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International Journal of Oral Science Aug 2022Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics...
Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (βAR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp)-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
Topics: Adrenergic Agents; Apoptosis Regulatory Proteins; Bone Diseases, Metabolic; Humans; Liposomes; MicroRNAs; Nanoparticles; Osteoclasts; Osteogenesis; RNA-Binding Proteins
PubMed: 35915088
DOI: 10.1038/s41368-022-00193-1 -
Nature Communications Mar 2024G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors...
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors and their G protein signaling properties are based on assays mainly performed with modified receptors expressed in heterologous cells. However, GPCR responses may differ in their native environment. Here, by using highly sensitive G sensors, we reveal specific properties of G protein-mediated responses triggered by GABA, α adrenergic and cannabinoid CB1 receptors in primary neurons, different from those in heterologous cells. These include different profiles in the G protein subtypes-mediated responses, and differences in the potencies of some ligands even at similar receptor expression levels. Altogether, our results show the importance of using biosensors compatible with primary cells for evaluating the activities of endogenous GPCRs in their native environment.
Topics: Neurons; Receptors, G-Protein-Coupled; Signal Transduction; Adrenergic Agents; Biological Assay; GTP-Binding Protein alpha Subunits, Gi-Go
PubMed: 38443355
DOI: 10.1038/s41467-024-46177-z -
Cancer Metastasis Reviews Sep 2022Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide... (Review)
Review
Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.
Topics: Adipose Tissue; Adrenergic Agents; Extracellular Matrix; Humans; Neoplasms; Obesity
PubMed: 36074318
DOI: 10.1007/s10555-022-10058-y -
Thorax Oct 2019
Topics: Adrenergic Agents; Bronchodilator Agents; Genotype; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2
PubMed: 31481632
DOI: 10.1136/thoraxjnl-2019-213697 -
Neurotherapeutics : the Journal of the... Jan 2014Huntington's disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between... (Review)
Review
Huntington's disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between body regions. HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to family members at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate, mainly involving the neurotransmitters dopamine, glutamate, and γ-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic interventions have yielded positive results and current treatments have focused on the motor aspects of HD. Tetrabenazine is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer neuroleptic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse effect profile than older neuroleptic agents for treating chorea and psychosis. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.
Topics: Adrenergic Uptake Inhibitors; Humans; Huntington Disease; Tetrabenazine
PubMed: 24366610
DOI: 10.1007/s13311-013-0244-z -
Archives of Razi Institute Feb 2022The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first...
The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first experiment, the intracerebroventricular (ICV) injection of solutions was conducted which included 10 nmol of prazosin (an α-receptor antagonist), 300 nmol of histamine, co-injection of prazosin and histamine. Experiments two to five were conducted similarly the same as the first experiment, in which chickens were ICV injected with 13 nmol of yohimbine (an α-receptor antagonist), 24 nmol of metoprolol (a β adrenergic receptor antagonist), 5 nmol of ICI 118,551 (a β adrenergic receptor antagonist), and 20 nmol of SR 59230R (a β adrenergic receptor antagonist). The injected solutions in the sixth experiment included 300 nmol of noradrenaline, 250 nmol of α-FMH (an alpha fluoromethyl histidine), noradrenaline, and α-FMH. Seventh to ninth experiments were similar to the sixth experiment, except that the chickens were ICV injected with 300 nmol of chlorpheniramine (a histamine H receptors antagonist), 82 nmol of famotidine (a histamine H receptors antagonist), and 300 nmol of thioperamide (a histamine H receptors antagonist), rather than α-FMH. Afterward, the cumulative food intake was measured 120 min after injection. Based on the obtained results, both histamine ICV injection and noradrenaline injection reduced food intake (<0.05). Moreover, co-injection of histamine and ICI 118,551 (<0.05), and co-injection of noradrenaline and Chlorpheniramine reduced food intake (<0.05). In addition, noradrenaline and Thioperamide co-injection improved hypophagic effect of noradrenaline in neonatal chicken (<0.05). These findings suggested the effect of interconnection between adrenergic and histaminergic systems, which may be mediated by H and H histaminergic and β adrenergic receptors, on the regulation of food intake in the neonatal broiler chicken.
Topics: Adrenergic Agents; Adrenergic Antagonists; Animals; Animals, Newborn; Appetite; Chickens; Chlorpheniramine; Feeding Behavior; Histamine; Norepinephrine; Prazosin; Receptors, Adrenergic; Receptors, Histamine
PubMed: 35891757
DOI: 10.22092/ARI.2021.354450.1638 -
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 -
Therapeutic Advances in Cardiovascular... Aug 2009beta-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral... (Review)
Review
beta-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral resistance. Third-generation beta-blockers avoid this adverse effect by inducing vasodilation through different mechanisms. In particular, nebivolol, a highly selective blocker of beta(1)-adrenergic receptors, is the only beta-blocker known to induce vascular production of nitric oxide, the main endothelial vasodilator. The specific mechanism of nebivolol is particularly relevant in hypertension, where nitric oxide dysfunction occurs. Indeed, nebivolol is able to reverse endothelial dysfunction. Nebivolol induces nitric oxide production via activation of beta(3)-adrenergic receptors, which can explain the good metabolic profile observed after treatment with this drug. Moreover, nebivolol can also stimulate the beta(3)-adrenergic receptor-mediated production of nitric oxide in the heart, and this stimulation can result in a greater protection against heart failure. In conclusion, nebivolol has a unique profile among antihypertensive drugs, adding to a very high selectivity against beta(1) adrenergic receptors, and an agonist action on beta(3) receptors and nitric oxide (NO), which has led to clinically significant improvements in hypertensive patients.
Topics: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Benzopyrans; Cardiovascular Diseases; Endothelium, Vascular; Ethanolamines; Humans; Myocardium; Nebivolol; Nitric Oxide; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-3; Signal Transduction; Vasodilation; Vasodilator Agents
PubMed: 19443516
DOI: 10.1177/1753944709104496 -
Nature Communications Dec 2022The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in...
The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.
Topics: Mice; Animals; Humans; Adipose Tissue, Brown; Adipokines; Thermogenesis; Adipose Tissue, White; Obesity; Glucose; Adrenergic Agents; Adipocytes, Brown; Energy Metabolism
PubMed: 36496438
DOI: 10.1038/s41467-022-35335-w -
Neuropsychopharmacology : Official... Jan 2023Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid...
Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.
Topics: Animals; Mice; Adrenergic Agents; Brain; Hippocampus; Norepinephrine; Receptor, Cannabinoid, CB1
PubMed: 36088492
DOI: 10.1038/s41386-022-01436-9