Search Results (139)

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with known metabolic or anti-inflammatory effects. However, their direct roles in adipocyte browning and the mechanisms via β3-adrenergic receptor (β3-AR) signaling are not well defined, and this study addresses this gap. Methods: To evaluate browning potential, 3T3-L1 adipocytes were treated with catalpol and rhoifolin during differentiation. The expression of browning markers and lipid metabolism or catabolism transcription factors was analyzed using Western blotting and quantitative real-time polymerase chain reaction. The involvement of the β3-AR and adenosine monophosphate–activated protein kinase (AMPK) signaling pathways was further validated using specific agonists and antagonists. Results: Both compound treatments significantly upregulated beige-specific (Cd137, Cited, Tbx1, Cidea, Fgf21, Tmem26) and mitochondrial biogenesis markers (Cox4, Nrf1, Tfam), accompanied by a marked increase in thermogenic markers (UCP1, PGC-1α, Prdm16). Concurrently, lipolysis-related genes such as Atgl, Hsl, and Plin1 were elevated, while lipogenesis targets (Fasn, Lpl, Srebf1, Acaca) were downregulated through activation of the β3-AR signaling pathway. Conclusions: These findings suggest that catalpol and rhoifolin, key phytochemicals of YST, promote WAT browning and lipolysis. Our findings indicate that these compounds induce browning and modulate metabolism via the β3-AR pathway. These results serve as a cornerstone for natural anti-obesity therapy, pending further validation in vivo and clinical studies. Full article

Iron deficiency (ID) is frequent in patients with heart failure (HF) and is correlated with adverse outcomes, yet its involvement in HF pathophysiology is not fully understood. Hyperactivity of the sympathetic nervous system (SNS) is the central feature of HF. We aimed to compare the effects of isoproterenol (ISO), a β-adrenergic agonist (SNS stimulation), with those of the iron chelator deferoxamine (DEF), to evaluate how β-adrenergic stimulation influences cardiac iron. In this study, H9c2 cardiac cells were challenged with ISO, DEF or both and several parameters related to iron metabolism were analyzed. In all cases, the cells decreased their intracellular iron levels. ISO induced alterations in key cardiac iron metabolism molecules that were, in most cases, comparable to those elicited by DEF, emphasizing the direct impact of β-adrenergic stimuli on iron metabolism and mitochondrial dysfunction. Nevertheless, unlike DEF, ISO triggered a shift in mitochondrial energy metabolism. These findings suggest that β-adrenergic stimulation, as a major component of neurohormonal activation, may contribute to the development of ID in cardiac cells, highlighting the importance of iron homeostasis and the need to further investigate iron dysregulation in this context. Full article

Autoantibodies (AAbs) play an important role in the development of autoimmune diseases. While many AAbs induce apoptosis of target cells, a distinct subgroup, termed functional autoantibodies (fAAbs) against G protein–coupled receptors (GPCRs), can modulate physiological receptor signaling without inducing cell death. The functional activity of GPCR-fAAbs may be influenced by various cofactors, including inflammation (e.g., inflammatory cytokine, ciliary neurotrophic factor (CNTF)) and ischemia. As ischemia triggers a substantial release of arachidonic acid (AA) from membrane phospholipids, the present study aimed to examine exploratively the influence of AA, eicosapentaenoic acid (EPA), and CNTF on the responses of spontaneously beating neonatal rat cardiomyocytes to GPCR agonists and GPCR-fAAbs. AA and EPA differentially influenced responses in cardiomyocytes induced by GPCR-fAAbs: AA altered the functional responses associated with adrenergic β₂-fAAb, adrenergic α₁-fAAb, angiotensin II (AT1)-fAAb, endothelin A (ETA)-fAAb and angiotensin 1–7 MAS-fAAbs. However, muscarinergic M₂-fAAb responses remained largely unaffected. In contrast, EPA attenuated the responses to β₂-fAAb, α₁-fAAb, AT1-fAAb, and ETA-fAAb, while MAS-fAAb and M₂-fAAb responses were not markedly altered. CNTF acted as a time-dependent modulator of cardiomyocyte chronotropic responses and influenced the magnitude of GPCR-mediated signaling on a cardiomyocyte bioassay. Together, these findings might suggest that lipid mediators such as AA and EPA or CNTF may modulate functional responses of cardiomyocytes associated with GPCR-fAAbs. Full article

Background/Objectives: Repurposed cAMP-elevating agents may personalize fluoropyrimidine therapy by exploiting pathway-specific vulnerabilities. Methods: We tested the PDE3 inhibitor milrinone and the β2-agonist terbutaline alone or combined with 10 μM 5-fluorouracil (5-FU) in UM-UC-5 (bladder), A549 (lung), and PC-3 (prostate) cells. Viability, migration, clonogenicity, and intracellular ROS (DCFDA) were measured; drug interactions used Chou–Talalay/CompuSyn. Results: In UM-UC-5, both agents reduced viability, migration, and clonogenicity and synergized with 5-FU (CI < 1 across Fa ≈ 0.42–0.57). 5-FU increased ROS, whereas terbutaline consistently lowered ROS below baseline and blunted 5-FU-induced oxidative signals; milrinone showed a dose-dependent redox profile without consistent ROS suppression. A549 combinations did not outperform 5-FU; PC-3 was largely unresponsive. Conclusions: cAMP modulators selectively potentiate 5-FU in bladder cancer cells and modulate redox programs (notably with terbutaline), supporting a biomarker-guided combination strategy (e.g., β2-AR/PDE3/PI3K–Akt features) for personalized therapy in bladder cancer; mechanistic and in vivo validation are warranted. Full article

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states. Full article

Background/Objectives: Cardiotoxicity remains a leading cause of drug withdrawal. Conventional preclinical models, such as two-dimensional (2D) cell cultures and animal studies, often fail to accurately predict human cardiac responses. While 2D cultures lack the complex architecture and dynamic functionality of native myocardium, interspecies differences limit the translational relevance of animal models. The objective of this study was to develop a human-relevant, in vitro platform that enables predictive and functional assessment of drug-induced cardiotoxicity. Methods: Here, we present a high-throughput in vitro platform for cardiotoxicity screening using three-dimensional (3D) cardiac tissues derived from human induced pluripotent stem cells (hiPSCs) within a thermoresponsive extracellular matrix-derived hydrogel. The hydrogel enables homogeneous encapsulation, differentiation in 3D, and long-term assembly into a functional cardiac tissue. Maturation was validated by immunostaining for cardiac-specific markers, and calcium imaging was employed to monitor electrical signal propagation. Contractile performance, defined by beat rate and contraction amplitude, was quantified using video-based motion analysis. The platform was applied to evaluate the dose-dependent effects of various cardioactive compounds, including β-adrenergic agonists ((-) epinephrine and dopamine), a cardiotoxic chemotherapeutic (doxorubicin), a sinus node inhibitor (ivabradine), a calcium channel blocker (verapamil), and a β-adrenergic antagonist (metoprolol). Results: The engineered cardiac tissues exhibited functional maturation and stable contractile behavior. Drug testing demonstrated compound-specific, dose-dependent functional responses. For each compound, the system faithfully reproduced the expected physiological responses. Conclusions: This human-relevant, scalable platform enables sensitive, multiparametric functional assessment of cardiac tissues, offering a cost-effective and predictive tool for preclinical drug safety testing. By bridging the gap between in vitro assays and human physiology, it holds promise to enhance translational accuracy while reducing reliance on animal models. 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: Fixed-dose combination medications (FDCs) are recognized methods of increasing adherence to polytherapy in chronic diseases. However, the role of FDCs in patients with benign prostatic hyperplasia (BPH) associated with lower urinary tract symptoms (LUTS) remains uncertain. We designed this study to assess persistence, adherence, and patient satisfaction with FDCs recently introduced to the Polish pharmaceutical market, which contain tamsulosin (an α1-adrenergic receptor antagonist) in combination with solifenacin (a muscarinic receptor antagonist) or dutasteride (a 5-α reductase inhibitor). Methods: The analysis included 50,435 men (67.8 ± 8.8 years old) managed by urologists for BPH-associated LUTS, who had been on combination therapies for at least 3 months. Two study visits, with an interval of 2.1 ± 1.4 months, were conducted between February and December 2024. Results: Single-component drugs (83.1%) were more common forms of therapy compared to FDCs (16.9%). ARAs (α1-adrenergic receptor antagonists) with 5-α reductase inhibitors comprised 70.2%, while ARAs with muscarinic receptor antagonists or β3-adrenergic agonists comprised 29.5%. Persistence with therapy across two visits was 82.0% for single-component drugs and 93.6% for FDCs (p < 0.001); OR = 1.31 (95% CI: 1.02–1.63). Similarly, adherence was better in patients treated with FDCs (96.6% vs. 91.0% at visit 1, p < 0.001; 99.3% vs. 97.9% at visit 2, p < 0.05). Patients prescribed FDCs were satisfied with therapy more often than those prescribed single-component drugs (62.6% and 76.8% vs. 50.6% and 67.5% at visits 1 and 2, respectively; p < 0.001). Conclusions: 1. Combination therapies are still more commonly administered as separate tablets than FDCs in patients with BPH-associated LUTS. 2. The use of FDCs increases short-term satisfaction and persistence with therapy, with a mild effect on adherence. Full article

Metabolic syndrome (MetS) is a worldwide problem affecting at least one-third of the population. MetS patients have increased cardiovascular risk associated with an abnormal β-adrenergic response; however, it is not clear how MetS affects the cardiac β-adrenergic system. We analyzed cardiac function and the β-adrenergic response in an experimental model of MetS in rats by recording pressure–volume (PV) loops via an open-chest approach and performed a biochemical characterization of the cardiac β-adrenergic system through ELISA, radioligand binding assays, and Western blotting. Microscopy was employed to evaluate cardiac hypertrophy, fibrosis, and ultrastructure. MetS rats exhibited cardiac dysfunction, evidenced by a reduced cardiac output and ejection fraction, not explained by heart hypertrophy or fibrosis. MetS rats also had an elevated susceptibility to lethal arrhythmia following intra-cardiac administration of the non-selective β-adrenergic agonist isoproterenol, suggesting alterations in the β-adrenergic system. The total serum adrenaline and noradrenaline levels were higher in the MetS animals than those in the control group. The radioligand binding assays indicated no change in the βAR density; however, the Western blot analyses revealed decreased levels of Gα_s proteins and β-arrestin 1, but increased β₂AR and Gα_i protein levels. This study contributes to our understanding of how MetS can alter cardiac function, raising the risk of lethal arrhythmia induced by the β-adrenergic (fight or flight) response and underscores the relevance of therapeutically targeting MetS before its pathological progression toward cardiomyopathy. Full article

Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as positive inotropic agents but have shown potential anticancer effects. This review explores their mechanisms of action in cancer, focusing on their roles in modulating cyclic adenosine monophosphate (cAMP) levels, oxidative stress, and the tumor microenvironment. Terbutaline influences β2-adrenergic signaling, impacting cell proliferation, angiogenesis, and immune evasion. Milrinone, through PDE3 inhibition, elevates cAMP, promoting apoptosis and reducing tumor growth. Both agents exhibit anti-inflammatory and anti-angiogenic properties, suggesting their potential as adjuvant therapies in oncology. Despite promising preclinical data, clinical validation is required to confirm their efficacy and safety in cancer patients. This review highlights the therapeutic promise of repurposing Terbutaline and Milrinone, emphasizing the need for further research to optimize their application in cancer therapy. Full article

High-mobility group box 1 (HMGB1) is a nuclear protein that can be secreted or released into the extracellular environment during cellular stress, functioning as a damage-associated molecular pattern molecule. This study investigates the role of HMGB1 in adipocyte development and metabolism, explicitly examining its interaction with β3-adrenergic receptor-mediated lipolysis and caveolin-1 (CAV1) regulation, which may influence cardiovascular risk factors. Using 3T3-L1 preadipocytes and mouse embryonic fibroblasts, we demonstrated that HMGB1 expression increases progressively during adipogenesis, reaching peak levels in mature adipocytes. While exogenous HMGB1 treatment did not affect preadipocyte proliferation or differentiation, it inhibited lipolysis in mature adipocytes. Mechanistically, HMGB1 suppressed β3-adrenergic receptor agonist CL-316,243-induced hormone-sensitive lipase activation by reducing protein kinase A-mediated phosphorylation and attenuating extracellular signal-regulated kinase signaling without affecting upstream cyclic AMP levels. We discovered a novel regulatory mechanism wherein CAV1 physically interacts with HMGB1 in mature adipocytes, with c-Src-dependent CAV1 phosphorylation functioning as a negative regulator of HMGB1 secretion. This finding was confirmed in CAV1-deficient models, which displayed increased HMGB1 secretion and diminished lipolytic activity both in vitro and in vivo. Furthermore, administering HMGB1-neutralizing antibodies to wild-type mice enhanced fasting-induced lipolysis, establishing circulating HMGB1 as a crucial antilipolytic factor. These findings reveal HMGB1’s previously uncharacterized role in adipose tissue metabolism as a negative regulator of lipolysis through CAV1-dependent mechanisms. This work provides new insights into adipose tissue metabolism regulation and identifies potential therapeutic targets for obesity-related metabolic disorders and cardiovascular diseases. Full article

Background: Japanese guidelines recommend the addition of a long-acting muscarinic antagonist for patients with asthma uncontrolled on inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy, the effectiveness of which is evaluated here. Methods: Retrospective, observational, single-arm cohort study in patients with asthma initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) following ICS/LABA, using independently analyzed data from Japanese claims databases: JMDC and Medical Data Vision (MDV). The index date was that of the first FF/UMEC/VI prescription. Outcomes were assessed during a 12-month follow-up versus a 12-month pre-index period (baseline) and included asthma exacerbations, oral corticosteroid (OCS) use, and short-acting β₂-agonist (SABA) use. P-values associated with rate ratios (RRs) were estimated using Conditional Poisson regression. Results: Overall, 3229 patients in the JMDC database and 1135 in the MDV database were included. Following FF/UMEC/VI initiation, the total annualized moderate–severe asthma exacerbation rate in the JMDC database reduced from 0.50 to 0.40 per-person-per-year (PPPY) (RR [95% confidence interval]: 0.78 [0.73, 0.84]; p < 0.001), with similar reductions in the MDV database: 0.53 to 0.42 PPPY (0.79 [0.70, 0.89]; p < 0.001). In both databases, there was a 20% reduction (JMDC: 0.80 [0.73, 0.88]; p < 0.001; MDV: 0.80 [0.68, 0.94]; p = 0.005) in patients with ≥1 OCS prescription after FF/UMEC/VI initiation. The proportion of patients with ≥1 SABA canister prescription dropped by 31% 0.69 [0.57, 0.84]; p < 0.001) in the JMDC database and 23% (0.77 [0.66, 0.90]; p < 0.001) in the MDV database. Conclusions: This suggests FF/UMEC/VI is effective in improving asthma exacerbations and reducing OCS and SABA use in Japanese patients previously using ICS/LABA in real-world clinical practice. Full article

The beta-3 adrenergic receptor (β3-AR), whose expression is modulated by oxygen levels, was found to play a key role in organ maturation, and its agonism was reported to mitigate hyperoxia-induced large bowel damage by preventing organ hypoplasia, preserving epithelial integrity, vascularization, and the neurochemical coding in the colonic myenteric plexus. This study explored the effects of β3-AR agonism in preventing hyperoxia-related alterations on the ileal enteric nervous system (ENS). Sprague–Dawley rat pups were reared under normoxia or hyperoxia (85%) during the first two weeks after birth and treated or not with the β3-AR agonist BRL37344 at 1, 3, or 6 mg/kg. Hyperoxia caused an imbalance of inhibitory nitrergic and excitatory cholinergic neurons in both the myenteric and submucosal plexuses and decreased the amounts of neurons in the submucosal plexus and that of S100β⁺ and GFAP⁺ glial cells in the myenteric plexus. Administration of 3 mg/kg BRL37344 preserved the neuronal chemical coding and partially prevented the loss of myenteric GFAP⁺ glial cells, while it did not counteract submucosal neuronal loss. Our findings indicate the potential of β3-AR agonism as a new therapeutic strategy for hyperoxia-induced ileal ENS alterations. Full article

Background: Higenamine, a bioactive alkaloid derived from plants such as Aconitum and Annona squamosa, has been traditionally used in Chinese medicine for treating heart diseases like bradycardia, arrhythmia, and heart failure. It exhibits multiple pharmacological effects, including anti-oxidative stress, improved cellular energy metabolism, anti-apoptosis, and enhanced erectile dysfunction. Aim and Methods: To investigate the reasons for these functions of higenamine and its application in the clinic, the literature of the database was searched and read in this study. Results: As a non-selective β-agonist, higenamine activates both β₁- and β₂-adrenergic receptors, leading to cardiovascular benefits such as increased heart rate and myocardial contractility, as well as bronchodilation. It has also been studied for its potential in weight loss, anti-inflammatory properties, and antioxidant properties, with applications in treating asthma, cardiovascular diseases, and ischemia-reperfusion injuries. However, its clinical use is limited by the need for further research on its long-term safety, pharmacokinetics, and interactions with other drugs. Despite its promising therapeutic potential, higenamine’s inclusion in the World Anti-Doping Agency’s banned list highlights concerns over its stimulant effects and safety in athletic contexts. Conclusions: Future studies should focus on optimizing its clinical applications while ensuring safety and efficacy. In terms of clinical applications, future research will also be able to explore more possibilities to use higenamine more in the treatment of diseases. Full article

Background: Myocardial injury (MI) is characterized by an increased level of at least one cardiac troponin. Experimental MI can be induced by isoprenaline, a β-adrenergic agonist, and it can lead to heart failure (HF). Liraglutide is glucagon-like 1 peptide receptor agonist used in diabetes management, but it has anti-inflammatory and antioxidative effects, which can be beneficial in treatment of HF. The aim of this study was to investigate the effects of liraglutide on isoprenaline-induced MI and prevention of HF. Methods: Male Wistar albino rats were divided into four groups: Con—received saline the first 2 days + saline the next 7 days; Iso—isoprenaline the first 2 days + saline the next 7 days; Lir—saline the first 2 days + liraglutide the next 7 days; Iso + Lir—isoprenaline the first 2 days + liraglutide the next 7 days. On day 10, blood samples were taken for biochemical analysis and oxidative stress marker evaluation, and hearts were isolated for pathohistological analysis. Cardiac function was assessed by electrocardiography (ECG) and echocardiography (ECHO). Results: Liraglutide treatment significantly attenuated oxidative stress, repaired ECG and ECHO parameters, and mitigated myocardial morphological changes induced by isoprenaline. Conclusions: Liraglutide restores cardiac function in isoprenaline-induced HF. Full article