

Keita Okoshi,1 Shotaro Ito,1 Megumi Matsuoka,1 Yoshinori Kinugasa,1 Eri Shimizu,2 Kosei Tanaka,2 Joji Okada,3 Takahiro Nishizaka,1 Azumi Nagasawa,1 Tsuyoshi Seki,1 Makoto Iijima,1 Masatoshi Abe,4 Osamu Nemoto4 1Human Health Care Products Research, Kao Corporation, Tokyo, Japan; 2Analytical Science Research, Kao Corporation, Tochigi, Japan; 3Skin Care Products Research, Kao Corporation, Tokyo, Japan; 4Sapporo Skin Clinic, Sapporo, JapanCorrespondence: Azumi Nagasawa, Human Health Care Products Research, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo, 131-8501, Japan, Tel +81-3-5630-7690, Fax +81-3-5630-9342, Email nagasawa.azumi@kao.comPurpose: Atopic dermatitis is characterized by chronic inflammation and dryness accompanied by severe itching. The combined use of moisturizers and topical anti-inflammatory drugs is essential for alleviating atopic dermatitis. We have developed a topical anti-inflammatory drug with a steroid and a moisturizer with heparinoid, both in lamellar structure-based formulations containing synthetic pseudo-ceramides. Here, assessed the efficacy of this combination in the treatment of atopic dermatitis.Methods: We included 22 patients with mild to moderate atopic dermatitis and subjected them to a seven-week treatment with the test formulations, followed by a four-week post-treatment period.Results: Clinical findings and the quality of life of participants remarkably improved after one week of treatment. Furthermore, skin hydration and transepidermal water loss considerably improved at weeks one and three, respectively. The Cer [NP]/[NS] ratio, an indicator of epidermal turnover, substantially increased during the treatment period and remained elevated even thereafter. The improvement in stratum corneum function was distinctive in participants with lower barrier function.Conclusion: These findings indicated that the combined use of the anti-inflammatory drug and moisturizer, both in lamellar structure-based formulations, is effective in treating atopic dermatitis in patients with fragile barrier function.Keywords: base formulations, lamellar structure, steroid, heparinoid, barrier function, TEWL

Megumi Matsuoka,1 Keita Okoshi,1 Shotaro Ito,1 Takuji Kume,2 Tsuyoshi Seki,1 Takahiro Nishizaka,1 Joji Okada,3 Azumi Nagasawa,1 Makoto Iijima,1 Masatoshi Abe,4 Osamu Nemoto4 1Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan; 2Analytical Science Research, Kao Corporation, Wakayama, Japan; 3Skin Care Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan; 4Sapporo Skin Clinic, Sapporo, Hokkaido, JapanCorrespondence: Azumi NagasawaHealth & Wellness Products Research, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo, 131-8501, JapanTel +81-3-5630-9443Fax +81-3-5630-9342Email nagasawa.azumi@kao.comPurpose: Atopic dermatitis (AD) is characterized by chronic inflammation, which frequently recurs, is exacerbated, and enters remission. A maintenance remission period is important for AD patients. We developed a formulation for use during AD remission, containing heparinoid and pseudo-ceramide that forms a lamellar structure. We evaluated the allergen permeability and examined the formulation’s efficacy in maintaining remission in patients with AD.Materials and Methods: Seventeen AD patients applied a cream containing 0.3% heparinoid and pseudo-ceramide (test cream group, n = 10), or a general cream containing 0.3% heparinoid (control cream group, n = 7) to their arm for four weeks after inducing remission with the application of a steroid cream for two weeks.Results: The lamellar structure of the test cream was confirmed with small- and wide-angle x-ray scattering analysis and observation by transmission electron microscopy. The test cream inhibited the penetration of V8 protease significantly compared to the control cream in vitro. According to AD severity score by dermatologists, the effects remission maintenance of the test cream group were comparable to those of the control cream group. However, the test cream group had a significantly increased skin hydration value compared to the control cream group. A significant decrease in transepidermal water loss, an indicator of skin barrier function, was shown in the test cream group compared to the control cream group.Conclusion: The cream with lamellar structures containing heparinoid and pseudo-ceramides may inhibit allergen penetration. Moreover, skin properties improved during the remission period; thus, the formulation we developed was suitable for use during the AD remission period.Keywords: atopic dermatitis, barrier, lamellar, heparinoid, ceramide, skin hydration, transepidermal water loss

Masashi Uehara,1 Yukio Nakamura,1 Jun Takahashi,1 Takako Suzuki,1 Mari Iijima,2 Yuko Arakawa,3 Koichi Ida,4 Tomoki Kosho,5,6 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine; 2Department of Clinical Nutrition, Shinshu University School of Medicine; 3Department of Dentistry and Oral Surgery, Shinshu University School of Medicine; 4Department of Obstetrics and Gynecology, Shinshu University School of Medicine; 5Department of Medical Genetics, Shinshu University School of Medicine; 6Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan Abstract: Appropriate management for osteoporosis in adult patients with Prader-Willi syndrome (PWS) has not been established. We report on a 21-year-old woman with PWS, who underwent denosumab treatment for osteoporosis. She presented with fractures and was shown to have very low bone mineral density (BMD), while she had been treated with supplementation of growth hormone for 7–14 years of age and estrogen from 15 years of age. BMD was monitored in the total hip region by dual-energy X-ray absorptiometry. Laboratory tests included bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, tartrate-resistant acid phosphatase 5b, 1-alpha, 25-dihydroxyvitamin D3, and parathyroid hormone. BMD and laboratory data were evaluated before and at 4, 8, and 13 months of treatment. After 13 months of denosumab therapy, BMD increased by 4.5%, and bone turnover markers notably improved. No fractures occurred. To the best of our knowledge, this is the first report to describe the clinical outcomes of denosumab treatment for osteoporosis in patients with PWS. Based on our findings, denosumab could represent an effective treatment option for osteoporosis in PWS patients. Keywords: bone mineral density, denosumab, fracture, case report, osteoporosis

Qiushi Liu,1,2 Joohee Jung,3,4 Masaharu Somiya,1,2,5 Masumi Iijima,1,2 Nobuo Yoshimoto,1,2 Tomoaki Niimi,1 Andrés D Maturana,1 Seol Hwa Shin,3,6 Seong-Yun Jeong,3,6 Eun Kyung Choi,3,7,8 Shun’ichi Kuroda1,21Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan; 2The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan; 3Institute for Innovative Cancer Research, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea; 5Japan Society for the Promotion of Science, Tokyo, Japan; 6ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 7Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 8Center for Development and Commercialization of Anti-Cancer Therapeutics, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaAbstract: Bionanocapsules (BNCs) are hollow nanoparticles consisting of hepatitis B virus (HBV) envelope L proteins and have been shown to deliver drugs and genes specifically to human hepatic tissues by utilizing HBV-derived infection machinery. The complex of BNCs with liposomes (LPs), the BNC–LP complexes (a LP surrounded by BNCs in a rugged spherical form), could also become active targeting nanocarriers by the BNC function. In this study, under acidic conditions and high temperature, BNCs were found to fully fuse with LPs (smooth-surfaced spherical form), deploying L proteins with a membrane topology similar to that of BNCs (ie, virosomes displaying L proteins). Doxorubicin (DOX) was efficiently encapsulated via the remote loading method at 14.2%±1.0% of total lipid weight (mean ± SD, n=3), with a capsule size of 118.2±4.7 nm and a ζ-potential of -51.1±1.0 mV (mean ± SD, n=5). When mammalian cells were exposed to the virosomes, the virosomes showed strong cytotoxicity in human hepatic cells (target cells of BNCs), but not in human colon cancer cells (nontarget cells of BNCs), whereas LPs containing DOX and DOXOVES (structurally stabilized PEGylated LPs containing DOX) did not show strong cytotoxicity in either cell type. Furthermore, the virosomes preferentially delivered DOX to the nuclei of human hepatic cells. Xenograft mice harboring either target or nontarget cell-derived tumors were injected twice intravenously with the virosomes containing DOX at a low dose (2.3 mg/kg as DOX, 5 days interval). The growth of target cell-derived tumors was retarded effectively and specifically. Next, the combination of high dose (10.0 mg/kg as DOX, once) with tumor-specific radiotherapy (3 Gy, once after 2 hours) exhibited the most effective antitumor growth activity in mice harboring target cell-derived tumors. These results demonstrated that the HBV-based virosomes containing DOX could be an effective antitumor nanomedicine specific to human hepatic tissues, especially in combination with radiotherapy.Keywords: drug delivery system, liposomes, bionanocapsule, doxorubicin, targeting, chemoradiotherapy

Hidenori Matsuo,1 Nobuo Yoshimoto,1 Masumi Iijima,1 Tomoaki Niimi,1 Joohee Jung,2,3 Seong-Yun Jeong,3 Eun Kyung Choi,3,4 Tomomitsu Sewaki,5 Takeshi Arakawa,6,7 Shun’ichi Kuroda11Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan; 2College of Pharmacy, Duksung Women’s University, Seoul, South Korea; 3Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, South Korea; 4Department of Radiation Oncology, University of Ulsan College of Medicine, Seoul, South Korea; 5GenoLac BL Corporation, Okinawa, Japan; 6COMB, Tropical Biosphere Research Center, 7Graduate School of Medicine, University of the Ryukyus, Okinawa, JapanAbstract: Dendritic cells (DCs) are key regulators of adaptive T-cell responses. By capturing exogenous antigens and presenting antigen-derived peptides via major histocompatibility complex molecules to naïve T cells, DCs induce antigen-specific immune responses in vivo. In order to induce effective host immune responses, active delivery of exogenous antigens to DCs is considered important for future vaccine development. We recently generated bionanocapsules (BNCs) consisting of hepatitis B virus surface antigens that mediate stringent in vivo cell targeting and efficient endosomal escape, and after the fusion with liposomes (LP) containing therapeutic materials, the BNC-LP complexes deliver them to human liver-derived tissues in vivo. BNCs were further modified to present the immunoglobulin G (IgG) Fc-interacting domain (Z domain) derived from Staphylococcus aureus protein A in tandem. When mixed with IgGs, modified BNCs (ZZ-BNCs) displayed the IgG Fv regions outwardly for efficient binding to antigens in an oriented-immobilization manner. Due to the affinity of the displayed IgGs, the IgG-ZZ-BNC complexes accumulated in specific cells and tissues in vitro and in vivo. After mixing ZZ-BNCs with antibodies against DCs, we used immunocytochemistry to examine which antibodies delivered ZZ-BNCs to mouse splenic DCs following intravenous injection of the ZZ-BNCs. ZZ-BNCs displaying anti-CD11c monoclonal antibodies (α-CD11c-ZZ-BNCs) were found to accumulate with approximately 62% of splenic DCs, and reside within some of them. After the fusion with liposomes containing antigens, the α-CD11c-ZZ-BNCs could elicit the respective antibodies more efficiently than other nontargeting control vaccines, suggesting that this DC-specific nanocarrier is promising for future vaccines.Keywords: drug-delivery system, gene-delivery system, liposomes, protein A, vaccine, ZZ domain

The periodontal ligament (PDL) contains mesenchymal stem cells (MSCs) that can differentiate into osteoblasts, cementoblasts, and fibroblasts. Nevertheless, the distribution and characteristics of these cells remain uncertain. Gli1, an essential hedgehog signaling transcription factor, functions in undifferentiated cells during embryogenesis. Therefore, in the present study, the differentiation ability of Gli1+ cells was examined using Gli1-CreERT2/ROSA26-loxP-stop-loxP-tdTomato (iGli1/Tomato) mice. In 4-wk-old iGli1/Tomato mice, Gli1/Tomato+ cells were only slightly detected in the PDL, around endomucin-expressing blood vessels. These cells had proliferated over time, localizing in the PDL as well as on the bone and cementum surfaces at day 28. However, in 8-wk-old iGli1/Tomato mice, Gli1/Tomato+ cells were quiescent, as most cells were not immunoreactive for Ki-67. These cells in 8-wk-old mice exhibited high colony-forming unit fibroblast activity and were capable of osteogenic, chondrogenic, and adipogenic differentiation in vitro. In addition, after transplantation of teeth of iGli1/Tomato mice into the hypodermis of wild-type mice, Tomato fluorescence indicating the progeny of Gli1+ cells was detected in the osteoblasts and osteocytes of the regenerated bone. These results demonstrate that Gli1+ cells in the PDL were MSCs and could contribute to the alveolar bone regeneration. [ABSTRACT FROM AUTHOR]