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Nature Medicine Dec 2023Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB-D melanoma, but potential biomarkers of response, such as...
Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB-D melanoma, but potential biomarkers of response, such as interferon-gamma (IFNγ) signature and tumor mutational burden (TMB), are insufficient. Preclinical studies suggest that emotional distress (ED) can negatively affect antitumor immune responses via β-adrenergic or glucocorticoid signaling. We performed a post hoc analysis evaluating the association between pretreatment ED and clinical responses after neoadjuvant ICB treatment in patients with stage IIIB-D melanoma in the phase 2 PRADO trial ( NCT02977052 ). The European Organisation for Research and Treatment of Cancer scale for emotional functioning was used to identify patients with ED (n = 28) versus those without (n = 60). Pretreatment ED was significantly associated with reduced major pathologic responses (46% versus 65%, adjusted odds ratio 0.20, P = 0.038) after adjusting for IFNγ signature and TMB, reduced 2-year relapse-free survival (74% versus 91%, adjusted hazard ratio 3.81, P = 0.034) and reduced 2-year distant metastasis-free survival (78% versus 95%, adjusted hazard ratio 4.33, P = 0.040) after adjusting for IFNγ signature. RNA sequencing analyses of baseline patient samples could not identify clear β-adrenergic- or glucocorticoid-driven mechanisms associated with these reduced outcomes. Pretreatment ED may be a marker associated with clinical responses after neoadjuvant ICB in melanoma and warrants further investigation. ClinicalTrials.gov registration: NCT02977052 .
Topics: Humans; Melanoma; Immune Checkpoint Inhibitors; Neoadjuvant Therapy; Glucocorticoids; Neoplasm Recurrence, Local; Biomarkers, Tumor; Interferon-gamma; Psychological Distress; Adrenergic Agents
PubMed: 37957378
DOI: 10.1038/s41591-023-02631-x -
Function (Oxford, England) 2022
Topics: Adrenergic Agents; Myocytes, Cardiac; A Kinase Anchor Proteins; Cyclic AMP-Dependent Protein Kinases; Biochemical Phenomena
PubMed: 36156892
DOI: 10.1093/function/zqac024 -
Nature Communications Oct 2023Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry...
Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTS-neurons. Optogenetic activation of rostral-NTS → PVN projection elicited strong motivation to eat comparable to overnight fasting whereas its inhibition attenuated both fasting-induced & hypoglycemic feeding. We found that NTS-axons functionally targeted PVN-neurons by predominantly inhibiting them, in part, through α1-AR mediated potentiation of GABA release from ARC presynaptic terminals. Furthermore, glucoprivation suppressed PVN activity, which was required for hypoglycemic feeding response. These results define an ascending nor/adrenergic circuit, NTS → PVN, that conveys peripheral hunger signals to melanocortin pathway.
Topics: Hunger; Melanocortins; Adrenergic Agents; Appetite; Paraventricular Hypothalamic Nucleus; Norepinephrine; Hypoglycemic Agents
PubMed: 37857606
DOI: 10.1038/s41467-023-42362-8 -
Methods in Molecular Biology (Clifton,... 2022Pineal gland secretes the hormone melatonin at night with a circadian rhythm. The synthesis and secretion of melatonin are stimulated at night by norepinephrine released...
Pineal gland secretes the hormone melatonin at night with a circadian rhythm. The synthesis and secretion of melatonin are stimulated at night by norepinephrine released by sympathetic postganglionic neurons projecting from the superior cervical ganglia. Norepinephrine simultaneously activates α- and β-adrenoceptors, triggering melatonin synthesis.To study the regulation of melatonin production and secretion, it is very convenient to use an ex vivo preparation. Thus, it is possible to keep intact pineal glands in culture and to study the actions of agonists, antagonists, modulators, toxic agents, etc., in melatonin synthesis. Artificial melatonin synthesis stimulation in vitro is usually achieved by using a β-adrenergic agonist alone or in association with an α-adrenergic agonist. In this chapter, the methodology of cultured pineal glands will be described. Several papers were published by our group using this methodology, approaching the role played in melatonin synthesis control by angiotensin II and IV, insulin, glutamate, voltage-gated calcium channels, anhydroecgonine methyl ester (AEME, crack-cocaine product), monosodium glutamate (MSG), signaling pathways like NFkB, pathophysiological conditions like diabetes, etc.
Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Angiotensin II; Calcium Channels; Circadian Rhythm; Cocaine; Insulins; Melatonin; Norepinephrine; Pineal Gland; Receptors, Adrenergic, beta; Sodium Glutamate
PubMed: 36180681
DOI: 10.1007/978-1-0716-2593-4_12 -
Journal of Neuroimmune Pharmacology :... Mar 2020Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells... (Review)
Review
Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are found mainly adjacent to the BM vascular sinusoids where endothelial cells and mesenchimal stromal cells promote HSC maintenance by producing a variety of factors. Other cell types that regulate HSC niches include sympathetic nerves, non-myelinating Schwann cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes. This review will focus on the role of adrenergic signals, i.e. of catecholamines, in the regulation of the HSC niche. The available evidence is rather controversial possibly due to the fact that adrenergic receptors are expressed by many cellular components of the niche and also by the often neglected observation that catecholamines may be produced and released also by the BM cells themselves. In addition one has to consider that, physiologically, the sympathetic nervous system (SNS) activity follows a circadian rhythmicity as driven by the suprachiasmatic nucleus (SCN) of the hypothalamus but may be also activated by cognitive and non-cognitive environmental stimuli. The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of hematopoietic disorders and for HSC transplantation however the complexity of the system demands further studies. Graphical Abstract Sympathetic nerve termini may release NE while mature BM cells may release norepinephrine (NE) and / or epinephrine (E). Both may bind to β-adrenergic receptor (AR) expressed in nestin+MSC in the hematopoietic stem cell (HSC) niche and regulate the physiological trafficking of HSC by modulating the expression of CXCL12 and SCF. Both NE and E may also activate Lin - c-Kit+ Sca-1+ (LKS) cell via another AR. In addition, NE may also signal to α1-AR expressed in pre-B cells which by TGF-β secretion might regulate proliferation of their lymphoid progenitors in an autocrine manner and/or inhibit myeloid progenitors.
Topics: Adrenergic Agents; Adrenergic Fibers; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Cell Differentiation; Epinephrine; Hematopoiesis; Hematopoietic Stem Cells; Humans; Norepinephrine; Receptors, Adrenergic, beta
PubMed: 30762159
DOI: 10.1007/s11481-019-09840-7 -
Journal of Clinical Sleep Medicine :... Apr 2020Su P-L, Lin C-Y, Lin S-H. Author response. . 2020;16(4):645–646.
Su P-L, Lin C-Y, Lin S-H. Author response. . 2020;16(4):645–646.
Topics: Adrenergic Agents; Cohort Studies; Humans; Publishing; Research Design; Sleep Apnea Syndromes
PubMed: 32022676
DOI: 10.5664/jcsm.8298 -
Neuron Mar 2024Glucose homeostasis is controlled by brain-gut communications. Yet our understanding of the neuron-gut interface in the glucoregulatory system remains incomplete. Here,...
Glucose homeostasis is controlled by brain-gut communications. Yet our understanding of the neuron-gut interface in the glucoregulatory system remains incomplete. Here, we find that sympathetic nerves elevate postprandial blood glucose but restrict brain glucose utilization by repressing the release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells. Sympathetic nerves are in close apposition with the L cells. Importantly, sympathetic denervation or intestinal deletion of the adrenergic receptor α2 (Adra2a) augments postprandial GLP-1 secretion, leading to reduced blood glucose levels and increased brain glucose uptake. Conversely, sympathetic activation shows the opposite effects. At the cellular level, adrenergic signaling suppresses calcium flux to limit GLP-1 secretion upon sugar ingestion. Consequently, abrogation of adrenergic signal results in a significant improvement in learning and memory ability. Together, our results reveal a sympathetic nerve-enteroendocrine unit in constraining GLP-1 secretion, thus providing a therapeutic nexus of mobilizing endogenous GLP-1 for glucose management and cognitive improvement.
Topics: Glucose; Glucagon-Like Peptide 1; Blood Glucose; Cell Communication; Brain; Cognition; Adrenergic Agents
PubMed: 38242116
DOI: 10.1016/j.neuron.2023.12.012 -
Journal of Pharmacy Practice Aug 2019Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and... (Review)
Review
Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.
Topics: Adrenergic Uptake Inhibitors; Dopamine Antagonists; Drug Labeling; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 29455579
DOI: 10.1177/0897190018756512 -
Expert Opinion on Therapeutic Patents Oct 2019: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field.... (Review)
Review
: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field. Elevated intraocular pressure (IOP) is an important contributor for the progression of glaucoma. The current therapeutic arsenal for reducing IOP includes prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors, α-adrenergic agonist, miotics, rho-kinase inhibitors and combinations thereof, generally administered as eye drops. : This manuscript reviews the state of art on adrenergic modulators for treating glaucoma. Both monotherapy and fixed-drugs combinations including α-adrenergic agonists and β-blockers are discussed as well as drug delivery systems where these classes of drugs are used. The review then covers the patent literature involving adrenoceptors modulators over the period 2013-2019. : While the scientific community is moving forward novel targets and related modulators for treating glaucoma and ocular hypertension, adrenergic modulators held a prominent position in the therapy of glaucoma and related disorders. Indeed, though not embodying anymore the first-choice monotherapy, they are widely marketed worldwide ordinarily in combination with other drugs, are subjects of many studies for identifying new drug compositions and have been assessed as active ingredients in several innovative ocular drug delivery systems.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Animals; Drug Combinations; Drug Delivery Systems; Drug Design; Glaucoma; Humans; Intraocular Pressure; Ocular Hypertension; Patents as Topic
PubMed: 31486689
DOI: 10.1080/13543776.2019.1665023 -
The Journal of Allergy and Clinical... Dec 2019
Topics: Adrenergic Agents; Asthma; Disease Susceptibility; Humans
PubMed: 31564471
DOI: 10.1016/j.jaci.2019.08.016