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1.
Inorg Chem ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31680517

RESUMO

Hydro(solvo)thermal syntheses of quaternary copper sulfides containing alkaline earth metal ions remain a great challenge because of the low solubility of Cu-S compounds. Herein, a new facile solvothermal method was developed, and four quaternary copper sulfides, i.e., BaCu3InS4 (1), BaCu3GaS4 (2), BaCu2SnS4 (3), and BaCu2GeS4 (4), were prepared using excess sulfur as a mineralizer. Compound 1 possesses a novel three-dimensional (3D) anionic [Cu3InS4]2- framework constructed by an 8-membered ring of [Cu4S4] and [Cu2In2S4] alternatively. Compound 2 features a unique 3D anionic [Cu3GaS4]2- framework composed of [Cu3GaS10]n14n- anionic chains and 8-membered rings, in which [Cu4S4] and [Cu2Ga2S4] reside alternatively. Compounds 3 and 4 feature 3D anionic [Cu2MS4]2- (M = Sn, Ge) frameworks composed of CuS4 and MS4 tetrahedra with Ba2+ located in the channels. It is worth noting that different 3D Cu-S frameworks exist in the title crystal structures, in which main group ions are incorporated. This paper provides a new synthetic strategy for new quaternary sulfides.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31654453

RESUMO

Large nonlinear optical (NLO) coefficient and wide band gap are two crucial but contradictory parameters that are difficult to simultaneously achieve in a single infrared (IR) NLO compound. Here, a new salt-inclusion chalcogenide (SIC), Li[LiCs 2 Cl][Ga 3 S 6 ] ( 1 ), which presents the first nano-sized tunnel framework constructed by monotype chalcogenide tetrahedra, is successfully obtained. Highly oriented covalent GaS 4 tetrahedra in the host lead to moderate second harmonic generation response (0.7×AgGaS 2 ), and ionic guests effectively broaden the band gap to the widest value (4.18 eV) among all IR NLO chalcogenides, thereby achieving remarkable balance between NLO efficiency and band gap.

3.
Sheng Li Xue Bao ; 71(4): 555-561, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440752

RESUMO

The aim of the present study was to establish a cell model of volume-regulated anion channel subunit LRRC8A and investigate the physiological characteristics of LRRC8A. The eukaryotic expression vectors of LRRC8A and YFP-H148Q/I152L were constructed and transfected into Fischer rat thyroid (FRT) cells by Lipofectamine 2000. The FRT cell lines co-expressing LRRC8A and YFP-H148Q/I152L were obtained by antibiotic screening. The expression of LRRC8A and YFP-H148Q/I152L in FRT cells was detected by the inverted fluorescence microscope. The fluorescence quenching kinetic experiment was done to verify the function and effectiveness of the cell model. Then the cell model was utilized to study the physiological characteristics of LRRC8A, such as the characteristics of anion transport, the opening of LRRC8A by osmotic pressure, the effect of anion transport velocity, and the effect of chloride channel inhibitors on LRRC8A anion channel. The results of the inverted fluorescence microscope showed that LRRC8A was expressed on the cell membrane and YFP-H148Q/I152L was expressed in the cytoplasm. The results of fluorescence quenching kinetic test showed that under the condition of low osmotic state, LRRC8A could transport some kinds of anions, such as iodine and chloride ions. Osmotic pressure played a key role in the regulation of LRRC8A volume-regulated anion channel opening. Chloride channel inhibitors inhibited ion transport of LRRC8A channel in a dose-dependent manner. It is suggested that LRRC8A has the characteristics of classic volume-regulated anion channels by using the cell model of FRT cells co-expressing LRRC8A and YFP-H148Q/I152L.


Assuntos
Canais de Cloreto/antagonistas & inibidores , Transporte de Íons , Proteínas de Membrana/fisiologia , Animais , Ânions , Células Cultivadas , Microscopia de Fluorescência , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/citologia , Transfecção
4.
Food Chem Toxicol ; 131: 110537, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150782

RESUMO

Programmed death ligand-1 (PD-L1) is an important immune checkpoint for cancer immunotherapy in clinic. In this study, we reported that platycodin D, a natural product isolated from an edible and medicinal plant Platycodon grandiflorus (Jacq.) A. DC., down-regulated the protein level of PD-L1 in lung cancer cells. Flow cytometry and immunofluorescence assay showed a weaker surface PD-L1 signal in NCI-H1975 cells after the incubation with platycodin D (10 µM) for 15 min compared to the control group. Jurkat T cells showed enhancive interleukin-2 secretion when co-cultured with platycodin D-treated NCI-H1975 cells, suggesting that platycodin D-induced PD-L1 reduction increases the activation of Jurkat T cells. An augmentation of PD-L1 protein was detected in the cell culture medium from platycodin D treatment group. Chlorpromazine (60 µM) almost abolished the platycodin D-mediated PD-L1 extracellular release and restored the membrane PD-L1. Finally, hemolysis assay exhibited that platycodin D-triggered PD-L1 extracellular release was independent of the hemolytic mechanism. Taken together, our study demonstrates that platycodin D reduces the protein level of PD-L1 in lung cancer cells via triggering its release into the cell culture medium, which sheds new light for the application of natural products in cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Linhagem Celular Tumoral , Clorpromazina/farmacologia , Humanos , Interleucina-2/metabolismo , Células Jurkat , Transporte Proteico/efeitos dos fármacos
5.
Environ Sci Pollut Res Int ; 26(20): 20325-20343, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093916

RESUMO

In this study, integrate electrical resistivity tomography (ERT) tests were carried out in a large-scale (5.0 × 4.0 × 7.5 m) MSW landfill cell to investigate the possibility of detecting perched leachate mounds, leachate level, and gas accumulation zones at wet landfills. The resistivity of both bulk waste and waste components at different moisture states were measured and the three-phase volumetric relationships of the waste pile were analyzed to better interpret the ERT test results in the large-scale cell. The following observations were given: (1) The relationship between resistivity and volumetric moisture content (VMC) of waste sample can be reasonably fitted by Archie's law. The resistivity of waste components at a saturated state was all lower than 21 Ω m. (2) A significant amount of void gas was entrapped in the underwater waste, being 30.4-34.8% of the whole waste pile in volume. (3) Low-resistivity zones (< 5.0 Ω m) were observed in the waste pile being fully drained under a gravity condition, which was believed to be related to a perched leachate. (4) The average VMC values of the waste layer below and above the leachate level were in the ranges of 46.5-53.1% and 28.1-41.3%, respectively. (5) Irregular variations of high-resistivity zones (> 40 Ω m) observed in the underwater waste were associated with the accumulation and dissipation of gas pressure. It was found that the "gas-breaking value" in the gas accumulation zone was up to 10.5 kPa greater than the pore liquid pressure in the stable methanogenesis stage. These findings shone a light on the possibility of using the ERT method as an efficient tool for mapping the gas/leachate distribution and improving operations at wet landfills.


Assuntos
Gases/análise , Tomografia/métodos , Instalações de Eliminação de Resíduos , Poluentes Químicos da Água/análise , Eletricidade , Eliminação de Resíduos/métodos
6.
Angew Chem Int Ed Engl ; 58(24): 8087-8091, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31002447

RESUMO

A big challenge for nonlinear optical (NLO) materials is the application in high power lasers, which needs the simultaneous occurrence of large second harmonic generation (SHG) and high laser induced damage threshold (LIDT). Herein we report the preparation of a new Ga2 Se3 phase, which shows the SHG intensities of around 2.3 times and the LIDT of around 16.7 times those of AgGaS2 (AGS), respectively. In addition, its IR transparent window ca. 0.59-25 µm is also significantly wider than that of AGS (ca. 0.48-≈11.4 µm). The occurrence of the strong SHG responses and good phase-matching indicate that the structure of the new Ga2 Se3 phase can only be non-centrosymmetric and have a lower symmetry than the cubic γ-phase. The observed excellent SHG and phase-matching properties are consistent with our diffraction experiments and can be well explained by using the orthorhombic models obtained through our high throughput simulations.

7.
Anticancer Agents Med Chem ; 19(6): 731-739, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30848214

RESUMO

BACKGROUND: Pemetrexed (PMT) is a multitargeted antifolate agent that is used for treating patients with Non-Small Cell Lung Cancer (NSCLC). However, patients have presented clinical responses of drug resistance to PMT. OBJECTIVE: This study aimed to explore the underlying mechanisms of PMT resistance in NSCLC cells. METHODS: PMT-resistant NCI-H460/PMT cells were established by treating with PMT in a concentrationescalation manner. MTT assay and colony formation were performed to detect cell proliferation. Immunofluorescence was used to detect the expression of Ki-67. Transwell assay was performed to measure cell migration ability. qPCR and Western blot were used to detect the mRNA and protein expression levels of indicated genes. Small interfering RNAs (siRNA) were used to knockdown ATP binding cassette subfamily B member 1 (ABCB1) and Thymidylate Synthase (TYMS). RESULTS: This study showed that compared with the parental cells, the NCI-H460/PMT cells displayed weakened proliferation and enhanced cell mobility. In addition, the NCI-H460/PMT cells demonstrated cellular senescence, which might result in PMT resistance. The NCI-H460/PMT cells exhibited cross-resistance to other chemotherapeutics, including fluorouracil, paclitaxel, doxorubicin, etoposide and gemcitabine, possibly because of the upregulated expression of ABCB1. However, the ABCB1 knockdown by siRNA failed to eradicate PMT resistance. Moreover, TYMS, a target of PMT, was obviously upregulated in the resistant cells. The genetic silence of TYMS partially abrogated PMT resistance, suggesting that the overexpression of TYMS was a key resistant mechanism of PMT. CONCLUSION: The overexpression of TYMS was an important resistance mechanism of PMT for KRAS-mutated NCI-H460 cells. Cross-resistance to other chemotherapeutics should be considered in addressing PMT resistance.

8.
Phytomedicine ; 52: 32-39, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599910

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death around the world. Epithelial-mesenchymal transition (EMT) has been documented to increase motility and invasiveness of cancer cells, which promotes cancer metastasis. PURPOSE: This study aims to investigate the inhibitory effects and mechanisms of the dinorditerpenoids and norditerpenoids isolated from the seeds of Podocarpus nagi against transforming growth factor (TGF)-ß1-induced EMT. METHODS: A series of dinorditerpenoids and norditerpenoids were isolated from the seeds of P. nagi. Western blot and quantitative real-time PCR assays were performed to determine the expression levels of relative proteins and mRNA, along with immunofluorescence, Smad-binding element (SBE)-luciferase and chromatin immunoprecipitation (ChIP) assays for the mechanism study. Transwell assays were conducted to determine the effect of the compounds on cell migration and invasion. RESULTS: Nagilactone E (NLE) showed the superior inhibitory effect against TGF-ß1-induced EMT. NLE treatment dramatically inhibited TGF-ß1-induced expression of EMT markers in A549 cells. Mechanism study indicated that NLE markedly suppressed TGF-ß1-induced Smad2 and Smad3 activation and nuclear translocation. SBE-luciferase and ChIP assays showed that NLE inhibited the combining of Smad3 to SBE in the promoters of the cell signaling factors. NLE co-treatment attenuated TGF-ß1-induced up-regulation of the protein and mRNA levels of TGF-ß receptor TßRI. Furthermore, NLE inhibited TGF-ß1-stimulated cell migration and invasion, as well as up-regulation of the key signaling proteins related with migration and invasion. CONCLUSION: NLE inhibited TGF-ß/Smad signaling pathway, thereafter suppressed TGF-ß1-induced EMT, migration and invasion in NSCLC A549 cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Fator de Crescimento Transformador beta1/farmacologia , Células A549 , Movimento Celular/efeitos dos fármacos , Gleiquênias/química , Humanos , Invasividade Neoplásica , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
9.
Chem Sci ; 9(26): 5700-5708, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30079178

RESUMO

To circumvent the incompatibility between large nonlinear optical (NLO) efficiencies and high laser-induced damage thresholds (LIDTs) in mid-infrared NLO materials, a new strategy for designing materials with both excellent properties is proposed. This strategy involves narrowing the band gap for large NLO efficiencies and reducing the thermal effect for a high LIDT. To support these proposals, a series of isostructural chalcogenides with various tetrahedral center cations, Na2Ga2MQ6 (M = Ge, Sn; Q = S, Se), were synthesized and studied in detail. Compared with the benchmark AGS, these chalcogenides exhibit significantly narrower band gaps (1.56-1.73 eV, AGS: 2.62 eV) and high NLO efficiencies (1.6-3.9 times that of AGS at 1910 nm), and also outstanding LIDTs of 8.5-13.3 × those of AGS for potential high-power applications, which are contrary to the conventional band gap view but can be attributed to their small thermal expansion anisotropy, surmounting the NLO-LIDT incompatibility. These results shed light on the search for practical IR NLO materials with excellent performance not restricted by NLO-LIDT incompatibility.

10.
Mol Med Rep ; 18(1): 610-616, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749525

RESUMO

With extensive pharmacological actions, quercetin has anti­oxidant, free radical scavenging, anti­tumor, anti­inflammatory, anti­bacterial and anti­viral activity. Quercetin also reduces blood glucose and reduces high blood pressure, and has immunoregulation and cardiovascular protection functions. Additionally, it has been reported that it can reduce depression. The current study evaluated whether quercetin protects against inflammation, matrix metalloproteinase­2 (MMP­2) activation and apoptosis induction in a rat model of cardiopulmonary resuscitation (CPR), and whether Bmi­1 expression was involved in the effects. In CPR model rats, treatment with quercetin significantly recovered left ventricular ejection fraction, left ventricular fractional shortening, ejection fraction (%), and left ventricle weight/body weight. Treatment with quercetin significantly inhibited ROS generation, inflammation and MMP­2 protein expression in the rat model CPR. Finally, quercetin significantly suppressed caspase­3 activity and activated Bmi­1 protein expression in the rat model of CPR. The results demonstrated that quercetin protects against inflammation, MMP­2 activation and apoptosis induction in a rat model of CPR, and that this may be mediated by modulating Bmi­1 expression.


Assuntos
Reanimação Cardiopulmonar , Inflamação , Metaloproteinase 2 da Matriz/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Quercetina/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Apoptose , Modelos Animais , Substâncias Protetoras/farmacologia , Ratos
11.
Physiol Res ; 67(4): 637-646, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-29750875

RESUMO

Ulinastatin [or called as urinary trypsin inhibitor (UTI)] plays a role in regulating neurological deficits evoked by transient cerebral ischemia. However, the underlying mechanisms still need to be determined. The present study was to examine the effects of UTI on autophagy, Nrf2-ARE and apoptosis signal pathway in the hippocampus in the process of neurological functions after cerebral ischemia using a rat model of cardiac arrest (CA). CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Western blot analysis was employed to determine the expression of representative autophagy (namely, Atg5, LC3, Beclin 1), p62 protein (a maker of autophagic flux), and Nrf2-ARE pathways. Neuronal apoptosis was assessed by determining expression levels of Caspase-3 and Caspase-9, and by examining terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL). The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. Our results show that CA amplified autophagy and apoptotic Caspase-3/Caspase-9, and downregulated Nrf2-ARE pathway in the hippocampus CA1 region. Systemic administration of UTI attenuated autophagy and apoptosis, and largely restored Nrf2-ARE signal pathway following cerebral ischemia and thereby alleviated neurological deficits with increasing survival of CA rats. Our data suggest that UTI improves the worsened protein expression of autophagy and apoptosis, and restores Nrf2-ARE signals in the hippocampus and this is linked to inhibition of neurological deficiencies in transient cerebral ischemia. UTI plays a beneficial role in modulating neurological deficits induced by transient cerebral ischemia via central autophagy, apoptosis and Nrf2-ARE mechanisms.

12.
Inorg Chem ; 57(12): 6783-6786, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29808675

RESUMO

Two new infrared (IR) nonlinear optical (NLO) sulfides, Na2Ga2GeS6 and Na2Ga2SnS6, were obtained by mixing different typical NLO-active motifs GaS4 and GeS4/SnS4 in the alkali metal-containing system. The IR NLO sulfides present laser-induced damage thresholds that are 18.1 and 17.9 times that of the reference AgGaS2 (AGS) and second-harmonic generation efficiencies that are 0.8 and 1.1 times that of AGS. These properties originate from the GaS4, GeS4, and SnS4 tetrahedral blocks in the structures of the sulfides. Both compounds also exhibit a broad transparency range and type-I phase-matching behavior, which support their high potential in high-power laser applications. This work sheds new light on the development of promising mid-IR NLO materials by combining different NLO-active motifs.

13.
Eur J Pharmacol ; 830: 17-25, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29680228

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most common forms and leading causes of cancer-related mortality worldwide, and discovery of new effective drugs still remains imperative to improve the survival rate. Nagilactone E (NLE) is a natural product isolated from Podocarpus nagi seeds, which has been used as raw materials for edible oil and industrial oil extraction. This study aimed to investigate the anticancer potential of NLE against NSCLC A549 and NCI-H1975 cells. MTT assay revealed that NLE inhibited the proliferation of A549 and NCI-H1975 cells with IC50s of 5.18 ±â€¯0.49 and 3.57 ±â€¯0.29 µM, respectively. NLE treatment inhibited clone formation in both cancer cell lines. Cell cycle analysis indicated that NLE treatment effectively induced G2 phase cell cycle arrest in A549 and NCI-H1975 cells. NLE downregulated the phosphorylation of cdc2 (Tyr15) and cdc25C (Ser216) as well as the expression level of the protein kinase Wee1 in concentration- and time-dependent manners. In addition, NLE treatment decreased the protein level of Cyclin B1 as well as its nuclear localization, which might decrease the activity of the Cyclin B1/cdc2 complex and induce G2 phase arrest. Long-term NLE treatment also induced caspase-dependent cell apoptosis, as evidenced by increase in Annexin V positive cells and the cleavage of PARP. To sum, NLE inhibited proliferation, induced G2 phase arrest, and triggered caspase-dependent apoptosis in NSCLC cells, suggesting it to be a potential leading compound for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclina B1/metabolismo , Diterpenos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/genética , Regulação para Baixo , Humanos
14.
J Am Chem Soc ; 140(8): 2805-2811, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29421867

RESUMO

Broad absorption, long-lived photogenerated carriers, high conductance, and high stability are all required for a light absorber toward its real application on solar cells. Inorganic-organic hybrid lead-halide materials have shown tremendous potential for applications in solar cells. This work offers a new design strategy to improve the absorption range, conductance, photoconductance, and stability of these materials. We synthesized a new photochromic lead-chloride semiconductor by incorporating a photoactive viologen zwitterion into a lead-chloride system in the coordinating mode. This semiconductor has a novel inorganic-organic hybrid structure, where 1-D semiconducting inorganic lead-chloride nanoribbons covalently bond to 1-D semiconducting organic π-aggregates. It shows high stability against light, heat, and moisture. After photoinduced electron transfer (PIET), it yields a long-lived charge-separated state with a broad absorption band covering the 200-900 nm region while increasing its conductance and photoconductance. This work is the first to modify the photoconductance of semiconductors by PIET. The observed increasing times of conductivity reached 3 orders of magnitude, which represents a record for photoswitchable semiconductors. The increasing photocurrent comes mainly from the semiconducting organic π-aggregates, which indicates a chance to improve the photocurrent by modifying the organic component. These findings contribute to the exploration of light absorbers for solar cells.

15.
Mol Med Rep ; 17(3): 4747-4752, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328383

RESUMO

Previous studies have demonstrated that oxymatrine may inhibit ventricular remodeling and serves an important role in the treatment of cardiovascular disease. The present study investigated whether oxymatrine treatment protects against the effects of cardiopulmonary resuscitation (CPR) via regulation of the transforming growth factor­ß1 (TGF­ß1)/mothers against decapentaplegic (Smad) signaling pathway. A CPR model was established in Sprague­Dawley (SD) rats by asphyxiation, and rats were subsequently anaesthetized by intraperitoneal injection of chloral hydrate. SD rats were then administered 25 or 50 mg/kg oxymatrine once a day for 4 weeks. Oxymatrine treatment significantly improved troponin I levels, the ejection fraction, hydroxyproline content and the myocardial performance index in model rats. However, treatment with oxymatrine significantly reduced arterial oxygen tension, arterial lactate levels and oxygen extraction. Treatment with oxymatrine following CPR significantly inhibited the protein expression levels of TGF­ß1, TGF­ß1 receptor type 1 and Smad homolog 3 (Smad3) in model rats. The results of this research indicated that oxymatrine treatment may protect against the effects of CPR via regulation of the TGF­ß1/Smad3 signaling pathway and may be a novel drug for CPR in a clinical setting.


Assuntos
Alcaloides/farmacologia , Substâncias Protetoras/farmacologia , Quinolizinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Alcaloides/química , Animais , Reanimação Cardiopulmonar , Ensaio de Imunoadsorção Enzimática , Hidroxiprolina/metabolismo , Ácido Láctico/metabolismo , Masculino , Oxigênio/metabolismo , Substâncias Protetoras/química , Proteínas Serina-Treonina Quinases/metabolismo , Quinolizinas/química , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Troponina I/análise
16.
Anticancer Agents Med Chem ; 18(4): 550-555, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28730963

RESUMO

BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay. The gene was silenced by small interfering RNA. The cellular morphology was observed by using an optical microscope. The viable cell numbers were counted by trypan blue staining assay. RESULTS: The OSI-resistant HCC827/OSIR cells were established on HCC827 cells with naive EGFR-sensitive mutation, and the resistant effects of HCC827/OSIR cells were confirmed through MTT and colony formation assays. The IC50s of HCC827/OSIR cells to other EGFR TKIs, such as gefitinib, erlotinib, afatinib, and rociletinib was higher than that of the HCC827 cells. The anti-proliferative effects of paclitaxel, pemetrexed, doxorubicin, and fluorouracil in HCC827 and HCC827/OSIR cells were similar. The expression of inositolrequiring enzyme 1α (IRE1α) was increased after the cells developed resistance to OSI. The number of viable cells in both cell lines, particularly in HCC827/OSIR cells, was decreased through knockdown of IRE1α or pretreatment with STF-083010, an IRE1α inhibitor. CONCLUSION: An increased expression of IRE1α may be one of the resistant mechanisms for OSI-resistant NSCLC.

17.
Acta Pharmacol Sin ; 38(11): 1512-1520, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28880013

RESUMO

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells. Pretreatment with the N-linked glycosylation inhibitor tunicamycin, osimertinib clearly decreased the production of new PD-L1 protein probably due to a reduction in mRNA. After blocking transcription and translation processes with actinomycin D and cycloheximide, respectively, osimertinib continued to reduce the expression of PD-L1, demonstrating that osimertinib might degrade PD-L1 at the post-translational level, which was confirmed by a cycloheximide chase assay, revealing that osimertinib (125 nmol/L) decreased the half-life of PD-L1 from approximately 17.8 h and 13.8 h to 8.6 h and 4.6 h, respectively, in NCI-H1975 and HCC827 cells. Pretreatment with the proteasome inhibitors (MG-132 or bortezomib) blocked the osimertinib-induced degradation of PD-L1, but an inhibitor of autophagy (chloroquine) did not. In addition, inhibition of GSK3ß by LiCl prevented osimertinib-induced PD-L1 degradation. The results demonstrate that osimertinib reduces PD-L1 mRNA expression and induces its protein degradation, suggesting that osimertinib may reactivate the immune activity of T cells in the tumor microenvironment in EGFR-mutated NSCLC patients.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma , Proteólise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Microambiente Tumoral
18.
Chem Commun (Camb) ; 53(66): 9269-9272, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28771268

RESUMO

White light emission from single-component small organic triazole molecules in the solid state was observed for the first time. This unusual intrinsic broadband emission, stemming from the supramolecular aggregate instead of the excimer, can be tuned by controlling the degree of electron delocalization and intensities of intermolecular interactions.

19.
Inorg Chem ; 56(4): 1906-1918, 2017 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-28169534

RESUMO

In situ alkylation or protonation reactions on the thiazolyl-N donors of benzothiazole (btz) and its derivative 2-aminobenzothiazole (abtz) occurred to form four structure directing agents (SDAs), which feature different structure directing abilities and hydrophobicities. The thiazolyl-N alkylated and protonated btz cations direct to form an α-type (AgI2)- iodoargentate chain in (Etbtz)(AgI2) (1), (Prbtz)(AgI2) (2), and (Hbtz)(AgI2) (3), respectively, while the thiazolyl-N protonated abtz cation directs to form a new type of (Ag2I3)- anionic chain in (Habtz)(Ag2I3) (4). Compounds 1 and 4 represent the first noncentrosymmetric (NCS) hybrid iodoargentates with organic S-containing N-heterocycle derivative cations as SDAs. Further, 1 exhibits high water stability and is second harmonic generation (SHG) active with a response about twice that of KDP (KH2PO4). Importantly, the water stability studies indicate that hybrid iodoargentates with hydrophobic N-alkylated SDAs are more stable in water than those with relative hydrophilic N-protonated SDAs.

20.
Inorg Chem ; 56(3): 1036-1040, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28071902

RESUMO

Vapor-responsive magnetic materials are highly promising for applications as chemical switches or sensors. Compared with porous materials, nonporous species benefit in overcoming the intrinsic conflict between magnetic exchange and porosity but usually suffer from the powdering of single crystals, which hinders the understanding of the structural nature of vapor response and magnetic switch. Single-crystal-to-single-crystal (SCSC) transformation of nonporous compounds through the desorption/absorption of gaseous HCl is unprecedented. Reported here is a discrete nonporous copper(II) complex, (H3O)[K(15-crown-5)2][CuCl4], that exhibits reversible SCSC transformation and magnetic change by the chemisorption/desorption of HCl and H2O. Significant changes in the coordination number (4 ↔ 3), space group (P1̅ ↔ P21/c), color (green ↔ red), and magnetic behavior (antiferromagnetic ↔ paramagnetic) were found during the SCSC transformation.

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