Trial watch: beta-blockers in cancer therapy.

Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines directly act on ß-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic receptors slows tumor growth, suggesting potential clinical benefits of using ß-blockers in cancer therapy. Much of these positive effects of ß-blockade are mediated by improved immunosurveillance. The present trial watch summarizes current knowledge from preclinical and clinical studies investigating the anticancer effects of ß-blockers either as standalone agents or in combination with conventional antineoplastic treatments or immunotherapy.

Catecholamine Derivatives: Natural Occurrence, Structural Diversity, and Biological Activity.

Catecholamines (CAs) are aromatic amines containing a 3,4-dihydroxyphenyl nucleus and an amine side chain. Representative CAs included the endogenous neurotransmitters epinephrine, norepinephrine, and dopamine. CAs and their derivatives are good resources for the development of sympathomimetic or central nervous system drugs, while they also provide ligands important for G-protein coupled receptor (GPCR) research. CAs are of broad interest in the fields of chemical, biological, medical, and material sciences due to their high adhesive capacities, chemical reactivities, metal-chelating abilities, redox activities, excellent biocompatibilities, and ease of degradability. Herein, we summarize CAs derivatives isolated and identified from microorganisms, plants, insects, and marine invertebrates in recent decades, alongside their wide range of reported biological activities. The aim of this review is to provide an overview of the structural and biological diversities of CAs, the regularity of their natural occurrences, and insights toward future research and development pertinent to this important class of naturally occurring compounds.

Dopamine and norepinephrine are embracing their immune side and so should we.

While the history of neuroimmunology is long, the explicit study of neuroimmune communication, and particularly the role of catecholamines in neuroimmunity, is still emerging. Recent studies have shown that catecholamines, norepinephrine, epinephrine, and dopamine, are central to multiple complex mechanisms regulating immune function. These studies show that catecholamines can be released from both the nervous system and directly from immune cells, mediating both autocrine and paracrine signaling. This commentary highlights the importance of catecholaminergic immunomodulation and discusses new considerations needed to study the role of catecholamines in immune homeostasis to best leverage their contribution to disease processes for the development of new therapeutic approaches.

Eukaryotic catecholamine hormones influence the chemotactic control of Vibrio campbellii by binding to the coupling protein CheW.

SignificanceHost-emitted stress hormones significantly influence the growth and behavior of various bacterial species; however, their cellular targets have so far remained elusive. Here, we used customized probes and quantitative proteomics to identify the target of epinephrine and the α-adrenoceptor agonist phenylephrine in live cells of the aquatic pathogen Vibrio campbellii. Consequently, we have discovered the coupling protein CheW, which is in the center of the chemotaxis signaling network, as a target of both molecules. We not only demonstrate direct ligand binding to CheW but also elucidate how this affects chemotactic control. These findings are pivotal for further research on hormone-specific effects on bacterial behavior.

Insulin and takotsubo syndrome: plausible pathophysiologic, diagnostic, prognostic, and therapeutic roles.

The pathophysiology of takotsubo syndrome (TTS) is elusive. Heightened adrenergic surge via the sympathetic nervous system (mainly by norepinephrine secretion) and/or elevated blood-borne catecholamines (mainly epinephrine, secreted by the adrenals) probably mediate TTS. Patients with TTS have a low prevalence of diabetes mellitus (DM), and it has been postulated that DM, via its associated neuropathy, prevents the emergence of TTS. Insulin, in animal experiments, has been shown to greatly attenuate the effects of NE on the cardiomyocytes; also, insulin in a limited clinical experience, has been found to improve heart function in patients with neurogenic stress-cardiomyopathy and TTS. Accordingly, it is postulated that high levels of insulin encountered in patients with type 2 DM are at the roots of the protective effect of DM for the emergence of TTS. Thus, a role of insulin in the pathophysiology, diagnosis, prognosis, and therapy of TTS appears to be plausible, and needs exploration.

Catecholaminergic stimulation restores high-sucrose diet-induced hippocampal dysfunction.

Increasing evidence suggests that long-term consumption of high-caloric diets increases the risk of developing cognitive dysfunctions. In the present study, we assessed the catecholaminergic activity in the hippocampus as a modulatory mechanism that is altered in rats exposed to six months of a high-sucrose diet (HSD). Male Wistar rats fed with this diet developed a metabolic disorder and showed impaired spatial memory in both water maze and object location memory (OLM) tasks. Intrahippocampal free-movement microdialysis showed a diminished dopaminergic and noradrenergic response to object exploration during OLM acquisition compared to rats fed with normal diet. In addition, electrophysiological results revealed an impaired long-term potentiation (LTP) of the perforant to dentate gyrus pathway in rats exposed to a HSD. Local administration of nomifensine, a catecholaminergic reuptake inhibitor, prior to OLM acquisition or LTP induction, improved long-term memory and electrophysiological responses, respectively. These results suggest that chronic exposure to HSD induces a hippocampal deterioration which impacts on cognitive and neural plasticity events negatively; these impairments can be ameliorated by increasing or restituting the affected catecholaminergic activity.

Catecholaminergic Modulation of Semantic Processing in Sentence Comprehension.

Catecholamine (CA) function has been widely implicated in cognitive functions that are tied to the prefrontal cortex and striatal areas. The present study investigated the effects of methylphenidate, which is a CA agonist, on the electroencephalogram (EEG) response related to semantic processing using a double-blind, placebo-controlled, randomized, crossover, within-subject design. Forty-eight healthy participants read semantically congruent or incongruent sentences after receiving 20-mg methylphenidate or a placebo while their brain activity was monitored with EEG. To probe whether the catecholaminergic modulation is task-dependent, in one condition participants had to focus on comprehending the sentences, while in the other condition, they only had to attend to the font size of the sentence. The results demonstrate that methylphenidate has a task-dependent effect on semantic processing. Compared to placebo, when semantic processing was task-irrelevant, methylphenidate enhanced the detection of semantic incongruence as indexed by a larger N400 amplitude in the incongruent sentences; when semantic processing was task-relevant, methylphenidate induced a larger N400 amplitude in the semantically congruent condition, which was followed by a larger late positive complex effect. These results suggest that CA-related neurotransmitters influence language processing, possibly through the projections between the prefrontal cortex and the striatum, which contain many CA receptors.

Circulating catecholamines partially regulate T-wave morphology but not heart rate variability during repeated umbilical cord occlusions in fetal sheep.

Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. ß-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (ß-adrenergic blockade; n = 10) or saline (n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.

Task experience eliminates catecholaminergic effects on inhibitory control - A randomized, double-blind cross-over neurophysiological study.

Catecholaminergic neural transmission plays an important role during the inhibition of prepotent responses. Methylphenidate (MPH) is an important drug that modulates the catecholaminergic system. However, theoretical considerations suggest that the effects of drugs (e.g. MPH) on cognitive control may depend on prior learning effects. Here we investigate this in a conflict-modulated Go/Nogo task and evaluate neurophysiological processes associated with this dynamic using EEG signal decomposition methods and source localization analysis. The behavioral data show that prior learning experiences eliminate effects of MPH on response inhibition processes. On a neurophysiological level, we show that MPH modulates specific processes in medial frontal brain regions. Although MPH seems to consistently modulate neurophysiological processes associated with response inhibition, this is no longer sufficient to modulate behavioral performance once learning or task familiarization processes have taken place. An important consequence of this study finding is that it may be important to adjust MPH dosage depending on learning effects in a specific setting to constantly increase cognitive control functions in that setting. This has important implications for clinical practice, since MPH is the first-line pharmacological therapy in attention-deficit hyperactivity disorder (ADHD). Cross-over study designs with constant doses of MPH can mask effects on cognitive functions. The impact of learning needs careful consideration in cross-over study designs examining catecholaminergic drug effects.

Differences in behavior between surface and cave Astyanax mexicanus may be mediated by changes in catecholamine signaling.

Astyanax mexicanus is a teleost fish that is in the process of allopatric speciation. Ancestral Astyanax are found in surface rivers and derived blind forms are found in cave systems. Adaptation to life in nutrient poor caves without predation includes the evolution of enhanced food seeking behaviors and loss of defensive responses. These behavioral adaptations may be mediated by changes in catecholaminergic control systems in the brain. We examined the distribution of tyrosine hydroxylase, a conserved precursor for the synthesis of the catecholamines dopamine and noradrenaline, in the brains of surface and cave Astyanax using immunohistochemistry. We found differences in tyrosine hydroxylase staining in regions that are associated with nonvisual sensory perception, motor control, endocrine release, and attention. These differences included significant increases in the diameters of tyrosine hydroxylase immunoreactive soma in cave Astyanax in the olfactory bulb, basal telencephalon, preoptic nuclei, ventral thalamus, posterior tuberculum, and locus coeruleus. These increases in modulation by dopamine and noradrenaline likely indicate changes in behavioral control that underlie adaptations to the cave environment.

Catecholamines Induce Endoplasmic Reticulum Stress Via Both Alpha and Beta Receptors.

Severely burned patients suffer from a hypermetabolic syndrome that can last for years after the injury has resolved. The underlying cause of these metabolic alterations most likely involves the persistent elevated catecholamine levels that follow the surge induced by thermal injury. At the cellular level, endoplasmic reticulum (ER) stress in metabolic tissues is a hallmark observed in patients following burn injury and is associated with several detrimental effects. Therefore, ER stress could be the underlying cellular mechanism of persistent hypermetabolism in burned patients. Here, we show that catecholamines induce ER stress and that adreno-receptor blockers reduce stress responses in the HepG2 hepatocyte cell line. Our results also indicate that norepinephrine (NE) significantly induces ER stress in HepG2 cells and 3T3L1 mouse adipocytes. Furthermore, we demonstrate that the alpha-1 blocker, prazosin, and beta blocker, propranolol, block ER stress induced by NE. We also show that the effects of catecholamines in inducing ER stress are cell type-specific, as NE treatment failed to evoke ER stress in human fibroblasts. Thus, these findings reveal the mechanisms used by catecholamines to alter metabolism and suggest inhibition of the receptors utilized by these agents should be further explored as a potential target for the treatment of ER stress-mediated disease.

Drug-induced endocrine blood pressure elevation.

Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed.

An age- and sex-dependent role of catecholaminergic neurons in the control of breathing and hypoxic chemoreflex during postnatal development.

The respiratory system undergoes significant development during the postnatal phase. Maturation of brainstem catecholaminergic (CA) neurons is important for the control and modulation of respiratory rhythmogenesis, as well as for chemoreception in early life. We demonstrated an inhibitory role for CA neurons in CO2 chemosensitivity in neonatal and juvenile male and female rats, but information regarding their role in the hypoxic ventilatory response (HVR) is lacking. We evaluated the contribution of brainstem CA neurons in the HVR during postnatal (P) development (P7-8, P14-15 and P20-21) in male and female rats through chemical injury with conjugated saporin anti-dopamine beta-hydroxylase (DßH-SAP, 420 ng·µL-1) injected in the fourth ventricle. Ventilation (V̇E) and oxygen consumption were recorded one week after the lesion in unanesthetized rats during exposure to normoxia and hypoxia. Hypoxia reduced breathing variability in P7-8 control rats of both sexes. At P7-8, the HVR for lesioned males and females increased 27% and 24%, respectively. Additionally, the lesion reduced the normoxic breathing variability in both sexes at P7-8, but hypoxia partially reverted this effect. For P14-15, the increase in V̇E during hypoxia was 30% higher for male and 24% higher for female lesioned animals. A sex-specific difference was detected at P20-21, as lesioned males exhibited a 24% decrease in the HVR, while lesioned females experienced a 22% increase. Furthermore, the hypoxia-induced body temperature reduction was attenuated in P20-21 lesioned females. We conclude that brainstem CA neurons modulate the HRV during the postnatal phase, and possibly thermoregulation during hypoxia.

Drug screens of NGLY1 deficiency in worm and fly models reveal catecholamine, NRF2 and anti-inflammatory-pathway activation as potential clinical approaches.

N-glycanase 1 (NGLY1) deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator NRF1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole-animal and cellular models of NGLY1 deficiency. Here, we describe unbiased phenotypic drug screens to identify FDA-approved drugs that are generally recognized as safe natural products, and novel chemical entities, that rescue growth and development of NGLY1-deficient worm and fly larvae treated with a toxic dose of bortezomib. We used image-based larval size and number assays for use in screens of a 2560-member drug-repurposing library and a 20,240-member lead-discovery library. A total of 91 validated hit compounds from primary invertebrate screens were tested in a human cell line in an NRF2 activity assay. NRF2 is a transcriptional regulator that regulates cellular redox homeostasis, and it can compensate for loss of NRF1. Plant-based polyphenols make up the largest class of hit compounds and NRF2 inducers. Catecholamines and catecholamine receptor activators make up the second largest class of hits. Steroidal and non-steroidal anti-inflammatory drugs make up the third largest class. Only one compound was active in all assays and species: the atypical antipsychotic and dopamine receptor agonist aripiprazole. Worm and fly models of NGLY1 deficiency validate therapeutic rationales for activation of NRF2 and anti-inflammatory pathways based on results in mice and human cell models, and suggest a novel therapeutic rationale for boosting catecholamine levels and/or signaling in the brain.

Pheochromocytoma as a Clinical Model of Peripheral Sympathetic Overdrive: Old and New Findings.

PURPOSE OF REVIEW: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma. RECENT FINDINGS: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages.

PURPOSE: Elevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development. EXPERIMENTAL DESIGN: We established in vitro and in vivo models to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. RESULTS: Catecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells' (MDSCs) recruitment and facilitating dendritic cells' (DCs) activation, potentially resulting in a positive antitumor immune response. CONCLUSION: Our study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.

The Effect of Exercise on Glucoregulatory Hormones: A Countermeasure to Human Aging: Insights from a Comprehensive Review of the Literature.

Hormones are secreted in a circadian rhythm, but also follow larger-scale timetables, such as monthly (hormones of the menstrual cycle), seasonal (i.e., winter, summer), and, ultimately, lifespan-related patterns. Several contexts modulate their secretion, such as genetics, lifestyle, environment, diet, and exercise. They play significant roles in human physiology, influencing growth of muscle, bone, and regulating metabolism. Exercise training alters hormone secretion, depending on the frequency, duration, intensity, and mode of training which has an impact on the magnitude of the secretion. However, there remains ambiguity over the effects of exercise training on certain hormones such as glucoregulatory hormones in aging adults. With advancing age, there are many alterations with the endocrine system, which may ultimately alter human physiology. Some recent studies have reported an anti-aging effect of exercise training on the endocrine system and especially cortisol, growth hormone and insulin. As such, this review examines the effects of endurance, interval, resistance and combined training on hormones (i.e., at rest and after) exercise in older individuals. We summarize the influence of age on glucoregulatory hormones, the influence of exercise training, and where possible, examine masters' athletes' endocrinological profile.

Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction often triggered by emotional or physical stress. Severe activation of the sympathetic nervous system with catecholamine release caused by a dysfunctional limbic system has been proposed as a potential mechanism. We hypothesize that brain regions responsible for autonomic integration and/or limbic processing might be involved in the development of TTS. Here, we investigated alterations in resting state functional connectivity in TTS patients compared with healthy controls. METHODS AND RESULTS: Using brain functional magnetic resonance imaging (fMRI), resting state functional connectivity has been assessed in 15 subjects with TTS and 39 healthy controls. Network-based statistical analyses were conducted to identify subnetworks with altered resting state functional connectivity. Sympathetic and parasympathetic networks have been constructed in addition to the default mode network and whole-brain network. We found parasympathetic- and sympathetic-associated subnetworks both showing reduced resting state functional connectivity in TTS patients compared with controls. Important brain regions constituting parasympathetic- and sympathetic-associated subnetworks included the amygdala, hippocampus, and insula as well as cingulate, parietal, temporal, and cerebellar regions. Additionally, the default mode network as well as limbic regions in the whole-brain analysis demonstrated reduced resting state functional connectivity in TTS, including the hippocampus, parahippocampal, and medial prefrontal regions. CONCLUSION: For the first time, we demonstrate hypoconnectivity of central brain regions associated with autonomic functions and regulation of the limbic system in patients with TTS. These findings suggest that autonomic-limbic integration might play an important role in the pathophysiology and contribute to the understanding of TTS.

Hermann (Hugh) Blaschko (1900-1993): His fundamental contributions to biochemical pharmacology and clinical medicine.

Hermann (Hugh) Blaschko was a biochemical pharmacologist best known for discovering how adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine were synthesized, stored, and metabolized in adrenomedullary cells and sympathetic nerves. Blaschko's work not only supported the validity of the concept of neurochemical synaptic transmission but he also made fundamental contributions to the development of drugs used in clinical medicine to treat diseases such as depression, hypertension, and Parkinson's Disease.