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1.
Acc Chem Res ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820922

RESUMO

Indole-based chiral heterocycles constitute a class of important heterocyclic compounds that are found in numerous pharmaceuticals, functional materials, and chiral catalysts or ligands. Catalytic asymmetric synthesis, for which the 2001 Nobel Prize in Chemistry was awarded, has been demonstrated to be the most efficient method for accessing chiral compounds. Therefore, the catalytic asymmetric synthesis of indole-based chiral heterocycles has attracted great interest from the scientific community. However, the strategies toward this goal are rather limited, and great challenges remain in this field, such as metal contamination in the products, the limited number of platform molecules with versatile reactivity, and the limited number of catalytic asymmetric reactions that offer high step economy, atom economy, and excellent enantiocontrol. Therefore, novel strategies for the catalytic asymmetric synthesis of indole-based chiral heterocycles are urgently needed. To achieve this goal, our group has developed a series of unique strategies, such as designing and developing versatile platform molecules and their corresponding organocatalytic asymmetric reactions to access indole-based chiral heterocycles. In this Account, we describe our efforts to address the remaining challenges in this research field. Namely, we have designed and developed vinylindoles, indolylmethanols, arylindoles and indole derivatives as versatile platform molecules for the construction of indole-based chiral heterocyclic scaffolds with structural diversity and complexity. Based on the reactivities of these platform molecules, we have designed and accomplished a series of organocatalytic asymmetric cycloaddition, cyclization, addition and dearomatization reactions with a high step economy, atom economy and excellent enantiocontrol. Using these strategies, a wide range of indole-based chiral heterocycles, including five-membered to seven-membered heterocycles, axially chiral heterocycles and tetrasubstituted heterocycles, have been synthesized with high efficiency and excellent enantioselectivity. In addition, we have investigated the properties of some indole-based chiral heterocycles, including their bioactivities and catalytic activities, and showed that these chiral heterocycles have potent anticancer activities and promising catalytic activities in asymmetric catalysis. These results help elucidate the potential applications of indole-based chiral heterocycles in drug development and chiral catalysts. The organocatalytic asymmetric synthesis of indole-based chiral heterocycles has undoubtedly become and will continue to be a hot topic in the field of asymmetric catalysis and synthesis. Our efforts, summarized in this Account, will not only open a window for the future development of innovative strategies toward organocatalytic asymmetric synthesis of indole-based chiral heterocycles but also inspire chemists worldwide to confront the remaining challenges in this field and prompt further advances.

2.
Org Lett ; 21(19): 7897-7901, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31525932

RESUMO

Highly enantioselective [4 + 2] cyclizations of azadienes with in situ generated ketenes were developed through sequential visible-light photoactivation/isothiourea catalysis, which offers a novel approach for the creation of all-carbon quaternary stereocenters through disubstituted C1-ammonium enolates. The visible-light-induced sustained release of reactive ketene species through Wolff rearrangement of α-diazoketones is crucial for achieving high levels of chemical efficiency and stereoinduction.

3.
Jpn J Radiol ; 37(10): 701-709, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401722

RESUMO

OBJECTIVES: To evaluate quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) in the assessment of tumor angiogenesis using an orthotropic liver tumor model. METHODS: Nine New Zealand white rabbits with liver orthotropic VX2 tumors were established and imaged by two-dimensional (2D) and 3D DCE-US after SonoVue® bolus injections. The intraclass correlation coefficients of perfusion parameters, including peak intensity (PI), mean transit time, time to peak, and area under the curve, were calculated based on time-intensity curve. The percentage area of microvascular (PAMV) and the expression of vascular endothelial growth factor (VEGF) were both evaluated by immunohistochemical analysis and weighted by the tumor activity area ratio. Correlations between quantitative and histologic parameters were analyzed. RESULTS: The reproducibility of 3D DCE-US quantitative parameters was excellent (ICC 0.91-0.99); but only PI showed high reproducibility (ICC 0.97) in 2D. None of the parameters of quantitative 2D DCE-US were significantly correlated with weighted PAMV or VEGF. For 3D DCE-US, there was a positive correlation between PI and weighted PAMV (r = 0.74, P = 0.04) as well as VEGF (r = 0.79, P = 0.02). CONCLUSION: Quantitative parameters of 3D DCE-US show feasibility, higher reproducibility and accuracy for the assessment of tumor angiogenesis using an orthotropic liver tumor model compared with 2D DCE-US.


Assuntos
Meios de Contraste , Aumento da Imagem/métodos , Imagem Tridimensional/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neovascularização Patológica/diagnóstico por imagem , Ultrassonografia/métodos , Animais , Modelos Animais de Doenças , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/patologia , Neovascularização Patológica/patologia , Coelhos , Reprodutibilidade dos Testes
4.
Angew Chem Int Ed Engl ; 58(42): 15104-15110, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31441203

RESUMO

A new strategy for enantioselective synthesis of axially chiral naphthyl-indoles has been established through catalytic asymmetric addition reactions of racemic naphthyl-indoles with bulky electrophiles. Under chiral phosphoric acid catalysis, azodicarboxylates and o-hydroxybenzyl alcohols served as bulky but reactive electrophiles that were attacked by C2-unsubstituted naphthyl-indoles, which underwent a dynamic kinetic resolution to afford two series of axially chiral naphthyl-indoles in good yields (up to 98 %) and high enantioselectivities (up to 98:2 er).

5.
Autophagy ; 15(4): 707-725, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30612517

RESUMO

Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca2+ release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans. Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A1; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-ß-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor.

6.
Org Lett ; 20(24): 7907-7911, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30540196

RESUMO

The first catalytic asymmetric decarboxylative [3 + 2] cycloaddition reaction of ethynylethylene carbonates with malononitrile has been developed successfully by an organo/copper cooperative system. This strategy led to a series of optically active polysubstituted dihydrofurans in good yields with high levels of enantioselectivities (up to 99% yield, 97% ee). The presence of the terminal alkynyl and the cyano group in the dihydrofuran products provides a wide scope for further structural transformations. More importantly, this organo/metal cooperative catalytic system will broaden the substrate scope and enable fundamentally new reactions.

7.
Org Lett ; 20(9): 2792-2795, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29676576

RESUMO

The first catalytic enantioselective decarboxylative propargylation/hydroamination reaction of ethynyl benzoxazinanones with malononitriles enabled by organo/copper cooperative catalysis was established. Various 3-indolin-malononitrile derivatives, displaying a high tolerance for functional groups, could be obtained in good yields with high levels of enantioselectivity (up to 85% yield, 96:4 er). More importantly, this organo/metal cooperative catalytic system will provide a powerful synthetic strategy for new reaction development.

8.
Zygote ; 25(4): 453-461, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28712374

RESUMO

We examined the in vitro developmental competence of parthenogenetic activation (PA) oocytes activated by an electric pulse (EP) and treated with various concentrations of AZD5438 for 4 h. Treatment with 10 µM AZD5438 for 4 h significantly improved the blastocyst formation rate of PA oocytes in comparison with 0, 20, or 50 µM AZD5438 treatment (46.4% vs. 34.5%, 32.3%, and 24.0%, respectively; P 0.05). Furthermore, 66.67% of blastocysts derived from these AZD5438-treated PA oocytes had a diploid karyotype. The blastocyst formation rate of PA and somatic cell nuclear transfer (SCNT) embryos was similar between oocytes activated by an EP and treated with 2 mM 6-dimethylaminopurine for 4 h and those activated by an EP and treated with 10 µM AZD5438 for 4 h (11.11% vs. 13.40%, P > 0.05). In addition, the level of maturation-promoting factor (MPF) was significantly decreased in oocytes activated by an EP and treated with 10 µM AZD5438 for 4 h. Finally, the mRNA expression levels of apoptosis-related genes (Bax and Bcl-2) and pluripotency-related genes (Oct4, Nanog, and Sox2) were checked by RT-PCR; however, there were no differences between the AZD5438-treated and non-treated control groups. Our results demonstrate that porcine oocyte activation via an EP in combination with AZD5438 treatment can lead to a high blastocyst formation rate in PA and SCNT experiments.


Assuntos
Blastocisto/fisiologia , Imidazóis/farmacologia , Técnicas de Maturação in Vitro de Oócitos/métodos , Partenogênese/fisiologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Estimulação Elétrica , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Imidazóis/administração & dosagem , Cariotipagem , Técnicas de Transferência Nuclear , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Partenogênese/efeitos dos fármacos , Pirimidinas/administração & dosagem , Suínos
9.
Ann Hematol ; 96(7): 1085-1095, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28421266

RESUMO

The adverse effects of iron overload have raised more concerns as a growing number of studies reported its association with immune disorders. This study aimed to investigate alterations in the immune system by iron overload in patients with myelodysplastic syndrome (MDS) and an iron-overloaded mouse model. The peripheral blood from patients was harvested to test the effect of iron overload on the subsets of T lymphocytes, and the level of reactive oxygen species (ROS) was also evaluated. The data showed that iron-overloaded patients had a lower percentage of CD3+ T cells and disrupted T cell subsets, concomitant with higher ROS level in lymphocytes. In order to explore the mechanism, male C57Bl/6 mice were intraperitoneally injected with iron dextran at a dose of 250 mg/kg every 3 days for 4 weeks to establish an iron-overloaded mouse model and the blood of each mouse was collected for the analysis of the T lymphocyte subsets and T cell apoptosis. The results showed that iron overload could reduce the percentage of CD3+ T cells and the ratio of Th1/Th2 and Tc1/Tc2 but increase the percentage of regulatory T (Treg) cells and the ratio of CD4/CD8. We also found that iron overload induced the apoptosis of T lymphocytes and increased its ROS level. Furthermore, these effects could be partially recovered after treating with antioxidant N-acetyl-L-cysteine (NAC) or iron chelator deferasirox (DFX). Taken together, these observations indicated that iron overload could selectively affect peripheral T lymphocytes and induce an impaired cellular immunity by increasing ROS level.


Assuntos
Sobrecarga de Ferro/metabolismo , Síndromes Mielodisplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Subpopulações de Linfócitos T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Complexo CD3/sangue , Relação CD4-CD8 , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Sobrecarga de Ferro/sangue , Contagem de Linfócitos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
10.
Biotechnol Lett ; 39(5): 775-783, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28247195

RESUMO

OBJECTIVE: To investigate the effect of the small molecule, RepSox, on the expression of developmentally important genes and the pre-implantation development of rhesus monkey-pig interspecies somatic cell nuclear transfer (iSCNT) embryos. RESULTS: Rhesus monkey cells expressing the monomeric red fluorescent protein 1 which have a normal (42) chromosome complement, were used as donor cells to generate iSCNT embryos. RepSox increased the expression levels of the pluripotency-related genes, Oct4 and Nanog (p < 0.05), but not of Sox2 compared with untreated embryos at the 2-4-cell stage. Expression of the anti-apoptotic gene, Bcl2, and the pro-apoptotic gene Bax was also affected at the 2-4-cell stage. RepSox treatment also increased the immunostaining intensity of Oct4 at the blastocyst stage (p < 0.05). Although the blastocyst developmental rate was higher in the group treated with 25 µM RepSox for 24 h than in the untreated control group (2.4 vs. 1.2%, p > 0.05), this was not significant. CONCLUSION: RepSox can improve the developmental potential of rhesus monkey-pig iSCNT embryos by regulating the expression of pluripotency-related genes.


Assuntos
Clonagem de Organismos/métodos , Embrião de Mamíferos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Transferência Nuclear , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Células-Tronco Pluripotentes Induzidas/metabolismo , Macaca mulatta , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero , Oócitos/metabolismo , Suínos
11.
Biotechnol Lett ; 39(7): 951-957, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28315059

RESUMO

OBJECTIVE: To examine the effect of SU9516, a cyclin-dependent kinase inhibitor, on the induction of tetraploid blastocyst formation in porcine embryos by parthenogenetic activation. RESULTS: Karyotype analysis of blastocysts showed that in the SU9516-treatment group 56% were tetraploid, whereas in the cytochalasin B (CB) group 67% were diploid. The level of maturation-promoting factor (MPF) in stimulated embryos treated with 10 µM SU9516 for 4 h was lower than in embryos treated with CB group (103 vs. 131 pg/ml). The mRNA expression levels of Nanog significantly increased in SU9516-treated embryos than CB group. CONCLUSION: SU9516 can induce tetraploid blastocyst formation at high efficiency. SU9516 can significantly influence the in vitro developmental competence of porcine parthenogenetically activated embryos by influencing the level of MPF and the gene related apoptosis and pluripotency.


Assuntos
Blastocisto/efeitos dos fármacos , Imidazóis/metabolismo , Indóis/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Tetraploidia , Animais , Citocalasina B/metabolismo , Cariotipagem , Suínos/embriologia
12.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 33(2): 174-178, 2017 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-29931927

RESUMO

OBJECTIVE: To research the hormone secretion levels of progesterone and estrogen and the gene expression levels of two go-nadotropin receptors follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in granular cells of laying hen, and the effect of culture time on the levels of hormone secretion and expression of related receptor gene in granulosa cells was inferred. METHODS: The experiment using the method of cells culture in vitro, the granular cells supernatants of hens were collected at 0 h, 24 h, 48 h, 72 h, 96 h, the progesterone and estrogen concentrations in cell supernatants were determined by ELISA kits, and detected the expression of FSHR and LHR gene in granular cells by real-time fluorescent quantitative PCR. RESULTS: The results showed that the progesterone and estrogen secretion reduced in the early culture of 0 h~48 h(P < 0.05), with the culture time increases to 72 h, the secretion of two hormones began to in-crease, and reaching the level of the initial level of culture. When the cells were cultured to 96 h, the rogesterone and estrogen secretion was reduced again. The lower levels of FSHR and LHR mRNA expression in granular cells appeared with the increase of culture time, compared with the group of cell culture to 0 h, the mRNA expression levels of each groups reduced obviously(P < 0.05). CONCLUSIONS: The amount of progesterone and estrogen in the cultured follicular granulosa cells decreased with the increase of in vitro culture time, and then increased. This might be related to the growth state of cells cultured in vitro. But on the whole, with the extension of the training time, the secretion of proges-terone and estrogen in the cells decreased. This may be related to the decreased expression of the FSHR and LHR genes in the two go-nadotropin receptors.


Assuntos
Galinhas/fisiologia , Estrogênios/metabolismo , Células da Granulosa/citologia , Progesterona/metabolismo , Receptores do FSH/genética , Receptores do LH/genética , Animais , Células Cultivadas , Feminino , Fatores de Tempo
13.
Biotechnol Lett ; 39(2): 189-196, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27864653

RESUMO

OBJECTIVE: The aim of this study was to investigate the developmental competence of oocytes parthenogenetically activated by an electric pulse (EP) and treated with anisomycin and to determine whether this method is applicable to somatic cell nuclear transfer (SCNT). RESULTS: Embryos derived from porcine oocytes parthenogenetically activated by an EP and treatment with 0.01 µg/mL anisomycin had a significantly improved in vitro developmental capacity. Furthermore, 66.6% of blastocysts derived from these embryos had a diploid karyotype. The blastocyst formation rate of cloned embryos was similar between oocytes activated by an EP and treated with 2 mM 6-dimethylaminopurine for 4 h and those activated by an EP and treated with 0.01 µg/mL anisomycin for 4 h. The level of maturation-promoting factor was significantly decreased in oocytes activated by an EP and treated with anisomycin. Finally, the mRNA expression levels of apoptosis-related genes (Bax and Bcl-2) and pluripotency-related genes (Oct4, Nanog, and Sox2) were checked by RT-PCR. CONCLUSION: Our results demonstrate that porcine oocyte activation via an EP in combination with anisomycin treatment can lead to a high blastocyst formation rate in parthenogenetic activation and SCNT experiments.


Assuntos
Anisomicina/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Partenogênese/efeitos dos fármacos , Animais , Estimulação Elétrica , Desenvolvimento Embrionário , Feminino , Técnicas de Transferência Nuclear , Oócitos/fisiologia , Gravidez , Suínos
14.
Theriogenology ; 87: 298-305, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27742403

RESUMO

Cloning remains as an important technique to enhance the reconstitution and distribution of animal population with high-genetic merit. One of the major detrimental factors of this technique is the abnormal epigenetic modifications. MGCD0103 is known as a histone deacetylase inhibitor. In this study, we investigated the effect of MGCD0103 on the in vitro blastocyst formation rate in porcine somatic cell nuclear transferred (SCNT) embryos and expression in acetylation of the histone H3 lysine 9 and histone H4 lysine 12. We compared the in vitro embryonic development of SCNT embryos treated with different concentrations of MGCD0103 for 24 hours. Our results reported that treating with 0.2-µM MGCD0103 for 24 hours effectively improved the development of SCNT embryos, in comparison to the control group (blastocyst formation rate, 25.5 vs. 10.7%, P < 0.05). Then we tested the in vitro development of SCNT embryos treated with 0.2-µM MGCD0103 for various intervals after activation. Treatment for 6 hours significantly improved the development of pig SCNT embryos, compared with the control group (blastocyst formation rate, 21.2 vs. 10.5%, P < 0.05). Furthermore, MGCD0103 supplementation significantly (P < 0.05) increases the average fluorescence intensity of AcH3K9 and AcH4K12 in embryos at the pseudo-pronuclear stage. To examine the in vivo development, MGCD0103-treated SCNT embryos were transferred into two surrogate sows, one of whom became pregnant and three fetuses developed. These results suggest that MGCD0103 can enhance the nuclear reprogramming and improve in vitro developmental potential of porcine SCNT embryos.


Assuntos
Benzamidas/farmacologia , Reprogramação Celular/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Histonas/metabolismo , Técnicas de Transferência Nuclear/veterinária , Pirimidinas/farmacologia , Suínos/embriologia , Acetilação/efeitos dos fármacos , Animais , Clonagem de Organismos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Gravidez
15.
J Org Chem ; 81(17): 7898-907, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27525450

RESUMO

The first catalytic enantioselective construction of biologically important tetrahydroquinolin-5-one-based spirooxindole has been developed via a chiral cinchona alkaloid catalyzed asymmetric three-component [3 + 3] cyclization of cyclic enaminone, isatin, and malononitrile, which afforded a series of tetrahydroquinolin-5-one-based spirooxindoles in high yields and with excellent enantioselectivities (up to 99% yield, 97:3 er). This reaction could be applicable to large-scale synthesis of enantioenriched tetrahydroquinolin-5-one-based spirooxindoles. This synthetic methodology will not only provide a unique approach for the construction of chiral tetrahydroquinolin-5-one-based spirooxindole scaffolds but also increase our understanding of catalytic enantioselective multicomponent reactions.

16.
Cancer Lett ; 381(1): 14-22, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27424523

RESUMO

Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Carcinoma/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Mimetismo Molecular , Neoplasias Nasofaríngeas/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Reguladoras de Apoptose , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/metabolismo , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biotechnol Lett ; 38(9): 1433-41, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27271328

RESUMO

OBJECTIVE: To examine the effect of PCI-24781 (abexinostat) on the blastocyst formation rate in pig somatic cell nuclear transferred (SCNT) embryos and acetylation levels of the histone H3 lysine 9 and histone H4 lysine 12. RESULTS: Treatment with 0.5 nM PCI-24781 for 6 h significantly improved the development of cloned embryos, in comparison to the control group (25.3 vs. 10.5 %, P < 0.05). Furthermore, PCI-24781 treatment led to elevated acetylation of H3K9 and H4K12. TUNEL assay and Hoechst 33342 staining revealed that the percentage of apoptotic cells in blastocysts was significantly lower in PCI-24781-treated SCNT embryos than in untreated embryos. Also, PCI-24781-treated embryos were transferred into three surrogate sows, one of whom became pregnant and two fetuses developed. CONCLUSION: PCI-24781 improves nuclear reprogramming and the developmental potential of pig SCNT embryos.


Assuntos
Benzofuranos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Animais , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Feminino , Inibidores de Histona Desacetilases/farmacologia , Técnicas de Transferência Nuclear , Gravidez , Suínos
18.
J Org Chem ; 81(12): 5056-65, 2016 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-27164054

RESUMO

The first catalytic asymmetric construction of the biologically important hexahydrocoumarin scaffold has been established, which takes advantage of chiral thiourea-tertiary amine-catalyzed enantioselective transformations. Besides, this reaction also realized the first catalytic asymmetric [3 + 3] cyclization of 4-arylidene-2-aryloxazol-5(4H)-ones with cyclohexane-1,3-diones, which afforded structurally diverse 3-aminohexahydrocoumarin derivatives in excellent diastereoselectivities and high enantioselectivities (all >95:5 dr, up to 96:4 er). The investigation on the activation mode suggested that the chiral thiourea-tertiary amine catalyst simultaneously activated the two substrates via hydrogen-bonding interaction. Moreover, this reaction could be applied to a large scale synthesis of enantioenriched hexahydrocoumarin. This approach will not only provide an efficient method for the construction of the chiral hexahydrocoumarin scaffold but also enrich the research areas of asymmetric organocatalysis and catalytic enantioselective [3 + 3] cyclizations.

19.
Sheng Li Xue Bao ; 68(2): 165-70, 2016 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-27108903

RESUMO

The study was aimed to observe mir-210 expression in liver tissue of acute cold stress rat and predict the function of mir-210 in cold stress. Thirty SPF Wistar male rats which were 12-week-old and weighed (340 ± 20) g were used. The rats were pre-fed in normal room temperature for one week, and then were randomly divided into acute cold stress group at (4 ± 0.1) °C and normal control group at (24 ± 0.1) °C. After the rats were treated with cold stress for 12 h, the liver tissue was extracted and the gene expression of mir-210 was assayed using qRT-PCR. The results demonstrated that the gene expression of mir-210 was significantly enhanced in acute cold stress group compared with that in normal control group (n = 3, P < 0.01). The bioinformatics analysis showed that mir-210 has over hundreds of target genes and four kinds of target genes such as E2F3, RAD52, ISCU and Ephrin-A3 are more relative with liver cold stress. ISCU regulates the cell respiratory metabolism and Ephrin-A3 is related with cell proliferation and apoptosis. On the other hand, up-regulated mir-210 affects the DNA repairing mechanism which usually leads to genetic instabilities. Our results suggest that cold stress-induced up-regulation of mir-210 in liver harmfully influences cell growth, energy metabolism and hereditary.


Assuntos
Fígado , Estresse Fisiológico , Animais , Apoptose , Ciclo Celular , Proliferação de Células , Temperatura Baixa , Metabolismo Energético , Masculino , MicroRNAs , Ratos , Ratos Wistar , Regulação para Cima
20.
J Org Chem ; 81(4): 1681-8, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26800116

RESUMO

An enantioselective [4 + 2] cycloaddition of o-hydroxylstyrenes with azlactones has been established by merging chiral Brønsted acid (chiral phosphoric acid) and base (chiral guanidine) catalysis, which constructed a biologically important dihydrocoumarin scaffold in an efficient and enantioselective style (up to 99% yield, 96:4 er). This approach has not only realized the successful application of o-hydroxylstyrenes as oxa-diene precursors in catalytic asymmetric cycloadditions but also established a new cooperative catalytic system of chiral phosphoric acid and chiral guanidine.

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