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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. 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. 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. 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. [Display omitted] • Novel compound ALD-R491 specifically binds to vimentin with no off-target effects. • ALD-R491 is significantly more effective than 5-ASA and Tofacitinib in DSS model. • ALD-R491 blocks the onset and progression of spontaneous colitis in IL-10 KO mice. • ALD-R491 impacts Th17/Treg, intestinal barrier, tissue fibrosis and gut microbiome. • Targeting vimentin by ALD-R491 represents a first-in-class MOA in treating IBD. [ABSTRACT FROM AUTHOR]

Treating high-strength nitrate wastewater effectively and economically has been a major challenge for some manufacturing industries. In this study, we fabricated a membrane-less two-phase bio-cathode microbial fuel cell (TPBC-MFC) by dividing the bio-cathode into a solid part (S-cathode, above the water surface) and a liquid part (L-cathode, below the water surface), on which performances and mechanisms for the treatment of pickling wastewater containing more than 1000 mg/L NO- 3-N (electron acceptor) by watermelon rind extracts (WMREs, electron donor) were explored. Results showed that the TPBC-MFC presented an excellent performance since the maximum power density, the greatest nitrate removal rate and the highest COD removal efficiency reached 16.6 mW/m2, 780 g/m3·d and 94.8%, respectively. There were identical microorganisms (unclassified- Chitinophagaceae and Comamonadaceae) predominating on all electrodes owing to WMREs as carbon sources. In addition, some special functional species were also enriched, including Anaeroarcus (3.48%, fermentation bacterium) and Desulfovibrio (12.57%, electricigen) for the anode, Thauera (5.02%, denitrifier) for the L-cathode and Chryseolinea (12.13%, denitrifier) for the S-cathode. The detection of denitrifying genes of narG, narK/S, norB and nosZ, as well as function prediction demonstrated that the anode degraded WMREs to release H+ and e− that were subsequently utilized by the cathode to reduce NO- 3-N to N 2. All these results proved that the membrane-less TPBC-MFC has a good capability in electricity generation, nitrate removal and WMREs degradation, most likely because the S-cathode benefits the promotion of mass transfer. [Display omitted] • TPBC-MFC consisting of S-cathode and L-cathode was developed. • Watermelon rinds fueled TPBC-MFC for sustainable pickling wastewater treatment. • S-cathode was vital for TPBC-MFC due to its role in promoting mass transfer. • Each of bio-electrodes possessed its own specific functional microorganisms. • Reduction of nitrate to N 2 was mainly carried out by S-cathode. [ABSTRACT FROM AUTHOR]