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Nature Communications Nov 2023
Topics: Carvedilol; Receptors, Adrenergic, beta-2; Adrenergic beta-Antagonists
PubMed: 38036531
DOI: 10.1038/s41467-023-42848-5 -
Frontiers in Pharmacology 2024
PubMed: 38405668
DOI: 10.3389/fphar.2024.1372317 -
BMC Medicine Nov 2023People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD.
METHODS
We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD.
RESULTS
In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33-4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19-2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04-2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73-0.99).
CONCLUSIONS
Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.
Topics: Humans; Antihypertensive Agents; Parkinson Disease; Adrenergic beta-Antagonists; Receptors, Adrenergic; Benzenesulfonamides
PubMed: 37964359
DOI: 10.1186/s12916-023-03122-z -
Endocrine Dec 2023Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild,... (Review)
Review
Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.
Topics: Humans; Insulin Resistance; Pheochromocytoma; Sodium-Glucose Transporter 2 Inhibitors; Insulin; Diabetic Ketoacidosis; Norepinephrine; Adrenal Gland Neoplasms; Diabetes Mellitus, Type 2
PubMed: 37731140
DOI: 10.1007/s12020-023-03492-7 -
Genes Feb 2024Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition... (Review)
Review
Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition (e.g., increased fat mass and reduced muscle mass). The mechanism of SO is not yet perfectly understood; however, the pathogenesis includes aging and its complications, chronic inflammation, insulin resistance (IR), and hormonal changes. Genetic background is apparent in the pathogenesis of isolated obesity, which is most often polygenic and is characterized by the additive effect of various genetic factors. The genetic etiology has not been strictly established in SO. Still, many data confirm the existence of pathogenic gene variants, e.g., Fat Mass and Obesity Associated Gene (), beta-2-adrenergic receptor () gene, melanocortin-4 receptor () and others with obesity. The literature on the role of these genes is scarce, and their role has not yet been thoroughly established. On the other hand, the involvement of systemic inflammation due to increased adipose tissue in SO plays a significant role in its pathophysiology through the synthesis of various cytokines such as monocyte chemoattractant protein-1 (MCP-1), IL-1Ra, IL-15, adiponectin or CRP. The lack of anti-inflammatory cytokine (e.g., IL-15) can increase SO risk, but further studies are needed to evaluate the exact mechanisms of implications of various cytokines in SO individuals. This manuscript analyses various immunogenetic and non-genetic factors and summarizes the recent findings on immunogenetics potentially impacting SO development.
Topics: Humans; Sarcopenia; Immunogenetics; Interleukin-15; Obesity; Inflammation; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 38397196
DOI: 10.3390/genes15020206 -
International Journal of Molecular... Jan 2024Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains... (Review)
Review
Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3β4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.
Topics: Humans; Nicotine; Tobacco Use Disorder; Reward; Corticotropin-Releasing Hormone; Recurrence; Receptors, Nicotinic
PubMed: 38338760
DOI: 10.3390/ijms25031482 -
Developmental Cell Nov 2023The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative...
The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative response of the heart to be dependent on immunomodulation. A pharmacological approach identified adrenergic receptor alpha-1 as a key regulator of macrophage phenotypic diversification following myocardial damage in zebrafish. Genetic manipulation and single-cell transcriptomics showed that the receptor signals activation of an "extracellular matrix remodeling" transcriptional program in a macrophage subset, which serves as a key regulator of matrix composition and turnover. Mechanistically, adrenergic receptor alpha-1-activated macrophages determine activation of collagen-12-expressing fibroblasts, a cellular determinant of cardiac regenerative niche, through midkine-mediated paracrine crosstalk, allowing lymphatic and blood vessel growth and cardiomyocyte proliferation at the lesion site. These findings identify the mechanism of adrenergic signaling in macrophage phenotypic and functional determination and highlight the potential of neural modulation for regulation of fibrosis and coordination of myocardial regenerative response.
Topics: Animals; Zebrafish; Adrenergic Agents; Myocardium; Extracellular Matrix; Macrophages; Fibrosis; Fibroblasts; Receptors, Adrenergic; Myocytes, Cardiac
PubMed: 37875117
DOI: 10.1016/j.devcel.2023.09.011 -
European Review For Medical and... Aug 2023The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for... (Review)
Review
The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for human use but is commonly used in veterinary medicine due to its sedative and muscle-relaxant properties. Cases of human intoxication due to accidental or voluntary use have been reported since the 1980s. However, reports of adulteration of illicit opioids (heroin and illicit fentanyl) with xylazine have been increasing all over Western countries. In humans, xylazine causes respiratory depression, bradycardia, and hypotension-posing individuals, using xylazine-adulterated opioids. We present a narrative review of the latest intoxication cases related to xylazine, to bring awareness to readers and also to help pathologists to detect and deal with xylazine cases.
Topics: Humans; Xylazine; Analgesics, Opioid; Adrenergic alpha-2 Receptor Agonists; Hypnotics and Sedatives; Bradycardia
PubMed: 37606142
DOI: 10.26355/eurrev_202308_33305 -
Nutrients Jul 2023The relationship between vitamin E intake or circulating α-tocopherol and various health outcomes is still debatable and uncertain. We conducted an umbrella review to... (Review)
Review
The relationship between vitamin E intake or circulating α-tocopherol and various health outcomes is still debatable and uncertain. We conducted an umbrella review to identify the relationships between vitamin E intake or circulating tocopherol and health outcomes by merging and recalculating earlier meta-analyses. The connections that were found to be statistically significant were then classified into different evidence levels based on values, between-study heterogeneity, prediction intervals, and small study effects. We finally included 32 eligible meta-analyses with four vitamin E sources and 64 unique health outcomes. Only the association between circulating α-tocopherol and wheeze or asthma in children was substantiated by consistent evidence. Suggestive evidence was suggested for seven results on endothelial function (supplemental vitamin E): serum C-reactive protein (CRP) concentrations (supplemental vitamin E), cervical cancer (dietary vitamin E), esophageal cancer (dietary vitamin E), cervical intraepithelial neoplasia (CIN, dietary vitamin E), pancreatic cancer (total vitamin E intake), and colorectal cancer (circulating α-tocopherol levels); all of these showed a protective effect consistent with the vitamin E source. In conclusion, our work has indicated that vitamin E is protective for several particular health outcomes. Further prospective studies are required when other factors that may contribute to bias are considered.
Topics: Child; Humans; Vitamin E; alpha-Tocopherol; Antioxidants; Tocopherols; Diet
PubMed: 37571239
DOI: 10.3390/nu15153301