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1.
Phys Chem Chem Phys ; 26(14): 11037-11047, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38526740

RESUMO

Electrochemical CO2 transformation to fuels and chemicals is an effective strategy for conversion of renewable electric energy into storable chemical energy in combination with reducing green-house gas emission. Metal-nitrogen-carbon (M-N-C) single atom catalysts (SAC) have shown great potential in the electrochemical CO2 reduction reaction (CO2RR). However, exploring advanced SACs with simultaneously high catalytic activity and high product selectivity remains a great challenge. In this study, density functional theory (DFT) calculations are combined with machine learning (ML) for rapid and high-throughput screening of high performance CO reduction catalysts. Firstly, the electrochemical properties of 99 M-N-C SACs were calculated by DFT and used as a database. By using different machine learning models with simple features, the investigated SACs were expanded from 99 to 297. Through several effective indicators of catalyst stability, inhibition of the hydrogen evolution reaction, and CO adsorption strength, 33 SACs were finally selected. The catalytic activity and selectivity of the remaining 33 SACs were explored by micro-kinetic simulation based on Marcus theory. Among all the studied SACs, Mn-NC2, Pt-NC2, and Au-NC2 deliver the best catalytic performance and can be used as potential catalysts for CO2/CO conversion to hydrocarbons with high energy density. This effective screening method using a machine learning algorithm can promote the exploration of CO2RR catalysts and significantly reduce the simulation cost.

3.
Anal Chem ; 95(51): 18859-18870, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38096265

RESUMO

Trivalent Au ions are easily reduced to be zerovalent atoms by coexisting reductant reagents, resulting in the subsequent accumulation of Au atoms and formation of plasmonic nanostructures. In the absence of stabilizers or presence of weak stabilizers, aggregative growth of Au nanoparticles (NPs) always occurs, and unregular multidimensional Au materials are consequently constructed. Herein, the addition of nanomole-level mercury ions can efficiently prevent the epitaxial accumulation of Au atoms, and separated Au NPs with mediated morphologies and superior plasmonic characteristics are obtained. Experimental results and theoretical simulation demonstrate the Hg-concentration-reliant formation of plasmonic nanostructures with their mediated sizes and shapes in the presence of weak reductants. Moreover, the sensitive plasmonic responses of reaction systems exhibit selectivity comparable to that of Hg species. As a concept of proof, polymeric carbon dots (CDs) were used as the initial reductant, and the reactions between trivalent Au and CDs were studies. Significantly, Hg atoms prevent the epitaxial accumulation of Au atoms, and plasmonic NPs with decreased sizes were in situ synthesized, corresponding to varied surface plasmonic resonance absorption performance of the CD-induced hybrids. Moreover, with the integration of sensing substrates of CD-doped hydrogels, superior response stabilities, analysis selectivity, and sensitivity of Hg2+ ions were achieved on the basis of the mercury-mediated in situ chemical reactions between trivalent Au ions and reductant CDs. Consequently, a high-performance sensing strategy with the use of Au NP-staining hydrogels (nanostaining hydrogels) was exhibited. In addition to Hg sensing, the nanostaining hydrogels facilitated by doping of emerging materials and advanced chem/biostrategies can be developed as high-performance on-site monitoring routes to various pollutant species.

4.
Aging Cell ; 22(1): e13743, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36468256

RESUMO

Atrial fibrosis induced by aging is one of the main causes of atrial fibrillation (AF), but the potential molecular mechanism is not clear. Acetyltransferase p300 participates in the cellular senescence and fibrosis, which might be involved in the age-related atrial fibrosis. Four microarray datasets generated from atrial tissue of AF patients and sinus rhythm (SR) controls were analyzed to find the possible relationship of p300 (EP300) with senescence and fibrosis. And then, biochemical assays and in vivo electrophysiological examination were performed on older AF patients, aging mice, and senescent atrial fibroblasts. The results showed that (1) the left atrial tissues of older AF patients, aging mouse, and senescence human atrial fibroblasts had more severe atrial fibrosis and higher protein expression levels of p300, p53/acetylated p53 (ac-p53)/p21, Smad3/p-Smads, and fibrosis-related factors. (2) p300 inhibitor curcumin and p300 knockdown treated aging mouse and senescence human atrial fibroblasts reduced the senescence ratio of atrial fibroblasts, ameliorated the atrial fibrosis, and decreased the AF inducibility. In contrast, over-expression of p300 can lead to the senescence of atrial fibroblasts and atrial fibrosis. (3) p53 knockdown decreased the expression of aging and fibrosis-related proteins. (4) Co-immunoprecipitation and immunofluorescence showed that p53 forms a complex with smad3 and directly regulates the expression of smad3 in atrial fibroblasts. Our findings suggest that the mechanism of atrial fibrosis induced by aging is, at least, partially dependent on the regulation of p300, which provides new sights into the AF treatment, especially for the elderly.


Assuntos
Fibrilação Atrial , Proteína Supressora de Tumor p53 , Humanos , Animais , Camundongos , Idoso , Proteína Supressora de Tumor p53/metabolismo , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Acetiltransferases/metabolismo , Fibrose , Fibroblastos/metabolismo , Senescência Celular/fisiologia , Proteína Smad3/metabolismo
5.
Clin Exp Pharmacol Physiol ; 49(1): 25-34, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34438468

RESUMO

Atrial fibrillation (AF) is associated with atrial conduction disturbances caused by electrical and/or structural remodelling. In the present study, we hypothesized that connexin might interact with the calcium channel through forming a protein complex and, then, participates in the pathogenesis of AF. Western blot and whole-cell patch clamp showed that protein levels of Cav1.2 and connexin 43 (Cx43) and basal ICa,L were decreased in AF subjects compared to sinus rhythm (SR) controls. In cultured atrium-derived myocytes (HL-1 cells), knocking-down of Cx43 or incubation with 30 mmol/L glycyrrhetinic acid significantly inhibited protein levels of Cav1.2 and Cav3.1 and the current density of ICa,L and ICa,T . Incubation with nifedipine or mibefradil decreased the protein level of Cx43 in HL-1 cells. Moreover, Cx43 was colocalized with Cav1.2 and Cav3.1 in atrial myocytes. Therefore, Cx43 might regulate the ICa,L and ICa,T through colocalization with calcium channel subunits in atrial myocytes, representing a potential pathogenic mechanism in AF.


Assuntos
Remodelamento Atrial , Canais de Cálcio/fisiologia , Conexina 43/fisiologia , Átrios do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Fibrilação Atrial/metabolismo , Remodelamento Atrial/fisiologia , Western Blotting , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/fisiologia , Linhagem Celular , Células Cultivadas , Conexina 43/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Humanos , Mibefradil/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Nifedipino/farmacologia , Técnicas de Patch-Clamp
6.
Clin Exp Pharmacol Physiol ; 48(3): 435-442, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32966616

RESUMO

The atrial-specific ultra-rapid delayed rectifier K+ current (Ikur) plays an important role in the progression of atrial fibrillation (AF). Because inflammation is known to lead to the onset of AF, we aimed to investigate whether tumour necrosis factor-α (TNF-α) played a role in regulating Ikur and the potential signalling pathways involved. Whole-cell patch-clamp and biochemical assays were used to study the regulation and expression of Ikur in myocytes and in tissues from left atrial appendages (LAAs) obtained from patients with sinus rhythm (SR) or AF, as well as in rat cardiomyocytes (H9c2 cells) and mouse atrial myocytes (HL-1 cells). Ikur current density was markedly reduced in atrial myocytes from AF patients compared with SR controls. Reduction of Kv1.5 protein levels was accompanied by increased expression of TNF-α and protein kinase C (PKC)α activation in AF patients. Treatment with TNF-α dose-dependently reduced Ikur and protein expression of Kv1.5 but not Kv3.1b in H9c2 cells and HL-1 cells. TNF-α also increased activity of PKCα. Specific PKCα inhibitor Gö6976 alleviated the reduction in Ikur induced by TNF-α, but not the reduction in Kv1.5 protein. TNF-α was involved in the electrical remodelling associated with AF, probably by depressing Ikur in atrial myocytes via activation of PKCα.


Assuntos
Fator de Necrose Tumoral alfa , Animais , Átrios do Coração/metabolismo , Camundongos , Miócitos Cardíacos , Proteína Quinase C-alfa/metabolismo , Ratos
7.
J Mol Cell Cardiol ; 140: 10-21, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32006532

RESUMO

Hypertension is an independent risk factor for atrial fibrillation (AF), although its specific mechanisms remain unclear. Previous research has been focused on cyclic stretch, ignoring the role of high hydrostatic pressure. The present study aimed to explore the effect of high hydrostatic pressure stimulation on electrical remodeling in atrial myocytes and its potential signaling pathways. Experiments were performed on left atrial appendages from patients with chronic AF or sinus rhythm, spontaneously hypertensive rats (SHRs) treated with or without valsartan (10 mg/kg/day) and HL-1 cells were exposed to high hydrostatic pressure using a self-developed device. Whole-cell patch-clamp recordings and western blots demonstrated that the amplitudes of ICa,L, Ito, and IKur were reduced in AF patients with corresponding changes in protein expression. Angiotensin protein levels increased and Ang1-7 decreased, while focal adhesion kinase (FAK) and Src kinase were enhanced in atrial tissue from AF patients and SHRs. After rapid atrial pacing, AF inducibility in SHR was significantly higher, accompanied by a decrease in ICa,L, upregulation of Ito and IKur, and a shortened action potential duration. Angiotensin upregulation and FAK/Src activation in SHR were inhibited by angiotensin type 1 receptor inhibitor valsartan, thus, preventing electrical remodeling and reducing AF susceptibility. These results were verified in HL-1 cells treated with high hydrostatic pressure, and demonstrated that electrical remodeling regulated by the FAK-Src pathway could be modulated by valsartan. The present study indicated that high hydrostatic pressure stimulation increases AF susceptibility by activating the renin-angiotensin system and FAK-Src pathway in atrial myocytes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Remodelamento Atrial/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Fragmentos de Peptídeos/metabolismo , Regulação para Cima/efeitos dos fármacos , Quinases da Família src/metabolismo , Animais , Antiarrítmicos/farmacologia , Apêndice Atrial/metabolismo , Fibrilação Atrial/patologia , Linhagem Celular Tumoral , Humanos , Pressão Hidrostática , Camundongos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Valsartana/farmacologia
8.
Naunyn Schmiedebergs Arch Pharmacol ; 393(11): 2165-2176, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31980857

RESUMO

Hypertension is one of the risk factors for coronary heart disease. The present study investigated the mechanism of contractile dysfunction induced by serotonin (5-HT) in coronary artery in spontaneously hypertensive rats (SHRs). Coronary arteries were isolated form SHRs and Wistar rats. Arterial ring contraction was measured using a multi myograph system. Intracellular calcium concentration was measured with a Ca2+ probe fluo-4/AM in vascular smooth muscle cells (VSMCs) isolated from coronary arteries. Signaling pathway-related proteins were assayed by western blotting. A 5-HT2A receptor blocker, sarpogrelate, completely eliminated coronary artery contraction induced by 5-HT. PLCß inhibitor U73122 also significantly inhibited the response to 5-HT. Compared with the Wistar rats, serotonin (5-HT)- and CaCl2-induced coronary vasoconstriction in the SHRs was significantly reduced. Rho-associated protein kinase inhibitor Y27632, PKC inhibitor rottlerin, and L-type calcium channel blocker nifedipine inhibited the 5-HT-induced coronary artery contraction in a dose-dependent manner in SHRs and Wistar rats. However, the inhibitory effects were reduced in SHRs. In addition, store-operated Ca2+ (SOC) induced an obvious Ca2+ influx in coronary arterial smooth muscle cells, whereas SOC-mediated contraction was very slight in coronary arteries. At the same time, it was found that 5-HT2AR, IP3R, and Cav1.2 protein expression and PKCδ activity were decreased, and STIM1 and Orai1 were increased in VSMCs from coronary arteries of SHRs compared with Wistar rats. These results implicate calcium-handling dysfunction mediated by the 5-HT2A receptor and downstream signaling pathway might lead to a reduction in 5-HT-induced contraction in SHR coronary arteries.


Assuntos
Hipertensão/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Ratos Endogâmicos SHR , Ratos Wistar , Receptor 5-HT2A de Serotonina/metabolismo
9.
Life Sci ; 242: 117209, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870776

RESUMO

AIMS: Hypertension is an independent risk factor for atrial fibrillation (AF). However, the direct effect of hydrostatic pressure on atrial electrical remodeling is unclear. The present study investigated whether hydrostatic pressure is responsible for atrial electrical remodeling and addressed a potential role of inflammation in this pathology. MAIN METHODS: Whole-cell patch-clamp recordings and biochemical assays were used to study the regulation and expression of ion channels in left atrial appendages in patients with AF, spontaneously hypertensive rats (SHRs), and atrium-derived cells (HL-1 cells) exposed to standard (0 mmHg) and elevated (20, 40 mmHg) hydrostatic pressure. KEY FINDINGS: Both TNF-α and MIF were highly expressed in patients with AF and SHRs. AF inducibility in SHRs was higher after atrial burst pacing, accompanied by a decrease in the L-type calcium current (ICa,L), an increase in the transient outward K+ current (Ito) and ultra-rapid delayed rectifier K+ current (IKur), and a shortened action potential duration (APD), which could be inhibited by atorvastatin. Furthermore, exposure to elevated pressure was associated with electrical remodeling of the HL-1 cells. The peak current density of ICa,L was reduced, while Ito and IKur were increased. Moreover, the expression levels of Kv4.3, Kv1.5, TNF-α, and MIF were upregulated, while the expression of Cav1.2 was downregulated in HL-1 cells after treatment with high hydrostatic pressure (40 mmHg). Atorvastatin alleviated the electrical remodeling and increased inflammatory markers in HL-1 cells induced by high hydrostatic pressure. SIGNIFICANCE: Elevated hydrostatic pressure led to atrial electrical remodeling and increased AF susceptibility by upregulating inflammation.


Assuntos
Remodelamento Atrial , Citocinas/metabolismo , Pressão Hidrostática/efeitos adversos , Adulto , Animais , Western Blotting , Feminino , Átrios do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
10.
Apoptosis ; 23(9-10): 521-531, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30084053

RESUMO

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a core effector of necroptosis, and its function in necroptosis is widely studied. However, the function of MLKL in apoptosis remains unclear. In the present study, the role of MLKL in chelerythrine (CHE)-promoted apoptosis was studied. A special band of MLKL (i.e., *MLKL) was observed after treatment with CHE. MLKL and *MLKL were accumulated in the nucleus upon treatment with CHE and MLKL silencing reversed the CHE-induced apoptosis. Blockade of CHE-triggered reactive oxygen species (ROS) generation or inhibition of CHE-activated protein kinase-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α subunit (eIF2α) pathway reversed the apoptosis. A decreased ROS level inhibited CHE-mediated nuclear translocation of MLKL and *MLKL and the activation of eIF2α, whereas MLKL or eIF2α silencing did not affect the CHE-triggered ROS generation. Furthermore, MLKL silencing prevented the CHE-activated eIF2α signal, and eIF2α silencing blocked the CHE-induced nuclear translocation of MLKL and *MLKL. Our studies suggested that CHE possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK-eIF2α pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis.


Assuntos
Apoptose/genética , Fator de Iniciação 2 em Eucariotos/genética , Necrose/genética , Proteínas Quinases/genética , eIF-2 Quinase/genética , Apoptose/efeitos dos fármacos , Benzofenantridinas/farmacologia , Núcleo Celular/genética , Retículo Endoplasmático/genética , Inativação Gênica , Humanos , Necrose/patologia , Espécies Reativas de Oxigênio/metabolismo
11.
Dis Markers ; 2017: 8241953, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28947845

RESUMO

OBJECTIVE: To examine the relationship between the Sirtuin-3 (SIRT3) expression and the clinical indicators/prognosis of patients with non-small-cell lung cancer (NSCLC). METHODS: The mRNA level of SIRT3 was detected by real-time PCR, while the protein level was detected by Western blot and immunohistochemical staining. SPSS 16.0 software was used for statistical analysis. RESULTS: The expression of SIRT3 was significantly higher in NSCLC tissue than in adjacent tissue. The SIRT3 level was correlated significantly with lymph node metastasis and clinical stage of NSCLC patients. Moreover, univariate analysis showed that the expression of SIRT3, tumor size, lymph node metastasis, degree of differentiation, and clinical stage were correlated with the prognosis of NSCLC patients. Multivariate analysis demonstrated that lymph node metastasis, the tumor size, and SIRT3 expression were independent prognostic factors for NSCLC patients. CONCLUSIONS: SIRT3 is associated with the development and progression of NSCLC. The SIRT3 expression can be used as an independent prognostic factor for NSCLC patients and help identify prognosis of NSCLC. Therefore, SIRT3 has the potential to become a new factor for prognosis prediction and personalized treatment of NSCLC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Sirtuína 3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sirtuína 3/genética
12.
Clin Exp Pharmacol Physiol ; 44(7): 771-778, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28429502

RESUMO

Connexin 43 (Cx43) plays an important role in the pathogenesis of atrial fibrillation (AF). The present study sought to investigate the effect of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, on Cx43 expression and activity and determine the intracellular signalling pathways. Cx43 protein and mRNA levels were assayed using immunofluorescence, real-time polymerase chain reaction (PCR), and western blot. We found that increased MIF and extracellular regulated protein kinases (ERK) expression was accompanied by a significant reduction in Cx43 protein expression in atrial tissues from patients with AF compared with those with sinus rhythm. In cultured atrium-derived myocytes (HL-1 cells), mouse recombinant-MIF (rMIF, 20 or 40 nmol/L, 24 hours) down-regulated gene and protein expression of Cx43 in a concentration-dependent manner. U0126, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK) could reverse the decrease in expression of Cx43 protein induced by rMIF. Further studies revealed that rMIF (40 nmol/L, 15, 30, and 45 minutes) was able to stimulate phospho-Erk1/2 (Thr202/Tyr204) production in a time-dependent manner. These results suggest that MIF is involved in the pathogenesis of AF, probably by down-regulating the protein and gene expression of Cx43 via ERK1/2 kinase activation. Our findings represent a potential pathogenic mechanism in AF.


Assuntos
Conexina 43/metabolismo , Átrios do Coração/citologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos Cardíacos/metabolismo , Adulto , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Conexina 43/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Átrios do Coração/patologia , Humanos , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Nó Sinoatrial/fisiologia , Nó Sinoatrial/fisiopatologia
13.
World J Surg Oncol ; 15(1): 64, 2017 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-28302176

RESUMO

BACKGROUND: Lymph node involvement could help to predict the prognosis of pathological T1 (pT1, diameters of ≤3 cm) non-small cell lung cancer (NSCLC). This study assessed the clinicopathological factors and associated lymph node involvement in invasive lung adenocarcinoma (IAC) and squamous cell lung cancer (SCC) and the overall and disease-free survival associated with these factors. METHODS: Three hundred and twenty-five patients with pathological T1 NSCLC (253 IAC and 72 SCC) were retrospectively analyzed from a pool of 1094 primary lung cancer patients. The data were assessed using multiple logistic regression, Kaplan-Meier curves and multivariable analyses. RESULTS: Among patients with a ≤30-mm tumor lesion (N = 325), N1 and N2 lymph node involvement was found in 28 (8.6%) and 34 (10.4%) patients, respectively. Lymph node metastasis occurred in 13.0% (33/253) of pT1 IAC patients and 40.3% (29/72) of SCC patients. Carcinoembryonic antigen (CEA) levels, SCC by histology, and tumor lesions larger than 1.0 cm were associated with lymph node involvement (P < 0.0001, <0.0001, and 0.048, respectively). In IAC patients, negative lymph nodes were associated with better overall survival compared with lymph node-positive ones (P = 0.021). No significant difference was observed in SCC patients regardless of lymph node status (P = 0.40). Multivariable Cox analysis revealed that lymph node involvement was an independent prognostic predictor of overall IAC patient survival (P = 0.041), but not of SCC patient survival (P = 0.470). Chemotherapy was administered to 72.2% (52/72) of SCC patients, a significantly higher rate when compared with that of IAC patients (42.3%, 107/253). CONCLUSIONS: Lymph node metastasis was inversely associated with the overall survival of IAP patients, but not with the survival of SCC patients. Patients with pT1 SCC exhibited a significantly higher rate of lymph node involvement when compared with IAC patients. Thus, a systematic lymph node dissection should be performed in pT1 IAC patients, especially in patients with IAC larger than 1.0 cm, for additional treatment selections to improve survival.


Assuntos
Adenocarcinoma/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pneumonectomia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
14.
Redox Biol ; 12: 367-376, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28288416

RESUMO

Chelerythrine (CHE), a natural benzo[c]phenanthridine alkaloid, shows anti-cancer effect through a number of mechanisms. Herein, the effect and mechanism of the CHE-induced autophagy, a type II programmed cell death, in non-small cell lung cancer (NSCLC) cells were studied for the first time. CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a concentration-dependent manner in NSCLC A549 and NCI-H1299 cells. In addition, CHE triggered the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II). The CHE-induced expression of LC3-II was further increased in the combination treatment with chloroquine (CQ), an autophagy inhibitor, and large amounts of red-puncta were observed in the CHE-treated A549 cells with stable expression of mRFP-EGFP-LC3, indicating that CHE induces autophagy flux. Silence of beclin 1 reversed the CHE-induced expression of LC3-II. Inhibition of autophagy remarkably reversed the CHE-induced cell viability decrease and apoptosis in NCI-H1299 cells but not in A549 cells. Furthermore, CHE triggered reactive oxygen species (ROS) generation in both cell lines. A decreased level of ROS through pretreatment with N-acetyl-L-cysteine reversed the CHE-induced cell viability decrease, apoptosis, and autophagy. Taken together, CHE induced distinctive autophagy in A549 (accompanied autophagy) and NCI-H1299 (pro-death autophagy) cells and a decreased level of ROS reversed the effect of CHE in NSCLC cells in terms of cell viability, apoptosis, and autophagy.


Assuntos
Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo
15.
Sci Rep ; 6: 26241, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27184816

RESUMO

Licochalcone A (LCA), a flavonoid isolated from the famous Chinese medicinal herb Glycyrrhiza uralensis Fisch, presents obvious anti-cancer effects. In this study, the anti-cancer effects and potential mechanisms of LCA in non-small cell lung cancer (NSCLC) cells were studied. LCA decreased cell viability, increased lactate dehydrogenase release, and induced apoptosis in a concentration-dependent manner in NSCLC cells while not in human embryonic lung fibroblast cells. The expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and formation of GFP-LC3 punta, two autophagic markers, were increased after treatment with LCA. LCA-induced LC3-II expression was increased when combined with chloroquine (CQ), while knock-down of autophagy related protein (ATG) 7 or ATG5 reversed LCA-induced LC3-II expression and GFP-LC3 punta formation, suggesting that LCA induced autophagy in NSCLC cells. Inhibition of autophagy could not reverse the LCA-induced cell viability decrease and apoptosis. In addition, LCA increased the expression of endoplasmic reticulum stress related proteins, such as binding immunoglobulin protein and C/EBP homologous protein (CHOP). Knock-down of CHOP reversed LCA-induced cell viability decrease, apoptosis, and autophagy. Taken together, LCA-induced autophagic effect is an accompanied phenomenon in NSCLC cells, and CHOP is critical for LCA-induced cell viability decrease, apoptosis, and autophagy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Chalconas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fator de Transcrição CHOP/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Técnicas de Silenciamento de Genes , Glycyrrhiza uralensis/química , Humanos , L-Lactato Desidrogenase/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/genética
16.
Appl Biochem Biotechnol ; 179(6): 1011-22, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27125959

RESUMO

Bio-based solvents have recently been discussed as sustainable green and promising alternatives to conventional organic media for enzymatic processes. In this paper, highly regioselective synthesis of the 6″-O-crotonyl-polydatin catalyzed by Thermomyces lanuginosus lipase (TLL) in biomass-derived 2-methyltetrahydrofuran (2-MeTHF) was successfully performed for the first time. The results indicated that TLL lipase displayed significantly improved catalytic performance in 2-MeTHF than in other traditional solvents. Under the optimal conditions, the initial reaction rate, 6″-regioselectivity, and maximum substrate conversion were as high as 12.38 mM h(-1), 100 %, and 100 %, respectively. Moreover, further investigations on the operational stability, kinetic parameters like V max, K m, V max/K m, and E a revealed that 2-MeTHF exhibited excellent biocompatibility and rendered the greener process of the enzymatic acylation.


Assuntos
Eurotiales/enzimologia , Furanos/química , Glucosídeos/biossíntese , Lipase/biossíntese , Acilação , Catálise , Glucosídeos/química , Cinética , Lipase/química , Pró-Fármacos/química , Solventes/química , Estereoisomerismo , Estilbenos/química , Especificidade por Substrato
17.
Dis Markers ; 2016: 9354680, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28115792

RESUMO

Aims. Identification of factors that can predict the subtypes of lung adenocarcinoma preoperatively is important for selecting the appropriate surgical procedure and for predicting postoperative survival. Methods. We retrospectively evaluated 87 patients with lung adenocarcinomas ≤30 mm. Results. Preoperative radiological findings, serum CEA level, serum microRNA-183 (miR-183) level, and tumour size differed significantly between patients with adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) and those with invasive adenocarcinoma (IAC). Receiver operating characteristic curves and univariate analysis revealed that patients who were older than 57 years or had a pure solid nodule or a tumour with mixed ground-glass opacity (mGGO), a tumour >11 mm, a serum CEA level >2.12 ng/mL, or a serum miR-183 level >1.233 (2-ΔΔCt) were more likely to be diagnosed with IAC than with AIS or MIA. The combination of all five factors had an area under the curve of 0.946, with a sensitivity of 89.13% and a specificity of 95.12%. Moreover, patients with a cut-off value >0.499 for the five-factor combination had poor overall survival. Conclusions. The five-factor combination enables clinicians to distinguish AIS or MIA from IAC, thereby aiding in selecting the appropriate treatment, and to predict the prognosis of lung adenocarcinoma patients.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/sangue , Neoplasias Pulmonares/patologia , MicroRNAs/sangue , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
18.
Eur J Cardiothorac Surg ; 49(4): 1095-102, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26374872

RESUMO

OBJECTIVES: Micro-sized lung adenocarcinoma with a tumour of 1.0 cm or less could help identify the patients who would undergo the surgery treatment with limited resection; however, its clinical characteristics and survival rates remain unclear and are to be tested further. METHODS: Histology, lymphatic metastasis, surgical procedure and survival rates of 366 lung adenocarcinoma patients (from January 2007 to December 2013) with a tumour of 2.0 cm or less were analysed retrospectively. Among these patients, 175 had a primary tumour with a diameter of 1.0 cm or less and 191 had a tumour of 1.1-2.0 cm. The survival of 366 patients was evaluated by the restricted mean survival time (RMST) test, and the risk factors were assessed by multivariable analysis. RESULTS: Larger lesion had a significant relation to old age, male sex, preoperatively carcinoembryonic antigen (CEA) positive, invasive adenocarcinoma (IAC) and advanced-stage disease (P < 0.0001, P = 0.001, P = 0.001, P < 0.0001 and P < 0.0001, respectively). Patients with adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma obtained a better prognosis than those with IAC (5-year overall survival rate: 98.5 vs 84.3%, P = 0.001; disease-related survival rate: 98.5 versus 85.2%, P = 0.001). The 5-year overall survival rates of patients with a tumour less than 1.0 cm in comparison with 1.1-2.0 cm were 100.0 and 88.4% (P < 0.001), whereas the 5-year lung adenocarcinoma-specific survival rates were 100.0 and 89.0% (P < 0.001), respectively. Multivariable analysis for prognosis of lung adenocarcinoma patients with a tumour 2.0 cm or less in diameter revealed that histology, lymphatic metastasis and advanced pathological stage affected the 5-year overall and disease-related survival rates unfavourably (P < 0.0001, 0.002, 0.001; and P < 0.0001, 0.005, 0.001, respectively), whereas tumour size did not have an obvious influence on survival. CONCLUSIONS: Micro-sized lung adenocarcinoma (1.0 cm or less) had specific clinical characteristics and more favourable survival rates. These tumours and a subtype of AIS evaluated by computed tomography images or intraoperative frozen section may be appropriate candidates for a limited resection without mediastinal lymph node dissection.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/fisiopatologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
19.
J Biotechnol ; 212: 153-8, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26325198

RESUMO

In this work, comparative experiments were explored to investigate the substrate specificity of Pseudomonas cepacia lipase in regioselective acylation of nucleosides carrying various substituents (such as the H, F, Cl, Br, I) at 2'- and 5-positions. Experimental data indicated that the catalytic performance of the enzyme depended very much on the halo-substituents in nucleosides. The increased bulk of 2'-substituents in ribose moiety of the nucleoside might contribute to the improved 3'-regioselectivity (90-98%, nucleosides a-d) in enzymatic decanoylation, while the enhancement of regioselectivity (93-99%) in 3'-O-acylated nucleosides e-h could be attributable to the increasing hydrophobicity of the halogen atoms at 5-positions. With regard to the chain-length selectivity, P. cepacia lipase displayed the highest 3'-regioselectivity toward the longer chain (C14) as compared to shorter (C6 and C10) ones. The position, orientation and property of the substituent, specific structure of the lipase's active site, and acyl structure could account for the diverse results.


Assuntos
Burkholderia cepacia/enzimologia , Enzimas Imobilizadas/metabolismo , Lipase/metabolismo , Nucleosídeos/metabolismo , Acilação , Catálise , Enzimas Imobilizadas/química , Lipase/química , Estereoisomerismo , Especificidade por Substrato
20.
Pain Med ; 16(7): 1373-85, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26176791

RESUMO

OBJECTIVES: The aim of this meta-analysis was to evaluate the efficacy and safety of duloxetine for management of osteoarthritis knee (OAK) pain. METHODS: A systematic literature search of articles for management of OAK using duloxetine were performed in PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, ClinicalTrials.gov, Google Scholar, and Cochrane Central Register of Controlled Trials from the available date of inception until the latest issue (October 2013). Potentially relevant randomized controlled trials (RCTs) regarding to comparison of efficacy and safety of duloxetine with placebo for managing OAK pain were included. Also, studies with specific data regarding to pain reductions and response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, Western Ontario and McMaster Osteoarthritis Index (WOMAC), adverse events (AEs), treatment-emergent AEs (TEAEs), mortality were included and analyzed, and those with confounding conditions were excluded. Studies were assessed for quality using the Jadad five-point score for RCTs. Finally, a meta-analysis of all RCTs eligible for inclusion criteria was performed using Review Manager 5.1 meta-analysis software. RESULTS: Three RCTs that enrolled 1,011 patients were included in our meta-analysis. There were statistically significant differences between patients taking duloxetine and those taking placebo with regard to the reductions in pain intensity (992 patients, mean difference [MD] = -0.88, 95% confidence interval [CI] -1.11--0.65, P < 0.0001), a moderate improvement in pain intensity (>= 30% response rate; 989 patients, risk ratio [RR] = 1.49, 95% CI 1.31-1.70, P < 0.0001), a substantial improvement in pain intensity (>=50% response rate; 989 patients, RR = 1.69, 95% CI 1.27-2.25, P = 0.0004). Statistically significant differences in PGI-I (976 patients, MD = -0.47, 95% CI -0.63 to -0.30, P < 0.0001) and WOMAC-physical function subscale (977 patients, MD = -4.25, 95% CI -5.82 to -2.68, P < 0.0001) were observed. Similarly, more AEs, TEAEs, and discontinuations for any reason were associated with the use of duloxetine than with placebo (1,011 patients, RR = 2.15, 95% CI 1.48-3.11, P < 0.0001; 1,011 patients, RR = 1.32, 95% CI 1.16-1.49, P < 0.0001; 1,011 patients, RR = 1.43, 95% CI 1.14-1.78, P = 0.002, respectively). However, differences in serious AEs were not significantly statistically different. Moreover, no deaths occurred during these three studies. CONCLUSION: This analysis suggests duloxetine (60/120 mg quaque die (QD)), compared with placebo control, resulted in a greater reduction in pain, improved function and patient-rated impression of improvement, and acceptable adverse effects for the treatment of OAK pain after approximately 10-13 weeks of treatment.


Assuntos
Cloridrato de Duloxetina/uso terapêutico , Articulação do Joelho/efeitos dos fármacos , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/fisiopatologia , Manejo da Dor/métodos , Analgésicos/uso terapêutico , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina/administração & dosagem , Cloridrato de Duloxetina/efeitos adversos , Humanos , Articulação do Joelho/patologia , Medição da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
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