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1.
Molecules ; 27(8)2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35458746

RESUMO

The aim of the present study was to evaluate the potential protective effect of glutathione (GSH) on Escherichia coli cells grown in a high concentration of thymoquinone (TQ). This quinone, as the main active compound of Nigella sativa seed oil, exhibits a wide range of biological activities. At low concentrations, it acts as an antioxidant, and at high concentrations, an antimicrobial agent. Therefore, any interactions between thymoquinone and glutathione are crucial for cellular defense against oxidative stress. In this study, we found that GSH can conjugate with thymoquinone and its derivatives in vitro, and only fivefold excess of GSH was sufficient to completely deplete TQ and its derivatives. We also carried out studies on cultures of GSH-deficient Escherichia coli strains grown on a minimal medium in the presence of different concentrations of TQ. The strains harboring mutations in gene ΔgshA and ΔgshB were about two- and fourfold more sensitive (256 and 128 µg/mL, respectively) than the wild type. It was also revealed that TQ concentration has an influence on reactive oxygen species (ROS) production in E. coli strains-at the same thymoquinone concentration, the level of ROS was higher in GSH-deficient E. coli strains than in wild type.


Assuntos
Escherichia coli , Nigella sativa , Benzoquinonas/farmacologia , Escherichia coli/genética , Escherichia coli/metabolismo , Glutationa/metabolismo , Nigella sativa/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/farmacologia
2.
Braz J Biol ; 84: e250667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35475989

RESUMO

Nigella sativa is known for the safety profile, containing a wealth of useful antiviral compounds. The main protease (Mpro, 3CLpro) of severe acute respiratory syndrome 2 (SARS-CoV-2) is being considered as one of the most attractive viral target, processing the polyproteins during viral pathogenesis and replication. In the current investigation we analyzed the potency of active component, thymoquinone (TQ) of Nigella sativa against SARS-CoV-2 Mpro. The structures of TQ and Mpro was retrieved from PubChem (CID10281) and Protein Data Bank (PDB ID 6MO3) respectively. The Mpro and TQ were docked and the complex was subjected to molecular dynamic (MD) simulations for a period 50ns. Protein folding effect was analyzed using radius of gyration (Rg) while stability and flexibility was measured, using root means square deviations (RMSD) and root means square fluctuation (RMSF) respectively. The simulation results shows that TQ is exhibiting good binding activity against SARS-CoV-2 Mpro, interacting many residues, present in the active site (His41, Cys145) and also the Glu166, facilitating the pocket shape. Further, experimental approaches are needed to validate the role of TQ against virus infection. The TQ is interfering with pocket maintaining residues as well as active site of virus Mpro which may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19.


Assuntos
COVID-19 , Nigella sativa , Benzoquinonas , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Nigella sativa/metabolismo , SARS-CoV-2 , Proteínas Virais/química , Proteínas Virais/metabolismo
3.
J Nat Prod ; 85(4): 1029-1038, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35412828

RESUMO

Seven new naphthoquinone diglycosides (1-7), three new anthraquinones (8-10), and eight known analogues were obtained from the aerial parts of Mitracarpus hirtus collected from West Africa in a bioassay-guided phytochemical investigation. All isolated compounds were elucidated by comparison with the literature and interpretation of spectroscopic data, and the absolute configurations of the new naphthoquinone diglycosides (1-10) were confirmed by chemical methods and ECD calculations. Notably, compound 1 was found to be the first naphthoquinone diglycoside containing carboxylic acid and isopentenyl side chains isolated from a species in the genus Mitracarpus. Compounds 6-18 showed antibacterial activity against multiple Helicobacter pylori strains with MIC values ranging from 0.0625 to 64 µg/mL. Particularly, 1-hydroxybenzoisochromanquinone (17) and benzo[g]isoquinoline-5,10-dione (18), with MIC values of 0.0625 and 0.125 µg/mL, displayed 32-512-fold higher potencies than a positive control, metronidazole. Compound 18 also demonstrated high antibiofilm activity and killed biofilm-encased Helicobacter pylori cells more effectively than metronidazole.


Assuntos
Helicobacter pylori , Naftoquinonas , Rubiaceae , Antibacterianos/farmacologia , Benzoquinonas , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Naftoquinonas/farmacologia , Componentes Aéreos da Planta
4.
J Org Chem ; 87(8): 5213-5228, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35378040

RESUMO

The addition of α-ketoamide to p-quinone methide initiated by dialkylphosphite in the presence of organic base 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) is explored. Coupling of dialkylphosphites to α-ketoamides in the presence of a base follows [1,2]-phospha-Brook rearrangement, generating corresponding α-phosphonyloxy enolates that are subsequently seized by p-quinone methides (p-QMs). The two-step one-pot 1,6-conjugate addition provides effective access to a series of isatin-incorporated phosphate-bearing 1,6-adducts having two vicinal tertiary carbons with up to 90% yield and >20:1 dr.


Assuntos
Indolquinonas , Benzoquinonas , Ácidos Carboxílicos
5.
Nat Commun ; 13(1): 1977, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418573

RESUMO

The reaction center (RC) and light-harvesting complex 1 (LH1) form a RC-LH1 core supercomplex that is vital for the primary reactions of photosynthesis in purple phototrophic bacteria. Some species possess the dimeric RC-LH1 complex with a transmembrane polypeptide PufX, representing the largest photosynthetic complex in anoxygenic phototrophs. However, the details of the architecture and assembly mechanism of the RC-LH1 dimer are unclear. Here we report seven cryo-electron microscopy (cryo-EM) structures of RC-LH1 supercomplexes from Rhodobacter sphaeroides. Our structures reveal that two PufX polypeptides are positioned in the center of the S-shaped RC-LH1 dimer, interlocking association between the components and mediating RC-LH1 dimerization. Moreover, we identify another transmembrane peptide, designated PufY, which is located between the RC and LH1 subunits near the LH1 opening. PufY binds a quinone molecule and prevents LH1 subunits from completely encircling the RC, creating a channel for quinone/quinol exchange. Genetic mutagenesis, cryo-EM structures, and computational simulations provide a mechanistic understanding of the assembly and electron transport pathways of the RC-LH1 dimer and elucidate the roles of individual components in ensuring the structural and functional integrity of the photosynthetic supercomplex.


Assuntos
Complexo de Proteínas do Centro de Reação Fotossintética , Rhodobacter sphaeroides , Proteínas de Bactérias/metabolismo , Benzoquinonas , Microscopia Crioeletrônica , Complexos de Proteínas Captadores de Luz/metabolismo , Modelos Moleculares , Peptídeos/química , Fotossíntese , Complexo de Proteínas do Centro de Reação Fotossintética/metabolismo , Rhodobacter sphaeroides/metabolismo
6.
Drug Res (Stuttg) ; 72(4): 220-225, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35385883

RESUMO

BACKGROUND: Osteosarcoma (OS) as the most frequent primary bone malignancy in children and adolescents has a short survival rate in advanced stages. Alternative herbal medicines with fewer side effects or the potency to protect common therapy's side effects can be helpful in combinational therapies. Herein, we aim to explore the effects of Thymoquinone (TQ) combined with Methotrexate (MTX) on Saos-2 cells apoptosis. METHODS: The effects of TQ and MTX alone or in combination on Saos-2 cell viability were measured by MTT assay. Real-time PCR was applied for the measurement of Bax, BCL-2, and caspase-9 mRNA expression. Apoptosis evaluation was conducted by flow cytometry. RESULTS: TQ improves the cytotoxic effects of MTX on Saos-2 cells proliferation at lower doses. Indeed, the IC50 of MTX decreased from 26 µM to 15 µM when it combined with TQ. TQ and MTX can induce the expression level of pro-apoptotic factors, Bax and caspase-9 while inhibiting anti-apoptotic protein BCL-2. Moreover, the combination of TQ and MTX potentiates apoptosis to 73%, compared to either TQ (48%) or MTX (53%) treated cells. CONCLUSION: The co-treatment of TQ and MTX is associated with the up-regulation of apoptotic factors and down-regulation of anti-apoptotic factors, conducting apoptosis aggravation and OS cell death.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Apoptose , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Osteossarcoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
7.
Life Sci ; 296: 120442, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35245520

RESUMO

AIMS: This study measured the effects of 5-Fluorouracil (5-FU), calcitriol (VD3), and/or thymoquinone (TQ) single/dual/triple therapies on cell cycle progression, apoptosis, inhibition of the PI3K/AKT/mTOR pathway, and oxidative stress against colorectal cancer (CRC). MAIN METHODS: The HT29, SW480 and SW620 cell lines were treated with 5-FU (50 µM), VD3 (25 µM), and TQ (75 µM), alone or combined for 12 h, prior to cell cycle/apoptosis analyses. KEY FINDINGS: TQ monotherapy had greater anticancer effects to active VD3 or 5-FU, revealing higher expression of p21/p27/PTEN/BAX/Cyto-C/Casp-3 and increased levels of total glutathione, with inhibitions in CCND1/CCND3/BCL-2 and PI3K/AKT/mTOR molecules, alongside higher rates of apoptosis in HT29, SW480 and SW620 cells (P < 0.005 for all markers). Additionally, all combination protocols revealed enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway, higher expression of p21/p27/PTEN/BAX/Cyto-C/Casp-3, and better anti-oxidant effects, than the monotherapies. Although TQ/5-FU and TQ/VD3 co-therapies were better relative to the VD3/5-FU regimen, the best tumoricidal effects were observed with triple therapy in the HT29 and SW480 cell lines, possibly by boosted attenuations of the PI3K/AKT/mTOR oncogenic pathway. In contrast, TQ single treatment was more effective than the triple therapy regimen in metastatic SW620 cells, suggesting that this protocol would be more useful therapeutically in late-stage CRC. SIGNIFICANCE: In conclusion, this study is the first to demonstrated enhanced anti-tumorigenic effects for VD3, TQ, and 5-FU triple therapy against CRC cells and could represent the best strategy for treating early stages of malignancy, whereas TQ monotherapy could be a better approach for treating metastatic forms of the disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzoquinonas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzoquinonas/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colecalciferol/administração & dosagem , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
8.
J Hazard Mater ; 431: 128595, 2022 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-35247734

RESUMO

The immobilized anthraquinone-2-sulfonate (iAQS) could significantly promote anaerobic biotransformation of the contaminants. During this process, the role of flavins secreted by bacteria remains unclear. In the present study, mutual interaction between extracellular flavins and AQS-modified polyurethane foam (AQS-PUF) during the reduction of azo dye Acid Red 18 and 3-nitrobenzenesulfonate (3-NBS) was investigated. Results showed that the amount of extracellular flavins secreted by Shewanella sp. RQs-106 was positively correlated with the concentration of iAQS ranging from 10 to 100 µM. The presence of iAQS resulted in the increased concentration of extracellular and intracellular flavins, implying that iAQS could induce the synthesis and secretion of flavins. The deletion of gene bfe encoding the flavin adenine dinucleotide exporter resulted in approximately 63.8% decrease in the amount of extracellular flavins. Further analysis showed that the decreased amount of extracellular flavins could contribute to around 50.8% reduction of iAQS. Moreover, around 23.2% and 34.0% decreases were observed in AQS-PUF-mediated removal rates of AR 18 and 3-NBS by mutant lacking bfe gene, respectively, compared with that by wild type strain RQs-106. These results indicated that the secreted flavins played an important role in the bio-reduction of AQS-PUF, resulting in their contribution to AQS-PUF-mediated removals of high-polarity aromatic compounds containing nitrogen.


Assuntos
Shewanella , Anaerobiose , Benzoquinonas , Flavinas/metabolismo , Nitrogênio/metabolismo , Oxirredução , Shewanella/metabolismo
9.
Drug Res (Stuttg) ; 72(3): 171-176, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35255515

RESUMO

INTRODUCTION: Osteosarcoma (OS) is a primary bone sarcoma with a high recurrence rate and poorer prognosis. The application of natural agents in combinational therapies can increase the efficacy of treatment and decrease the side effects. Herein, we aimed to evaluate the effects of Thymoquinone (TQ) combined with Cisplatin on apoptosis and its underlying mechanisms in the Saos-2 cells. METHODS: The effects of TQ and Cisplatin on Saos-2 cell viability were measured using an MTT assay. Western blotting was applied for the measurement of γH2AX protein expression. The expression levels of 8-Hydroxy-2'-deoxyguanosine (8-oxo-dG) were evaluated by enzyme-linked immunosorbent assay (ELISA). DCFH-DA fluorescence dye was used to detect reactive oxygen species (ROS) formation. For evaluation of apoptosis, flow cytometry was employed. RESULTS: TQ dramatically promotes the cytotoxic effects of Cisplatin. TQ considerably enhanced the expression levels of 8-oxo-dG and γ-H2AX in Saos-2 cells. After TQ treatment, ROS levels were increased; furthermore, TQ treatment resulted in the potentiation of Cisplatin-induced apoptosis in Saos-2 cells compared to either TQ or Cisplatin treated cells. CONCLUSION: In general, TQ plus Cisplatin resulted in potentiated cellular cytotoxicity by increasing ROS level and inducing oxidative DNA damage, leading to the potent induction of apoptosis in tumor cells.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Osteossarcoma/tratamento farmacológico
10.
J Oral Sci ; 64(2): 161-166, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35321964

RESUMO

PURPOSE: This study was designed to investigate the in vitro effects of geraniol (GE) and thymoquinone (TQ) on Candida biofilms on denture acrylic and any accompanying changes in acrylic surface roughness or color. METHODS: The susceptibility of Candida species to GE and TQ was determined using the broth microdilution method and time-kill assay. A minimum biofilm eradication concentration (MBEC) assay was performed using 7-day Candida biofilms grown on denture acrylic. RESULTS: The minimum inhibitory concentration (MIC) of GE and TQ for Candida spp. was 256 and 32 µg/mL, respectively. The Candida strain complete kill rates for GE and TQ at 5-fold MIC were determined after 1 h of incubation. At 5-fold MIC, GE and TQ inhibited the preformed biofilm activity (MBEC80) of all Candida strains on denture acrylic by more than 80% after treatment for 3 h. At sub-MIC levels, GE and TQ prevented the development of C. albicans and C. tropicalis hyphae. SEM images demonstrated that GE and TQ damaged the fungal cell membrane and induced cell lysis. On the other hand, GE and TQ at 10-fold MIC did not alter the surface roughness or color of the denture acrylic. CONCLUSION: GE and TQ are interesting natural substances that could be developed as promising disinfectants for removable dentures.


Assuntos
Resinas Acrílicas , Candida , Resinas Acrílicas/farmacologia , Monoterpenos Acíclicos , Antifúngicos/farmacologia , Benzoquinonas , Biofilmes , Dentaduras/microbiologia
11.
Biochem Soc Trans ; 50(2): 877-893, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35356963

RESUMO

Cytochrome (cyt) bc1, bcc and b6f complexes, collectively referred to as cyt bc complexes, are homologous isoprenoid quinol oxidising enzymes present in diverse phylogenetic lineages. Cyt bc1 and bcc complexes are constituents of the electron transport chain (ETC) of cellular respiration, and cyt b6f complex is a component of the photosynthetic ETC. Cyt bc complexes share in general the same Mitchellian Q cycle mechanism, with which they accomplish proton translocation and thus contribute to the generation of proton motive force which drives ATP synthesis. They therefore require a quinol oxidation (Qo) and a quinone reduction (Qi) site. Yet, cyt bc complexes evolved to adapt to specific electrochemical properties of different quinone species and exhibit structural diversity. This review summarises structural information on native quinones and quinone-like inhibitors bound in cyt bc complexes resolved by X-ray crystallography and cryo-EM structures. Although the Qi site architecture of cyt bc1 complex and cyt bcc complex differs considerably, quinone molecules were resolved at the respective Qi sites in very similar distance to haem bH. In contrast, more diverse positions of native quinone molecules were resolved at Qo sites, suggesting multiple quinone binding positions or captured snapshots of trajectories toward the catalytic site. A wide spectrum of inhibitors resolved at Qo or Qi site covers fungicides, antimalarial and antituberculosis medications and drug candidates. The impact of these structures for characterising the Q cycle mechanism, as well as their relevance for the development of medications and agrochemicals are discussed.


Assuntos
Hidroquinonas , Quinonas , Benzoquinonas , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Transporte de Elétrons , Oxirredução , Filogenia , Quinonas/química
12.
J Photochem Photobiol B ; 230: 112427, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35338920

RESUMO

Fewer antibiotics are available for effective management of bacterial infections to date owing to increasing multiple-drug resistance (MDR). Here, we expand our early success in combination of 405 nm blue light irradiation with phenolic compounds to sufficiently kill blue light-refractory MDR Escherichia coli (E. coli). p-Toluquinone (p-TQ) alongside blue light inactivated 7.3 log10E. coli within 6 min, whereas either alone was totally ineffective. A similar killing efficacy was attained with four other pathogens commonly seen in hospital-acquired infections and Enterococcus faecalis (Ef) that don't produce porphyrins-like molecules. The combinatory therapy prevented recurrence of E. coli infection in skin scratch wounds of murine. The bactericidal activity was ascribed to reactive oxygen species (ROS) generation triggered by blue light-mediated excitation of p-TQ, which is less likely to induce resistance because of multi-targeted and non-specific nature of ROS. Remarkably, toxic p-TQ became harmless to mammalian cells after brief exposure to blue light while retaining its bactericidal activity. The opposite effect of blue light on p-TQ activity unravels a novel, simple strategy to detoxify p-TQ and its combination with blue light as a safe and efficacious bactericidal modality for managing MDR bacterial infections.


Assuntos
Infecções Bacterianas , Escherichia coli , Animais , Antibacterianos/farmacologia , Benzoquinonas , Luz , Mamíferos , Camundongos , Espécies Reativas de Oxigênio/farmacologia
13.
Appl Environ Microbiol ; 88(8): e0018822, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35348388

RESUMO

Brown rot fungi dominate wood decomposition in coniferous forests, and their carbohydrate-selective mechanisms are of commercial interest. Brown rot was recently described as a two-step, sequential mechanism orchestrated by fungi using differentially expressed genes (DEGs) and consisting of oxidation via reactive oxygen species (ROS) followed by enzymatic saccharification. There have been indications, however, that the initial oxidation step itself might require induction. To capture this early gene regulation event, here, we integrated fine-scale cryosectioning with whole-transcriptome sequencing to dissect gene expression at the single-hyphal-cell scale (tens of micrometers). This improved the spatial resolution 50-fold, relative to previous work, and we were able to capture the activity of the first 100 µm of hyphal front growth by Rhodonia placenta in aspen wood. This early decay period was dominated by delayed gene expression patterns as the fungus ramped up its mechanism. These delayed DEGs included many genes implicated in ROS pathways (lignocellulose oxidation [LOX]) that were previously and incorrectly assumed to be constitutively expressed. These delayed DEGs, which include those with and without predicted functions, also create a focused subset of target genes for functional genomics. However, this delayed pattern was not universal, with a few genes being upregulated immediately at the hyphal front. Most notably, this included a gene commonly implicated in hydroquinone and iron redox cycling: benzoquinone reductase. IMPORTANCE Earth's aboveground terrestrial biomass is primarily wood, and fungi dominate wood decomposition. Here, we studied these fungal pathways in a common "brown rot"-type fungus, Rhodonia placenta, that selectively extracts sugars from carbohydrates embedded within wood lignin. Using a space-for-time design to map fungal gene expression at the extreme hyphal front in wood, we made two discoveries. First, we found that many genes long assumed to be "on" (constitutively expressed) from the very beginning of decay were instead "off" before being upregulated, when mapped (via transcriptome sequencing [RNA-seq]) at a high resolution. Second, we found that the gene encoding benzoquinone reductase was "on" in incipient decay and quickly downregulated, implying a key role in "kick-starting" brown rot.


Assuntos
Polyporales , Madeira , Benzoquinonas/metabolismo , Expressão Gênica , Oxirredutases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Madeira/microbiologia
14.
Int J Mol Med ; 49(5)2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35293590

RESUMO

Herbal medicines have attracted much attention in recent years and are increasingly being used as alternatives to pharmaceutical medicines. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds, which has several beneficial properties, including anti­inflammatory, anti­oxidative stress, anti­hypertensive, anti­apoptotic and free radical­scavenging effects. Angiotensin II (Ang II) is involved in cardiovascular diseases. The present study aimed to investigate the potential protective effects of TQ against Ang II­induced cardiac damage in apolipoprotein E­deficient (ApoE­/­) mice. Briefly, 8­week­old male ApoE­/­ mice were randomly divided into four groups: Control, TQ, Ang II and Ang II + TQ groups. Osmotic minipumps, filled with either a saline vehicle or an Ang II solution (1,000 ng/kg/min), were implanted in ApoE­/­ mice for up to 4 weeks. The serum levels of high­sensitivity C­reactive protein (hs­CRP) and histopathological alterations in heart tissue were assessed. In addition, the mRNA and protein expression levels of molecules associated with fibrosis (collagen I and III), oxidative stress and apoptosis (Nox4 and p53), and inflammation [tumor necrosis factor (TNF)­α, interleukin (IL)­1ß and IL­6] were analyzed by reverse transcription­quantitative PCR (RT­qPCR) and western blotting. In the in vitro study, H9c2 cells were incubated with different concentrations of Ang II, and the expression levels of pro­inflammatory cytokines were evaluated using RT­qPCR, whereas the protein expression levels of phosphorylated­extracellular signal­regulated kinase (p­ERK) were determined using western blotting. Western blotting was also performed to detect the expression levels of collagen I, collagen III, Nox4 and p53 in H9c2 cells. The results revealed that TQ inhibited the Ang II­induced increases in serum hs­CRP levels. TQ also significantly inhibited the high levels of TNF­α, IL­1ß, IL­6, collagen I, collagen III, Nox4 and p53 in Ang II­treated mice. Furthermore, TQ protected against Ang II­induced cardiac damage by inhibiting inflammatory cell infiltration, proinflammatory cytokine expression, fibrosis, oxidative stress and apoptosis by suppressing activation of the p­ERK signaling pathway. In conclusion, TQ could be considered a potential therapeutic agent for Ang II­induced cardiac damage.


Assuntos
Angiotensina II , Coração , Angiotensina II/metabolismo , Animais , Apolipoproteínas E/genética , Benzoquinonas/farmacologia , Masculino , Camundongos
15.
Chemosphere ; 298: 134270, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35278452

RESUMO

The eco-friendly composite materials, micro-nano Fe-base/glucose-derived hydro-chars (Feb/HCs), were prepared, whose magnetic separation can be achieved in both preparation and water treatment stages. The performances of Feb/HCs after N2 heat-treatment to activate persulfate, chlorite, hydrogen peroxide, etc., in ultrasound field, obtained great improvement by extracting "O". For comparison, other different sized and magnetic iron-carbon based composites based on different carbon sources of activated carbons, cornstalk-derived bio-chars, and glucose-derived pyrolytic carbons were prepared and applied to systematically compare the performance of activation. The Feb/HCs with optimizing preparation were utilized as activators to well treat different structures (triphenylmethane-, azo-, and xanthene-) contaminants. The detected p-Benzoquinone and 2-chloro-p-Benzoquinone could be considered as transitional and characteristic intermediates from carbocyclic compounds to chain compounds. The degradation mechanisms were evoked by pH and absorption to trigger via free/non-free radicals processes: high valence iron-oxo species, sulfate radicals, hydroxyl radicals, Cl-based substances, etc. The findings contrastively provided the potential applications of magnetically separable iron-carbon based composites for heterogeneous activation in environmental remediation.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Benzoquinonas , Glucose , Ferro/química , Oxirredução
16.
Chemosphere ; 298: 134135, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35283141

RESUMO

A series of cobalt-nitrogen modified catalysts were prepared and applied to the degradation of phenol. The Mott Schottky catalyst (CoO/NGr@C) with high pyridine nitrogen content was designed to activate potassium peroxodisulfate (PDS) to generate active free radicals for phenol degradation. The structural properties of the materials are analyzed by XPS, TEM and then the charge density calculation is performed by DFT, which proves the existence of the highly active interface effect. Co-N-CMCM-41 can only degrade phenol into benzoquinone and it is difficult to achieve further degradation of benzoquinone, while the modified CoO/NGr@C can achieve deep mineralization of the intermediate benzoquinone through UV spectrum. EPR was used to prove that both hydroxyl radicals and sulfate radicals exist in the degradation process of phenol. Through the DFT simulation calculation of the material, it is proved that the existence of carbon activated by nitrogen and the electron rearrangement between cobalt and nitrogen-rich carbon lead to the catalytic activity of the material. The degradation conditions of phenol were optimized and the reaction kinetics of further phenol degradation were studied. The activation energy of phenol degradation on CoO/NGr@C is calculated to be 34.38 kJ mol-1.


Assuntos
Carbono , Fenol , Benzoquinonas , Carbono/química , Cobalto , Nitrogênio , Oxirredução , Fenol/química , Fenóis
17.
Int J Mol Sci ; 23(4)2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35216429

RESUMO

Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.


Assuntos
Benzoquinonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Glicólise/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Células HCT116 , Hexoquinase/metabolismo , Humanos , Nigella sativa/efeitos dos fármacos , Nigella sativa/metabolismo , Transdução de Sinais/fisiologia
18.
Chemphyschem ; 23(5): e202100885, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35106876

RESUMO

As a H2 O2 -dependent bioluminescent substrate, tetrabromo-1,4-benzoquinone (TBBQ) was first isolated from acorn worm. The mechanism of chemiluminescence (CL) corresponding to the bioluminescence (BL) of acorn worm is largely unknown, let alone the mechanism of BL. In this article, we firstly studied the chemical and physical processes, and mechanism of H2 O2 -dependent CL from TBBQ by theoretical and experimental methods. The research results indicate: the CL process is initiated by a nucleophilic substitution reaction, which leads to the formation of an anionic dioxetane through five consecutive reactions; the anionic dioxetane decomposes to the first singlet excited state (S1 ) via a conical interaction of the potential energy surfaces (PESs) between the ground (S0 ) and S1 state; the anionic S1 -state changes to its neutral form by a proton transfer from the solvent and this neutral product is assigned as the actual luminophore. Moreover, the experimental detection of CL, . OH and the identifications of 2,3-dibromo maleic acid and 2-bromo malonic acid as the major final products provide direct evidence of the theoretically suggested mechanism. Finally, this study proves that the activity of the H2 O2 -dependent CL from TBBQ is significantly lower than the one from tetrachloro-1,4-benzoquinone (TCBQ), which is caused by the weaker electron withdrawing effect and the stronger heavy atomic effect of bromine.


Assuntos
Benzoquinonas , Luminescência
19.
Cancer Chemother Pharmacol ; 89(4): 431-440, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35190872

RESUMO

PURPOSE: Platinum-containing therapy is standard treatment for relapsed Diffuse Large B-Cell Lymphoma (DLBCL). However, the efficacy of treatment is limited by drug resistance leading to relapse. Cisplatin resistance has been linked to impairments of the DNA damage response, and several DNA repair proteins have been identified as clients of the molecular chaperone Hsp90. Here, we investigated the combinatory treatment of cisplatin and the Hsp90 inhibitor, 17AAG, in DLBCL cells to evaluate if inhibition of Hsp90 could sensitize DLBCL cells to cisplatin treatment. METHODS: Cell viability was assessed for cisplatin and 17AAG as monotherapies and for 25 different combinations in 7 DLBCL cell lines, where the Bliss Independence Model and the Combination Index were applied to assess their interaction. Induction of apoptosis and DNA damage response were evaluated by measuring Annexin V and γH2AX levels after 48 h of exposure. RESULTS: 17AAG synergized with cisplatin in DLBCL cells as detected in both interaction assessment models, resulting in a lower viability after 48 h for the combination-treated cells compared to both vehicle and single drug-treated cells. The combination also induced a stronger apoptotic response and an increase in DNA damage in 17AAG, cisplatin- and combination-treated cells compared to vehicle-treated cells, with the effect of the combination generally being higher than compared to both single drugs. CONCLUSION: This study demonstrates that 17AAG sensitizes DLBCL cells to cisplatin treatment. This effect is correlated with increased apoptotic and DNA damage response, potentially mediated by downregulation of Hsp90 clients in DNA repair pathways. Thus, cisplatin resistance could plausibly be overcome by combining the treatment with an Hsp90 inhibiting drug.


Assuntos
Antineoplásicos , Linfoma Difuso de Grandes Células B , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Proteínas de Choque Térmico HSP90 , Humanos , Lactamas Macrocíclicas/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/tratamento farmacológico
20.
Int Immunopharmacol ; 105: 108567, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35114442

RESUMO

Basophils and mast cells are characteristic effector cells in allergic reactions. Sargahydorquinoic acid (SHQA), a compound isolated from Sargassum serratifolium (marine alga), possesses various biochemical properties, including potent antioxidant activities. The objective of the present study was to investigate inhibitory effects of SHQA on the activation of human basophilic KU812F cells induced by phorbol myristate acetate and A23187 (PMACI), a calcium ionophore. Furthermore, we confirmed the inhibitory effects of SHQA on the activation of rat basophilic leukemia (RBL)-2H3 cells induced by compound 48/80 (com 48/80), bone marrow-derived mast cells (BMCMCs) induced by anti-dinitrophenyl(DNP)-immunoglobulin E (IgE)/DNP-bovine serum albumin (BSA), DNP/IgE and on the reaction of passive cutaneous anaphylaxis (PCA) mediated by IgE. SHQA reduced PMACI-induced intracellular reactive oxygen species (ROS) and calcium levels. Western blot analysis revealed that SHQA downregulated the activation of ERK, p38, and NF-κB in a dose-dependent manner. Moreover, SHQA suppressed the production and gene expression of various cytokines, including interleukin (IL)-1 ß, IL-4, IL-6, and IL-8 in PMACI-induced KU812F cells and IL-4 and tumor necrosis factor (TNF)- α in com 48/80-induced RBL-2H3 cells. It also determined the inhibition of PMACI, com 48/80- and IgE/DNP-induced degranulation by reducing the release of ß -hexosaminidase. Furthermore, it attenuated the IgE/DNP-induced PCA reaction in the ears of BALB/c mice. These results suggest that SHQA isolated from S. serratifolium is a potential therapeutic functional food material for inhibiting effector cell activation in allergic reactions and anaphylaxis in animal model.


Assuntos
Anafilaxia , Sargassum , Alcenos , Anafilaxia/metabolismo , Animais , Basófilos , Benzoquinonas , Mastócitos , Camundongos , Camundongos Endogâmicos BALB C , Anafilaxia Cutânea Passiva , Ratos
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