Central Administration of Insulin Combined With Resistin Reduces Renal Sympathetic Nerve Activity in Rats Fed a High Fat Diet

Insulin receptors are widely distributed in the central nervous system and their activation by insulin elicits renal sympatho-excitatory effects. Resistin, an adipokine, promotes resistance to the metabolic effects of insulin. Resistin also induces increases in renal sympathetic nerve activity (RSNA) by acting in the brain, but whether it can influence insulin’s actions on RSNA is unknown. In the present study we investigated, in male Sprague-Dawley rats (7–8 weeks of age), the effects of central administration of insulin combined with resistin on RSNA following a normal diet (ND) and a high fat diet (HFD) (22% fat), since HFD can reportedly attenuate insulin’s actions. RSNA, mean arterial pressure (MAP) and heart rate (HR) responses were monitored and recorded before and for 180 min after intracerebroventricular injection of saline (control) (n = 5 HFD and ND), resistin (7 μg; n = 4 ND, n = 5 HFD), insulin (500 mU; n = 6 ND, n = 5 HFD), and the combination of both resistin and insulin (n = 7 ND, n = 5 HFD). The key finding of the present study was that when resistin and insulin were combined there was no increase in RSNA induced in rats fed a normal diet or the high fat diet. This contrasted with the sympatho-excitatory RSNA effects of the hormones when each was administered alone in rats fed the ND and the HFD

High Fat Diet Decreases Neuronal Activation in the Brain Induced by Resistin and Leptin

Resistin and leptin are adipokines which act in the brain to regulate metabolic and cardiovascular functions which in some instances are similar, suggesting activation of some common brain pathways. High-fat feeding can reduce the number of activated neurons observed following the central administration of leptin in animals, but the effects on resistin are unknown. The present work compared the distribution of neurons in the brain that are activated by centrally administered resistin, or leptin alone, and, in combination, in rats fed a high fat (HFD) compared to a normal chow diet (ND). Immunohistochemistry for the protein, Fos, was used as a marker of activated neurons. The key findings are (i) following resistin or leptin, either alone or combined, in rats fed the HFD, there were no significant increases in the number of activated neurons in the paraventricular and arcuate nuclei, and in the lateral hypothalamic area (LHA). This contrasted with observations in rats fed a normal chow diet; (ii) in the OVLT and MnPO of HFD rats there were significantly less activated neurons compared to ND following the combined administration of resistin and leptin; (iii) In the PAG, RVMM, and NTS of HFD rats there were significantly less activated neurons compared to ND following resistin. The results suggest that the sensitivity to resistin in the brain was reduced in rats fed a HFD. This has similarities with leptin but there were instances where there was reduced sensitivity to resistin with no significant effects following leptin. This suggests diet influences neuronal effects of resistin

Central Administration of Insulin and Leptin Together Enhance Renal Sympathetic Nerve Activity and Fos Production in the Arcuate Nucleus

There is considerable interest in the central actions of insulin and leptin. Both induce sympatho-excitation. This study (i) investigated whether centrally administered leptin and insulin together elicits greater increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) than when given alone, and (ii) quantified the number of activated neurons in brain regions influencing SNA, to identify potential central sites of interaction. In anesthetised (urethane 1.4-1.6 g/kg iv) male Sprague-Dawley rats, RSNA, MAP, and HR were recorded following intracerebroventricular (ICV) saline (control; n = 5), leptin (7 μg; n = 5), insulin (500 mU; n = 4) and the combination of leptin and insulin; (n = 4). Following leptin or insulin alone, RSNA was significantly increased (74 and 62% respectively). MAP responses were not significantly different between the groups. Insulin alone significantly increased HR. Leptin alone also increased HR but it was significantly less than following insulin alone (P < 0.005). When leptin and insulin were combined, the RSNA increase (124%) was significantly greater than the response to either alone. There were no differences between the groups in MAP responses, however, the increase in HR induced by insulin was attenuated by leptin. Of the brain regions examined, only in the arcuate nucleus did leptin and insulin together increase the number of Fos-positive cell nuclei significantly more than leptin or insulin alone. In the lamina terminalis and rostroventrolateral medulla, leptin and insulin together increased Fos, but the effect was not greater than leptin alone. The results suggest that when central leptin and insulin levels are elevated, the sympatho-excitatory response in RSNA will be greater. The arcuate nucleus may be a common site of cardiovascular integration

The Antimicrobial Resistance and Prevalence of Enterococcus Species in Saudi Arabia

Monitoring the distribution and resistance of antibiotics to enterococcal species is critical aspect to controlling and preventing enterococcal infection. The aim of the present study is to screen the antimicrobial resistance genes within Enterococcus species isolates that collected from Taif governorate, Saudi Arabia. Out of 134 clinical samples, nineteen enterococcal isolates were identified using 16S rRNA sequence gene. Phylogenetic tree analysis using 16S rRNA gene sequence of the 19 strains divided them into 15 strains as E. faecalis and 4 strains as E. faecium. In addition, these the species of these isolates were recognized using VITEK-2 COMPACT system. The PCR technique was used to screen the multi-drug resistant genes within enterococcal isolates. The KpsII, tetL, aac(6)-Ie-aph(2)-Ia, vanA and Erm(B) genes were found in all strains. The distribute of resistance against antibiotic drugs were differs greatly between the two species, a considerably higher prevalence of resistance to penicillin, gentamicin, cefoxitin, cefotaxime, clindamycin, erthromycin and fusidic acid was identified in E. faecalis than in E. faecium, while greater spread was detected to resist to Trim/Sulf and tetracycline in E. faecalis. Finally, rep-PCR markers investigated genomic diversity of Enterococcus strains. Results of rep-PCR markers generated 142 distinct loci; 96 were polymorphic (67.6%) and 46 were monomorphic (32.4%). Number of loci for individual rep-PCR primers ranged from 9 for rep-08 to 18 for rep-02

Enhancing the Antipsychotic Effect of Risperidone by Increasing Its Binding Affinity to Serotonin Receptor via Picric Acid: A Molecular Dynamics Simulation

The aim of this study was to assess the utility of inexpensive techniques in evaluating the interactions of risperidone (Ris) with different traditional &pi;-acceptors, with subsequent application of the findings into a Ris pharmaceutical formulation with improved therapeutic properties. Molecular docking calculations were performed using Ris and its different charge-transfer complexes (CT) with picric acid (PA), 2,3-dichloro-5,6-dicyanop-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-pquinon (BL), and tetrachloro-p-quinon (CL), as donors, and three receptors (serotonin, dopamine, and adrenergic) as acceptors to study the comparative interactions among them. To refine the docking results and further investigate the molecular processes of receptor&ndash;ligand interactions, a molecular dynamics simulation was run with output obtained from AutoDock Vina. Among all investigated complexes, the [(Ris) (PA)]-serotonin (CTcS) complex showed the highest binding energy. Molecular dynamics simulation of the 100 ns run revealed that both the Ris-serotonin (RisS) and CTcS complexes had a stable conformation; however, the CTcS complex was more stable

Multispectral and Molecular Docking Studies Reveal Potential Effectiveness of Antidepressant Fluoxetine by Forming π-Acceptor Complexes

Poor mood, lack of pleasure, reduced focus, remorse, unpleasant thoughts, and sleep difficulties are all symptoms of depression. The only approved treatment for children and adolescents with major depressive disorder (MDD) is fluoxetine hydrochloride (FXN), a serotonin selective reuptake inhibitor antidepressant. MDD is the most common cause of disability worldwide. In the present research, picric acid (PA); dinitrobenzene; p-nitro benzoic acid; 2,6-dichloroquinone-4-chloroimide; 2,6-dibromoquinone-4-chloroimide; and 7,7′,8,8′-tetracyanoquinodimethane were used to make 1:1 FXN charge-transfer compounds in solid and liquid forms. The isolated complexes were then characterized by elemental analysis, conductivity, infrared, Raman, and 1H-NMR spectra, thermogravimetric analysis, scanning electron microscopy, and X-ray powder diffraction. Additionally, a molecular docking investigation was conducted on the donor moiety using FXN alone and the resulting charge transfer complex [(FXN)(PA)] as an acceptor to examine the interactions against two protein receptors (serotonin or dopamine). Interestingly, the [(FXN)(PA)] complex binds to both serotonin and dopamine more effectively than the FXN drug alone. Furthermore, [(FXN)(PA)]–serotonin had a greater binding energy than [FXN]–serotonin. Theoretical data were also generated by density functional theory simulations, which aided the molecular geometry investigation and could be beneficial to researchers in the future

Spectroscopic and Molecular Docking Analysis of π-Acceptor Complexes with the Drug Barbital

The drug barbital (Bar) has a strong sedative–hypnotic effect. The intermolecular charge transfer compounds associated with the chemical reactions between Bar and some π acceptors, such as 2,6-dibromoquinone-4-chloroimide (DBQ), tetracyanoquinodimethane (TCNQ), chloranil (CHL), and chloranilic acid (CLA), have been synthesized and isolated in solid state. The synthesized products have the molecular formulas (Bar–DBQ), (Bar–TCNQ), (Bar–CHL), and (Bar–CLA) with 1:1 stoichiometry based on Raman, IR, TG, 1H NMR, XRD, SEM, and UV-visible analysis techniques. Additionally, the comparative analysis of molecular docking between the donor reactant moiety, Bar, and its four CT complexes was conducted using two neurotransmitter receptors (dopamine and serotonin). The docking results obtained from AutoDockVina software were investigated by a molecular dynamics simulation technique with 100ns run. The molecular mechanisms behind receptor–ligand interactions were also looked into. The DFT computations were conducted using theory at the B3LYP/6-311G++ level. In addition, the HOMO LUMO electronic energy gap and the CT complex’s optimal geometry and molecule electrostatic potential were examined

Increasing the Efficacy of Seproxetine as an Antidepressant Using Charge&ndash;Transfer Complexes

The charge transfer interactions between the seproxetine (SRX) donor and &pi;-electron acceptors [picric acid (PA), dinitrobenzene (DNB), p-nitrobenzoic acid (p-NBA), 2,6-dichloroquinone-4-chloroimide (DCQ), 2,6-dibromoquinone-4-chloroimide (DBQ), and 7,7&prime;,8,8&prime;-tetracyanoquinodi methane (TCNQ)] were studied in a liquid medium, and the solid form was isolated and characterized. The spectrophotometric analysis confirmed that the charge&ndash;transfer interactions between the electrons of the donor and acceptors were 1:1 (SRX: &pi;-acceptor). To study the comparative interactions between SRX and the other &pi;-electron acceptors, molecular docking calculations were performed between SRX and the charge transfer (CT) complexes against three receptors (serotonin, dopamine, and TrkB kinase receptor). According to molecular docking, the CT complex [(SRX)(TCNQ)] binds with all three receptors more efficiently than SRX alone, and [(SRX)(TCNQ)]-dopamine (CTcD) has the highest binding energy value. The results of AutoDock Vina revealed that the molecular dynamics simulation of the 100 ns run revealed that both the SRX-dopamine and CTcD complexes had a stable conformation; however, the CTcD complex was more stable. The optimized structure of the CT complexes was obtained using density functional theory (B-3LYP/6-311G++) and was compared

Enhancement of Haloperidol Binding Affinity to Dopamine Receptor via Forming a Charge-Transfer Complex with Picric Acid and 7,7,8,8-Tetracyanoquinodimethane for Improvement of the Antipsychotic Efficacy

Haloperidol (HPL) is a typical antipsychotic drug used to treat acute psychotic conditions, delirium, and schizophrenia. Solid charge transfer (CT) products of HPL with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have not been reported till date. Therefore, we conducted this study to investigate the donor&ndash;acceptor CT interactions between HPL (donor) and TCNQ and PA (&pi;-acceptors) in liquid and solid states. The complete spectroscopic and analytical analyses deduced that the stoichiometry of these synthesized complexes was 1:1 molar ratio. Molecular docking calculations were performed for HPL as a donor and the resulting CT complexes with TCNQ and PA as acceptors with two protein receptors, serotonin and dopamine, to study the comparative interactions among them, as they are important neurotransmitters that play a large role in mental health. A molecular dynamics simulation was ran for 100 ns with the output from AutoDock Vina to refine docking results and better examine the molecular processes of receptor&ndash;ligand interactions. When compared to the reactant donor, the CT complex [(HPL)(TCNQ)] interacted with serotonin and dopamine more efficiently than HPL only. CT complex [(HPL)(TCNQ)] with dopamine (CTtD) showed the greatest binding energy value among all. Additionally, CTtD complex established more a stable interaction with dopamine than HPL&ndash;dopamine