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1.
Life Sci ; 241: 117155, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837330

RESUMO

AIMS: ß-Adrenoceptors (ß-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on ß-ADR-mediated relaxation were examined. MAIN METHODS: The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA ß-ADR was detected using RT-PCR. KEY FINDINGS: In endothelium-denuded SMAs contracted with ≥10-7 M phenylephrine (an α1-ADR agonist), isoprenaline (a ß-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10-9-10-8 M propranolol (a ß1,2-ADR antagonist), but not further affected by ≥10-8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10-9-10-8 M; a ß2-ADR antagonist), it was competitively inhibited by atenolol (10-7-3 × 10-7 M; a ß1-ADR antagonist) in the presence of ICI-118,551. In the presence of 10-7 M propranolol, isoprenaline- and CGP-12177A (a ß3-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a ß1,2,3-ADR antagonist), with pA2 values of 6.49 and 5.76, respectively. We detected the mRNA of ß1- and ß3-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10-7 M propranolol, but not CGP-12177A-induced relaxation. SIGNIFICANCE: Isoprenaline-induced relaxation of rat SMAs is mediated by ß1- and ß3-ADRs. ß-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple ß3-ADRs with different pharmacological properties.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Artéria Mesentérica Superior/fisiologia , Relaxamento Muscular/fisiologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Simpatectomia Química/métodos , Animais , Isoproterenol/farmacologia , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , Ratos , Ratos Wistar
2.
Invest Ophthalmol Vis Sci ; 60(14): 4924-4930, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770432

RESUMO

Purpose: In the dark, photoreceptor outer segments contain high levels of cyclic guanosine 3'-5' monophosphate (cGMP), which binds to ion channels, holding them open and allowing an influx of cations. Ion pumping activity, which balances cation influx, uses considerable amounts of adenosine triphosphate (ATP) and oxygen. Light reduces cation influx and thereby lowers metabolic demand. Blood vessels are compromised in the diabetic retina and may not be able to meet the higher metabolic demand in darkness. Emixustat is a visual cycle modulator (VCM) that reduces chromophore levels and, therefore, may mimic light conditions. We evaluated the effect of emixustat on oxygen consumption and cation influx in dark conditions. Methods: Cation influx was measured in rats using Mn2+-magnetic resonance imaging (MEMRI). Retinal oxygen profiles were recorded to evaluate oxygen consumption. In the MEMRI protocol, animals were treated with either emixustat or vehicle. In the oxygen protocol, animals were untreated or treated with emixustat. Results: In vehicle-treated animals, cation channel activity increased in the dark. Emixustat treatment reduced cation channel activity; activity was comparable to vehicle-treated controls in light conditions. In vehicle-treated animals, minimum retinal oxygen tension decreased as the retina recovered from a photobleach, indicating that more oxygen was being consumed. Emixustat treatment prevented the decrease in oxygen pressure after photobleach. Conclusions: Emixustat reduced the cation influx and retinal oxygen consumption associated with dark conditions. VCMs are a promising potential treatment for ischemic retinal neovascularization, such as that in diabetic retinopathy.


Assuntos
Adaptação à Escuridão/fisiologia , Manganês/metabolismo , Consumo de Oxigênio/fisiologia , Éteres Fenílicos/farmacologia , Propanolaminas/farmacologia , Retina/efeitos dos fármacos , Animais , Imagem por Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Long-Evans , Retina/metabolismo , cis-trans-Isomerases/antagonistas & inibidores
3.
J Agric Food Chem ; 67(48): 13212-13220, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31702905

RESUMO

Because only a handful of agrochemicals can manage bacterial infections, the discovery and development of innovative, inexpensive, and high-efficiency antibacterial agents targeting these infections are challenging. Herein, a series of novel epimeric and chiral 18ß-glycyrrhetinic acid (GA) ester derivatives with various tertiary amine pendants were designed, synthesized, and screened for pharmacological activity. Results showed that some of the title compounds were conferred with significantly enhanced antibacterial activity toward phytopathogens Xanthomonas oryzae pv oryzae (A2, B1-B3, and C1, EC50 values within 3.81-4.82 µg/mL) and Xanthomonas axonopodis pv citri (B1, EC50 = 3.18 µg/mL; B2, EC50 = 2.76 µg/mL). These activities are superior to those of GA (EC50 > 400 µg/mL), thiodiazole copper, and bismerthiazol. Pharmacophore studies revealed that the synergistic combination of GA skeleton and tertiary amine scaffolds contributed to the biological actions. In vivo experiments displayed their promising applications in controlling bacterial infections. Antibacterial mechanism studies revealed that the title compounds could trigger apoptosis in the tested pathogens, evident by bacteria morphological changes observed in scanning electron microscopy images. This outcome should motivate the development of various apoptosis inducers against plant bacterial diseases by a novel mode of action compared to that of existing agricultural chemicals.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Antibacterianos/síntese química , Desenho de Drogas , Ésteres/química , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Testes de Sensibilidade Microbiana , Doenças das Plantas/microbiologia , Propanolaminas/química , Estereoisomerismo , Relação Estrutura-Atividade , Xanthomonas/citologia , Xanthomonas/efeitos dos fármacos
4.
Nat Neurosci ; 22(11): 1771-1781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636449

RESUMO

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/genética , Clozapina/análogos & derivados , Clozapina/farmacologia , Isoflurano/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microinjeções , Muscimol/farmacologia , Norepinefrina/farmacologia , Optogenética , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Purinérgicos P2Y12/genética , Privação Sensorial/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Tetrodotoxina/farmacologia , Vigília
5.
Nat Neurosci ; 22(11): 1782-1792, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636451

RESUMO

Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ß2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ß2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.


Assuntos
Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/fisiologia , Córtex Visual/fisiologia , Animais , Benzilaminas/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Ritmo Circadiano/fisiologia , Clembuterol/farmacologia , Dexmedetomidina/farmacologia , Dominância Ocular , Feminino , Fentanila/farmacologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Nadolol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Restrição Física/fisiologia , Terbutalina/farmacologia , Vigília , Ferimentos e Lesões/fisiopatologia
6.
Dtsch Med Wochenschr ; 144(18): 1280-1285, 2019 09.
Artigo em Alemão | MEDLINE | ID: mdl-31514219

RESUMO

Supraventricular tachyarrhythmias, especially atrial fibrillation, are common in cardiac and non-cardiac patients with or without surgery. Prolonged rhythm disturbances may impair cardiac function and worsen the clinical outcome and prognosis. Therefore, heart rate control may be necessary to prevent cardiovascular events.Esmolol and landiolol as ultrashort and rapid acting highly selective ß 1 -adrenergic blockers are of particular interest in the prevention and management of cardiac arrhythmias. This review gives an update on both betablockers and their role in the management of arrhythmias in emergency medicine and perioperative setting.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Estado Terminal/terapia , Morfolinas/uso terapêutico , Propanolaminas/uso terapêutico , Ureia/análogos & derivados , Fibrilação Atrial/tratamento farmacológico , Humanos , Ureia/uso terapêutico
7.
Oxid Med Cell Longev ; 2019: 6325424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360296

RESUMO

The increased circulation of norepinephrine, found in the diseased heart as a result of sympathetic nervous system overactivation, is responsible for its cardiotoxic effects including pathological hypertrophy, cell death, and oxidative stress. Bucindolol is a third generation adrenergic blocker, which acts on the ß1 and ß2 receptors, and has additional α1 antagonist activity. Thus, the aim of this study was to investigate the action of bucindolol on oxidative stress, hypertrophy, cell survival, and cell death signaling pathways in H9c2 cardiac cells exposed to norepinephrine. H9c2 cells were incubated with 10 µM norepinephrine for 24 h in the presence or absence of bucindolol (10 µM) treatment for 8 h. Western blot was used to determine the expression of proteins for hypertrophy/survival and death signaling pathways. Flow cytometry was used to assess cell death via caspase-3/7 activity and propidium iodide and reactive oxygen species via measuring the fluorescence of CM-H2DCFDA. Norepinephrine exposure resulted in an increase in oxidative stress as well as cell death. This was accompanied by an increased protein expression of LC3B-II/I. The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress.


Assuntos
Norepinefrina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
J Agric Food Chem ; 67(26): 7512-7525, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180659

RESUMO

Recent observations on the emergence of drug-resistant plant pathogenic bacteria have highlighted and elicited an acute campaign to develop novel, highly efficient antibiotic surrogates for managing bacterial diseases in agriculture. Thus, a type of racemic and chiral carbazole derivative containing an isopropanolamine pattern was systematically synthesized to discover low-cost and efficient antibacterial candidates. Screening results showed that compounds 2f, 6c, and 2j could significantly suppress the growth of tested plant pathogens, namely Xanthomonas oryzae pv oryzae, X. axonopodis pv citri, and Pseudomonas syringae pv actinidiae, and provided the corresponding EC50 values of 1.27, 0.993, and 0.603 µg/mL, which were significantly better than those of existing commercial drugs. In vivo studies confirmed their prospective applications for controlling plant bacterial diseases. Label-free quantitative proteomics analysis indicated that compound 2f could dramatically induce the up- and down-regulation of a total of 247 differentially expressed proteins, which was further validated by the parallel reaction monitoring technique. Moreover, fluorescence spectra and SEM images were obtained to further explore the antibacterial mechanism.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Doenças das Plantas/microbiologia , Propanolaminas/química , Pseudomonas syringae/efeitos dos fármacos , Xanthomonas/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Proteômica , Pseudomonas syringae/química , Pseudomonas syringae/genética , Pseudomonas syringae/metabolismo , Relação Estrutura-Atividade , Xanthomonas/química , Xanthomonas/genética , Xanthomonas/metabolismo
9.
Carbohydr Res ; 481: 23-30, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220628

RESUMO

We synthesized phenylacetylenes containing ß-lactoside, ß-cellobioside, or ß-maltoside, and polymerized them to produce the corresponding poly (phenylacetylene)s. In these poly (phenylacetylene)s, the pendent carbohydrates were tethered to the mainchains by serinol spacers. Because similar glycosyl serinol units are found in the natural glycosphingolipids in cell membranes, the densely packed carbohydrate clusters along the poly (phenylacetylene) mainchains act as molecular mimics of cell surface glycoclusters. We analyzed the conformation of the glycosylated poly (phenylacetylene)s using circular dichroism spectroscopy, and found that the spatial carbohydrate packing within the glycoclusters changed on the addition of salts.


Assuntos
Acetileno/análogos & derivados , Conformação Molecular , Propanolaminas/química , Propilenoglicóis/química , Açúcares/química , Acetileno/síntese química , Acetileno/química , Técnicas de Química Sintética , Glicosilação , Simulação de Dinâmica Molecular , Polimerização , Sais/química , Estereoisomerismo , Água/química
10.
J Vet Emerg Crit Care (San Antonio) ; 29(3): 326-330, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31044499

RESUMO

OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short-acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4-year-old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7-year-old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long-term follow-up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.


Assuntos
Doenças do Cão/tratamento farmacológico , Choque Séptico/veterinária , Taquicardia Supraventricular/veterinária , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Animais , Procedimentos Cirúrgicos do Sistema Digestório/veterinária , Cães , Quimioterapia Combinada/veterinária , Feminino , Norepinefrina/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/veterinária , Propanolaminas/administração & dosagem , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Taquicardia Supraventricular/complicações , Taquicardia Supraventricular/tratamento farmacológico , Vasoconstritores/administração & dosagem
11.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052299

RESUMO

Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, ß3-adrenergic receptor (ß3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of ß3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying ß3-AR as a potential discriminating factor that could address the use of apigenin in ES.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Sarcoma de Ewing/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Propanolaminas/farmacologia
12.
Biomed Res Int ; 2019: 6791971, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139645

RESUMO

The present study aims to investigate whether intravenous dexmedetomidine shows superiority to esmolol for hemodynamic response to tracheal intubation after rapid sequence induction. In the present meta-analysis, PubMed, EMBASE, and the Cochrane Library were searched for trials comparing dexmedetomidine with esmolol for the attenuation of the hemodynamic response to intubation. Ten trials were selected in the present meta-analysis. Compared to esmolol, the use of dexmedetomidine maintains stable heart rates (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) at 1 min, 3 min, and 5 min after tracheal intubation. Dexmedetomidine causes less hemodynamic response to tracheal intubation after rapid sequence induction compared with esmolol.


Assuntos
Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Hemodinâmica/efeitos dos fármacos , Intubação Intratraqueal , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Administração Intravenosa , Adulto , Pressão Sanguínea/efeitos dos fármacos , Diástole/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Viés de Publicação , Sístole/efeitos dos fármacos , Adulto Jovem
13.
Zhonghua Yi Xue Za Zhi ; 99(17): 1317-1322, 2019 May 07.
Artigo em Chinês | MEDLINE | ID: mdl-31091579

RESUMO

Objective: To investigate the effect of esmolol in septic shock patients with tachycardia. Methods: A prospective randomized controlled trial was conducted. Screening septic shock patients that admitted to Department of General Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University from June 2016 to August 2017. After 24 h resuscitation therapy, 100 cases of septic shock patients with tachycardia (heart rate>100 bpm) were divided into esmolol group (n=50) and control group (n=50) with random number table. Patients in esmolol group accepted standard treatment plus esmolol injection with an initial dose of 25 mg/h. Heart rate target is 80 to 100 bpm. Patients in esmolol group continued to use esmolol for 7 days or to the day the patient left the ICU when the heart rate didn't achieve the target. Patients in control group were given standard treatment. Primary outcome was 28 d mortality. Secondary outcomes included heart rate, norepinephrine dosages, lactate level, inflammatory markers in per day during the trial; acute physiology and chronic health evaluation (APACHE Ⅱ) and sequential organ failure assessment (SOFA) on day 1, 3, 5, 7; length of hospital stay, length of mechanical ventilation, medication time of vasoactive agent. The data were compared with t test or rank sum test between the two groups. Results: The 28 d mortality of esmolol group and control group was 62%, 68%, respectively(χ(2)=0.529, P=0.529). Logistic regression analysis showed that primary heart rate (increase of 10 bpm, OR=1.568, 95%CI: 1.039-1.238, P=0.027), primary APACHEⅡ (OR=1.134, 95%CI: 1.026-1.239, P=0.005), integral heart rate (per 10 bpm, OR=2.207, 95%CI: 1.400-3.479, P=0.001) were independent risk factors for 28 d mortality. Compared with control group, the esmolol group had a lower heart rate on day 1-7; but over all, there was no statistically significant difference in heart rate between the two groups (P>0.05). There was no significant difference in total does of norepinephrine, lactate level, inflammatory markers, APACHE Ⅱ, SOFA, length of hospital stay between the two groups (all P>0.05). Conclusion: Tachycardia significantly increases the risk of death in patients with septic shock, esmolol may decrease the mortality by controlling heart rate.


Assuntos
Propanolaminas/uso terapêutico , Choque Séptico , Humanos , Estudos Prospectivos , Choque Séptico/tratamento farmacológico , Taquicardia
14.
Mol Brain ; 12(1): 31, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943999

RESUMO

Merkel discs, located in skin touch domes and whisker hair follicles, are tactile end organs essential for environmental exploration, social interaction, and tactile discrimination. Recent studies from our group and two others have shown that mechanical stimulation excites Merkel cells via Piezo2 channel activation to subsequently activate sensory neural pathways. We have further shown that mechanical stimulation leads to the release of 5-HT from Merkel cells to synaptically transmit tactile signals to whisker afferent nerves. However, a more recent study using skin touch domes has raised the possibility that Merkel discs are adrenergic synapses. It was proposed that norepinephrine is released from Merkel cells upon mechanical stimulation to subsequently activate ß2 adrenergic receptors on Merkel disc nerve endings leading to nerve impulses. In the present study, we examined effects of norepinephrine and ß2 adrenergic receptor antagonist ICI 118,551 on Merkel disc mechanoreceptors in mouse whisker hair follicles. We show that norepinephrine did not directly induce impulses from Merkel disc mechanoreceptors. Furthermore, we found that ICI 118,551 at 50 µM inhibited voltage-gated Na+ channels and suppressed impulses of Merkel disc mechanoreceptors, but ICI 118,551 at 1 µM had no effects on the impulse. These findings challenge the hypothesis of Merkel discs being adrenergic synapses.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Folículo Piloso/metabolismo , Mecanorreceptores/metabolismo , Células de Merkel/metabolismo , Norepinefrina/farmacologia , Propanolaminas/farmacologia , Sinapses/metabolismo , Vibrissas/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Folículo Piloso/efeitos dos fármacos , Células de Merkel/efeitos dos fármacos , Sinapses/efeitos dos fármacos
16.
Methods Mol Biol ; 1973: 261-279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016708

RESUMO

Molecular beacons composed of the artificial serinol nucleic acid (SNA) have demonstrated utility as novel fluorescence probes for visualization of RNA in fixed cells using both conventional fluorescence in situ hybridization (FISH) and wash-free FISH protocols. The SNA molecular beacons have higher affinity for target RNA and greater sensitivity than molecular beacons composed of DNA. Here we describe facile synthesis of the SNA using a conventional DNA synthesizer and protocols for purification by PAGE and HPLC as well as methods for use of the SNA molecular beacon in FISH.


Assuntos
Corantes Fluorescentes/química , Hibridização in Situ Fluorescente/métodos , Ácidos Nucleicos/química , Sondas de Oligonucleotídeos/química , Propanolaminas/química , Propilenoglicóis/química , RNA/análise , Hibridização de Ácido Nucleico
18.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(2): 193-197, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30827308

RESUMO

OBJECTIVE: To explore whether ß1 receptor blocker could decrease the myocardial inflammation through the Toll-like receptor 4/nuclear factor-ΚB (TLR4/NF-ΚB) signaling pathway in the sepsis adult rats. METHODS: Sixty male Wistar rats (250-300 g) aged 3 months old were allocated to four groups by random number table (n = 15): sham operation group (S group), sepsis model group (CLP group), ß1 receptor blocker esmolol intervention group (ES group), and inhibitor of the TLR4 E5564 intervention group (E5564 group). The rat sepsis model was established by cecal ligation and puncture (CLP); S group of rats underwent only an incision. Rats in S group, CLP group and E5564 group were subcutaneous injected with 0.9% sodium chloride (NaCl) 2.0 mL/kg. Besides, the rats in ES group were injected with esmolol (15 mg×kg-1×h-1) by micro pump through the caudal vein. The rats in E5564 group were injected with E5564 (0.3 mg×kg-1×h-1) by micro pump through the caudal vein 1 hour before the CLP surgery. Samples were collected 6 hours after the modelling in each group. The average arterial pressure (MAP) and cardiac output index (CI) were monitored by PU electrical conduction ECG monitor. The levels of serum cardiac troponin I (cTnI), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA). The expressions of TLR4, NF-ΚB p65, IL-1ß, TNF-α in myocardial tissue was detected by Western Blot. RESULTS: There was no significant difference in MAP in each group. Compared with the S group, the CI in the CLP group was significantly decreased, the levels of serum cTnI, IL-1ß, TNF-α were significantly increased, the protein expressions of myocardial tissue TLR4, NF-ΚB p65, IL-1ß and TNF-α were significantly increased. Compared with the CLP group, the CI in the ES group and E5564 group were significantly increased (mL×s-1×m-2: 58.6±4.3, 58.9±4.4 vs. 41.2±3.9, both P < 0.01), the levels of serum cTnI, IL-1ß and TNF-α were significantly decreased [cTnI (µg/L): 1 113.81±26.64, 1 115.74±25.90 vs. 1 975.96±42.74; IL-1ß (ng/L): 39.6±4.3, 38.9±4.4 vs. 61.2±3.9; TNF-α (ng/L): 43.1±2.8, 48.7±2.6 vs. 81.3±4.4, all P < 0.01], the protein expressions of myocardial tissue NF-ΚB p65, IL-1ß, TNF-α were significantly decreased (NF-ΚB p65/ß-actin: 0.31±0.03, 0.43±0.04 vs. 0.85±0.08; IL-1ß/ß-actin: 0.28±0.05, 0.32±0.03 vs. 0.71±0.06; TNF-α/ß-actin: 0.18±0.04, 0.28±0.03 vs. 0.78±0.07, all P < 0.01), but there was no significant difference in protein expression of TLR4 (TLR4/ß-actin: 0.89±0.07, 0.87±0.09 vs. 0.95±0.09, both P > 0.05). There was no significant difference in CI, the levels of serum cTnI, IL-1ß, TNF-α, and the protein expressions of myocardial tissue TLR4, NF-ΚB p65, IL-1ß, TNF-α between ES group and E5564 group (all P > 0.05). CONCLUSIONS: ß1 receptor blocker esmolol may inhibit myocardial inflammatory response in sepsis adult rats through TLR4/NF-ΚB signaling pathway, thereby alleviating sepsis-induced myocardial injury.


Assuntos
Inflamação/prevenção & controle , Miocárdio/patologia , NF-kappa B/metabolismo , Propanolaminas/farmacologia , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Interleucina-1beta , Masculino , Ratos , Ratos Wistar , Sepse/complicações , Fator de Necrose Tumoral alfa
19.
Molecules ; 24(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823583

RESUMO

This paper presents an application of high performance liquid chromatography coupled with quadrupole orbitrap high-resolution mass spectrometry (HPLC-Q-Orbitrap HRMS) for the analysis of 27 ß-blockers and metabolites in milk powder. Homogenized milk power samples were extracted by acetonitrile and purified by using Oasis PRiME HLB solid-phase extraction cartridges. The Ascentis® C8 chromatographic column was used to separate the analytes. The quantification was achieved by using matrix-matched standard calibration curves with carazolol-d7 and propranolol-d7 as the internal standards. The results show an exceptional linear relationship with the concentrations of analytes over wide concentration ranges (0.5⁻500 µg kg-1) as all the fitting coefficients of determination r² are > 0.995. All the limits of detection (LODs) and quantitation (LOQs) values were within the respective range of 0.2⁻1.5 µg kg-1 and 0.5⁻5.0 µg kg-1. Overall average recoveries were able to reach 66.1⁻100.4% with the intra- and inter-day variability under 10%. This method has been successfully applied to the screening of ß-blockers and metabolites in commercial milk powders. At the same time, the corresponding characteristic fragmentation behavior of the 27 compounds was explored. The characteristic product ions were determined and applied to the actual samples screening.


Assuntos
Antagonistas Adrenérgicos beta/análise , Leite/química , Acebutolol/análogos & derivados , Acebutolol/análise , Animais , Cromatografia Líquida de Alta Pressão , Etanolaminas/análise , Limite de Detecção , Estrutura Molecular , Análise de Componente Principal , Propanolaminas/análise , Propranolol , Extração em Fase Sólida , Espectrometria de Massas em Tandem
20.
BMJ Case Rep ; 12(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30852502

RESUMO

Current advanced cardiac life support (ACLS) guidelines for the management of ventricular fibrillation (VF) and pulseless ventricular tachycardia is defibrillation. However, refractory VF, which is defined as VF that persists despite three defibrillation attempts, is challenging for all ACLS providers; the best resuscitation strategy for patients that persist in refractory VF remains unclear. We report on a 51-year-old man who presented to the emergency department with chest pain and subsequently went into witnessed VF cardiac arrest. Despite standard ACLS management consisting of high-quality cardiopulmonary resuscitation, serial epinephrine and serial defibrillation, the return of spontaneous circulation (ROSC) was unable to be achieved. Double sequential defibrillation (DSD) was attempted multiple times unsuccessfully. After administration of low-dose esmolol, he immediately achieved ROSC. DSD and ß-blockade are increasingly recognised in the literature and practice for refractory VF. However, to the best of our knowledge, this is the first case of refractory VF that responded to low-dose esmolol ß-blockade.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Propanolaminas/uso terapêutico , Fibrilação Ventricular/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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