RESUMEN
Nicotine, the primary constituent of tobacco, is one of the important factors that induce the occurrence of hepatocellular carcinoma (HCC). The ß2-adrenergic receptor (ß2-AR) is implicated in the growth and advancement of tumors. However, the role of ß2-AR and its mediated cascades in nicotine-induced HCC remains unclear. This present study aims to observe the effects of nicotine on the proliferation, migration, and invasion of immortalized human liver epithelial (THLE-2) cells, as well as to explore the underlying mechanisms of action. The results of cell counting kit-8 (CCK-8) assay showed that 0.3125⯵M nicotine had the ability to promote the proliferation of THLE-2 cells with a significant time-dependent manner. Therefore, THLE-2 cells were mainly selected for chronic treatment with 0.3125⯵M nicotine in the later stage to cause transformation. After 30 passages of THLE-2 cells with 0.3125⯵M nicotine treatment, chronic exposure to nicotine significantly enhanced the proliferation, metastasis, and invasion of cells. Besides, it also upregulated the intracellular levels of ß2-AR, phosphoinositide 3-kinase (PI3K), AKT, matrix metalloproteinase-2 (MMP-2) and Cyclin D1, as well as downregulated the expression of p53. More importantly, the ß2-AR/PI3K/AKT pathway was found to mediate the expression of MMP-2, Cyclin D1, and p53 in THLE-2 cells, playing a crucial role in their proliferation, migration, and invasion after continuous exposure to nicotine. Simply put, it demonstrated the role of ß2-AR/PI3K/AKT pathway in the transformation of THLE-2 cells induced by nicotine. This study could provide valuable insights into the relationship between nicotine and HCC. Additionally, it lays the groundwork for investigating potential anticancer treatments for liver cancer linked to tobacco consumption.
Asunto(s)
Movimiento Celular , Proliferación Celular , Nicotina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Receptores Adrenérgicos beta 2 , Transducción de Señal , Nicotina/toxicidad , Nicotina/farmacología , Humanos , Proliferación Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Movimiento Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Línea Celular , Invasividad Neoplásica , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/inducido químicamente , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patologíaRESUMEN
Presynaptic α2-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α2A-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α2-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α2-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. ß2-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.
Asunto(s)
Receptores Adrenérgicos alfa 2 , Animales , Humanos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Receptores Presinapticos/efectos de los fármacos , Receptores Presinapticos/fisiología , Receptores Presinapticos/metabolismo , Transmisión Sináptica/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacosRESUMEN
Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment and so far no effective drug is available for treatment of the serious side effect. Previous studies have demonstrated ß2-adrenoreceptor (ADRB2) agonists can attenuate neuropathic pain. However, the role of ADRB2 in paclitaxel -induced neuropathic pain (PINP) remains unclear. In this study, we investigated the effect of formoterol, a long-acting ADRB2 agonist, and related mechanisms in PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to evaluate mechanical allodynia. Western blot was used to examine the expression of ADRB2, peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factors 1 (NRF1) and mitochondrial transcription factor A (TFAM) and the immunofluorescence was to detect the cellular localization of ADRB2 and PGC-1α in the spinal cord. Moreover, we measured mitochondrial DNA (mtDNA) copy number by qPCR. In our study, formoterol attenuated established PINP and delayed the onset of PINP. Formoterol restored ADRB2 expression as well as mtDNA copy number and PGC-1α, NRF1, and TFAM protein expression, which are major genes involved in mitochondrial biogenesis, in the spinal cord of PINP rats. Moreover, we found the analgesic effect of formoterol against PINP was partially abolished by PGC-1α inhibitor SR-18292. Collectively, these results demonstrated the activation of ADRB2 with formoterol ameliorates PINP at least partially through induction of mitochondrial biogenesis.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/farmacología , Analgésicos/farmacología , Fumarato de Formoterol/farmacología , Mitocondrias/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Biogénesis de Organelos , Umbral del Dolor/efectos de los fármacos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Modelos Animales de Enfermedad , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/fisiopatología , Paclitaxel , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Médula Espinal/metabolismo , Médula Espinal/fisiopatologíaRESUMEN
Moderate elevations of extracellular K+ concentration ([K+]o) occur during exercise and have been shown to potentiate force during contractions elicited with subtetanic frequencies. Here, we investigated whether lactic acid (reduced chloride conductance), ß2-adrenoceptor activation, and increased temperature would influence the potentiating effect of potassium in slow- and fast-twitch muscles. Isometric contractions were elicited by electrical stimulation at various frequencies in isolated rat soleus and extensor digitorum longus (EDL) muscles incubated at normal (4 mM) or elevated K+, in combination with salbutamol (5 µM), lactic acid (18.1 mM), 9-anthracene-carboxylic acid (9-AC; 25 µM), or increased temperature (30-35°C). Elevating [K+]o from 4 mM to 7 mM (soleus) and 10 mM (EDL) potentiated isometric twitch and subtetanic force while slightly reducing tetanic force. In EDL, salbutamol further augmented twitch force (+27 ± 3%, P < 0.001) and subtetanic force (+22 ± 4%, P < 0.001). In contrast, salbutamol reduced subtetanic force (-28 ± 6%, P < 0.001) in soleus muscles. Lactic acid and 9-AC had no significant effects on isometric force of muscles already exposed to moderate elevations of [K+]o. The potentiating effect of elevated [K+]o was still well maintained at 35°C. Addition of salbutamol exerts a further force-potentiating effect in fast-twitch but not in slow-twitch muscles already potentiated by moderately elevated [K+]o, whereas lactic acid, 9-AC, or increased temperature does not exert any further augmentation. However, the potentiating effect of elevated [K+]o was still maintained in the presence of these, thus emphasizing the positive influence of moderately elevated [K+]o for contractile performance during exercise.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/farmacología , Albuterol/farmacología , Ácido Láctico/farmacología , Contracción Muscular/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Potasio/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Temperatura , Animales , Antracenos/farmacología , Estimulación Eléctrica , Femenino , Técnicas In Vitro , Masculino , Músculo Esquelético/fisiología , Ratas Wistar , Receptores Adrenérgicos beta 2/metabolismoRESUMEN
ß2-adrenoceptor (ß2AR) agonists can stimulate skeletal muscle growth. Their illegal use in food-producing animals, human athletes and bodybuilders causes adverse health effects. In the present study, we developed 3D-QSAR models for predicting the activity of chemicals which can stimulate skeletal muscle growth through ß2AR. The activity of 25 ß2AR agonists was measured by ß2AR-cAMP response element (CRE) -luciferase (Luc) reporter assay. The 3D-QSAR models were built using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models displayed high external predictability (R2 0.996 and 0.992, respectively) and good statistical robustness, and revealed that electrostatic effects were the most prominent forces influencing the activity of ß2AR agonists. The CoMFA and CoMSIA contour plots provided clues regarding the main chemical features responsible for the activity variations and also resulted in predictions which correlate very well with the observed activity. In vitro study with differentiated myotubes showed that the potency orders of ß2AR agonists in activating the ß2AR-CRE-Luc reporter and in upregulating CREB target genes related to muscle growth were consistent. These 3D-QSAR models provide tools for predicting the activity of chemicals which might be illegally used in livestock or humans to stimulate skeletal muscle growth.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/farmacología , Modelos Moleculares , Desarrollo de Músculos/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Receptores Adrenérgicos beta 2/efectos de los fármacos , Animales , Células HEK293/efectos de los fármacos , Humanos , Ratones , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Rationale: Inhaled corticosteroids (ICS) are commonly prescribed with long-acting ß2-agonists (LABA) in chronic obstructive pulmonary disease (COPD). To date, the effects of ICS therapy on the airway microbiome in COPD are unknown. Objectives: To determine the effects of ICS/LABA on the airway microbiome of patients with COPD. Methods: Clinically stable patients with COPD were enrolled into a 4-week run-in period during which ICS was discontinued and all participants were placed on formoterol (Form) 12 µg twice daily (BID). The participants were then randomized to budesonide/formoterol (Bud + Form; 400/12 µg BID), fluticasone/salmeterol (Flu + Salm; 250/50 µg BID), or formoterol only (12 µg BID) for 12 weeks. Participants underwent bronchoscopy before and after the 12-week treatment period. The primary endpoint was the comparison of changes in the airway microbiome over the trial period between the ICS/LABA and LABA-only groups. Measurements and Main Results: Sixty-three participants underwent randomization: Bud + Form (n = 20), Flu + Salm (n = 22), and Form (n = 21) groups; 56 subjects completed all visits. After the treatment period, changes in α-diversity were significantly different across groups, especially between Flu + Salm and Form groups (Δrichness: P = 0.02; ΔShannon index: P = 0.03). Longitudinal differential abundance analyses revealed more pronounced microbial shifts from baseline in the fluticasone (vs. budesonide or formoterol only) group. Conclusions: Fluticasone-based ICS/LABA therapy modifies the airway microbiome in COPD, leading to a relative reduction in α-diversity and a greater number of bacterial taxa changes. These data may have implications in patients who develop pneumonia on ICS. Clinical trial registered with www.clinicaltrials.gov (NCT02833480).
Asunto(s)
Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Combinación de Medicamentos , Microbiota/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/uso terapéutico , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/ß2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the ß2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Artritis Experimental/prevención & control , Articulaciones/efectos de los fármacos , Fentolamina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Terbutalina/farmacología , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Experimental/patología , Combinación de Medicamentos , Adyuvante de Freund , Articulaciones/diagnóstico por imagen , Articulaciones/metabolismo , Articulaciones/patología , Masculino , Ratas Endogámicas Lew , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transducción de SeñalRESUMEN
Approximately 14% of the general population suffer from chronic kidney disease that can lead to acute kidney injury (AKI), a condition with up to 50% mortality for which there is no effective treatment. Hypertension, diabetes, and cardiovascular disease are the main comorbidities, and more than 660,000 Americans have kidney failure. ß2-Adrenergic receptors (ß2ARs) have been extensively studied in association with lung and cardiovascular disease, but with limited scope in kidney and renal diseases. ß2ARs are expressed in multiple parts of the kidney including proximal and distal convoluted tubules, glomeruli, and podocytes. Classical and noncanonical ß2AR signaling pathways interface with other intracellular mechanisms in the kidney to regulate important cellular functions including renal blood flow, electrolyte balance and salt handling, and tubular function that in turn exert control over critical physiology and pathology such as blood pressure and inflammatory responses. Nephroprotection through activation of ß2ARs has surfaced as a promising field of investigation; however, there is limited data on the pharmacology and potential side effects of renal ß2AR modulation. Here, we provide updates on some of the major areas of preclinical kidney research involving ß2AR signaling that have advanced to describe molecular pathways and identify potential drug targets some of which are currently under clinical development for the treatment of kidney-related diseases.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Enfermedades Renales/tratamiento farmacológico , Riñón/efectos de los fármacos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacos , Animales , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Receptores Adrenérgicos beta 2/metabolismo , Transducción de SeñalRESUMEN
The ß2-adrenergic receptor (ß2AR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly "non-deleterious" substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response. We are able to identify hydration sites in the transmembrane domain that are essential to maintain the integrity of the binding site but are absent in the variant. The loss of these hydration sites in the variant correlates with perturbations in the intra-protein interaction network and rearrangements in the orthosteric ligand binding site. In conjunction, we observe an altered binding and reduced free energy of a series of agonists, in line with experimental trends. Our work identifies a functional allosteric pathway connected by specific hydration sites in ß2AR that has not been reported before and provides insight into water-mediated networks in GPCRs in general. Overall, the work is one of the first step towards developing variant-specific potent and selective agonists.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Receptores Adrenérgicos beta 2/efectos de los fármacos , Agua/química , Humanos , Unión Proteica , Conformación Proteica , Receptores Adrenérgicos beta 2/químicaRESUMEN
Over the past decade, dexmedetomidine (DEX) has been found to possess an anti-inflammatory effect. However, the local anti-inflammatory mechanism of DEX has not been fully clarified. Some intracellular inflammatory pathways lead to negative feedback during the inflammatory process. The cyclooxygenase (COX) cascade synthesizes prostaglandins (PGs) and plays a key role in inflammation, but is known to also have anti-inflammatory properties through an alternative route of a PGD2 metabolite, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), and its receptor, peroxisome proliferator-activated receptor gamma (PPARγ). Therefore, we hypothesized that DEX inhibits LPS-induced inflammatory responses through 15d-PGJ2 and/or PPARγ activation, and evaluated the effects of DEX on these responses. The RAW264.7 mouse macrophage-like cells were pre-incubated with DEX, followed by the addition of LPS to induce inflammatory responses. Concentrations of TNFα, IL-6, PGE2, and 15d-PGJ2 in the supernatants of the cells were measured, and gene expressions of PPARγ and COX-2 were evaluated in the cells. Furthermore, we evaluated whether a selective α2 adrenoceptor antagonist, yohimbine or a selective PPARγ antagonist, T0070907, reversed the effects of DEX on the LPS-induced inflammatory responses. DEX inhibited LPS-induced TNFα, IL-6, and PGE2 productions and COX-2 mRNA expression, and the effects of DEX were reversed by yohimbine. On the other hand, DEX significantly increased 15d-PGJ2 production and PPARγ mRNA expression, and yohimbine reversed these DEX's effects. Furthermore, T0070907 reversed the anti-inflammatory effects of DEX on TNFα and IL-6 productions in the cells. These results suggest that DEX inhibits LPS-induced inflammatory responses through PPARγ activation following binding to α2 adrenoceptors.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Antiinflamatorios/farmacología , Dexmedetomidina/farmacología , Inflamación/prevención & control , Macrófagos/efectos de los fármacos , PPAR gamma/agonistas , Receptores Adrenérgicos beta 2/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/metabolismo , Animales , Antiinflamatorios/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dexmedetomidina/metabolismo , Dinoprostona/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/metabolismo , Macrófagos/patología , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo , Unión Proteica , Células RAW 264.7 , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Mitochondrial dysfunction is a well-characterized consequence of spinal cord injury (SCI). We previously reported that treatment with the FDA-approved ß2-adrenergic receptor agonist formoterol beginning 8 h post-SCI induces mitochondrial biogenesis (MB) and improves body composition and locomotor recovery in female mice. To determine the time-to-treatment window of formoterol, female mice were subjected to 80 kdyn contusion SCI and daily administration of vehicle or formoterol (0.3 mg/kg) beginning 24 h after injury. This delayed treatment paradigm improved body composition in female mice by 21 DPI, returning body weight to pre-surgery weight and restoring gastrocnemius mass to sham levels; however, there was no effect on locomotor recovery, as measured by the Basso-Mouse Scale (BMS), or lesion volume. To assess the cross-sex potential of formoterol, injured male mice were treated with vehicle or formoterol (0.3 or 1.0 mg/kg) beginning 8 h after SCI. Formoterol also improved body composition post-SCI in male mice, restoring body weight and muscle mass regardless of dose. Interestingly, however, improved BMS scores and decreased lesion volume was observed only in male mice treated with 0.3 mg/kg. Additionally, 0.3 mg/kg formoterol induced MB in the gastrocnemius and injured spinal cord, as evidenced by increased MB protein expression and mitochondrial number. These data indicate that formoterol treatment improves recovery post-SCI in both male and female mice in a dose- and initiation time-dependent manner. Furthermore, formoterol-induced functional recovery post-SCI is not directly associated with peripheral effects, such as muscle mass and body weight.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Fumarato de Formoterol/administración & dosificación , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Biogénesis de Organelos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Médula Espinal/efectos de los fármacos , Tiempo de Tratamiento , Animales , Composición Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Masculino , Ratones Endogámicos C57BL , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/ultraestructura , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Receptores Adrenérgicos beta 2/metabolismo , Recuperación de la Función , Factores Sexuales , Médula Espinal/metabolismo , Médula Espinal/ultraestructura , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Factores de TiempoRESUMEN
Beta-2 adrenergic receptors (ß2-ARs) have important roles in the pathogenesis and treatment of chronic obstructive pulmonary disease (COPD). In recent years, progress has been made in the study of ß2-ARs. Here, we introduce the basic concepts of ß2-ARs, related pathways, as well as application of blockers/agonists of ß2-ARs, and ß2-AR autoantibodies in COPD. Drugs targeting the ß2-AR are being developed rapidly, and we expect them to improve the symptoms and prognosis of COPD patients in the future.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Autoanticuerpos/inmunología , Desarrollo de Medicamentos , Humanos , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/inmunologíaRESUMEN
SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I-viral response, stage II-pulmonary phase, and stage III-hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , Receptores Adrenérgicos beta 2/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , COVID-19 , Síndrome de Liberación de Citoquinas/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pandemias , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2 , Células Th17/inmunologíaRESUMEN
Diabetes mellitus (DM) might increase the incidence and mortality of cardiac failure after acute myocardial infarction (AMI) in patients. We attempted to investigate whether Caveolin-3 showed beneficial effects in DM patient post-MI injury through the cAMP/PKA and BDNF/TrkB signaling pathways. The activity of ADRB2 and cAMP/PKA signaling were impaired in nondiabetic ischemia-reperfusion (I/R) group compared with the sham and DM groups and were more impaired in diabetic I/R group than in the I/R group. In H9C2 cells, high-glucose (HG) stimulation further enhanced H/R injury by promoting cell apoptosis, inhibiting cell viability, and suppressing TrkB and Akt signaling; in contrast, the ADRB2 agonist isoprenaline (ISO) significantly attenuated the above-described effects of HG stimulation. Caveolin-3 overexpression promoted the localization of ADRB2 on the membrane of the HG-stimulated H9C2 cells, subsequently inhibiting apoptosis and promoting cell viability. Under HG stimulation, Caveolin-3 overexpression enhanced the activity of the cAMP/PKA and BDNF/TrkB signaling pathways, whereas ADRB2 silencing reversed the effects of Caveolin-3 overexpression. In conclusion, ADRB2 agonist promoted the activity of the BDNF/TrkB and cAMP/PKA signaling pathways, mitigating the HG-aggravated H/R injuries in H9C2 cells. Caveolin-3 exerts a protective effect on diabetic hearts against I/R damage through the ß2AR, cAMP/PKA, and BDNF/TrkB signaling pathways.
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Cardiotónicos/uso terapéutico , Caveolina 3/uso terapéutico , Cardiomiopatías Diabéticas/prevención & control , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo , Línea Celular , AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico , Electrocardiografía , Glucosa/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Receptor trkB , Receptores Adrenérgicos beta 2/efectos de los fármacosRESUMEN
Circulating catecholamines contribute to the regulation of retinal vascular tone. Our previous studies have demonstrated that the activation of large-conductance Ca2+-activated K+ (BKCa) channels is involved in the ß2-adrenoceptor-mediated dilation of retinal arterioles in rats. The present study aimed to examine the role of Gi protein in the ß2-adrenoceptor-mediated activation of BKCa channels in the retinal arterioles. Images of in vivo rat ocular fundi were captured, and the diameters of retinal arterioles were measured. Systemic blood pressure and heart rate were recorded continuously. Intravenous infusion of formoterol (0.01-0.3 µg/kg/min), a ß2-adrenoceptor agonist, increased the diameter of retinal arterioles but decreased mean arterial pressure in a dose-dependent manner. Intravitreal injection of iberiotoxin (20 pmol/eye), an inhibitor of BKCa channels, significantly attenuated the formoterol-induced dilation of retinal arterioles. Similar results were obtained when salbutamol (0.03-3 µg/kg/min), another ß2-adrenoceptor agonist, was used instead of formoterol. However, iberiotoxin had no significant effect on retinal vasodilator responses to intravenous infusion of denopamine (1-30 µg/kg/min; a ß1-adrenoceptor agonist), CL316243 (0.3-10 µg/kg/min; a ß3-adrenoceptor agonist), prostaglandin I2 (0.03-10 µg/kg/min; a prostanoid IP receptor agonist), and forskolin (1-10 µg/kg/min; an adenylyl cyclase activator). Intravitreal injection of pertussis toxin (66 ng/eye; a Gi protein inhibitor) significantly attenuated the dilation of retinal arterioles induced by formoterol but not by denopamine and CL316243. In the presence of pertussis toxin, iberiotoxin had no inhibitory effect on formoterol-induced dilation of retinal arterioles. These results suggest that stimulation of ß2-adrenoceptors dilates retinal arterioles through pertussis toxin-sensitive Gi protein-dependent activation of BKCa channels in rats in vivo.
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Agonistas de Receptores Adrenérgicos beta 2/farmacología , Arteriolas/efectos de los fármacos , Fumarato de Formoterol/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Vasos Retinianos/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Albuterol/farmacología , Animales , Arteriolas/metabolismo , Señalización del Calcio , Masculino , Ratas Wistar , Receptores Adrenérgicos beta 2/metabolismo , Vasos Retinianos/metabolismoRESUMEN
Salbutamol (SBAL), a kind of short-acting beta 2-adrenergic agonist, has been mainly used to treat bronchial asthma and other allergic airway diseases clinically. In this study, the interaction mechanism between salbutamol and human serum albumin was researched by the multispectral method and molecular docking. The fluorescence intensity of HSA could be regularly enhanced with the increase of SBAL concentration. Both the results of the multispectral method and molecular docking showed that SBAL could bind HSA with van der Waals force and hydrogen bonds. The binding mechanism was further analysed by UV-Vis and synchronous fluorescence spectra. The contents of the secondary structure of free HSA and SBAL-HSA complex were evaluated using CD spectra.
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Agonistas de Receptores Adrenérgicos beta 2/química , Albuterol/química , Simulación del Acoplamiento Molecular , Albúmina Sérica Humana/química , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Humanos , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/efectos de los fármacosRESUMEN
BACKGROUND: Hypoxia reportedly increases free radical generation in the body, causing oxidative stress and inhibiting ß2-AR signaling. The present study correlates the prophylactic potential of quercetin and salbutamol in ameliorating fluid clearing capacity of lungs by re-sensitizing ß2-AR signaling under hypoxia. METHODS: Male SD rats supplemented orally with quercetin (50 mg/Kg BW), and salbutamol (2 mg/Kg BW) were exposed to hypobaric hypoxia at 7620 m for 6 h. Western blotting and ELISA quantitated NFĸB and related genes and GPCR pathway proteins. The binding affinities of drugs with receptor were determined by SPR spectroscopy and further confirmed insilico. RESULTS: Quercetin and salbutamol pre-treatment significantly up-regulated the expressions of ß2-AR, GPR-1, GPR-10, GCSα, cAMP content, and down-regulated GRK-2, ß-arrestin, ROS, NFκB (p < 0.001), thus, enhancing alveolar fluid clearance (AFC). SPR and insilico findings revealed a higher binding affinity of ß2-AR with quercetin over salbutamol. CONCLUSION: Results indicated quercetin to be a better prophylactic that augmented AFC in rats exposed to hypoxia by attenuating inflammation and stimulating ß2-AR.
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Agonistas de Receptores Adrenérgicos beta 2/farmacología , Albuterol/farmacología , Antioxidantes/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hipoxia/metabolismo , Inflamación/tratamiento farmacológico , Alveolos Pulmonares/efectos de los fármacos , Quercetina/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Albuterol/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Líquidos Corporales/efectos de los fármacos , Modelos Animales de Enfermedad , Hipoxia/tratamiento farmacológico , Masculino , Quercetina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/efectos de los fármacos , Regulación hacia ArribaRESUMEN
ß2-adrenoceptors are G-protein coupled receptors expressed on both astrocytes and microglia that play a key role in mediating the anti-inflammatory actions of noradrenaline in the CNS. Here the effect of an inflammatory stimulus (LPSâ¯+â¯IFN-γ) was examined on glial ß2-adrenoceptor expression and function. Exposure of glia to LPSâ¯+â¯IFN-γ decreased ß2-adrenoceptor mRNA and agonist-stimulated production of the intracellular second messenger cAMP. Pre-treatment with the synthetic glucocorticoid and potent anti-inflammatory agent dexamethasone prevented the LPSâ¯+â¯IFN-γ-induced suppression of ß2-adrenoceptor mRNA expression. These results raise the possibility that inflammation-mediated ß2-adrenoceptor downregulation in glia may dampen the innate anti-inflammatory properties of noradrenaline in the CNS.
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Dexametasona/farmacología , Inflamación/metabolismo , Neuroglía/efectos de los fármacos , Receptores Adrenérgicos beta 2/efectos de los fármacos , Animales , Células Cultivadas , AMP Cíclico/biosíntesis , Interferón beta/farmacología , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Neuroglía/metabolismo , Ratas , Ratas Wistar , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/fisiología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND AND PURPOSE: Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD. EXPERIMENTAL APPROACH: The impact of treatment with the ß2 -adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed. KEY RESULTS: LPS-induced deficits in motor function (akinesia and forelimb-use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co-treatment with the ß2 -adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1ß production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment. CONCLUSION AND IMPLICATIONS: The results indicate that pharmacologically targeting ß2 -adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as ß2 -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.
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Inhibidores de Captación Adrenérgica/farmacología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/prevención & control , Receptores Adrenérgicos beta 2/efectos de los fármacos , Animales , Clorhidrato de Atomoxetina/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Clenbuterol/farmacología , Modelos Animales de Enfermedad , Fumarato de Formoterol/farmacología , Lipopolisacáridos , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa , Neuronas/metabolismo , Neuronas/patología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Ratas Wistar , Receptores Adrenérgicos beta 2/metabolismoRESUMEN
Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and ß adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic ß2 adrenergic receptor and two of its most important targets, the L-type Ca2+ channel CaV1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric Gs protein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease.