Electrochemical preparation of epinephrine/Nafion chemically modified electrodes and their electrocatalytic oxidation of ascorbic acid and dopamine

Two types of epinephrine and cyclized epinephrine quinone films have been prepared using cyclic voltammetry from the epinephrine in the strong acidic solutions and neutral aqueous solutions over different scanning potential ranges. The cyclic voltammogram of the epinephrine film is characterized by one redox couple at about +0.5 V (versus Ag|AgCl) and cyclized epinephrine quinone film exhibits one redox couples at about −0.15 V (versus Ag|AgCl) .In addition to cyclic voltammetry and an electrochemical quartz crystal microbalance (EQCM) were used to study the growth mechanism of the epinephrine and cyclized epinephrine quinone molecules. The electrocatalytic oxidation of catecholamines (dopamine and norepinephrine) and also ascorbic acid were investigated in acidic aqueous solutions using epinephrine films. The rotating ring-disk electrode technique was used to investigate the mechanism of electrochemical oxidation of dopamine and ascorbic acid.     

Plant Neurobiology,a Fascinating Perspective in the Field of Research on Plant Secondary Metabolites

In this Editorial, I comment on the exciting and original topic of plant neurobiology, focusing on natural products whose biosynthesis is shared by animal and plant organisms, i.e., indoleamines (melatonin and serotonin) and catecholamines (dopamine, norepinephrine and epinephrine).     

Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.     

发现天然活性物质的潜在途径--生物胺转运体的靶标筛选

生物胺转运体(BAT)是生物膜上的一种蛋白质,它通过将底物从细胞外转运到神经末端来终止多巴胺(DA)、5-羟色胺(5-HT)和去甲肾上腺素(NE)的作用.大量药物和给药方法以BAT为靶点,以底物或抑制剂的形式发挥作用.本文总结了作用于BAT上的药物活性的几种测量方法,并以麻黄碱及其立体异构体为例来讨论这些方法用来发现天然活性物质的潜在应用.     

Comparative effect of glucagon,dibutyryl cyclic AMP,and epinephrine on the desaturation and elongation of linoleic acid by rat liver microsomes

The effect of glucagon, dibutyryl cyclic adenosine 3′,5′-monophosphate, and epinephrine on the biosynthesis of polyunsaturated fatty acids of the linoleic acid family was studied. The incubations were performed with rat liver microsomes and labeled linoleic acid under desaturating and elongating conditions. Under desaturating conditions, linoleic acid was converted to γ-linolenic acid, whereas under elongating conditions it was converted to 20∶2ω6. Glucagon, dibutyryl cyclic AMP, and epinephrine decreased the oxidative desaturation of linoleic acid to γ-linolenic acid while the elongating reaction was not modified in the experimental conditions tested. Consequently, the results support the hypothesis that the oxidative desaturation of linoleic acid to γ-linolenic acid is the main controllable step in the biosynthesis of polyunsaturated fatty acids of the linoleic acid family in the microsomes.     

聚L-天冬氨酸修饰玻碳电极的最优化制备

扫速为100 mV/s时,在不同的条件下于一定浓度的天冬氨酸聚合底液中制作玻碳修饰电极,分别利用肾上腺素（EP）、去甲肾上腺素（NE）和多巴胺（DA）作为探针进行伏安测定,探讨了聚L-天冬氨酸修饰玻碳电极（PL-ASP/GCE）的最佳制备条件,实验表明,在最佳制备条件下PL-ASP/GCE的稳定性和重现性良好。     

高效液相色谱法检测化妆品中儿茶酚胺类药物的残留量

采用高效液相色谱法,研究检测了化妆品中肾上腺素、去甲肾上腺素、异丙肾上腺素的残留量.得到的色谱条件:Waters Atlantis C_(18)柱(5μm,250 mm×4.60 mm)为分析柱,流动相V(甲醇):V(0.02 mol/L磷酸二氢钾溶液)=4:96,荧光检测器检测,激发波长为285 nm,发射波长为340 nm.结果表明,肾上腺素、去甲肾上腺素在0.025 mg/L～2.5 mg/L内,异丙肾上腺素在0.05 mg/L～5.0 mg/L内,其峰面积与质量浓度呈良好的线性关系.该方法回收率为95.6%～99.4%,RSD为3.6%～6.1%(n=8).     

New Succinimides with Potent Anticancer Activity: Synthesis,Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.     

The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. All pyrovalerone cathinones were potent DAT (IC₅₀ = 0.02–8.7 μM) and NET inhibitors (IC₅₀ = 0.03–4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC₅₀ = 0.17–0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264–356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.     

Bio-inspired functionalization and redox charge transfer of graphene oxide sponges for pseudocapacitive electrodes

Bio-inspired and environmentally friendly chemical functionalization method for reducing of graphene oxide (GO) sponge using dopamine derivatives is developed. The GO sponge is readily modified by poly(norepinephrine) (p(Nor)) through a simple wet chemistry, and mechanical properties of the GO sponge is improved with structural stability. The oxidative polymerization of norepinephrine can considerably remove oxygen-containing species from the GO sponge surface as well as provide redox active quinone moieties for pseudocapacitive electrodes. Furthermore, three-dimensional (3D) macroporous networks of the reduced GO (rGO) sponge provide a large surface area and continuous ion pathways. As a result, p(Nor)-functionalized rGO (p(Nor)@rGO) sponge exhibits enhanced capacitive performance. The p(Nor)@rGO sponge shows that a specific capacitance of 232.1 F g⁻¹ (2.5 times higher than that of chemically converted rGO sponge) and good cyclic stability over 2000 charge/discharge cycling tests.     

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.     

Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β₂-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β₂-AR-induced cAMP is immunosuppressive. However, many studies report actions of β₂-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β₂-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β₂-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.     

The electrochemical study of catecholamine reactions in the presence of nitrite ion under mild acidic conditions

The conversion of some catecholamines, such as l-dopa, dopamine and methyldopa, to their corresponding nitro-derivatives, or their oxidative degradation, in the presence of nitrous acid/nitrite ion equilibria has been studied using voltammetric techniques in aqueous solution. The results indicate that nitrous acid, as an oxidant, converts the catecholamines to their quinone derivatives and that the produced quinones are attacked by their side chain amine group or the nitrite ion. Oxidation as the first step and a competition between an intramolecular and intermolecular Michael addition as the second reactions were studied at various pH values. The homogeneous rate constants for the oxidation and Michael addition reactions were estimated by fitting through the selective current-time profiles.     

A novel multi-walled carbon nanotube modified sensor for the selective determination of epinephrine in smokers

Epinephrine (EP), an important neurotransmitter, energizes and speeds up the various body systems and plays an important role during the time of stress and low blood sugar level. There is a close relation between the release of epinephrine and smoking. Edge plane pyrolytic graphite electrode modified with multi-walled carbon nanotubes (MWNTs/EPPGE) has been used as a sensor for the efficient quantitative determination of epinephrine in body fluids of smokers and nonsmokers in resting stage at physiological pH 7.2 by using cyclic voltammetry (CV) and square wave voltammetry (SWV). The oxidation of epinephrine occurred in a well-defined peak having peak potential (E_p) ∼150 mV at pH 7.2. The limit of detection (3σ/slope) and limit of quantification were found to be 0.15 × 10⁻⁹ and 0.48 × 10⁻⁹ M using proposed sensor, respectively. The modified electrode was also utilized for the analysis of commercial sample of epinephrine in order to examine the accuracy of the proposed method. The analytical performance of the modified electrode has been evaluated for quantification of EP in real samples even in the presence of common coexisting biomolecules such as uric acid, ascorbic acid, dopamine and norepinephrine. The voltammetric response of the developed nanosensor towards epinephrine determination in body fluids is fast, sensitive and selective having desirable reproducibility and stability. A comparison of results with high performance liquid chromatography (HPLC) shows a good agreement.     

Protoporphyrin-modified gold surfaces for the selective monitoring of catecholamines

Protoporphyrin IX (PPIX) was immobilized on Au surfaces for the electrochemical oxidation of dopamine (DA) and epinephrine (EP). Two procedures for the immobilization were employed. One class of modified electrodes was prepared by immobilizing the PPIX into polypyrrole (PPy) films synthesized by anodic electropolymerization. The other procedure involved the immobilization of PPIX on an electrode modified by a 11-mercaptoundecanoic acid (MUA) self-assembled monolayer (SAM). The modified surfaces were characterized by cyclic voltammetry (CV).The efficiency of these modified surfaces for the electrochemical oxidation of DA and EP was investigated and compared. The peak potential for the oxidation of each analyte at the different electrode surfaces was determined by square-wave voltammetry (SWV).The dependence of the sensitivity of the electrodes for the detection of the catecholamines on the applied potential was also measured. The SAM-based electrodes showed better selectivity for detecting DA in the potential range between 0.2 and 0.4 V versus Pt (QRE). However, higher sensitivity and linearity were observed for the film-based electrodes.     

Deregulation of Ca2+-Signaling Systems in White Adipocytes,Manifested as the Loss of Rhythmic Activity,Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca²⁺-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP₃-receptors (PLC/IP₃R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)–dependent Ca²⁺ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors’ interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca²⁺]_i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP₃R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5–15% vs. 30–80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca²⁺-signaling systems deregulation, and development of general hormonal resistance to obesity.     

Diurnal Profiles of Melatonin Synthesis-Related Indoles,Catecholamines and Their Metabolites in the Duck Pineal Organ

This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D cycle, were killed at two-hour intervals. The indole contents were measured using HPLC with fluorescence detection, whereas the levels of catecholamines and their metabolites were measured using HPLC with electrochemical detection. All indole contents, except for tryptophan, showed significant diurnal variations. The 5-hydroxytryptophan level was approximately two-fold higher during the scotophase than during the photophase. The serotonin content increased during the first half of the photophase, remained elevated for approximately 10 h and then rapidly decreased in the middle of the scotophase. N-acetylserotonin showed the most prominent changes, with a more than 15-fold increase at night. The melatonin cycle demonstrated only an approximately 5-fold difference between the peak and nadir. The 5-methoxytryptamine content was markedly elevated during the scotophase. The 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid and 5-methoxytryptophol profiles were analogous to the serotonin rhythm. The norepinephrine and dopamine contents showed no significant changes. The DOPA, DOPAC and homovanillic acid levels were higher during the scotophase than during the photophase. Vanillylmandelic acid showed the opposite rhythm, with an elevated level during the daytime.     

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.     

Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.     

Computer-based de novo design, synthesis, and evaluation of boronic acid-based artificial receptors for selective recognition of dopamine

Dopamine is an important neurotransmitter that plays important roles in various physiological and pathological processes, such as Parkinson's disease. Chemosensors for dopamine have a number of potential applications. On the basis both of the strong and reversible complexation between the boronic acid moiety and a diol functional group and computational chemistry studies, we have designed a series of four compounds for selective three-point recognition of dopamine, which include boronic acid-diol complexation, aromatic-hydrophobic interactions, and ionic interactions between a carboxylate and a protonated amino group. These compounds were synthesized in seven or eight linear steps and showed dopamine selectivity of up to tenfold over epinephrine. NMR spectroscopy experiments were conducted to probe the structures of the receptor-dopamine complexes. These receptors are the first to show such significant selectivity for dopamine over epinephrine in aqueous solution under near physiological conditions.