| 1 | Colon-targeted S100A8/A9-specific peptide systems ameliorate colitis and colitis-associated colorectal cancer in mouse models显示文摘The link between chronic inflammation and cancer development is well acknowledged.Inflammatory bowel disease including ulcerative colitis and Crohn’s disease frequently promotes colon cancer development.Thus,control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer(CRC).Recently,gut mucosal damage-associated molecular patterns S100A8 and S100A9,acting via interactions with their pattern recognition receptors(PRRs),especially TLR4 and RAGE,have emerged as key players in the pathogenesis of colonic inflammation.We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR,TLR4,and RAGE.In this study we developed a dual PRR-inhibiting peptide system(rCT-S100A8/A9)that consisted of TLR4-and RAGE-inhibiting motifs derived from S100A8 and S100A9,and conjugated with a CT peptide(TWYKIAFQRNRK)for colon-specific delivery.In human monocyte THP-1 and mouse BMDMs,S100A8/A9-derived peptide comprising TLR4-and RAGE-interacting motif(0.01,0.1,1μM)dose-dependently inhibited the binding of S100 to TLR4 or RAGE,and effectively inhibited NLRP3 inflammasome activation.We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities.In mouse models of DSS-induced acute and chronic colitis,injection of rCT-S100A8/A9(50μg·kg^(-1)·d^(-1),i.p.for certain consecutive days)significantly increased the survival rates and alleviated the pathological injuries of the colon.In AOM/DSS-induced colitis-associated colorectal cancer(CAC)mouse model,injection of rCT-S100A8/A9(50μg·kg^(-1)·d^(-1),i.p.)increased the body weight,decreased tumor burden in the distal colon,and significantly alleviated histological colonic damage.In mice bearing oxaliplatin-resistant CRC xenografts,injection of rCT-S100A8/A9(20μg/kg,i.p.,every 3 days for 24–30 days)significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues.Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC. | Euni Cho Seok-Jun Mun Hyo Keun Kim Yu Seong Ham Woo Jin Gil Chul-Su Yang | 2024 | Acta Pharmacologica Sinica2024，45，3： | 0 |
| 2 | Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3显示文摘CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells;however, information on the NLRP3 inflammasome is limited. Herein, we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro, CD82 deficiency decreased the severity of colitis in mice. Furthermore, two binding partners of CD82, NLRP3 and BRCC3, were identified. CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination. Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus (B. vulgatus) regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome. Accordingly, we observed that B. vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis. Overall, this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination. Based on our findings, we propose that B. vulgatus is a novel therapeutic candidate for colitis. | Jae-Sung Kim Hyo Keun Kim Joongho Lee Sein Jang Euni Cho Seok-Jun Mun Seokhyun Yoon Chul-Su Yang | 2023 | Cellular & Molecular Immunology2023，20，2： | 0 |
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