Role of ß-adrenergic signaling and the NLRP3 inflammasome in chronic intermittent hypoxia-induced murine lung cancer progression.

BACKGROUND: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-ß-adrenergic receptor (ßAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice. METHODS: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a ßAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1ß. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH. RESULTS: CIH led to an increase in catecholamine. Catecholamine-ßAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1ß, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited. CONCLUSIONS: Our study underscores the significant contribution of ß-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms. METHODS: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software. RESULTS: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and ß1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), ß2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01). CONCLUSION: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease.

While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer's disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse ß-amyloid1-42 (Aß1-42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aß1-42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aß on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aß plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.

Effects of spatially dense adrenergic stimulation to rotor behaviour in simulated atrial sheets.

Sympathetic hyperactivity via spatially dense adrenergic stimulation may create pro-arrhythmic substrates even without structural remodelling. However, the effect of sympathetic hyperactivity on arrhythmic activity, such as rotors, is unknown. Using simulations, we examined the effects of gradually increasing the spatial density of adrenergic stimulation (AS) in atrial sheets on rotors. We compared their characteristics against rotors hosted in atrial sheets with increasing spatial density of minimally conductive (MC) elements to simulate structural remodelling due to injury or disease. We generated rotors using an S1-S2 stimulation protocol. Then, we created phase maps to identify phase singularities and map their trajectory over time. We measured each rotor's duration (s), angular speed (rad/s), and spatiotemporal organization. We demonstrated that atrial sheets with increased AS spatial densities could maintain rotors longer than with MC elements (2.6 ± 0.1 s vs. 1.5 ± 0.2 s, p<0.001). Moreover, rotors have higher angular speed (70 ± 7 rads/s vs. 60 ± 15 rads/s, p<0.05) and better spatiotemporal organization (0.56 ± 0.05 vs. 0.58 ± 0.18, p<0.05) in atrial sheets with less than 25% AS elements compared to MC elements. Our findings may help elucidate electrophysiological potential alterations in atrial substrates due to sympathetic hyperactivity, particularly among individuals with autonomic derangements caused by chronic distress.

[Establishment and evaluation of haloalkane dehalogenase tagged α1A-adrenergic receptor chromatography].

Receptor chromatography is an efficient analytical technique that combines the high separation ability of chromatography with the high specificity of receptors for drug recognition. In addition, this technique offers the advantages of active recognition, online separation, and convenient multidimensional target tracking. This strategy allows target active ingredients in complex systems, such as traditional Chinese medicines, to be efficiently screened and accurately identified. Furthermore, the interactions between ligands and immobilized proteins can be studied. To avoid a loss in function, receptor chromatography requires efficient, mild, and simple immobilization methods that do not damage the structure of the immobilized receptors. Improvements in the activity, stability, and ligand-recognition specificity of immobilized functional proteins can be achieved by selecting appropriate immobilization conditions. Notably, the protein immobilization method is not only closely related to the recognition ability of receptor chromatography but also determines the accuracy of the technique. Common methods for immobilizing functional proteins include physical adsorption, chemical reactions, biological affinity reactions, and click chemistry. Despite being easy to operate under mild reaction conditions, these methods have shortcomings, including poor reaction specificity and the necessity of using high-purity functional proteins to prepare chromatography columns. Maintaining the high activity of immobilized receptors and ensuring excellent identification and separation abilities are key challenges in the further development of receptor chromatography. In this work, these issues were addressed by introducing a specific bioorthogonal reaction involving haloalkane dehalogenase (Halo) and 6-chlorohexanoic acid for the immobilization of the α1A-adrenergic receptor (α1A-AR). Specifically, Halo-α1A-AR was immobilized on the surface of 6-chlorohexanoic acid-modified aminopropyl silica gel in one step. The stationary phase with immobilized Halo-α1A-AR was characterized using scanning electron microscopy. Moreover, the activity of the Halo-α1A-AR chromatographic column was evaluated using specific ligands (terazosin hydrochloride, phentolamine mesylate, tamsulosin hydrochloride, and urapidil) and nonspecific ligands (yohimbe and metoprolol) for α1A-AR. Halo-α1A-AR was successfully immobilized on the silica gel surface with good stability over 30 days, and the Halo-α1A-AR chromatographic column exhibited good ligand-recognition activity. The nonlinear chromatography results indicated that prazosin hydrochloride, terazosin hydrochloride, and urapidil interacted with immobilized Halo-α1A-AR through one type of binding site, with association constants of 3.85×105, 5.00×105, and 5.90×105L/mol, respectively. In contrast, phentolamine mesylate and tamsulosin hydrochloride interacted with immobilized Halo-α1A-AR through two types of binding site. The association constants with the high- and low-affinity binding sites were 3.12×106 and 6.01×105L/mol, respectively, for phentolamine mesylate and 9.98×105 and 0.21×105L/mol, respectively, for tamsulosin hydrochloride. Compared with the traditional carbonyldiimidazole method, the immobilization method developed in this work did not require receptor purification and thus minimized the loss of receptor activity. The affinity constants obtained with immobilized Halo-α1A-AR were consistent with the values determined for receptor-ligand binding in solution, indicating that the Halo-α1A-AR chromatography column is suitable for studying drug-protein interactions. This approach also provides a foundation for the efficient screening and accurate determination of target active ingredients in complex systems.

Cooperation of aquaporin 5 and the adrenergic system in the initiation of birth in rat model.

Aquaporins (AQPs) are involved in the process of implantation, regulate myometrial contractions and cervical ripening, and maintain appropriate placental functioning. The molecular mechanism of these functions is not fully understood. Our study aimed to investigate the physiological significance of AQP5 during pregnancy and to determine the cooperation between the adrenergic system and the AQP5 in uterine contraction in the late-pregnant rat uterus. After administering AQP5 siRNA intraperitoneally to Sprague-Dawley rats, the length of the gestational period was determined and the changes in uterine contractions were measured in an isolated organ bath system. Pharmacological influence on AQP5 expression and uterine contraction was investigated by treatment with terbutaline (10 mg/kg, subcutaneously) and doxazosin (5 mg/kg, orally) in vivo; and mercuric chloride (HgCl2), in vitro. Moreover, the levels of cAMP response element binding protein (CREB) were measured in the uterus by an ELISA kit. The gestational period became shorter, AQP5 expression significantly decreased and rat uterus contraction increased after AQP5 siRNA treatment compared to the control. Treatment with terbutaline significantly increased AQP5 mRNA and protein expression after 30 min and continuously reduced it until 90 min, whereas doxazosin treatment did not significantly alter AQP5 expression. Treatment with the AQP5 antagonist HgCl2 increased spontaneous uterus contraction and decreased norepinephrine-induced uterus contraction with decreasing AQP5 expression in pregnant rat uterus. Moreover, the tocolytic effect through the adrenergic system was amplified in the presence of an AQP5 antagonist, presumably via the changes in cAMP level. In conclusion, our findings elucidate the collaborative role of aquaporin 5 (AQP5) and adrenergic systems in the regulation of uterine contractions in late-pregnant rats. Our findings suggest this may be a good starting point for developing a new tocolytic therapy.

Pan-cancer analysis of the role of α2C-adrenergic receptor (ADRA2C) in human tumors and validation in glioblastoma multiforme models.

Background: Several studies have reported the relationship between α2C-adrenergic receptor (ADRA2C) and both neoplastic and non-neoplastic diseases. However, a comprehensive pan-cancer analysis is currently lacking. Methods: Utilizing the RNA sequencing (RNA-seq) datasets from The Cancer Genome Atlas (TCGA) database, the roles of ADRA2C in human pan-cancer were analyzed through a variety of bioinformatics approaches, including R programming language and single-cell sequencing data analysis, et al. Besides, cell migration assay and immunochemistry were employed to further validate the role of ADRA2C in glioblastoma multiforme (GBM) cell lines and GBM mouse model. Results: A total of 33 cancer types were involved in this study. It was revealed that the expression level of ADRA2C varied across different clinical stages in patients with breast invasive carcinoma (BRCA), esophageal adenocarcinoma (ESCA), kidney renal papillary cell carcinoma (KIRP) and lung squamous cell carcinoma (LUSC). Meanwhile, it was found that ADRA2C may play roles in prognosis of adrenocortical carcinoma (ACC), glioblastoma multiforme and lower grade glioma (GBM-LGG), and uveal melanoma (UVM). Functional enrichment analysis suggested that ADRA2C expression level was highly correlated with neuronal system-related pathways. Moreover, ADRA2C may be a promising diagnostic marker for cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), GBM, GBMLGG, kidney chromophobe (KICH), and KIRP. Additionally, ADRA2C expression level was correlated with the levels of several infiltrating cells and immune checkpoint genes. Besides, the single-cell sequencing data analysis indicated that ADRA2C played a role in multiple tumor development processes in GBM, retinoblastoma (RB), and UVM. Finally, in vitro and in vivo experiments confirmed that the expression level of ADRA2C may be associated with glioma cell migration, apoptosis, and invasion. Conclusion: ADRA2C exhibited to play a notable role in several cancer types, suggesting that ADRA2C could serve as a promising biomarker or target for cancer diagnosis, prognosis, and treatment, particularly for GBM.

Impaired Peripheral Vascular Function Following Ischemic Stroke in Mice: Potential Insights into Blood Pressure Variations in the Post-Stroke Patient.

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine-induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham = -7.499, LogIC50 Stroke = -7.350, p = 0.0132, n = 19, 31 respectively). The vasodilatory responses to SNP were identical in the isolated aortas in the sham and stroke groups. Phenylephrine-induced vasoconstriction was impaired in the aortas isolated from the stroke animals in comparison to their sham treatment counterparts (Sham LogEC50= -6.652 vs. Stroke LogEC50 = -6.475, p < 0.001). Our study demonstrates that 24 h post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. The aortas from the stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while the endothelium-independent vasodilatory responses were preserved. Since both the vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution.

PURPOSE: Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. DESIGN: Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. SUBJECTS: 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. METHODS: Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). MAIN OUTCOME MEASURES: Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. RESULTS: In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). CONCLUSION: POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

ß-Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s-limonene in the rat heart.

S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of ß-adrenoceptor (ß-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the ß-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 µM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 µM and reduced heart rate at the concentrations of 30 (12.4%) and 50 µM (16.6%). s-Lim (10 µM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 µM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker ß1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists ß1-AR), presenting a similar effect to propranolol (a non-selective blocker ß-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 µM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of ß-AR in the heart.

Allosteric Inhibition of the ß2-Adrenergic Receptor: Design and Synthesis of Cmpd-15 Analogs.

We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (ß2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed ß-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in ß2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in ß2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable ß2AR-targeting NAMs.

Tadalafil use is associated with a lower incidence of Type 2 diabetes in men with benign prostatic hyperplasia: A population-based cohort study.

BACKGROUND: Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated. METHODS: We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47-48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs). RESULTS: A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0-47.9) in tadalafil users and 31.3 months (IQR, 13.7-57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0-7.2) and 8.8 (95% CI, 7.8-9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39-0.62; 5-year CID, -0.031; 95% CI, -0.040 to -0.019). CONCLUSION: The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM.

The Impact of Beta-Blocker Maintenance on Decompensated Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute Heart Failure (HF) is related to a significant hospital mortality rate and functional impairment in many patients. However, there is still a lack of studies that support the use of Beta-blockers (BB) in the management of decompensated HF. OBJECTIVE: This study aimed to evaluate the impact on mortality of maintaining BB in patients with decompensated HF. METHODS: A systematic review and meta-analysis was performed, using the databases PubMed, Cochrane Library, SCIELO and BVS, selecting only cohort studies and Randomized Clinical Trials (RCTs) from the last 10 years, which have been selected based on inclusion and exclusion criteria. RESULTS: An 86% reduction in the risk of in-hospital death was found (RR=0.14, 95% CI: 0.10- 0.18) in patients with HF who maintained the use of BB during hospitalization. A second analysis found a 44% (RR=0.56, 95% CI: 0.47-0.66) lower chance of in-hospital death in the group that previously used BB. Regarding the analysis of mortality after hospital discharge, only studies that have evaluated the use of BB in HF with reduced ejection fraction pointed to a reduction in mortality. Furthermore, some articles have found a relationship between the reduction in readmissions and the use of post-discharge BB. CONCLUSION: There is still no consensus regarding the use of BB in patients hospitalized with decompensated HF. In view of the limitations of the data found in the present study, the need for more RCTs that address this topic is emphasized in order to resolve this uncertainty in the management of cardiovascular patients.

Liver adrenoceptor alpha-1b plays a key role in energy and glucose homeostasis in female mice.

The liver plays a major role in glucose and lipid homeostasis and acts as a key organ in the pathophysiology of metabolic diseases. Intriguingly, increased sympathetic nervous system (SNS) activity to the liver has been associated with the development and progression of type 2 diabetes and obesity. However, the precise mechanisms by which the SNS regulates hepatic metabolism remain to be defined. While liver alpha1-adrenoceptors were suggested to play a role in glucose homeostasis, the specific subtypes involved are unknown mainly because of the limitations of pharmacological tools. Here we generated and validated a novel mouse model allowing tissue-specific deletion of alpha-1b adrenoceptor (Adra1b) in hepatocytes to investigate the role of liver ADRA1B in energy and glucose metabolism. We found that selective deletion of Adra1b in mouse liver has limited metabolic impact in lean mice. However, loss of Adra1bin hepatocytes exacerbated diet-induced obesity, insulin resistance and glucose intolerance in female, but not male mice. In obese females, this was accompanied by reduced hepatic gluconeogenic capacity and reprogramming of gonadal adipose tissue with hyperleptinemia. Our data highlight sex-dependent mechanisms by which the SNS regulates energy and glucose homeostasis through liver ADRA1B.

Beta-blockers and breastfeeding: a real-life prospective study.

PURPOSE: At Lille University Hospital, a pregnancy heart team including cardiologists, obstetricians, pediatricians, anesthetists, geneticists, and pharmacologists discusses about treatment compatibility taken during breastfeeding in pregnant women (or those wishing to be pregnant) with complex cardiovascular pathologies. Beta-blockers are among the drug most often used in these patients, and data are missing or suggest a risk to the breastfed child. The aim of this study was to evaluate the proportion of women treated with beta-blockers, identified during the multidisciplinary meeting, who breastfed and to monitor adverse effects (AEs) in newborns. METHODS: A prospective descriptive study was conducted from 1 December 2017 to 1 December 2021. All pregnant patients followed up by the pregnancy heart team in Lille University Hospital, treated with beta-blockers and who gave birth, were contacted as part of the pharmacovigilance follow-up. RESULTS: The proportion of women treated with beta-blockers intending to breastfeed was 69.8%. Among the 53 women interviewed, 49% did not breastfeed, including 10 because of the theoretical incompatibility of their beta-blocker with breastfeeding. Among the 27 women who breastfed, 30% breastfed while treated with a theoretically incompatible beta-blocker; 56% was changed from their initial beta-blocker to allow safe breastfeeding. No serious AE was observed. CONCLUSION: To our knowledge, our study is the largest series of patients treated with beta-blockers during breastfeeding. Taking a treatment can be an obstacle to breastfeeding, but for the particular case of beta-blockers, even if the available data are few and sometimes worrying, the data from this study are reassuring.

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via ß2 Adrenergic Receptor Signaling.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an ß2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

The Impact of Sedative Choice in the Management of Aneurysmal Subarachnoid Hemorrhage: A Scoping Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high mortality and morbidity. This scoping review assesses the current evidence regarding the use of sedatives and analgesics in the acute intensive care unit management of aSAH. We conducted a systematic search of Ovid MEDLINE, Ovid Embase, Ovid EmCare, APA PsycInfo, CINAHL, and the Cochrane Database of Systematic Reviews from inception to June 2023. Studies were included if they enrolled intensive care unit patients aged 18 or older with a significant proportion (> 20%) who had aSAH and evaluated the impact of one or more commonly used analgosedatives on physiological parameters in the management of aSAH. The methodological quality of the studies was assessed using the Methodological Index for Nonrandomized Studies score. Of 2,583 articles, 11 met the inclusion criteria. The median sample size was 47 (interquartile range 10-127), and the median Methodological Index for Nonrandomized Studies score was 9.5 (interquartile range 8-11). The studies' publication years ranged from 1980 to 2023. Dexmedetomidine and ketamine showed potential benefits in reducing the incidence of cortical spreading depolarization and delayed cerebral ischemia. Propofol and opioids appeared safe but lacked robust evidence for efficacy. Benzodiazepines were associated with increased delayed cerebral ischemia-related cerebral infarctions and cortical spreading depolarization events. The evidence available to guide the use of analgosedative medications in aSAH is critically inadequate. Dexmedetomidine and ketamine warrant further exploration in large-scale prospective studies because of their potential benefits. Improved study designs with consistent definitions and a focus on patient-centered outcomes are necessary to inform clinical practice.

Noradrenergic mechanisms and circuitry of hyperkatifeia in alcohol use disorder.

Hyperkatifeia, the manifestation of emotional distress or pain, is a conceptual framework gaining traction throughout the alcohol and other substance use fields as an important driver of addiction. It is well known that previous or current negative life experiences can serve as powerful motivators for excessive alcohol consumption and precipitate the development of an alcohol use disorder (AUD). A major hallmark of later stages of AUD is the emergence of hyperkatifeia during withdrawal, which can persist well into protracted abstinence to drive relapse. Given these complex interactions, understanding the specific neuroadaptations that lie at the intersection of hyperkatifeia and AUD can inform ongoing therapeutic development. Of particular interest is the monoamine norepinephrine (NE). Noradrenergic dysfunction is implicated in AUD, anxiety, chronic stress, depression, and emotional and physical pain. Importantly, there are key sexual dimorphisms within the noradrenergic system that are thought to differentially impact the development and trajectory of AUD in women and men. The present review discusses past and recent work on noradrenergic influences at each stage of the AUD cycle (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) through the lens of hyperkatifeia. Evidence from these studies support the prioritization of NE-specific drug development to treat AUD and the identification of AUD subpopulations that may benefit the most from these therapies (e.g., women and people with comorbid chronic pain or anxiety/stress disorders).

Asthma beliefs and overuse of short-acting beta-adrenergic receptor agonists among older adults.

OBJECTIVE: Short-acting Beta-adrenergic Receptor Agonists (SABA) carry a risk of worse asthma outcomes when overused. Beliefs about asthma controller medications are associated with medication-taking behaviors in older adults, but the association of medication beliefs with SABA use has not been previously examined. We aimed to investigate the association of asthma and controller medication beliefs with SABA use among older patients with asthma. METHODS: We performed a cross-sectional analysis of data on adults ≥ 60 years old with moderate to severe asthma in New York City, NY (n = 234). SABA overuse was defined as the average of ≥1 inhalation per day and controller medication adherence as ≥80% of expected inhalations, measured electronically. Illness and medication beliefs were measured using the Brief-Illness Perception Questionnaire and Beliefs about Medications Questionnaire, respectively. The associations of medication-taking behaviors with beliefs were examined in multivariable logistic regression models. RESULTS: The mean age was 67.6 ± 6.5 years, 84% were female, 26% were Black and 53% were Hispanic. 35% of participants overused SABA and 21% had adequate controller medication adherence. Overuse of SABA was not significantly associated with controller medication beliefs (Necessity: odds ratio [OR] 1.04, 95% confidence interval [CI] [0.97-1.12], p = 0.28, Concerns: OR 0.95 [95% CI 0.88, 1.03], p = 0.23) or asthma beliefs (OR 1.06 [95% CI 0.99, 1.15], p = 0.11). SABA overuse was also not significantly associated with controller medication adherence (OR 2.20 [95% CI 0.88, 5.51], p = 0.09). CONCLUSIONS: SABA overuse was common among older adults with asthma and was not significantly associated with asthma controller medication or illness beliefs.

Efficacy of ß-Blockers in Decreasing Mortality in Sepsis and Septic Shock Patients: A Systematic Review.

Sepsis is a life-threatening condition leading to various organ dysfunction due to an underlying infection. Despite providing appropriate treatment, it is still one of the most common causes of death among patients who are admitted to the intensive care unit (ICU). So, multiple studies have been conducted to identify the potential benefits of various drugs in decreasing mortality in sepsis apart from its traditional treatment options. This study aims to identify whether ß-blockers play a role in decreasing mortality in sepsis and septic shock patients because of their potential benefits on several organ systems. Medical databases such as Google Scholar, Summon, PubMed Medical Subject Headings (MeSH), PubMed, Science Direct, Cochrane Library, and Multidisciplinary Digital Publishing Institute (MDPI) were systematically searched for relevant publications. The identified articles were assessed based on the inclusion and exclusion criteria, and 11 research articles were finalized, for which quality appraisal was done using appropriate appraisal tools. ß-blockers significantly lowered the in-hospital mortality in sepsis and septic shock patients, and they were also associated with better patient outcomes. As there are limited studies, further research needs to be done to explore the role of ß-blockers in decreasing mortality in critically ill populations such as sepsis and septic shock patients.