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1.
BMC Neurosci ; 24(1): 2, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631757

RESUMO

BACKGROUND: The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT2A receptor agonists such as ( ±)- 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT1A receptors, but enhanced DOI-evoked c-fos expression. d-Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d-fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d-fenfluramine-evoked c-fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors would prevent suppressive effect of MA on d-fenfluramine-induced HTR. RESULTS: EMD 281014 (0.001-0.05 mg/kg) or MA (0.1-5 mg/kg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT1A antagonist WAY 100635 countered the inhibitory effect of MA on d-fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ2 antagonist RS 79948 reversed MA's inhibitory effect in both 20- and 30- day old mice. d-Fenfluramine significantly increased c-fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d-fenfluramine-evoked c-fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d-fenfluramine-induced c-fos expression, but significantly increased it in one PFC region (PrL at - 2.68 mm). CONCLUSION: EMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT2A- and the inhibitory 5-HT1A- and ɑ2-receptors. MA-evoked increases in c-fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d-fenfluramine-evoked changes in c-fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.


Assuntos
Fenfluramina , Metanfetamina , Humanos , Camundongos , Animais , Fenfluramina/metabolismo , Fenfluramina/farmacologia , Metanfetamina/farmacologia , Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Córtex Pré-Frontal , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Envelhecimento
2.
Curr Protoc ; 3(1): e649, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36602296

RESUMO

ß-adrenergic receptors regulate cardiac function in both the healthy and failing heart. Their expression is decreased in heart failure due to chronic overactivation of the sympathetic nervous system, contributing to declines in cardiac function and disease progression. Furthermore, therapies that prevent ß-adrenergic receptor downregulation or restore ß-adrenergic receptor levels are beneficial, making the determination of cardiac ß-adrenergic receptor expression in the heart an important consideration. Although quantitative RT-PCR can provide an indication of ß-adrenergic receptor density and subtype expression, mRNA levels do not always correlate with functional protein levels. Additionally, antibodies to ß-adrenergic receptors lack specificity, making immunoblotting and other antibody-based techniques unreliable. Radioligand binding assays were developed over 50 years ago and remain the gold standard for quantifying ß-adrenergic receptor densities in biological samples. This technique capitalizes on the binding of high-affinity, highly specific ligands to receptors and can give quantifiable levels of receptor expression. Furthermore, competition assays using subtype-selective antagonists generate binding profiles and can differentiate ß-adrenergic receptor subtype expression in cardiac tissue. This article focuses on the quantification of ß-adrenergic receptors in the heart using saturation and competition radioligand binding techniques to quantify ß-adrenergic receptor density and ligand affinities in cardiac membranes. © 2023 Wiley Periodicals LLC. Basic Protocol: Radioligand binding to quantify adrenergic receptor expression in the heart.


Assuntos
Adrenérgicos , Insuficiência Cardíaca , Humanos , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Coração , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Insuficiência Cardíaca/genética
3.
Commun Biol ; 6(1): 10, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604595

RESUMO

Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive behaviour. ACC astrocytic Gi manipulation suppressed aversive behaviour and early plasticity gene expression induced by opto-activation of LC neurons projecting to ACC. Evidences for the critical role of ß2AR in ACC astrocytes were provided using AAV encoding ß2AR miRNAi to knockdown ß2AR in astrocytes. In contrast, opto-activation of ACC astrocytic ß2ARs promotes aversion memory. Our findings suggest that projection-specific adrenergic astrocytic signalling in ACC is integral to system-wide neuromodulation in response to visceral stimuli, and plays a key role in mediating pain-related aversion consolidation and memory formation.


Assuntos
Adrenérgicos , Giro do Cíngulo , Ratos , Animais , Giro do Cíngulo/fisiologia , Adrenérgicos/metabolismo , Astrócitos/fisiologia , Dor , Transdução de Sinais
4.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674669

RESUMO

G-protein-coupled receptors (GPCRs) are cell membrane proteins of relevance as therapeutic targets, and are associated to the development of treatments for illnesses such as diabetes, Alzheimer's, or even cancer. Therefore, comprehending the underlying mechanisms of the receptor functional properties is of particular interest in pharmacoproteomics and in disease therapy at large. Their interaction with ligands elicits multiple molecular rearrangements all along their structure, inducing activation pathways that distinctly influence the cell response. In this work, we studied GPCR signaling pathways from molecular dynamics simulations as they provide rich information about the dynamic nature of the receptors. We focused on studying the molecular properties of the receptors using deep-learning-based methods. In particular, we designed and trained a one-dimensional convolution neural network and illustrated its use in a classification of conformational states: active, intermediate, or inactive, of the ß2-adrenergic receptor when bound to the full agonist BI-167107. Through a novel explainability-oriented investigation of the prediction results, we were able to identify and assess the contribution of individual motifs (residues) influencing a particular activation pathway. Consequently, we contribute a methodology that assists in the elucidation of the underlying mechanisms of receptor activation-deactivation.


Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , Receptores Acoplados a Proteínas G/metabolismo , Simulação de Dinâmica Molecular , Conformação Molecular , Adrenérgicos , Receptores Adrenérgicos beta 2/metabolismo , Ligantes , Conformação Proteica
5.
Clin Transl Med ; 12(12): e1108, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36480426

RESUMO

BACKGROUND: Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis. METHODS AND RESULTS: This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole-body MB knockout resulted in impaired thermoregulation and cold- as well as drug-induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential. CONCLUSIONS: These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes.


Assuntos
Adipócitos Marrons , Adipócitos Brancos , Adrenérgicos , Animais , Humanos , Camundongos , Lipídeos , Mioglobina , Obesidade/genética , Oxigênio
6.
J Med Case Rep ; 16(1): 479, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36566235

RESUMO

BACKGROUND: Bladder paraganglioma is a neuroendocrine tumor that accounts for less than 0.1% of all bladder tumors. Symptoms caused by catecholamine release such as hypertension, palpitation, syncope, and macroscopic hematuria are the most common findings. Treatment modalities include transurethral resection, and partial or total cystectomy. CASE PRESENTATION: A 38-year-old Turkish female patient was examined for hematuria that had been persisting for 6 months. Among the clinical findings, only hematuria was present. Absence of adrenergic symptoms such as hypertension, palpitations, and syncope at the first presentation made it difficult to consider bladder paraganglioma in the differential diagnosis. Therefore, cystoscopy and transurethral resection were performed with the thought of urothelial cancer. Findings such as hypertension and bradycardia that developed during diagnostic transurethral resection suggested that it might be bladder paraganglioma. After the radiological evaluation and endocrinological preparation, the patient underwent partial cystectomy. CONCLUSION: The rarity of cases having been reported in the literature leads to uncertainties in the management of bladder paraganglioma. Adrenergic symptoms developing during transurethral resection should suggest paraganglioma in the differential diagnosis. A multidisciplinary approach and medical treatment are mandatory to prevent life-threatening complications such as hypertensive crisis, vascular collapse, and multiple-organ system failure. We aimed to report the clinical presentation that includes only macroscopic hematuria mimicking urothelial cancer and to emphasize the multidisciplinary approach in the treatment.


Assuntos
Neoplasias das Glândulas Suprarrenais , Carcinoma de Células de Transição , Hipertensão , Paraganglioma , Feocromocitoma , Neoplasias da Bexiga Urinária , Humanos , Feminino , Adulto , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/cirurgia , Bexiga Urinária/patologia , Cistectomia/efeitos adversos , Hematúria/etiologia , Neoplasias da Bexiga Urinária/diagnóstico , Feocromocitoma/complicações , Paraganglioma/diagnóstico , Paraganglioma/cirurgia , Paraganglioma/patologia , Hipertensão/complicações , Carcinoma de Células de Transição/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenérgicos
7.
J Vis Exp ; (190)2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36533840

RESUMO

Growing evidence suggests that the sympathetic nervous system plays an important role in cancer progression. Adrenergic innervation regulates salivary gland secretion, circadian rhythm, macular degeneration, immune function, and cardiac physiology. Murine surgical sympathectomy is a method for studying the effects of adrenergic innervation by allowing for complete, unilateral adrenergic ablation while avoiding the need for repeated pharmacologic intervention and the associated side effects. However, surgical sympathectomy in mice is technically challenging because of the small size of the superior cervical ganglion. This study describes a surgical technique for reliably identifying and resecting the superior cervical ganglion to ablate the sympathetic nervous system. The successful identification and removal of the ganglion are validated by imaging the fluorescent sympathetic ganglia using a transgenic mouse, identifying post-resection Horner's syndrome, staining for adrenergic markers in the resected ganglia, and observing diminished adrenergic immunofluorescence in the target organs following sympathectomy. This model enables future studies of cancer progression as well as other physiological processes regulated by the sympathetic nervous system.


Assuntos
Ganglionectomia , Simpatectomia , Animais , Camundongos , Modelos Animais de Doenças , Gânglios Simpáticos/cirurgia , Sistema Nervoso Simpático/cirurgia , Sistema Nervoso Simpático/fisiologia , Gânglio Cervical Superior/cirurgia , Adrenérgicos
8.
Environ Health Perspect ; 130(12): 127006, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36542476

RESUMO

BACKGROUND: Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. OBJECTIVES: We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. METHODS: First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8 ppm) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. RESULTS: Ozone (0.8 ppm) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4-6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. DISCUSSION: We demonstrated the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088.


Assuntos
Poluentes Atmosféricos , Ozônio , Ratos , Masculino , Animais , Glucose , Receptores de Glucocorticoides , Automonitorização da Glicemia , Irritantes , Glicemia , Ratos Endogâmicos WKY , Corticosterona , Ozônio/toxicidade , Poluentes Atmosféricos/toxicidade , Adrenérgicos
9.
Nat Commun ; 13(1): 7633, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496438

RESUMO

The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by ß3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of ß-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.


Assuntos
Adipocinas , Tecido Adiposo Marrom , Camundongos , Animais , Humanos , Tecido Adiposo Marrom/metabolismo , Termogênese , Tecido Adiposo Branco/metabolismo , Obesidade/metabolismo , Glucose/metabolismo , Adrenérgicos/metabolismo , Adipócitos Marrons/metabolismo , Metabolismo Energético
10.
Sci Rep ; 12(1): 21383, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496470

RESUMO

Brown adipose tissue (BAT) is a fat tissue specialized in heat production (non-shivering thermogenesis) and used by mammals to defend core body temperature when exposed to cold. Several studies have shown that during non-shivering thermogenesis the increase in BAT oxygen demand is met by a local and specific increase in tissue's blood flow. While the vasculature of BAT has been extensively studied postmortem in rodents using histology, optical and CT imaging techniques, vasculature changes during stimulation of non-shivering thermogenesis have never been directly detected in vivo. Here, by using computed tomography (CT) angiography with gold nanoparticles we investigate, non-invasively, changes in BAT vasculature during adrenergic stimulation of non-shivering thermogenesis by norepinephrine, a vasoconstrictor known to mediate brown fat heat production, and by CL 316,243, a specific ß3-adrenergic agonist also known to elicit BAT thermogenesis in rodents. We found that while CL 316,243 causes local vasodilation in BAT, with little impact on the rest of the vasculature throughout the body, norepinephrine leads to local vasodilation in addition to peripheral vasoconstriction. As a result, a significantly greater relative increase in BAT perfusion is observed following the injection of NE compared to CL. This study demonstrates the use of in vivo CT angiography as an effective tool in assessing vascular reactivity in BAT both qualitatively and quantitatively in preclinical studies.


Assuntos
Tecido Adiposo Marrom , Nanopartículas Metálicas , Animais , Camundongos , Tecido Adiposo Marrom/fisiologia , Adrenérgicos , Ouro , Termogênese/fisiologia , Temperatura Baixa , Norepinefrina/farmacologia , Mamíferos
11.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36498840

RESUMO

Octopamine (OA) is structurally and functionally similar to adrenaline/noradrenaline in vertebrates, and OA modulates diverse physiological and behavioral processes in invertebrates. OA exerts its actions by binding to specific octopamine receptors (OARs). Functional and pharmacological characterization of OARs have been investigated in several insects. However, the literature on OARs is scarce for parasitoids. Here we cloned three ß-adrenergic-like OARs (CcOctßRs) from Cotesia chilonis. CcOctßRs share high similarity with their own orthologous receptors. The transcript levels of CcOctßRs were varied in different tissues. When heterologously expressed in CHO-K1 cells, CcOctßRs induced cAMP production, and were dose-dependently activated by OA, TA and putative octopaminergic agonists. Their activities were inhibited by potential antagonists and were most efficiently blocked by epinastine. Our study offers important information about the molecular and pharmacological properties of ß-adrenergic-like OARs from C. chilonis that will provide the basis to reveal the contribution of individual receptors to the physiological processes and behaviors in parasitoids.


Assuntos
Himenópteros , Receptores de Amina Biogênica , Animais , Adrenérgicos , Receptores de Amina Biogênica/metabolismo , Octopamina/farmacologia , Octopamina/metabolismo
12.
Nutrients ; 14(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36500973

RESUMO

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α1-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms.


Assuntos
Isoflavonas , Hiperplasia Prostática , Masculino , Humanos , Próstata/metabolismo , Genisteína/farmacologia , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Músculo Liso , Contração Muscular , Hiperplasia Prostática/metabolismo , Células Estromais , Isoflavonas/farmacologia , Isoflavonas/metabolismo
13.
Sci Rep ; 12(1): 20051, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414707

RESUMO

Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder characterized by excessive heart rate increase on standing, leading to debilitating symptoms with limited therapeutic possibilities. Proteomics is a large-scale study of proteins that enables a systematic unbiased view on disease and health, allowing stratification of patients based on their protein background. The aim of the present study was to determine plasma protein biomarkers of POTS and to reveal proteomic pathways differentially regulated in POTS. We performed an age- and sex-matched, case-control study in 130 individuals (case-control ratio 1:1) including POTS and healthy controls. Mean age in POTS was 30 ± 9.8 years (84.6% women) versus controls 31 ± 9.8 years (80.0% women). We analyzed plasma proteins using data-independent acquisition (DIA) mass spectrometry. Pathway analysis of significantly differently expressed proteins was executed using a cutoff log2 fold change set to 1.2 and false discovery rate (p-value) of < 0.05. A total of 393 differential plasma proteins were identified. Label-free quantification of DIA-data identified 30 differentially expressed proteins in POTS compared with healthy controls. Pathway analysis identified the strongest network interactions particularly for proteins involved in thrombogenicity and enhanced platelet activity, but also inflammation, cardiac contractility and hypertrophy, and increased adrenergic activity. Our observations generated by the first use a label-free unbiased quantification reveal the proteomic footprint of POTS in terms of a hypercoagulable state, proinflammatory state, enhanced cardiac contractility and hypertrophy, skeletal muscle expression, and adrenergic activity. These findings support the hypothesis that POTS may be an autoimmune, inflammatory and hyperadrenergic disorder.


Assuntos
Síndrome da Taquicardia Postural Ortostática , Humanos , Feminino , Adulto Jovem , Adulto , Masculino , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Estudos de Casos e Controles , Proteômica , Adrenérgicos , Hipertrofia
14.
Pain Res Manag ; 2022: 2757101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339068

RESUMO

Objective: Endogenous pain inhibition can be investigated using conditioned pain modulation (CPM). CPM efficacy has been reported to be influenced by various factors, such as gender and cardiovascular (autonomic) activity. The aim of this study is to describe the effect of pharmacological manipulations of autonomic activity on CPM efficacy. Methods: Thirty healthy participants were enrolled to assess CPM efficacy in 4 experimental sessions. The first session consisted of the determination of baseline CPM effectiveness. The three following sessions were performed in a randomized order and consisted of the injection of (1) esmolol, (2) ephedrine, or (3) placebo, before the conditioning stimulus. Pain intensity induced by using a contact heat stimulation thermode was compared before and after a cold-pressure conditioning stimulus to evaluate CPM effectiveness. Results: Our results show that inhibiting sympathetic nervous activity with esmolol did not have a significant effect on CPM. Conversely, enhancing sympathetic nervous activity with ephedrine increased CPM effectiveness in healthy women but decreased it in men. Conclusions: Increasing sympathetic activity with adrenergic agonists, such as ephedrine, could improve CPM effectiveness in women. It will be interesting to verify if the same results are present in patients suffering from chronic pain and if adrenergic agonists could have better therapeutic effects in women showing reduced CPM effectiveness.


Assuntos
Adrenérgicos , Dor Crônica , Masculino , Humanos , Feminino , Efedrina/farmacologia , Efedrina/uso terapêutico , Agonistas Adrenérgicos , Limiar da Dor/fisiologia
15.
Nature ; 611(7934): 173-179, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36289326

RESUMO

G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival1. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood2-4. Here we investigated how spatially organized ß2-adrenergic receptor (ß2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors5, we show that ß2AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated ß2AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gαs, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal ß2AR and Gαs signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.


Assuntos
Adrenérgicos , Endossomos , MAP Quinases Reguladas por Sinal Extracelular , Receptores Adrenérgicos beta 2 , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Proliferação de Células , Endossomos/efeitos dos fármacos , Endossomos/enzimologia , Endossomos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes myc , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
16.
Int J Mol Sci ; 23(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36232680

RESUMO

Authors investigated the catecholaminergic neurotransmitters (chNs) quantitative modifications in pregnant uterine Lower Uterine Segment (LUS) during prolonged labor (PL) with the fetus in an occiput-posterior position (OPP), in occiput transverse position (OTP) and in fetal head asynclitism, all diagnosed by Intrapartum Ultrasonography (IU). The chNs neurotransmitters, particularly adrenaline (or epinephrine-A) and noradrenaline (or norepinephrine-N), were evaluated in LUS fragments sampled during CS of 34 patients undergoing urgent cesarean section (CS) in PL, compared to chNs fibers in the LUS of 36 women submitted to elective CS. All results were statistically analyzed to understand the differences in neurotransmitters morphological analysis by scanning electronic microscopy examination (SEM). The LUS fragments analysis revealed a reduction of A and N fibers in LUS during PL, compared with the expression of A and N fibers in LUS during elective CS. The PL for OPP, the OTP and asynclitism, all positions causing dystocia in labor lead to a reduction in neurotransmitters in LUS, with a uterine vascularization modification and a reduction in the contractility of smooth uterine cells. The A and N neurotransmitters reduction observed in PL negatively interferes with uterine contraction during labor.


Assuntos
Cesárea , Distocia , Adrenérgicos , Epinefrina , Feminino , Humanos , Neurotransmissores , Norepinefrina , Fenilpropionatos , Gravidez
17.
Front Endocrinol (Lausanne) ; 13: 1020000, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36237181

RESUMO

During embryonic development, nerve-associated Schwann cell precursors (SCPs) give rise to chromaffin cells of the adrenal gland via the "bridge" transient stage, according to recent functional experiments and single cell data from humans and mice. However, currently existing data do not resolve the finest heterogeneity of developing chromaffin populations. Here we took advantage of deep SmartSeq2 transcriptomic sequencing to expand our collection of individual cells from the developing murine sympatho-adrenal anlage and uncover the microheterogeneity of embryonic chromaffin cells and their corresponding developmental paths. We discovered that SCPs on the splachnic nerve show a high degree of microheterogeneity corresponding to early biases towards either Schwann or chromaffin terminal fates. Furthermore, we found that a post-"bridge" population of developing chromaffin cells gives rise to persisting oxygen-sensing chromaffin cells and the two terminal populations (adrenergic and noradrenergic) via diverging differentiation paths. Taken together, we provide a thorough identification of novel markers of adrenergic and noradrenergic populations in developing adrenal glands and report novel differentiation paths leading to them.


Assuntos
Células Cromafins , Glândulas Suprarrenais , Adrenérgicos , Animais , Diferenciação Celular/fisiologia , Feminino , Humanos , Camundongos , Norepinefrina , Oxigênio , Gravidez
18.
Adipocyte ; 11(1): 616-629, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36260113

RESUMO

Brown adipose tissue (BAT) generates heat through non-shivering thermogenesis, and increasing BAT amounts or activity could facilitate obesity treatment and provide metabolic benefits. In mice, BAT has been reported in perirenal, thoracic and cranial sites. Here, we describe new pelvic and lower abdominal BAT depots located around the urethra, internal reproductive and urinary tract organs and major lower pelvic blood vessels, as well as between adjacent muscles where the upper hind leg meets the abdominal cavity. Immunohistochemical, western blot and PCR analyses revealed that these tissues expressed BAT markers such as uncoupling protein 1 (UCP1) and CIDEA, but not white adipose markers, and ß3-adrenergic stimulation increased UCP1 amounts, a classic characteristic of BAT tissue. The newly identified BAT stores contained extensive sympathetic innervation with high mitochondrial density and multilocular lipid droplets similar to interscapular BAT. BAT repositories were present and functional neonatally, and showed developmental changes between the neonatal and adult periods. In summary, several new depots showing classical BAT characteristics are reported and characterized in the lower abdominal/pelvic region of mice. These BAT stores are likely significant metabolic regulators in the mouse and some data suggests that similar BAT depots may also exist in humans.


Assuntos
Tecido Adiposo Marrom , Termogênese , Animais , Camundongos , Tecido Adiposo Marrom/metabolismo , Adrenérgicos/metabolismo , Pelve , Termogênese/fisiologia , Proteína Desacopladora 1/metabolismo
19.
Cell Rep ; 41(3): 111509, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36261014

RESUMO

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via α1 adrenoreceptor activation. Noradrenergic afferents are recruited preferentially by somatic, rather than psychological, stress stimuli. Stress-induced glucocorticoids feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure and neuropathology. Whether negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we describe a desensitization of the α1 adrenoreceptor activation of the HPA axis following acute stress in male mice that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons. Glucocorticoid-induced α1 receptor trafficking desensitizes the HPA axis to a somatic but not a psychological stressor. Our findings demonstrate a rapid glucocorticoid suppression of adrenergic signaling in CRH neurons that is specific to somatic stress activation, and they reveal a rapid, stress modality-selective glucocorticoid negative feedback mechanism.


Assuntos
Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Animais , Camundongos , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Glucocorticoides , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico , Adrenérgicos
20.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234730

RESUMO

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = -7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = -7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.


Assuntos
Fosfatase Alcalina , Troponina I , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Alanina Transaminase , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases , Atenolol , Bilirrubina/metabolismo , Biomarcadores/metabolismo , Canais de Cálcio/metabolismo , Creatinina/metabolismo , Fluoruracila/farmacologia , Humanos , Lactato Desidrogenases/metabolismo , Lipídeos/farmacologia , Fígado , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Succinimidas/metabolismo , Troponina I/metabolismo
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