The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent neurons. On the proximal nerve ending within the spinal dorsal horn, TRPA1 regulates transmission to spinal interneurons, and thereby pain hypersensitivity. Here we assessed whether the contribution of the spinal TRPA1 channel to pain hypersensitivity varies with the experimental pain model, properties of test stimulation or the behavioral pain response. The antihypersensitivity effect of intrathecally (i.t.) administered Chembridge-5861528 (CHEM; a selective TRPA1 channel antagonist; 5-10μg) was determined in various experimental models of pain hypersensitivity in the rat. In spinal nerve ligation and rapid eye movement (REM) sleep deprivation models, i.t. CHEM attenuated mechanical hypersensitivity. Capsaicin-induced secondary (central) but not primary (peripheral) mechanical hypersensitivity was also reduced by i.t. administration of CHEM or A-967079, another TRPA1 channel antagonist. Formalin-induced secondary mechanical hypersensitivity, but not spontaneous pain, was suppressed by i.t. CHEM. Moreover, mechanical hypersensitivity induced by cholekystokinin in the rostroventromedial medulla was attenuated by i.t. pretreatment with CHEM. Independent of the model, the antihypersensitivity effect induced by i.t. CHEM was predominant on responses evoked by low-intensity stimuli (⩽6g). CHEM (10μg i.t.) failed to attenuate pain behavior in healthy controls or mechanical hypersensitivities induced by i.t. administrations of a GABA(A) receptor antagonist, or NMDA or 5-HT(3) receptor agonists. Conversely, i.t. administration of a TRPA1 channel agonist, cinnamon aldehyde, induced mechanical hypersensitivity. The results indicate that the spinal TRPA1 channel exerts an important role in secondary (central) pain hypersensitivity to low-intensity mechanical stimulation in various pain hypersensitivity conditions. The spinal TRPA1 channel provides a promising target for the selective attenuation of a central mechanism contributing to pathophysiological pain.

Surface chemistry is a key enabler for various biosensing applications. Biosensors based on surface plasmon resonance routinely employ thiol-based chemistry for the linker layer between gold-coated support surfaces and functional biosensor surfaces. However, there is a growing awareness that such sensor surfaces are prone to oxidation/degradation problems in the presence of oxygen, and previous efforts to improve the stability have shown limited advancements. As an alternative, recent studies employing N-heterocyclic carbene (NHC) self-assembled monolayers (SAMs) deposited on gold have shown significant promise in this area. Here, we describe a sensor surface employing an NHC SAM to couple a modified carboxymethylated dextran onto a gold surface. Such a dextran matrix is also used for affinity chromatography, and it is the most commonly employed matrix for commercial biosensor surfaces today. The performance reliability of the dextran-modified NHC chip to act as an alternative biosensing platform is compared with that of a thiol-based commercial chip in the proof-of-concept tests. The resultant NHC sensor surface shows a higher thermal stability compared to thiol analogues. Moreover, the plasma protein/drug and antibody/antigen interactions were validated on the NHC-based dextran chip and showed similar performance as compared to the thiol-based commercial chip. Ultimately, this study shows the strong potential applicability of chemical modifications to gold surfaces using NHC ligands for biosensing applications.

1. The study provides the evidence that a novel lncRNA IL6-AS1 is highly expressed in COPD and is associated with inflammation. 2. IL6-AS1 acts as the competitive endogenous RNA (ceRNA) to competitively bind to hsa-miR-149-5p to regulate IL-6 expression. 3. IL6-AS1 acts as a guide to promote the gene expression via recruiting EBF1 to the region of the IL-6 promoter.

Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.