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.     

The Ameliorative Effect of Empagliflozin in Vigabatrin-Induced Cerebellar/Neurobehavioral Deficits: Targeting mTOR/AMPK/SIRT-1 Signaling Pathways

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity.     

Synthesis,refinement of the structure,and AC conductivity behavior of sodium lithium orthonavadates

The Na _x Li_1-x CdVO₄ (x = 0.5, 1) orthovanadates were prepared using a solid-state reaction method. The x-ray diffraction patterns (XRDP) of both materials reveal the formation of the Na₂CrO₄ structure. Vibrational study confirms the existence of [VO₄]^3? group. Electrical measurements of our compounds have been investigated using complex impedance spectroscopy (CIS) in the frequency and temperature range 209 Hz–1 MHz and 589–703 K, respectively. Nyquist plots reveal the presence of tow contributions, an equivalent circuit was proposed. DC conductivity shows electrical conduction in the material as a thermally activated process. The AC conductivity is explained using the non-overlapping small polaron tunneling (NSPT) conduction mechanism. A relationship between crystal structure and ionic conductivity was established and discussed.     

Uniqueness and existence of solutions for a singular system with nonlocal operator via perturbation method

In this work, we investigate the existence and the uniqueness of solutions for the nonlocal elliptic system involving a singular nonlinearity as follows: $$ \left\{\begin{array}{ll} (-\Delta_p)^su = a(x)|u|^{q-2}u +\frac{1-\alpha}{2-\alpha-\beta} c(x)|u|^{-\alpha}|v|^{1-\beta}, \quad \text{in }\Omega,\ (-\Delta_p)^s v= b(x)|v|^{q-2}v +\frac{1-\beta}{2-\alpha-\beta} c(x)|u|^{1-\alpha}|v|^{-\beta}, \quad \text{in }\Omega,\ u=v = 0 ,\;\;\mbox{ in }\,\mathbb{R}^N\setminus\Omega, \end{array} \right. $$ where $\Omega $ is a bounded domain in $\mathbb{R}^{n}$ with smooth boundary, $0<\alpha <1,$ $0<\beta <1,$ $2-\alpha -\beta 相似文献   

Bounded starlike functions of complex order

LetF(b, M) (b ≠ 0 complex,M>1/2) denote the class of functionsf(z) =z + Σ _n=2 ^∞ a _n z ⁿ analytic in U={z:|z|<1} which satisfy for fixedM, f(z)/z ≠ 0 inU and \(\left| {\frac{{b - 1 + \left[ {zf'{{\left( z \right)} \mathord{\left/ {\vphantom {{\left( z \right)} {f\left( z \right)}}} \right. \kern-0em} {f\left( z \right)}}} \right]}}{b} - M} \right|< M, z \in U\) . In this note we obtain various representations for functions inF(b, M). We maximize |a₃=μa ₂ ² | over the classF(b, M). Also sharp coefficient bounds are established for functions inF(b, M). We also obtain the sharp radius of starlikeness of the classF(b, M).     

Magnetic properties of nanostructured MnZn ferrite

Mn_0.5Zn_0.5Fe₂O₄ nanoparticles (10-30 nm) have been prepared via mechanochemical processing, using a mixture of two single-phase ferrites, MnFe₂O₄ and ZnFe₂O₄. SQUID measurements (field-cooled magnetization curves and hysteresis loops) were performed to follow the mechanically induced evolution of the MnFe₂O₄/ZnFe₂O₄ mixture submitted to the high-energy milling process. The resulting single MnZn nanoferrite phase was characterized by SQUID (M-H curve), Faraday balance (M-T curve) and transmission electron microscopy. The magnetic characteristics of the mechanosynthesized material were compared with those of bulk Mn_0.5Zn_0.5Fe₂O₄. It was found that the saturation magnetization of nanostructured Mn_0.5Zn_0.5Fe₂O₄ (87.2 emu/g) is lower than that of the bulk Mn_0.5Zn_0.5Fe₂O₄, but, the Néel temperature of the sample (583 K) is higher than that of the bulk Mn_0.5Zn_0.5Fe₂O₄.     

Bochner algebras and their compact multipliers

Let \mathfrakA\mathfrak{A} be a normed algebra with identity, Ω be a locally compact Hausdorf space and λ be a positive Radon measure on Ω with supp(λ) = Ω. In this paper, we establish a necessary and sufficient condition for L ¹(Ω, \mathfrakA\mathfrak{A}) to be an algebra with pointwise multiplication. Under this condition, we then characterize compact and weakly compact left multipliers on L ¹(Ω, \mathfrakA\mathfrak{A}).     

Mathematical Modeling to Simulate the Movement of Contaminants in Groundwater

The objectives of this paper are twofold. Firstly, we formulate a system of partial differential equations that models the contamination of groundwater due to migration of dissolved contaminants through unsaturated to saturated zone. A closed form solution using the singular perturbation techniques for the flow and solute transport equations in the unsaturated zone is obtained. Indeed, the solution can be used as a tool to verify the accuracy of numerical models of water flow and solute transport. The second part of this paper, deals with how the water level in a water reserve drops due to pumping water out of a well that is some distance away.     

On rubin's harmonic analysis and its related positive definite functions

In this paper, a new formulation of the Rubin's q-translation is given, which leads to a reliable q-harmonic analysis. Next, related q-positive definite functions are introduced and studied, and a Bochner's theorem is proved.