Search Results (14)

Monitoring dopamine (DA) has attracted increasing attention due to alterations in DA levels associated with brain disorders. In addition, the urinary DA concentration plays a significant role in the sympathoadrenal system. A decrease in DA can impair reward-seeking behavior and cognitive flexibility. Therefore, accurate and precise DA detection is necessary. In this study, a poly(3-aminobenzylamine)/functionalized multi-walled carbon nanotube (PABA/f-CNT) composite thin film was fabricated by electrochemical synthesis, or electropolymerization, of 3-aminobenzylamine (3-ABA) monomer and f-CNTs through cyclic voltammetry (CV) on a fluorine-doped tin oxide (FTO)-coated glass substrate, which also served as a working electrode for label-free DA detection in artificial urine. The formation of the film was confirmed by the obtained cyclic voltammogram, electrochemical impedance spectroscopy (EIS) plots, and scanning electron microscope (SEM) and transmission electron microscope (TEM) images. The chemical components of the films were analyzed using attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). For label-free DA detection, various concentrations (50–1000 nM) of DA were determined in buffer solution through differential pulse voltammetry (DPV). The fabricated PABA/f-CNT film presented two linear ranges of 50–400 nM (R² = 0.9915) and 500–1000 nM (R² = 0.9443), with sensitivities of 1.97 and 0.95 µA·cm⁻²·µM⁻¹, respectively. The limit of detection (LOD) and the limit of quantity (LOQ) were 119.54 nM and 398.48 nM, respectively. In addition, the PABA/f-CNT film provided excellent selectivity against common interferents (ascorbic acid, uric acid, and glucose) with high stability, reproducibility, and repeatability. For potential future medical applications, DA detection was further performed in artificial urine, yielding a high percentage of recovery. Full article

Childhood neuroblastoma (NB) is a malignant tumour that is a member of a class of embryonic tumours that have their origins in sympathoadrenal progenitor cells. There are five stages in the clinical NB staging system: 1, 2A, 2B, 3, 4S, and 4. For those diagnosed with stage 4 neuroblastoma (NBS4), the treatment options are limited with a survival rate of between 40 and 50%. Since 1975, more than 15 targets have been identified in the search for a treatment for high-risk NBS4. This article is concerned with the search for a multi-target drug treatment for high-risk NBS4 and focuses on four possible treatment targets that research has identified as having a role in the development of NBS4 and includes the inhibitors Histone Deacetylase (HDAC), Bromodomain (BRD), Hedgehog (HH), and Tropomyosin Kinase (TRK). Computer-aided drug design and molecular modelling have greatly assisted drug discovery in medicinal chemistry. Computational methods such as molecular docking, homology modelling, molecular dynamics, and quantitative structure–activity relationships (QSAR) are frequently used as part of the process for finding new therapeutic drug targets. Relying on these techniques, the authors describe a medicinal chemistry strategy that successfully identified eight compounds (inhibitors) that were thought to be potential inhibitors for each of the four targets listed above. Results revealed that all four targets BRD, HDAC, HH and TRK receptors binding sites share similar amino acid sequencing that ranges from 80 to 100%, offering the possibility of further testing for multi-target drug use. Two additional targets were also tested as part of this work, Retinoic Acid (RA) and c-Src (Csk), which showed similarity (of the binding pocket) across their receptors of 80–100% but lower than 80% for the other four targets. The work for these two targets is the subject of a paper currently in progress. Full article

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article

The aim of this study was to evaluate the combined effects of L-arginine, intermittent hypoxia training (IHT), and acute stress on oxygen-dependent processes in rats, including mitochondrial oxidative phosphorylation, microsomal oxidation, and the intensity of lipoperoxidation processes. In addition, our study investigated how the modulatory effect of the NO synthase mechanism on the concentration of catecholamines (CA), such as adrenaline and noradrenaline, and their biosynthetic precursors (DOPA, dopamine) varies depending on the cholinergic (acetylcholine, Ach-acetylcholinesterase, AChE) status in rats. This study investigated the protective stress-limiting effects of L-arginine impact and IHT in the blood and liver of rats. The results showed that L-arginine promoted the maintenance of NAD-dependent oxidation in mitochondria, which was detrimental compared to succinate oxidation, and was accompanied by depletion of respiratory activity reserves under stress induced by high concentrations of CA. The interdependence of SC-dependent oxidation and the functional role of NAD-dependent substrate oxidation in the mitochondrial respiratory chain in stress conditions induced using inhibitors revealed the importance of the NO system. Administration of L-arginine during the IHT course prior to stress exposure increased the compensatory capacity of the organism. L-arginine increased the compensatory capacity of the sympathoadrenal system in stress-exposed rats. In the early stages of IHT, modulation of the CA concentration was observed with a concomitant increase in lipoperoxidation processes, and in the final stages of IHT, the CA concentrations increased, but there was also an inhibition of lipoperoxidation, which was particularly enhanced by the administration of L-arginine. The increase in blood concentrations of CA and ACh was accompanied by a decrease in AChE activity at different stages of adaptation to hypoxia induced by IHT (days 5, 10, and 14). Thus, the IHT method significantly mobilises the reserve capacity of oxygen-dependent processes through the system of CA, ACh-AChE mediated by nitric oxide. Full article

Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development. Full article

Neuropsychiatric complications, in particular cognitive and depressive disorders, are common consequences of ischemic stroke (IS) and complicate the rehabilitation, quality of life, and social adaptation of patients. The hypothalamic–pituitary–adrenal (HPA) system, sympathoadrenal medullary system (SAMS), and inflammatory processes are believed to be involved in the pathogenesis of these disorders. This study aimed to explore these systems in IS patients, including those with post-stroke cognitive and depressive disorders, within a year after IS. Indices of the HPA axis, inflammatory system, and SAMS were measured in blood serum (cortisol, interleukin-6 (IL-6)), plasma (adrenocorticotropic hormone), and saliva (cortisol, α-amylase). During one year after mild/moderate IS (NIHSS score 5.9 ± 4.3), serum cortisol and salivary α-amylase levels remained elevated in the total cohort. In the group with further cognitive decline, serum and salivary cortisol levels were elevated during the acute period of IS. In the group with poststroke depressive disorder, salivary α-amylase was constantly elevated, while serum IL-6 was minimal during the acute period. The results suggest prolonged hyperactivation of the HPA axis and SAMS after IS. Specifically, post-stroke cognitive impairment was associated with hyperactivation of the HPA axis during the acute IS period, while post-stroke depressive disorder was associated with the chronic inflammatory process and hyperactivation of SAMS during the follow-up period. Full article

Human chromogranin A (CgA), a 439 residue-long member of the “granin” secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the many biological activities observed in experimental and preclinical models for CgA and its most investigated fragments (vasostatin-I and catestatin), limited information is available on the receptor mechanisms underlying these effects. The interaction of vasostatin-1 with membrane phospholipids and the binding of catestatin to nicotinic and b2-adrenergic receptors have been proposed as important mechanisms for some of their effects on the cardiovascular and sympathoadrenal systems. Recent studies have shown that neuropilin-1 and certain integrins may also work as high-affinity receptors for CgA, vasostatin-1 and other fragments. In this case, we review the results of these studies and discuss the structural requirements for the interactions of CgA-related peptides with neuropilin-1 and integrins, their biological effects, their mechanisms, and the potential exploitation of compounds that target these ligand-receptor systems for cancer diagnosis and therapy. The results obtained so far suggest that integrins (particularly the integrin avb6) and neuropilin-1 are important receptors that mediate relevant pathophysiological functions of CgA and CgA fragments in angiogenesis, wound healing, and tumor growth, and that these interactions may represent important targets for cancer imaging and therapy. Full article

In modern life, the use of plant stress-protectors has taken on particular significance due to the wide distribution of neurosis-like and neurotic diseases caused by neuroendocrine-immune system imbalance. Special attention has been paid to the plants containing ecdysteroids, i.e., hormone-like bioactive substances with high adaptogenic activity. The article deals with the study of bioactivity of two plant extracts as Rhaponticum uniflorum (L.) DC. and Serratula centauroides L. with a high content of ecdysteroids and phenolic compounds. The models of acute and chronic emotional stress in white rats were used to estimate the stress-protective activity of R. uniflorum and S. centauroides extracts. Both extracts showed the stress-protective effect via inhibiting the development of signs induced by single and long-term effects of stress factors. In acute stress, the development of Selye's triad signs was less pronounced against the background of the plant remedies introduction. In chronic stress, the extracts prevented the development of anxiety-depressive syndrome. Besides, R. uniflorum and S. centauroides extracts banned the development of stress-induced injuries in the brain cortex and had a neuroprotective effect on ischemia against chronic stress. The stress-protective effects of both plant extracts were based on a decrease of hyperactivation of the central stress-promoting systems (sympathoadrenal, hypothalamic-pituitary-adrenal) due to their GABA-mimetic effects. Peripheral mechanisms were connected with the inhibition of free radical oxidation processes and with an increase in the endogenous antioxidant system activity. Thus, R. uniflorum and S. centauroides extracts have a high potential to increase non-specific body resistance against acute and chronic emotional stress effects. Full article

In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1^G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1^G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1^G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS. Full article

The sympathoadrenal counterregulatory response to hypoglycemia is critical for individuals with type 1 diabetes due to impaired ability to produce glucagon. Ketogenic diets (KD) are an increasingly popular diabetes management tool; however, the effects of KD on the sympathoadrenal response are largely unknown. Here, we determined the effects of KD-induced ketosis on the sympathoadrenal response to a single insulin-induced hypoglycemic challenge. We investigated how a 3 week KD feeding regimen affected the main components of the sympathoadrenal counterregulatory response: adrenal sympathetic nerve activity (ASNA), adrenal gland activity, plasma epinephrine, and brainstem glucose-responsive C1 neuronal activation in anesthetized, nondiabetic male Sprague-Dawley rats. Rats on KD had similar blood glucose (BG) levels and elevated ketone body β-hydroxybutyrate (BHB) levels compared to the control Chow diet group. All KD rats responded to hypoglycemia with a robust increase in ASNA, which was initiated at significantly lower BG levels compared to Chow-fed rats. The delay in hypoglycemia-induced ASNA increase was concurrent with rapid disappearance of BHB from cerebral and peripheral circulation. Adrenal gland activity paralleled epinephrine and ASNA response. Overall, KD-induced ketosis was associated with initiation of the sympathoadrenal response at lower blood glucose levels; however, the magnitude of the response was not diminished. Full article

The GATA family of transcription factors consists of six proteins (GATA1-6) that control a variety of physiological and pathological processes. In particular, GATA2 and GATA3 are coexpressed in a number of tissues, including in the urogenital and sympathoadrenal systems, in which both factors participate in the developmental process and tissue maintenance. Furthermore, accumulating studies have demonstrated that GATA2 and GATA3 are involved in distinct types of inherited diseases as well as carcinogenesis in diverse tissues. This review summarizes our current knowledge of how GATA2 and GATA3 participate in the transcriptional regulatory circuitry during the development of the sympathoadrenal and urogenital systems, and how their dysregulation results in the carcinogenesis of neuroblastoma, renal urothelial, and gynecologic cancers. Full article

The development and progression of cancer depends on both tumor micro- and macroenvironments. In addition, psychosocial and spiritual “environments” might also affect cancer. It has been found that the nervous system, via neural and humoral pathways, significantly modulates processes related to cancer at the level of the tumor micro- and macroenvironments. The nervous system also mediates the effects of psychosocial and noetic factors on cancer. Importantly, data accumulated in the last two decades have clearly shown that effects of the nervous system on cancer initiation, progression, and the development of metastases are mediated by the sympathoadrenal system mainly via β-adrenergic receptor signaling. Here, we provide a new complex view of the role of β-adrenergic receptor signaling within the tumor micro- and macroenvironments as well as in mediating the effects of the psychosocial and spiritual environments. In addition, we describe potential preventive and therapeutic implications. Full article

Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines—stored in noradrenergic and adrenergic cells—plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington’s disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated [Ca²⁺]c transients with faster Ca²⁺ clearance. In the SOD1^G93A mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer’s disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson’s disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington’s disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy. Full article

We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve–chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca²⁺ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain. Full article