Search Results (345)

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. HIV-1-infected and uninfected Hu-mice served as controls. After one month of infection (HIV-1_ADA), ECG intervals/segments were significantly altered. ECG changes progressively worsened as the duration of untreated infection increased. Treating HIV-1-infected animals with the DTG/TDF/FTC for eight weeks, starting four weeks after infection, prevented worsening, but did not restore ECG intervals/segments to those before infection. In hearts from DTG/TDF/FTC-treated animals, steady-state levels of the sarco-(endo) plasmic reticulum Ca²⁺ ATPase (SERCA2) were reduced by 35%. Steady-state levels of type 2 ryanodine receptor (RyR2) did not change, but its phosphorylation status at Ser2808 was 2-fold higher than that of uninfected controls, indicative of a gain-of-function. The density of perfused micro vessels and fibrosis in hearts of DTG/TDF/FTC-treated animals was not significantly different from that of HIV-1-infected and uninfected Hu-mice. These data show for the first time that HIV-1 infection is triggering abnormalities in the ECG of Hu-mice, and changes in ECG persisted with DTG/TDF/FTC treatment, independent of ischemia and/or fibrosis. They also indicate that chronic DTG/TDF/FTC treatment did not worsen ECG changes, including the QT interval. Since phosphorylation of RyR2 at Ser2808 occurs via β-adrenergic activation of protein kinase A, these new data also suggest that chronic hyperadrenergic activity may be increasing the risk of SCD via Ca²⁺ leak through RyR2. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that mediate diverse cellular processes, including signalling, survival, proliferation, immune response and metabolism, through both genomic and non-genomic mechanisms in response to hormones and metabolic ligands. Given their central role in inter-organ, tissue, and cellular communication, NRs are critical for maintaining homeostasis and have become a major focus in biomedical research and drug discovery due to their association with numerous diseases. Among NRs, the NR4A subfamily (NR4A1/Nur77, NR4A2/Nurr1, and NR4A3/Nor1) responds to various stimuli—such as insulin, growth factors, inflammatory cytokines, and β-adrenergic signals—though their endogenous ligands remain unidentified. Their expression is tissue-dependent, particularly in energy-demanding tissues, where they modulate leukocyte function and promote an anti-inflammatory profile. Like other NRs, NR4As regulate acute and chronic inflammation by suppressing pro-inflammatory transcription factors (e.g., NF-κB) or enhancing their inhibitors, thereby polarising macrophages toward an anti-inflammatory phenotype. This review summarises current knowledge on the role of NR4A receptors in immune responses. Given their well-documented involvement in autoimmune diseases, inflammatory conditions, and cancer, elucidating their contributions to neuro–immune–endocrine crosstalk may uncover their therapeutic potential for immunopathological disorders. Full article

Astrocytes are increasingly recognized as active participants of synaptic communication, yet their role in the basal ganglia circuitry remains poorly defined. Emerging evidence indicates that astrocytes in this region express a diverse array of neurotransmitter receptors thought to regulate intracellular calcium signaling, gliotransmitter release, synaptic plasticity, and neuroimmune responses. However, the literature is limited by methodological variability and a pronounced focus on the striatum, with comparatively little data on other basal ganglia nuclei. This review aims to organize the current literature on astrocytic receptor systems within the basal ganglia, including dopaminergic (D1–D5), glutamatergic (AMPA, NMDA, mGluRs), GABAergic (GABA-A, GABA-B), purinergic (P1, P2), and adrenergic (α, β) receptors. By organizing receptor-specific findings across basal ganglia structures, this review provides a foundation for future investigations into astrocytic function in this complex neural network. Full article

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice (8–12 weeks old) respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H₂O₂)-induced Ca²⁺ influx characteristic of TRPM2; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling. Full article

Memory function is susceptible to decline with age, stress, and neurological diseases, highlighting the importance of exploring effective and sustainable strategies to enhance memory consolidation. Epinephrine plays a key role in memory consolidation; acute, moderate elevations enhance memory, while chronic high levels are inhibitory. Given the limitations of pharmacological interventions, this study aims to investigate exercise as a non-pharmacological means to promote post-learning memory consolidation by inducing acute epinephrine release, focusing on its mechanisms and optimized implementation strategies. This narrative review systematically reviews evidence from neurophysiology, molecular biology, and behavioral experiments and finds that exercise can safely and controllably activate the sympathetic–adrenal system, leading to a rapid rise in epinephrine. The release kinetics align highly with the critical time window for memory consolidation. Moderate-intensity aerobic exercise implemented within 30 min post-learning can significantly improve memory retention. The mechanisms involve not only epinephrine enhancing synaptic plasticity and LTP by activating hippocampal β-adrenergic receptors, but also synergistic effects across multiple systems, such as promoting osteocalcin signaling, upregulating BDNF expression, inducing neurogenesis, and optimizing cerebral metabolism and blood flow. Evidence suggests that exercise, as a non-pharmacological intervention, significantly enhances post-learning memory consolidation through the precise modulation of epinephrine release and multi-system synergy, offering both high efficacy and safety. Future research should focus on developing precise exercise prescriptions based on individual characteristics and leveraging wearable devices and digital technologies to improve intervention adherence and applicability, promoting its widespread use in educational and clinical settings. Full article

The β3-adrenergic receptor is an exceptional member of the β-adrenergic receptor family. Recent findings suggest that it may play a more significant role in the cardiovascular system than previously recognized, partly through its potential anti-inflammatory actions. For this reason, it has been extensively studied as a potential target in cardiovascular therapy. In this review, we focus on the β3-adrenergic receptor agonists and their pharmacodynamics regarding receptor binding and activation. We then describe the mechanisms of action mediated by the β3-adrenergic receptor in blood vessels and in the heart under both physiological and pathological conditions. We particularly concentrate on the therapeutic potential in the arterial, pulmonary, and portal hypertension as well as cardiac arrhythmias, ischemia, and heart failure, considering both receptor agonism and antagonism. Full article

Background/Objectives: Obesity, a metabolic disorder resulting from an energy imbalance, often leads to excess fat and related diseases. Browning of white adipose tissue, which increases energy expenditure, is a promising anti-obesity strategy. Herbal medicines are considered safer than conventional drugs, but their fat browning mechanisms remain unclear. Therefore, this study aims to examine the effects of Coix lacryma-jobi L. and Raphanus sativus L., alongside their active compounds, coixol and sinigrin. Methods: Cytotoxicity in 3T3-L1 cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Lipid accumulation was quantified by the Oil Red O (ORO) staining. Immunofluorescence staining was employed to evaluate mitochondrial activity and uncoupling protein 1 (UCP1). Protein and mRNA expressions were analysed using western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Results: In 3T3-L1 adipocytes, ORO staining showed reduced lipid accumulation and droplet size after treatment. qRT-PCR, western blot, and immunostaining revealed that coixol and sinigrin upregulated browning markers (UCP1, PGC-1α, PRDM16) and beige fat genes (Cd137, Cidea, Cited, Fgf21, Tbx1, Tmem26). They also upregulated mitochondrial biogenesis genes (Cox4, Nrf1, Tfam), downregulated lipogenic genes (Fasn, Lpl, Srebf1, Acaca), and increased lipolytic (Atgl, Hsl, Plin1) and fatty acid oxidation genes (Aco1, Cpt1, Ppara). Mechanistic studies revealed that fat browning was associated with β3-adrenergic receptor activation and AMPK phosphorylation. Conclusions: Overall, coixol and sinigrin promote fat browning and metabolic improvement, highlighting their potential as natural anti-obesity agents. Full article

Background: Hypertension and its complications are a major global health problem, and natural compounds with vasorelaxant effects are being investigated as potential antihypertensive agents. Objective: This study aimed to determine whether rosmarinic acid (RA) induces vasorelaxation in the rat thoracic aorta and to elucidate the underlying mechanisms. Methods: Isolated thoracic aortic rings, with or without endothelium, were precontracted with phenylephrine and subsequently exposed to cumulative concentrations of RA. The roles of endothelium-derived factors, potassium channels, and calcium signaling were evaluated using selective pharmacological inhibitors and activators. In addition, the involvement of the AMPK pathway, adenylate cyclase/cAMP pathway, PKC signaling, β-adrenergic receptors, muscarinic receptors, and angiotensin II in RA-induced vasorelaxation was investigated. Results: RA induced a concentration-dependent vasorelaxation in endothelium-intact thoracic aortic rings (p < 0.001; pD₂ = 7.67 ± 0.04). The vasorelaxant effect of RA was attenuated in endothelium-denuded vessels (pD2: 5.26 ± 0.18). The relaxation response was significantly attenuated by inhibitors of the PI3K/Akt/eNOS/NO/cGMP pathway and by blockers of BK_Ca, IK_Ca, and Kv potassium channels (p < 0.001). Furthermore, RA markedly inhibited both extracellular Ca²⁺ influx and intracellular Ca²⁺ release from the sarcoplasmic reticulum (p < 0.001). RA incubation also significantly reduced the contractions induced by angiotensin II (Ang II) and by the PKC activator PMA (p < 0.001). Other tested pathways had no significant influence on the vasorelaxant effect of RA (p > 0.05). Conclusions: These findings demonstrate that rosmarinic acid induces both endothelium-dependent and endothelium-independent vasorelaxation in the rat thoracic aorta through activation of the PI3K/Akt/eNOS/NO/cGMP pathway, opening of BK_Ca, IK_Ca, and Kv potassium channels, and suppression of Ca²⁺ mobilization. Additionally, inhibition of PKC- and angiotensin II-mediated vascular contraction contributes to RA-induced vasorelaxation. RA may therefore have therapeutic potential in the management of hypertension. Full article

Background: β3 adrenergic receptors (β3-ARs) have recently gained scientific attention due to their widespread body expression and their heterogeneous span of tissue-related functions. Recent research has hypothesized their involvement in the pathogenesis of some of the most common complications in preterm infants. The aim of the present systematic review is to examine the published scientific literature on the topic. Methods: PubMED/Medline and Cochrane databases were searched for studies reporting an association between β3-ARs, fetal development, and preterm newborns’ diseases. Results: Of 1596 articles found, 16 studies were selected for the review. Data currently available in the literature show that β3-ARs are upregulated in a hypoxic environment in several tissues and that their activation triggers a downstream cascade that promotes pro-angiogenic, anti-inflammatory, and immunoregulating effects, as well as metabolic adaptative processes and chemoresistance to xenobiotics. These characteristics seem to be central in the development of the fetus. Conclusions: Available preclinical data suggest the possible role of β3-ARs in the pathogenesis of a large number of premature newborn pathologies. Since fetal growth takes place in a low oxygenated environment, preterm delivery exposes newborns to a relatively hyperoxic setting while their development is not fully completed. Given the β3-ARs upregulation in a hypoxic environment, premature exposure to higher oxygen concentration levels affects their expression and their activity, probably derailing fetal normal development and injuring several organs. β3-ARs might therefore represent a central element in the pathogenesis of some of the main pathologies that preterm babies often develop. Full article

Osteoporosis is a multifactorial disease, the pathogenesis of which is caused by a complex interaction of genetic, hormonal, and metabolic factors. The challenges of early diagnosis highlight the need to identify genetic predictors to prevent bone mineral density (BMD) loss. Given the critical role of G-protein-coupled receptors (GPCRs) in bone development and remodeling, we investigated osteoporosis-associated single-nucleotide polymorphisms (SNPs) within GPCR genes using next-generation sequencing of patient cohorts. Subsequent screening via Sanger sequencing identified three SNPs for further analysis: rs1991517 in the thyroid-stimulating hormone receptor gene (TSHR), rs6166 in the follicle-stimulating hormone receptor gene (FSHR), and rs1042713 in the β2-adrenergic receptor gene (ADRB2). Our results reveal a significant association between osteoporosis and a specific homozygous genotype combination (TSHR rs1991517 CC, FSHR rs6166 AA, and ADRB2 rs1042713 AA). The functional impairment in osteodifferentiation was further validated in patient-derived cell lines harboring this triple-SNP combination. Thus, this study is the first to identify a specific combination of GPCR gene polymorphisms that may serve as a predictive biomarker for osteoporosis in early genetic screening. Full article

We investigated whether the functional involvement of α1-adrenergic receptors (α1-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the α1-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three α1-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of α1-AR did not affect the density of other types of adrenergic receptors, α2- and β-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective knockout of the gene encoding a single α1-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus (HY). Next, we assessed how a specific mutation affects the chronic effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of genes encoding for α1-AR subtypes, gene expression profiling, and phosphorylation of selected signaling proteins (ERK1/2, Akt, GSK3β). The main finding is that the deletion of the α1D subtype predominantly reduced the chronic effects of milnacipran at the examined transcriptomic and proteomic levels. The pattern of changes differed by gender. Our study revealed the functional diversity between α1-AR subtypes in the molecular mechanisms of antidepressants’ drug action. Full article

Propranolol is a non-selective β-adrenergic receptor antagonist widely used in cardiovascular and neurological therapy. Its naphthalene-based structure contributes to its high lipophilicityand central nervous system penetration. Clinically, propranolol is indicated for hypertension, arrhythmias, anxiety, migraine, and other conditions. It undergoes extensive hepatic metabolism via cytochrome P450 enzymes, notably CYP2D6, with a significant first-pass effect limiting oral bioavailability. This review integrates pharmacological profiling with crystallographic analysis to explore propranolol’s molecular interactions and therapeutic versatility. High-resolution crystal structures of the human β₂-adrenergic receptor (hβ₂-AR), particularly PDB ID: 6PS5 obtained via serial femtosecond crystallography (SFX), reveal key binding determinants responsible for receptor affinity and antagonism. Comparative structural analysis with other β-blockers—alprenolol, timolol, and carvedilol—highlights how variations in aromatic and heterocyclic frameworks influence pharmacokinetics and receptor selectivity. Superimposition results (RMSD: 0.032 for propranolol–alprenolol, 0.078 for propranolol–carvedilol, and 1.078 for propranolol–timolol) quantitatively illustrate molecular similarity and divergence. The enantioselective behavior of propranolol is also discussed, with the S-enantiomer showing greater receptor affinity and pharmacological potency than the R-form. Beyond canonical β-adrenergic targets, propranolol interacts with non-canonical proteins such as the cellulase enzyme Cel7A and lactoferrin, suggesting off-target effects and novel therapeutic potential. These findings underscore the importance of propranolol’s amphiphilic character, stereochemistry, and electrostatic properties in shaping its pharmacological profile. Overall, the integration of crystallographic data with pharmacological insights supports the rational design of next-generation β-adrenergic ligands with enhanced selectivity, bioavailability, and clinical efficacy. Full article

Background and Objectives: Erlotinib, a tyrosine kinase inhibitor (TKI), is an established therapy for patients with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Preclinical and clinical evidence suggests that chronic stress, mediated through β-adrenergic signaling, promotes tumor progression, angiogenesis, and therapy resistance. Furthermore, interactions between β-adrenergic signaling and EGFR pathways have been hypothesized to negatively influence treatment responses. Based on this rationale, we investigated whether concomitant beta-blocker use may improve survival outcomes in EGFR-mutant NSCLC patients treated with erlotinib. Materials and Methods: This retrospective analysis included 103 patients with metastatic EGFR-mutant NSCLC who received erlotinib. Patients were classified according to concurrent beta-blocker use, defined as continuous therapy for at least six months prior to erlotinib initiation, prescribed for cardiovascular indications. Progression-free survival (PFS) and overall survival (OS) were compared between beta-blocker users and non-users. Results: Patients receiving erlotinib with concomitant beta-blocker therapy achieved a median PFS (mPFS) of 21.4 months (95% CI, 13.1–29.7), compared with 9.7 months (95% CI, 6.7–12.7) in non-users (p = 0.003). Median OS (mOS) was 32.4 months (95% CI, 14.8–50.0) in the beta-blocker group versus 19.9 months (95% CI, 14.8–25.0) in the non-beta-blocker group (p = 0.010). Multivariate Cox regression confirmed beta-blocker use as an independent prognostic factor for both PFS (p = 0.004) and OS (p = 0.014). Conclusions: Concomitant beta-blocker use was associated with significantly prolonged survival in patients with EGFR-mutant metastatic NSCLC receiving erlotinib. These findings support the hypothesis that β-adrenergic inhibition enhances the efficacy of EGFR-targeted therapy. Prospective studies are warranted to validate these results and to further elucidate the underlying biological mechanisms. Full article

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over time poses an ongoing clinical challenge. These limitations highlight the need for alternative or complementary pharmacologic strategies. One such approach involves stimulating thermogenesis, particularly through the activation of brown and beige adipose tissue. This narrative review focuses on β3 adrenergic receptors as key mediators of browning and thermogenic energy expenditure. We review preclinical and clinical data, address pharmacokinetic and delivery challenges, and assess the translational potential of targeting thermogenesis in the management of obesity. Future directions are proposed to guide the development of safe and effective therapies that utilize this underexplored pharmacologic pathway. Full article