Anti-microbial Peptides in Skin Barrier Functions

( Yoshikazu Uchida ),( Kyung Ho Park ) 한국피부장벽학회 2013 한국피부장벽학회지 Vol.15 No.2

The outermost layer of skin epidermis, the stratum corneum, is a border between the external and internal environment. Hence, the stratum corneum is responsible for protecting internal cells and tissues from external perturbations and for preventing excess loss of internal components. In addition to being a permeability barrier, mechanical and oxidative stress barrier, and ultraviolet light barrier, the stratum corneum is an antimicrobial barrier that prevents microbial infections. Very important innate immune elements of the antimicrobial barrier are antimicrobial peptides, that directly combat microbes. Because attenuation of any barrier function increases a risk of microbial infection, stimulation of antimicrobial peptide production occurs in response to external insults that affect one or more barrier(s). This review article focuses on the epidermal antimicrobial barrier, including a recently-discovered transcriptional regulatory mechanism of antimicrobial peptide expression.

The Yin-Yang role of external stress in modulation of skin function

( Yoshikazu Uchida ) 한국피부장벽학회 2020 한국피부장벽학회지 Vol.22 No.2

Is external stress always a burden on the skin? Ceramide, an essential component in forming the epidermal permeability barrier structure in the stratum corneum, is also a mediator in cell function modulation. In response to external stressors, such as oxidative stress, ultraviolet irradiation and inflammatory cytokines, ceramide production is increased. Depending upon the level of increased ceramide, determined by the amount of stress (physiological and pathological [toxicological]), ceramide can suppress cell proliferation, and induce differentiation and cell death. We reported that increases in ceramide by sphingomyelin hydrolysis suppress keratinocyte proliferation, while metabolic conversion of ceramide to glucosylceramide restores this proliferation. Moreover, we showed metabolic conversion of ceramide to sphingosine-1-phosphate prevents ceramide-mediated cell death. Cell death is caused by excess levels of external stress overwhelming this ceramide rescue mechanism. We then discovered that ceramide metabolites, sphingosine-1-phosphate and ceramide-1-phosphate, induce key antimicrobial peptides, cathelicidin anti-microbial peptide (CAMP), and human ß-defensin 2 and 3 production, respectively. Additionally, we recently found that an ichthyotic phenotype (hyperplasia and hyperkeratosis) is evident in newborn sphingomyelin synthase 2 knockout mice, while these abnormalities are normalized during neonatal development, suggesting that a dry terrestrial environment could activate an adaptation mechanism to normalize these ichthyotic skin abnormalities. These studies demonstrate that external stress can yield a positive outcome, but this is not always the case. Excess production of CAMP promotes inflammation and tumorigenesis. We recently found that CAMP stimulates Th17 cells to express ectonucleotidase CD73, leading to an increase in adenosine synthesis that suppresses anti-cancer immunity, suggesting that CAMP contributes to the progression of tumor growth by conversion of effector Th17 cells to suppressor Th17 cells. In summary, external stress has a yin-yang role in the modulation of skin function.

Abstracts : Session 4 ; Homeostasis in Skin Barrier : Anti-microbial Peptides in Skin Barrier Functions

( Yoshikazu Uchida ) 한국피부장벽학회 2013 한국피부장벽학회지 Vol.15 No.2

The outermost layer of skin epidermis, the stratum corneum, is a border between the external and internal environment. Hence, the stratum corneum is responsible for protecting internal cells and tissues from external perturbations and for preventing excess loss of internal components. In addition to being a permeability barrier, mechanical and oxidative stress barrier, and ultraviolet light barrier, the stratum corneum is an antimicrobial barrier that prevents microbial infections. Very important innate immune elements of the antimicrobial barrier are antimicrobial peptides, that directly combat microbes. Because attenuation of any barrier function increases a risk of microbial infection, stimulation of antimicrobial peptide production occurs in response to external insults that affect one or more barrier(s). This review article focuses on the epidermal antimicrobial barrier, including a recently-discovered transcriptional regulatory mechanism of antimicrobial peptide expression.

Ginsenoside Rb1 Enhances Keratinocyte Migration by a Sphingosine-1-Phosphate-Dependent Mechanism

신경오,최성재,Yoshikazu Uchida,김인용,정윤화,박경호 한국식품영양과학회 2018 Journal of medicinal food Vol.21 No.11

The cutaneous wound healing process is tightly regulated by a range of cellular responses, including migration. Sphingosine-1-phosphate (S1P) is a signaling lipid produced in keratinocytes (KC) and it is known to stimulate skin wound repair through increased KC migration. Of the multifunctional triterpene ginsenosides, Rb1 enhances cutaneous wound healing process by increasing KC migration, but cellular mechanisms responsible for the Rb1-mediated increase in KC migration are largely unknown. Therefore, we hypothesized that, and assessed whether, Rb1 could stimulate KC migration through S1P-dependent mechanisms. Rb1 significantly increases S1P production by regulating the activity of metabolic conversion enzymes associated with S1P generation and degradation, sphingosine kinase 1 (SPHK1) and S1P lyase, respectively, in parallel with enhanced KC migration. However, blockade of ceramide to S1P metabolic conversion using a specific inhibitor of SPHK1 attenuated the expected Rb1-mediated increase in KC migration. Furthermore, a pan-S1P receptor inhibitor pertussis toxin significantly attenuated Rb1-induced stimulation of KC migration. Moreover, the Rb1-induced increases in KC migration required S1P receptor(s)-mediated activation of ERK1/2 and NF-κB, leading to production of key cutaneous migrating proteins, matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, the results show that Rb1 stimulates KC migration through an S1P→S1P receptor(s)→ERK1/2→NF-κB→MMP-2/-9 pathway. This research revealed a previously unidentified cellular mechanism for Rb1 in enhancing KC migration and pointing to a new therapeutic approach to stimulate the cutaneous wound healing process.

A Rare Case of Primary Squamous Cell Carcinoma of the Stomach and a Review of the 56 Cases Reported in Japan

Hideyuki Wakabayashi,Itsurou Fujita,Yoshikazu Kanazawa,Tsutomu Nomura,Nobutoshi Hagiwara,,Masaru Hosone,Hironori Katayama,Eiji Uchida,Takeshi Matsutani 대한위암학회 2014 Journal of gastric cancer Vol.14 No.1

We report an extremely rare case of primary squamous cell carcinoma of the stomach. A 69-year-old man was admitted to our hospital with a 2-month history of dysphagia and tarry stools. Endoscopic examination revealed a cauliflower-shaped protruding mass along the lesser curvature of the gastric cardia. Biopsy of the lesion revealed squamous cell carcinoma of the stomach. Computed tomography revealed a thickened stomach wall and a mass protruding into the gastric lumen. Total gastrectomy with splenectomy, distal pancreatectomy,and Roux-en-Y reconstruction was performed, together with a lower thoracic esophagectomy via a left thoracotomy. Histopathological examination of the specimen revealed well-differentiated squamous cell carcinoma of the stomach. Postoperative follow-up was uneventful for the first 18 months. However, multiple liver metastases and para-aortic lymph node metastasis developed subsequently. Despite systemic combination chemotherapy, the patient died because of progression of the recurrent tumors. Here, we review the characteristicsof 56 cases of gastric squamous cell carcinoma reported in Japan.

A Rare Case of Primary Squamous Cell Carcinoma of the Stomach and a Review of the 56 Cases Reported in Japan

Wakabayashi, Hideyuki,Matsutani, Takeshi,Fujita, Itsurou,Kanazawa, Yoshikazu,Nomura, Tsutomu,Hagiwara, Nobutoshi,Hosone, Masaru,Katayama, Hironori,Uchida, Eiji The Korean Gastric Cancer Association 2014 Journal of gastric cancer Vol.14 No.1

We report an extremely rare case of primary squamous cell carcinoma of the stomach. A 69-year-old man was admitted to our hospital with a 2-month history of dysphagia and tarry stools. Endoscopic examination revealed a cauliflower-shaped protruding mass along the lesser curvature of the gastric cardia. Biopsy of the lesion revealed squamous cell carcinoma of the stomach. Computed tomography revealed a thickened stomach wall and a mass protruding into the gastric lumen. Total gastrectomy with splenectomy, distal pancreatectomy, and Roux-en-Y reconstruction was performed, together with a lower thoracic esophagectomy via a left thoracotomy. Histopathological examination of the specimen revealed well-differentiated squamous cell carcinoma of the stomach. Postoperative follow-up was uneventful for the first 18 months. However, multiple liver metastases and para-aortic lymph node metastasis developed subsequently. Despite systemic combination chemotherapy, the patient died because of progression of the recurrent tumors. Here, we review the characteristics of 56 cases of gastric squamous cell carcinoma reported in Japan.

Study of the cartilage matrix production-promoting effect of chicken leg extract and identification of the active ingredient

Hiroaki Yamada,Utano Nakamura,Toshio Nakamura,Yoshikazu Uchida,Atsushi Yamatsu,Mujo Kim 한국영양학회 2019 Nutrition Research and Practice Vol.13 No.6

BACKGROUND/OBJECTIVES: Osteoarthritis (OA) is a major public health issue in Japan and other countries, and foods that prevent or treat OA are in strong demand. Proteins and peptides in chicken meat and bones are known for being rich in functional and nutritional ingredients for the improvement of osteoporosis. We speculated that chicken legs, a food consumed in many regions of the world, may also contain such ingredients. In this study, we aim to (i) evaluate the effect of chicken leg extract (CLE) on the promotion of cartilage matrix production and (ii) identify the active ingredient in CLE that contributes to this function. MATERIALS/METHODS: Artificial CLE digest was prepared, and the acid mucopolysaccharide production-promoting activity of the CLE digest was evaluated by alcian blue staining of ATDC5 cells. CLE was orally administered to rabbits with burr holes in the knee joint of the femur, and the degree of regeneration of cartilage matrix was evaluated. Furthermore, we investigated orally administered CLE-derived peptides in human plasma using LC-MS. From measuring the acid mucopolysaccharide production-promotion activity of these peptides, a molecule considered to be an active ingredient in the CLE digest was identified. RESULTS: CLE digest promoted acid mucopolysaccharide production and facilitated regeneration of cartilage matrix in in vitro and in vivo experiments. Four peptides including phenylalanyl-hydroxyproline (Phe-Hyp) were detected as CLE-derived peptides in human plasma. The effect of CLE was inferred to be due to Phe-Hyp, which was confirmed to be present in the CLE digest. CONCLUSIONS: It was shown that CLE stimulated the production of articular cartilage matrix both in vitro and in vivo, and that CLE could be an effective food for preventing or treating OA. Furthermore, only Phe-Hyp was confirmed as the active compound in the CLE digest, suggesting that the activity of CLE was due to Phe-Hyp.

Naturally Occurring Hair Growth Peptide: Water-Soluble Chicken Egg Yolk Peptides Stimulate Hair Growth Through Induction of Vascular Endothelial Growth Factor Production

Toshio Nakamura,Haruo Yamamura,박경호,Caroline Pereira,Yoshikazu Uchida,Noriko Horie,김무조,Satoshi Itami 한국식품영양과학회 2018 Journal of medicinal food Vol.21 No.7

Alopecia is divided into two categories: androgenic alopecia and nonandrogenic alopecia. An androgen-dependent abnormality of biological functions causes alopecia in males, but the role of androgens is not yet elucidated in female pattern hair loss (FPHL). Modulation of androgenic activity is not effective in certain kinds of androgenic alopecia in females, as well as in cases of nonandrogenic alopecia in males and females. The hair growth drug, minoxidil, stimulates vascular endothelial growth factor (VEGF) production as well as vascularization and hair growth in females. Yet, because minoxidil has side effects with long-term use, a safe alternative hair growth agent is needed. Whereas hair develops after birth in mammalian species, hair mostly grows in a precocial bird, in the chicken, between hatching days 14 and 15. Therefore, we hypothesized that the chicken egg contains a key hair growth factor. In this study, we demonstrated that water-soluble peptides derived from the egg yolk stimulate VEGF production and human hair follicle dermal papilla cell growth. We also found that these peptides enhance murine hair growth and improve hair growth in FPHL. Finally, we characterized that water-soluble egg yolk peptides induce VEGF expression through insulin growth factor-1 receptor activation-induced hypoxia-inducible factor-1α transcription pathway. We have given the name “hair growth peptide (HGP)” to this water-soluble egg yolk peptide.

Study of the cartilage matrix production-promoting effect of chicken leg extract and identification of the active ingredient

Yamada, Hiroaki,Nakamura, Utano,Nakamura, Toshio,Uchida, Yoshikazu,Yamatsu, Atsushi,Kim, Mujo The Korean Nutrition Society 2019 Nutrition Research and Practice Vol.13 No.6

BACKGROUND/OBJECTIVES: Osteoarthritis (OA) is a major public health issue in Japan and other countries, and foods that prevent or treat OA are in strong demand. Proteins and peptides in chicken meat and bones are known for being rich in functional and nutritional ingredients for the improvement of osteoporosis. We speculated that chicken legs, a food consumed in many regions of the world, may also contain such ingredients. In this study, we aim to (i) evaluate the effect of chicken leg extract (CLE) on the promotion of cartilage matrix production and (ii) identify the active ingredient in CLE that contributes to this function. MATERIALS/METHODS: Artificial CLE digest was prepared, and the acid mucopolysaccharide production-promoting activity of the CLE digest was evaluated by alcian blue staining of ATDC5 cells. CLE was orally administered to rabbits with burr holes in the knee joint of the femur, and the degree of regeneration of cartilage matrix was evaluated. Furthermore, we investigated orally administered CLE-derived peptides in human plasma using LC-MS. From measuring the acid mucopolysaccharide production-promotion activity of these peptides, a molecule considered to be an active ingredient in the CLE digest was identified. RESULTS: CLE digest promoted acid mucopolysaccharide production and facilitated regeneration of cartilage matrix in in vitro and in vivo experiments. Four peptides including phenylalanyl-hydroxyproline (Phe-Hyp) were detected as CLE-derived peptides in human plasma. The effect of CLE was inferred to be due to Phe-Hyp, which was confirmed to be present in the CLE digest. CONCLUSIONS: It was shown that CLE stimulated the production of articular cartilage matrix both in vitro and in vivo, and that CLE could be an effective food for preventing or treating OA. Furthermore, only Phe-Hyp was confirmed as the active compound in the CLE digest, suggesting that the activity of CLE was due to Phe-Hyp.

[P8-90] Gromwell (Lithospermum erythrorhizon) enhances migration of human keratinocytes and fibroblasts with altered lipid syntheses in in vitro wound healing model

Hyunae Kim,Jungmin Kim,Hyejeong Yun,Youngae Kim,Uchida Yoshikazu,Holleran M Walter,Yunhi Cho 한국식품영양과학회 2009 한국식품영양과학회 학술대회발표집 Vol.2009 No.11