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1.
Int J Nanomedicine ; 14: 5257-5270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409988

RESUMO

Background: In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles (AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent. Methods: The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR). Results: The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50-100 nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410 nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals. Conclusion: In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.


Assuntos
Carcinoma de Ehrlich/patologia , Curcumina/farmacologia , Química Verde/métodos , Nanopartículas Metálicas/química , Prata/farmacologia , Neoplasias do Colo do Útero/patologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Camundongos , Tamanho da Partícula , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Difração de Raios X
2.
J Agric Food Chem ; 67(34): 9618-9629, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31381342

RESUMO

Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.


Assuntos
Astrócitos/efeitos dos fármacos , Hidroxianisol Butilado/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais , Astrócitos/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
3.
Folia Histochem Cytobiol ; 57(2): 64-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31246264

RESUMO

INTRODUCTION: This study endeavors to analyze the effects of miR-1204 on the expression of DEK oncogene in non-small cell lung cancer (NSCLC) cell lines and to study the molecular mechanisms of these effects. MATERIAL AND METHODS: The miR-1204 mimics and inhibitors were transfected into the (A549 and SPC) NSCLC cells. Then the mRNA levels, cell viability, apoptosis rate, morphology and caspase activity were determined. The expression of apoptosis-related proteins Bcl-2 and Bax was also analyzed. RESULTS: In NSCLC cell lines (A549 and SPC), DEK mRNA levels were down-regulated in miR-1204 overex-pression group. In miR-1204 inhibition group, the expression of DEK mRNA showed an opposite trend. The overexpression of miR-1204 increases the apoptosis rate in NSCLC cells. The Bcl-2 levels in the miR-1204 over-expression group were decreased, while the Bax level was increased. In the miR-1204 inhibition group, expression of Bcl-2 and Bax showed opposite trends. Cell staining revealed cell's morphological changes; the apoptosis in the miR-1204 overexpression group revealed significant morphological features, such as brighter nuclei and nu-clear condensation. Results indicated a typical characteristic of apoptosis in the miR-1204 overexpression group. Caspase-9 and Caspase-3 were involved in the apoptosis pathway, which was mediated by miR-1204 and DEK. CONCLUSIONS: The miR-1204 induces apoptosis of NSCLC cells by inhibiting the expression of DEK. The mech-anism of apoptosis involves down-regulation of Bcl-2 and up-regulation of Bax expression. Moreover, the apoptosis was mediated by mitochondria-related caspase 9/3 pathway.


Assuntos
Apoptose/fisiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Cromossômicas não Histona/genética , Neoplasias Pulmonares/genética , MicroRNAs/fisiologia , Proteínas Oncogênicas/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Mensageiro/fisiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
4.
Neuron ; 103(2): 323-334.e7, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31178114

RESUMO

A crucial step in understanding the sleep-control mechanism is to identify sleep neurons. Through systematic anatomical screening followed by functional testing, we identified two sleep-promoting neuronal populations along a thalamo-amygdala pathway, both expressing neurotensin (NTS). Rabies-mediated monosynaptic retrograde tracing identified the central nucleus of amygdala (CeA) as a major source of GABAergic inputs to multiple wake-promoting populations; gene profiling revealed NTS as a prominent marker for these CeA neurons. Optogenetic activation and inactivation of NTS-expressing CeA neurons promoted and suppressed non-REM (NREM) sleep, respectively, and optrode recording showed they are sleep active. Further tracing showed that CeA GABAergic NTS neurons are innervated by glutamatergic NTS neurons in a posterior thalamic region, which also promote NREM sleep. CRISPR/Cas9-mediated NTS knockdown in either the thalamic or CeA neurons greatly reduced their sleep-promoting effect. These results reveal a novel thalamo-amygdala circuit for sleep generation in which NTS signaling is essential for both the upstream glutamatergic and downstream GABAergic neurons.


Assuntos
Tonsila do Cerebelo/citologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Neurotensina/metabolismo , Sono/fisiologia , Tálamo/citologia , Potenciais de Ação/genética , Tonsila do Cerebelo/fisiologia , Animais , Caspase 9/metabolismo , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Vias Neurais/metabolismo , Neurotensina/genética , Técnicas de Patch-Clamp , Sono/genética , Privação do Sono/fisiopatologia , Tálamo/fisiologia , Transfecção , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
5.
Environ Pollut ; 252(Pt A): 917-923, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226516

RESUMO

Glyphosate-based herbicides (GBH) are the most widely used pesticides in the world. The extensive use of them increases the potential human health risk, including the human inhalation toxicity risk. We studied the effect of the most famous GBH Roundup® (RDP) in the concentration range from 50 to 125 µg/mL on Mitochondria-Associated apoptosis and DNA damage in Human alveolar carcinoma cells (A549 cells). Alkaline comet assay, immunofluorescence assay and Flow Cytometric Analysis assay were employed to detect DNA damages and apoptosis of A549 cells. We found RDP caused concentration-dependent increases in DNA damages and proportion of apoptotic cells in A549 cells. RDP induced the DNA single-strand breaks and double-strand breaks; the collapse of mitochondrial membrane by increasing Bax/Bcl-2, resulting in the release of cytochrome c into cytosol and then activated caspase-9/-3, cleaved poly (ADP-ribose) polymerase (PARP) in human lung tissue cells. The results demonstrate that RDP can induce A549 cells cytotoxic effects in vitro at the concentration lower than the occupational exposures level of workers, which means RDP has a potential threat to human health.


Assuntos
Apoptose/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Pulmão/patologia , Mitocôndrias/efeitos dos fármacos , Células A549 , Adenocarcinoma Bronquioloalveolar/genética , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Ensaio Cometa , Citocromos c/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Glicina/toxicidade , Humanos , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
6.
Environ Pollut ; 252(Pt B): 1288-1300, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252126

RESUMO

Glyphosate (GLY)-based herbicide, one of the most widely used herbicides, might cause a series of environmental problems and pose a toxicological risk to aquatic organisms. However, data on the potential hazard and toxicity mechanism of GLY to fish gills are relatively scarce. In this study, a subacute toxicity test of common carp (Cyprinus carpio L.) treated with commercial GLY at 52.08 and 104.15 mg L-1 for 7 d was conducted. The results revealed that GLY exposure significantly inhibited Na+/K+-ATPase and increased AST and ALT activities in the fish gills. The biochemical assays results revealed that GLY treatment remarkably altered the transcriptional levels of HSP70 and HSP90; inhibited the activities of SOD, CAT, GPx, GR, and T-AOC; reduced the contents of GSH, but remarkably promoted MDA and PC contents, suggesting that GLY exposure induced oxidative stress and lipids and proteins damage in the carp gills. Further research revealed that GLY exposure also promoted expression of NF-κB, iNOS, IL-1ß, IL-6, IL-8, and TNF-α; altered the levels of IL-10 and TGF-ß, indicating that GLY exposure induced inflammatory response in the fish gills. Additionally, we found that GLY exposure activated apaf-1 and bax and inhibited bcl-2, induced caspase-9 and caspase-3 expression and caused remarkable histological damage in the fish gills. These results may further enriches the toxicity mechanistic theory of GLY to fish gills, which may be useful for the risk assessment of GLY and aquatic organism protection.


Assuntos
Carpas/metabolismo , Brânquias/lesões , Glicina/análogos & derivados , Herbicidas/toxicidade , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Transcrição Genética/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Brânquias/efeitos dos fármacos , Glicina/toxicidade , Interleucina-10/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos
7.
Artif Cells Nanomed Biotechnol ; 47(1): 1610-1616, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072209

RESUMO

Nanotechnology has been materialized as a proficient technology for the development of anticancer nanoparticles all the way through an environment-friendly approach. Conventionally, nanoparticles have been assembled by dissimilar methods, but regrettably rely on the negative impact on the natural environment. Amalgamation of nanoparticles by means of plant extract is alternate conservative methods. In the present study, we equipped gold nanoparticles (AuNPs) from Strychni semen; displayed as a less toxic and environment-friendly. Integration of AuNPs was famed by UV-absorbance which displays peak values. Moreover, high-resolution transmission electron microscopy (HR-TEM), energy dispersive X-ray analysis (EDX) and atomic force microscopy (AFM) substantiate the shape of the AuNPs in the combined materials. FTIR results exhibit the active molecules positioned in the flat surface of the AuNPs. Similarly, the anticancer effectiveness of AuNPs is considered in KMCH-1 cells. Also, AuNPs successfully aggravate cytotoxicity and apoptosis by conjugating apoptotic gene expressions in KMCH-1 cells. Eventually, our results confirm the synthesis of AuNPs from Strychni Semen shows anticancer effects with environment-friendly manner.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas/química , Extratos Vegetais/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Química Verde , Humanos , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo
8.
Med Sci Monit ; 25: 3231-3237, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31043579

RESUMO

BACKGROUND Worldwide, ovarian cancer has a high mortality rate due to the difficulty in diagnosing early-stage disease and resistance to chemotherapy agents. Costunolide is a plant-derived sesquiterpene lactone with anti-oxidant properties. This study aimed to investigate the effects of costunolide on cell growth, apoptosis, autophagy, the production of reactive oxygen species (ROS), cleaved caspase-3, and cleaved caspase-9 on the multidrug-resistant ovarian cancer cell line, OAW42-A. MATERIAL AND METHODS The MTT assay determined the proliferation rate of OAW42-A multidrug-resistant ovarian cancer cells and the apoptosis rate was determined using propidium iodide (PI) staining. Autophagy was detected by measuring the expression of LC3 II. Fluorescence flow cytometry was used to measure the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. Protein expression of LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9 were measured by Western blot. RESULTS Costunolide treatment inhibited the growth of OAW42-A cells with an IC50 of 25 µM, resulted in apoptotic cell death, increased the expression of Bax, and decreased the expression of Bcl-2. Confocal electron microscopy showed that costunolide induced autophagy in the OAW42-A cells. Western blot showed that costunolide treatment of OAW42-A cells increased the expression of the LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9. Costunolide treatment significantly increased the levels of ROS and reduced the OAW42-A cell mitochondrial membrane potential. CONCLUSIONS Costunolide inhibited growth, apoptosis, ROS generation, and was associated with loss of mitochondrial membrane potential of OAW42-A multidrug-resistant ovarian cancer cells.


Assuntos
Caspase 3/metabolismo , Caspase 9/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Metástase Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia
9.
Chem Biol Interact ; 307: 167-178, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059704

RESUMO

Polyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1-3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Streptomyces/química , Produtos Biológicos/isolamento & purificação , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Conformação Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Streptomyces/metabolismo
10.
Nat Commun ; 10(1): 2091, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064994

RESUMO

Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Caspase 1/fisiologia , Inflamassomos/imunologia , Piroptose/imunologia , Receptores Estrogênicos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Córtex Cerebral/citologia , Embrião de Mamíferos , Técnicas de Inativação de Genes , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nigericina/farmacologia , Cultura Primária de Células , Piroptose/efeitos dos fármacos , Células RAW 264.7 , Salmonella typhimurium/imunologia
11.
Chem Biol Interact ; 308: 1-10, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071337

RESUMO

Diarylheptanoids display an array of biological and pharmacological properties. We previously reported the synthesis of a diarylheptanoid Alpinoid c and a series of its derivatives, evaluated their cytotoxicity against various human cancer cells. We found some of these derivatives were significantly more potent than Alpinoid c in preventing the proliferation of various cancer cell lines. Among these, (S, E)-1-(3, 4 dimethoxyphenyl)-6-hydroxy-7-phenylhept-4-en-3-one (DPHP) showed most potent cytotoxicity against COLO205 cells, however, the mechanism by which DPHP prevents the growth of these colon cancer cells remains unknown. In the current study, we investigated the molecular mechanism of DPHP on colon cancer cells. DPHP inhibited the proliferation of COLO205 (IC50 7.01 ±â€¯0.62 µM) and A549 (IC50 20.03 ±â€¯3.11 µM) cells more specifically than normal human colon epithelial cell line NCM460 (IC50 55.6 ±â€¯4.02 µM). In COLO205 cells, DPHP induced cell shrinkage, membrane blebbing, chromatin condensation, phosphatidylserine externalization, and an accumulation of cells at sub-G1 phase. Further analysis these cells treated with DPHP revealed a decrease in mitochondrial membrane potential, an increase in Bax/Bcl2 ratio, the release of cytochrome c, activation of caspases -9, -3/7, and cleavage of the poly-ADP-ribose polymerase. DPHP treatment resulted in inhibition of hypoxia induced VEGF downstream signaling pathway in COLO205 cells is concurrent with inhibition of angiogenesis in CAM. Based on these data we suggest that DPHP significantly induced apoptosis possibly via intrinsic mitochondrial apoptosis pathway and inhibited angiogenesis. Our study suggests DPHP could be a therapeutic agent in treating colon cancer.


Assuntos
Apoptose/efeitos dos fármacos , Diarileptanoides/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Células A549 , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Embrião de Galinha , Diarileptanoides/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
Eur J Med Chem ; 176: 1-10, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31082759

RESUMO

A class of vanadium complexes were prepared and investigated for their antiproliferative effects by MTT assay. The structure-activity relationship was extensively studied through the ligand variation. The results showed that the synthetic vanadium complexes demonstrated moderate to good antiproliferative activities against the four cancer cell lines including MGC803, EC109, MCF7 and HepG2, respectively. Of note was that most of the complexes showed preferential growth inhibitory activity to some degree toward gastric cancer line MGC803. Among them, complex 19 exhibited the most and broad-spectrum proliferative inhibition against the tested cell lines. In addition, mechanism studies illustrated that complex 19 could prevent the colony formation, migration and EMT process, as well as induce apoptosis of MGC803 cells. Furthermore, Western blot experiments revealed that the expression of apoptosis-related proteins changed, including up-regulation of Bax, PARP and caspase-3/9, as well as down-regulation of Bcl-2.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Vanádio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Regulação para Baixo , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
13.
Eur J Med Chem ; 176: 117-128, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108261

RESUMO

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 µM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 µM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Oximas/farmacologia , Xantinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/química , Oximas/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Xantinas/síntese química , Xantinas/química , Xantinas/toxicidade , Proteína X Associada a bcl-2/metabolismo
14.
Chem Biol Interact ; 308: 120-129, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129132

RESUMO

A preclinical study using DEN-induced HCC rat model was attempted to evaluate the antitumor potential of zolmitriptan (ZOL). The molecular insights were investigated using ELISA, qRT-PCR and Western blot techniques. The result confirmed that the HCC condition was developed in response to lower expressions of caspase 3 and 9 which, in turn, was due to the upstream regulation of iNOS, Bcl-xl and Bcl-2, and downstream regulation of eNOS, BAX, BAD and Cyt C. The treatment with ZOL caused the significant activation of caspase mediated apoptotic signals that could be responsible for its anti-HCC potential. Later, 1H NMR based serum metabolomics study confirmed that ZOL restored the perturbed metabolites associated with DEN-induced HCC. The antineoplastic potential of ZOL was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Oxazolidinonas/farmacologia , Triptaminas/farmacologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Citocinas/análise , Modelos Animais de Doenças , Glutationa/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxazolidinonas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Triptaminas/uso terapêutico , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Phytomedicine ; 58: 152770, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005716

RESUMO

BACKGROUND: Phenanthrenes isolated from Juncus species possess different biological activities, including antiproliferative and antimigratory effects. PURPOSE: In this study, nine phenanthrenes isolated from the roots of Juncus inflexus were investigated for their antiproliferative activity on several gynecological cancer cell lines, using non-cancerous cells as controls. METHODS: Antiproliferative activities of the compounds were determined by means of MTT assay. Flow cytometry was used for cell cycle analysis and determination of mitotic cells. Activities of caspase-3, -8, and -9 were detected by colorimetric kits. Tubulin polymerization was followed by kinetic absorbance determination. Action on tumor cell migration was described using wound healing assay. Western blot assays were used to determine apoptosis-related factors at protein level. RESULTS: Among the compounds tested, juncusol exhibited the most substantial antiproliferative effect against cervical cancer HeLa cells. It was also revealed that juncusol has a distinct growth inhibitory effect in cervical cancer cell lines of various HPV status: it was highly active in HPV type 18-positive HeLa cells, while it was inactive in HPV type 16-positive SiHa and CaSki cells. Cell cycle analysis showed an increase in G2/M and subG1 cell populations after juncusol treatment. Caspase-3, -8, and -9 were detected to be activated by juncusol in HeLa cells, indicating that juncusol induces apoptotic cell death. Moreover, juncusol inhibited tubulin polymerization, as well as EGFR activation, suggesting two possible additional mechanisms that may account for juncusol's inducing a G2/M-phase cell cycle arrest and inhibiting cell migration. CONCLUSION: These results suggest that juncusol is a potent antiproliferative agent against HPV-18 related cervical cancer and may be considered as a lead compound for the development of innovative anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Magnoliopsida/química , Fenantrenos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Fenantrenos/química , Multimerização Proteica/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
16.
Cell Mol Biol (Noisy-le-grand) ; 65(3): 114-118, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30942164

RESUMO

Prostate cancer (PC) has become a disease that pose a serious threat to men's health and life. In recent years, due to the changes of environment, lifestyle and other factors, the incidence of PC has been increasing rapidly in recent years, which is a serious threat to men's health. Ent-Dihydrotucumanoic Acid (DTA) is a compound isolated from Asteraceae of gymnosperms, which has many pharmacological effects. The effect of DTA on the growth of tumor cell line was studied by CCK-8 method, mitochondrial membrane potential and apoptosis were detected by flow cytometry, apoptosis-related genes were detected by Western blot assay, and the absorptivity of Caspase-3 and Caspase-9 was measured by spectrophotometer. It was found that DTA induces apoptosis of human prostate cancer cell line PC3 through mitochondrial pathway, thus preventing the development of prostate cancer. It lays the experimental foundation for the further development of DTA.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Neoplasias da Próstata/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias da Próstata/enzimologia
17.
Cell Mol Biol Lett ; 24: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936926

RESUMO

Background: MicroRNA (miRNA) plays a vital role in the pathogenesis of intervertebral disc degeneration (IDD). The expression and potential mechanism of miR-573 in human nucleus pulposus (NP) remains to be elucidated. In this study, we aimed to investigate the role of miR-573 in IDD. Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was applied to examine the expression of miR-573 and Bax in idiopathic scoliosis tissues and IDD tissues. Human NP cells were employed for analysis. Moreover, the proliferation and apoptosis of NP cells were detected using MTT and flow cytometry assay respectively. The expression levels of Bcl-2, cleaved caspase-3, cleaved caspase-9, caspase-3 and caspase-9 in degenerative NP cells were measured by Western blotting assay. Furthermore, a luciferase reporter assay was used to verify the relationship between miR-573 and Bax. Results: The results revealed that the mRNA expression level of miR-573 was down-regulated whereas Bax was up-regulated notably in degenerative NP cells. In addition, overexpression of miR-573 increased cell viability remarkably, coupled with inhibition of cell apoptosis. The expression level of Bcl-2 was increased while cleaved caspase-3 and cleaved caspase-9 expression levels were decreased in miR-573 overexpression NP cells. Additionally, the bioinformatics analysis underscored that Bax was a direct target gene of miR-573. Conclusion: These results suggest that overexpression of miR-573 inhibited NP cell apoptosis by down-regulating Bax, which proved to be a novel effective strategy for IDD therapies.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Núcleo Pulposo/metabolismo , Proteína X Associada a bcl-2/metabolismo , Sequência de Bases , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Humanos , Degeneração do Disco Intervertebral/genética , MicroRNAs/genética , Núcleo Pulposo/patologia , Escoliose/genética , Proteína X Associada a bcl-2/genética
18.
Pharmazie ; 74(3): 157-162, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961682

RESUMO

The aim of this study was to observe the effects of HIF-1α activation on myocardial I/R in diabetes. Diabetes was induced in an experimental rat model, and regulators of HIF-1α including KC7F2, deferoxamine and ginsenoside Rg1 were administered to observe the changes on diabetic rats. The results demonstrated that HIF-1α activation could effectively reduce myocardial injury following I/R in diabetic hearts via ERK but not MMP-2 signalling pathways. This activation promoted myocardial apoptosis, which was accompanied by modulation of Bax/Bcl-2, caspase-3 and caspase-9 expression following deferoxamine administration. Ginsenoside Rg1 application but not Re can activate HIF-1α, resulting in a similar protectively effect on these pathology processes. Our data demonstrated that ginsenoside Rg1 has a potential therapeutic effect by protecting diabetic hearts after myocardial injury following I/R via HIF-1α activation.


Assuntos
Ginsenosídeos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Desferroxamina/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ginsenosídeos/química , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos
19.
Carbohydr Polym ; 215: 99-107, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981376

RESUMO

Suaeda salsa, is an annual herbaceous plant that contains various bio-functional macromolecules. Herein, an acidic polysaccharide from Suaeda salsa, denoted as SSP2-2, with a molecular weight of 53.8 kDa was isolated, which composed of mannose, rhamnose, glucuronic acid, galacturonic acid, galactose and xylose in a molar ratio of 0.6: 8.0: 1.0: 83.6: 5.0: 7.2. An MTT assay showed that SSP2-2 induced apoptosis of MCF-7 cells in a dose-dependent manner in vitro. Morphological analysis and flow cytometry experiments indicated that SSP2-2 promotes MCF-7 cells death via apoptosis, while JC-1 staining results revealed that mitochondrial membrane potential was reduced in a dose-dependent manner. The data from the western blot showed an increase in the levels of Bax, cytochrome C (Cyto-c), caspase-3 and caspase-9 and a decrease in the level of Bcl-2 further demonstrated that SSP2-2 could induce apoptosis via a mitochondrial pathway. These results suggest that SSP2-2 can potentially be used as an antitumor agent.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Chenopodiaceae/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Polissacarídeos , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Citocromos c/metabolismo , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
20.
Front Biosci (Landmark Ed) ; 24: 833-848, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844716

RESUMO

Acute biliary pancreatitis (ABP) is a potentially life-threatening disease that is induced by the common bile duct (CBD) sludge or stones. This study aimed to investigate protective effects of Qingyi Decoction (QYT) on deoxycholic-acid-sodium salt (DCA) induced ABP in rats. Gpbar1 is a G-protein coupled receptor that can be activated by DCA. Both Gpbar1 overexpression vector and Gpbar1 RNAi were constructed and transfected into ABP cell models. Functional assays reveal that DCA significantly induced AR42J apoptosis and triggered Gpbar1 expression. Gpbar1 significantly activated caspase 8 and caspase 9 as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 significantly triggered apoptosis associated inflammatory factors as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 significantly induced calcium flux as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 up-regulated caspases and inflammatory factors in DCA treated pancreatic acinar cells. QYT reversed DCA induced apoptosis and inflammatory response. QYT significantly reduced Gpbar1 levels compared to no-QTY treated cells (p<0.05). In conclusion, QYT protects against DCA induced pancreatic acinar cell damage in ABP by inhibiting Gpbar1/NF-kB/p-RIP signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Doença Aguda , Animais , Apoptose , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Regulação Enzimológica da Expressão Gênica , Inflamação , Pancreatite/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
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