PHARMACOLOGICAL AND FUNCTIONAL CHARACTERISATION OF NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS IN LUNG CANCER CELL LINES: A CHALLENGE FOR NEW THERAPEUTICAL STRATEGIES?

Lung cancer is the leading cause of cancer-related deaths worldwide and cigarette smoking is related to 90% of all deaths due to lung cancer. Tobacco smoke contains many classes of carcinogens and, although nicotine, the addictive and most active component of tobacco smoke, is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis by inducing cell-cycle progression, cell migration, angiogenesis and the evasion of apoptosis in a variety of systems. Nicotine and its metabolites are highly lipophilic compounds that bind and activate a family of ligand-gated cation channels (the neuronal nicotinic acetylcholine receptors, nAChRs) that are widely expressed in the central and peripheral nervous systems. Over the last few decades, the extra-neuronal localisation of nAChRs has been demonstrated in a large number of cell types including endothelial cells, glia, immune cells, lung tissue and cancer cells, indicating that they might have functions well beyond simple neurotransmission. Recent studies have shown that most of the tumour-promoting effects of nicotine are primarily due to the binding and the activation of nAChRs, which lead to downstream intracellular signalling cascades. However, identifying the receptor subtypes expressed in lung tumour cells and their signalling pathways is still in its early stage. For these reasons, we investigated the pathophysiological role of nAChRs in lung cancer cells. We found that different non-small cell lung cancer (NSCLC) cells express distinctive nicotinic receptor subtypes and that this variety affects nicotine-induced proliferation and migration. In the A549 adenocarcinoma cell line, nAChRs containing the \u3b17, \u3b19 and \u3b15 subunits regulate not only the nicotine-induced cell proliferation and migration but also the activation of anti-apoptotic and proliferative pathways. Blocking nAChRs containing the \u3b17 or \u3b19 or \u3b15 subunits with specific toxins or silencing their expression by means of subunit-specific siRNAs abolishes the nicotine-induced proliferation, migration and signalling. Prompted by these results, we also studied oxystylbene compounds previously characterised by our group and started to syntehesise some new oxystylbene/resveratrol derivatives with specific modifications. We found that these 4-oxystilbene derivates act on both \u3b17 and \u3b19-containing receptors and block NSCLC cell proliferation and viability in a dose-dependent manner. These results highlight the pathophysiological role of specific nAChR subtypes in promoting NSCLC cell growth and migration and raise the possibility of targeting them in order to treat tobacco related cancer

Nonreciprocal Spin Waves in Nanoscale Domain Walls Detected by Scanning X-ray Microscopy in Perpendicular Magnetic Anisotropic Fe/Gd Multilayers

Spin wave nonreciprocity in domain walls (DWs) allows for unidirectional signal processing in reconfigurable magnonic circuits. Using scanning transmission x-ray microscopy (STXM), we examined coherently-excited magnons propagating in Bloch-like DWs in amorphous Fe/Gd multilayers with perpendicular magnetic anisotropy (PMA). Near 1 GHz we detected magnons with short wavelengths down to $\lambda = 281$ nm in DWs whose minimum width amounted to $\delta_{\rm DW} = 52$ nm. Consistent with micromagnetic simulations, the STXM data reveal their nonreciprocal magnon band structures. We identified Bloch points which disrupted the phase evolution of magnons and induced different $\lambda$ adjacent to the topological defects. Our observations provide direct evidence of nonreciprocal spin waves within Bloch-like DWs, serving as programmable waveguides in magnonic devices with directed information flow

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics. Thereafter, we discuss the seminal discoveries derived from genetically modified mouse models, which have greatly contributed to our understanding of nicotine's effects on the reward-related mesolimbic pathway and the aversion-related habenulo-interpeduncular pathway. Thereafter, emerging areas of research focusing on modulation of nAChR expression and/or function are considered. Taken together, these discoveries have provided a foundational understanding of various genetic, neurobiological, and behavioral factors underlying the motivation to use nicotine and related dependence processes, which are thereby advancing drug discovery efforts to promote long-term abstinence

Nicotinic acetylcholine receptors

This themed section of the British Journal of Pharmacology is the product of a conference that focussed on nicotinic ACh receptors (nAChRs) that was held on the Greek island of Crete from 7 to 11 May 2017. 'Nicotinic acetylcholine receptors 2017' was the fourth in a series of triennial international meetings that have provided a regular forum for scientists working on all aspects of nAChRs to meet and to discuss new developments. In addition to many of the regular participants, each meeting has also attracted a new group of scientists working in a fast-moving area of research. This themed section comprises both review articles and original research papers on nAChRs. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc/

Nanoimaging of ultrashort magnon emission by ferromagnetic grating couplers at GHz frequencies

On-chip signal processing at microwave frequencies is key for modern mobile communication. When one aims at small footprints, low power consumption, reprogrammable filters, and delay lines, magnons in low-damping ferrimagnets offer great promise. Ferromagnetic grating couplers have been reported to be specifically useful as microwave-to-magnon transducers. However, their interconversion efficiency is unknown and real-space measurements of the emitted magnon wavelengths have not yet been accomplished. Here, we image with subwavelength spatial resolution the magnon emission process into ferrimagnetic yttrium iron garnet (YIG) at frequencies up to 8 GHz. We evidence propagating magnons of a wavelength of 98.7 nm underneath the gratings, which enter the YIG without a phase jump. Counterintuitively, the magnons exhibit an even increased amplitude in YIG, which is unexpected and due to a further wavelength conversion process. Our results are of key importance for magnonic components, which efficiently control microwave signals on the nanoscale

Chemistry and pharmacology of a series of unichiral analogues of 2-(2-pyrrolidinyl)-1,4-benzodioxane, prolinol phenyl ether, and prolinol 3-pyridyl ether designed as α4β2-nicotinic acetylcholine receptor agonists

Some unichiral analogues of 2R,2′S-2-(1′-methyl-2′-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4β2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4β2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4β2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4β2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4β2 and α3β4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of Nmethylprolinol are α4β2 full agonists, but only the latter is highly α4β2/α3β4 selective, while potent and selective partial α4β2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues