Microglia are immune cells that play important roles in the formation of the innate immune response within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiple protein complex that is crucial for innate immunity, and excessive activation of the inflammasome for various reasons contributes to the pathogenesis of neurodegenerative diseases (NDs). β2-adrenoceptor agonists have become the focus of attention in studies on NDs due to the high synthesis of β2-adrenoceptors in the central nervous system (CNS). Promising results have been obtained from these studies targeting anti-inflammatory and neuroprotective effects. Formoterol is an effective, safe for long-term use, and FDA-approved β2-adrenoceptor agonist with demonstrated anti-inflammatory features in the CNS. In this study, we researched the effects of formoterol on LPS/ATP-stimulated NLRP3 inflammasome activation, pyroptosis, NF-κB, autophagy, and ESCRT-III-mediated plasma membrane repair pathways in the N9 microglia cells. The results showed that formoterol, through the IκBα/NF-κB axis, significantly inhibited NLRP3 inflammasome activation, reduced the level of active caspase-1, secretion of IL-1β and IL-18 proinflammatory cytokine levels, and the levels of pyroptosis. Additionally, we showed that formoterol activates autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair, which are significant pathways in the inhibition of NLRP3 inflammasome activation and pyroptosis. Our study suggests that formoterol efficaciously prevents the NLRP3 inflammasome activation and pyroptosis in microglial cells regulation through IκBα/NF-κB, autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair.

BACKGROUND: Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β2-adrenergic receptor (β2-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome.
OBJECTIVE: The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy.
METHODS: Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours.
RESULTS: The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β2-AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels.
CONCLUSIONS: Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β2-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.

UNASSIGNED: The combination of an inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) (ICS/LABA) has shown superiority in improving lung function (FEV1) compared with an ICS alone. The clinical effect of a ICS/LABA combination depends on the fine-particle fraction and the pulmonary deposition.
UNASSIGNED: We sought to compare the efficacy of 2 combinations of an ICS and LABA, namely, fluticasone propionate (FP) and formoterol (FORM) (FP/FORM) and fluticasone furoate (FF) and vilanterol (VI) (FF/VI), in asthmatic adolescents with chronic bronchial obstruction.
UNASSIGNED: FP/FORM (125 μg/5 μg, 2 doses twice daily via the k-haler [Mundipharma, Cambridge, UK]) and FF/VI (92 μg/22 μg, once daily via the Ellipta inhaler [GlaxoSmithKline]) were administered to adolescents aged 12 to 17 years who required regular antiasthmatic medication and had a ratio of FEV1 to forced vital capacity (FEV1/FVC) less than -1.65 SD in a 2-sequence, 16-week crossover trial. The primary efficacy end point was change in FEV1 compared with baseline. Secondary end points were FEV1/FVC ratio, maximal expiratory flow at 50% of the FVC, impulse oscillometry indices respiratory resistance at 5 Hz (R5), difference between R5 and respiratory resistance at 20 Hz (R20), area of reactance, and Asthma Control Test score.
UNASSIGNED: Both ICS/LABA combinations resulted in a significant improvement in FEV1 and maximal expiratory flow at 50% of the FVC z scores without any significant difference between FP/FORM and FF/VI, with 40% of patients with either treatment achieving a normal prebronchodilator FEV1/FVC z score. Neither area of reactance nor difference between R5 and R20 improved significantly with either treatment.
UNASSIGNED: Both ICS/LABA combinations demonstrated significant improvements in FEV1z score. More than one-third of the asthmatic adolescents with prolonged bronchial obstruction achieved a normal prebronchodilator FEV1/FVC ratio.

Chronic obstructive pulmonary disease (COPD) imposes a significant burden on individuals and healthcare systems globally. While bronchodilators, such as glycopyrronium and formoterol, are cornerstone therapies for COPD management, combining these agents has gained attention for potentially improving outcomes compared to monotherapy. This comprehensive review aims to assess the efficacy and safety of glycopyrronium/formoterol (GFF) combination therapy versus glycopyrronium monotherapy in patients with moderate-to-severe COPD. Through a systematic evaluation of clinical trials and real-world evidence, we analyze the impact of combination therapy on lung function, symptom control, exacerbation rates, and health-related quality of life (HRQoL). Furthermore, we examine the safety profile of combination therapy, including adverse cardiovascular and respiratory events. Comparative analyses with glycopyrronium monotherapy provide insights into the relative benefits and considerations for treatment selection. Factors influencing treatment choice and future directions in COPD management are also discussed. This review underscores the potential of combination therapy in optimizing COPD treatment outcomes and highlights areas for further research and clinical practice refinement.

BACKGROUND: Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, induced mitochondrial biogenesis (MB) in podocytes and led to renoprotection in mice. However, it is not clear whether this effect was mediated by formoterol acting through the β2-AR or if it occurred through \"off-target\" effects.
METHODS: We genetically deleted the β2-AR specifically in murine podocytes and used these mice to determine whether formoterol acting through the podocyte β2-AR alone is sufficient for recovery of renal filtration function following injury. The podocyte-specific β2-AR knockout mice (β2-ARfl/fl/PodCre) were generated by crossing β2-AR floxed mice with podocin Cre (B6.Cg-Tg(NPHS2-cre)295Lbh/J) mice. These mice were then subjected to both acute and chronic glomerular injury using nephrotoxic serum (NTS) and adriamycin (ADR), respectively. The extent of injury was evaluated by measuring albuminuria and histological and immunostaining analysis of the murine kidney sections.
RESULTS: A similar level of injury was observed in β2-AR knockout and control mice; however, the β2-ARfl/fl/PodCre mice failed to recover in response to formoterol. Functional evaluation of the β2-ARfl/fl/PodCre mice following injury plus formoterol showed similar albuminuria and glomerular injury to control mice that were not treated with formoterol.
CONCLUSIONS: These results indicate that the podocyte β2-AR is a critical component of the recovery mechanism and may serve as a novel therapeutic target for treating podocytopathies.

Formoterol, a β2-adrenergic receptor (β2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson\'s disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of β2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD.

UNASSIGNED: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma.
UNASSIGNED: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety.
UNASSIGNED: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study.
UNASSIGNED: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

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Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease but effective drugs for treatment of AAA are still lacking. Recently, erythropoietin (EPO) is reported to induce AAA formation in apolipoprotein-E knock out (ApoE-/-) mice but an effective antagonist is unknown. In this study, formoterol, a β2 adrenergic receptor (β2AR) agonist, is found to be a promising agent for inhibiting AAA. To test this hypothesis, ApoE-/- mice are treated with vehicle, EPO, and EPO plus low-, medium-, and high-dose formoterol, respectively. The incidence of AAA is 0, 55%, 35%,10%, and 55% in these 5 groups, respectively. Mechanistically, senescence of vascular smooth muscle cell (VSMC) is increased by EPO while decreased by medium-dose formoterol both in vivo and in vitro, manifested by the altered expression of senescence biomarkers including phosphorylation of H2AXserine139, senescence-associated β-galactosidase activity, and P21 protein level. In addition, expression of sirtuin 1 (SIRT1) in aorta is decreased in EPO-induced AAA but remarkably elevated by medium-dose formoterol. Knockdown of β2AR and blockage of cyclic adenosine monophosphate (cAMP) attenuate the inhibitory role of formoterol in EPO-induced VSMC senescence. In summary, medium-dose formoterol attenuates EPO-induced AAA via β2AR/cAMP/SIRT1 pathways, which provides a promising medication for the treatment of AAA.

Overuse of reliever as short-acting beta-agonist and associated underuse of controller as inhaled corticosteroid (ICS) administered via separate inhalers results in worse asthma outcomes. Such discordance can be obviated by combining both controller and reliever in the same inhaler. So-called anti-inflammatory reliever (AIR) therapy comprises the use of a single inhaler containing an ICS such as budesonide (BUD) in conjunction with a reliever as either albuterol (ALB) or formoterol (FORM), to be used on demand, with variable dosing driven by asthma symptoms in a flexible patient-centered regimen. Global guidelines now support the use of BUD-ALB as AIR therapy to reduce exacerbations, either on its own in mild asthma or in conjunction with fixed-dose maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Using BUD-FORM on its own allows patients to seamlessly move in an intuitive flexible fashion between AIR and maintenance and reliever therapy, by stepping up and down the dosing escalator across a spectrum of asthma severities. Head-to-head clinical studies are indicated to compare BUD-FORM versus BUD-ALB as AIR in mild asthma, and also BUD-FORM as maintenance and reliever therapy versus BUD-ALB as AIR plus maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Patients should be encouraged to make an informed decision in conjunction with their health care professional regarding the best therapeutic option tailored to their individual needs, which in turn is likely to result in long-term compliance and associated optimal asthma control.