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1.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166267, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508829

RESUMO

Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genética , Tadalafila/farmacologia , Proteínas de Sinalização YAP/genética , Animais , Azepinas/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Hippo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibidores da Fosfodiesterase 5/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Receptores de Superfície Celular/antagonistas & inibidores , Triazóis/farmacologia
2.
Theranostics ; 11(14): 6983-7004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093866

RESUMO

Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.


Assuntos
Astrócitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gliose/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas Correpressoras/antagonistas & inibidores , Dieta Hiperlipídica , Proteína Glial Fibrilar Ácida/metabolismo , Glucose/metabolismo , Proteínas de Grupo de Alta Mobilidade/antagonistas & inibidores , Proteínas de Grupo de Alta Mobilidade/genética , Histona Desmetilases/antagonistas & inibidores , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , RNA Interferente Pequeno , RNA-Seq
3.
Biochem Biophys Res Commun ; 545: 125-131, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33548625

RESUMO

Bromodomain and PHD finger containing transcription factor (BPTF) is a multidomain protein that regulates the transcription of chromatin and is related to many cancers. Herein, we report the screening-based discovery of Cpd1, a compound with micromolar affinity to the BPTF bromodomain. Through structure-guided optimization, we synthesized a variety of new inhibitors. Among these compounds, Cpd8 and Cpd10 were highly potent and selective inhibitors, with KD values of 428 nM and 655 nM in ITC assays, respectively. The high activity was explained by the cocrystal structure of Cpd8 in complex with the BPTF bromodomain protein. Cpd8 and Cpd10 were able to stabilize the BPTF bromodomain protein in cells in a cellular thermal shift assay (CETSA). Cpd8 downregulated c-MYC expression in A549 cells. All experiments prove that these two compounds are potential BPTF inhibitors.


Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Células A549 , Antígenos Nucleares/química , Antígenos Nucleares/genética , Calorimetria , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Fluorometria , Regulação da Expressão Gênica/efeitos dos fármacos , Genes myc , Células HEK293 , Humanos , Modelos Moleculares , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Domínios Proteicos , Estabilidade Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/genética
4.
Neuropeptides ; 87: 102134, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33639357

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra and the deposition of Lewy bodies. Mitochondrial dysfunction, oxidative stress, and autophagy dysfunction are involved in the pathogenesis of PD. Ghrelin is a brain-gut peptide that has been reported that protected against 1-methyl-4-phenyl-1,2,3,6- tetrahydropyran (MPTP)/MPP+-induced toxic effects. In the present work, human neuroblastoma SH-SY5Y cells were exposed to rotenone as a PD model to explore the underlying mechanism of ghrelin. We found that ghrelin inhibited rotenone-induced cytotoxicity, mitochondrial dysfunction, and apoptosis by improving cell viability, increasing the ratio of red/green of JC-1, inhibiting the production of reactive oxidative species (ROS), and regulating Bcl-2, Bax, Cytochrome c, caspase-9, and caspase-3 expression. Besides, ghrelin promoted mitophagy accompanied by up-regulating microtubule-associated protein 1 Light Chain 3B-II/I(LC3B-II/I) and Beclin1 but decreasing the expression of p62. Moreover, ghrelin promoted PINK1/Parkin mitochondrial translocation. Additionally, we investigated that ghrelin activated the AMPK/SIRT1/PGC1α pathway and pharmacological inhibition of AMPK and SIRT1 abolished the cytoprotection of ghrelin, decreased the level of mitophagy, and PINK1/Parkin mitochondrial translocation. Taken together, our findings suggested that mitophagy and AMPK/SIRT1/PGC1α pathways were related to the cytoprotection of ghrelin. These findings provided novel insights into the underlying mechanisms of ghrelin, further mechanistic studies on preclinical and clinical levels are required to be conducted with ghrelin to avail and foresee it as a potential agent in the treatment and management of PD.


Assuntos
Grelina/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitofagia/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Rotenona/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/fisiologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuroblastoma , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Proteínas Quinases/metabolismo , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio , Rotenona/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/biossíntese , alfa-Sinucleína/genética
5.
Phytomedicine ; 82: 153461, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33497927

RESUMO

BACKGROUND: Cardiac hypertrophy and fibrosis are closely related to cardiac dysfunction, especially diastolic dysfunction. Limited medications can be used to simultaneously delay cardiac hypertrophy and fibrosis in clinical practice. Piperlongumine (PLG) is an amide alkaloid extracted from Piper longum and has been shown to have multiple biological effects, including anticancer and antioxidant effects. However, the role of PLG in cardiac hypertrophy and fibrosis is not clear. PURPOSE: The aim of this study was to reveal the role of PLG in cardiac hypertrophy and fibrosis and the associated mechanism. METHODS: Cardiac hypertrophy and fibrosis were induced by angiotensin II (Ang II) in vivo and in vitro. The effect of PLG in vivo, in vitro and its mechanism were investigated by proliferation and apoptosis assays, western blot, real-time PCR, immunofluorescence, histochemistry, echocardiography, flow cytometry and chromatin immunoprecipitation. RESULTS: Proliferation and apoptosis assays showed that 2.5 µM PLG slightly inhibited proliferation and did not promote apoptosis. Treatment with 5 mg/kg PLG obviously inhibited Ang II-induced cardiac hypertrophy and fibrosis in vivo. In vitro studies of neonatal rat cardiomyocytes (NRCMs) showed that the anti-hypertrophic effect of PLG was mediated by reducing the phosphorylation of Akt and thereby preserving the level of Forkhead box transcription factor O1 (FoxO1), since knockdown of FoxO1 by siRNA reversed the protective effect of PLG on NRCMs. In addition, PLG significantly decreased the Ang II-induced expression of profibrotic proteins in neonatal cardiac fibroblasts by reducing the expression of Krüppel-like factor 4 (KLF4) and the recruitment of KLF4 to the promoter regions of transforming growth factor-ß and connective tissue growth factor. CONCLUSION: We demonstrate the cardioprotective effects of PLG in both cardiac hypertrophy and fibrosis and the potential value of PLG for developing novel medications for pathological cardiac hypertrophy and heart failure.


Assuntos
Angiotensina II/fisiologia , Cardiomegalia/prevenção & controle , Dioxolanos/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibrose/prevenção & controle , Insuficiência Cardíaca/metabolismo , Fator 4 Semelhante a Kruppel , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
6.
J Cereb Blood Flow Metab ; 41(4): 819-830, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32538280

RESUMO

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.


Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/lesões , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Sinapses/metabolismo , Animais , Anticonvulsivantes/farmacologia , Autorradiografia , Feminino , Doença de Huntington/induzido quimicamente , Doença de Huntington/patologia , Doença de Huntington/psicologia , Hidroxidopaminas/farmacocinética , Cinética , Levetiracetam/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/psicologia , Ácido Quinolínico/farmacocinética , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-Dawley
7.
Front Immunol ; 11: 2119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072073

RESUMO

Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.


Assuntos
Antineoplásicos/toxicidade , Bortezomib/toxicidade , Hormônios Gastrointestinais/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuropeptídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Células Receptoras Sensoriais/efeitos dos fármacos , Triazinas/farmacologia , Vincristina/toxicidade , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , Hormônios Gastrointestinais/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Neuritos/efeitos dos fármacos , Neuritos/ultraestrutura , Neuroimunomodulação/efeitos dos fármacos , Neuropeptídeos/fisiologia , Fármacos Neuroprotetores/uso terapêutico , RNA Mensageiro/biossíntese , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/ultraestrutura , Triazinas/uso terapêutico
8.
J Am Heart Assoc ; 9(10): e015751, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32390491

RESUMO

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK-1; hK2P3.1) two-pore-domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK-1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK-1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK-1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high-affinity TASK-1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK-1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK-1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK-1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Sulfonamidas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Estudo de Prova de Conceito , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sus scrofa , Fatores de Tempo , Xenopus laevis
9.
Front Immunol ; 11: 703, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32391014

RESUMO

Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2- (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.


Assuntos
Cumarínicos/administração & dosagem , Edema/tratamento farmacológico , Mastócitos/imunologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Sinalização do Cálcio/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Edema/imunologia , Feminino , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Doadores de Tecidos , Resultado do Tratamento
10.
J Sep Sci ; 43(13): 2571-2578, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32281296

RESUMO

Mas-related G protein-coupled receptor X2 was a mast cell-specific receptor mediating anaphylactoid reactions by activating mast cells degranulation, and it was also identified as a target for modulating mast cell-mediated anaphylactoid and inflammatory diseases. The anti-anaphylactoid drugs used clinically disturb the partial effect of partial mediators released by mast cells. The small molecule of Mas-related G protein-coupled receptor X2 specific antagonists may provide therapeutic action for the anaphylactoid and inflammatory diseases in the early stage. In this study, the Mas-related G protein-coupled receptor X2 high expression cell membrane chromatography was coupled online with liquid chromatography and mass spectrometry and successfully used to screen anti-anaphylactoid components from Magnolia biondii Pamp. Fargesin and pinoresinol dimethyl ether were identified as potential anti-anaphylactoid components. Bioactivity of these two components were investigated by ß hexosaminidase and histamine release assays on mast cells, and it was found that these two components could inhibit ß hexosaminidase and histamine release in a concentration-dependent manner. This Mas-related G protein-coupled receptor X2 high expression cell membrane chromatography coupled online with liquid chromatography and mass spectrometry system could be applied for screening potential anti-anaphylactoid components from natural medicinal herbs. This study also provided a powerful system for drug discovery in natural medicinal herbs.


Assuntos
Anafilaxia/tratamento farmacológico , Membrana Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Magnolia/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Extratos Vegetais/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Anafilaxia/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Cromatografia Líquida , Medicamentos de Ervas Chinesas/química , Células HEK293 , Humanos , Espectrometria de Massas , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Medicina Tradicional Chinesa , Proteínas do Tecido Nervoso/metabolismo , Extratos Vegetais/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo
11.
Phytomedicine ; 68: 153149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032836

RESUMO

BACKGROUND: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China. PURPOSE: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2. RESULTS: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein. CONCLUSION: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization.


Assuntos
Anafilaxia/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas do Tecido Nervoso/imunologia , Receptores Acoplados a Proteínas G/imunologia , Receptores de Neuropeptídeos/imunologia , Anafilaxia/induzido quimicamente , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Hipersensibilidade/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Naftoquinonas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Fosfolipase C gama/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Secretagogos/toxicidade , p-Metoxi-N-metilfenetilamina/toxicidade
12.
Sci Rep ; 10(1): 1143, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980673

RESUMO

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.


Assuntos
Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Tauopatias/prevenção & controle , Envelhecimento/psicologia , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Células Cultivadas , Transtornos Cognitivos/tratamento farmacológico , Donepezila/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacocinética , Fosforilação/efeitos dos fármacos , Proibitinas , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo
13.
Histochem Cell Biol ; 153(3): 165-175, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858211

RESUMO

In diabetic nephropathy (DN), intercellular communication is disrupted. Connexins (Cx) have a crucial role in that process. Dietary ratios and supplementation with polyunsaturated fatty acids (PUFAs) can alleviate diabetic complications and cause alterations in Cx levels. Although pannexins (Panx) share similarities with members of the Cx family, their function in diabetic nephropathy has still not been fully determined. We studied the influence of PUFA supplementation on the immunoexpression of Px1 and Cx family members in diabetic kidneys of rats. Four groups of rats in experimental DM1 model were supplemented with different dietary n-6/n-3 ratios; ≈7 in control (C) and diabetic groups (STZ), ≈ 60 in the STZ + N6 group and ≈ 1 (containing 16% EPA and 19% DHA) in the STZ + N3 group. Immunoexpression of Cx40, Cx43, Cx45 and Panx1 was evaluated in the renal tissue of diabetic rats using immunohistochemistry. Diabetes significantly decreased the protein expression of Cx40 and Cx43 and increased Panx1 protein expression in the renal cortex (p < 0.05-p < 0.01). There was a significant impact of diet on Cx and Panx1 immunoexpression. Dietary supplementation with a high n-6/n-3 ratio downregulated the protein expression of Cx45 and Panx1 in diabetic rats (p < 0.05-p < 0.01), while Cx43 immunoexpression was increased in diabetic rats fed with high and low n-6/n-3 ratios (p < 0.01-p < 0.001). Hyperglycaemic conditions in DN interfere with cell-to-cell communication and disturb the connection between cells and their immediate environment due to variations in connexin and pannexin immunoexpression. These variations can be regulated by PUFA dietary intake, suggesting their beneficial effect and possible therapeutic option.


Assuntos
Conexinas/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ácidos Graxos Insaturados/farmacologia , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Animais , Conexinas/análise , Conexinas/biossíntese , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Suplementos Nutricionais , Ácidos Graxos Insaturados/administração & dosagem , Rim/metabolismo , Rim/patologia , Masculino , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/biossíntese , Ratos , Ratos Wistar , Estreptozocina
14.
Channels (Austin) ; 13(1): 498-504, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31680630

RESUMO

We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1 -{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate), a candidate therapeutic for Alzheimer's disease was reported to be a novel CRMP2 binding compound with the potential to decrease its phosphorylation level in cortical tissues in vivo. Here we sought to determine the mechanism of action of edonerpic maleate and test its possible effect in a rodent model of chronic pain. We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate.


Assuntos
Hiperalgesia/tratamento farmacológico , Maleatos/administração & dosagem , Proteínas do Tecido Nervoso/antagonistas & inibidores , Tiofenos/administração & dosagem , Animais , Cálcio/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Gânglios Espinais/metabolismo , Humanos , Hiperalgesia/genética , Hiperalgesia/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fosforilação
15.
Inflammation ; 42(3): 1082-1092, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30725252

RESUMO

Acute brain dysfunction and the following neurological manifestation are common complications in septic patients, which are associated with increased morbidity and mortality. However, the therapeutic strategy of this disorder remains a major challenge. Given the emerging role of a clinically approved drug, probenecid (PRB) has been recently identified as an inhibitor of pannexin 1 (PANX1) channel, which restrains extracellular ATP release-induced purinergic pathway activation and inflammatory response contributing to diverse pathological processes. In this study, we explored whether PRB administration attenuated neuroinflammatory response and cognitive impairment during sepsis. In mice suffered from cecal ligation and puncture (CLP)-induced sepsis, treatment with PRB improved memory retention and lessened behavioral deficits. This neuroprotective effect was coupled with restricted overproduction of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and interleukin (IL)-1ß in the hippocampus. Since this damped neuroinflammation was replicated by inhibition of ATP release, it suggested that PANX1 channel modulates a purinergic-related pathway contributing to the neurohistological damage. Therefore, we identified PRB could be a promising therapeutic approach for the therapy of cerebral dysfunction of sepsis.


Assuntos
Trifosfato de Adenosina/metabolismo , Conexinas/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Probenecid/farmacologia , Sepse/tratamento farmacológico , Adjuvantes Farmacêuticos , Animais , Córtex Cerebral/fisiopatologia , Transtornos Cognitivos/prevenção & controle , Conexinas/metabolismo , Inflamação/prevenção & controle , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fármacos Neuroprotetores/farmacologia , Probenecid/uso terapêutico , Sepse/complicações
16.
Int J Mol Med ; 43(2): 717-726, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535505

RESUMO

Oxidative stress and neuroinflammation are important in the pathogenesis of ageing and age­related neurodegenerative diseases, including Alzheimer's disease. NADPH oxidase 2 (NOX2) is a major source of reactive oxygen species (ROS) in the brain. The nucleotide­binding oligomerisation domain (NOD)­like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro­inflammatory molecules in neurons. Whether the NOX2­NLRP1 inflammasome signalling pathway is involved in neuronal ageing and age­related damage remains to be elucidated. Ginsenoside Rg1 (Rg1) is a steroidal saponin found in ginseng. In the present study, the primary hippocampal neurons were treated with H2O2 (200 µM) and Rg1 (1, 5 and 10 µM) for 24 h to investigate the protective effects and mechanisms of Rg1 on H2O2­induced hippocampal neuron damage, which mimics age­related damage. The results showed that H2O2 treatment significantly increased ROS production and upregulated the expression of NOX2 and the NLRP1 inflammasome, and led to neuronal senescence and damage to hippocampal neurons. Rg1 decreased ROS production, reducing the expression of NOX2 and the NLRP1 inflammasome in H2O2­treated hippocampal neurons. Furthermore, Rg1 and tempol treatment significantly decreased neuronal apoptosis and the expression of ß­galactosidase, and alleviated the neuronal senescence and damage induced by H2O2. The present study indicates that Rg1 may reduce NOX2­mediated ROS generation, inhibit NLRP1 inflammasome activation, and inhibit neuronal senescence and damage.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Ginsenosídeos/farmacologia , Hipocampo/patologia , Inflamassomos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 1/metabolismo , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Peróxido de Hidrogênio , Inflamassomos/efeitos dos fármacos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , Proteínas NLR/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , beta-Galactosidase/biossíntese
17.
PLoS One ; 13(11): e0207750, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30462746

RESUMO

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Pirimidinas/farmacologia , Triazinas/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Camundongos , Bloqueadores dos Canais de Potássio/uso terapêutico , Pirimidinas/uso terapêutico , Ratos , Triazinas/uso terapêutico
18.
PLoS One ; 13(8): e0201092, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30110354

RESUMO

We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin-related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 µM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Canais de Potássio de Domínios Poros em Tandem/agonistas , Umbeliferonas/farmacologia , Anlodipino/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Células HEK293 , Humanos , Canal de Potássio Kv1.4/antagonistas & inibidores , Canal de Potássio Kv1.4/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/farmacologia , Compostos Fitoquímicos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/metabolismo
19.
Nutrients ; 10(7)2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30018265

RESUMO

Cholinergic dysfunction, impaired brain-derived neurotrophic factor and cAMP response element binding protein (BDNF-CREB) signaling are one of the major pathological hallmarks of cognitive impairment. Therefore, improving cholinergic neurotransmission, and regulating the BDNF-CREB pathway by downregulating apoptosis genes is one strategy for inhibiting the etiology of dementia. This study evaluates the potential effects of Stachys sieboldii MIQ (SS) extract against cognitive dysfunction and its underlying mechanisms. SS supplementation for 33 days improved scopolamine-induced memory impairment symptoms in Morris water maze test and Y-maze test. SS reduced the acetylcholineesterase activity and significantly increase acetylcholine and cholineacetyltransferase activity in the brain. In the subsequent mechanism study, SS regulated the mRNA expression level of neuronal plasticity molecules such as (nerve growth factor) NGF, BDNF, CREB, and its downstream molecules such as Bcl-2 and Egr-1 by downregulating the neuronal apoptosis targets in both hippocampus and frontal cortex. Additionally, inward currents caused by SS in hippocampal CA1 neurons was partially blocked by the GABA receptor antagonist picrotoxin (50 µM), suggesting that SS acts on synaptic/extrasynaptic GABAA receptors. These findings indicate that SS may function in a way that is similar to nootropic drugs by inhibiting cholinergic abnormalities, and neuronal apoptosis targets and ultimately increasing the expression of BDNF-CREB.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Suplementos Nutricionais , Transtornos da Memória/prevenção & controle , Nootrópicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Stachys/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/genética , Colina O-Acetiltransferase/química , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/enzimologia , Neurônios Colinérgicos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/agonistas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Etnofarmacologia , Lobo Frontal/enzimologia , Lobo Frontal/crescimento & desenvolvimento , Lobo Frontal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/enzimologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Masculino , Medicina Tradicional Coreana , Transtornos da Memória/enzimologia , Transtornos da Memória/metabolismo , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nootrópicos/administração & dosagem , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Ratos Sprague-Dawley , República da Coreia
20.
Nutrients ; 10(7)2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30029533

RESUMO

Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Taraxacum officinale has been reported to possess antioxidant activities. However, whether it can protect neurons against oxidative damage and the underlying molecular mechanisms have not been fully determined. In the present study, we examined the neuroprotective effects of ethanol extracts of this plant (ETOW) on glutamate-induced oxidative stress in HT22 cells. Both cell viability and reactive oxygen species (ROS) assays showed that ETOW effectively attenuated glutamate-induced cytotoxicity and ROS generation. Furthermore, our results revealed that ETOW increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor-2 (Nrf2). The inhibitory effects of ETOW on glutamate-stimulated cell toxicity and ROS production were partially reversed by tin protoporphyrin (SnPP), an HO activity inhibitor. Taken together, these results demonstrate that ETOW can protect HT22 cells against glutamate-induced oxidative damage by inducing the Nrf2/HO-1 pathways. Our study supports the idea that Taraxacum officinale Wigg. is a promising agent for preventing neurodegenerative diseases.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Proteínas de Membrana/agonistas , Fator 2 Relacionado a NF-E2/agonistas , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Taraxacum/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ácido Glutâmico/intoxicação , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metaloporfirinas/farmacologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
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