Search Results (219)

Alpha-1 adrenergic receptor antagonists are widely used in the management of lower urinary tract symptoms, where they can induce ejaculatory dysfunction as a pharmacodynamic effect, particularly with α1A-selective agents. This observation has led to growing interest in their potential role as non-hormonal male contraceptives. This narrative review evaluates current clinical and preclinical evidence regarding the impact of α-blockers on the ejaculatory mechanism, with a focus on their potential application in male contraception. Both human and animal data were examined to contextualize the mechanistic basis for contraceptive potential. Evidence from clinical and pharmacological studies indicates that inhibition of α1-adrenoceptor-mediated smooth-muscle contraction in tissues involved in seminal emission, including the vas deferens, seminal vesicles, and prostate, can impair the emission phase of ejaculation. Agents such as tamsulosin and silodosin have been reported to induce anejaculation or markedly reduce semen volume, providing pharmacodynamic evidence of impaired seminal emission; however, these effects should not be considered equivalent to demonstrated contraceptive efficacy. Prospective clinical evidence currently includes one prospective pilot study and one randomized placebo-controlled clinical trial evaluating silodosin as a potential reversible non-hormonal male contraceptive. The prospective evidence includes marked and progressive suppression of sperm output and semen volume with repeated silodosin administration; at week 12, 94% of participants achieved a total sperm count ≤ 1 × 10⁶ per ejaculate, while the observed pregnancy incidence was 4% versus 17% with placebo. However, the available evidence remains insufficient to establish reliable contraceptive effectiveness for individual sexual exposures. Safety considerations, including cardiovascular effects and sexual dysfunction, also remain insufficiently characterized in healthy men. α1-adrenoceptor antagonists represent a biologically plausible pharmacologic strategy for male non-hormonal contraception by interfering with seminal emission and sperm delivery without directly suppressing spermatogenesis. Further pharmacokinetic–pharmacodynamic studies and rigorously designed multicentre clinical trials are required to determine the optimal dosing strategy, completeness and consistency of seminal emission suppression, contraceptive effectiveness, safety, acceptability, and reversibility of this approach. Full article

Hedera helix L. leaf extracts are regulated expectorants for productive cough, yet their evidence is dispersed across pharmaceutical quality, nonclinical pharmacology, disposition, toxicology, clinical pharmacology, efficacy, safety, and regulatory assessment. This review integrates those domains in a single study-level account and explicitly distinguishes isolated constituents, incompletely specified extracts, defined monograph preparations, proprietary extracts, and combination products. Hederacoside C is the pharmacopoeial marker, while α-hederin is the constituent most extensively examined in β2-adrenergic receptor models. Cell studies documented reduced agonist-induced receptor internalisation, greater ligand binding and cAMP responsiveness, and altered GRK2/β-arrestin signalling. Isolated tissue and animal studies reported antispasmodic, anti-inflammatory, antitussive, and tracheobronchial secretory effects. Rat studies showed low, matrix-dependent oral exposure to hederacoside C and α-hederin. Small exploratory human studies detected no or only trace α-hederin and did not permit conventional pharmacokinetic analysis. Clinical evidence includes placebo-controlled adult trials, active comparator studies, paediatric investigations, postmarketing cohorts, systematic reviews, and pharmacovigilance reports. Controlled adult trials of EA 575 reported greater short-term improvement in cough or Bronchitis Severity Score than placebo; paediatric efficacy evidence is dominated by observational studies and small airway function trials. Short-term tolerability was generally favourable, with gastrointestinal and hypersensitivity reactions as the principal recognised adverse effects. The European Union monograph recognises specified extracts for productive cough, contraindicates use below two years, and does not recommend use during pregnancy or lactation. The distinctive contribution of this review is the complete quality-to-clinic evidence map, including dose, model, endpoint, study design, extract identity, and unresolved evidence domain for each major dataset. Full article

Background: Norepinephrine is commonly used during acute burn resuscitation to maintain adequate perfusion pressure. However, its effects, together with the burn-induced catecholamine surge, on arterial α₁-adrenergic receptors (α₁-AR) remain unclear. This study examined whether burn injury and continuous norepinephrine infusion alter arterial α₁-AR subtype expression at the transcriptional and protein levels. Methods: Sprague–Dawley rats were randomized to full-thickness scald burn involving 25% total body surface area with continuous intravenous norepinephrine or sodium chloride (NaCl) infusion, sham injury with norepinephrine infusion, or untreated controls. Mean arterial pressure (MAP) was measured at baseline and before euthanasia (six or 24 h). Aorta, carotid, and renal arteries were collected for analysis of α₁-AR subtypes (Adra1a, Adra1b, and Adra1d) using quantitative PCR (qPCR) and immunohistochemistry (IHC). Results: Norepinephrine efficiently increased MAP in sham animals. In burned animals with norepinephrine, MAP increased at six hours (+10.6 mmHg) but fell below baseline at 24 h (−6.4 mmHg). Burned animals given NaCl had persistently lower MAP than those given norepinephrine, at six hours (−19.1 mmHg) and 24 h (−21.1 mmHg). qPCR demonstrated significant downregulation of Adra1b in the renal artery across all groups compared to control (7.8–16.4-fold, p < 0.001). Overall, changes in protein expression across different vascular beds and receptor subtypes were inconsistent. Conclusions: Norepinephrine increased MAP in both sham and burned animals, confirming the drug’s efficacy. Burn injury and sustained norepinephrine exposure were associated with early, vessel-specific alterations in α₁-AR mRNA expression. The absence of consistent protein-level changes within 24 h suggests a delay in receptor expression on protein level. Full article

This case–control study investigated the association between β-adrenergic receptors, ADRB1 rs1801252 (A-to-G/Ser49Gly) and ADRB2 rs1042714 (C-to-G/Gln27Glu), polymorphisms and primary open-angle glaucoma (POAG) in a Saudi cohort. Genotyping of 418 participants (167 cases and 251 controls) was performed using real-time PCR assays. Analysis was performed among 412 participants with complete genotype data for both SNPs (163 cases and 249 controls). The ADRB1 rs1801252-G (Gly49) allele was significantly associated with increased POAG risk across allelic (adjusted odds ratio (OR) = 1.93; 95% confidence interval (CI) = 1.22–3.08; p = 0.005), dominant (adjusted OR = 2.13; 95% CI = 1.23–3.70; p = 0.007), and additive (adjusted OR per G allele = 1.93; 95% CI = 1.22–3.08; p = 0.005) models, surviving Bonferroni correction (α = 0.025). In contrast, ADRB2 rs1042714 showed no significant association under any model. Combined two-locus allelic analysis suggested a nominally increased risk for the C–G combined profile (ADRB2C + ADRB1G; OR = 1.91; p = 0.033). No significant genotype associations were observed with intraocular pressure or cup-to-disc ratio within the POAG cohort. These findings suggest that ADRB1 rs1801252 may contribute to POAG susceptibility in this population; replication in larger cohorts and targeted functional follow-up studies are warranted to elucidate pressure-independent mechanisms. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

Background: Melanoma incidence is rising rapidly worldwide and stands out due to its high lethality. Despite advances in clinical treatment and in understanding melanoma-sensitive genes and molecular pathogenesis, a specific area of ongoing research is the connection between stress-related β-adrenergic receptors (ARs), hypoxia, and neovascularization in melanoma tumor progression. This exploratory study aimed to investigate the expression of β3-AR, HIF-1α, and CD31 in several cellular subsets of atypical melanocytic lesions and their interplay in promoting melanoma malignancy. Methods: Twenty-seven patients with melanocytic lesions at different stages that were surgically removed were retrospectively selected; clinical-pathological and dermoscopic data were collected. Results: Immunohistochemical and digital evaluation revealed a significant upregulation of β3-AR in malignant melanoma melanocytes and in macrophages from invasive >pT1a melanomas compared to dysplastic nevi. Increased HIF-1α expression in malignant melanocytes and CD31 expression levels in >pT1a melanomas were observed. Ulcerated lesions exhibited a higher percentage of β3-AR, HIF-1α, and CD31 expression. Pearson correlation analysis revealed positive associations among these markers in human malignant melanoma, suggesting a potential relationship between adrenergic signaling, hypoxia, and tumor vascularization. Conclusions: These exploratory findings suggest that β3-AR, HIF-1α, and CD31 may represent interconnected components of the melanoma microenvironment. Unraveling these interactions in larger, independent cohorts and functional studies may provide additional insights into melanoma biology and help define their potential translational relevance. Full article

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

Endometriosis is a chronic, estrogen-dependent inflammatory disease including aberrant local steroidogenesis, inflammation, angiogenesis, oxidative stress, and prostaglandin-mediated pain. Given the elevated adrenergic receptor expression in endometriotic lesions and the potential of terazosin to downregulate Steroidogenic Factor-1 (SF-1), this study aimed to evaluate terazosin as a non-hormonal therapy in a surgically induced rat endometriosis model. Forty female Wistar rats were randomized to sham, untreated endometriosis, leuprolide acetate or terazosin; two postoperative deaths yielded final group sizes of 10/9/10/9. Blinded histopathology verified successful lesion establishment. ELISA quantified SF-1, IL-6, IL-8, TNF-α, NF-κB, VEGF, HIF-1α, and PGE2 in lesion tissue, serum, and peritoneal lavage; oxidative status was assessed by TAS, TOS, and OSI. Compared with untreated endometriosis, terazosin significantly reduced SF-1, PGE2, IL-6, IL-8, TNF-α, VEGF and HIF-1α across compartments (all p < 0.001), comparable to leuprolide (p = 1.000). Terazosin also normalized oxidative stress by decreasing TOS/OSI and restoring TAS in tissue, serum, and peritoneal fluid (p < 0.001). NF-κB decreased in tissue and serum (p < 0.001) but not in peritoneal fluid (p = 0.206). Overall, terazosin produced leuprolide-like molecular benefits without hormonal suppression, supporting repurposing as a candidate non-hormonal therapy, while highlighting the need for longer-duration studies and randomized clinical trials given model and pain-assessment limitations. Full article

Hydrolyzed collagen (HC) derived from salmon skin is a promising source of bioactive peptides. In this study, the vasorelaxant effects and potential mechanisms of action of HC on isolated rat thoracic aorta rings were investigated using the organ bath technique. The vasorelaxant properties of HC were evaluated using aortic rings from Wistar rats pre-contracted with phenylephrine (PE) or potassium chloride (KCl). HC induced significant vasorelaxation in both endothelium-intact and endothelium-denuded rings, indicating that its mechanism of action was independent of the endothelium and involved direct effects on vascular smooth muscle cells. The vasorelaxant effect of HC was reduced when pre-contraction was induced by tetraethylammonium chloride (TEA). However, the vasodilatory effects of HC were not significantly inhibited by all K⁺ channel blockers, including glibenclamide, barium chloride (BaCl₂), or 4-aminopyridine (4-AP). Additionally, pre-incubation with prazosin, an α-adrenoceptor blocker, significantly reduced the vasorelaxation induced by HC, whereas propranolol, a β-adrenoceptor blocker, had no effect. In addition, HC inhibited CaCl₂-induced contractions induced by both PE and caffeine in a Ca²⁺-free solution. Therefore, HC exhibited the vasorelaxant effects through an endothelium-independent mechanism. The vasodilatory effects of HC were associated with the activation of K_Ca channels, suppression of PE-induced contraction via α₁-adrenergic receptor pathways, and inhibition of CaCl₂-induced contractions by modulating intracellular Ca²⁺ release and extracellular Ca²⁺ influx in vascular cells. Full article

Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose–response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α₂-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide—cyclic guanosine monophosphate (NO–cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed. Full article

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with blast TBI (bTBI) particularly affecting military personnel and individuals exposed to explosive environments, yet there are no available curative treatments to date. While adrenergic receptor antagonists have shown promise in reducing neuroinflammation and improving TBI mortality rates, systemic administration of these drugs can have deleterious effects including bradycardia and hypotension. Here, we introduce a polymeric nanoparticle system for the delivery of adrenergic receptor antagonists, which allows for size-based targeting of the injured blood–brain barrier (BBB). These nanoparticles consist of chitosan-coated polylactic co-glycolic acid encapsulating the β-adrenergic receptor antagonist propranolol and/or the α-adrenergic receptor antagonist phenoxybenzamine. Particles designed with a 200 nm hydrodynamic diameter showed a 20–24% increase in permeability on an in vitro contact co-culture BBB model exposed to a 23 or 35 PSI acoustic blast when compared to uninjured controls, whereas 100 nm particles show no difference, suggesting blast injury induces BBB damage that enables the accumulation of larger particles. Treatment of blast-injured human brain microvascular cells with our nanoformulation reduced extracellular inflammatory cytokine levels and reduced the expression of pro-inflammatory markers in microglia. Moreover, these particles mitigated the upregulation of extracellular TNFα induced by free phenoxybenzamine in injured and uninjured microglia, suggesting nanoparticle drug encapsulation can reduce adverse drug reactions in the brain. Together, these findings provide proof-of-concept for size-based targeting and the potential anti-inflammatory effects of CS-PLGA nanoparticles containing adrenergic receptor antagonists for treatment of TBI and bTBI. Full article

Objectives: Obesity remains a global health challenge, and promoting white adipose tissue browning has emerged as a promising anti-obesity strategy. This study aimed to investigate the anti-obesity effects of denatonium benzoate (DB) and elucidate its underlying mechanisms. Methods: In order to study the anti-obesity effects of DB and its mechanisms, we used in vivo and in vitro obesity models to study whether DB has anti-obesity effects by participating in fat browning. We investigated the role of DB in high-fat diet (HFD)-induced obese C57BL/6J mice using 36 male animals (8 weeks old, 25 ± 2 g), and evaluated the expression of the adipogenic marker genes Fatty acid-binding protein 4 (Fabp4) and Peroxisome Proliferator-Activated Receptor gamma (PPAR-γ); the thermogenic genes uncoupling protein 1 (Ucp1), Transcription Factor A, Mitochondrial (TFAM), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (Pgc1α), and Adrenergic receptor beta 3 (Adrb3); as well as the adipose browning marker genes Deiodinase, Iodothyronine, Type II (Dio2), PR domain containing 16 (PRDM16), and Peroxisome Proliferator-Activated Receptor alpha (PPAR-α) in 3T3-L1 cells and primary adipocytes with DB treatment. Conclusions: These results indicate that the anti-obesity effects of DB may be related to the browning of white fat, providing a novel potential candidate for anti-obesity drug development. Full article

Novel pharmacological approaches advocate developing multitarget drugs, that is, molecules capable of simultaneously acting on two or more pharmacological targets to produce synergistic effects from a single compound in each disease. This strategy may help reduce required doses and prevent drug–drug interactions typically associated with polypharmacy. Coumarins are natural products with diverse pharmacological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, cardioprotective, and antithrombotic effects. The pleiotropic actions of these molecules suggest that modifying the coumarin structure could yield new multi-target antiplatelet agents with greater efficacy and safety than those currently available in clinical practice. In this work, we began with a theoretical approach using molecular docking and designed three coumarins that simultaneously inhibited platelet aggregation induced by epinephrine, collagen, and ADP. Experimentally, we evaluated the structure activity relationship of three coumarins: (A) 6,7-dimethoxy-3-(1H-pyrrol-1-yl)-2H-chromen-2-one, (B) 7,8-dimethoxy-3-(1H-pyrrol-1-yl)-2H-chromen-2-one, and (C) 3-(1H-imidazol-1-yl)-6,7-dimethoxy-2H-chromen-2-one. In silico studies suggest that compounds B and C may exhibit antagonistic interactions at the α₂-adrenergic, GPVI collagen, and P₂Y₁₂ ADP receptors. Additionally, molecular docking indicates essential interactions between the compounds and the GPIIb/IIIa fibrinogen receptor. 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

Obesity is characterized by abnormal adipose tissue expansion and energy metabolism imbalance. Browning of white adipose tissue (WAT), wherein white adipocytes acquire thermogenic properties similar to brown adipose tissue, represents a key mechanism for increasing energy expenditure. Although ginseng (Panax ginseng C.A. Meyer) is widely recognized as a health-promoting botanical, its role in WAT browning has not been fully elucidated. This review summarizes evidence that ginseng and its bioactive components regulate major thermogenic pathways, including β-adrenergic/cyclic adenosine monophosphate-protein kinase (cAMP-PKA) signaling, AMP-activated protein kinase (AMPK), and the peroxisome proliferator-activated receptor γ (PPARγ)/coactivator 1α (PGC-1α) axis, thereby upregulating key markers such as uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and type II iodothyronine deiodinase (DIO2). These effects promote mitochondrial function and fatty acid oxidation, reduce lipogenesis, alleviate inflammation, and improve insulin sensitivity, collectively fostering a microenvironment conducive to browning. Furthermore, fermentation has been found to enhance the bioactivity and thermogenic efficacy of ginseng. Recent evidence indicates that gut microbiota and their metabolites—such as short-chain fatty acids, unsaturated fatty acids, and bile acids—play a notable role in ginseng-induced thermogenesis via receptors including G-protein-coupled receptor 41/43 (GPR41/43), takeda G-protein-coupled receptor 5 (TGR5), and farnesoid X receptor (FXR). These multi-organ interaction networks involving the gut–fat, gut–liver, and gut–brain axes reflect the role of ginseng in integrating systemic metabolism. In summary, this review discusses the multi-level regulatory network through which ginseng promotes WAT browning, providing a mechanistic basis for its potential application in body weight and metabolic health management. Full article