Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice
Background: Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate p...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223014464 |
| _version_ | 1797630681196527616 |
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| author | Jianping Wu Xueting Wu Cheng Cheng Lu Liu Le Xu Zijing Xu Shuaishuai Wang Deebie Symmes Lian Mo Ruihuan Chen Junfeng Zhang |
| author_facet | Jianping Wu Xueting Wu Cheng Cheng Lu Liu Le Xu Zijing Xu Shuaishuai Wang Deebie Symmes Lian Mo Ruihuan Chen Junfeng Zhang |
| author_sort | Jianping Wu |
| collection | DOAJ |
| description | Background: Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies. Methods: The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling. Results: ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics. Conclusions: Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD. |
| first_indexed | 2024-03-11T11:11:37Z |
| format | Article |
| id | doaj.art-729e6cd96b084820bc8dc3cb8853d486 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T11:11:37Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-729e6cd96b084820bc8dc3cb8853d4862023-11-12T04:38:46ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-12-01168115648Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in miceJianping Wu0Xueting Wu1Cheng Cheng2Lu Liu3Le Xu4Zijing Xu5Shuaishuai Wang6Deebie Symmes7Lian Mo8Ruihuan Chen9Junfeng Zhang10School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Laboratory Animal Center, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, ChinaLaboratory Animal Center, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaAluda Pharmaceuticals, Inc., Union City, CA 94587, USAAluda Pharmaceuticals, Inc., Union City, CA 94587, USAAluda Pharmaceuticals, Inc., Union City, CA 94587, USA; Luoda Biosciences, Inc., Chuzhou, Anhui, China; Corresponding author at: Aluda Pharmaceuticals, Inc., Union City, CA 94587, USA.School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Correspondence to: School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.Background: Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies. Methods: The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling. Results: ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics. Conclusions: Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD.http://www.sciencedirect.com/science/article/pii/S0753332223014464Vimentin targetingALD-R491IBDTreg/Th17Gut microbiota |
| spellingShingle | Jianping Wu Xueting Wu Cheng Cheng Lu Liu Le Xu Zijing Xu Shuaishuai Wang Deebie Symmes Lian Mo Ruihuan Chen Junfeng Zhang Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice Biomedicine & Pharmacotherapy Vimentin targeting ALD-R491 IBD Treg/Th17 Gut microbiota |
| title | Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| title_full | Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| title_fullStr | Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| title_full_unstemmed | Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| title_short | Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| title_sort | therapeutic targeting of vimentin by ald r491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice |
| topic | Vimentin targeting ALD-R491 IBD Treg/Th17 Gut microbiota |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223014464 |
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