PubMed · 14689549
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Robert Boyd. 2004. John Herbert Beynon.. https://doi.org/10.1002/rcm.1300
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The stria vascularis (SV) is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and mature mice to create a platform for advancing SV research. We validated our model by demonstrating that the proliferative behavior of the SV in vitro mimics SV in vivo. We also provided evidence for pharmacological experimentation by investigating the role of Wnt/β-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from in vivo neonatal and mature mouse SV and surrounding tissue and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss.
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 1) and related compounds [for example, CDDO-Me (2) and CDDO-Im (3)] are potential anti-inflammatory, cancer chemopreventive, and chemotherapeutic agents. However, the mechanisms responsible for the multiple effects of CDDO are still unclear. Clarification of these mechanisms and particularly isolation of the protein targets are essential for the development of CDDO and its analogues as clinically useful drugs. Such knowledge would provide superior opportunities for designing new compounds with improved potency and selectivity. Therefore, to isolate protein targets using affinity chromatography with immobilized streptavidin as a carrier, we have designed and synthesized C-17 and C-23 biotin conjugates of CDDO (4, 5, and 6) on the basis of our established structure-activity relationships. For the synthesis of 6, a new important precursor, 23-hydroxy-CDDO-Me (29) was synthesized from 20 by a C-23 oxidation protocol, which involves cyclopalladation of the C-4 methyl group from a 3-one oxime. The inhibitory activity of C-23 conjugate 6 is only about 3 times less potent than the mother compound, CDDO, against the proliferation of MCF-7 breast cancer cells. Consequently, 6 may be a very promising tool for the isolation of the protein targets of CDDO.
Four new acinetoferrin homologues were synthesized using a modular synthetic approach. Two linear and two cyclic imide derivatives were generated and evaluated for growth stimulating behavior in Mycobacterium avium subsp paratuberculosis. The yield for the tandem coupling of a functionalized aminohydroxamic acid motif (2 equiv) to a tert-butyl citrate derivative was significantly improved using DCC and N-hydroxysuccinimide. (1)H NMR spectroscopy (CD(3)OD) provided a convenient method for monitoring the final imidization step in TFA using the doublet patterns between 2.5 and 3.06 ppm. New protocols demonstrated that only a 20% growth enhancement was observed with M. avium subsp. paratuberculosis using the imide of acinetoferrin. Last, a siderophore from Streptomyces pilosus, deferrioxamine B, was shown to cross-feed M. avium subsp. paratuberculosis with the same efficiency as the more costly, native chelator, mycobactin J.