755 results on '"Hideoki Ogawa"'
Search Results
2. The protective role of conjunctival goblet cell mucin sialylation
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Moe Matsuzawa, Tomoaki Ando, Saaya Fukase, Meiko Kimura, Yasuharu Kume, Takuma Ide, Kumi Izawa, Ayako Kaitani, Mutsuko Hara, Eri Nakamura, Anna Kamei, Akira Matsuda, Nobuhiro Nakano, Keiko Maeda, Norihiro Tada, Hideoki Ogawa, Ko Okumura, Akira Murakami, Nobuyuki Ebihara, and Jiro Kitaura
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Gel-forming mucins secreted by conjunctival goblet cells have been implicated in the clearance of allergens, pathogens, and debris. However, their roles remain incompletely understood. Here we show that human and mouse conjunctival goblet cell mucins have Alcian blue-detectable sialic acids, but not sulfates in the steady state. Interestingly, Balb/c mouse strain lacks this sialylation due to a point mutation in a sialyltransferase gene, St6galnac1, which is responsible for sialyl-Tn synthesis. Introduction of intact St6galnac1 to Balb/c restores the sialylation of conjunctival goblet cell mucus. Sialylated mucus efficiently captures and encapsulates the allergen particles in an impenetrable layer, leading to the protection of mice from the development of allergic conjunctivitis. Expression of ST6GALNAC1 and sialyl-Tn is upregulated in humans under conditions with chronic stimuli. These results indicate that the sialylated glycans on the ocular mucins play an essential role in maintaining the conjunctival mucosa by protecting from the incoming foreign bodies such as allergen particles.
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- 2023
3. Antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 improves diabetic wound healing
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Hainan Yue, Pu Song, Nutda Sutthammikorn, Yoshie Umehara, Juan Valentin Trujillo‐Paez, Hai Le Thanh Nguyen, Miho Takahashi, Ge Peng, Risa Ikutama, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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Keratinocytes ,Mice ,Wound Healing ,Glucose ,Cell Movement ,Somatomedins ,Animals ,Surgery ,Dermatology ,Adenosine Monophosphate ,Antimicrobial Peptides ,Diabetes Mellitus, Experimental - Abstract
Impaired keratinocyte functions are major factors that are responsible for delayed diabetic wound healing. In addition to its antimicrobial activity, the antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) activates mast cells and promotes keratinocyte and fibroblast proliferation and migration. However, its effects on diabetic wound healing remain unclear. Human keratinocytes were cultured in normal or high glucose milieus. The production of angiogenic growth factor and cell proliferation and migration were evaluated. Wounds in normal and streptozotocin-induced diabetic mice were monitored and histologically examined. We found that AMP-IBP5 rescued the high glucose-induced attenuation of proliferation and migration as well as the production of angiogenin and vascular endothelial growth factors in keratinocytes. The AMP-IBP5-induced activity was mediated by the epidermal growth factor receptor, signal transducer and activator of transcription 1 and 3, and mitogen-activated protein kinase pathways, as indicated by the inhibitory effects of pathway-specific inhibitors. In vivo, AMP-IBP5 markedly accelerated wound healing, increased the expression of angiogenic factors and promoted vessel formation in both normal and diabetic mice. Overall, the finding that AMP-IBP5 accelerated diabetic wound healing by protecting against glucotoxicity and promoting angiogenesis suggests that AMP-IBP5 might be a potential therapeutic target for treating chronic diabetic wounds.
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- 2022
4. Pollen shells and soluble factors play non-redundant roles in the development of allergic conjunctivitis in mice
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Keiko Maeda, Hideoki Ogawa, Yusuke Sone, Ko Okumura, Nobuyuki Ebihara, Mayuki Kojima, Tomoaki Ando, Toshiaki Shimizu, Jiro Kitaura, Kumi Izawa, Meiko Kimura, Moe Matsuzawa, Ayako Kaitani, Nobuhiro Nakano, Anna Kamei, Saaya Fukase, Akira Murakami, and Makoto Nishiyama
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Mice, Inbred BALB C ,Conjunctiva ,biology ,Chemistry ,Allergens ,Eosinophil ,medicine.disease_cause ,medicine.disease ,Allergic conjunctivitis ,Interleukin 33 ,Mice ,Ophthalmology ,medicine.anatomical_structure ,Immune system ,Pollen ,Immunology ,otorhinolaryngologic diseases ,medicine ,biology.protein ,Animals ,Antibody ,Sensitization ,Conjunctivitis, Allergic - Abstract
Purpose We aimed to clarify the role of particulate allergen exposure to the conjunctiva in the development of allergic conjunctivitis. Methods We administered ragweed pollen suspension, pollen extract, pollen shell, particulate air pollutants, and their combinations to the mouse conjunctiva five days a week without prior sensitization. Clinical signs were scored. Histological changes, cellular infiltrations, mRNA expressions, lymph node cell recall responses, and serum immunoglobulin levels were assessed. Immune cell-depleting antibodies and ST2 knockout mice were used to investigate the cellular and molecular requirements. Results Pollen suspension, but not the extract or shell alone, induced robust eosinophilic conjunctivitis, accompanied by a proliferative response of epithelial cells. A combination of pollen extract and shell completely restored eosinophil accumulation. In addition, eosinophilic conjunctivitis was induced by a mixture of particulate air pollutants and pollen extract. Mechanistically, eosinophil accumulation was ameliorated by deficiency of the IL-33 receptor ST2 and abolished by depleting CD4+ T cells. Pollen shells, but not the extract, induced IL-33 release from conjunctival epithelial cells in vivo. Conclusions Our results indicate the non-redundant roles for the allergens’ particulate properties and soluble factors in the development of allergic conjunctivitis.
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- 2021
5. Lysophosphatidylglucoside is a GPR55 -mediated chemotactic molecule for human monocytes and macrophages
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Hideoki Ogawa, Yasuko Nagatsuka, Madoka Kage, Tomomi Hotta, Yoshio Hirabayashi, Kenji Takamori, Kazuhisa Iwabuchi, Hitoshi Nakayama, Kei Hanafusa, Koki Kano, Ichiro Matsuo, Eriko Oshima, Noriko Yokoyama, and Xiaojia Li
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THP-1 Cells ,Blotting, Western ,Biophysics ,Biochemistry ,Monocytes ,chemistry.chemical_compound ,Glucosides ,Cell Movement ,medicine ,Cannabinoid receptor type 2 ,Humans ,Inverse agonist ,Macrophage ,Receptors, Cannabinoid ,Receptor ,Neutrophil homeostasis ,Molecular Biology ,Chemotaxis ,Macrophages ,Monocyte ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,chemistry ,Lysophosphatidylinositol ,RNA Interference ,Lysophospholipids - Abstract
Neutrophils undergo spontaneous apoptosis within 24–48 h after leaving bone marrow. Apoptotic neutrophils are subsequently phagocytosed and cleared by macrophages, thereby maintaining neutrophil homeostasis. Previous studies have demonstrated involvement of lysophosphatidylglucoside (lysoPtdGlc), a degradation product of PtdGlc, in modality-specific repulsive guidance of spinal sensory axons, via its specific receptor GPR55. In the present study, using human monocytic cell line THP-1 as a model, we demonstrated that lysoPtdGlc induces monocyte/macrophage migration with typical bell-haped curve and a peak at concentration 10−9 M. Lysophosphatidylinositol (lysoPtdIns), a known GPR55 ligand, induced migration at higher concentration (10−7 M). LysoPtdGlc-treated cells had a polarized shape, whereas lysoPtdIns-treated cells had a spherical shape. In EZ-TAXIScan (chemotaxis) assay, lysoPtdGlc induced chemotactic migration activity of THP-1 cells, while lysoPtdIns induced random migration activity. GPR55 antagonist ML193 inhibited lysoPtdGlc-induced THP-1 cell migration, whereas lysoPtdIns-induced migration was inhibited by CB2-receptor inverse agonist. SiRNA experiments showed that GPR55 mediated lysoPtdGlc-induced migration, while lysoPtdIns-induced migration was mediated by CB2 receptor. Our findings, taken together, suggest that lysoPtdGlc functions as a chemotactic molecule for human monocytes/macrophages via GPR55 receptor, while lysoPtdIns induces random migration activity via CB2 receptor.
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- 2021
6. ESDR180 - The antimicrobial peptide derived from insulin-like growth factor-binding protein 5 promotes skin barrier function and relieves dermatitis-like symptoms in a mouse model of atopic dermatitis
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François Niyonsaba, Shigaku Ikeda, Hideoki Ogawa, Ko Okumura, Hainan Yue, Juan Valentin Jujillo-paez, Ge Peng, and Hai Nguyen
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- 2022
7. ESDR192 - Betacellulin alleviates Th2 cytokine-mediated impairment of skin tight junction barrier through epidermal growth factor receptor and protein kinase C pathway
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François Niyonsaba, Shigaku Ikeda, Hideoki Ogawa, Ko Okumura, Saya Tsukamoto, and Ge Peng
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- 2022
8. Sensitization to macadamia 7S globulin amino-terminus with clinical relevance in Japanese children with macadamia nut allergy
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Tomoaki Ando, Jiro Kitaura, Nobuyuki Maruyama, Masami Narita, Katsushi Miura, Yoshihiro Takasato, Kazutaka Nogami, Mizuho Nagao, Ko Okumura, Hideoki Ogawa, Hiroaki Onishi, Takashi Watanabe, Komei Ito, Takao Fujisawa, Motohiro Ebisawa, Toshiaki Kawakami, Kenji Matsumoto, Shunji Hasegawa, Yukihiro Ohya, and Hiroki Yasudo
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Immunology and Allergy ,General Medicine - Published
- 2022
9. Calcitriol, an Active Form of Vitamin D3, Mitigates Skin Barrier Dysfunction in Atopic Dermatitis NC/Nga Mice
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Yoshie Umehara, Juan Valentin Trujillo-Paez, Hainan Yue, Ge Peng, Hai Le Thanh Nguyen, Ko Okumura, Hideoki Ogawa, and François Niyonsaba
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Inorganic Chemistry ,calcitriol ,atopic dermatitis ,skin barrier function ,tight junction ,Dermatophagoides farinae body ointment-induced NC/Nga mouse model of atopic dermatitis ,transepidermal water loss ,tight junction permeability assay ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients’ quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.
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- 2023
10. Cathelicidin LL-37 Activates Human Keratinocyte Autophagy through the P2X₇, Mechanistic Target of Rapamycin, and MAPK Pathways
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Risa Ikutama, Ge Peng, Saya Tsukamoto, Yoshie Umehara, Juan Valentin Trujillo-Paez, Hainan Yue, Hai Le Thanh Nguyen, Miho Takahashi, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry - Abstract
Human cathelicidin LL-37 is a multifunctional antimicrobial peptide that exhibits antimicrobial and immunomodulatory activities. LL-37 regulates skin barrier function and was recently reported to activate autophagy in macrophages. Because autophagy deficiency is associated with skin diseases characterized by a dysfunctional epidermal barrier, we hypothesized that LL-37 might regulate the skin barrier through autophagy modulation. We showed that LL-37 activated autophagy in human keratinocytes and three-dimensional skin equivalent models as indicated by increases in LC3 puncta formation, decreases in p62, and autophagosome and autolysosome formation. LL-37‒induced autophagy was suppressed by P2X
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- 2023
11. A Possible Association Between a Nucleotide‐Binding Domain LRR‐Containing Protein Family PYD‐Containing Protein 1 Mutation and an Autoinflammatory Disease Involving Liver Cirrhosis
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Junko Takita, Toshiaki Shimizu, Ayako Kaitani, Hideoki Ogawa, Anna Kamei, Kenichi Yoshida, Junichi Kaneko, Nobuhiro Nakano, Hexing Wang, Koichiro Uchida, Masafumi Seki, Shigeru Nomura, Tomoaki Ando, Kiyoshi Hasegawa, Hiroki Yasudo, Seishi Ogawa, Yoko Okamoto, Nobuyuki Ebihara, Akie Maehara, Kumi Izawa, Ko Okumura, Mayuki Kojima, Hirotsugu Oda, Naoto Tamura, Atsushi Tanabe, Taiki Ando, Meiko Kimura, and Jiro Kitaura
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Liver Cirrhosis ,0301 basic medicine ,Cirrhosis ,Adolescent ,Protein family ,Inflammasomes ,Autoimmunity ,NLR Proteins ,Biology ,03 medical and health sciences ,Papillon-Lefevre Disease ,0302 clinical medicine ,medicine ,Humans ,Autoinflammatory disease ,Genetics ,Hepatology ,Interleukin-18 ,Inflammasome ,medicine.disease ,Liver Transplantation ,Treatment Outcome ,030104 developmental biology ,Liver ,Cyclic nucleotide-binding domain ,Mutation ,Mutation (genetic algorithm) ,Female ,030211 gastroenterology & hepatology ,Interleukin 18 ,medicine.drug - Published
- 2021
12. Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections
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Juan Valentin Trujillo-Paez, Ko Okumura, Shigaku Ikeda, Ge Peng, Panjit Chieosilapatham, Pu Song, François Niyonsaba, Chanisa Kiatsurayanon, Yoshie Umehara, Hai Le Thanh Nguyen, Hideoki Ogawa, and Hainan Yue
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0301 basic medicine ,Molluscum Contagiosum ,Immunology ,Provocation test ,Kaposi Varicelliform Eruption ,Disease ,Dermatitis, Atopic ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Food allergy ,medicine ,Genetic predisposition ,Humans ,Immunology and Allergy ,Skin Diseases, Infectious ,Skin ,Asthma ,business.industry ,Microbiota ,Atopic dermatitis ,medicine.disease ,030104 developmental biology ,030228 respiratory system ,Irritants ,Etiology ,business - Abstract
Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and health-care costs. The pathogenesis of AD is complicated and multifactorial. Although the etiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction, and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal, and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.
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- 2021
13. Identification of Fungi by Conventional Microscopy Combined with Novel MALDI-TOF MS Mass Spectrometry
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Jeerapa Damrongpokkaphan, Shigaku Ikeda, Shigeki Misawa, Takasuke Ogawa, Masayoshi Chonan, Arunwan Chantarat, Satoshi Hirayama, Takashi Miida, Hideoki Ogawa, and Yoko Tabe
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Matrix-assisted laser desorption/ionization ,Chromatography ,Chemistry ,Microscopy ,Identification (biology) ,Mass spectrometry - Published
- 2021
14. Inhibition of Both Cyclooxygenase-1 and -2 Promotes Epicutaneous Th2 and Th17 Sensitization and Allergic Airway Inflammation on Subsequent Airway Exposure to Protease Allergen in Mice
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Shigaku Ikeda, Seiji Kamijo, Yukihiko Sugimoto, Punyada Suchiva, Hideoki Ogawa, Natsuko Maruyama, Takehiko Yokomizo, Ko Okumura, and Toshiro Takai
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Proteases ,Allergy ,medicine.medical_treatment ,Immunology ,Immunoglobulin E ,medicine.disease_cause ,Mice ,Th2 Cells ,Immune system ,Allergen ,T-Lymphocyte Subsets ,Papain ,Respiratory Hypersensitivity ,medicine ,Animals ,Immunology and Allergy ,Cyclooxygenase Inhibitors ,Sensitization ,Skin ,biology ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Cell Differentiation ,General Medicine ,Allergens ,respiratory system ,medicine.disease ,respiratory tract diseases ,Cytokine ,medicine.anatomical_structure ,Cyclooxygenase 2 ,Cyclooxygenase 1 ,Experimental Allergy − Research Article ,biology.protein ,Th17 Cells ,Female ,Immunization ,Cyclooxygenase ,business ,Peptide Hydrolases - Abstract
Introduction: Epicutaneous (e.c.) allergen exposure is an important route of sensitization toward allergic diseases in the atopic march. Allergen sources such as house dust mites contain proteases that involve in the pathogenesis of allergy. Prostanoids produced via pathways downstream of cyclooxygenases (COXs) regulate immune responses. Here, we demonstrate effects of COX inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) on e.c. sensitization to protease allergen and subsequent airway inflammation in mice. Methods: Mice were treated with NSAIDs during e.c. sensitization to a model protease allergen, papain, and/or subsequent intranasal challenge with low-dose papain. Serum antibodies, cytokine production in antigen-restimulated skin or bronchial draining lymph node (DLN) cells, and airway inflammation were analyzed. Results: In e.c. sensitization, treatment with a nonspecific COX inhibitor, indomethacin, promoted serum total and papain-specific IgE response and Th2 and Th17 cytokine production in skin DLN cells. After intranasal challenge, treatment with indomethacin promoted allergic airway inflammation and Th2 and Th17 cytokine production in bronchial DLN cells, which depended modestly or largely on COX inhibition during e.c. sensitization or intranasal challenge, respectively. Co-treatment with COX-1-selective and COX-2-selective inhibitors promoted the skin and bronchial DLN cell Th cytokine responses and airway inflammation more efficiently than treatment with either selective inhibitor. Conclusion: The results suggest that the overall effects of COX downstream prostanoids are suppressive for development and expansion of not only Th2 but also, unexpectedly, Th17 upon exposure to protease allergens via skin or airways and allergic airway inflammation.
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- 2021
15. Skin Treatment with Detergent Induces Dermatitis with H1-Antihistamine-Refractory Itch and Upregulates IL-4 and Th17/Th22 Cytokine Gene Expression in C57BL/6 Mice
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Yurie Masutani, Toshiro Takai, Seiji Kamijo, Toru Kimitsu, Tomoko Yoshimura, Saori Ichikawa, Saya Shimizu, Takasuke Ogawa, Keiko Takada, Mitsutoshi Tominaga, Hajime Suto, Kenji Takamori, Hideoki Ogawa, Ko Okumura, and Shigaku Ikeda
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Inflammation ,Pruritus ,Immunology ,Detergents ,Interleukin-17 ,Sodium ,Histamine Antagonists ,Gene Expression ,Water ,Dermatitis ,Forkhead Transcription Factors ,General Medicine ,T-Lymphocytes, Helper-Inducer ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Mice, Inbred C57BL ,Mice ,Irritants ,Immunology and Allergy ,Animals ,Cytokines ,Interleukin-4 ,Skin - Abstract
Introduction: Repeated skin contact to detergents causes chronic irritant contact dermatitis (ICD) associated with itch sensation and eczema. However, the mechanisms of detergent-induced ICD are poorly understood. Here, we established a new murine model of detergent-induced ICD with H1-antihistamine-refractory itch. Methods: Ear skin of wild-type and mast cell-deficient mice on the C57BL/6 genetic background was treated with a detergent, sodium dodecyl/lauryl sulfate (SDS), daily for approximately 2 weeks with or without administration of an H1-antihistamine, fexofenadine. Skin inflammation, barrier dysfunction, and itching were analyzed. Quantitative PCR for earlobe gene expression and flow cytometry analysis for draining lymph node cells were conducted. Results: SDS treatment induced skin inflammation with ear swelling, increased transepidermal water loss, and hind-paw scratching behaviors in the wild-type and mast cell-deficient mice. The peak value of scratching bouts was retained for at least 48 h after the last SDS treatment. H1-antihistamine administration showed no or little reduction in the responses. SDS treatment upregulated gene expression for a Th2 cytokine IL-4 and Th17/Th22 cytokines, IL-17A, IL-17F, and IL-22, and increased cell numbers in draining lymph nodes of CD4+ T, CD8+ T, and γδT cells with enhanced expression of GATA3, RORγt, T-bet, or FOXP3 compared with untreated mice. Conclusions: The present study showed that SDS treatment of ear skin in C57BL/6 mice induces mast cell-independent skin inflammation with H1-antihistamine-refractory itch and suggested a possible Th cytokine- and/or lymphocyte-mediated regulation of the model. The model would be useful for elucidation of mechanisms for inflammation with H1-antihistamine-refractory itch in detergent-induced ICD.
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- 2022
16. Soluble CD30 Levels in the Sera of Patients With Psoriasis in Myanmar
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Myat Sanda Kyaw, Shigaku Ikeda, Hideoki Ogawa, and Hitoshi Tsuchihashi
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0301 basic medicine ,Thesaurus (information retrieval) ,business.industry ,Dermatology ,Disease ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Soluble cd30 ,Rheumatology ,030220 oncology & carcinogenesis ,Psoriasis ,Immunology ,Medicine ,Family history ,business - Abstract
Background: Although psoriasis is a Th1-dominant disease, certain investigations have also revealed the involvement of Th2 cells in the disease. Soluble CD30 (sCD30) is predominantly associated with various Th2 diseases. Therefore, the role of sCD30 in psoriasis requires further evaluation. Objectives: To evaluate the association between sCD30 and psoriasis. Methods: In this cross-sectional analytical study, the association between serum sCD30 levels and psoriasis was evaluated using enzyme-linked immunosorbent assay in sera obtained from patients with psoriasis. Results: The results indicated elevated sCD30 levels in 79 patients with psoriasis, and the levels were significantly higher in those with a prolonged duration of disease (duration > 10 years). Furthermore, there was a significant positive correlation between the duration of disease (years) and sCD30 (pg/mL) levels. These findings suggest that sCD30 is a useful marker for chronicity of psoriasis. Conclusion: Elevated sCD30 levels in psoriasis are associated with disease duration, and they may reflect the chronicity of psoriasis. Further research is required to determine the role of sCD30 in psoriasis.
- Published
- 2020
17. Effects of Kakato‐tsurutsuru socks on dry heels in healthy volunteer subjects
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Atsuko Kamo, Yayoi Kamata, Hideoki Ogawa, Kenji Takamori, Mitsutoshi Tominaga, Yasushi Suga, Yoshie Umehara, Makoto Iwata, and Osamu Negi
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Male ,medicine.medical_specialty ,Heel ,Visual analogue scale ,computer.internet_protocol ,Dermatology ,Clothing ,SWEAT ,Desquamation ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Skin hydration ,0302 clinical medicine ,Double-Blind Method ,Japan ,parasitic diseases ,Healthy volunteers ,medicine ,Humans ,Aged ,Cross-Over Studies ,Emollients ,integumentary system ,business.industry ,General Medicine ,Middle Aged ,Water Loss, Insensible ,Healthy Volunteers ,Treatment Outcome ,medicine.anatomical_structure ,SOCKS ,030220 oncology & carcinogenesis ,Dryness ,Female ,Epidermis ,medicine.symptom ,business ,computer - Abstract
Kakato-tsurutsuru (Kt) socks have been selling for almost 30 years in Japan. Wearers claim they improve heel dryness despite no scientific evidence. We investigated the effects of Kt socks on heel dryness by questionnaire, clinical scores and non-invasive skin measurements. In a double-blind, randomized cross-over study, 10 healthy volunteers wore control or Kt socks over 2 weeks in sequence for 4 weeks. Skin hydration and evaporation of the medial and dorsal heel were measured before and every week during the trial. Clinical evaluations of desquamation and cracked skin were scored by a dermatologist. A visual analog scale (VAS) questionnaire of comfort, sock climate humidity and skin dryness was conducted. The VAS of comfort was significantly higher in Kt than controls. Average Δskin dryness in control and Kt groups was -1.63 and 2.22, respectively, showing a significant improvement. In the clinical findings of the dorsal side of the heel, Δdesquamation and Δcracked skin scores were significantly decreased and Δstratum corneum hydration significantly increased in Kt compared with controls. Kt socks may retain evaporated sweat with components of natural moisturizing factors, supporting the water-holding ability of the heel stratum corneum. These findings suggest that Kt socks may improve heel skin dryness.
- Published
- 2020
18. A Case of Bullous Pemphigoid Patient Suggesting the Importance of Anti-BP180 Measurement
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Takasuke Ogawa, Yoko Tabe, Shigaku Ikeda, Kotoko Yamatani, Takashi Miida, Mika Iimura, Hideoki Ogawa, Jeerapa Damrongpokkaphan, Arunwan Chantarat, Etsuko Urabe, Masami Sugihara, Keiichi Sasahara, and Satoshi Hirayama
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medicine.medical_specialty ,business.industry ,medicine ,Bullous pemphigoid ,medicine.disease ,business ,Dermatology - Published
- 2020
19. The Antimicrobial Peptides Human β-Defensins Induce the Secretion of Angiogenin in Human Dermal Fibroblasts
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Yoshie Umehara, Miho Takahashi, Hainan Yue, Juan Valentin Trujillo-Paez, Ge Peng, Hai Le Thanh Nguyen, Ko Okumura, Hideoki Ogawa, and François Niyonsaba
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beta-Defensins ,Organic Chemistry ,NF-kappa B ,General Medicine ,Ribonuclease, Pancreatic ,Fibroblasts ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,ErbB Receptors ,Anti-Infective Agents ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,human β-defensin (hBD) ,dermal fibroblast ,angiogenin ,angiogenesis ,Spectroscopy ,Antimicrobial Peptides ,Cells, Cultured - Abstract
The skin produces a plethora of antimicrobial peptides that not only show antimicrobial activities against pathogens but also exhibit various immunomodulatory functions. Human β-defensins (hBDs) are the most well-characterized skin-derived antimicrobial peptides and contribute to diverse biological processes, including cytokine production and the migration, proliferation, and differentiation of host cells. Additionally, hBD-3 was recently reported to promote wound healing and angiogenesis, by inducing the expression of various angiogenic factors and the migration and proliferation of fibroblasts. Angiogenin is one of the most potent angiogenic factors; however, the effects of hBDs on angiogenin production in fibroblasts remain unclear. Here, we investigated the effects of hBDs on the secretion of angiogenin by human dermal fibroblasts. Both in vitro and ex vivo studies demonstrated that hBD-1, hBD-2, hBD-3, and hBD-4 dose-dependently increased angiogenin production by fibroblasts. hBD-mediated angiogenin secretion involved the epidermal growth factor receptor (EGFR), Src family kinase, c-Jun N-terminal kinase (JNK), p38, and nuclear factor-kappa B (NF-κB) pathways, as evidenced by the inhibitory effects of specific inhibitors for these pathways. Indeed, we confirmed that hBDs induced the activation of the EGFR, Src, JNK, p38, and NF-κB pathways. This study identified a novel role of hBDs in angiogenesis, through the production of angiogenin, in addition to their antimicrobial activities and other immunomodulatory properties.
- Published
- 2022
20. Psoriatic lesional expression of SARS-CoV-2 receptor ACE2 is reduced by blockade of IL-17 signaling but not by other biologic treatments
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Ge Peng, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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Molecule-targeted therapy ,Biological Products ,IL-17 ,SARS-CoV-2 ,Interleukin-17 ,COVID-19 ,Humans ,Psoriasis ,ACE2 ,Dermatology ,Angiotensin-Converting Enzyme 2 ,Article - Published
- 2021
21. Human β-defensin-3 attenuates atopic dermatitis-like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway
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Ge Peng, Saya Tsukamoto, Risa Ikutama, Hai Le Thanh Nguyen, Yoshie Umehara, Juan V. Trujillo-Paez, Hainan Yue, Miho Takahashi, Takasuke Ogawa, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Jiro Kitaura, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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Inflammation ,Keratinocytes ,Mice ,beta-Defensins ,Receptors, Aryl Hydrocarbon ,Autophagy ,Animals ,Humans ,General Medicine ,Dermatitis, Atopic ,Signal Transduction - Abstract
Human β-defensin-3 (hBD-3) exhibits antimicrobial and immunomodulatory activities; however, its contribution to autophagy regulation remains unclear, and the role of autophagy in the regulation of the epidermal barrier in atopic dermatitis (AD) is poorly understood. Here, keratinocyte autophagy was restrained in the skin lesions of patients with AD and murine models of AD. Interestingly, hBD-3 alleviated the IL-4- and IL-13-mediated impairment of the tight junction (TJ) barrier through keratinocyte autophagy activation, which involved aryl hydrocarbon receptor (AhR) signaling. While autophagy deficiency impaired the epidermal barrier and exacerbated inflammation, hBD-3 attenuated skin inflammation and enhanced the TJ barrier in AD. Importantly, hBD-3-mediated improvement of the TJ barrier was abolished in autophagy-deficient AD mice and in AhR-suppressed AD mice, suggesting a role for hBD-3-mediated autophagy in the regulation of the epidermal barrier and inflammation in AD. Thus, autophagy contributes to the pathogenesis of AD, and hBD-3 could be used for therapeutic purposes.
- Published
- 2021
22. The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway
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Miho Takahashi, Yoshie Umehara, Hainan Yue, Juan Valentin Trujillo-Paez, Ge Peng, Hai Le Thanh Nguyen, Risa Ikutama, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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STAT3 Transcription Factor ,beta-Defensins ,Angiogenesis ,proliferation ,medicine.medical_treatment ,Immunology ,wound healing ,migration ,Fibroblast growth factor ,Models, Biological ,fibroblast ,angiogenesis ,Mice ,Cell Movement ,medicine ,Animals ,Humans ,Immunology and Allergy ,Phosphorylation ,Fibroblast ,Original Research ,Cell Proliferation ,Chemistry ,Fibroblast growth factor receptor 1 ,Growth factor ,human β-defensin ,Cell migration ,RC581-607 ,Fibroblasts ,Janus Kinase 2 ,Receptors, Fibroblast Growth Factor ,Cell biology ,medicine.anatomical_structure ,Fibroblast growth factor receptor ,Matrix Metalloproteinase 2 ,Angiogenesis Inducing Agents ,Immunologic diseases. Allergy ,Wound healing ,Antimicrobial Peptides ,Biomarkers ,Signal Transduction - Abstract
In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.
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- 2021
23. Experimental and Clinical Evidence Suggests That Treatment with Betacellulin Can Alleviate Th2-Type Cytokine-Mediated Impairment of Skin Barrier Function
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Ge Peng, Saya Tsukamoto, Yoshie Umehara, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba
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Keratinocytes ,Interleukin-13 ,Organic Chemistry ,General Medicine ,Ligands ,Catalysis ,Dermatitis, Atopic ,Computer Science Applications ,ErbB Receptors ,Inorganic Chemistry ,betacellulin ,atopic dermatitis ,biomarker ,keratinocyte ,skin barrier ,Cytokines ,Humans ,Interleukin-4 ,Betacellulin ,Physical and Theoretical Chemistry ,Molecular Biology ,Protein Kinase C ,Spectroscopy ,Skin - Abstract
Betacellulin (BTC) is a peptide ligand that belongs to the epidermal growth factor family, the members of which have been implicated in skin morphogenesis, homeostasis, repair, and angiogenesis; however, the role of BTC in the regulation of the skin barrier remains unknown. To examine the role of BTC in skin barrier function, we analyzed atopic dermatitis (AD) transcriptomic data from Gene Expression Omnibus (GEO) datasets, performed BTC immunohistochemistry using human skin tissues, and evaluated the effects of BTC on primary human keratinocytes by real-time PCR, Western blotting, and assay of the transepidermal electrical resistance (TER), a functional parameter to monitor the tight junction barrier. We found that the gene expression of BTC was downregulated in skin lesions from patients with AD, and this downregulated expression recovered following biological treatments. Consistently, the BTC protein levels were downregulated in the lesional skin of AD patients compared with the normal skin of healthy participants, suggesting that the BTC levels in skin might be a biomarker for the diagnosis and therapy of AD. Furthermore, in human keratinocytes, BTC knockdown reduced the levels of skin-derived antimicrobial peptides and skin barrier-related genes, whereas BTC addition enhanced their levels. Importantly, in human skin equivalents, BTC restored the increased tight junction permeability induced by Th2 cytokine IL-4/IL-13 treatment. In addition, specific inhibitors of epidermal growth factor receptor (EGFR) and protein kinase C (PKC) abolished the BTC-mediated improvement in skin barrier-related proteins in keratinocyte monolayers. Collectively, our findings suggest that treatment with BTC might improve the Th2-type cytokine-mediated impairment of skin barrier function through the EGFR/PKC axis and that BTC might be a novel potential biomarker and therapeutic target for the treatment of skin conditions characterized by the overproduction of Th2 cytokines and dysfunctional skin barriers, such as AD.
- Published
- 2022
24. Regulatory T Cells Exhibit Interleukin-33-Dependent Migratory Behavior during Skin Barrier Disruption
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Catharina Sagita Moniaga, Sumika Toyama, Mitsutoshi Tominaga, Masaru Kurosawa, Hideoki Ogawa, Kenji Takamori, and Susumu Nakae
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0301 basic medicine ,Male ,QH301-705.5 ,chemical and pharmacologic phenomena ,Dermatitis ,T-Lymphocytes, Regulatory ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Cell Movement ,homeostasis ,Animals ,skin barrier ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Skin ,Mice, Knockout ,integumentary system ,Chemistry ,Chemotaxis ,Organic Chemistry ,FOXP3 ,Interleukin ,Forkhead Transcription Factors ,General Medicine ,Interleukin-33 ,Computer Science Applications ,Cell biology ,Interleukin 33 ,Mice, Inbred C57BL ,Treg ,030104 developmental biology ,030220 oncology & carcinogenesis ,Knockout mouse ,IL-33 ,dry skin ,Homeostasis ,Transforming growth factor ,Chemotaxis assay ,acanthosis - Abstract
Regulatory T cells (Tregs) suppress immune responses and maintain immunological self-tolerance and homeostasis. We currently investigated relationships between skin barrier condition and Treg behavior using skin barrier-disrupted mice. Skin barrier disruption was induced by repeated topical application of 4% sodium dodecyl sulfate (SDS) on mice. The number of CD4+ forkhead box protein P3 (Foxp3)+ Tregs was higher in 4% SDS-treated skins than in controls. This increasing was correlated with the degree of acanthosis. The numbers of interleukin (IL)-10+ and transforming growth factor (TGF)-β+ Tregs also increased in 4% SDS-treated skins. Localization of IL-33 in keratinocytes shifted from nucleus to cytoplasm after skin barrier disruption. Notably, IL-33 promoted the migration of Tregs in chemotaxis assay. The skin infiltration of Tregs was cancelled in IL-33 neutralizing antibody-treated mice and IL-33 knockout mice. Thus, keratinocyte-derived IL-33 may induce Treg migration into barrier-disrupted skin to control the phase transition between healthy and inflammatory conditions.
- Published
- 2021
25. Implication of Antimicrobial Peptides in Atopic Dermatitis: Role in Regulation of Skin Barrier
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Shigaku Ikeda, Ge Peng, Hai Le Thanh Nguyen, François Niyonsaba, Panjit Chieosilapatham, Juan Valentin Trujillo-Paez, Pu Song, Hainan Yue, Chanisa Kiatsurayanon, Yoshie Umehara, Hideoki Ogawa, and Ko Okumura
- Subjects
filaggrin ,Innate immune system ,Tight junction ,integumentary system ,atopic dermatitis ,epidermal barrier ,business.industry ,Antimicrobial peptides ,Atopic dermatitis ,Immune dysregulation ,medicine.disease ,medicine.disease_cause ,Pathogenesis ,skin barrier repair ,Immunology ,Medicine ,business ,Antimicrobial peptide ,barrier function ,Barrier function ,Filaggrin - Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Antimicrobial peptides (AMPs) are considered a rapid and first-line response of the innate immune system to microbial pathogens. Furthermore, antimicrobial peptides, such as LL-37, human b-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This chapter analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.
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- 2021
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26. Cyclooxygenase inhibition in mice heightens adaptive‐ and innate‐type responses against inhaled protease allergen and <scp>IL</scp> ‐33
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Mayu Suzuki, Katsuko Sudo, Punyada Suchiva, Susumu Nakae, Sonoko Harada, Natsuko Maruyama, Kei Matsuno, Hideoki Ogawa, Seiji Kamijo, Mutsuko Hara, Toshiro Takai, Norihiro Harada, Ko Okumura, Mai Ohba, Tomohito Takeshige, Shigaku Ikeda, Takehiko Yokomizo, and Toshiaki Okuno
- Subjects
medicine.medical_treatment ,Immunology ,Adaptive Immunity ,medicine.disease_cause ,Mice ,Allergen ,Cytokines metabolism ,T-Lymphocyte Subsets ,Immunity ,Animals ,Immunology and Allergy ,Medicine ,Cyclooxygenase Inhibitors ,Asthma ,Interleukin-13 ,Protease ,biology ,business.industry ,Allergens ,medicine.disease ,Immunity, Innate ,Interleukin 33 ,Disease Models, Animal ,Prostaglandin-Endoperoxide Synthases ,biology.protein ,Cytokines ,Cyclooxygenase ,business ,Peptide Hydrolases - Published
- 2019
27. Kras promotes myeloid differentiation through Wnt/β‐catenin signaling
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Yoshio Hirabayashi, Yoko Tabe, Kazuhisa Iwabuchi, Hideoki Ogawa, Kenji Takamori, Yeon-Jeong Kim, and Noriko Yokoyama
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Cancer Research ,Myeloid ,tumor suppressor ,Physiology ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,law.invention ,law ,medicine ,Small GTPase ,Receptor ,lcsh:QH301-705.5 ,Research Articles ,Wnt/β-catenin ,Chemistry ,Wnt signaling pathway ,GSK3β ,Myeloid leukemia ,digestive system diseases ,medicine.anatomical_structure ,lcsh:Biology (General) ,HL‐60 cell differentiation ,wild‐type Kras ,Cancer research ,Molecular Medicine ,Suppressor ,Phosphorylation ,KRAS ,Research Article - Abstract
Wild‐type Kras, a small GTPase, inactivates Ras growth‐promoting signaling. However, the role of Kras in differentiation of myeloid cells remains unclear. This study showed the involvement of Kras in a novel regulatory mechanism underlying the dimethyl sulfoxide (DMSO)‐induced differentiation of human acute myeloid leukemia HL‐60 cells. Kras was found to positively regulate DMSO‐induced differentiation, with the activity of Kras increasing upon DMSO. Inhibition of Kras attenuated CD11b expression in differentiated HL‐60 cells. GSK3β, an important component of Wnt signaling, was found to be a downstream signal of Kras. Phosphorylation of GSK3β was markedly enhanced by DMSO treatment. Moreover, inhibition of GSK3β enhanced CD11b expression and triggered the accumulation in the nucleus of β‐catenin and Tcf in response to DMSO. Inhibitors of β‐catenin‐mediated pathways blocked CD11b expression, further indicating that β‐catenin is involved in the differentiation of HL‐60 cells. Elevated expression of C/EBPα and C/EBPɛ accompanied by the expression of granulocyte colony‐stimulating factor (G‐CSF) receptor was observed during differentiation. Taken together, these findings suggest that Kras engages in cross talk with the Wnt/β‐catenin pathway upon DMSO treatment of HL‐60 cells, thereby regulating the granulocytic differentiation of HL‐60 cells. These results indicate that Kras acts as a tumor suppressor during the differentiation of myeloid cells.
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- 2019
28. An Antimicrobial Peptide with Angiogenic Properties, AG-30/5C, Activates Human Mast Cells Through the MAPK and NF-κB Pathways
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Ko Okumura, François Niyonsaba, Hideoki Ogawa, and Kazo Kanazawa
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0301 basic medicine ,Chemokine ,Mast cell chemotaxis ,medicine.medical_treatment ,Immunology ,Antimicrobial peptides ,Inflammation ,Cell Degranulation ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Mast Cells ,biology ,Chemistry ,Chemotaxis ,NF-kappa B ,030229 sport sciences ,Mast cell ,Lipids ,Cell biology ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Pertussis Toxin ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,Prostaglandin D2 ,Inflammation Mediators ,Mitogen-Activated Protein Kinases ,medicine.symptom ,Antimicrobial Cationic Peptides ,Signal Transduction - Abstract
Apart from their direct antimicrobial activities against invading pathogens, antimicrobial peptides exhibit additional protective functions that have led to their being named host defense peptides (HDPs). These functions include the stimulation of the production of cytokines/chemokines, the promotion of chemotaxis and cell proliferation and the induction of angiogenesis and wound healing. AG-30/5C is a novel angiogenic HDP that in addition to its antimicrobial activity also activates fibroblasts and endothelial cells and promotes angiogenesis and wound healing. Given that mast cells are found primarily in the vicinity of vessels, where they are intimately involved in wound healing, we hypothesized that AG-30/5C may activate mast cells. We demonstrated that AG-30/5C activated LAD2 human mast cells to degranulate and produce lipid mediators including leukotriene C4, prostaglandin D2 and E2. Moreover, AG-30/5C increased mast cell chemotaxis and induced the production of the cytokines GM-CSF and TNF-α and various chemokines, such as IL-8, MCP-1, MCP-3, MIP-1α and MIP-1β. The chemotaxis and cytokine/chemokine production induced by AG-30/5C were suppressed by both pertussis toxin and U-73122, suggesting the involvement of the G protein and phospholipase C pathways in AG-30/5C-induced mast cell activation. Furthermore, these pathways were activated downstream of the MAPK and NF-κB signaling molecules, as demonstrated by the inhibitory effects of ERK-, JNK-, p38- and NF-κB-specific inhibitors on cytokine/chemokine production. Interestingly, AG-30/5C caused the phosphorylation of MAPKs and IκB. We suggest that the angiogenic and antimicrobial peptide AG-30/5C plays a key role in the recruitment and activation of human mast cells at inflammation and wound sites.
- Published
- 2019
29. Innate Defense Regulator IDR-1018 Activates Human Mast Cells Through G Protein-, Phospholipase C-, MAPK- and NF-κB-Sensitive Pathways
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Kensuke Yanashima, Panjit Chieosilapatham, François Niyonsaba, Eri Yoshimoto, Hideoki Ogawa, and Ko Okumura
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0301 basic medicine ,MAPK/ERK pathway ,Chemokine ,Mast cell chemotaxis ,G protein ,Immunology ,Regulator ,Inflammation ,Cell Degranulation ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,GTP-Binding Proteins ,medicine ,Humans ,Immunologic Factors ,Mast Cells ,Extracellular Signal-Regulated MAP Kinases ,Wound Healing ,biology ,Phospholipase C ,Chemistry ,Monocyte ,NF-kappa B ,Degranulation ,NF-κB ,Mast cell ,Immunity, Innate ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Type C Phospholipases ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,medicine.symptom ,Wound healing ,Antimicrobial Cationic Peptides ,Signal Transduction ,030215 immunology - Abstract
Host defense (antimicrobial) peptides not only display antimicrobial activities against numerous pathogens but also exert a broader spectrum of immune-modulating functions. Innate defense regulators (IDRs) are a class of host defense peptides synthetically developed from natural or endogenous cationic host defense peptides. Of the IDRs developed to date, IDR-1018 is more efficient not only in killing bacteria but also in regulating the various functions of macrophages and neutrophils and accelerating the wound healing process. Because mast cells intimately participate in wound healing and a number of host defense peptides involved in wound healing are also known to activate mast cells, this study aimed to investigate the effects of IDR-1018 on mast cell activation. Here, we showed that IDR-1018 induced the degranulation of LAD2 human mast cells and caused their production of leukotrienes, prostaglandins and various cytokines and chemokines, including granulocyte-macrophage colony-stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and -3, macrophage-inflammatory protein-1α and -1β, and tumor necrosis factor-α. Furthermore, IDR-1018 increased intracellular calcium mobilization and induced mast cell chemotaxis. The mast cell activation was markedly suppressed by pertussis toxin, U-73122, U0126, SB203580, JNK inhibitor II, and NF-κB activation inhibitor II, suggesting the involvement of G-protein, phospholipase C, ERK, p38, JNK and NF-κB pathways, respectively, in IDR-1018-induced mast cell activation. Notably, we confirmed that IDR-1018 caused the phosphorylation of MAPKs and IκB. Altogether, the current study suggests a novel immunomodulatory role of IDR-1018 through its ability to recruit and activate human mast cells at the sites of inflammation and wounds.We report that IDR-1018 stimulates various functions of human mast cells. IDR-1018-induced mast cell activation is mediated through G protein, PLC, MAPK and NF-κB pathways. IDR-1018 will be a useful therapeutic agent for wound healing.
- Published
- 2019
30. Candidalysin, a Virulence Factor of Candida albicans, Stimulates Mast Cells by Mediating Cross-Talk Between Signaling Pathways Activated by the Dectin-1 Receptor and MAPKs
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Pu Song, Ge Peng, Hainan Yue, Takasuke Ogawa, Shigaku Ikeda, Ko Okumura, Hideoki Ogawa, and François Niyonsaba
- Subjects
Virulence Factors ,Immunology ,Candidiasis ,Fungal Proteins ,Mice ,Candida albicans ,Immunology and Allergy ,Animals ,Cytokines ,Eicosanoids ,Humans ,Lectins, C-Type ,Mast Cells ,Reactive Oxygen Species ,Signal Transduction - Abstract
Although mast cells (MCs) modulate the activity of effector cells during Candida albicans infection, their role in the pathogenesis of candidiasis remains unclear. Candidalysin, a C. albicans-derived peptide toxin, is a crucial factor in fungal infections. We aimed to investigate the effect of candidalysin on MC activation and the underlying molecular mechanism.Serum from candidalysin-immunized mice was used to measure candidalysin expression in patients infected with C. albicans. MC degranulation and migration were evaluated by β-hexosaminidase release assay and chemotaxis assay, respectively. EIA and ELISA were used to evaluate the production of eicosanoids and cytokines/chemokines, respectively. The production of nitric oxide (NO) was measured with a DAF-FM diacetate kit, while reactive oxygen species (ROS) production was analyzed by flow cytometry. MAPK activation was evaluated by Western blotting.We detected high candidalysin expression in the lesions of patients infected with C. albicans, and the MC number was increased in these lesions. LL-37 colocalized with MCs in the lesions of candidiasis patients. Candidalysin-enhanced MC accumulation in mice and treating LAD2 and HMC-1 cells with candidalysin induced their degranulation, migration, and production of pro- and anti-inflammatory cytokines/chemokines, eicosanoids, ROS, NO, and LL-37. Interestingly, C. albicans strains lacking candidalysin failed to induce MC activation. Moreover, candidalysin increased dectin-1 expression, and the inhibition of dectin-1 decreased MC activation. Downstream dectin-1 signaling involved the MAPK pathways.The finding that candidalysin causes cutaneous MC activation may improve our understanding of the role of MCs in the pathology of cutaneous C. albicans infection.
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- 2021
31. Mucosal Mast Cell-Specific Gene Expression Is Promoted by Interdependent Action of Notch and TGF-β Signaling
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Ayako Kaitani, Takuya Yashiro, Mutsuko Hara, Tomoaki Ando, Nobuhiro Nakano, Hideoki Ogawa, Jiro Kitaura, Ko Okumura, Kazumi Kasakura, Kazuki Saida, Kumi Izawa, and Chiharu Nishiyama
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Inflammation ,Mucous Membrane ,Immunology ,Integrin ,Notch signaling pathway ,Connective tissue ,Gene Expression ,Biology ,Mast cell ,Cell biology ,Allergic inflammation ,Mice ,medicine.anatomical_structure ,Downregulation and upregulation ,Transforming Growth Factor beta ,parasitic diseases ,Gene expression ,medicine ,biology.protein ,Immunology and Allergy ,Animals ,Mast Cells ,Progenitor cell - Abstract
Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-β is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor–mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-β signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-β signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-β signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-β–mediated transcription of MMC marker genes were both dependent on the TGF-β signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-β signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation.
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- 2021
32. Epicutaneous vaccination with protease inhibitor-treated papain prevents papain-induced Th2-mediated airway inflammation without inducing Th17 in mice
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Yurie Masutani, Punyada Suchiva, Toru Kimitsu, Natsuko Maruyama, Seiji Kamijo, Tomoko Yoshimura, Shigaku Ikeda, Ko Okumura, Shinya Kunimine, Hideoki Ogawa, Toshiro Takai, and Saya Shimizu
- Subjects
0301 basic medicine ,Proteases ,Ovalbumin ,medicine.medical_treatment ,Biophysics ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Allergen ,Th2 Cells ,Administration, Inhalation ,Papain ,medicine ,Animals ,Molecular Biology ,Sensitization ,Inflammation ,Protease ,biology ,business.industry ,Innate lymphoid cell ,Vaccination ,Cell Biology ,respiratory system ,Immunoglobulin E ,Interleukin-33 ,Protease inhibitor (biology) ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Th17 Cells ,Female ,Inflammation Mediators ,business ,medicine.drug - Abstract
Environmental allergen sources such as house dust mites contain proteases, which are frequently allergens themselves. Inhalation with the exogenous proteases, such as a model of protease allergen, papain, to airways evokes release and activation of IL-33, which promotes innate and adaptive allergic airway inflammation and Th2 sensitization in mice. Here, we examine whether epicutaneous (e.c.) vaccination with antigens with and without protease activity shows prophylactic effect on the Th airway sensitization and Th2-medated airway inflammation, which are driven by exogenous or endogenous IL-33. E.c. vaccination with ovalbumin restrained ovalbumin-specific Th2 airway sensitization and/or airway inflammation on subsequent inhalation with ovalbumin plus papain or ovalbumin plus recombinant IL-33. E.c. vaccination with papain or protease inhibitor-treated papain restrained papain-specific Th2 and Th9 airway sensitization, eosinophilia, and infiltration of IL-33-responsive Th2 and group 2 innate lymphoid cells on subsequent inhalation with papain. However, e.c. vaccination with papain but not protease inhibitor-treated papain induced Th17 response in bronchial draining lymph node cells. In conclusions, we demonstrated that e.c. allergen vaccination via intact skin in mice restrained even protease allergen-activated IL-33-driven airway Th2 sensitization to attenuate allergic airway inflammation and that e.c. vaccination with protease allergen attenuated the airway inflammation similar to its derivative lacking the protease activity, although the former but not the latter promoted Th17 development. In addition, the present study suggests that modified allergens, of which Th17-inducing e.c. adjuvant activity such as the protease activity was eliminated, might be preferable for safer clinical applications of the e.c. allergen administration.
- Published
- 2020
33. Robust induction of neural crest cells to derive peripheral sensory neurons from human induced pluripotent stem cells
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François Niyonsaba, Hironori Matsuda, Hideoki Ogawa, Mitsutoshi Tominaga, Sumika Toyama, Yayoi Kamata, Kenji Takamori, Nobuaki Takahashi, and Yoshie Umehara
- Subjects
0301 basic medicine ,Cell signaling ,Sensory Receptor Cells ,Neurogenesis ,Induced Pluripotent Stem Cells ,SOX10 ,Fluorescent Antibody Technique ,lcsh:Medicine ,Apoptosis ,Sensory system ,Biology ,Article ,Immunophenotyping ,TFAP2A ,03 medical and health sciences ,0302 clinical medicine ,Calcium imaging ,otorhinolaryngologic diseases ,Humans ,lcsh:Science ,skin and connective tissue diseases ,Receptor ,Cells, Cultured ,Multidisciplinary ,lcsh:R ,Neural crest ,Cell Differentiation ,Peripherin ,eye diseases ,030104 developmental biology ,nervous system ,Neural Crest ,lcsh:Q ,Peripheral nervous system ,Neuroscience ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Because intractable itch reduces quality of life, understanding the fundamental mechanisms of itch is required to develop antipruritic treatments. Itch is mediated by peripheral sensory neurons, which originate from the neural crest (NC) during development. Itch-associated signaling molecules have been detected in genetically engineered animals and in cultures of peripheral neurons from dorsal root ganglia (DRG). Ethical difficulties collecting peripheral neurons from human DRG have limited analysis of itch in humans. This study describes a method of differentiating peripheral neurons from human induced pluripotent stem cells (hiPSCs) for physiological study of itch. This method resulted in the robust induction of p75 and HNK1 double-positive NC cells from hiPSCs. The expression of NC markers TFAP2A, SOX10 and SNAI1 increased during NC induction. The induction efficiency was nearly 90%, and human peripheral neurons expressing peripherin were efficiently differentiated from hiPSC-derived NC cells. Moreover, induced peripheral neurons expressed the sensory neuronal marker BRN3A and the itch-related receptors HRH1, MRGPRX1, IL31R and IL-4R. Calcium imaging analyses indicated that these peripheral neurons included sensory neurons responsive to itch-related stimuli such as histamine, BAM8-22, IL-31 and IL-4. These findings may enable detailed analyses of human DRG neurons and may result in new therapies for intractable itch.
- Published
- 2020
34. Bepotastine besilate downregulates the expression of nerve elongation factors in normal human epidermal keratinocytes
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Hideoki Ogawa, Yasushi Suga, Mitsutoshi Tominaga, Azumi Sakaguchi, Kenji Takamori, Yoshie Umehara, and Yayoi Kamata
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Elongation factor ,BEPOTASTINE BESILATE ,Chemistry ,Dermatology ,Molecular Biology ,Biochemistry ,Cell biology - Published
- 2018
35. Involvement of the lipoprotein receptor LRP1 in AMP-IBP5-mediated migration and proliferation of human keratinocytes and fibroblasts
- Author
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François Niyonsaba, Shigaku Ikeda, Hainan Yue, Panjit Chieosilapatham, and Hideoki Ogawa
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Keratinocytes ,Pore Forming Cytotoxic Proteins ,MAP Kinase Signaling System ,medicine.medical_treatment ,p38 mitogen-activated protein kinases ,Primary Cell Culture ,Dermatology ,Biochemistry ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,medicine ,Humans ,RNA, Small Interfering ,Receptor ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Wound Healing ,Cell growth ,Chemistry ,Kinase ,Growth factor ,Cell migration ,Fibroblasts ,LRP1 ,Cell biology ,030104 developmental biology ,Gene Knockdown Techniques ,Insulin-Like Growth Factor Binding Protein 5 ,Low Density Lipoprotein Receptor-Related Protein-1 - Abstract
Background Antimicrobial peptide derived from insulin-like growth factor binding protein-5 (AMP-IBP5) is a potent antimicrobial agent that possesses various immunomodulatory activities. The parent protein of AMP-IBP5, IGFBP-5, has been shown to exert its effects via an insulin-like growth factor-1 receptor-independent mechanism, including binding to multifunctional low-density lipoprotein receptor-related protein 1 (LRP1), which contributes to several biological processes involved in skin wound healing. Objectives To investigate whether LRP1 is involved in AMP-IBP5-induced migration and proliferation of human epidermal keratinocytes and dermal fibroblasts. Methods The mRNA expression of LRP1 and IGFBP-5 was assessed by quantitative real-time PCR, whereas Western blotting was used to evaluate the protein expression. Production of cytokines was determined by ELISA. Cell migration was measured by the scratch wound assay, whereas cell proliferation was analyzed using the BrdU labeling assay. MAPK activation was determined by Western blotting. Results We found that AMP-IBP5 markedly induced the migration and proliferation of keratinocytes and fibroblasts, and this effect was reversed by specific siRNA and neutralizing antibody targeting the LRP1 receptor. In addition, LRP1 was upregulated by lipopolysaccharide, flagellin and AMP-IBP5 in keratinocytes and fibroblasts. LRP1 knockdown also inhibited MAPK pathway activation, which was required for AMP-IBP5-mediated cell migration and proliferation, as evidenced by the specific inhibitors for extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38. Conclusions Our results suggest that LRP1 expressed in human epidermal keratinocytes and dermal fibroblasts contributes to AMP-IBP5-mediated cell migration and proliferation, supporting its crucial role in cutaneous wound healing process.
- Published
- 2019
36. The Role of Host Defense Peptide Human β-defensins in the Maintenance of Skin Barriers
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Chanisa Kiatsurayanon, Hideoki Ogawa, and François Niyonsaba
- Subjects
0301 basic medicine ,beta-Defensins ,Antimicrobial peptides ,Inflammation ,Peptide ,Biology ,Dermatitis, Atopic ,03 medical and health sciences ,Immune system ,Psoriasis ,Drug Discovery ,medicine ,Humans ,Skin ,Pharmacology ,chemistry.chemical_classification ,integumentary system ,Epidermis (botany) ,Atopic dermatitis ,medicine.disease ,Immunity, Innate ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Immunology ,medicine.symptom ,Keratinocyte ,Antimicrobial Cationic Peptides - Abstract
The epidermis functions as a first-line defense barrier that protects the body from the external environment. As a chemical hindrance, the epidermis possesses acidic pH, highly organized lipids and various host defense peptides, also known as antimicrobial peptides. Human β-defensins (hBDs), one of the most important host defense peptide families found in our skin, are well-known for their broad-spectrum microbicidal activities. However, there is a growing body of evidence indicating that hBDs also orchestrate several immunomodulatory functions and are the cornerstone that bridges the innate and adaptive immune responses during skin inflammation and infection. Moreover, recent work identified the potential role of hBDs in the regulation and maintenance of the skin barrier function. In this review, we describe the current knowledge concerning the role of hBDs in skin barriers and discuss the potential clinical implications of these peptides in cutaneous biology. Understanding the roles of hBDs in the regulation and maintenance of skin barriers may aid in the development of novel therapeutic strategies for skin conditions where the skin barrier is impaired, such as atopic dermatitis and psoriasis.
- Published
- 2018
37. Role of the Ceramide-CD300f Interaction in Gram-Negative Bacterial Skin Infections
- Author
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Ayako Kaitani, Emiko Shiba, Ayako Takamori, Keiko Maeda, Masamichi Isobe, Nobuhiro Nakano, Akie Maehara, Axel Roers, Toshio Kitamura, Shino Uchida, Koichiro Uchida, Jiro Kitaura, Tomoaki Ando, David Voehringer, Kumi Izawa, Ko Okumura, Hideoki Ogawa, Toshiaki Shimizu, and Masakazu Nagamine
- Subjects
0301 basic medicine ,Ceramide ,Lipopolysaccharide ,Dermatology ,Skin infection ,Ceramides ,Biochemistry ,Microbiology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Receptors, Immunologic ,Molecular Biology ,Gram-Positive Bacterial Infections ,Gram ,biology ,Wild type ,Skin Diseases, Bacterial ,Cell Biology ,medicine.disease ,030104 developmental biology ,chemistry ,biology.protein ,Antibody - Published
- 2018
38. Topical Gynura procumbens as a Novel Therapeutic Improves Wound Healing in Diabetic Mice
- Author
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Miho Takahashi, Hainan Yue, Shigaku Ikeda, Nobuhiro Nakano, Pu Song, Nutda Sutthammikorn, Sunee Chansakaow, François Niyonsaba, Takasuke Ogawa, Volaluck Supajatura, Ko Okumura, and Hideoki Ogawa
- Subjects
0301 basic medicine ,skin ,Angiogenesis ,Gynura procumbens ,wound healing ,Plant Science ,Pharmacology ,traditional medicine ,Fibroblast growth factor ,Article ,angiogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Epidermal growth factor ,Medicine ,Ecology, Evolution, Behavior and Systematics ,integumentary system ,Ecology ,biology ,business.industry ,Botany ,Streptozotocin ,biology.organism_classification ,Vascular endothelial growth factor ,030104 developmental biology ,chemistry ,G. procumbens ,QK1-989 ,030220 oncology & carcinogenesis ,business ,Wound healing ,Transforming growth factor ,medicine.drug - Abstract
Nonhealing wounds are major socioeconomic challenges to healthcare systems worldwide. Therefore, there is a substantially unmet need to develop new drugs for wound healing. Gynura procumbens, a herb found in Southeast Asia, may be an effective therapeutic for nonhealing diabetic wounds. The aim of this study was to evaluate the efficacy of G. procumbens on wound healing in the diabetic milieu. G. procumbens extract was obtained using 95% ethanol and its components were determined by thin layer chromatography. Diabetes was induced in mice using streptozotocin. We found that G. procumbens extract contained stigmasterol, kaempferol and quercetin compounds. Topical application of G. procumbens on the wounded skin of diabetic mice accelerated wound healing and induced the expression of angiogenin, epidermal growth factor, fibroblast growth factor, transforming growth factor and vascular endothelial growth factor. Furthermore, G. procumbens promoted in vitro wound healing and enhanced the migration and/or proliferation of human endothelial cells, fibroblasts, keratinocytes and mast cells cultured in diabetic conditions. Finally, G. procumbens promoted vascular formation in the diabetic mice. To the best of our knowledge, this is the first study that evaluates in vivo wound healing activities of G. procumbens and activation of cells involved in wound healing process in diabetic conditions. The findings that G. procumbens accelerates wound healing and activates cells involved in the wound healing process suggest that G. procumbens might be an effective alternative therapeutic option for nonhealing diabetic wounds.
- Published
- 2021
39. Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin
- Author
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Yoshie Umehara, Hironori Matsuda, Nobuaki Takahashi, Azumi Sakaguchi, R. Kosaka, Hideoki Ogawa, Mitsutoshi Tominaga, Yayoi Kamata, and Kenji Takamori
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Administration, Oral ,Semaphorins ,Dermatology ,Mice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Semaphorin ,Oral administration ,Skin Physiological Phenomena ,Internal medicine ,Nerve Growth Factor ,Dry skin ,medicine ,Animals ,Phospholipids ,Sensitization ,Mice, Inbred ICR ,integumentary system ,Chemistry ,Pruritus ,Cutaneous nerve ,SEMA3A ,Penetration (firestop) ,Disease Models, Animal ,Milk ,030104 developmental biology ,Endocrinology ,Nerve growth factor ,medicine.anatomical_structure ,Epidermis ,medicine.symptom - Abstract
The density of intraepidermal nerve fibres has been shown to be higher in itchy dry skin than in healthy skin, suggesting that epidermal hyperinnervation is at least partly involved in peripheral itch sensitization. We investigated whether oral administration of milk-derived phospholipids (MPLs) would inhibit epidermal hyperinnervation in a mouse model of dry skin. We found that the number of intraepidermal nerve fibres was significantly lower in the MPL group than in the control group. Expression of nerve growth factor (NGF) levels in the epidermis was significantly decreased by oral administration of MPLs, whereas expression of semaphorin (Sema)3A, a nerve repulsion factor, was increased in the MPL group. These results suggest that dietary MPLs attenuate the penetration of nerve fibres into the epidermis by reducing epidermal NGF levels and increasing Sema3A level. Thus, dietary MPLs may have beneficial effects in the prevention and/or alleviation of dry skin-induced itch by reducing intraepidermal nerve fibre density.
- Published
- 2017
40. Skin Treatment with Detergent Promotes Protease Allergen-Dependent Epicutaneous Sensitization in a Manner Different from Tape Stripping in Mice
- Author
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Toshiro Takai, Ko Okumura, Sakiko Shimura, Susumu Nakae, Hideoki Ogawa, Shigaku Ikeda, Izumi Nishioka, Natsuko Maruyama, Hideo Iida, Seiji Kamijo, and Hirono Ochi
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Detergents ,Dermatology ,Administration, Cutaneous ,medicine.disease_cause ,Biochemistry ,Stripping (fiber) ,Dermatitis, Atopic ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Allergen ,medicine ,Animals ,Epicutaneous sensitization ,Sodium dodecyl sulfate ,Skin pathology ,Molecular Biology ,Skin ,Mice, Inbred BALB C ,Protease ,Cell Biology ,Allergens ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,Female ,TSLP Receptor ,Nasal administration ,Peptide Hydrolases - Published
- 2017
41. Differences in therapeutic effects of topically applied corticosteroid and tacrolimus on atopic dermatitis-like symptoms in NC/Nga mice
- Author
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Kyi Chan Ko, Yasushi Suga, Mitsutoshi Tominaga, Hironori Matsuda, Nobuaki Takahashi, Kenji Takamori, Yayoi Kamata, Yoshie Umehara, Atsushi Noguchi, and Hideoki Ogawa
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Thymic stromal lymphopoietin ,Petrolatum ,medicine.drug_class ,Administration, Topical ,Dermatology ,Biochemistry ,Tacrolimus ,Dermatitis, Atopic ,Ointments ,Mice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Thymic Stromal Lymphopoietin ,Adrenal Cortex Hormones ,Internal medicine ,Animals ,Humans ,Medicine ,Mast Cells ,Molecular Biology ,Betamethasone Valerate ,Clobetasol ,Transepidermal water loss ,Dermatophagoides farinae ,Emollients ,business.industry ,Pruritus ,Therapeutic effect ,Atopic dermatitis ,medicine.disease ,Calcineurin ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,Endocrinology ,Cytokines ,Corticosteroid ,Epidermis ,Clobetasol propionate ,business ,Ubiquitin Thiolesterase ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Topical corticosteroid and calcineurin inhibitor have similar therapeutic benefits in atopic dermatitis (AD), but the differences in therapeutic mechanisms of action of these agents against AD symptoms are not fully understood. Objective This study was performed to examine the different effects of topical betamethasone valerate (BMV), clobetasol propionate (CBP), and tacrolimus (TAC) on itch-related behavior and dermatitis in NC/Nga mice with AD-like symptoms. Methods AD-like dermatitis was induced in the dorsal skin of NC/Nga mice by repeated topical application of Dermatophagoides farinae body (Dfb) ointment twice weekly for three weeks. Mice with dermatitis scores over 5 were divided into five groups with equal dermatitis scores and treated with BMV, CBP, TAC, or Vaseline (Vas) once daily for two consecutive days, or were not treated (NT). Scratching behavior was analyzed using a SCLABA ® -Real system. Transepidermal water loss (TEWL) before and after treatment was measured using a Tewameter ® TM210. Skin collected from each group was analyzed histologically. Results After the second treatment, dermatitis showed significantly greater improvement in the CBP and TAC-treated groups than in the Vas-treated and NT groups. The numbers of scratching bouts were significantly lower in CBP and TAC-treated mice than in Vas-treated mice. TEWL was significantly lower in TAC-, but not in CBP-, treated mice than in Vas-treated mice. Immunohistochemical examination showed that BMV, CBP and TAC did not reduce the increased densities of epidermal protein gene product 9.5- and substance P-immunoreactive fibers. The numbers of dermal CD4-immunoreactive T cells were significantly lower in BMV and CBP-treated mice than in Vas-treated and NT mice. The numbers of dermal eosinophils were significantly lower in BMV, CBP and TAC-treated mice than in Vas-treated and NT mice, with CBP showing the strongest effect. CBP significantly reduced epidermal thickness compared with Vas and NT. There were no significant differences in the numbers of interleukin-31-immunoreactive cells and mast cells, or in expression of epidermal thymic stromal lymphopoietin among all five groups. Conclusion The therapeutic potency of TAC against AD-like symptoms, including pruritus, is equal to that of the corticosteroid CBP. Epidermal innervation of sensory nerves itself might not be related to the therapeutic effects of topical tacrolimus and corticosteroids in its early phase.
- Published
- 2017
42. The hematopoietic cell-specific transcription factor PU.1 is critical for expression of CD11c
- Author
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Chiharu Nishiyama, Mutsuko Hara, Hokuto Yokoyama, Akihito Inoue, Takuya Yashiro, Kazumi Kasakura, Kanako Fukuyama, Nao Kitamura, Makoto Nishiyama, Yoshihito Oda, Hideoki Ogawa, Ko Okumura, and Shusuke Nakamura
- Subjects
Transcriptional Activation ,0301 basic medicine ,Small interfering RNA ,Immunology ,Histones ,Mice ,03 medical and health sciences ,Transactivation ,Sp3 transcription factor ,Proto-Oncogene Proteins ,Gene expression ,Animals ,Immunology and Allergy ,RNA, Small Interfering ,Promoter Regions, Genetic ,Transcription factor ,Cells, Cultured ,Mice, Inbred BALB C ,Chemistry ,GATA2 ,Acetylation ,Dendritic Cells ,General Medicine ,CD11c Antigen ,Hematopoiesis ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,Gene Expression Regulation ,Organ Specificity ,Interferon Regulatory Factors ,Trans-Activators ,ITGAX Gene ,IRF8 - Abstract
PU.1 is a hematopoietic cell-specific transcription factor belonging to the Ets family, which plays an important role in the development of dendritic cells (DCs). CD11c (encoded by Itgax) is well established as a characteristic marker of hematopoietic lineages including DCs. In the present study, we analyzed the role of PU.1 (encoded by Spi-1) in the expression of CD11c. When small interfering RNA (siRNA) for Spi-1 was introduced into bone marrow-derived DCs (BMDCs), the mRNA level and cell surface expression of CD11c were dramatically reduced. Using reporter assays, the TTCC sequence at −56/−53 was identified to be critical for PU.1-mediated activation of the promoter. An EMSA showed that PU.1 directly bound to this region. ChIP assays demonstrated that a significant amount of PU.1 bound to this region on chromosomal DNA in BMDCs, which was decreased in LPS-stimulated BMDCs in accordance with the reduced levels of mRNAs of Itgax and Spi-1, and the histone acetylation degree. Enforced expression of exogenous PU.1 induced the expression of the CD11c protein on the cell surface of mast cells, whereas control transfectants rarely expressed CD11c. Quantitative RT–PCR also showed that the expression of a transcription factor Irf4, which is a partner molecule of PU.1, was reduced in PU.1-knocked down BMDCs. IRF4 transactivated the Itgax gene in a synergistic manner with PU.1. Taken together, these results indicate that PU.1 functions as a positive regulator of CD11c gene expression by directly binding to the Itgax promoter and through transactivation of the Irf4 gene.
- Published
- 2017
43. Involvement of µ-opioid Receptors and κ-opioid Receptors in Itch-related Scratching Behaviour of Imiquimod-induced Psoriasis-like Dermatitis in Mice
- Author
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Kenji Takamori, Azumi Sakaguchi, Hideoki Ogawa, Hironori Matsuda, Yayoi Kamata, Nobuaki Takahashi, Ryohei Kosaka, Mitsutoshi Tominaga, and Yoshie Umehara
- Subjects
Male ,Agonist ,medicine.drug_class ,Narcotic Antagonists ,Receptors, Opioid, mu ,Dermatology ,(+)-Naloxone ,Pharmacology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,opioidreceptor ,itch ,Receptor ,Skin ,Behavior, Animal ,business.industry ,Receptors, Opioid, kappa ,Antagonist ,psoriasis ,General Medicine ,Scratching ,Spinal cord ,Mice, Inbred C57BL ,imiquimod ,Disease Models, Animal ,medicine.anatomical_structure ,Spinal Cord ,Opioid ,RL1-803 ,Aminoquinolines ,Asimadoline ,Drug Eruptions ,business ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
The pathogenesis of psoriatic itch is poorly understood. The aim of this study was to investigate the involvement of opioid receptors in scratching behaviour of imiquimod-induced psoriasis-like dermatitis model mice. Topical application of 5% imiquimod cream to the rostral back skin of mice induced antihistamine-resistant scratching behaviour. The expression of µ-opioid receptor (MOR) protein increased in the epidermis, dorsal root ganglia (DRG) and spinal cord of imiquimod-treated mice. In contrast, the expression of κ-opioid receptor (KOR) protein decreased in the DRG and spinal cord of imiquimod-treated mice, and was undetectable in the epidermis of both groups. Topical or intraperitoneal administration of the MOR antagonist naloxone and oral administration of the centrally acting KOR agonist ICI-199,441 inhibited scratching behaviour, whereas oral administration of the peri-pherally-selective KOR agonist asimadoline did not. These results suggest that peripheral and central MOR and central KOR may be involved in the modulation of scratching behaviour in imiquimod-treated mice.
- Published
- 2017
44. The role of human β-defensins in allergic diseases
- Author
-
Chanisa Kiatsurayanon, Hideoki Ogawa, and François Niyonsaba
- Subjects
0301 basic medicine ,Chemokine ,Cell type ,beta-Defensins ,biology ,Angiogenesis ,medicine.medical_treatment ,Immunology ,Antimicrobial peptides ,Cell migration ,Immunomodulation ,Cathelicidins ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cytokine ,Beta defensin ,Hypersensitivity ,biology.protein ,medicine ,Animals ,Humans ,Immunology and Allergy ,030215 immunology - Abstract
Antimicrobial peptides (AMPs), also referred to as host defence peptides (HDPs), comprise a large family of small molecules broadly distributed throughout the animal and plant kingdom, historically serving as natural antibiotics. In mammals, there are two major families of AMPs/HDPs, the defensins and the cathelicidins. These peptides have evolved to protect against a wide range of infections from bacteria, viruses, fungi and some parasites. However, in addition to their broad-spectrum killing activities, AMPs/HDPs also possess various biological functions. They activate a variety of cell types, such as keratinocytes, airway epithelial cells and mast cells, among others, and regulate cytokine/chemokine production, cell migration, proliferation, differentiation, angiogenesis, the wound healing process and maintenance of the skin barrier function. Recently, it has become clear that alterations in the level of AMPs/HDPs are associated with the initiation and development of various inflammatory and allergic diseases. In this review, we will discuss the regulation and functions of human β-defensins and outline the current evidence supporting the role of these peptides in the pathogenesis of allergic diseases, including atopic dermatitis, allergic rhinitis, asthma and chronic rhinosinusitis. Understanding the functions and mechanisms of human β-defensins may aid in the development of novel therapeutic strategies for allergic diseases.
- Published
- 2016
45. Hydrogen sulfide modulates the expression of axon-guidance molecules in human keratinocytes
- Author
-
Yayoi Kamata, Mitsutoshi Tominaga, Hideoki Ogawa, Kenji Takamori, Yasushi Suga, and Catharina Sagita Moniaga
- Subjects
Adult ,Keratinocytes ,Male ,Hydrogen sulfide metabolism ,Hydrogen sulfide ,Nerve Tissue Proteins ,Dermatology ,Sulfides ,Biochemistry ,Cell Line ,Dermatitis, Atopic ,chemistry.chemical_compound ,Healthy volunteers ,Nerve Growth Factor ,Molecule ,Humans ,Hydrogen Sulfide ,Skin pathology ,Molecular Biology ,Skin ,Semaphorin-3A ,Healthy Volunteers ,Cell biology ,Axon Guidance ,chemistry ,Cell culture ,Case-Control Studies ,Axon guidance ,Female - Published
- 2019
46. Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy
- Author
-
Hiromichi Yamada, Ko Okumura, Tomoaki Ando, Hideoki Ogawa, Ayako Kaitani, Mutsuko Hara, Nobuhiro Nakano, Koichiro Uchida, Yoshikazu Ohtsuka, Kumi Izawa, Toshiaki Shimizu, Toshiyuki Yoneyama, and Jiro Kitaura
- Subjects
0301 basic medicine ,Ovalbumin ,medicine.medical_treatment ,Immunology ,Notch signaling pathway ,Administration, Oral ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Th2 Cells ,Food allergy ,medicine ,Immune Tolerance ,Immunology and Allergy ,Animals ,Humans ,Cells, Cultured ,Desensitization (medicine) ,Mice, Inbred BALB C ,biology ,Receptors, Notch ,Chemistry ,Myeloid-Derived Suppressor Cells ,Allergens ,medicine.disease ,Interleukin-10 ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Desensitization, Immunologic ,030220 oncology & carcinogenesis ,biology.protein ,Myeloid-derived Suppressor Cell ,Cancer research ,Female ,Bone marrow ,Antibody ,Food Hypersensitivity ,Signal Transduction - Abstract
Background Oral immunotherapy (OIT) aims to establish desensitization and sustained unresponsiveness (SU) in patients with food allergy by ingestion of gradually increasing doses of specific food allergens. However, little is known about the mechanisms by which OIT induces SU to specific allergens. Objectives We investigated the role of Notch signaling, which controls cell fate decisions in many types of immune cells in the induction of SU by OIT treatment. Methods Two types of mouse models, ovalbumin-induced food allergy and OIT, were generated. To elucidate the role of Notch signaling in OIT-induced SU, mice were intraperitoneally injected with the Notch signaling inhibitor N-[(3,5-difluorophenyl)acetyl]- l -alanyl-2-phenylglycine-1,1-dimethylethyl ester during the OIT treatment period. Results Ovalbumin-sensitized mice were desensitized and also had SU induced by OIT treatment, whereas repeated challenges with ovalbumin caused the development of severe allergic reactions in ovalbumin-sensitized mice. Administration of N-[(3,5-difluorophenyl)acetyl]- l -alanyl-2-phenylglycine-1,1-dimethylethyl ester to mice during the OIT treatment period inhibited the establishment of SU to ovalbumin but did not affect the induction of desensitization. OIT induced a systemic expansion of IL-10–producing CD4+ T cells, including TH2 cells, and myeloid-derived suppressor cells (MDSCs), particularly the monocytic MDSC subpopulation. Inhibition of Notch signaling prevented the OIT-induced expansion of those cells. In vitro cultures of bone marrow cells showed that Notch signaling directly promoted the generation of monocytic MDSCs. In addition, the contribution of MDSCs to OIT-induced SU was confirmed by MDSC depletion with the anti-Gr1 antibody. Conclusion Notch signaling contributes to the establishment of SU induced by OIT through systemic expansion of immunosuppressive cells, such as IL-10–producing CD4+ T cells and MDSCs.
- Published
- 2019
47. Innate IL-17A Enhances IL-33-Independent Skin Eosinophilia and IgE Response on Subcutaneous Papain Sensitization
- Author
-
Toshiro Takai, Ko Okumura, Seiji Kamijo, Susumu Nakae, Mutsuko Hara, Mayu Suzuki, and Hideoki Ogawa
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Injections, Subcutaneous ,Inflammation ,Dermatitis ,Dermatology ,Immunoglobulin E ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Eosinophilia ,Papain ,medicine ,Animals ,Humans ,Molecular Biology ,Skin ,biology ,Chemistry ,Innate lymphoid cell ,Interleukin-17 ,Cell Biology ,T helper cell ,Interleukin-33 ,Immunity, Innate ,Interleukin 33 ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Lymph ,medicine.symptom - Abstract
IL-33-activated group 2 innate lymphoid cells critically contribute to protease allergen-induced airway inflammation models. However, IL-33 is dispensable for a subcutaneous (s.c.) papain-induced skin inflammation model, suggesting distinct mechanisms between intranasal and s.c. sensitization. Here, we examined the role of IL-17A in the s.c. model. Papain-exposed skin produced IL-17A and an excess amount of a soluble decoy receptor for IL-33, with the latter being a possible reason for the independence of the s.c. model from IL-33. An IL-17A deficiency attenuated papain-induced skin eosinophilia and serum papain-specific IgE and IgG1 levels, whereas the s.c. administration of IL-17A with enzymatically inactive papain enhanced serum papain-specific IgE and IgG1 levels and T helper 2 development in draining lymph nodes in an IL-33-independent manner, suggesting IL-33-independent enhancement of papain-specific type 2 responses by IL-17A. The s.c. papain increased IL-17A+ γδ T cells in draining lymph nodes, approximately half of which were Vγ4+, as the majority of IL-17A+ cells, and increased Vγ5+ and Vγ4+ γδ T cells in the skin. Depletion of γδ TCR+ cells reduced T helper cytokine production in antigen-restimulated draining lymph node cells. These results suggest a novel role for IL-17A as an enhancer of skin eosinophilia and serum antigen-specific IgE production and for γδ T cells as an enhancer of T helper cell activation in the s.c. papain model.
- Published
- 2019
48. The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide–dependent neutrophil recruitment
- Author
-
Jiro Kitaura, Hiromichi Yamada, Ayako Takamori, Toshiaki Shimizu, Ayako Kaitani, Yoshinori Yamanishi, Mariko Takahashi, Hideoki Ogawa, Toshio Kitamura, Shino Uchida, Toshihiro Matsukawa, Masakazu Nagamine, Makoto Urai, Tomoaki Ando, Ko Okumura, Akie Maehara, Kumi Izawa, Masamichi Isobe, and Yuki Kinjo
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,Neutrophils ,Arthritis ,Nitric Oxide ,Biochemistry ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Sphingosine ,Immunity ,medicine ,Animals ,Receptors, Immunologic ,Receptor ,Molecular Biology ,030304 developmental biology ,Inflammation ,Mice, Knockout ,0303 health sciences ,Liposome ,Zymosan ,Dendritic Cells ,Cell Biology ,medicine.disease ,Cell biology ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,chemistry ,030220 oncology & carcinogenesis ,TLR4 ,Protein Binding ,Signal Transduction - Abstract
Zymosan is a glucan that is a component of the yeast cell wall. Here, we determined the mechanisms underlying the zymosan-induced accumulation of neutrophils in mice. Loss of the receptor CD300b reduced the number of neutrophils recruited to dorsal air pouches in response to zymosan, but not in response to lipopolysaccharide (LPS), a bacterial membrane component recognized by Toll-like receptor 4 (TLR4). An inhibitor of nitric oxide (NO) synthesis reduced the number of neutrophils in the zymosan-treated air pouches of wild-type mice to an amount comparable to that in CD300b-/- mice. Treatment with clodronate liposomes decreased the number of NO-producing, CD300b+ inflammatory dendritic cells (DCs) in wild-type mice, thus decreasing NO production and neutrophil recruitment. Similarly, CD300b deficiency decreased the NO-dependent recruitment of neutrophils to zymosan-treated joint cavities, thus ameliorating subsequent arthritis. We identified phytosphingosine, a lipid component of zymosan, as a potential ligand of CD300b. Phytosphingosine stimulated NO production in inflammatory DCs and promoted neutrophil recruitment in a CD300b-dependent manner. Together, these results suggest that the phytosphingosine-CD300b interaction promotes zymosan-dependent neutrophil accumulation by inducing NO production by inflammatory DCs and that CD300b may contribute to antifungal immunity.
- Published
- 2019
49. Antimicrobial peptides human LL-37 and β-defensin-3 modulate the expression of nerve elongation factors in human epidermal keratinocytes
- Author
-
François Niyonsaba, Hideoki Ogawa, Yoshie Umehara, Kenji Takamori, Mitsutoshi Tominaga, and Yayoi Kamata
- Subjects
Keratinocytes ,0301 basic medicine ,beta-Defensins ,Pruritus ,Antimicrobial peptides ,Nerve Tissue Proteins ,Dermatology ,Biology ,Amphiregulin ,Biochemistry ,Cell Line ,Cell biology ,Elongation factor ,03 medical and health sciences ,030104 developmental biology ,Hyperalgesia ,Touch ,Cathelicidins ,Cell culture ,Nerve Growth Factor ,Humans ,Epidermis ,Molecular Biology ,Defensin ,Antimicrobial Cationic Peptides - Published
- 2017
50. The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study
- Author
-
Kazuhisa Nozawa, Keigo Ikeda, Kunihiro Hayakawa, Naoto Tamura, Iwao Sekigawa, Kenji Takamori, Maki Fujishiro, Ayako Yamaguchi, Shinji Morimoto, Hiroshi Tsushima, Hideoki Ogawa, Satoshi Suzuki, Yoshinari Takasaki, and Takuya Hirai
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Cathepsin K ,Osteoclasts ,Disease ,Pharmacology ,Real-Time Polymerase Chain Reaction ,Severity of Illness Index ,Tacrolimus ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Refractory ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Bone Resorption ,Adverse effect ,030203 arthritis & rheumatology ,Mizoribine ,business.industry ,Cell Differentiation ,General Medicine ,Middle Aged ,medicine.disease ,Methotrexate ,030104 developmental biology ,Matrix Metalloproteinase 9 ,Antirheumatic Agents ,Rheumatoid arthritis ,Drug Therapy, Combination ,Female ,Matrix Metalloproteinase 3 ,Ribonucleosides ,business ,medicine.drug - Abstract
The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.
- Published
- 2016
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