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Nature Communications Nov 2023Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis....
Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.
Topics: Animals; Adipose Tissue, White; Adipose Tissue, Brown; Acetanilides; Energy Metabolism; Thermogenesis; Neoplasms; Uncoupling Protein 1
PubMed: 37993438
DOI: 10.1038/s41467-023-43350-8 -
Veterinary Sciences Sep 2023Improving beef production efficiency, sustainability, and food security is crucial for meeting the growing global demand for beef while minimizing environmental impact,... (Review)
Review
Improving beef production efficiency, sustainability, and food security is crucial for meeting the growing global demand for beef while minimizing environmental impact, conserving resources, ensuring economic viability, and promoting animal welfare. Beta-adrenergic agonists and dietary protein have been critical factors in beef cattle production. Beta-agonists enhance growth, improve feed efficiency, and influence carcass composition, while dietary protein provides the necessary nutrients for muscle development and overall health. A balanced approach to their use and incorporation into cattle diets can lead to more efficient and sustainable beef production. However, microbiome technologies play an increasingly important role in beef cattle production, particularly by optimizing rumen fermentation, enhancing nutrient utilization, supporting gut health, and enhancing feed efficiency. Therefore, optimizing rumen fermentation, diet, and growth-promoting technologies has the potential to increase energy capture and improve performance. This review addresses the interactions among beta-adrenergic agonists, protein level and source, and the ruminal microbiome. By adopting innovative technologies, sustainable practices, and responsible management strategies, the beef industry can contribute to a more secure and sustainable food future. Continued research and development in this field can lead to innovative solutions that benefit both producers and the environment.
PubMed: 37756100
DOI: 10.3390/vetsci10090579 -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6 -
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 -
The Clinical Respiratory Journal Oct 2023Montelukast is a highly selective and specific cysteinyl leukotriene receptor antagonist used in the treatment of asthma. Whether montelukast as adjuvant therapy can... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Montelukast is a highly selective and specific cysteinyl leukotriene receptor antagonist used in the treatment of asthma. Whether montelukast as adjuvant therapy can significantly and safely treat adults with cough variant asthma (CVA) remains inconclusive.
AIMS
This meta-analysis systematically evaluated the efficacy and safety of montelukast as an adjuvant treatment for adults with CVA.
MATERIALS AND METHODS
Randomized controlled trials (RCTs) on montelukast combined with inhaled corticosteroids (ICS) and long-acting β2 agonists (LABAs) to treat CVA in adults, from inception to March 6, 2023, were retrieved from the CNKI, Wanfang, VIP, CBM, PubMed, Embase, Cochrane Library, and Web of Science databases and Clinical Trials website. Review Manager (version 5.4) and Stata (version 15.0) were used to conduct the meta-analysis.
RESULTS
A total of 15 RCTs were ultimately included in the meta-analysis. It was established that montelukast as adjuvant therapy raised the total effective rate (RR = 1.20, 95% confidence interval [CI] [1.13, 1.27], P < 0.01) and improved the FEV1% (SMD = 0.91, 95% CI [0.40, 1.41], P < 0.01), PEF% (SMD = 0.63, 95% CI [0.38, 0.88], P < 0.01), FEV1 (SMD = 1.15, 95% CI [0.53, 1.77], P < 0.01), PEF (SMD = 0.64, 95% CI [0.42, 0.86], P < 0.01), and FEV1/FVC% (SMD = 0.76, 95% CI [0.51, 1.01], P < 0.01) and reduced the recurrence rate (RR = 0.28, 95% CI [0.15, 0.53], P < 0.01). The incidence of adverse reactions was higher in the montelukast auxiliary group compared to the control group but with no statistical difference (RR = 1.32, 95% CI [0.89, 1.96], P = 0.17).
CONCLUSION
Existing evidence indicated that the use of montelukast as an adjuvant therapy had therapeutic efficacy superior to ICS + LABA alone for the treatment of adult patients with CVA. However, further research is needed, especially a combination of high-quality long-term prospective studies and carefully designed RCTs.
Topics: Adult; Humans; Anti-Asthmatic Agents; Cough; Adrenergic beta-Agonists; Drug Therapy, Combination; Asthma; Adrenal Cortex Hormones
PubMed: 37218346
DOI: 10.1111/crj.13629 -
Diabetes Feb 2024Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat...
Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impaired the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice displayed increased fasting blood glucose levels and hepatic steatosis while on a chow diet. Foxj3 deficiency inhibited the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduced the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhanced the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and iWAT increased energy expenditure and improved systemic metabolism on either a chow or high-fat diet. Finally, Foxj3 deletion in fat inhibited the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulated the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. This study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.
Topics: Mice; Animals; Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Adipocytes, Brown; Energy Metabolism; Obesity; Thermogenesis; Mice, Inbred C57BL
PubMed: 37939221
DOI: 10.2337/db23-0454 -
Sympathetic activity regulates epithelial proliferation and wound healing via adrenergic receptor α.Scientific Reports Oct 2023Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium...
Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding.
Topics: Animals; Mice; Cell Proliferation; Epithelial Cells; Intestinal Mucosa; Intestines; Receptors, Adrenergic; Receptors, Adrenergic, alpha-2; Wound Healing
PubMed: 37863979
DOI: 10.1038/s41598-023-45160-w -
Inflammation Apr 2024Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of...
Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of damage-associated molecular patterns (DAMPs) that is critically involved in the pathogenesis of heart failure, thus considered a promising target for pharmacological intervention. In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the β-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in β-adrenergic overactivation-mediated heart failure. This finding was further confirmed by the cardiomyocyte-specific silencing of S100A9 via the use of the adeno-associated virus (AAV) 9-mediated short hairpin RNA (shRNA) gene silencing system. Most importantly, in the assessment of the underlying cellular mechanism by which activated S100A8/A9 cause aggravated progression of cardiac fibrosis and heart failure, we discovered that the activated S100A8/A9 can promote fibroblast-macrophage interaction, independent of inflammation, which is likely a key mechanism leading to the enhanced collagen production. Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development.
Topics: Animals; Mice; Adrenergic beta-Agonists; Calgranulin A; Calgranulin B; Fibroblasts; Fibrosis; Heart Failure; Inflammation; Macrophages; Myocytes, Cardiac
PubMed: 38446361
DOI: 10.1007/s10753-023-01944-w -
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 -
JAMA Cardiology Nov 2023Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling.
OBJECTIVE
To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF.
DESIGN, SETTING, AND PARTICIPANTS
The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022.
INTERVENTION
Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months.
MAIN OUTCOMES AND MEASURES
The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication.
RESULTS
Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial.
CONCLUSIONS
In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02599480.
Topics: Female; Humans; Male; Middle Aged; Adrenergic Agonists; Diabetes Mellitus, Type 2; Heart Failure; Hypertrophy, Left Ventricular; Prospective Studies; Aged
PubMed: 37728907
DOI: 10.1001/jamacardio.2023.3003