Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca2+ responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.

Three new perylenetetracarboxylic diimide (PDI) compounds substituted with hydrophobic and/or hydrophilic groups at the two imide nitrogen positions, namely N,N'-di[N-(4-aminophenyl)-3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzamide]-1,7-di(4-tert-butylphenoxy)perylene-3,4;9,10-tetracarboxylic diimide (1), N,N'-di[N-amido-3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzamide]-1,7-di(4-tert-butylphenoxy)perylene-3,4;9,10-tetracarboxylic diimide (2), and N-amido-3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzamide-N'-amido-3,4,5-tris(dodecyloxy)benzamide-1,7-di(4-tert-butylphenoxy)perylene-3,4;9,10-tetracarboxylate diimide (3), have been designed and prepared. The gelating abilities of them in different solvents have been investigated, and the results indicated that compounds 1 and 3 can form fluorescent gels whereas compound 2 cannot. The properties of the gels of compounds 1 and 3 have been investigated by UV-vis absorption and emission spectra. The results indicate that the gel of compound 1 is composed of H-aggregates, whereas the gel of compound 3 is composed of J-aggregates. The reversible transformation between gel and solution states induced by temperature change is observed. The structure of dried gel has been investigated by X-ray diffraction (XRD) experiments, and the morphology has been measured by atomic force microscopy (AFM). This research revealed successfully the crucial roles of amphiphilic properties and the side-chain conformations in controlling the gelating properties of PDI molecules. This information may be useful for the design of novel organogels based on perylenetetracarboxylic diimides.

All reported attempts to synthesize the tert-butyl-substituted adamantoid phosph(III)azane P4 (N(t) Bu)6 have failed, leading to the classification of this molecule as inaccessible and a literature example of steric control in chemistry of phosphorus-nitrogen compounds. We now demonstrate that this structure is readily accessible by a solvent-free mechanochemical milling approach, highlighting the importance of mechanochemical reaction environments in evaluating chemical reactivity.

Reaction of 4-CN-PhOH with [ClP(μ-N(t)Bu)]2 (1) (2:1 ratio) in the presence of Et3N produced the functionalized cyclodiphosph(III/III)azane [(4-CN-PhO)P(μ-N(t)Bu)]2 (2). Oxidation of 2 produced cyclodiphosph(V/V)azanes [(4-CN-PhO)(E)P(μ-N(t)Bu)]2 [E = O (3), S (4), and Se (5)]. This is the first example of a series of cyclodiphosph(V/V)azane derivatives obtained from a single cyclophosph(III/III)azane precursor where all the accessible chalcogen oxidized products are air-stable over prolonged periods of time.

Cu atoms and a hollow structure are helpful for the improvement of the MOR activity of Pt. Trace Ir atoms might promise a superior durability for the Pt-based catalysts while maintaining the MOR catalytic activity.