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JACC. Basic To Translational Science Aug 2023The decrease in β-adrenergic receptor responsiveness in heart failure is attributed conventionally to agonist-dependent desensitization. We identify elastase-dependent...
The decrease in β-adrenergic receptor responsiveness in heart failure is attributed conventionally to agonist-dependent desensitization. We identify elastase-dependent β-adrenergic receptor cleavage as a novel proteolytic mechanism that disrupts β-adrenergic receptor responsiveness in the setting of tissue injury or inflammation.
PubMed: 37719436
DOI: 10.1016/j.jacbts.2023.02.002 -
Molecular Metabolism Aug 2023Norepinephrine stimulates the adipose tissue thermogenic program through a β-adrenergic receptor (βAR)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)...
OBJECTIVE
Norepinephrine stimulates the adipose tissue thermogenic program through a β-adrenergic receptor (βAR)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade. We discovered that a noncanonical activation of the mechanistic target of rapamycin complex 1 (mTORC1) by PKA is required for the βAR-stimulation of adipose tissue browning. However, the downstream events triggered by PKA-phosphorylated mTORC1 activation that drive this thermogenic response are not well understood.
METHODS
We used a proteomic approach of Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC) to characterize the global protein phosphorylation profile in brown adipocytes treated with the βAR agonist. We identified salt-inducible kinase 3 (SIK3) as a candidate mTORC1 substrate and further tested the effect of SIK3 deficiency or SIK inhibition on the thermogenic gene expression program in brown adipocytes and in mouse adipose tissue.
RESULTS
SIK3 interacts with RAPTOR, the defining component of the mTORC1 complex, and is phosphorylated at Ser in a rapamycin-sensitive manner. Pharmacological SIK inhibition by a pan-SIK inhibitor (HG-9-91-01) in brown adipocytes increases basal Ucp1 gene expression and restores its expression upon blockade of either mTORC1 or PKA. Short-hairpin RNA (shRNA) knockdown of Sik3 augments, while overexpression of SIK3 suppresses, Ucp1 gene expression in brown adipocytes. The regulatory PKA phosphorylation domain of SIK3 is essential for its inhibition. CRISPR-mediated Sik3 deletion in brown adipocytes increases type IIa histone deacetylase (HDAC) activity and enhances the expression of genes involved in thermogenesis such as Ucp1, Pgc1α, and mitochondrial OXPHOS complex protein. We further show that HDAC4 interacts with PGC1α after βAR stimulation and reduces lysine acetylation in PGC1α. Finally, a SIK inhibitor well-tolerated in vivo (YKL-05-099) can stimulate the expression of thermogenesis-related genes and browning of mouse subcutaneous adipose tissue.
CONCLUSIONS
Taken together, our data reveal that SIK3, with the possible contribution of other SIKs, functions as a phosphorylation switch for β-adrenergic activation to drive the adipose tissue thermogenic program and indicates that more work to understand the role of the SIKs is warranted. Our findings also suggest that maneuvers targeting SIKs could be beneficial for obesity and related cardiometabolic disease.
Topics: Mice; Animals; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proteomics; Adipose Tissue; Adipocytes, Brown; Receptors, Adrenergic, beta; Mechanistic Target of Rapamycin Complex 1; Thermogenesis; Protein Serine-Threonine Kinases
PubMed: 37321371
DOI: 10.1016/j.molmet.2023.101753 -
European Journal of Neurology May 2024Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants...
BACKGROUND
Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research.
METHODS
MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings.
RESULTS
Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended.
CONCLUSIONS
Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Middle Aged; Aged; Myasthenia Gravis; Receptors, Cholinergic; Neuromuscular Diseases; Pyridostigmine Bromide; Immunosuppressive Agents; Thymus Neoplasms; Autoantibodies; Thymectomy
PubMed: 38321574
DOI: 10.1111/ene.16229 -
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 -
Clinical Practice and Epidemiology in... 2023Depressive disorders (DD) are common, and their prevalence is expected to rise over the next decade. Depressive disorders are linked to significant morbidity and... (Review)
Review
Depressive disorders (DD) are common, and their prevalence is expected to rise over the next decade. Depressive disorders are linked to significant morbidity and mortality. The clinical conundrum of depressive disorders lies in the heterogeneity of their phenomenology and etiology. Further, the currently available antidepressants have several limitations, including a delayed onset of action, limited efficacy, and an unfavorable side effect profile. In this review, Dexmedetomidine (DEX), a highly selective and potent α2-adrenergic receptor (α2-AR) agonist, is proposed as a potentially novel antidepressant with multiple mechanisms of action targeting various depression pathophysiological processes. These mechanisms include modulation of the noradrenergic system, regulation of neuroinflammation and oxidative stress, influence on the Brain-Derived Neurotrophic Factor (BDNF) levels, and modulation of neurotransmitter systems, such as glutamate. The review begins with an introduction before moving on to a discussion of DEX's pharmacological features. The pathophysiological and phenomenological targets of DD are also explored, along with the review of the existing preclinical and clinical evidence for DEX's putative anti-depressant effects. Finally, the review ends by presenting the pertinent conclusions and future directions.
PubMed: 37916205
DOI: 10.2174/17450179-v19-230823-2023-4 -
Cardiovascular Research Dec 2023The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases...
AIMS
The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease.
METHODS AND RESULTS
C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.
CONCLUSIONS
AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.
Topics: Animals; Mice; Arrhythmias, Cardiac; Isoproterenol; Mice, Inbred C57BL; Myocytes, Cardiac; Receptors, Adrenergic, beta; Signal Transduction; Sinoatrial Node; Hypertension; Cyclic Nucleotide Phosphodiesterases, Type 4
PubMed: 37643895
DOI: 10.1093/cvr/cvad138 -
European Journal of Pharmacology Nov 2023Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models.
METHODS
Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models.
RESULTS
There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)).
CONCLUSIONS
DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.
Topics: Rats; Animals; Dexmedetomidine; Rats, Sprague-Dawley; Adrenergic alpha-2 Receptor Agonists; Reperfusion Injury; Inflammation; Ischemia
PubMed: 37778612
DOI: 10.1016/j.ejphar.2023.176090 -
Molecular Aspects of Medicine Oct 2023Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with... (Review)
Review
Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with eye drops. A major challenge in the topical treatment of glaucoma patients is the many side effects and the resulting reduced adherence. Side effects may of course be due to the molecular properties of the active pharmaceutical ingredients (APIs). There are currently six different APIs available: prostaglandin analogues, β-adrenergic inhibitors, α-adrenergic agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors and muscarinic 3 agonists. But the additives used in eye drops are also known to cause damage to the ocular surface and to some extent also to the deeper tissues. Said additives are considered inactive molecular components and are added to secure for instance viscosity and pH value, and to prevent contamination. There has been an increasing focus on the harmful effects of preservatives, with the most commonly used preservative benzalkonium chloride (BAK) being particularly controversial. BAK has long been recognized as a toxin that increases the risk of ocular discomfort. This can affect the adherence and ultimately result in lack of disease control. Other issues include the addition of certain buffers, such as phosphates, and varying pH values. This review will address the different molecular components of the IOP-lowering eye drops and what to be aware of when prescribing topical glaucoma treatment.
Topics: Humans; Glaucoma; Intraocular Pressure; Eye; Preservatives, Pharmaceutical; Ophthalmic Solutions
PubMed: 37459821
DOI: 10.1016/j.mam.2023.101195 -
International Journal of Psychiatry in... Sep 2023Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other... (Review)
Review
Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics.
Topics: Humans; Antipsychotic Agents; Dopamine Agonists; Dopamine; Aripiprazole; Receptors, Dopamine D2
PubMed: 36495086
DOI: 10.1080/13651501.2022.2151473 -
Proceedings of the National Academy of... Aug 2023Catecholamine-stimulated β-adrenergic receptor (βAR) signaling via the canonical G-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions,...
Catecholamine-stimulated β-adrenergic receptor (βAR) signaling via the canonical G-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. βAR signaling is tightly regulated by GRKs and β-arrestins, which together promote βAR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to βAR signaling toward the G pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of βAR activation. Since attempts to develop G-biased agonists and allosteric modulators for the βAR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit β-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of β-arrestin recruitment to the βAR while having no effect on βAR coupling to G. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the βAR and protects against the functional desensitization of β-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the βAR with minimal effects on the βAR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the βAR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the βAR.
Topics: beta-Arrestins; Arrestin; Signal Transduction; beta-Arrestin 1; Receptors, Adrenergic; Receptors, Adrenergic, beta-2
PubMed: 37490535
DOI: 10.1073/pnas.2302668120