Photolipid excitation triggers depolarizing optocapacitive currents and action potentials.

Optically-induced changes in membrane capacitance may regulate neuronal activity without requiring genetic modifications. Previously, they mainly relied on sudden temperature jumps due to light absorption by membrane-associated nanomaterials or water. Yet, nanomaterial targeting or the required high infrared light intensities obstruct broad applicability.

Photolipid excitation triggers depolarizing optocapacitive currents and action potentials.

Optically-induced changes in membrane capacitance may regulate neuronal activity without requiring genetic modifications. Previously, they mainly relied on sudden temperature jumps due to light absorption by membrane-associated nanomaterials or water. Yet, nanomaterial targeting or the required high infrared light intensities obstruct broad applicability.

Determinants of Lipid Domain Size.

Lipid domains less than 200 nm in size may form a scaffold, enabling the concerted function of plasma membrane proteins. The size-regulating mechanism is under debate. We tested the hypotheses that large values of spontaneous monolayer curvature are incompatible with micrometer-sized domains.

Photoswitching of model ion channels in lipid bilayers.

Membrane proteins can be regulated by alterations in material properties intrinsic to the hosting lipid bilayer. Here, we investigated whether the reversible photoisomerization of bilayer-embedded diacylglycerols (OptoDArG) with two azobenzene-containing acyl chains may trigger such regulatory events. We observed an augmented open probability of the mechanosensitive model channel gramicidin A (gA) upon photoisomerizing OptoDArG's acyl chains from trans to cis: integral planar bilayer conductance brought forth by hundreds of simultaneously conducting gA dimers increased by typically >50% - in good agreement with the observed increase in single-channel lifetime.

Ordered Lipid Domains Assemble via Concerted Recruitment of Constituents from Both Membrane Leaflets.

Lipid rafts serve as anchoring platforms for membrane proteins. Thus far they escaped direct observation by light microscopy due to their small size. Here we used differently colored dyes as reporters for the registration of both ordered and disordered lipids from the two leaves of a freestanding bilayer.

In Situ Observation of Photoswitching by NMR Spectroscopy: A Photochemical Analogue to the Exchange Spectroscopy Experiment.

We present 1D and 2D NMR experiments that provide in situ insights into photoinduced isomerizations. Irradiation during the mixing period of an exchange spectroscopy (EXSY) experiment leads to characteristic cross peaks in 2D spectra. The phototriggered exchange of magnetization occurring in photoswitchable ()- and ()-isomers of three selected azo compounds provides information on the dynamic / equilibria.

Lipid-independent control of endothelial and neuronal TRPC3 channels by light.

Lipid-gated TRPC channels are highly expressed in cardiovascular and neuronal tissues. Exerting precise pharmacological control over their activity in native cells is expected to serve as a basis for the development of novel therapies. Here we report on a new photopharmacological tool that enables manipulation of TRPC3 channels by light, in a manner independent of lipid metabolism and with higher temporal precision than lipid photopharmacology.

A single point mutation in the TRPC3 lipid-recognition window generates supersensitivity to benzimidazole channel activators.

Mutation of a single residue within the recently identified lipid (diacylglycerol) recognition window of TRPC3 (G652A) was found to abolish channel activation via endogenous lipid mediators while retaining sensitivity to the non-lipid activator GSK1702934A (abb. GSK). The mechanism of this change in chemical sensing by TRPC3 was analysed by whole-cell and single channel electrophysiology as well as Ca imaging.

Homoarsenocholine - A novel arsenic compound detected for the first time in nature.

The arsenic speciation was determined in macrofungi of the Ramaria genus with HPLC coupled to inductively coupled plasma mass spectrometry. Besides arsenic species that are already known for macrofungi, like arsenobetaine or arsenocholine, two compounds that were only known from marine samples so far (trimethylarsoniopropanate and dimethylarsinoylacetate) were found for the first time in a terrestrial sample. An unknown arsenical was isolated and identified as homoarsenocholine.

An optically controlled probe identifies lipid-gating fenestrations within the TRPC3 channel.

Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light.

Intensified Microwave-Assisted N-Acylation Procedure - Synthesis and Activity Evaluation of TRPC3 Channel Agonists with a 1,3-Dihydro-2-benzo[]imidazol-2-one Core.

Upon controlled microwave heating and using cyanuric chloride as a coupling reagent, an efficient amidation procedure for the synthesis of 1,3-dihydro-2-benzo[]imidazol-2-one-based agonists of TRPC3/6 ion channels has been developed. Compared to the few conventional protocols, a drastic reduction in processing time from ca. 2 days down to 10 minutes was achieved accompanied by significantly improved product yields.

Optopharmacological control of TRPC channels by coumarin-caged lipids is associated with a phototoxic membrane effect.

Photouncaging of second messengers has been successfully employed to gain mechanistic insight of cellular signaling pathways. One of the most enigmatic processes of ion channel regulation is lipid recognition and lipid-gating of TRPC channels, which represents pivotal mechanisms of cellular Ca(2+) homeostasis. Recently, optopharmacological tools including caged lipid mediators became available, enabling an unprecedented level of temporal and spatial control of the activating lipid species within a cellular environment.

Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction.

Aims: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF.

Methods And Results: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham).

Assessment of electrophile damage in a human brain endothelial cell line utilizing a clickable alkyne analog of 2-chlorohexadecanal.

Peripheral leukocytes aggravate brain damage by releasing cytotoxic mediators that compromise blood-brain barrier function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system. The reaction of HOCl with the endogenous plasmalogen pool of brain endothelial cells results in the generation of 2-chlorohexadecanal (2-ClHDA), a toxic, lipid-derived electrophile that induces blood-brain barrier dysfunction in vivo.

Continuous flow reduction of artemisinic acid utilizing multi-injection strategies-closing the gap towards a fully continuous synthesis of antimalarial drugs.

One of the rare alternative reagents for the reduction of carbon-carbon double bonds is diimide (HN=NH), which can be generated in situ from hydrazine hydrate (N2H4⋅H2O) and O2. Although this selective method is extremely clean and powerful, it is rarely used, as the rate-determining oxidation of hydrazine in the absence of a catalyst is relatively slow using conventional batch protocols. A continuous high-temperature/high-pressure methodology dramatically enhances the initial oxidation step, at the same time allowing for a safe and scalable processing of the hazardous reaction mixture.

TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.

Aim: TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart.

Methods And Results: We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3.

Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin.

Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H2O2-Cl(-) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of chlorinated long-chain fatty aldehydes, has potent neurotoxic potential by inflicting blood-brain barrier (BBB) damage.

Immobilized iron oxide nanoparticles as stable and reusable catalysts for hydrazine-mediated nitro reductions in continuous flow.

An experimentally easy to perform method for the generation of alumina-supported Fe3O4 nanoparticles [(6±1) nm size, 0.67 wt %]and the use of this material in hydrazine-mediated heterogeneously catalyzed reductions of nitroarenes to anilines under batch and continuous-flow conditions is presented. The bench-stable, reusable nano-Fe3O4@Al2O3 catalyst can selectively reduce functionalized nitroarenes at 1 mol % catalyst loading by using a 20 mol % excess of hydrazine hydrate in an elevated temperature regime (150 °C, reaction time 2-6 min in batch).

Shifting chemical equilibria in flow--efficient decarbonylation driven by annular flow regimes.

To efficiently drive chemical reactions, it is often necessary to influence an equilibrium by removing one or more components from the reaction space. Such manipulation is straightforward in open systems, for example, by distillation of a volatile product from the reaction mixture. Herein we describe a unique high-temperature/high-pressure gas/liquid continuous-flow process for the rhodium-catalyzed decarbonylation of aldehydes.

Store-operated Ca2+ entry does not control proliferation in primary cultures of human metastatic renal cellular carcinoma.

Store-operated Ca(2+) entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca(2+) pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca(2+) levels within the endoplasmic reticulum (ER) Ca(2+) reservoir, and a number of a Ca(2+)-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1-7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients.

Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS.

In Alzheimer's disease (AD), astrocytes undergo complex morphological and functional changes that include early atrophy, reactive activation and Ca(2+) deregulation. Recently, we proposed a mechanism by which nanomolar Aβ42 deregulates mGluR5 and InsP3 receptors, the key elements of astrocytic Ca(2+) signalling toolkit. To evaluate the specificity of these changes, we have now investigated whether the effects of Aβ42 on Ca(2+) signalling machinery can be reproduced by pro-inflammatory agents (TNFα, IL-1β, LPS).

A three step continuous flow synthesis of the biaryl unit of the HIV protease inhibitor Atazanavir.

The development of multistep continuous flow reactions for the synthesis of important intermediates for the pharmaceutical industry is still a significant challenge. In the present contribution the biaryl-hydrazine unit of Atazanavir, an important HIV protease inhibitor, was prepared in a three-step continuous flow sequence in 74% overall yield. The synthesis involved Pd-catalyzed Suzuki–Miyaura cross-coupling, followed by hydrazone formation and a subsequent hydrogenation step, and additionally incorporates a liquid–liquid extraction step.

The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous-flow processes.

The popularity of dedicated microwave reactors in many academic and industrial laboratories has produced a plethora of synthetic protocols that are based on this enabling technology. In the majority of examples, transformations that require several hours when performed using conventional heating under reflux conditions reach completion in a few minutes or even seconds in sealed-vessel, autoclave-type, microwave reactors. However, one severe drawback of microwave chemistry is the difficulty in scaling this technology to a production-scale level.