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Cancer Research Aug 2023Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic...
UNLABELLED
Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using α1/α1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacologic target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease.
SIGNIFICANCE
Targeting α-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse.
Topics: Humans; Mice; Child; Animals; Isotretinoin; Adrenergic alpha-1 Receptor Antagonists; Cell Line, Tumor; Neoplasm Recurrence, Local; Neuroblastoma; Cell Differentiation; Receptors, Adrenergic; Recurrence; N-Myc Proto-Oncogene Protein
PubMed: 37289021
DOI: 10.1158/0008-5472.CAN-22-1913 -
CNS Drugs Jul 2023In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due...
BACKGROUND AND OBJECTIVE
In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER.
METHODS
50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05.
RESULTS
From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER.
CONCLUSIONS
Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.
Topics: Adult; Humans; Child; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Viloxazine; Sleep Initiation and Maintenance Disorders; Retrospective Studies; Propylamines; Treatment Outcome; Central Nervous System Stimulants; Adrenergic alpha-2 Receptor Agonists; Adrenergic Uptake Inhibitors; Double-Blind Method
PubMed: 37430151
DOI: 10.1007/s40263-023-01023-6 -
European Journal of Internal Medicine Sep 2023The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension... (Review)
Review
The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension including diuretics, beta blockers, calcium channel blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, alpha blockers, central acting alpha receptor agonists, neprilysin inhibitors and vasodilators. However, despite the numerous number of medications, the prevalence of hypertension is on the rise, a considerable proportion of the hypertensive population is resistant to these therapeutic modalities and a definitive cure is not possible with the current treatment approaches. Therefore, there is a need for novel therapeutic strategies to provide better treatment and control of hypertension. In this review, our aim is to describe the latest developments in the treatment of hypertension including novel medication classes, gene therapies and RNA-based modalities.
Topics: Humans; United States; Antihypertensive Agents; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Adrenergic beta-Antagonists; Diuretics; Angiotensin Receptor Antagonists
PubMed: 37330317
DOI: 10.1016/j.ejim.2023.06.008 -
Nutrition, Metabolism, and... Jul 2023Heart failure (HF) is often triggered by hypertension and can benefit from antihypertensive treatment. We aimed to investigate whether pulse pressure (PP) could...
BACKGROUND AND AIMS
Heart failure (HF) is often triggered by hypertension and can benefit from antihypertensive treatment. We aimed to investigate whether pulse pressure (PP) could independently raise the risk of HF beyond systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as explore the potential mechanisms of antihypertensives in HF prevention.
METHODS AND RESULTS
We generated genetic proxies for SBP, DBP, PP, and five drug classes based on a massive genome-wide association study. We applied two-sample Mendelian randomization (MR) using summary statistics derived from European individuals and conducted summary data-based MR (SMR) with gene expression data. In univariate analysis, PP showed an obvious association with HF risk (OR, 1.24 per 10 mm Hg increment; 95% CI, 1.16 to 1.32), which was largely attenuated in multivariable analysis when adjusted for SBP (0.89; 0.77 to 1.04). A significant decrease in HF risk was obtained with genetically proxied β-blockers (equivalent to a 10 mm Hg reduction in SBP, 0.71; 0.62 to 0.82) and calcium channel blockers (0.71; 0.65 to 0.78), but not with genetically proxied angiotensin-converting enzyme inhibitors (0.69; 0.40 to 1.19) and thiazide diuretics (0.80; 0.47 to 1.37). Additionally, the enrichment of expression for the KCNH2 gene, a target gene of β-blockers, in blood vessels and nerves was significantly associated with HF risk.
CONCLUSION
Our findings suggest that PP may not be an independent risk factor for HF. β-blockers and calcium channel blockers have a protective effect against HF, which at least partly depends on their blood pressure-lowering effect.
Topics: Humans; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Genome-Wide Association Study; Mendelian Randomization Analysis; Hypertension; Adrenergic beta-Antagonists; Heart Failure
PubMed: 37156668
DOI: 10.1016/j.numecd.2023.04.007 -
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 -
Cell Reports Dec 2023Neuroblastoma originates from developing neural crest and can interconvert between the mesenchymal (MES) and adrenergic (ADRN) states, each of which are controlled by...
Neuroblastoma originates from developing neural crest and can interconvert between the mesenchymal (MES) and adrenergic (ADRN) states, each of which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, the roles of CRC factors in induction and maintenance of specific state are poorly understood. Here, we demonstrate that overexpression of ASCL1, an ADRN CRC factor, in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, initiating the ADRN gene expression program. ASCL1 inhibits the transforming growth factor β-SMAD2/3 pathway but activates the bone morphogenetic protein SMAD1-ID3/4 pathway. ASCL1 and other CRC members potentiate each other's activity, increasing the expression of the original targets and inducing a new set of genes, thereby fully inducing the ADRN program. Our results demonstrate that ASCL1 serves as a pioneer factor and cooperates with CRC factors to characterize the ADRN gene expression program.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Adrenergic Agents; Transcription Factors; Promoter Regions, Genetic; Neuroblastoma
PubMed: 38060444
DOI: 10.1016/j.celrep.2023.113541 -
Veterinary Immunology and... Jun 2024Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of...
Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of adrenergic receptor (AR) expression and function in bovine PMNs is limited but both neutrophils and eosinophils express numerous AR genes but differ significantly in their expression of individual AR genes. A flow cytometric technique was developed to differentiate between bovine neutrophils and eosinophils so both neutrophil and eosinophil responses to adrenergic agonists could be analysed. Neutrophils and eosinophils displayed significantly different changes in CD11b, L-selectin, and CD44 expression when activated by bovine serum opsonized zymosan and recombinant bovine interferon gamma. The responses of activated and resting neutrophils and eosinophils were then compared following stimulation with endogenous adrenergic agonists, epinephrine (E) norepinephrine (NE), and synthetic agonists targeting α1-, α2-, or β-ARs. Both resting and activated neutrophils and eosinophils displayed differences in iROS, CD44, and L-selectin expression following stimulation with E and NE. Resting neutrophils displayed pro-inflammatory responses to both E and NE, while resting eosinophils displayed a pro-inflammatory response to only NE. No single synthetic adrenergic agonist fully recapitulated responses observed with either E or NE and responses to adrenergic agonists were dose-dependent. In conclusion, bovine eosinophils and neutrophils responded to multiple adrenergic agonists by altering expression of proteins involved in immune surveillance and pro-inflammatory responses. Significant differences in neutrophil and eosinophil responses to adrenergic agonists are consistent with their differences in AR gene expression. This highlights the importance of analysing separately these two PMN subpopulations when investigating the effects of either endogenous or synthetic AR agonists.
Topics: Animals; Cattle; Neutrophils; Eosinophils; L-Selectin; Norepinephrine; Epinephrine; Adrenergic Agonists; Hyaluronan Receptors; Flow Cytometry; CD11b Antigen; Neutrophil Activation; Receptors, Adrenergic
PubMed: 38669937
DOI: 10.1016/j.vetimm.2024.110758 -
Current Urology Reports May 2024This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower... (Review)
Review
PURPOSE OF REVIEW
This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower urinary tract symptoms resulting from benign prostatic hyperplasia.
RECENT FINDINGS
The latest advancements in BPH therapy have been in combination strategies. Alpha blockers continue to be the mainstay of treatment, but research is exploring the synergistic benefits of combining them with 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase-5 (PDE5) inhibitors, and beta-3 agonists. The alpha-blocker + 5-ARI combination remains ideal for enlarged, significantly reducing clinical progression risk compared to monotherapy. Alpha-blocker + PDE5 inhibitor combinations appear safe and potentially beneficial for men with concomitant erectile dysfunction; sildenafil might hold an edge over tadalafil based on limited data. Beta-3 agonists show synergistic effects with alpha blockers for residual storage symptoms, offering similar efficacy to anticholinergics but with a better side effect profile.
Topics: Male; Humans; Prostatic Hyperplasia; Drug Therapy, Combination; Erectile Dysfunction; Phosphodiesterase 5 Inhibitors; Tadalafil; Lower Urinary Tract Symptoms; Adrenergic alpha-Antagonists; Treatment Outcome
PubMed: 38448685
DOI: 10.1007/s11934-024-01199-4 -
Acta Physiologica (Oxford, England) Apr 2024Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve...
AIM
Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve both in vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model.
METHODS
12-week-old male C57BL/6J mice were fed regular chow (control) or a high-fat diet and L-NAME (HFpEF) for 15 weeks. At 27 weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes.
RESULTS
HFpEF mice (preserved left ventricular ejection fraction, increased E/e', pulmonary congestion [wet lung weight/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF.
CONCLUSION
In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro-oxidative signaling.
Topics: Humans; Male; Animals; Mice; Stroke Volume; Ventricular Function, Left; Heart Failure; Adrenergic Agents; Disease Models, Animal; Nitric Oxide; Mice, Inbred C57BL
PubMed: 38436094
DOI: 10.1111/apha.14124 -
Circulation Research Jul 2023Beta-2 adrenergic receptors (βARs) but not beta-2 adrenergic receptors (βARs) form a functional complex with L-type Ca channels (LTCCs) on the cardiomyocyte membrane....
BACKGROUND
Beta-2 adrenergic receptors (βARs) but not beta-2 adrenergic receptors (βARs) form a functional complex with L-type Ca channels (LTCCs) on the cardiomyocyte membrane. However, how microdomain localization in the plasma membrane affects the function of these complexes is unknown. We aim to study the coupling between LTCC and β adrenergic receptors in different cardiomyocyte microdomains, the distinct involvement of PKA and CAMKII (Ca/calmodulin-dependent protein kinase II) and explore how this functional complex is disrupted in heart failure.
METHODS
Global signaling between LTCCs and β adrenergic receptors was assessed with whole-cell current recordings and western blot analysis. Super-resolution scanning patch-clamp was used to explore the local coupling between single LTCCs and βAR or βAR in different membrane microdomains in control and failing cardiomyocytes.
RESULTS
LTCC open probability (Po) showed an increase from 0.054±0.003 to 0.092±0.008 when βAR was locally stimulated in the proximity of the channel (<350 nm) in the transverse tubule microdomain. In failing cardiomyocytes, from both rodents and humans, this transverse tubule coupling between LTCC and βAR was lost. Interestingly, local stimulation of βAR did not elicit any change in the Po of LTCCs, indicating a lack of proximal functional interaction between the two, but we confirmed a general activation of LTCC via βAR. By using blockers of PKA and CaMKII and a Caveolin-3-knockout mouse model, we conclude that the βAR-LTCC regulation requires the presence of caveolin-3 and the activation of the CaMKII pathway. By contrast, at a cellular "global" level PKA plays a major role downstream βAR and results in an increase in LTCC current.
CONCLUSIONS
Regulation of the LTCC activity by proximity coupling mechanisms occurs only via βAR, but not βAR. This may explain how βARs tune the response of LTCCs to adrenergic stimulation in healthy conditions. This coupling is lost in heart failure; restoring it could improve the adrenergic response of failing cardiomyocytes.
Topics: Mice; Animals; Humans; Caveolin 3; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Heart Failure; Myocytes, Cardiac; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-2; Adrenergic Agents; Calcium Channels, L-Type
PubMed: 37313722
DOI: 10.1161/CIRCRESAHA.123.322508