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1.
J Cell Physiol ; 234(3): 2807-2821, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30067871

RESUMEN

The application of pulsed electromagnetic fields (PEMFs) in the prevention and treatment of osteoporosis has long been an area of interest. However, the clinical application of PEMFs remains limited because of the poor understanding of the PEMF action mechanism. Here, we report that PEMFs promote bone formation by activating soluble adenylyl cyclase (sAC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) signaling pathways. First, it was found that 50 Hz 0.6 millitesla (mT) PEMFs promoted osteogenic differentiation of rat calvarial osteoblasts (ROBs), and that PEMFs activated cAMP-PKA-CREB signaling by increasing intracellular cAMP levels, facilitating phosphorylation of PKA and CREB, and inducing nuclear translocation of phosphorylated (p)-CREB. Blocking the signaling by adenylate cyclase (AC) and PKA inhibitors both abolished the osteogenic effect of PEMFs. Second, expression of sAC isoform was found to be increased significantly by PEMF treatment. Blocking sAC using sAC-specific inhibitor KH7 dramatically inhibited the osteogenic differentiation of ROBs. Finally, the peak bone mass of growing rats was significantly increased after 2 months of PEMF treatment with 90 min/day. The serum cAMP content, p-PKA, and p-CREB as well as the sAC protein expression levels were all increased significantly in femurs of treated rats. The current study indicated that PEMFs promote bone formation in vitro and in vivo by activating sAC-cAMP-PKA-CREB signaling pathway of osteoblasts directly or indirectly.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Magnetoterapia , Osteogénesis/efectos de la radiación , Osteoporosis/terapia , Inhibidores de Adenilato Ciclasa/farmacología , Adenilil Ciclasas/genética , Adenilil Ciclasas/farmacología , Animales , Densidad Ósea/efectos de la radiación , Diferenciación Celular/efectos de la radiación , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Modelos Animales de Enfermedad , Fémur/crecimiento & desarrollo , Fémur/patología , Fémur/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Osteoblastos/efectos de la radiación , Osteoporosis/genética , Osteoporosis/patología , Ratas , Transducción de Señal/efectos de la radiación
2.
PLoS One ; 13(1): e0188212, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29304113

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 µM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 µM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 µM), hepatotoxicity (up to 30 µM) or cardiotoxicity (up to 30 µM).


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Antiparkinsonianos/farmacología , Agonistas de Dopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Inhibidores de Adenilato Ciclasa/química , Inhibidores de Adenilato Ciclasa/farmacocinética , Inhibidores de Adenilato Ciclasa/farmacología , Animales , Animales Modificados Genéticamente , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Células CHO , Cricetulus , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Drosophila/genética , Drosophila/metabolismo , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Máquina de Vectores de Soporte
3.
Brain Struct Funct ; 223(3): 1537-1564, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29168010

RESUMEN

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I h, in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b-/-). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K+ current, I A, in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.


Asunto(s)
Corteza Cerebral/fisiología , Proteínas de la Membrana/metabolismo , Vías Nerviosas/fisiología , Peroxinas/metabolismo , Tálamo/fisiología , Potenciales de Acción/genética , Adenina/análogos & derivados , Adenina/farmacología , Inhibidores de Adenilato Ciclasa/farmacología , Animales , Fármacos Cardiovasculares/farmacología , Corteza Cerebral/citología , AMP Cíclico/farmacología , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacología , Femenino , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/fisiología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Neurológicos , Peroxinas/genética , Pirimidinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Tionucleótidos/farmacología
4.
J Ocul Pharmacol Ther ; 33(8): 574-581, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28686538

RESUMEN

PURPOSE: To validate the increase in intraocular pressure (IOP) caused by soluble adenylyl cyclase (sAC) inhibitors and determine reasons behind variation in IOP measurements performed by tonometry. METHODS: C57BL/6J mice were administered DMSO solubilized sAC inhibitors (KH7 or LRE-1) by intraperitoneal injection. Two hours post-treatment, mice were anesthetized with avertin or ketamine/xylazine/acepromazine (KXA). IOP was measured by a rebound tonometer or direct cannulation of the anterior chamber. Spectral-domain optical coherence tomography was used to measure anterior chamber depth and corneal thickness in live mice. Outflow facility was measured in perfused, enucleated mouse eyes. RESULTS: Compared with DMSO controls, KH7 treatment caused an increased IOP in avertin- and KXA-anesthetized mice when measured by direct cannulation [avertin: 14.4 ± 2.1 mmHg vs. 11.1 ± 1.0 mmHg (P = 0.003); KXA: 14.4 ± 1.0 mmHg vs. 11.3 ± 0.8 mmHg (P < 0.001)] and tonometry [avertin: 10.8 ± 1.4 mmHg vs. 7.4 ± 0.6 mmHg (P < 0.001); KXA: 11.9 ± 0.9 mmHg vs. 10.3 ± 1.7 mmHg (P = 0.283)]. However, treatment with KH7 in nonanesthetized mice showed a significant decrease in IOP measured by tonometry and compared with DMSO-treated animals [13.1 ± 2.6 mmHg vs. 15.6 ± 0.5 mmHg (P = 0.003)]. Both KH7- and DMSO-treated groups anesthetized with avertin showed increased corneal thickness, whereas KH7-treated mice anesthetized with KXA exhibited a shallower anterior chamber compared with untreated mice. KH7 decreased outflow facility by 85.1% in nonanesthetized, enucleated eyes (P < 0.003). CONCLUSIONS: Systemically administered DMSO and anesthesia have significant effects on anterior chamber characteristics, resulting in altered IOP readings measured by tonometry. In the presence of DMSO and anesthesia, tonometry IOP readings should be confirmed with direct cannulation.


Asunto(s)
Inhibidores de Adenilato Ciclasa/farmacología , Anestésicos/administración & dosificación , Presión Intraocular/efectos de los fármacos , Tonometría Ocular/métodos , Acepromazina/administración & dosificación , Acepromazina/farmacología , Anestésicos/farmacología , Animales , Cámara Anterior/metabolismo , Cateterismo , Etanol/administración & dosificación , Etanol/análogos & derivados , Etanol/farmacología , Femenino , Humanos , Inyecciones Intraperitoneales , Ketamina/administración & dosificación , Ketamina/farmacología , Ratones , Ratones Endogámicos C57BL , Tomografía de Coherencia Óptica , Xilazina/administración & dosificación , Xilazina/farmacología
5.
Mol Nutr Food Res ; 61(11)2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28699236

RESUMEN

SCOPE: Piperonal is an aromatic compound found in vanilla and has a floral odor resembling vanillin. This study was aimed to test whether piperonal attenuates visceral adiposity induced by a high-fat diet (HFD) in mice and to explore the underlying molecular mechanisms. METHODS AND RESULTS: Male C57BL/6N mice were fed a normal diet, HFD, or 0.05% piperonal-supplemented HFD (PSD) for 10 weeks. PSD-fed mice showed attenuation of body weight gain, total visceral fat pad weights, and plasma lipid levels compared to HFD-fed mice. Piperonal supplementation of the HFD increased the mRNA expression of certain isotypes of adenylate cyclase (Adcy) and protein kinase A (PKA) in the white adipose tissue (WAT) of mice. The adipogenesis-related genes were downregulated, whereas fatty acid oxidation- and thermogenesis-related genes were upregulated in the WAT of PSD-fed mice compared to those in HFD-fed mice. Piperonal directly activated Adcy by decreasing the Km for its substrate (ATP) in plasma membranes prepared from the WAT of mice. Furthermore, piperonal-induced inhibition of adipocyte differentiation and elevation of Adcy and PKA activities in 3T3-L1 cells were abrogated by an Adcy inhibitor. CONCLUSION: The anti-adipogenic effect of piperonal in mice fed the high-fat diet appears to be associated with increased Adcy-PKA signaling in WAT.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adenilil Ciclasas/metabolismo , Adiposidad , Fármacos Antiobesidad/uso terapéutico , Benzaldehídos/uso terapéutico , Benzodioxoles/uso terapéutico , Grasa Intraabdominal/patología , Obesidad Abdominal/prevención & control , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/genética , Inhibidores de Adenilato Ciclasa/farmacología , Adenilil Ciclasas/química , Adenilil Ciclasas/genética , Adipogénesis/efectos de los fármacos , Adiposidad/efectos de los fármacos , Animales , Fármacos Antiobesidad/metabolismo , Benzaldehídos/metabolismo , Benzodioxoles/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/enzimología , Grasa Intraabdominal/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad Abdominal/etiología , Obesidad Abdominal/metabolismo , Obesidad Abdominal/patología , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Organismos Libres de Patógenos Específicos , Termogénesis/efectos de los fármacos
6.
Phytomedicine ; 30: 18-27, 2017 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-28545666

RESUMEN

BACKGROUND: Based on the traditional application of traditional Chinese Medicines (TCMs), Ephedra Herba (EH) is used to cure cold fever by inducing sweating, whereas Ephedra Radix (ER) is used to treat hyperhidrosis. Although they come from the same plant, Ephedra sinica Stapf, but have play opposing roles in clinical applications. EH is known to contain ephedrine alkaloids, which is the driver of the physiological changes in sweating, heart rate and blood pressure. However, the active pharmacological ingredients (APIs) of ER and the mechanisms by which it restricts sweating remain unknown. PURPOSE: The current work aims to discover the hidroschesis APIs from ER, as well as to establish its action mechanism. METHODS: UPLC-Q/TOF-MS, PCA, and heat map were utilized for identifying the differences between EH and ER. HPLC integrated with a ß2-adrenoceptor (ß2-AR) activity luciferase reporter assay system was used to screen active inhibitors; molecular docking and a series of biological assays centered on ß2-AR-related signaling pathways were evaluated to understand the roles of APIs. RESULTS: The opposite effect on sweating of EH and ER can be attributed to the APIs of amphetamine-type alkaloids and flavonoid derivatives. Mahuannin B is an effective anti-hydrotic agent, inhibiting the production of cAMP via suppression of adenylate cyclase (AC) activity. CONCLUSION: The effects of EH and ER on sweat and ß2-AR-related signaling pathway are opposite due to different alkaloids and flavonoids of APIs in EH and ER. The present work not only sheds light on the hidroschesis action of mahuannin B, but also presents a potential target of AC in the treatment of hyperhidrosis.


Asunto(s)
Inhibidores de Adenilato Ciclasa/farmacología , Alcaloides/farmacología , AMP Cíclico/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ephedra/química , Flavonoides/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Inhibidores de Adenilato Ciclasa/química , Antagonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Alcaloides/química , Animales , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos/métodos , Medicamentos Herbarios Chinos/química , Ephedra sinica/química , Efedrina/farmacología , Flavonoides/química , Masculino , Ratones , Simulación del Acoplamiento Molecular , Receptores Adrenérgicos , Transducción de Señal/efectos de los fármacos , Especificidad de la Especie , Sudoración/efectos de los fármacos
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