Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.
Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes, Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
Retinoid X receptor (RXR) heterodimers
such as PPAR/RXR, LXR/RXR,
and FXR/RXR can be activated by RXR agonists alone and are therefore
designated as permissive. Similarly, existing RXR antagonists show
allosteric antagonism toward partner receptor agonists in these permissive
RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (14, CBTF-EE) as the first RXR antagonist that does not show
allosteric inhibition in permissive RXR heterodimers. This compound
was designed based on the hypothesis that RXR antagonists that do
not induce conformational changes of RXR would not exhibit such allosteric
inhibition. CD spectra and X-ray co-crystallography of the complex
of 14 and the RXR ligand binding domain (LBD) confirmed
that 14 does not change the conformation of hRXR-LBD.
The X-ray structure analysis revealed that 14 binds at
the entrance of the ligand binding pocket (LBP), blocking access to
the LBP and thus serving as a “gatekeeper”.
Positron
emission tomography (PET) is useful for noninvasive in
vivo visualization of disease-related receptors, for evaluation of
receptor occupancy to determine an appropriate drug dosage, and for
proof-of-concept of drug candidates in translational research. For
these purposes, the specificity of the PET tracer for the target receptor
is critical. Here, we review work in this area, focusing on the chemical
structures of reported PET tracers, their K
i/K
d values, and the physical properties
relevant to target receptor selectivity. Among these physical properties,
such as cLogP, cLogD, molecular
weight, topological polar surface area, number of hydrogen bond donors,
and pK
a, we focus especially on LogD and LogP as important physical properties
that can be easily compared across a range of studies. We discuss
the success of PET tracers in evaluating receptor occupancy and consider
likely future developments in the field.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.