Nakane, K. | bioRxiv Science

bioRxiv2024

In vivo-Active Soluble Epoxide Hydrolase-targeting PROTACs with Improved Potency and Stability

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis-targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound 8) exhibits a half-maximal degradation concentration in the sub-nM range, is stable in vivo, and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.

biochemistry↗

bioRxiv2022

Sedimentary DNA can reveal past pelagic copepod population dynamics

O_LICopepods play a key trophic role as secondary producers, transferring primary production to higher trophic levels such as fish. Copepod production contributes significantly to successful fish recruitment. Despite their importance, knowledge of copepod dynamics over several decades remains limited due to the lack of long-term data series with adequate sampling and analysis. However, an understanding of long-term copepod dynamics is urgently required to strive toward better management for sustainable aquatic ecosystems and fish recruitment. C_LIO_LISedimentary DNA (sedDNA) has been developing as a useful tool for reconstructing past plankton dynamics. This study evaluates whether sedDNA targeting the pelagic copepod, Eodiaptomus japonicus, in Lake Biwa (Japan) can be an effective tool for elucidating its past population dynamics. C_LIO_LIWe applied a quantitative polymerase chain reaction method targeting the mitochondrial cytochrome c oxidase subunit I gene on two sediment cores and compared the detected sedDNA concentrations with the unique long-term dataset of demographic traits, biomass, specific growth rate, production, subitaneous eggs, and resting eggs of E. japonicus. C_LIO_LIThe sedDNA concentration of E. japonicus recovered from sediment layers correlated significantly with in situ production, biomass, and production of immediately hatching eggs but not with resting eggs or specific growth rate. Our study provides evidence for the effective use of sedDNA as a tracking tool for assessing past copepod production dynamics. C_LI

ecology↗