Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence.inflammation ͉ pain ͉ TRP channel ͉ vasodilation ͉ natural products

TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1 − / − mice. The electrophilic metabolites N-acetylp-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-pbenzoquinoneimine metabolite l-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1 − / − mice. Intrathecal injection of a non-electrophilic cannabinoid, ∆ 9 -tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.

Significance Prostate cancer is the most common malignancy and the third leading cancer-related cause of death among men of the Western world. Treatment options at advanced stages of the disease are scarce, and better therapies are in urgent need. In our study, we show that the clinically relevant lipid kinase phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) plays an important role in cancer cell invasion and survival by regulating the PI3K/AKT/androgen receptor pathways. Elevated levels of PIP5K1α contribute to cancer cell proliferation, survival, and invasion. In this context we introduce a newly developed compound, ISA-2011B, with promising anticancer effects by inhibiting the PIP5K1α-associated AKT pathways. Conclusively, we propose that PIP5K1α may be used as a potential therapeutic target for treatment of advanced prostate cancer.

The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB 1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV 1 ) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV 1 on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV 1 gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV 1 . Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB 1 receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV 1 and the cannabinoid CB 1 receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV 1 and thus may play a role as endogenous TRPV 1 modulators. Long chain C18 N-acylethanolamines (NAEs)2 are a group of bioactive lipids generated following hydrolysis of membrane N-acylphosphatidylethanolamine (NAPE) lipids, a reaction catalyzed by phospholipase D-like enzymes (1-4). In 1992, one member of this group, anandamide (N-arachidonoylethanolamine), was identified as a ligand for the central cannabinoid CB 1 receptor (5). This receptor is also present on a subpopulation of primary sensory neurons, which express the vanilloid receptor (TRPV 1 ), a marker of nociceptive sensory neurons (6 -8). TRPV 1 is a heat-activated cation channel, belonging to the transient receptor potential (TRP) superfamily of cation channels (9), of which TRPV 2 , TRPM 8 (the menthol receptor), and TRPA 1 (ANKTM 1 ) are also temperature-sensitive and present on primary sensory neurons (10 -14). Activation of TRPV 1 and TRPA 1 , e.g. by the pungent ingredients in hot chili pepper (capsaicin) and mustard (isothiocyanates), causes acute pain and local release of inflammatory neuropeptides (6, 14 -16). Other mediators of inflammation, such as bradykinin, prostaglandin E 2 , or nerve growth factor, promote TRPV 1 and TRPA 1 activation via multiple signaling pathways, which is consistent with TRPV 1 and TRPA 1 being essential for the development of inflammation-induced hyperalgesia (14 -19).Since our discovery that anandamide directly activates TRPV 1 (20), this lipid has emerged as a potential mediator of i...