Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.
The reactions of bromomethyllithium with tert-alkylboronic esters could be of great potential for the formation of quaternary carbon centers but often give poor yields/conversions. Calculations and experimental evidence show that tert-alkyl groups migrate less effectively than other types of alkyl group in such reactions and that O-migration competes. Furthermore, slow/incomplete capture of the bromomethyl reagent by the boronic ester is a problem in more hindered systems, and an additional competing reaction, possibly Li-Br exchange on the bromomethylborate species, also leads to lower yields of migrated products. Based on this, experimental protocols have been devised in which the competing reactions are largely suppressed, leading to higher conversions to migrated product for several substrates.
A novel three-component reaction of pyridine N-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine N-oxide with an acyl chloride in the presence of a cyclic ether at 25-50 °C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate.
Polymorphisms
in the region of the calmodulin-dependent kinase
isoform D (CaMK1D) gene are associated with increased incidence of
diabetes, with the most common polymorphism resulting in increased
recognition by transcription factors and increased protein expression.
While reducing CaMK1D expression has a potentially beneficial effect
on glucose processing in human hepatocytes, there are no known selective
inhibitors of CaMK1 kinases that can be used to validate or translate
these findings. Here we describe the development of a series of potent,
selective, and drug-like CaMK1 inhibitors that are able to provide
significant free target cover in mouse models and are therefore useful
as
in vivo
tool compounds. Our results show that
a lead compound from this series improves insulin sensitivity and
glucose control in the diet-induced obesity mouse model after both
acute and chronic administration, providing the first
in vivo
validation of CaMK1D as a target for diabetes therapeutics.
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