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Can J Physiol Pharmacol ; 98(3): 156-161, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32078386


Hyperglycemia mediates oxidative stress, thus inducing transcription factor nuclear factor kappa B (NF-κB) activation, increasing endothelial adhesion molecule expression and monocyte/endothelial interaction, and resulting in endothelial injury. Ketamine was reported to attenuate oxidative stress in many cases. In this research, we determined whether and how ketamine protects against high-glucose-mediated augmentation of monocyte/endothelial interaction and endothelial adhesion molecule expression in human umbilical vein endothelial cells. High glucose augmented monocyte/endothelial adhesion and endothelial adhesion molecule expression. High glucose induced reactive oxygen species (ROS) production and augmented phospho-protein kinase C (p-PKC) ßII expression and PKC activity. Moreover, high glucose inhibited the inhibitory subunit of nuclear factor-κBα (IκBα) expression in the cytoplasm and induced NF-κB nuclear translocation. Importantly, the effects induced by high glucose were counteracted by ketamine treatment. Further, CGP53353, a PKC ßII inhibitor, inhibited high-glucose-mediated NF-κB nuclear translocation, attenuated adhesion molecule expression, and reduced monocyte/endothelial interaction. Further, these effects of ketamine against high-glucose-induced endothelial injury were inhibited by phorbol 12-myristate 13-acetate, a PKC ßII activator. In conclusion, ketamine, via reducing ROS accumulation, inhibited PKC ßII Ser660 phosphorylation and PKC and NF-κB activation and reduced high-glucose-induced expression of endothelial adhesion molecules and monocyte/endothelial interaction.

Aging (Albany NY) ; 11(19): 8681-8700, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613226


BACKGROUND: As an important downstream factor in the Hippo pathway, yes-associated protein 1(YAP1) has been detected to be elevated in various cancers and demonstrated to play a role in tumor development. Therefore, we evaluated by a meta-analysis the prognostic value of YAP1 in cancer patients. RESULTS: Sixty-eight studies with 8631 patients were identified. The results indicated that YAP1 overexpression predicted unfavorable patient prognosis in studies with overall survival (OS) (HR=1.76, 95%CI: 1.50-2.06, p<0.001) and disease-free survival (DFS) (HR=1.39, 95%CI: 1.22-1.59, p<0.001), as well as in studies with recurrence-free survival (RFS) (HR=2.38, 95%CI: 1.73-3.27, p<0.001), and disease-specific survival (DSS) (HR=2.04, 95%CI: 1.55-2.70, p<0.001). Meanwhile, YAP1 overexpression was also observed to be significantly associated with worse OS in GEPIA (HR=1.2, p<0.001). CONCLUSIONS: Overexpression of YAP1 showed great association with poorer prognosis in patients with various cancers, particularly liver cancer. Therefore, YAP1 might be an important prognostic marker and a novel target of cancer therapy. METHODS: We searched for potential publications in several online databases and retrieved relevant data. Overall and subgroup analyses were performed. Begg's and Egger's tests were used to assess publication bias. Online dataset GEPIA was used to generate the survival curves and verify the prognostic role of YAP1 in patients with tumors.

Eur J Pharmacol ; 846: 63-72, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30586550


Postoperative cognitive dysfunction (POCD) is commonly seen in patients undergoing major surgeries and may persist. Although neuroinflammation is one of the important contributors to the development of POCD, the mechanisms underlying POCD remain unclear. We performed stabilized tibial fracture operation in male mice. In comparison with sham mice (anesthesia only), the surgery mice exhibited cognitive deficits in a fear conditioning paradigm at postsurgery day 3-7, and increased numbers of microglia and elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) without change of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Electrophysiological recordings from CA1 hippocampal neurons revealed that POCD mice exhibited impairment in AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) without alteration in the rectification property of AMPA receptors. Interestingly, daily intraperitoneal administration of galantamine, an inhibitor of acetylcholinesterase, reversed cognitive dysfunction in surgery mice and attenuated accumulation of microglia and protein levels of IL-1ß, IL-6 and TNF-α in the hippocampus. Additionally, galantamine potentiated AMPA receptor-mediated eEPSCs in the hippocampus more prominent in surgery mice than in sham mice. Therefore, enhancement of cholinergic tone in the hippocampus might be a therapeutic strategy for early POCD in terms of suppression of inflammation and normalization of excitatory synaptic transmission.

Região CA1 Hipocampal/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Galantamina/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Transmissão Sináptica/efeitos dos fármacos , Animais , Região CA1 Hipocampal/patologia , Citocinas/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Galantamina/farmacologia , Inflamação/tratamento farmacológico , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Fraturas da Tíbia/cirurgia , Fator de Necrose Tumoral alfa/metabolismo
Medicine (Baltimore) ; 97(30): e11648, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30045314


Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for EGFR-mutant nonsmall cell lung cancer (NSCLC) patients. However, studies have reported that not all NSCLC patients harboring kinase domain mutations in epidermal growth factor receptor (EGFR) show significant clinical benefits from EGFR-targeted tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to establish feasible biomarkers to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs. This study aimed to determine biomarkers using inflammatory parameters from complete blood counts to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs.We retrospectively investigated 127 stage IIIB/IV NSCLC patients with activating EGFR mutations who were treated with EGFR-TKIs. We used receiver operating characteristic (ROC) curves to determine the optimal cut-off for the inflammatory markers as prognostic factors. Additionally, univariate and multivariate analyses were used to identify prognostic factors for progression-free survival (PFS) and overall survival (OS) of EGFR-mutant NSCLC patients treated with EGFR-TKIs.The receiver operating characteristic analysis indicated that the lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) cut-off values were 3.37 and 2.90, respectively. The univariate analysis showed that a high LMR (>3.37) and low NLR (≤2.90) were significantly correlated with long-term PFS and OS (LMR, P = .007; NLR, P < .001). The multivariate Cox regression analysis revealed that only low NLR was an independent prognostic factor for long-term PFS and OS (PFS, HR = 0.573, 95% CI: 0.340-0.964, P = .036; OS, HR = 0.491, 95% CI: 0.262-0.920, P = .026).The data show that a low NLR was a good prognostic factor in EGFR-mutant NSCLC patients receiving EGFR-TKIs treatment. Moreover, the NLR measurement has better prognostic value than LMR.

Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Linfócitos/fisiologia , Neutrófilos/fisiologia , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores