Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV 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 NaV 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-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 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 NaV channels, with promising therapeutical applications. 相似文献
Mosquitoes represent one of the most important vectors and are responsible for the transmission of many arboviruses that affect human and animal health. The chemical method using synthetic insecticides disturbs the environmental system and promotes the appearance of resistant insect species. Therefore, this study investigated the insecticidal effect of some binary monoterpene combinations (1,8 cineole + α-pinene and carvone + R (+)-pulegone) using a mixture design approach. The fumigant toxicity was evaluated against Culex pipiens female adults using glass jars. The results show that the toxicity varies according to the proportions of each compound. Indeed, Mixture 1 (1,8-cineole + α-pinene) displayed a strong toxic effect (51.00 ± 0.86% after 24 h and 100.00 ± 0.70% after 48 h) when the pure compounds were tested at 0.25/0.75 proportions of 1,8-cineole and α-pinene, respectively. Nevertheless, the equal proportion (0.5/0.5) of carvone and R (+)-pulegone in Mixture 2 exhibited a toxic effect of 54.35 ± 0.75% after 24 h and 89.96 ± 0.14% after 48 h, respectively. For Mixture 1, the maximum area of mortality that the proposed model indicated was obtained between 0/1 and 0.25/0.75, while the maximum area of mortality in the case of Mixture 2 was obtained between 0.25/0.75 and 0.75/0.25. Moreover, the maximum possible values of mortality that could be achieved by the validated model were found to be 51.44% (after 24 h) and 100.24% (after 48 h) for Mixture 1 and 54.67% (after 24 h) and 89.99% (after 48 h) for Mixture 2. It can be said that all purev molecules tested through the binary mixtures acted together, which enhanced the insecticide’s effectiveness. These findings are very promising, as the chemical insecticide (deltamethrin) killed only 19.29 ± 0.01% and 34.05 ± 1.01% of the female adults after 24 h and 48 h, respectively. Thus, the findings of our research could help with the development of botanical insecticides that might contribute to management programs for controlling vectors of important diseases. 相似文献
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. 相似文献
A key challenge in the design of magnetic molecular switches is to obtain bistability at room temperature. Here, we show that application of moderate pressure makes it possible to convert a paramagnetic FeIII2CoII2 square complex into a molecular switch exhibiting a full dia‐ to paramagnetic transition: FeIICoIII ? FeIIICoII. Moreover, the complex follows a rare behavior: the higher the pressure, the broader the magnetic hysteresis. Thus, the application of an adequate pressure allows inducing a magnetic bistability at room temperature with predictable hysteresis width. The structural studies at different pressures suggest that the pressure‐enhanced bistability is due to the strengthening of intermolecular interactions upon pressure increase. An original microscopic Ising‐like model including pressure effects is developed to simulate this unprecedented behavior. Overall, this study shows that FeCo complexes could be very sensitive piezo switches with potential use as sensors. 相似文献
Jet flows provide an effective mode of energy transfer or mass transfer in industrial applications. When compared to traditional cooling through convection, jet flows have high heat and mass transfer coefficients. Further, the devices equipped with jet flow provides efficient use of fluid and also offers enhanced heat and mass transfer rates. Hence in this study, the jet flow of Casson nanofluid containing gyrotactic microorganisms that stabilises the nanoparticle suspension is discussed. To control the fluid from outside external magnetic field is imposed. The model with these characteristics are useful in the appliances like coolants in automobiles, nuclear reactors, micro-manufacturing, metallurgical process etc. Such a model is created by employing PDE, which are then transformed into a system of ODE. The DTM is employed to obtain the solution to system of equations, and the results are interpreted using graphs. It is perceived that the velocity of the nanofluid flow is decreased because of the increased yield stress created by the greater values of the Casson parameter. As a result, the temperature profile is found to be increasing. Meanwhile, it is observed that for increased value of chemical reaction parameter diminishes the nanoparticle concentration. The motile density is found to decrease for increase in the Peclet number and the bioconvection Schmidt number. Further, the thermophoresis improves the temperature and concentration profile of the nanofluid. 相似文献
The development of new techniques for rapid and continuous monitoring of urea in biomedical and clinical analysis is very important. Thus, conductive polymer-supported carbon nanotube as an effective electrochemical biosensing platform for direct detection of urea in blood samples was designed. For the assay optimization, several conductive polymers were synthesized and tested as electrode modifiers; among the tested polymers, poly-o-toluidine (PoT) showed the highest electrochemical signals. However, after the enzyme immobilization, direct bioelectrochemical signals were not obtained when the PoT was used alone. Due to the lower electrocatalytic feature of PoT, integration of carbon nanotube, to form a composite with the PoT, was exploited to enable the direct electron transfer. Successfully, using the hybrid, the catalytic activity of the immobilized urease enzyme was retained. Consequently, a sensitive and specific chronoamperometric signals were achieved after the bioassay optimization. Eventually, a standard calibration curve for urea determination was obtained. A linear range was found from 0.1 to 11 mM with the limit of detection of 0.03 mM. Successfully, several blood samples were analyzed and urea level was correlated with the reference analytical method.
Graphical abstract Scheme 1: Schematic representation of screen-printed electrode-modified urease biosensors. Three-layer functionalized surface (multi-walled carbon nanotube/poly(o-toluidine) nanocomposite, with glutaraldehyde (cross-linker and urease-immobilized enzyme), was designed for urea biosensors.
The relaxation of the metastable state of the spin-crossover compound [Fe(L)(2)](ClO(4))(2).H(2)O, with L = 2,6-bis(pyrazol-1-ylmethyl)pyridine, populated by the LIESST (light induced excited spin state trapping) effect, has been investigated by magnetic measurements. The time dependence of the relaxation curve at several temperatures, starting from different initial states, is in the shape of stretched exponentials, and the thermal variation of the photostationary state under constant photoexcitation is progressive and reversible. These features are satisfactorily modeled by considering noninteracting two-level systems with a distribution of activation energies. A suggested origin for the distribution is the conformational flexibility of the nonplanar heterocyclic ligands. The effect of the intensity distribution during the LIESST process is also accounted for in a simple way. 相似文献
ESI and CID mass spectra were obtained for two purine nucleoside antiviral agents (acycloguanosine and vidarabine) and one purine nucleotide (vidarabine monophosphate) and the corresponding compounds in which the labile hydrogens were replaced by deuterium gas phase exchange. The number of labile hydrogens, x, was determined from a comparison of ESI spectra obtained with N(2) and with ND(3) as the nebulizer gas. CID mass spectra were obtained for [M+H](+) and [M -H](-) ions and the exchanged analogs, [M(Dx)+D](+) and [M(Dx)-D](-), produced by ESI using a Sciex API-IIIplus mass spectrometer. Compositions of product ions and mechanisms of decomposition were determined by comparison of the CID mass spectra of the undeuterated and deuterated species. Protonated purine antiviral agents dissociate through rearrangement decompositions of base-protonated [M+H](+) ions by cleavage of the glycosidic bonds to give the protonated bases with a sugar moiety as the neutral fragment. Cleavage of the same bonds with charge retention on the sugar moiety gives low abundance ions, due to the low proton affinity of the sugar moiety compared to that of purine base. CID of protonated purine bases [B+H](+) occurs through two major pathways: (1) elimination of NH(3) (ND(3)) and (2) loss of NH(2)CN (ND(2)CN). Minor pathways include elimination of HNCO (DNCO), loss of CO, and loss of HCN (DCN). Deprotonated acycloguanosine and vidarabine exhibit the deprotonated base [B-H](-) as a major fragment from glycosidic bond cleavage and charge delocalization on the base. Deprotonated vidarabine monophosphate, however, shows predominantly phosphate related product ions. CID of deprotonated guanine shows two principal pathways: (1) elimination of NH(3) (ND(3)) and (2) loss of NH(2)CN (ND(2)CN). Minor pathways include elimination of HNCO (DNCO), loss of CO, and loss of HCN (DCN). The dissociation reactions of deprotonated adenine, however, proceed by elimination of HCN and (2) elimination of NCHNH (NCHND). The mass spectra of the antiviral agents studied in this paper may be useful in predicting reaction pathways in other heteroaromatic ring decompositions of nucleosides and nucleotides. 相似文献