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International Journal of Molecular... Aug 2023The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for... (Review)
Review
The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu.
Topics: Receptors, Chimeric Antigen; T-Lymphocytes; Adrenergic Agents; Norepinephrine; Cell- and Tissue-Based Therapy; Epinephrine
PubMed: 37629018
DOI: 10.3390/ijms241612837 -
Journal of Endocrinological... Nov 2023Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and... (Review)
Review
BACKGROUND
Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment.
PURPOSE
This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. β3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.
PubMed: 37378828
DOI: 10.1007/s40618-023-02125-0 -
Journal of Cardiovascular Development... Sep 2023A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the β-adrenergic receptor (βAR-AAb) have been the... (Review)
Review
A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the β-adrenergic receptor (βAR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). ΒAR-Aabs have agonist effects inducing desensitization of βAR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. ΒAR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including βAR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of βAR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with βAR-AAb better responded to β-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of β1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.
PubMed: 37754819
DOI: 10.3390/jcdd10090390 -
JACC. Basic To Translational Science Aug 2023
PubMed: 37719428
DOI: 10.1016/j.jacbts.2023.05.005 -
Biomedicines Jul 2023Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known.... (Review)
Review
Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through calcium transients. In addition, calcium transients play an important role in cardiac arrhythmias. The present review summarizes the calcium handling system and its role in cardiac function in cirrhotic cardiomyopathy and its mechanisms. The calcium handling system includes calcium channels on the sarcolemmal plasma membrane of cardiomyocytes, the intracellular calcium-regulatory apparatus, and pertinent proteins in the cytosol. L-type calcium channels, the main calcium channel in the plasma membrane of cardiomyocytes, are decreased in the cirrhotic heart, and the calcium current is decreased during the action potential both at baseline and under stimulation of beta-adrenergic receptors, which reduces the signal to calcium-induced calcium release. The study of sarcomere length fluctuations and calcium transients demonstrated that calcium leakage exists in cirrhotic cardiomyocytes, which decreases the amount of calcium storage in the sarcoplasmic reticulum (SR). The decreased storage of calcium in the SR underlies the reduced calcium released from the SR, which results in decreased cardiac contractility. Based on studies of heart failure with non-cirrhotic cardiomyopathy, it is believed that the calcium leakage is due to the destabilization of interdomain interactions (dispersion) of ryanodine receptors (RyRs). A similar dispersion of RyRs may also play an important role in reduced contractility. Multiple defects in calcium handling thus contribute to the pathogenesis of cirrhotic cardiomyopathy.
PubMed: 37509534
DOI: 10.3390/biomedicines11071895 -
Nature Neuroscience Oct 2023Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter...
Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter receptors. However, the mechanisms that affect OPC activity in vivo and the physiological roles of neurotransmitter signaling in OPCs are unclear. In this study, we generated a transgenic mouse line that expresses membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor OPC calcium (Ca) dynamics in the cerebral cortex. OPCs exhibit focal and transient Ca increases within their processes that are enhanced during locomotion-induced increases in arousal. The Ca transients occur independently of excitatory neuron activity, rapidly decline when OPCs differentiate and are inhibited by anesthesia, sedative agents or noradrenergic receptor antagonists. Conditional knockout of α1A adrenergic receptors in OPCs suppresses spontaneous and locomotion-induced Ca increases and reduces OPC proliferation. Our results demonstrate that OPCs are directly modulated by norepinephrine in vivo to enhance Ca dynamics and promote population homeostasis.
Topics: Mice; Animals; Oligodendrocyte Precursor Cells; Calcium; Norepinephrine; Mice, Transgenic; Oligodendroglia; Cerebral Cortex; Cell Proliferation; Arousal; Cell Differentiation
PubMed: 37697112
DOI: 10.1038/s41593-023-01426-0 -
Biological Psychiatry Oct 2023Globally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous...
BACKGROUND
Globally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous classification does not reflect the diversity of their pharmacological and clinical profiles. There is a need for a data-driven antipsychotic classification scheme suitable for clinicians and researchers that maps onto both pharmacological and clinical effects. Receptor affinity provides one starting point for such a scheme.
METHODS
We analyzed affinities of 27 antipsychotics for 42 receptors from 3325 in vitro receptor binding studies. We used a clustering algorithm to group antipsychotics based on receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced clinical effects quantified according to an umbrella review of clinical trial and treatment guideline data.
RESULTS
Clustering resulted in 4 groups of antipsychotics. The predominant receptor affinity and clinical effect "fingerprints" of these 4 groups were defined as follows: group 1, muscarinic (M-M) receptor antagonism (cholinergic and metabolic side effects); group 2, dopamine (D) partial agonism and adrenergic antagonism (overall low side-effect burden); group 3, serotonergic and dopaminergic antagonism (overall moderate side-effect burden); and group 4, dopaminergic antagonism (extrapyramidal side effects and hyperprolactinemia). Groups 1 and 4 were more efficacious than groups 2 and 3. The classification was shown to predict out-of-sample clinical effects of individual drugs.
CONCLUSIONS
A receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences. This approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.
Topics: Humans; Antipsychotic Agents; Receptors, Dopamine D2; Dopamine
PubMed: 37061079
DOI: 10.1016/j.biopsych.2023.04.004 -
Journal of Molecular and Cellular... Jul 2023β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent...
β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent kinase II (CaMKII) and protein kinase D (PKD). Unlike CaMKII, the effects of PKD on excitation-contraction coupling (ECC) remain unclear. To elucidate the mechanisms of PKD-dependent ECC regulation, we used hearts from cardiac-specific PKD1 knockout (PKD1 cKO) mice and wild-type (WT) littermates. We measured calcium transients (CaT), Ca sparks, contraction and L-type Ca current in paced cardiomyocytes under acute β-AR stimulation with isoproterenol (ISO; 100 nM). Sarcoplasmic reticulum (SR) Ca load was assessed by rapid caffeine (10 mM) induced Ca release. Expression and phosphorylation of ECC proteins phospholambam (PLB), troponin I (TnI), ryanodine receptor (RyR), sarcoendoplasmic reticulum Ca ATPase (SERCA) were evaluated by western blotting. At baseline, CaT amplitude and decay tau, Ca spark frequency, SR Ca load, L-type Ca current, contractility, and expression and phosphorylation of ECC protein were all similar in PKD1 cKO vs. WT. However, PKD1 cKO cardiomyocytes presented a diminished ISO response vs. WT with less increase in CaT amplitude, slower [Ca] decline, lower Ca spark rate and lower RyR phosphorylation, but with similar SR Ca load, L-type Ca current, contraction and phosphorylation of PLB and TnI. We infer that the presence of PKD1 allows full cardiomyocyte β-adrenergic responsiveness by allowing optimal enhancement in SR Ca uptake and RyR sensitivity, but not altering L-type Ca current, TnI phosphorylation or contractile response. Further studies are necessary to elucidate the specific mechanisms by which PKD1 is regulating RyR sensitivity. We conclude that the presence of basal PKD1 activity in cardiac ventricular myocytes contributes to normal β-adrenergic responses in Ca handling.
Topics: Animals; Mice; Adrenergic Agents; Adrenergic beta-Agonists; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Mice, Knockout; Myocytes, Cardiac; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Protein Kinase C
PubMed: 37149124
DOI: 10.1016/j.yjmcc.2023.05.001 -
The Journal of Clinical Investigation Sep 2023Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with...
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
Topics: Humans; Mice; Animals; Guinea Pigs; Methacholine Chloride; Ligands; Asthma; Lung; Binding Sites; Receptors, Adrenergic, beta-2
PubMed: 37432742
DOI: 10.1172/JCI167337