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The Journal of Biological Chemistry Jun 2024During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin...
During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb following treatment with serum or the α-adrenergic agonist phenylephrine (PE). Depletion of Bmal1 decreased expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting Nppb transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented PE-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.
PubMed: 38830405
DOI: 10.1016/j.jbc.2024.107434 -
Respiratory Research May 2024COPD is associated with the development of lung cancer. A protective effect of inhaled corticosteroids (ICS) on lung cancer is still controversial. Hence, this study...
BACKGROUND
COPD is associated with the development of lung cancer. A protective effect of inhaled corticosteroids (ICS) on lung cancer is still controversial. Hence, this study investigated the development of lung cancer according to inhaler prescription and comorbidties in COPD.
METHODS
A retrospective cohort study was conducted based on the Korean Health Insurance Review and Assessment Service database. The development of lung cancer was investigated from the index date to December 31, 2020. This cohort included COPD patients (≥ 40 years) with new prescription of inhalers. Patients with a previous history of any cancer during screening period or a switch of inhaler after the index date were excluded.
RESULTS
Of the 63,442 eligible patients, 39,588 patients (62.4%) were in the long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) group, 22,718 (35.8%) in the ICS/LABA group, and 1,136 (1.8%) in the LABA group. Multivariate analysis showed no significant difference in the development of lung cancer according to inhaler prescription. Multivariate analysis, adjusted for age, sex, and significant factors in the univariate analysis, demonstrated that diffuse interstitial lung disease (DILD) (HR = 2.68; 95%CI = 1.86-3.85), a higher Charlson Comorbidity Index score (HR = 1.05; 95%CI = 1.01-1.08), and two or more hospitalizations during screening period (HR = 1.19; 95%CI = 1.01-1.39), along with older age and male sex, were independently associated with the development of lung cancer.
CONCLUSION
Our data suggest that the development of lung cancer is not independently associated with inhaler prescription, but with coexisting DILD, a higher Charlson Comorbidity Index score, and frequent hospitalization.
Topics: Humans; Male; Female; Lung Neoplasms; Middle Aged; Retrospective Studies; Aged; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Administration, Inhalation; Nebulizers and Vaporizers; Adult; Cohort Studies; Adrenal Cortex Hormones; Population Surveillance; Adrenergic beta-2 Receptor Agonists; Muscarinic Antagonists
PubMed: 38822332
DOI: 10.1186/s12931-024-02838-7 -
International Journal of Chronic... 2024Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the... (Observational Study)
Observational Study
PURPOSE
Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data.
PATIENTS AND METHODS
Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori).
RESULTS
Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV: 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting β-agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period.
CONCLUSION
The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Female; Aged; Primary Health Care; Treatment Outcome; Bronchodilator Agents; Middle Aged; Time Factors; Adrenergic beta-2 Receptor Agonists; United Kingdom; Glycopyrrolate; Databases, Factual; Budesonide, Formoterol Fumarate Drug Combination; Lung; Muscarinic Antagonists; Drug Combinations; Retrospective Studies; Glucocorticoids; Aged, 80 and over
PubMed: 38813078
DOI: 10.2147/COPD.S452624 -
Journal of Medicinal Chemistry Jun 2024Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we...
Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6,10)-8-[3-(4-fluorophenoxy)propyl]-6,7,8,9,10,10-hexahydro-1-pyrido[3',4':4,5]pyrrolo[1,2,3-]quinoxalin-2(3)-one (compound , ITI-333), which exhibited potent binding affinity to serotonin 5-HT ( = 8.3 nM) and μ-opioid receptors (MOR, = 11 nM) and moderate affinity to adrenergic α ( = 28 nM) and dopamine D ( = 50 nM) receptors. ITI-333 acts as a 5-HT receptor antagonist, a MOR partial agonist, and an adrenergic α receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.
Topics: Animals; Humans; Analgesics; Structure-Activity Relationship; Administration, Oral; Pain; Mice; Male; Rats; Drug Discovery; Rats, Sprague-Dawley; Biological Availability; Receptors, Opioid, mu; Pyridines; Pyrroles
PubMed: 38805667
DOI: 10.1021/acs.jmedchem.4c00480 -
Journal of Insect Science (Online) May 2024The parasitic mite Varroa destructor (Anderson and Trueman) is one of the greatest stressors of Apis mellifera (L.) honey bee colonies. When Varroa infestations reach...
The parasitic mite Varroa destructor (Anderson and Trueman) is one of the greatest stressors of Apis mellifera (L.) honey bee colonies. When Varroa infestations reach damaging levels during fall, rapid control is necessary to minimize damage to colonies. We performed a field trial in the US Southeast to determine if a combination of registered treatments (Apivar, amitraz-based; and Apiguard, thymol-based) could provide rapid and effective control of Varroa. We compared colonies that received this combination treatment against colonies that received amitraz-based positive control treatments: (i) Apivar alone; or (ii) amitraz emulsifiable concentrate ("amitraz EC"). While not registered, amitraz EC is used by beekeepers in the United States in part because it is thought to control Varroa more rapidly and effectively than registered products. Based on measurements of Varroa infestation rates of colonies after 21 days of treatment, we found that the combination treatment controlled Varroa nearly as rapidly as the amitraz EC treatment: this or other combinations could be useful for Varroa management. At the end of the 42-day trial, colonies in the amitraz EC group had higher bee populations than those in the Apivar group, which suggests that rapid control helps reduce Varroa damage. Colonies in the combination group had lower bee populations than those in the amitraz EC group, which indicates that the combination treatment needs to be optimized to avoid damage to colonies.
Topics: Animals; Toluidines; Bees; Varroidae; Thymol; Acaricides; Beekeeping
PubMed: 38805647
DOI: 10.1093/jisesa/ieae022 -
Respiratory Investigation Jul 2024Real-world data assessing characteristics of patients with asthma initiating inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β-agonist... (Observational Study)
Observational Study
BACKGROUND
Real-world data assessing characteristics of patients with asthma initiating inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β-agonist (ICS/LAMA/LABA) triple therapy in Japan are limited.
METHODS
Descriptive, observational study of patients with asthma aged ≥15 years newly initiating single- or multiple-inhaler triple therapy (SITT: fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI], SITT: indacaterol/glycopyrronium bromide/mometasone furoate [IND/GLY/MF] or MITT) or ICS/LABA using JMDC/Medical Data Vision (MDV) health insurance databases from February 2021-February 2022 (first prescription date: index date). Patients were assigned to three non-mutually exclusive cohorts: A) new FF/UMEC/VI initiators; B) new FF/UMEC/VI, IND/GLY/MF, or MITT initiators; C) new FF/UMEC/VI, IND/GLY/MF, MITT or ICS/LABA initiators as initial maintenance therapy (IMT). Patient characteristics were assessed descriptively for 12-months pre-treatment initiation (baseline period).
RESULTS
Cohort A: among new FF/UMEC/VI initiators, 12.8% and 0.1% (JMDC) and 21.7% and 0.9% (MDV) of patients had ≥1 moderate and severe exacerbation; 52.0% (JMDC) and 79.2% (MDV) had ICS/LABA use. Cohort B: most patients initiated FF/UMEC/VI and IND/GLY/MF over MITT (JMDC: 91.3% vs 8.7%; MDV: 67.8% vs 32.2%), with fewer exacerbations and lower rescue medication use. Cohort C: a greater proportion of FF/UMEC/VI initiators as IMT experienced a moderate exacerbation at index versus ICS/LABA initiators as IMT (JMDC: 17.8% vs 10.7%; MDV: 8.0% vs 5.1%).
CONCLUSIONS
Patient characteristics were generally similar between treatment groups; SITT initiators had fewer exacerbations and lower rescue medication use than MITT initiators, represented by the greater proportion of IMT among SITT versus MITT initiators. Physicians may have prescribed triple over dual therapy as IMT in response to an exacerbation.
Topics: Humans; Benzyl Alcohols; Chlorobenzenes; Asthma; Male; Female; Middle Aged; Quinuclidines; Japan; Adult; Administration, Inhalation; Androstadienes; Aged; Drug Combinations; Muscarinic Antagonists; Adrenergic beta-2 Receptor Agonists; Nebulizers and Vaporizers; Adolescent; Young Adult; Drug Therapy, Combination; Glycopyrrolate; Quinolones
PubMed: 38796907
DOI: 10.1016/j.resinv.2024.05.011 -
Molecular Metabolism Jul 2024Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT)....
OBJECTIVE
Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.
METHODS
In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.
RESULTS
Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.
CONCLUSIONS
Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.
Topics: Animals; Adipose Tissue, Brown; Mice; Muscle, Skeletal; Male; Mice, Inbred C57BL; Rats; Obesity; Fatty Liver; Thermogenesis; Adrenergic Agonists
PubMed: 38796310
DOI: 10.1016/j.molmet.2024.101931 -
Molecules (Basel, Switzerland) May 2024The β-adrenergic drug Mirabegron, a drug initially used for the treatment of an overactive bladder, has new potential indications and is hydrolyzed by...
The β-adrenergic drug Mirabegron, a drug initially used for the treatment of an overactive bladder, has new potential indications and is hydrolyzed by butyrylcholinesterase (BChE). This compound is one of the only arylacylamide substrates to be catabolized by BChE. A steady-state kinetic analysis at 25 °C and pH 7.0 showed that the enzyme behavior is Michaelian with this substrate and displays a long pre-steady-state phase characterized by a burst. The induction time, , increased with substrate concentration ( ≈ 18 min at maximum velocity). The kinetic behavior was interpreted in terms of hysteretic behavior, resulting from a slow equilibrium between two enzyme active forms, E and E'. The pre-steady-state phase with the highest activity corresponds to action of the E form, and the steady state corresponds to action of the E' form. The catalytic parameters were determined as = 7.3 min and = 23.5 μM for the initial (burst) form E, and = 1.6 min and = 3.9 μM for the final form E'. Thus, the higher affinity of E' for Mirabegron triggers the slow enzyme state equilibrium toward a slow steady state. Despite the complexity of the reaction mechanism of Mirabegron with BChE, slow BChE-catalyzed degradation of Mirabegron in blood should have no impact on the pharmacological activities of this drug.
Topics: Butyrylcholinesterase; Acetanilides; Thiazoles; Kinetics; Hydrolysis; Humans; Catalysis
PubMed: 38792217
DOI: 10.3390/molecules29102356 -
Biomedicines May 2024Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition...
Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition stimulates reactive oxygen species (ROS) and pro-inflammatory cytokine production in different organs and also in the central nervous system (CNS). Levosimendan, a cardioprotective inodilator, and dobutamine, a β1-adrenergic agonist, are commonly used for the treatment of hypovolemic shock, thanks to their anti-inflammatory and antioxidant effects. For this reason, we aimed at investigating levosimendan and dobutamine's neuroprotective effects in an "in vitro" model of lipopolysaccharide (LPS)-induced neuroinflammation. Human microglial cells (HMC3) were challenged with LPS (0.1 µg/mL) to induce an inflammatory phenotype and then treated with levosimendan (10 µM) or dobutamine (50 µM) for 24 h. Levosimendan and dobutamine significantly reduced the ROS levels and markedly increased Nrf2 and HO-1 protein expression in LPS-challenged cells. Levosimendan and dobutamine also decreased p-NF-κB expression and turned off the NLRP3 inflammasome together with its downstream signals, caspase-1 and IL-1β. Moreover, a reduction in TNF-α and IL-6 expression and an increase in IL-10 levels in LPS-stimulated HMC3 cells was observed following treatment. In conclusion, levosimendan and dobutamine attenuated LPS-induced neuroinflammation through NF-κB pathway inhibition and NLRP3 inflammasome activation via Nrf2/HO-1 signalling, suggesting that these drugs could represent a promising therapeutic approach for the treatment of neuroinflammation consequent to hypovolemic shock.
PubMed: 38790971
DOI: 10.3390/biomedicines12051009 -
Italian Journal of Pediatrics May 2024Short-acting bronchodilators are a class of medications commonly used to treat asthma, chronic obstructive pulmonary disease, and other respiratory conditions. The use... (Review)
Review
Short-acting bronchodilators are a class of medications commonly used to treat asthma, chronic obstructive pulmonary disease, and other respiratory conditions. The use of these medications has evolved over time as we have gained a better understanding of their effectiveness and safety in the pediatric population. This comprehensive review synthesizes the current understanding of short-acting β2-agonists and short-acting anticholinergics in children. It addresses indications, contraindications, safety considerations, and highlights areas where further research is needed to guide the most effective use of short-acting bronchodilators.
Topics: Humans; Bronchodilator Agents; Child; Asthma; Cholinergic Antagonists; Adrenergic beta-2 Receptor Agonists; Pulmonary Disease, Chronic Obstructive
PubMed: 38783314
DOI: 10.1186/s13052-024-01675-0