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1.
Curr Drug Deliv ; 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35598247

RESUMO

BACKGROUND: Cationic lipids can be used as nonviral vectors in gene delivery therapy. Most cationic lipids contain quaternary ammonium that can bond to negative phosphates of the plasmid. In this study, sulfonium-a trialkylated sulfur cation was adopted in the synthesis of a series of cationic lipids which were evaluated ability as gene delivery vectors. METHODS: The sulfonium lipids were synthesized by condensing cyclic thioether and aliphatic carbon chains with ethoxy linkage and characterized the structure by NMR and mass. The DNA condensing abilities of sulfonium lipids were evaluated using a gel retardation experiment. Sulfonium lipids/DNA condensates were measured for particle size and Zeta potential. The cytotoxicity of sulfoniums was evaluated with MTT assay. The intracellular uptakes of sulfonium lipid/DNA complexes were observed with a fluorescence microscope. RESULTS: The results showed that the sulfonium head can effectively bond to the phosphate of DNA. When S/P ratio is larger than 10/1, sulfonium lipids with longer carbon chains can completely condense DNA to form a nanoparticle with particle size ranging from 135 nm to 155 nm and zeta potential ranging from 28 mV to 42 mV. The IC50 of sulfonium lipids on HepG2 cells ranged from 2.37 µg/mL to 3.67 µg/mL. Cellular uptake experiments showed that sulfonium lipids/DNA condensate can be taken into cells. CONCLUSION: Sulfonium lipids can effectively condense DNA and transfer DNA into cells. The sulfonium compound is worth of further development to reduce the cytotoxicity and increase transfection rate as gene vectors.

2.
Drug Chem Toxicol ; 45(1): 33-43, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35100937

RESUMO

1,4-naphthoquinone and its derivatives have attracted widespread attention due to their multiple biological activities, such as induction of cancer cell apoptosis; however, most of these compounds have high cytotoxicity. In this study, in order to reduce their toxicity and increase their potential anti-tumor effects, we synthesized a novel 1,4-naphthoquinone derivative named 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ), and investigated its apoptotic effects and underlying mechanism. Our results showed that NTDMNQ inhibited the viability of HepG2, Hep3B, and Huh7 human hepatocellular carcinoma (HCC) cells. It also increased the accumulation of cells in the G0/G1 phase of the cell cycle by increasing the expression levels of p-p53, p21 and p27, while decreasing the levels of Cyclin D1, Cyclin E, Cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. Inhibition of reactive oxygen species (ROS) by the ROS scavenger N-acetyl-L-cysteine (NAC) decreased apoptosis in NTDMNQ-treated cells. Western blot analysis showed that NTDMNQ increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and signal transducer and activator of transcription-3 (STAT3); these effects were blocked by NAC. Both the JNK inhibitor (SP600125) and p38 inhibitor (SB203580) reversed the phosphorylation of STAT3, and the ERK inhibitor (FR180204) and AKT inhibitor (LY294002) reduced the expression of STAT3. Taken together, these findings suggest that NTDMNQ induces apoptosis via ROS-mediated MAPK, AKT and STAT3 signaling pathways in HepG2 cells, and may be a potent anticancer agent.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Naftalenos , Naftoquinonas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3 , Transdução de Sinais
3.
Bioresour Technol ; 344(Pt B): 126168, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34737050

RESUMO

To improve the lignin degradation efficiency, we established a co-culture consortium (LDFC) consisting of Trametes hirsuta BYL-3, Trametes versicolor BYL-7 and Trametes hirsuta BYL-8. The testing results showed that the constructed consortium showed improved the lignin degradation rate by fungi. The optimal cultivation conditions were mixture at 1:1:1 vol ratio of each fungus, 7% (w/v) of inoculum amount, culture temperature at 26 °C, pH was 6.9 and 10 days of culturing time. Under these conditions, the degradation rate of lignin was 39.7%, which was 9.3% higher than those before optimization (30.4%). Using rice straw for treatment by LDFC to papermaking, the paper tensile strength was 8 N, and the ring pressure index was 2.46 N·m/g, which meets the standards for the production of corrugated paper for packaging. These results indicate that LDFC has potential application value to convert rice straw resources for bio-pulping to make papers.


Assuntos
Lignina , Oryza , Temperatura , Trametes
4.
Appl Environ Microbiol ; 87(23): e0135521, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34524901

RESUMO

Lignin is a complex natural organic polymer and is one of the primary components of lignocellulose. The efficient utilization of lignocellulose is limited because it is difficult to degrade lignin. In this study, we screened a lacz1 gene fragment encoding laccase from the macrotranscriptome data of a microbial consortium WSC-6, which can efficiently degrade lignocellulose. The reverse transcription-quantitative PCR (RT-qPCR) results demonstrated that the expression level of the lacz1 gene during the peak period of lignocellulose degradation by WSC-6 increased by 30.63 times compared to the initial degradation period. Phylogenetic tree analysis demonstrated that the complete lacz1 gene is derived from a Bacillus sp. and encoded laccase. The corresponding protein, LacZ1, was expressed and purified by Ni-chelating affinity chromatography. The optimum temperature was 75°C, the optimum pH was 4.5, and the highest enzyme activity reached 16.39 U/mg. We found that Cu2+ was an important cofactor needed for LacZ1 to have enzyme activity. The molecular weight distribution of lignin was determined by gel permeation chromatography (GPC), and changes in the lignin structure were determined by 1H nuclear magnetic resonance (1H NMR) spectra. The degradation products of lignin by LacZ1 were determined by gas chromatography and mass spectrometry (GC-MS), and three lignin degradation pathways (the gentian acid pathway, benzoic acid pathway, and protocatechuic acid pathway) were proposed. This study provides insight into the degradation of lignin and new insights into high-temperature bacterial laccase. IMPORTANCE Lignin is a natural aromatic polymer that is not easily degraded, hindering the efficient use of lignocellulose-rich biomass resources, such as straw. Biodegradation is a method of decomposing lignin that has recently received increasing attention. In this study, we screened a gene encoding laccase from the lignocellulose-degrading microbial consortium WSC-6, purified the corresponding protein LacZ1, characterized the enzymatic properties of laccase LacZ1, and speculated that the degradation pathway of LacZ1 degrades lignin. This study identified a new, high-temperature bacterial laccase that can degrade lignin, providing insight into lignin degradation by this laccase.


Assuntos
Bacillus/enzimologia , Lacase , Lignina , Bacillus/genética , Lacase/genética , Lacase/isolamento & purificação , Lignina/metabolismo , Filogenia
5.
Bioresour Technol ; 331: 125066, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33812140

RESUMO

The degradation of lignin is the main rate-limiting step in the bio-pulping of rice straw. A lignin-degrading bacterial consortium LDC, which can efficiently degrade lignin of reed, was screened in the early stage of our laboratory work. In present study, 7-day incubation of LDC can degrade rice straw lignin by 31.18% in mineral salt medium. The communities' structure of different incubation phases varied greatly, in which high abundance (44.78%) of Anaerocolumna was first found. The expression levels of lignin degradation enzyme class II peroxidase (AA2), vanillyl alcohol oxidase (AA4) and 1,4-benzoquinone reductase (AA6) during peak phase (48 h) were significantly up-regulated than initial phase (24 h), increasing by 112%, 165% and 67%, respectively, and 42.86% AA2 was from Thaurea; 100% AA4 was from Clostridium; 62.5% AA6 was from Pseudomonas. These provide microbial resources and data support for the industrialization of rice straw bio-pulping.


Assuntos
Lignina , Oryza , Bactérias , Consórcios Microbianos
6.
Ecotoxicology ; 30(8): 1754-1768, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33432458

RESUMO

Long-term frequent tillage would cause black soil degradation and serious soil erosion as soil microbial communities and soil structure are extremely sensitive to tillage process. However, there is no unified conclusion on the relationship between the distribution of soil water-stable aggregates (WSAs), and microbial community construction and diversity under long-term tillage in black soil during different seasons. In this study, we used wet-sieving method to evaluate the composition and stability of soil WSAs and employed Illumina MiSeq high-throughput sequencing technology to study the diversity, taxonomic composition and co-occurrence network properties of microbial community, comparing outcomes between uncultivated soil and long-term cultivated soil for 60 years in Keshan farm of Heilongjiang Province. The results showed that after long-term tillage, the proportion of larger than 1 mm WSAs reduced by 34.17-51.37%, and the stability of WSAs, soil pH, organic matter (OM), total nitrogen (TN) contents decreased significantly in all seasons (P < 0.05), while soil available phosphorus (AP) and available potassium (AK) contents increased remarkably (P < 0.05). The diversity of bacteria increased, while that of fungi decreased. Soil fungal communities were more susceptible to long-term tillage than bacterial and archaeal communities. Actinobacteria mainly exist in large WSAs (˃1 mm), and when their relative abundance is high, it is beneficial to improve the water-stability of black soil; while Proteobacteria and Gemmatimonadetes may exist in small WSAs (˂1 mm), whose high relative abundance will weaken the water-stability of black soil. The experimental results provide a scientific theoretical basis for sustainable utilization of black soil.


Assuntos
Microbiota , Solo , Agricultura , China , Microbiologia do Solo , Água
7.
Exp Ther Med ; 20(5): 82, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32968439

RESUMO

The aim of the present study was to verify the pro-apoptotic anticancer potential of several 5,8-dimethoxy-1,4-phthoquinone (DMNQ) derivatives in Ras-mediated tumorigenesis. MTT assays were used to detect cellular viability and flow cytometry was performed to assess intracellular reactive oxygen species (ROS) levels and apoptosis. The expression levels of proteins were detected via western blotting. Among the 12 newly synthesized DMNQ derivatives, 2-benzylthio-5,8-dimethoxynaphthalene-1,4-dione (BZNQ; component #1) significantly reduced cell viability both in mouse NIH3T3 embryonic fibroblasts cells (NC) and H-RasG12V transfected mouse NIH3T3 embryonic fibroblasts cells (NR). Moreover, BZNQ resulted in increased cytotoxic sensitivity in Ras-mutant transfected cells. Furthermore, the reactive oxygen species (ROS) levels in H-RasG12V transfected HepG2 liver cancer cells (HR) were significantly higher compared with the levels in HepG2 liver cancer cells (HC) following BZNQ treatment, which further resulted in increased cellular apoptosis. Eliminating cellular ROS using an ROS scavenger N-acetyl-L-cysteine markedly reversed BZNQ-induced cellular ROS accumulation and cell apoptosis in HC and HR cells. Western blotting results revealed that BZNQ significantly downregulated H-Ras protein expression and inhibited the Ras-mediated downstream signaling pathways such as protein kinase B, extracellular signal-related kinase and glycogen synthase kinase phosphorylation and ß-catenin protein expression. These results indicated that the novel DMNQ derivative BZNQ may be a therapeutic drug for Ras-mediated liver tumorigenesis. The results of the current study suggest that BZNQ exerts its effect by downregulating H-Ras protein expression and Ras-mediated signaling pathways.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32849902

RESUMO

Two novel compounds, 2-(2-hydroxyethylthio)-5,8-dimethoxy-1,4-naphthoquinone (HEDMNQ) and 2-(6-hydroxyhexylthio)-5,8-dimethoxy-1,4-naphthoquinone (HHDMNQ), were synthesized to investigate the kill effects and mechanism of 1,4-naphthoquinone derivatives in lung cancer cells. The results of the CCK-8 assay showed that HEDMNQ and HHDMNQ had significant cytotoxic effects on A549, NCI-H23, and NCI-H460 NSCLC cells. Flow cytometry and western blot results indicated that HHDMNQ induced A549 cell cycle arrest at the G2/M phase by decreasing the expression levels of cyclin-dependent kinase 1/2 and cyclin B1. Fluorescence microscopy and flow cytometry results indicated that HHDMNQ could induce A549 cell apoptosis, and western blot analysis showed that HHDMNQ induced apoptosis through regulating the mitochondria pathway, as well as the MAPK, STAT3, and NF-κB signalling pathways. Flow cytometry results showed that intracellular reactive oxygen species (ROS) levels were increased after HHDMNQ treatment, and western blot showed that ROS could modulate the intrinsic pathway and MAPK, STAT3, and NF-κB signalling pathways. These effects were blocked by the ROS inhibitor N-acetyl-L-cysteine in A549 cells. Our findings suggest that compared with HEDMNQ, HHDMNQ had the stronger ability to inhibit the cell viability of lung cancer cells and induce apoptosis by regulating the ROS-mediated intrinsic pathway and MAPK/STAT3/NF-κB signalling pathways. Thus, HHDMNQ might be a potential antitumour compound for treating lung cancer.

9.
In Vivo ; 34(4): 1823-1833, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606152

RESUMO

BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis. MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract. CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.


Assuntos
Picrasma , Neoplasias do Colo do Útero , Apoptose , Feminino , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Picrasma/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
10.
Int J Oncol ; 57(2): 550-561, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32626938

RESUMO

Isoorientin (ISO) is a naturally occurring C­glycosyl flavone that has various pharmacological properties, such as anti­bacterial and anti­inflammatory effects. However, its underlying molecular mechanisms in human lung cancer cells remain unknown. In the present study, the effects of ISO on the induction of apoptosis and relative molecular mechanisms in A549 human lung cancer cells were investigated. The results of Cell Counting Kit­8 assay (CCK­8) indicated that ISO exerted significant cytotoxic effects on 3 lung cancer cell lines, but had no obvious side­effects on normal cells. Moreover, flow cytometry and western blot analysis revealed that ISO induced mitochondrial­dependent apoptosis by reducing mitochondrial membrane potential. ISO also increased the expression levels of Bax, cleaved­caspase­3 (cle­cas­3) and poly(ADP­ribose) polymerase (PARP; cle­PARP), and decreased the expression levels of Bcl­2 in A549 cells. Furthermore, ISO induced G2/M cell cycle arrest by decreasing the expression levels of cyclin B1 and CDK1/2, and increasing the expression levels of p21 and p27 in A549 cells. As the duration of ISO treatment increased, intracellular reactive oxygen species (ROS) levels in A549 cells also increased. However, pre­treatment of the cells with the ROS scavenger, N­acetylcysteine (NAC), inhibited ISO­induced apoptosis. In addition, ISO increased the expression levels of p­p38, p­JNK and IκB­α; and decreased the expression levels of p­extracellular signal­regulated kinase (ERK), p­signal transducer and activator of transcription (STAT)3, p­nuclear factor (NF)­κB, NF­κB and p­IκB; these effects were induced by mitogen­activated protein kinase (MAPK) inhibitors and blocked by NAC. Taken together, the results of the present study indicate that ISO induces the apoptosis of A549 lung cancer cells via the ROS­mediated MAPK/STAT3/NF­κB signaling pathway, and thus may be a potential drug for use in the treatment of lung cancer.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Luteolina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Luteolina/uso terapêutico , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo
11.
Mol Med Rep ; 22(3): 1831-1838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705184

RESUMO

Apoptosis of pancreatic ß­cells is involved in the pathogenesis of type I and II diabetes. Peroxiredoxin I (Prx I) serves an important role in regulating cellular apoptosis; however, the role of Prx I in pancreatic ß­cell apoptosis is not completely understood. In the present study, the role of peroxiredoxin 1 (Prx I) during streptozotocin (STZ)­induced apoptosis of pancreatic ß­cells was investigated. The expression level of Prx I was decreased by STZ treatment in a time­dependent manner, and apoptosis of Prx I knockdown MIN6 cells was increased by STZ stimulation, compared with untransduced MIN6 cells. Furthermore, an intraperitoneal injection of STZ increased pancreatic islet damage in Prx I knockout mice, compared with wild­type and Prx II knockout mice. AKT and glycogen synthase kinase (GSK)­3ß phosphorylation significantly decreased following Prx I knockdown in MIN6 cells. However, phosphorylated ß­catenin and p65 levels significantly increased after STZ stimulation, compared with untransduced cells. The results of the present study indicate that deletion of Prx I mediated STZ­induced pancreatic ß­cell death in vivo and in vitro by regulating the AKT/GSK­3ß/ß­catenin signaling pathway, as well as NF­κB signaling. These findings provide a theoretical basis for treatment of pancreatic damage.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo , Células Secretoras de Insulina/citologia , Peroxirredoxinas/genética , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
12.
Sheng Wu Gong Cheng Xue Bao ; 35(11): 2081-2091, 2019 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-31814356

RESUMO

Lignocellulose is widely found in the nature. The highly efficient degradation of lignocellulose requires synergistic interactions of varieties of microorganisms. The mechanism of synergistic interaction relationship is not entirely clear because it needs multitudinous microorganisms to participate in the process of lignocellulose degradation. With the development of microbial molecular biology and omics technology, some new methods will be provided for the research on the mechanism of microbial synergistic degradation of lignocellulose. Our previous research found that the bacterial composite microbial system shows strong degradation ability of lignocellulose at 50 °C. The consortium is composed of cultured and uncultured bacteria, but the former has no degradation ability. Metagenomics and metatranscriptomics show that the expression levels of some genes related to lignocellulosic degradation change significantly. It is possible to explain the microbiological and enzymatic mechanisms of lignocellulosic degradation by microorganisms through omics in the future. The research progress of lignocellulose microbial degradation is reviewed from the aspects of enzyme, pure culture strain, and microbial consortium. The current situation and application prospect of omics technology in analyzing the function mechanism of microbial consortium are also introduced, to provide reference for exploring synergistic interactions of lignocellulose microbial degradation.


Assuntos
Bactérias , Lignina , Bactérias/classificação , Bactérias/enzimologia , Bactérias/metabolismo , Lignina/metabolismo , Metagenômica
13.
Antioxidants (Basel) ; 9(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861323

RESUMO

Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3ß (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3ß in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.

14.
In Vivo ; 33(4): 1183-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280208

RESUMO

BACKGROUND/AIM: Peroxiredoxin (Prx) protein family is aberrantly expressed in various cancers including gastric cancer. Among the six family members, Prx V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS) and modulates cellular apoptosis. This study aimed at investigating the role of Prx V in apoptosis of gastric cancer cells. MATERIALS AND METHODS: Stably constructed Prx V knockdown, over-expression and mock AGS cells (a human gastric adenocarcinoma cell line) were used to study the effect of Prx V on emodin-induced apoptosis by western blotting, cell viability, apoptosis and ROS detection assays. RESULTS: Overexpression of Prx V significantly decreased emodin-induced cellular apoptosis and ROS levels compared to Mock and Prx V knockdown AGS cells. Also, overexpression of Prx V down-regulated the expression of pro-apoptotic proteins, Bad and cleaved PARP, and increased the expression of anti-apoptotic protein, Bcl2. CONCLUSION: Prx V suppresses AGS cell apoptosis via scavenging intracellular ROS and modulating apoptosis-related markers.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Emodina/farmacologia , Peroxirredoxinas/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Imunofluorescência , Expressão Gênica , Humanos , Peroxirredoxinas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
15.
Mol Med Rep ; 20(3): 2571-2582, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322207

RESUMO

1,4­Naphthoquinone derivatives have superior anticancer effects, but their use has been severely limited in clinical practice due to adverse side effects. To reduce the side effects and extend the anticancer effects of 1,4­naphthoquinone derivatives, 2­(butane­1­sulfinyl)­1,4­naphthoquinone (BQ) and 2­(octane­1­sulfinyl)­1,4­naphthoquinone (OQ) were synthesized, and their anticancer activities were investigated. The anti­proliferation effects, determined by MTT assays, showed that BQ and OQ significantly inhibited the viability of gastric cancer cells and had no significant cytotoxic effect on normal cell lines. The apoptotic effect was determined by flow cytometry, and the results showed that BQ and OQ induced cell apoptosis by regulating the mitochondrial pathway and cell cycle arrest at the G2/M phase via inhibition of the Akt signaling pathway in AGS cells. Furthermore, BQ and OQ significantly increased the levels of reactive oxygen species (ROS) and this effect was blocked by the ROS scavenger NAC in AGS cells. BQ and OQ induced apoptosis by upregulating the protein expression of p38 and JNK and downregulating the levels of ERK and STAT3. Furthermore, expression levels of these proteins were also blocked after NAC treatment. These results demonstrated that BQ and OQ induced apoptosis and cell cycle arrest at the G2/M phase in AGS cells by stimulating ROS generation, which caused subsequent activation of MAPK, Akt and STAT3 signaling pathways. Thus, BQ and OQ may serve as potential therapeutic agents for the treatment of human gastric cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Naftoquinonas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
16.
Anticancer Res ; 39(7): 3677-3686, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262894

RESUMO

BACKGROUND/AIM: Peroxiredoxin (Prx) V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS). Also, Prx V has been shown to mediate cell apoptosis in various cancers. However, the mechanism of Prx V-induced apoptosis in colon cancer cells remains unknown. Thus, in this study we analyzed the effects of Prx V in ß-lapachone-induced apoptosis in SW480 human colon cancer cells. MATERIALS AND METHODS: ß-lapachone-induced apoptosis was analyzed by the MTT assay, western blotting, fluorescence microscopy, Annexin V staining and flow cytometry. RESULTS: Overexpression of Prx V, significantly decreased ß-lapachone-induced cellular apoptosis and Prx V silencing increased ß-lapachone-induced cellular apoptosis via modulating ROS scavenging activity compared to mock SW480 cells. In addition, to further explore the mechanism of Prx V regulated ß-lapachone-induced SW480 cells apoptosis, the Wnt/ß-catenin signaling was studied. The Wnt/ ß-catenin signaling pathway was found to be induced by ß-lapachone. CONCLUSION: Prx V regulates SW480 cell apoptosis via scavenging ROS cellular levels and mediating the Wnt/ß-catenin signaling pathway, which was induced by ß-lapachone.


Assuntos
Apoptose , Neoplasias do Colo/metabolismo , Naftoquinonas , Peroxirredoxinas/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Colo/metabolismo , Humanos
17.
J Chemother ; 31(4): 214-226, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074342

RESUMO

The 1,4-naphthoquinones and their derivatives have garnered great interest due to their antitumor pharmacological properties in various cancers; however, their clinical application is limited by side effects. In this study, to reduce side effects and improve therapeutic efficacy, a novel 1,4-naphthoquinone derivative-2-(4-methoxyphenylthio)-5,8-dimethoxy-1,4-naphthoquinone (MPTDMNQ) was synthesized. We investigated the effects and underlying mechanisms of MPTDMNQ on cell viability, apoptosis, and reactive oxygen species (ROS) generation in human gastric cancer cells. Our results showed that MPTDMNQ decreased cell viability in nine human gastric cancer cell lines. MPTDMNQ significantly induced apoptosis accompanied by the accumulation of ROS in GC cells. However, pre-treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the MPTDMNQ-induced apoptosis. Moreover, MPTDMNQ decreased the phosphorylation levels of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3); and increased the phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 kinase. However, phosphorylation was inhibited by NAC and a mitogen-activated protein kinase (MAPK) inhibitor. These findings showed that MPTDMNQ induced AGS cell apoptosis via ROS-mediated MAPK and STAT3 signaling pathways. Thus, MPTDMNQ may be a promising candidate for treating gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Naftoquinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo
18.
Chem Biol Interact ; 304: 148-157, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30871965

RESUMO

1,4-Naphthoquinone compounds are a class of organic compounds derived from naphthalene. They exert a wide variety of biological effects, but when used as anticancer drugs, have varying levels of side effects. In the present study, in order to reduce toxicity and improve the antitumor activity, we synthesized two novel 1,4-naphthoquinone derivatives, 2-(butane-1-sulfinyl)-1,4-naphthoquinone (BSQ) and 2-(octane-1-sulfinyl)-1,4-naphthoquinone (OSQ). We investigated the antitumor effects of BSQ and OSQ in human lung cancer cells and the underlying molecular mechanisms of these effects, focusing on the relationship between these compounds and reactive oxygen species (ROS) production. MTT assay and trypan blue exclusion assay results showed that BSQ and OSQ had significant cytotoxic effects in human lung cancer cells. Flow cytometry results indicated that the number of apoptotic cells and the intracellular ROS levels significantly increased after treatment with BSQ and OSQ. However, cell apoptosis was inhibited by pretreatment with the ROS scavenger N-acetyl-l-cysteine (NAC). Western blotting results showed that BSQ and OSQ increased the expression levels of p-p38 kinase and p-c-Jun N-terminal kinase (p-JNK), and decreased the expression levels of p-extracellular signal-regulated kinase (p-ERK), p-protein kinase B (p-Akt), and p-signal transducer and activator of transcription-3 (p-STAT3). These phenomena were blocked by mitogen-activated protein kinase (MAPK) inhibitors, Akt inhibitors and NAC. In conclusion, BSQ and OSQ induce human lung cancer A549 cell apoptosis by ROS-mediated MAPKs, Akt, and STAT3 signaling pathways. Therefore, BSQ and OSQ may be therapeutic potential agents for the treatment of human lung cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Naftalenos/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Bioorg Med Chem ; 27(8): 1577-1587, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30846406

RESUMO

The natural compound 1,4-naphthoquinone has potent anti-tumor activity. However, the clinical application of 1,4-naphthoquinone and its derivatives has been limited by their side effects. In this study, we attempted to reduce the toxicity of 1,4-naphthoquinone by synthesizing two derivatives: 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ). Then we evaluated the cytotoxicity and molecular mechanisms of these compounds in lung cancer cells. EPDMNQ and ENDMNQ significantly inhibited the viabilities of three lung cancer cell lines and induced A549 cell cycle arrest at the G1 phase. In addition, they induced the apoptosis of A549 lung cancer cells by increasing the phosphorylation of p38 and c-Jun N-terminal kinase (p-JNK), and decreasing the phosphorylation of extracellular signal-related kinase (p-ERK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Furthermore, they increased reactive oxygen species (ROS) levels in A549 cells; however, pretreatment with the ROS inhibitor N-acetyl-l-cysteine significantly inhibited EPDMNQ- and ENDMNQ-mediated apoptosis and reversed apoptotic proteins expression. In conclusion, EPDMNQ and ENDMNQ induced G1 phase cell cycle arrest and apoptosis in A549 cells via the ROS-mediated activation of mitogen activated protein kinase (MAPK), Akt and STAT3 signaling pathways.


Assuntos
Apoptose , Desenho de Fármacos , Naftoquinonas/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Naftoquinonas/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Int J Mol Med ; 43(2): 1067-1075, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535477

RESUMO

The present study investigated the mechanisms of apoptosis induced by cryptotanshinone (CT) in human rheumatoid arthritis fibroblast­like synoviocytes (RA­FLSs). Cell Counting kit­8 assay was performed to determine the cytotoxic effects of CT in human RA­FLSs, including primary RA­FLS, HFLS­RA and MH7A cells, and in HFLS cells derived from normal synovial tissue. Annexin V­FITC/PI staining was used to detect the apoptotic effects of CT in HFLS­RA and MH7A cells. Flow cytometry was performed to detect the apoptotic and reactive oxygen species (ROS) levels induced by CT in HFLS­RA cells. Western blotting was used to assess the expression levels of proteins associated with apoptosis and with the mitogen­activated protein kinase (MAPK), protein kinase B (Akt), and signal transducer and activator of transcription­3 (STAT3) signaling pathways. The results demonstrated that CT treatment significantly suppressed HFLS­RA and MH7A cell growth, whereas no clear inhibitory effect was observed in normal HFLS cells. CT exposure downregulated the expression levels of B­cell lymphoma 2 (Bcl­2), p­Akt, p­extracellular signal­related kinase and p­STAT3, while it upregulated the expression levels of Bcl­2­associated death promoter (Bad), caspase­3, poly (ADP­ribose) polymerase (PARP), p­p38 and p­c­Jun N­terminal kinase. Following ROS scavenging, the CT­induced apoptosis and altered expression levels of Bcl­2, Bad, cleaved caspase­3 and cleaved PARP were restored. Furthermore, the Akt, MAPK and STAT3 signaling pathways were regulated by intracellular ROS. These results suggest that ROS­mediated Akt, MAPK and STAT3 signaling pathways serve important roles in the CT­induced apoptosis of RA­FLSs.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/metabolismo , Fenantrenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo
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