Structure–Activity Relationship Study on Isothiocyanates: Comparison of TRPA1-Activating Ability between Allyl Isothiocyanate and Specific Flavor Components of Wasabi, Horseradish, and White Mustard

Allyl isothiocyanate (ITC) (<b>4</b>) is the main pungent component in wasabi, and it generates an acrid sensation by activating TRPA1. The flavor and pungency of ITCs vary depending on the compound. However, the differences in activity to activate TRPA1 between ITCs are not known except for a few compounds. To investigate the effect of carbon chain length and substituents of ITCs, the TRPA1-activiting ability of 16 ITCs was measured. Since most of the ITCs showed nearly equal TRPA1-activiting potency, the ITC moiety is likely the predominant contributor to their TRPA1-activating abilities, and contributions of other functional groups to their activities to activate TRPA1 are comparatively small

Hyaluronan Inhibits Tlr-4-Dependent RANKL Expression in Human Rheumatoid Arthritis Synovial Fibroblasts

<div><p>The Toll-like receptor (TLR) signaling pathway is activated in synovial fibroblast cells in patients with rheumatoid arthritis (RA). The receptor activator of nuclear factor-κB (RANK) and its ligand, RANKL, are key molecules involved in the differentiation of osteoclasts and joint destruction in RA. Hyaluronan (HA) is a major extracellular component and an important immune regulator. In this study, we show that lipopolysaccharide (LPS) stimulation significantly increases RANKL expression via a TLR-4 signaling pathway. We also demonstrate that HA suppresses LPS-induced RANKL expression, which is dependent on CD44, but not intercellular adhesion molecule-1 (ICAM-1). Our study provides evidence for HA-mediated suppression of TLR-4-dependent RANKL expression. This could present an alternative target for the treatment of destructed joint bones and cartilages in RA.</p></div

Expression of RANKL enhanced by LPS via TLR-4.

<p>(A) RANKL mRNA expression is induced by LPS. n = 5 independent replicates using 5 different samples. *p<0.05. P values were calculated by comparisons with the indicated sample. (B) Western blot analysis showing RANKL expression in human rheumatoid arthritis synovial fibroblasts. (C) Effect of anti-TLR4 monoclonal antibody pre-treatment on LPS-induced RANKL protein expression. n = 5 independent replicates using 5 different samples. *p<0.05.</p

Inhibitory effect of HMW-HA on RANKL expression induced by LPS.

<p>Pre-incubation of cells for 1 hour and co-incubation with 1 mg/ml HMW-HA suppresses LPS-induced RANKL mRNA expression. This inhibitory effect was dose-dependent. HMW-HA alone had no effect. n = 5 independent replicates using 5 different samples. *p<0.05.</p

Identification of Indole Alkaloid Structural Units Important for Stimulus-Selective TRPM8 Inhibition: SAR Study of Naturally Occurring Iboga Derivatives

The iboga alkaloid voacangine (<b>1</b>) has been reported previously to be the first stimulus-selective TRPM8 antagonist. In the present report, a structure–activity relationship (SAR) study is described on the effects of some naturally occurring indole alkaloid analogues on TRPM8 inhibition. Dihydrocatharanthine (<b>10</b>) and catharanthine (<b>11</b>) were found to be inhibitors of TRPM8 activity, and their IC₅₀ values were equivalent to that of BCTC, a potent and representative TRPM8 antagonist. Furthermore, it was shown that the iboga moiety is the most crucial unit for TRPM8 blockade and that its stereostructure, as found in <b>1</b> but not in <b>10</b> and <b>11</b>, is essential for chemical agonist-selective TRPM8 inhibition. These findings should provide useful information for synthesizing additional stimulus-selective and TRPM8-selective blockers