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1.
Artigo em Inglês | MEDLINE | ID: mdl-34813573

RESUMO

ABSTRACT: The optimal duration of dual antiplatelet therapy (DAPT) for patients implanted with new-generation drug-eluting stents (DES) in East Asians is currently still controversial. The purpose of this meta-analysis was to investigate the efficacy and safety of short-term DAPT in patients with those. In this study, randomized controlled trials from PubMed, EMBASE, and Cochrane Library were searched to compare the efficacy and safety of short-term DAPT (6- month or less) with long-term DAPT (12- month or more) in patients implanted with new-generation DES in East Asian from inception to September 2020. The primary efficacy outcome was all-cause death, the primary safety outcome was major bleeding, and the secondary outcomes included cardiovascular death, myocardial infarction, definite or possible stent thrombosis, and stroke.A total of six randomized controlled trials with 15688 patients met inclusion criteria, there were no significant differences in the incidence of all-cause death (RR 1.03, 0.76-1.39, P=0.856), cardiovascular death (RR 0.83, 0.55-1.24, P=0.361), myocardial infarction (RR 0.97, 0.72-1.31, P=0.853), definite or possible stent thrombosis (RR 1.52, 0.83-2.78, P=0.170) and stroke (RR 0.90, 0.61-1.31, P=0.574) between short- term and long- term DAPTs. However, there was a significant difference in the risk of major bleeding (RR 0.64, 0.49-0.85, P=0.002) between the two groups. Compared with long-term DAPT, the short-term DAPT can reduce the risk of major bleeding without increasing the risk of death or ischemia for East Asians (Registered by PROSPERO, CRD42020213266).

2.
Fish Shellfish Immunol ; 119: 373-378, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34688862

RESUMO

Soya-saponins represent key anti-nutritional factors that contribute to soybean meal-induced enteritis, and glutamine is an effective fish intestine protectant that combats the negative effects of soya-saponins. Nuclear transcription factor-kappa B (NF-кB) systems are involved in the interactions between soya-saponins and glutamine, and the goal of the present work was to clarify the related molecular mechanisms used by the NF-кB kinase (IKK)/inhibitor of NF-κB (IκB)/NF-кB system. Primary cultured turbot (Scophthalmus maximus L.) intestinal epithelial cells were concurrently administrated with 1 mg/mL of soya-saponins and several levels of glutamine (0, 0.5, 1.0 and 2.0 mM) for 12 h and then subjected to real-time PCR and Western blot assays. Compared with cells treated with soya-saponins alone, glutamine significantly decreased the expression of interleukin-1 beta, interleukin 8 and tumor necrosis factor α genes, significantly reduced nuclear and cytosolic NF-κB p65 abundance levels in a dose-dependent manner, increased the IκBα protein level but decreased its phosphorylation, and down-regulated the IKKα/ß and phosphorylated IKKα/ß levels. In conclusion, this in vitro work confirmed that glutamine attenuated soya-saponin-induced inflammatory responses in turbot intestines. Moreover, it identified molecular pathways in which glutamine first decreased the p65 level and then prevented its nuclear translocation. In addition, glutamine reduced IκBα phosphorylation and maintained its level. Finally, glutamine decreased IKK expression and phosphorylation.

3.
J Cardiovasc Pharmacol ; 78(6): 819-825, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524259

RESUMO

ABSTRACT: The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.

4.
Anal Methods ; 13(39): 4585-4593, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34532726

RESUMO

Background: A liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method: For the quantification of voriconazole in human cerebrospinal fluid (CSF) was developed and validated, to guide the clinical use of voriconazole in the treatment of central nervous system infections. CSF samples were treated by protein precipitation with methanol containing fluconazole as the internal standard (IS). The supernatant was analyzed by LC-MS/MS using an Agilent EclipsePlus C18 column eluted with a methanol and water mobile phase at a flow rate of 0.4 mL min-1. Quantification was performed by multiple-reaction monitoring using the precursor and product ion pair 350/280.9 for voriconazole and 307/219.9 for fluconazole. Results: The calibration curve was linear over the range of 0.1-10.0 µg mL-1 (R2 = 0.9991). The inter-day and intra-day precisions were <4.20% and <9.97%, respectively. The recoveries for the three concentrations (0.2, 1.0, and 8.0 µg mL-1) were 99.96%, 107.00%, and 99.85%, and the matrix effects were 99.35%, 103.41%, and 99.64%, respectively. The stability under various conditions was also acceptable. The study also demonstrated that the CSF matrix could be replaced by plasma and artificial CSF. Conclusion: A simple and accurate method for the determination of voriconazole concentrations in human CSF was developed and validated, which can be used for drug monitoring in the treatment of central nervous system infections.


Assuntos
Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Voriconazol
5.
Front Cardiovasc Med ; 8: 660360, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557526

RESUMO

Background and Objective: Dual antiplatelet therapy (DAPT) is the basis for preventing ischemic events after percutaneous coronary intervention (PCI), and DAPT for 12 months has been the standard strategy recommended by the guidelines. However, patients with acute coronary syndrome (ACS) have a higher risk of thrombosis, and the application of very short-term DAPT (1-3 months) in patients with ACS is consistently controversial. The purpose of this study is to explore the efficacy and safety of DAPT for 1-3 months in patients with ACS who were implanted with drug-eluting stents (DES). Methods: We conducted a systematic review and meta-analysis of randomized controlled trials that compared the very short-term (3 months or less) with long-term (12 months or more) DAPT in patients with ACS after PCI. The randomized controlled trials were included by searching PubMed, EMBASE, and Cochrane Library database. The relative risk (RR) and 95% CIs for endpoint events were calculated by the fixed effects model, and trial sequential analysis was applied to calculate the anticipated sample size and assess the results. Result: A total of eight randomized controlled trials with 16,492 patients who met the inclusion criteria were conducted. There were no significant statistic differences in myocardial infarction (RR 1.05, 0.82-1.35, P = 0.68), stents thrombosis (RR 1.32, 0.85-2.07, P = 0.22), all-cause death (RR 0.87, 0.66-1.13, P = 0.29), and target vessel revascularization (RR 0.93, 0.76-1.13, P = 0.47). However, there were significant differences in major bleeding (RR 0.60, 0.50-0.73, P < 0.00001) and the net adverse cardiac and cerebrovascular events (RR 0.84, 0.74-0.95, P = 0.007). Conclusions: The strategy of DAPT for 1-3 months not only has a significant effect in patients with ACS who were implanted with DES but also reduces the risk of major bleeding. The scheme of short-term DAPT followed by P2Y12 receptor inhibitor monotherapy is especially beneficial for patients with ACS. The results of this systematic review and meta-analysis are based on the application of new generation DES and new oral antiplatelet drugs in patients with ACS, which are difficult to use in the general population (Registered by PROSPERO, CRD 42020210520). Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD 42020210520.

6.
Front Endocrinol (Lausanne) ; 12: 704596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34385977

RESUMO

Background: The staging system for patients with anaplastic thyroid cancer (ATC) was updated in the 8th edition of the American Joint Committee on Cancer Staging Manual. A cut-off age of 55 years was stipulated as a prognostic factor for differentiated thyroid cancer; however, age was not considered for ATC patients. To this end, this study investigated the relationship between age at diagnosis and prognosis of ATC patients. Methods: The clinical information on ATC patients was acquired from the Surveillance, Epidemiology, and End Results Program public database. Youden's index and X-tile analyses were used to calculate the high-point age at diagnosis associated with prognosis. Cox proportional hazards models, Kaplan-Meier curves, and 1000-person-year were then used for verifying the accuracy of the high-point age. Results: After inclusion/exclusion criteria was applied, 586 patients were included in this study. The high-point age was determined to be 70 years by both the Youden's index and X-tile plot methods. The hazard ratio was 1.662 (95% confidence interval [CI]: 1.321-2.092), indicating that there was an increased risk of poor prognosis for patients > 70 years of age. The cancer-specific mortality rates per 1000-person-years for patients ≤ and > 70 years-old were 949.980 (95% CI: 827.323-1090.822) and 1546.667 (95% CI: 1333.114-1794.428), respectively. P-values were < 0.001 for the results shown above. Conclusion: Our study found that age influenced the prognosis of ATC patients. Furthermore, we determined that the high-point age at diagnosis was 70 years and that > 70 years of age was associated with a poor prognosis. These results provide a useful addition to the staging manual and can improve the diagnosis, treatment strategies and prognosis of ATC patients.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34448914

RESUMO

OBJECTIVE: A smartphone augmented reality (AR) application (app) was explored for clinical use in presurgical planning and lesion scalp localization. METHODS: We programmed an AR App on a smartphone. The accuracy of the AR app was tested on a 3D-printed head model, using the Euclidean distance of displacement of virtual objects. For clinical validation, 14 patients with brain tumors were included in the study. Preoperative MRI images were used to generate 3D models for AR contents. The 3D models were then transferred to the smartphone AR app. Tumor scalp localization was marked, and a surgical corridor was planned on the patient's head by viewing AR images on the smartphone screen. Standard neuronavigation was applied to evaluate the accuracy of the smartphone. Max-margin distance (MMD) and area overlap ratio (AOR) were measured to quantitatively validate the clinical accuracy of the smartphone AR technique. RESULTS: In model validation, the total mean Euclidean distance of virtual object displacement using the smartphone AR app was 4.7 ± 2.3 mm. In clinical validation, the mean duration of AR app usage was 168.5 ± 73.9 s. The total mean MMD was 6.7 ± 3.7 mm, and total mean AOR was 79%. CONCLUSIONS: The smartphone AR app provides a new way of experience to observe intracranial anatomy in situ, and it makes surgical planning more intuitive and efficient. Localization accuracy is satisfactory with lesions larger than 15 mm.

8.
Eur J Pharmacol ; 906: 174217, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087223

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers and is associated with high morbidity and mortality rates. Recent research indicated that imatinib, a selective tyrosine kinase inhibitor, suppressed the growth of hepatocellular carcinoma. However, the effect of imatinib on HCC and its mechanism remain under investigated. In this study, we demonstrated that imatinib inhibited the proliferation, migration and invasion of HCC cells in vitro and exerted antitumour effects on HCC xenografts in mice in vivo. Imatinib treatment decreased the phosphorylation of AKT and increased the levels of both p62 (protein sequestosome 1) and LC3 (microtubule-associated protein 1A/1B-light chain 3) in HCC cells and HCC xenografts. Scanning confocal microscopy analysis with a mRFP-GFP-LC3 reporter and transmission electron microscopy analysis revealed that imatinib suppressed the autophagic flux by obstructing the formation of autolysosomes. Moreover, imatinib reversed the autophagy induced by sorafenib, and combined treatment with imatinib and sorafenib exerted a synergetic effect in HCC cells compared with monotherapy. Our collective data suggested that imatinib may target HCC by acting as an inhibitor of both tyrosine kinase and autophagy; here, we propose that imatinib could be a promising therapeutic agent for HCC in the clinic.

9.
Fish Shellfish Immunol ; 114: 49-57, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33887442

RESUMO

Soy saponins, as thermo-stable anti-nutrients in soybean meal (SBM), are the primary causal agents of SBM-induced enteritis, which represents a well-documented pathologic alternation involving the distal intestines of various farmed fish. Our previous work showed that soy saponins might lead to SBM-induced enteritis, destroy tight junction structure and induce oxidative damage in juvenile turbot. Glutamine, as a conditionally essential amino acid, is an important substrate utilized for the growth of intestinal epithelial cells. An 8-week feeding trial was carried out to determine whether glutamine can attenuate the detrimental effects of soy saponins. Three isonitrogenous-isolipidic experimental diets were formulated as follows: (i) fish meal-based diet (FM), considered as control; (ii) FM + 10 g/kg soy saponins, SAP; and (iii) SAP + 15 g/kg glutamine, GLN. The results showed that dietary soy saponins significantly increased the gene expression levels of inflammatory markers (IL-1ß, IL-8 and TNF-α) and related signaling factors (NF-кB, AP-1, p38, JNK and ERK), which were remarkably attenuated by dietary glutamine. Compared to SAP group, GLN-fed fish exhibited significantly higher expression levels of tight junction genes (CLDN3, CLDN4, OCLN, Tricellulin and ZO-1). Glutamine supplementation in SAP diet markedly suppressed the production of reactive oxygen species, malondialdehyde and protein carbonyl, and enhanced the activities of antioxidant enzymes as well as the mRNA levels of HO-1, SOD, GPX and Nrf2. Furthermore, GLN-fed fish had a remarkably lower number of autophagosomes compared to SAP-fed fish. In conclusion, our study indicated that glutamine could reverse the harmful effects of soy saponins on intestinal inflammation, tight junction disruption and oxidative damage, via attenuation of NF-кB, AP-1 and MAPK pathways and activation of Nrf2 pathway. Glutamine may have the function of controlling autophaghic process within an appropriate level of encountering inflammation.


Assuntos
Enterite/induzido quimicamente , Doenças dos Peixes/induzido quimicamente , Linguados/fisiologia , Glutamina/farmacologia , Saponinas/toxicidade , Soja/química , Ração Animal/análise , Animais , Autofagia/efeitos dos fármacos , Dieta/veterinária , Enterite/prevenção & controle , Doenças dos Peixes/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos
10.
Clin Pharmacol Drug Dev ; 10(10): 1231-1241, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33855805

RESUMO

Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double-blind, placebo-controlled single- and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.

11.
Exp Ther Med ; 21(4): 377, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33680099

RESUMO

Transient receptor potential cation channel subfamily M member (TRPM8) is abnormally expressed in many malignant tumors, such as breast cancer and pancreatic cancer, but its expression in gastric cancer (GC) has remained unclear. The present study aimed to detect TRPM8 expression and to explore its clinical significance in GC. Western blotting and immunohistochemistry were used to detect the protein expression of TRPM8 in 134 pairs of GC and adjacent healthy tissues. The association of TRMP8 with the 5-year overall survival rate of patients with GC was assessed using a Cox regression model. TRPM8 protein expression was significantly elevated (P<0.05) in gastric tumor cells (SUN-1, AGS, SNU-5 and NCI-N87) and was significantly associated with tumor diameter (P=0.003), Tumor-Node-Metastasis stage (P=0.003), lymph node metastasis (P=0.001) and cancer cell remote metastasis (P=0.010) in patients with GC. The expression of TRPM8 protein was significantly higher in GC patients with a tumor diameter of ≥2.5 cm. Additionally, TRPM8 protein expression in patients with metastases was significantly higher compared with patients without metastasis. Cox regression analysis revealed that TRPM8 protein expression was an independent risk factor for prognosis (odds ratio, 1.625; 95% CI=0.552-3.128) in patients with GC. In addition, the 5-year overall survival rate of patients with high expression of TRPM8 protein (64.44%) in GC was significantly lower compared with patients with low expression (12.36%). TRPM8 was highly expressed in GC tissues and may promote GC cell proliferation and metastasis in vivo.

12.
J Chem Inf Model ; 61(3): 1368-1382, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33625214

RESUMO

Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating the suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components and then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined. We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation and that members of a structurally conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Ubiquitina-Proteína Ligases , Proteólise , Estudos Retrospectivos , Ubiquitina-Proteína Ligases/metabolismo
13.
Br J Nutr ; 126(11): 1651-1662, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33550994

RESUMO

An 8-week feeding experiment was conducted to investigate and confront the putative functions of chitosan (CTS) and chitooligosaccharide (COS) in the growth and homoeostasis of distal intestine in juvenile turbots fed diets containing soyabean meal (SBM). Three isolipidic and isonitrogenous diets were formulated by supplemented basal diet (based on a 400 g/kg SBM) with 7·5 g/kg CTS or with 2·0 g/kg COS. Our results indicated that both CTS and COS supplementation could significantly improve (i) the growth performance and feed efficiency ratio; (ii) antioxidant activity driven by metabolic enzymes (i.e. catalase, glutathione reductase, glutathione peroxidase and superoxide dismutase); (iii) glutathione levels; (iv) acid phosphatase and lysozyme activity and (v) IgM content. As a result, these two particular prebiotics were able to significantly attenuate the histological alterations due to local inflammation as well as to decrease the transcriptional levels of proinflammatory cytokines (i.e. IL-1ß, IL-8 and TNF-α) and major pathway effectors (i.e. activator protein-1 (AP-1), NF-кB, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase and extracellular regulated kinase). High-throughput sequencing data indicated that dietary CTS and COS could significantly decrease the diversity of intestinal bacteria but elevate the relative abundances of Bacillus, Lactobacillus and Pseudomonas genera. Altogether, these findings suggest that CTS and COS can improve growth of turbot, enhance intestinal immune and anti-oxidant systems and promote the balance of intestinal microbiota. The protective effects, elicited by these two prebiotics, against SBM-induced inflammation could be attributed to their roles in alleviating the overexpression of inflammatory cytokines by possibly down-regulating NF-кB, AP-1 and/or mitogen-activated protein kinases pathways.

14.
Medicine (Baltimore) ; 100(1): e24151, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429796

RESUMO

ABSTRACT: Coronavirus disease 2019 (COVID-19) is still developing worldwide. The prognosis of the disease will become worse and mortality will be even higher when it is combined with cardiovascular disease. Furthermore, COVID-19 is highly infectious and requires strict isolation measures. For acute coronary syndromes (ACS), a common cardiovascular disease, infection may aggravate the occurrence and development of ACS, making the management of more difficult. It will be an enormous challenge for clinical practice to deal with ACS in this setting of COVID-19.Aim to reduce the mortality of ACS patients during the epidemic of COVID-19 by standardizing procedures as much as possible.Pubmed and other relevant databases were searched to retrieve articles on COVID-19 and articles on ACS management strategies during previous influenza epidemics. The data was described and synthesized to summarize the diagnosis and management strategy of ACS, the preparation of catheter laboratory, and the protection of the medical staff in the context of COVID-19. Ethical approval is not required in this study, because it is a review with no recourse to patient identifiable information.Standardized diagnosis and treatment advice can help reduce the mortality of COVID-19 patients with ACS. In the absence of contraindications, the third generation of thrombolytic drugs should be the first choice for thrombolytic treatment in the isolation ward. For patients who have to receive PCI, this article provides detailed protective measures to avoid nosocomial infection.


Assuntos
Síndrome Coronariana Aguda/terapia , Síndrome Coronariana Aguda/virologia , COVID-19/epidemiologia , Infecção Hospitalar/prevenção & controle , Controle de Infecções/normas , Pneumonia Viral/epidemiologia , Síndrome Coronariana Aguda/mortalidade , COVID-19/transmissão , Humanos , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2
15.
Cancer Res ; 81(4): 860-872, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33361394

RESUMO

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Células Cultivadas , Progressão da Doença , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Glicólise/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Fatores de Transcrição de p300-CBP/genética
16.
Life Sci ; 267: 118984, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383049

RESUMO

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.


Assuntos
Angiotensina II/efeitos dos fármacos , Cardiomegalia/metabolismo , Doxorrubicina/efeitos adversos , ortoaminobenzoatos/farmacologia , Angiotensina II/biossíntese , Angiotensina II/metabolismo , Animais , Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Doxorrubicina/farmacologia , Fibrose , Cardiopatias/etiologia , Masculino , Mastócitos/efeitos dos fármacos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , ortoaminobenzoatos/metabolismo
17.
Neural Regen Res ; 16(2): 333-337, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32859793

RESUMO

The arcuate fasciculus is a critical component of the neural substrate of human language function. Surgical resection of glioma adjacent to the arcuate fasciculus likely damages this region. In this study, we evaluated the outcome of surgical resection of glioma adjacent to the arcuate fasciculus under the guidance of magnetic resonance imaging and diffusion tensor imaging, and we aimed to identify the risk factors for postoperative linguistic deficit. In total, 54 patients with primary glioma adjacent to the arcuate fasciculus were included in this observational study. These patients comprised 38 men and 16 women (aged 43 ± 11 years). All patients underwent surgical resenction of glioma under the guidance of magnetic resonance imaging and diffusion tensor imaging. Intraoperative images were updated when necessary for further resection. The gross total resection rate of the 54 patients increased from 38.9% to 70.4% by intraoperative magnetic resonance imaging. Preoperative language function and glioma-to-arcuate fasciculus distance were associated with poor language outcome. Multivariable logistic regression analyses showed that glioma-to-arcuate fasciculus distance was the major independent risk factor for poor outcome. The cutoff point of glioma-to-arcuate fasciculus distance for poor outcome was 3.2 mm. These findings suggest that intraoperative magnetic resonance imaging combined with diffusion tensor imaging of the arcuate fasciculus can help optimize tumor resection and result in the least damage to the arcuate fasciculus. Notably, glioma-to-arcuate fasciculus distance is a key independent risk factor for poor postoperative language outcome. This study was approved by the Ethics Committee of the Chinese PLA General Hospital, China (approval No. S2014-096-01) on October 11, 2014.

18.
Polymers (Basel) ; 14(1)2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-35012161

RESUMO

The dynamic crosslinking method has been widely used to prepare rubber/plastic blends with thermoplastic properties, and the rubber phase is crosslinked in these blends. Both polyolefin elastomer (POE) and ethylene-propylene-diene monomer rubber (EPDM) can be crosslinked, which is different from usual dynamic crosslinking components. In this paper, dynamic crosslinked POE/EPDM blends were prepared. For POE/EPDM blends without dynamic crosslinking, EPDM can play a nucleation role, leading to POE crystallizing at a higher temperature. After dynamic crosslinking, the crosslinking points hinder the mobility of POE chains, resulting in smaller crystals, but having too many crosslinking points suppresses POE crystallization. Synchrotron radiation studies show that phase separation occurs and phase regions form in non-crosslinked blends. After crosslinking, crosslinking points connecting EPDM and part of POE chains, enabling more POE to enter the EPDM phase and thus weakening phase separation, indicates that dynamic crosslinking improves the compatibility of POE/EPDM, also evidenced by a lower ß conversion temperature and higher α conversion temperature than neat POE from dynamic mechanical analysis. Moreover, crosslinking networks hinder the crystal fragmentation during stretching and provide higher strength, resulting in 8.3% higher tensile strength of a 10 wt% EPDM blend than neat POE and almost the same elongation at break. Though excessive crosslinking points offer higher strength, they weaken the elongation at break.

19.
Front Oncol ; 10: 1441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983973

RESUMO

The controversy of adjuvant radiotherapy of meningiomas is at least partially due to the insufficient understanding on meningioma cells' response to irradiation and the shortage of radiosensitivity-promotion methods. MicroRNA-221 and microRNA-222 were identified as critical regulators of radiosensitivity in several other tumors. However, their effect in meningiomas has yet to be confirmed. Therefore, the malignant meningioma IOMM-Lee cells were adopted, transfected with microRNA-221/222 mimics or inhibitors, and irradiated with different dosages. The effects of radiation and microRNA-221/222 were then assessed in vitro and in vivo. Radiation dose increases and microRNA-221/222 downregulation synergistically inhibited cell proliferation and colony formation, prevented xenograft tumor progression, and promoted apoptosis, but antagonistically regulated cell invasiveness. Pairwise comparisons revealed that only high-dose radiations (6 and 8 Gy) can significantly promote cell invasiveness in comparison with unirradiated counterparts. Further comparisons exhibited that downregulating the microRNA-221/222 expression can reverse this radiation-induced cell invasiveness to a level of untransfected and unirradiated cells only if cells were irradiated with no more than 6 Gy. In addition, this approach can promote IOMM-Lee's radiosensitivity. Meanwhile, we also detected that the dose rate of irradiation affects cell cycle distribution and cell apoptosis of IOMM-Lee. A high dose rate irradiation induces G0/G1 cell cycle arrest and apoptosis-promoting effect. Therefore, for malignant meningiomas, high-dose irradiation can facilitate cell invasiveness significantly. Downregulating the microRNA-221/222 level can reverse the radiation-induced cell invasiveness while enhancing the apoptosis-promoting and proliferation-inhibiting effects of radiation and promoting cell radiosensitivity.

20.
J Gastric Cancer ; 20(1): 95-105, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32269848

RESUMO

Purpose: Gastric cancer is a highly metastatic malignant tumor, often characterized by chemoresistance and high mortality. In the present study, we aimed to investigate the role of B-cell lymphoma 3 (Bcl-3) protein on cell migration and chemosensitivity of gastric cancer. Materials and Methods: The gastric cancer cell lines, AGS and NCI-N87, were used for the in vitro studies and the in vivo studies were performed using BALB/c nude mice. Western blotting, wound healing assay, Cell Counting Kit-8 assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to evaluate the role of Bcl-3 in gastric cancer. Results: We found that the protein expression of hypoxia (HYP)-inducible factor-1α and Bcl-3 were markedly upregulated under hypoxic conditions in both AGS and NCI-N87 cells in a time-dependent manner. Interestingly, small interfering RNA-mediated knockdown of Bcl-3 expression affected the migration and chemosensitivity of the gastric cancer cells. AGS and NCI-N87 cells transfected with si-RNA-Bcl-3 (si-Bcl-3) showed significantly reduced migratory ability and increased chemosensitivity to oxaliplatin, 5-fluorouracil, and irinotecan. In addition, si-Bcl-3 restored the autophagy induced by HYP. Further, the protective role of si-Bcl-3 on the gastric cancer cells could be reversed by the autophagy inducer, rapamycin. Importantly, the in vivo xenograft tumor experiments showed similar results. Conclusions: Our present study reveals that Bcl-3 knockdown inhibits cell migration and chemoresistance of gastric cancer cells through restoring HYP-induced autophagy.

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