Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

Voltage-gated Na⁺ (Na_V) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel Na_V channel ligands. With the objective of discovering new blockers of Na_V channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of Na_V channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC₅₀. These five alkaloids were then assayed using the Na⁺ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNa_V1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na⁺ currents elicited by the hNa_V1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na⁺ currents elicited by the hNav1.2 and hNav1.6 channels, with IC₅₀ values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block Na_V channels, with promising therapeutical applications.     

Jacobson’s Lemma for Generalized Drazin–Riesz Inverses

Acta Mathematica Sinica, English Series - For bounded linear operators A, B, C and D on a Banach space X, we show that if BAC = BDB and CDB = CAC then I — AC is generalized Drazin—Riesz...     

Stabilization of nonlinear switched systems using control Lyapunov functions

In this paper, we study the stabilization of general nonlinear switched systems by using control Lyapunov functions. The concept of control Lyapunov function for nonlinear control systems is generalized to switched control systems. The first part of our contribution provides a necessary and sufficient condition of stabilization. The main idea is to use a common control Lyapunov function; this is achieved with the converse Lyapunov theorem dedicated to switched systems. In the second part, an explicit construction of a common control Lyapunov function is addressed with respect to a finite family of switched systems. The approach uses a family of control Lyapunov functions attached to the subsystems.     

PYRIDINATION OF POLY（VINYL CHLORIDE） via A HOMOLYTIC PATHWAY

PVC was subjected to a chemical modification aiming at replacing the chlorine atoms by pyridine groups via a homolytic route. Pyridine groups were peculiarly affixed to the PVC matrix via a carbon-carbon bond rather than a carbon-nitrogen one. PVC was first iodinated using the Conant-Finkelstein reaction, followed by the application of the homolytic conditions of Minisci to generate pyridinated PVC with a varying degree of substitution. The extent of substitution was not high; the reaction on 30% iodinated PVC afforded a degree of modification no greater than 3%.     

Cycloaddition reactions in aqueous systems: A two-decade trend endeavor

Cycloaddition reactions are an integral and weighty part of organic chemistry in pedagogy and research as well. The wealthy literature on cycloaddition reactions from their birth up to now, unequivocally witnesses to their leading chemistry. The so-called “conventional solvents” are organic solvents that have indubitably promoted their success. Yet, the toxicity facet of these solvents impedes their use freely and with no fear. Not only is the operating chemist uncomfortable while experimenting, but also the environment is equally threatened. Working out the cycloaddition reactions and other organic ones in aqueous systems would certainly bring some relief to the chemist and to the environment as well. Unusual outcomes in terms of yield, reactivity and selectivity compared to those performed in organic solvents were commonly observed, and have overwhelmed the chemists with surprise indeed. In this review, homo Diels–Alder reactions in aqueous media include those involving the following dienophiles: maleimides, α,β-unsaturated esters, p-benzoquinones, vinyl ketones, phenyl-1-(2-pyridyl)-2-propen-1-one, α,β-unsaturated esters. A special case is the organocatalysis of Diels–Alder cycloaddition of α,β-unsaturated ketones (aldehydes). Of no less importance, some hetero Diels–Alder cycloaddition reactions in water systems are delineated. The impact of additives (salts, organic and inorganic chemicals), micellar catalysis and Lewis/Brønstëd acid catalysis on outcomes of such cycloaddition reactions is discussed. The 1,3-dipolar cycloaddition methodology applied to aqueous media has brought forth a number of heterocyclic compounds, usually with a regio- and stereoselectivity pecularity. These heterocycles include triazoles, tetrazoles, pyrazoles, isoxazoles, isoxazolidines, pyrroles and pyrrolidines. The superiority of copper(I) catalysis in the azide-alkyne cycloaddition (Huisgen cycloaddition) in water is endorsed by a number of examples.     

Entropy and renormalized solutions for nonlinear elliptic problem involving variable exponent and measure data

We give an existence result of entropy and renormalized solutions for strongly nonlinear elliptic equations in the framework of Sobolev spaces with variable exponents of the type:-div(a(x, u, u) + φ(u)) + g(x, u, u) = μ, where the right-hand side belongs to L1(Ω) + W-1,p(x)(Ω),-div(a(x, u, u)) is a Leray–Lions oper- ator defined from W-1,p(x)(Ω) into its dual and φ∈ C0(R, RN). The function g(x, u, u) is a non linear lower order term with natural growth with respect to |u| satisfying the sign condition, that is,g(x, u, u)u ≥ 0.     

Use of inverse gas chromatography to account for the pervaporation performance in monitoring the oxidation of primary alcohols

The oxidation of n-propanol and n-butanol to their corresponding aldehydes was monitored by the pervaporation technique. Mass transfer phenomenon that occurs in the pervaporation process was confirmed by the results of inverse gas chromatography. Polydimethylsiloxane (PDMS), a hydrophobic polymer widely employed as a membrane in pervaporation technique, was evaluated as a stationary phase in this study. The retention times of the different molecules probes (n-propanol, n-butanol, propionaldehyde, and butyraldehyde), molecules involved as reactants and products in the oxidation reaction, gave an insight into the extent of the interactions between each of these molecules and the stationary phase. The infinite dilution conditions allowed to measure the infinite dilution activity coefficient, gamma(infinity), and the specific retention volume, V(g)(0), and to estimate the Flory-Huggins parameter interactions, chi(12)(infinity). The magnitudes of these parameters threw some light on the permselectivity of the membranes in the pervaporation operation.