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1.
J Surg Res ; 246: 6-18, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31541709

RESUMO

BACKGROUND: Remote ischemic postconditioning (RIPost) has been shown to reduce the ischemia-reperfusion injury of the heart and brain. However, the protection mechanisms have not yet been fully elucidated. We have observed that RIPost could alleviate the brain injury after cardiac arrest (CA). The aim of this study was to explore whether α7 nicotinic acetylcholine receptor (α7nAChR) mediates the neuroprotection of RIPost in a rat model of asphyxial CA. MATERIALS AND METHODS: Asphyxial CA model was induced by occlusion of the tracheal tube for 8 min and resuscitated later. RIPost produced by three cycles of 15-min occlusion and 15-min release of the right hind limb by a tourniquet was performed respectively at the moment and the third hour after restoration of spontaneous circulation. The α7nAChR agonist PHA-543613 and the antagonist methyllycaconitine (MLA) were used to investigate the role of α7nAChR in mediating neuroprotective effects. RESULTS: Results showed that α7nAChR was decreased in hippocampus and cortex after resuscitation, whereas RIPost could attenuate the reduction. The use of PHA-543613 provided neuroprotective effects against cerebral injury after CA. Furthermore, RIPost decreased the levels of neuron-specific enolase, inflammatory mediators, the number of apoptotic cells, and phosphorylation of nuclear factor-κB while increased the phosphorylation of signal transducer and activator of transcription-3. However, the above effects of RIPost were attenuated by α7nAChR antagonist methyllycaconitine. CONCLUSIONS: Neuroprotection of RIPost was related with the activation of α7nAChR, which could suppress nuclear factor-κB and activate signal transducer and activator of transcription-3 in a rat asphyxial CA model.


Assuntos
Parada Cardíaca/terapia , Hipóxia Encefálica/terapia , Pós-Condicionamento Isquêmico , Neuroproteção/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Asfixia/complicações , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Parada Cardíaca/etiologia , Hipocampo/irrigação sanguínea , Hipocampo/patologia , Humanos , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/patologia , Masculino , NF-kappa B/metabolismo , Neuroproteção/efeitos dos fármacos , Quinuclidinas/farmacologia , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resultado do Tratamento , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
2.
Life Sci ; 239: 117075, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751587

RESUMO

AIMS: Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. METHODS: Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. KEY FINDINGS: In the telemetric rats post-MI, zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by zacopride treatment. SIGNIFICANCE: IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.


Assuntos
Benzamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Infarto do Miocárdio/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/tratamento farmacológico , Benzamidas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Eletrocardiografia/métodos , Ventrículos do Coração/metabolismo , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Ratos , Ratos Sprague-Dawley , Taquicardia Ventricular/metabolismo
3.
J Cancer Res Clin Oncol ; 145(12): 2921-2936, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620898

RESUMO

PURPOSE: The present study aims to determine whether co-targeting PI3K/Akt and MAPK/ERK pathways in human hypopharyngeal squamous cell carcinoma (HSCC) is a potential anticancer strategy. METHODS: We retrospectively analyzed the clinical data of HSCC patients, and the phosphorylation status of Akt and Erk in HSCC and tumor adjacent tissues was evaluated by immunohistochemistry. MTT and colony formation assay were performed to determine the anti-proliferative effect of PI3K/mTOR inhibitor GDC-0980 and MEK inhibitor Refametinib on HSCC cell line Fadu. Wound-healing and Transwell migration assay were used to analyze the anti-migrative capability of the two drugs. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. The combinational anticancer effect of GDC-0980 and Refametinib was evaluated according to Chou and Talalay's method. RESULTS: The levels of p-Akt and p-Erk were increased significantly with the progression of clinical stage of HSCC, suggesting PI3K/Akt and MAPK/ERK pathways might be associated with HSCC occurrence and progression. Furthermore, both GDC-0980 and Refametinib showed obvious antitumor effects on FaDu cells. Treatment by the two drugs arrested FaDu cell cycle progression in G1 phase, with reduction of cyclin D1 and p-Rb, in contrast to enhancement of p27. GDC-0980 inhibited FaDu cell migration and reduced metastasis related proteins including p-PKCζ, p-Integrin ß1 and uPA. Combination use of GDC-0980 and Refametinib exhibited strong synergistic anti-tumor effect. CONCLUSION: Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCC patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Sinergismo Farmacológico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Estudos Retrospectivos , Sulfonamidas/farmacologia
4.
World J Gastroenterol ; 25(33): 4835-4849, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543677

RESUMO

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Cirrose Hepática/imunologia , Fígado/patologia , Transdução de Sinais/imunologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Fígado/citologia , Fígado/imunologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
5.
Nat Commun ; 10(1): 3827, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444357

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.


Assuntos
Actinas/metabolismo , Esclerose Amiotrófica Lateral/patologia , Neurônios Motores/patologia , Poro Nuclear/patologia , Profilinas/metabolismo , Acrilamidas/farmacologia , Actinas/ultraestrutura , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Esclerose Amiotrófica Lateral/genética , Biópsia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Linhagem Celular , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Embrião de Mamíferos , Fibroblastos , Humanos , Microscopia Eletrônica de Transmissão , Neurônios Motores/citologia , Mutação , Poro Nuclear/efeitos dos fármacos , Poro Nuclear/ultraestrutura , Cultura Primária de Células , Profilinas/genética , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/genética , Pele/citologia , Pele/patologia , Tiazóis/farmacologia , Tiazolidinas/farmacologia
6.
Oxid Med Cell Longev ; 2019: 7450151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281589

RESUMO

Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.


Assuntos
Material Particulado/toxicidade , Pneumonia/etiologia , Hipersensibilidade Respiratória/etiologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Acrilamidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oximas/farmacologia , Tamanho da Partícula , Pneumonia/metabolismo , Pneumonia/patologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese
7.
Ann Clin Lab Sci ; 49(3): 291-296, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31308026

RESUMO

Osteosarcoma is one of the most aggressive primary malignant bone tumors, and the effect of first-line therapeutic schedule had no improvement in past few years. Therefore, it is extremely urgent to develop new drugs against osteosarcoma. In this study, human osteosarcoma U2 OS cells as a model in vitro were treated with LY404039 and dimethyl sulfoxide. CCK-8 proliferation test, transwell assay, and flow cytometry were used to assess cell proliferation, invasion/migration, and apoptosis, respectively. Moreover, western blotting was performed to determine the relative expression of protein related to apoptosis and PI3K signaling pathway. The proliferation of U2 OS cells was significantly inhibited 72 h after LY404039-treatment by CCK-8 proliferation test. Matrigel invasion analysis showed the numbers of invasive cells were significantly decreased in LY404039-treated group compared with the NC group. Furthermore, LY404039 led to the remarkable reduction of the number of U2 OS cells passing through the microwells of the transwell chamber. The expression levels of anti-apoptotic protein BCL-2 decreased, and the expression of pro-apoptotic proteins Active Caspase3, Bax increased concurrently after LY404039 stimulation using western blot. The phosphorylation of AKT and mTOR were significantly inhibited in U2 OS cells treated with LY404039. Also, the activity of the downstream proteins such as p70S6K and Cyclin D1 were also significantly decreased. LY404039 could inhibit proliferation and metastasis of osteosarcoma cells, which might be attributed to the enhancement of apoptosis via PI3K pathway.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Óxidos S-Cíclicos/farmacologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Molecules ; 24(14)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315184

RESUMO

Cyclophostin, the cyclipostins and the salinipostins are structurally related cyclic enolphosphate natural products. This mini review describes their isolation, synthesis and biological activities. In addition, the synthesis and biological activities of monocyclic enolphosphate and mono and bicyclic enolphosphonate analogs are presented.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Organofosforados/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Estrutura Molecular , Compostos Organofosforados/farmacologia , Estereoisomerismo
9.
Int J Mol Sci ; 20(14)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315217

RESUMO

Norcantharidin (NCTD), a demethylated analog of cantharidin isolated from blister beetles, has been used as a promising anticancer agent; however, the underlying function of NCTD against human oral squamous cell carcinoma (OSCC) has not been fully understood. Here, this study was aimed to investigate the apoptotic effect and molecular targets of NCTD in human OSCC in vitro and in vivo. The anticancer effects of NCTD and its related molecular mechanisms were evaluated by trypan blue exclusion assay, live/dead assay, western blotting, 4-6-Diamidino-2-Phenylindole (DAPI) staining, flow cytometric analysis, Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay, and immunohistochemistry. NCTD significantly inhibited cell growth and increased the number of dead cells in HSC-3 and HN22 cell lines. It induced the following apoptotic phenomena: (1) the cleavages of poly (ADP-ribose) polymerase and casepase-3; (2) increase in apoptotic morphological changes (nuclear condensation and fragmentation); (3) increase in annexin V-positive cells or sub-G1 population of cells. NCTD significantly activated the p38 mitogen-activated protein kinase (MAPK) pathway but inactivated the signal transducer and activator of transcription (STAT)3 pathway. A p38 MAPK inhibitor (SB203580) partially attenuated NCTD-induced programmed cell death (apoptosis) in both cell lines, whereas ectopic overexpression of STAT3 did not affect it. NCTD strongly suppressed tumor growth in the tumor xenograft bearing HSC-3 cells, and the number of TUNEL-positive cells increased in NCTD-treated tumor tissues. In addition, NCTD did not cause any histopathological changes in the liver nor the kidney. NCTD induced programmed cell death via the activation of p38 MAPK in OSCC. Therefore, these results suggest that NCTD could be a potential anticancer drug candidate for the treatment of OSCC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Bucais/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
10.
Mol Cell Biochem ; 461(1-2): 57-64, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31352610

RESUMO

Metabolic syndrome (MetS) is associated with alterations in coronary vascular smooth muscle and endothelial function. The current study examined the contractile response of the isolated coronary arterioles to serotonin in pigs with and without MetS and investigated the signaling pathways responsible for serotonin-induced vasomotor tone. The MetS pigs (8-weeks old) were fed with a hyper-caloric, fat/cholesterol diet and the control animals (lean) were fed with a regular diet for 12 weeks (n = 6/group). The coronary arterioles (90-180 µm in diameter) were dissected from the harvested pig myocardial tissues and the in vitro coronary arteriolar response to serotonin was measured in the presence of pharmacological inhibitors. The protein expressions of phospholipase A2 (PLA2), TXA2 synthase, and the thromboxane-prostanoid (TP) receptor in the pigs' left ventricular tissue samples were measured using Western blotting. Serotonin (10-9-10-5 M) induced dose-dependent contractions of coronary-resistant arterioles in both non-MetS control (lean) and MetS pigs. This effect was more pronounced in the MetS vessels compared with those of non-MetS controls (lean, P < 0.05]. Serotonin-induced contraction of the MetS vessels was significantly inhibited in the presence of the selective PLA2 inhibitor quinacrine (10-6 M), the COX inhibitor indomethacin (10-5 M), and the TP receptor antagonist SQ29548 (10-6 M), respectively (P < 0.05). MetS exhibited significant increases in tissue levels of TXA2 synthase and TP receptors (P < 0.05 vs. lean), respectively. MetS is associated with increased contractile response of porcine coronary arterioles to serotonin, which is in part via upregulation/activation of PLA2, COX, and subsequent TXA2, suggesting that alteration of vasomotor function may occur at an early stage of MetS and juvenile obesity.


Assuntos
Arteríolas/fisiopatologia , Vasos Coronários/fisiopatologia , Síndrome Metabólica/fisiopatologia , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Vasos Coronários/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos Insaturados/farmacologia , Hidrazinas/farmacologia , Indometacina/farmacologia , Masculino , Fosfolipases A2/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Quinacrina/farmacologia , Receptores de Tromboxanos/metabolismo , Suínos , Tromboxano A2/metabolismo
11.
Nat Commun ; 10(1): 2746, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227712

RESUMO

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of α7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for α7 nAChRs. Leveraging the robust recombinant expression of α7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on α7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal α7 receptor assembly. These results demonstrate that Bcl-2 proteins link α7 nAChR assembly to cell survival pathways.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neurônios/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Motivos de Aminoácidos/genética , Animais , Benzotiazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Chaperonas Moleculares/metabolismo , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/genética
12.
Int Rev Neurobiol ; 145: 177-209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208524

RESUMO

Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas overexpression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD+, prevents and reverses DPN, in part by increasing NAD+ levels and SIRT1 activity. In summary, we review the role of NAD+, mitochondria and the SIRT1-PGC-1α-TFAM pathway both from the perspective of pathogenesis and therapy in DPN.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neuropatias Diabéticas/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , NAD/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo , Aminoácidos/efeitos dos fármacos , Aminoácidos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , DNA Mitocondrial/metabolismo , Humanos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais
13.
Nat Cell Biol ; 21(7): 845-855, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209295

RESUMO

RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and experimental metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.


Assuntos
Actinas/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Actinas/efeitos dos fármacos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Citocalasina D/farmacologia , Proteínas Ativadoras de GTPase/efeitos dos fármacos , Proteínas Ativadoras de GTPase/genética , Guanosina Trifosfato/metabolismo , Humanos , Camundongos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Coelhos , Tiazolidinas/farmacologia , Proteína cdc42 de Ligação ao GTP/efeitos dos fármacos , Proteínas rac de Ligação ao GTP/metabolismo
14.
Nat Commun ; 10(1): 2477, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171770

RESUMO

Blood vessels in the central nervous system (CNS) develop unique features, but the contribution of CNS neurons to regulating those features is not fully understood. We report that inhibiting spontaneous cholinergic activity or reducing starburst amacrine cell numbers prevents invasion of endothelial cells into the deep layers of the retina and causes blood-retinal-barrier (BRB) dysfunction in mice. Vascular endothelial growth factor (VEGF), which drives angiogenesis, and Norrin, a Wnt ligand that induces BRB properties, are decreased after activity blockade. Exogenous VEGF restores vessel growth but not BRB function, whereas stabilizing beta-catenin in endothelial cells rescues BRB dysfunction but not vessel formation. We further identify that inhibiting cholinergic activity reduces angiogenesis during oxygen-induced retinopathy. Our findings demonstrate that neural activity lies upstream of VEGF and Norrin, coordinating angiogenesis and BRB formation. Neural activity originating from specific neural circuits may be a general mechanism for driving regional angiogenesis and barrier formation across CNS development.


Assuntos
Células Amácrinas/fisiologia , Barreira Hematorretiniana/crescimento & desenvolvimento , Neurônios Colinérgicos/fisiologia , Células Endoteliais/fisiologia , Neovascularização Fisiológica/fisiologia , Células Ganglionares da Retina/fisiologia , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Barreira Hematorretiniana/inervação , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Proteínas do Olho/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Agonistas Nicotínicos/farmacologia , Oxigênio/efeitos adversos , Piridinas/farmacologia , Doenças Retinianas , Células Ganglionares da Retina/metabolismo , Neovascularização Retiniana/etiologia , Tetrodotoxina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Catenina/metabolismo
15.
Expert Opin Ther Pat ; 29(7): 487-496, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31154862

RESUMO

INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies. AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations, in vitro and in vivo efficacy as well as the therapeutic application of venetoclax. EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia
17.
Int J Biol Macromol ; 136: 1-12, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158420

RESUMO

Novel polymer-drug conjugates (CNC) were prepared from carboxymethyl chitosan (CMCS) and norcantharidin (NCTD) via amidation reaction and characterized by FTIR and 1H NMR spectroscopy. The aim of this study was to elucidate the antitumor efficacy of CNC on gastric cancer and the possible underlying mechanisms. The CNC conjugates possessed significant inhibitory effects on the proliferation of SGC-7901 cells and suppressed the migration as well as tube formation of HUVECs. Besides, Hoechst 33258 staining and Annexin V-FITC/PI detection suggested that the conjugates were more effective in triggering apoptosis of SGC-7901 cells compared with free NCTD. Moreover, CNC remarkably reduced systemic toxicity and enhanced the antitumor efficacy in vivo with a tumor suppression rate of 59.57% against SGC-7901 gastric tumor in BALB/c nude mice. Further investigation about the underlying mechanisms indicated that CNC could upregulate expressions of TNF-α and Bax, and downregulate expressions of VEGF, Bcl-2, MMP-2 and MMP-9, thereby inhibiting tumor metastasis and inducing apoptosis in vivo. Overall, our results demonstrated that CNC might be a promising and feasible polymer therapeutics for gastrointestinal tumor therapy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Quitosana/análogos & derivados , Neoplasias Gástricas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/química , Feminino , Humanos , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cells ; 8(6)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216656

RESUMO

Postnatal female germline stem cells (FGSCs) are a type of germline stem cell with self-renewal ability and the capacity of differentiation toward oocyte. The proliferation, differentiation, and apoptosis of FGSCs have been researched in recent years, but autophagy in FGSCs has not been explored. This study investigated the effects of the small-molecule compound 89 (C89) on FGSCs and the underlying molecular mechanism in vitro. Cytometry, Cell Counting Kit-8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EdU) assay showed that the number, viability, and proliferation of FGSCs were significantly reduced in C89-treated groups (0.5, 1, and 2 µM) compared with controls. C89 had no impact on FGSC apoptosis or differentiation. However, C89 treatment induced the expression of light chain 3 beta II (LC3BII) and reduced the expression of sequestosome-1 (SQSTM1) in FGSCs, indicating that C89 induced FGSC autophagy. To investigate the mechanism of C89-induced FGSC autophagy, RNA-seq technology was used to compare the transcriptome differences between C89-treated FGSCs and controls. Bioinformatics analysis of the sequencing data indicated a potential involvement of the phosphatidylinositol 3 kinase and kinase Akt (PI3K-Akt) pathway in the effects of C89's induction of autophagy in FGSCs. Western blot confirmed that levels of p-PI3K and p-Akt were significantly reduced in the C89- or LY294002 (PI3K inhibitor)-treated groups compared with controls. Moreover, we found cooperative functions of C89 and LY294002 in inducing FGSC autophagy through suppressing the PI3K-Akt pathway. Taken together, this research demonstrates that C89 can reduce the number, viability, and proliferation of FGSCs by inducing autophagy. Furthermore, C89 induced FGSC autophagy by inhibiting the activity of PI3K and Akt. The PI3K-Akt pathway may be a target to regulate FGSC proliferation and death.


Assuntos
Compostos de Boro/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células-Tronco de Oogônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Células-Tronco Germinativas Adultas/citologia , Células-Tronco Germinativas Adultas/efeitos dos fármacos , Células-Tronco Germinativas Adultas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Camundongos , Células-Tronco de Oogônios/citologia , Células-Tronco de Oogônios/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Drug Des Devel Ther ; 13: 1281-1288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114164

RESUMO

Purpose: To evaluate the effects of dezocine on the prevention of postoperative catheter-related bladder discomfort (CRBD). Patients and methods: Ninety-six adult patients undergoing abdominal surgery with urinary catheterization under general anesthesia were randomized into dezocine and control (flurbiprofen) groups. The postoperative CRBD, pain score, sedation score and adverse effects were evaluated at 0, 1, 2 and 6 hrs after tracheal extubation. Results: The primary outcome showed a lower incidence of CRBD at 1 hr post-extubation in the dezocine group (29.17%) than the control group (58.33%, P<0.01). The incidences at 0 and 2 hrs post-extubation and the overall incidence were also lower in the dezocine group than the control group (all P<0.05). The severity of CRBD at 0, 1, 2 and 6 hrs and the pain, sedation score and other adverse effects were comparable between the two groups (P>0.05); however, the overall severity of CRBD was decreased in the dezocine group compared with the control group (P<0.05). Conclusion: Intraoperative dezocine reduces the incidence and severity of postoperative CRBD without clinically relevant adverse effects.


Assuntos
Analgésicos Opioides/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Bexiga Urinária/efeitos dos fármacos , Cateterismo Urinário , Adolescente , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/cirurgia , Estudos Prospectivos , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/administração & dosagem , Bexiga Urinária/cirurgia , Adulto Jovem
20.
Molecules ; 24(10)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109130

RESUMO

Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported to exhibit activity against various types of cancers. However, the anti-invasive effects of NCTD and its molecular mechanism in human mucoepidermoid carcinoma (MEC) remain incompletely elucidated. Clonogenic, wound healing, invasion, zymography, western blotting and immunocytochemistry assays were performed in YD-15 cells to investigate the anti-invasive effect of NCTD and its molecular mechanism of action. The inhibitory effects of NCTD on invasiveness were compared with those of a novel focal adhesion kinase (FAK) kinase inhibitor, PF-562271. NCTD markedly suppressed the colony formation, migration, and invasion of YD-15 cells as well as the activities of MMP-2 and MMP-9. It disrupted F-actin reorganization through suppressing the FAK/Paxillin axis. Moreover, NCTD exhibited a powerful anti-invasive effect compared with that of PF-562271 in YD-15 cells. Collectively, these results suggest that NCTD has a potential anti-invasive activity against YD-15 cells. This study may clarify the impact of NCTD on migration and invasion of human MEC cells.


Assuntos
Actinas/antagonistas & inibidores , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Movimento Celular/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Paxilina/antagonistas & inibidores , Carcinoma Mucoepidermoide/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Transdução de Sinais
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