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1.
Molecules ; 24(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083328

RESUMO

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/ß (GSK-3α/ß), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.


Assuntos
Fatores Imunológicos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Compostos Orgânicos/farmacologia , Compostos de Enxofre/farmacologia , Compostos Alílicos/farmacologia , Antioxidantes/metabolismo , Dissulfetos/farmacologia , Alho/química , Células HL-60 , Compostos Heterocíclicos/farmacologia , Humanos , Proteínas Quinases Ativadas por Mitógeno , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/farmacologia , Tiazolidinedionas/farmacologia
2.
Environ Toxicol ; 34(8): 950-957, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077537

RESUMO

In this report, liver cells were treated with cadmium chloride (CdCl2 ) and diallyl disulfide (DADS), a major compound from garlic to attenuate the toxic effect of Cd on transcriptome. The viability of Cd treated cells was reduced to 19.9% ± 2.4% in comparison to the untreated cells, whereas the viability of DADS pretreated cells was increased to 48.6% ± 2%. The attenuation effect of DADS was studied at shorter period (6 hours). Transcriptome analysis of CdCl2 alone treated cells resulted in 2119 and 982 (up and down) regulated genes (≥ 2 or ≤ 2-fold), whereas pretreated cells with DADS resulted in 2597 and 1784 genes. These genes were known to function in many important biological processes. Affymetrix array analysis was validated by the pathway specific PCR array that exhibited the same trend of expression. The current study clearly shows the DADS attenuation effect on transcriptome in CdCl2 -treated rat liver cells.


Assuntos
Compostos Alílicos/farmacologia , Cloreto de Cádmio/toxicidade , Dissulfetos/farmacologia , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fígado/metabolismo , Ratos
3.
Carbohydr Polym ; 215: 226-234, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981349

RESUMO

Bacterial infections have evolved as a life-threatening problem afflicting people due to the abuse of antibiotics and emergence of drug-resistant bacteria. Thus developing novel antibacterial materials is an urgent need. Herein, chitosan-MoS2 (CS-MoS2) nanocomposite was synthesized through thiol ligand functionalization and chemical modification to achieve more efficient bactericidal activity. CS-MoS2 exhibited synergistic remarkable bactericidal capability against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E.coli), where bacterial viabilities were significantly reduced. After treatment with 10 µg/mL of CS-MoS2, 100% and 98.1% of S. aureus and E.coli cells were killed respectively. A mechanism study revealed that the positively charged CS-MoS2 could interact with cell membrane, then cause damage to the membrane and cellular constituents by generation of reactive oxygen species (ROS) and glutathione (GSH) oxidation, finally inhibit bacterial growth. The CS-MoS2 could be an attractive antibacterial agent with improved efficiency and provide more strategies for application of MoS2.


Assuntos
Antibacterianos/química , Quitosana , Dissulfetos , Escherichia coli/efeitos dos fármacos , Molibdênio , Nanocompostos/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Quitosana/química , Quitosana/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Molibdênio/química , Molibdênio/farmacologia
4.
Cell Commun Signal ; 17(1): 31, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971268

RESUMO

BACKGROUND: p21-activated kinase 1 (PAK1) plays a fundamental role in promoting the development and progression of several cancers and is a potential therapeutic target. However, the biological function and underlying mechanism of PAK1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: The expression of PAK1 was detected in both ESCC cell lines and clinical samples. Cell growth was measured by MTT, focus formation and soft agar assays. Cell migration and invasion were detected by wound healing and transwell assays. Animal models of subcutaneous tumourigenicity and tail vein metastasis were performed to determine the inhibitory effect of pharmacological inhibitor IPA-3 on tumor growth and metastasis of ESCC cells. RESULTS: We found that PAK1 was frequently overexpressed in ESCC. Ectopic expression of PAK1 promoted cellular growth, colony formation and anchorage-independent growth. Overexpressing PAK1 also enhanced migration, invasion and the expression of MMP-2 and MMP-9 in ESCC cells. In contrast, silencing PAK1 by lentiviral knockdown or a specific inhibitor IPA-3 resulted in a contrary effect. Subsequent investigations revealed that Raf1/MEK1/ERK signaling pathway was involved in PAK1-mediated effect. Enhanced expression of Raf1 attenuated the inhibitory functions of PAK1 shRNA. Whereas blocking of Raf1 by shRNA or specific inhibition of MEK1 by U0126 antagonized the oncogenetic effect of PAK1 on ESCC cells. More importantly, Pharmacological inhibition of PAK1 by IPA-3 significantly suppressed tumor growth and lung metastasis of ESCC cells in vivo. CONCLUSIONS: These data support that PAK1 is an ideal target for the development of potential therapeutic drugs for ESCC patients even with metastasis.


Assuntos
Dissulfetos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Naftóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Dissulfetos/uso terapêutico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Humanos , MAP Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Naftóis/uso terapêutico , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , RNA Interferente Pequeno/metabolismo
5.
Oxid Med Cell Longev ; 2019: 9291683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911354

RESUMO

Background: Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC. Methods: We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed in vitro and in vivo through Trx-1 knockdown or overexpression. The antitumor effects of the Trx-1 inhibitor, PX-12, on GC cells were investigated. PTEN and p-AKT expressions were evaluated by Western blotting. Results: Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Conversely, overexpression of Trx-1 promoted GC cell growth, migration, and invasion. We also found that PX-12 inhibited GC cell growth, migration, and invasion. Overexpression of Trx-1 caused a decrease in PTEN and increase in p-AKT levels whereas silencing Trx-1 caused an increase in PTEN and decrease in p-AKT levels in GC cells. Inhibition of AKT signaling pathway by MK2206 also inhibited GC cell growth, migration, and invasion. Conclusion: Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.


Assuntos
Progressão da Doença , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Tiorredoxinas/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Movimento Celular , Proliferação de Células , Dissulfetos/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Lentivirus/metabolismo , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Nanoscale ; 11(15): 7209-7220, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30920555

RESUMO

Currently, one of the major hurdles hindering the clinical applications of photothermal therapy (PTT) and photothermal-chemo combination therapy (PCT) is the lack of highly efficient, readily derived, and irradiation-safe photothermal agents in the biologically transparent window. Herein, we report the first design and rational construction of 0D/2D/0D sandwich heterojunctions for greatly enhanced PTT and PCT performances using 0D N-doped carbon dots and 2D MoS2 nanosheets as the assembly units. The well-matching heterojunctions enabled an additional enhancement in NIR absorbance owing to the carrier injection from carbon dots to MoS2 nanosheets, and achieved a much higher photothermal conversion efficiency (78.2%) than that of single NIR-CDs (37.6%) and MoS2 (38.3%) only. In virtue of the heterojunction-based PTT, complete tumor recession without recurrence or pulmonary metastasis was realized at an ultralow and safe laser exposure (0.2 W cm-2) below the skin tolerance irradiation threshold. Furthermore, by taking advantage of the strong X-ray attenuation and effective drug loading capacity of MoS2 nanosheets, the CT imaging-guided PCT was achieved at 0.1 W cm-2, without inducing noticeable toxic side effects. Our findings can substantiate the potential of a novel 0D/2D heterojunction for cancer theranostics.


Assuntos
Carbono , Dissulfetos , Hipertermia Induzida , Molibdênio , Técnicas Fotoacústicas , Fotoquimioterapia , Pontos Quânticos , Tomografia Computadorizada por Raios X , Animais , Carbono/química , Carbono/farmacologia , Linhagem Celular Tumoral , Terapia Combinada , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Camundongos , Molibdênio/química , Molibdênio/farmacologia , Metástase Neoplásica , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Pontos Quânticos/química , Pontos Quânticos/uso terapêutico , Pontos Quânticos/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 19(1): 248, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894168

RESUMO

BACKGROUND: Garlic has been used for centuries for its flavour and health promoting properties that include protection against cancer. The vinyl disulfide-sulfoxide ajoene is one of the phytochemicals found in crushed cloves, hypothesised to act by S-thiolating reactive cysteines in target proteins. METHODS: Using our fluorescently labelled ajoene analogue called dansyl-ajoene, ajoene's protein targets in MDA-MB-231 breast cancer cells were tagged and separated by 2D electrophoresis. A predominant band was identified by MALDI-TOF MS/MS to be vimentin. Target validation experiments were performed using pure recombinant vimentin protein. Computational modelling of vimentin bound to ajoene was performed using Schrödinger and pKa calculations by Epik software. Cytotoxicity of ajoene in MDA-MB-231 and HeLa cells was measured by the MTT assay. The vimentin filament network was visualised in ajoene-treated and non-treated cells by immunofluorescence and vimentin protein expression was determined by immunoblot. The invasion and migration activity was measured by wound healing and transwell assays using wildtype cells and cells in which the vimentin protein had been transiently knocked down by siRNA or overexpressed. RESULTS: The dominant protein tagged by dansyl-ajoene was identified to be the 57 kDa protein vimentin. The vimentin target was validated to reveal that ajoene and dansyl-ajoene covalently bind to recombinant vimentin via a disulfide linkage at Cys-328. Computational modelling showed Cys-328 to be exposed at the termini of the vimentin tetramer. Treatment of MDA-MB-231 or HeLa cells with a non-cytotoxic concentration of ajoene caused the vimentin filament network to condense; and to increase vimentin protein expression. Ajoene inhibited the invasion and migration of both cancer cell lines which was found to be dependent on the presence of vimentin. Vimentin overexpression caused cells to become more migratory, an effect that was completely rescued by ajoene. CONCLUSIONS: The garlic-derived phytochemical ajoene targets and covalently modifies vimentin in cancer cells by S-thiolating Cys-328. This interaction results in the disruption of the vimentin filament network and contributes to the anti-metastatic activity of ajoene in cancer cells.


Assuntos
Movimento Celular/efeitos dos fármacos , Dissulfetos/farmacologia , Alho/química , Neoplasias/tratamento farmacológico , Vimentina/metabolismo , Linhagem Celular Tumoral , Simulação por Computador , Dissulfetos/metabolismo , Dissulfetos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Invasividade Neoplásica/prevenção & controle , Neoplasias/patologia , Ligação Proteica , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Vimentina/isolamento & purificação
8.
Int J Biol Macromol ; 128: 870-876, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30716371

RESUMO

In this study, cysteamine-functionalized molybdenum disulfide quantum dots (MoS2 QDs) were synthesized by a one-pot hydrothermal method. A range of techniques including of Thioflavin T and 8-Anilino-1-naphthalenesulfonic acid fluorescence assays, circular dichroism, and transmission electron microscope have been employed to determination the efficacy of MoS2 QDs on the inhibition/reversion of fibrillation and hindering cytotoxicity induced by protofibrils and amyloid fibrils of bovine serum albumin (BSA). Results demonstrated that MoS2 QDs could effectively inhibit the fibrillogenesis and destabilize preformed fibrils of BSA in a concentration-dependent manner. Cytotoxicity protection and imagine on Hela cells was investigated using the methyl thiazolyl tetrazolium (MTT) assay. It was found that MoS2 QDs not only has good biocompatibility, low toxicity and good cell penetration, but also could effectively decrease the cytotoxicity caused by the formed fibrils of BSA. The results obtained in this work suggested the potential biological application of MoS2 QDs in therapeutics and provided new insight into the design of multifunctional nanomaterials for amyloid-related diseases.


Assuntos
Amiloide/química , Cisteamina/química , Dissulfetos/química , Dissulfetos/farmacologia , Molibdênio/química , Molibdênio/farmacologia , Agregados Proteicos/efeitos dos fármacos , Pontos Quânticos/química , Soroalbumina Bovina/química , Animais , Transporte Biológico , Bovinos , Dissulfetos/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Molibdênio/metabolismo , Estrutura Secundária de Proteína
9.
Talanta ; 197: 567-577, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771977

RESUMO

With the development of deep eutectic solvents (DESs), more DES-based functional materials have been explored and applied in various areas. In this work, a novel choline chloride-acrylic acid (ChCl-AA) DES polymer, on a 2D magnetic base, was prepared for the recognition of ß-lactoglobulin (ß-LG) biomacromolecules in milk and for the inhibition of common bacteria such as Escherichia coli (E. coli), Pseudomonas fluorescens (P. fluorescens), Staphylococcus aureus (S. aureus), and Bacillus subtilis (B. subtilis). The ChCl-AA DESs were polymerized on the surface of 2D MoS2 sheets doped with nano Fe3O4 particles, and the resulting polymer was abbreviated poly(ChCl-AA DES)@Fe3O4@MoS2. The free energy (ΔG=-92) of ChCl-AA DES was calculated using the Gaussian software, the composition and structure of poly(ChCl-AA DES)@Fe3O4@MoS2 were characterized by field emission scanning electron microscopy, transmission electron microscopy, etc., the qualitative and quantitative analyses of ß-LG were done by fluorescence spectra, sodium dodecyl sulfate polyacrylamide gel electrophoresis and high performance liquid chromatography, and the bioactivity of bacteria was analyzed by flat colony counting. Based on the present analysis, poly(ChCl-AA DES)@Fe3O4@MoS2 specifically recognized ß-LG in a good fitting Langmuir isotherm (R2 = 0.9909) and second-order kinetic model (R2 = 0.9989) by affinity, and evidently inhibited three bacteria, namely, E. coil (65%), S. aureus (50%), and B. subtilis (54%), effectively reducing the relative colony number. As the poly(ChCl-AA DES)@Fe3O4@MoS2 material did not only exhibit specific recognition of biomacromolecules, but also had an antimicrobial effect against common bacteria, it could be an ideal separation media or carrier for biomacromolecules in real samples.


Assuntos
Acrilatos/química , Antibacterianos/análise , Colina/química , Lactoglobulinas/análise , Leite/química , Polímeros/química , Acrilatos/farmacologia , Animais , Antibacterianos/farmacologia , Colina/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Compostos Férricos/química , Compostos Férricos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Leite/microbiologia , Molibdênio/química , Molibdênio/farmacologia , Tamanho da Partícula , Polímeros/farmacologia , Solventes/química , Propriedades de Superfície
10.
J Enzyme Inhib Med Chem ; 34(1): 361-374, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734603

RESUMO

Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Descoberta de Drogas , Proteínas Serina-Treonina Quinases/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Azepinas/química , Azepinas/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia
11.
ACS Appl Mater Interfaces ; 11(7): 6829-6839, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30694645

RESUMO

The ability of nanoparticles to induce adverse consequences in human cells relies on their physical shapes. In this aspect, how two-dimensional nanoparticles differ from three-dimensional nanoparticles is not well-known. To elucidate this difference, combined experimental and theoretical approaches are employed to compare MoS2 nanosheets with 5-layer and 40-layer thicknesses for their cellular effects and the associated molecular events. At a concentration as defined by the nanosheet surface areas (10 cm2/mL), 40-layer nanosheets are internalized by cells, whereas 5-layer nanosheets mostly bind to the cell surface without internalization. Although they alter different autophagy-related genes, a common mechanism is that they both perturb cell surface protein amyloid precursor proteins and activate the mTOR signaling pathway. Our findings prove that the perturbation of cellular function without nanoparticle internalization has significant nanomedicinal and nanotoxicological significances.


Assuntos
Autofagia/efeitos dos fármacos , Dissulfetos , Molibdênio , Nanopartículas , Proteínas de Neoplasias/metabolismo , Neoplasias , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Molibdênio/química , Molibdênio/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Superfície Celular/metabolismo
12.
Biomater Sci ; 7(4): 1437-1447, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30666993

RESUMO

Implant materials are prone to bacterial infections and cause serious consequences, while traditional antibiotic therapy has a long treatment cycle and even causes bacterial resistance. In this work, a photothermal therapy (PTT) assisted drug release system has been developed on the implant surface for in situ rapid disinfection under 808 nm light irradiation within a short time, in which gentamicin (Gent) is loaded by polyethylene glycol (PEG) modified molybdenum disulfide (MoS2) on Ti surface, and then encapsulated with chitosan (CS) (CS/Gent/PEG/MoS2-Ti). The hyperthermia produced by the coatings irradiated by 808 nm near-infrared (NIR) light can not only accelerate the local release of Gent, but also reduce the activity of bacteria, which makes it easy for these locally released drugs to enter the interior of the bacteria to inhibit the protein synthesis and destroy the cell membrane. When maintained at 50 °C for 5 min under NIR irradiation, this system can achieve an antibacterial efficacy of 99.93% and 99.19% against Escherichia coli and Staphylococcus aureus, respectively. By contrast, even after treatment for 120 min, only a 93.79% antibacterial ratio can be obtained for Gent alone. This is because hyperthermia produced from the coatings during irradiation can assist antibiotics in killing bacteria in a short time. Even under a low dose of 2 µg mL-1, the photothermal effect assisted gentamicin can achieve an antibacterial efficacy of 96.86% within 5 min. In vitro cell culture shows that the modified surface can facilitate cell adhesion, spreading and proliferation. The 7 day subcutaneous infection model confirms that the prepared surface system can exhibit a much faster sterilization and tissue reconstruction than the control group with light assistance. Compared with the traditional drug release system, this photothermy controlled drug-loaded implant surface system can not only provide rapid and high-efficiency in situ sterilization, but also offer long-term prevention of local bacterial infection.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Gentamicinas/farmacologia , Fototerapia , Staphylococcus aureus/efeitos dos fármacos , Temperatura Ambiente , Animais , Antibacterianos/síntese química , Antibacterianos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Dissulfetos/química , Dissulfetos/farmacologia , Gentamicinas/síntese química , Gentamicinas/química , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Molibdênio/química , Molibdênio/farmacologia , Células NIH 3T3 , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Propriedades de Superfície , Titânio/química , Titânio/farmacologia
13.
Food Chem Toxicol ; 125: 354-360, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30677442

RESUMO

Ever since several targeted agents were introduced a decade ago, progress in new therapeutic strategies for colorectal cancer (CRC) has been much slower than that for other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is widely known to induce cellular apoptosis in numerous cancer cell types. However, many cancer cells are resistant to the effects of TRAIL, and thus, approaches are needed to overcome TRAIL resistance. We demonstrated that non-cytotoxic doses of diallyl disulfide (DADS) increased TRAIL-associated cell death in CRC cell lines. Additionally, synergistic effects between DADS and TRAIL were validated in vivo in nude mice. One process involved in these effects includes down-regulation of the anti-apoptotic protein Bcl-2, and the synergistic effect of DADS with TRAIL was attenuated in Bcl-2-over-expressing cells. Taken together, the results of this study give new insights into the role of DADS in TRAIL-related repression of CRC progression by inhibition of Bcl-2.


Assuntos
Compostos Alílicos/farmacologia , Apoptose/efeitos dos fármacos , Dissulfetos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
14.
ACS Appl Mater Interfaces ; 11(5): 4858-4866, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30628779

RESUMO

Molybdenum disulfide (MoS2) nanosheets have received considerable interest due to their superior physicochemical performances to graphene nanosheets. As the lateral size and layer thickness decrease, the formed MoS2 quantum dots (QDs) show more promise as photocatalysts, endowing them with potential antimicrobial properties under environmental conditions. However, studies on the antibacterial photodynamic therapy of MoS2 QDs have rarely been reported. Here, we show that MoS2 QDs more effectively promote the creation and separation of electron-hole pair than MoS2 nanosheets, resulting in the formation of multiple reactive oxygen species (ROS) under simulated solar light irradiation. As a result, photoexcited MoS2 QDs show remarkably enhanced antibacterial activity, and the ROS-mediated oxidative stress plays a dominant role in the antibacterial mechanism. The in vivo experiments showed that MoS2 QDs are efficacious in wound healing under simulated solar light irradiation and exert protective effects on normal tissues, suggesting good biocompatibility properties. Our findings provide a full description of the photochemical behavior of MoS2 QDs and the resulting antibacterial activity, which might advance the development of MoS2-based nanomaterials as photodynamic antibacterial agents under environmental conditions.


Assuntos
Antibacterianos , Dissulfetos , Molibdênio , Pontos Quânticos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/efeitos da radiação , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Dissulfetos/farmacologia , Dissulfetos/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Molibdênio/química , Molibdênio/farmacologia , Molibdênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Processos Fotoquímicos , Pontos Quânticos/química , Pontos Quânticos/efeitos da radiação , Pontos Quânticos/toxicidade , Espécies Reativas de Oxigênio , Infecção dos Ferimentos
15.
J Pept Sci ; 25(3): e3147, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30680847

RESUMO

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t-Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam-based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether-based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene-related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild-type-like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.


Assuntos
Adrenomedulina/química , Adrenomedulina/farmacologia , Dissulfetos/química , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/síntese química , Dissulfetos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 161: 594-606, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30396106

RESUMO

Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS-[C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox-SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS-[C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/farmacologia , Doxorrubicina/farmacologia , Peptídeos Cíclicos/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dissulfetos/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Citometria de Fluxo , Células HEK293 , Humanos , Camundongos , Conformação Molecular , Peptídeos Cíclicos/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/química
17.
Drug Dev Res ; 80(1): 171-178, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565263

RESUMO

Staphylococcus aureus is a WHO Priority II pathogen for its capability to cause acute to chronic infections and to resist antibiotics, thus severely impacting healthcare systems worldwide. In this context, it is urgently desired to discover novel molecules to thwart the continuing emergence of antimicrobial resistance. Disulphide containing small molecules has gained prominence as antibacterials. As their conventional synthesis requires tedious synthetic procedure and sometimes toxic reagents, a green and environmentally benign protocol for their synthesis has been developed through which a series of molecules were obtained and evaluated for antibacterial activity against ESKAPE pathogen panel. The hit compound was tested for cytotoxicity against Vero cells to determine its selectivity index and time-kill kinetics was determined. The activity of hit was determined against a panel of S. aureus multi-drug resistant clinical isolates. Also, its ability to synergize with FDA approved drugs was tested as was its ability to reduce biofilm. We identified bis(2-bromophenyl) disulphide (2t) as possessing equipotent antimicrobial activity against S. aureus including MRSA and VRSA strains. Further, 2t exhibited a selectivity index of 25 with concentration-dependent bactericidal activity, synergized with all drugs tested and significantly reduced preformed biofilm. Taken together, 2t exhibits all properties to be positioned as novel scaffold for anti-staphylococcal therapy.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Biocatálise , Dissulfetos/síntese química , Dissulfetos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana/métodos
18.
Cell Physiol Biochem ; 50(5): 1945-1963, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30396169

RESUMO

BACKGROUND/AIMS: Metastasis is the leading cause resulting in high mortality in triple negative breast cancer (TNBC) patients. Cancer cells are skilled at utilizing thioredoxin (Trx) system as an efficient antioxidant system to counteract oxidative damage, facilitating the occurrence of metastasis. Here, we identified an organosulfur compound named DATS isolated from garlic, that inhibits the expression of Trx-1 and the enzyme activity of Trx reductase in breast cancer cells. METHODS: Tissue microarray of breast cancer patients and immunohistochemical method were used to analyze the role of Trx-1 in breast cancer metastasis. Spotaneous metastasis model and experimental metastasis model combined with HE staining, immunohistochemistry were used to verify in vivo anti-metastatic effect of DATS as well as its regulation on thioredoxin. Western blot, immunofluorescence, redox state assessment and detection of enzyme activity were employed to determine the effect of DATS on thioredoxin system. Trx-1 siRNA interference was used to investigate the conclusive evidence that Trx-1 was the target of DATS. RESULTS: In agreement with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of reduced form of Trx-1 was dramatically decreased. Furthermore, in vivo, DATS administration was observed to significantly suppress spontaneous and experimental metastasis in nude mice. Delivery of DATS also resulted in decreased expression of Trx-1 as the direct target, as well as expression of NF-κB and MMP2/9 in primary tumor and lung tissue. Notably, the effects of DATS on the expression of downstream metastasis-associated genes were mediated by Trx-1, as demonstrated by the combination use of DATS and Trx-1 siRNA. CONCLUSION: Collectively, this present study indicates that targeting Trx system with DATS may provide a promising strategy for treating metastasis of TNBC.


Assuntos
Compostos Alílicos/farmacologia , Apoptose/efeitos dos fármacos , Sulfetos/farmacologia , Tiorredoxinas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Compostos Alílicos/metabolismo , Compostos Alílicos/uso terapêutico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dissulfetos/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Metástase Linfática , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sulfetos/metabolismo , Sulfetos/uso terapêutico , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Chem Commun (Camb) ; 54(68): 9462-9465, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30083687

RESUMO

The synergistic effect of two anticancer drugs can significantly overcome the multidrug resistance of tumor cells and improve the drug bioavailability. Herein, two different anticancer drugs, camptothecin and chlorambucil, are successfully connected together by a disulfide linkage to get a novel drug-drug conjugated prodrug (G). Using water-soluble pillar[6]arene (WP6) as a host molecule, a supramolecular host-guest complex WP6⊃G is formed, which can further self-assemble into supramolecular vesicles in aqueous solution. In the specific microenvironment of cancer cells, the disulfide linkage is destroyed and the two anticancer drugs can be released efficiently to achieve a better synergistic effect than a single anticancer drug. Notably, these prodrug nanocarriers can not only effectively kill the cancer cells but also obviously reduce the undesirable side effects on normal cells.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Clorambucila/farmacologia , Portadores de Fármacos/química , Compostos de Amônio Quaternário/química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Camptotecina/síntese química , Camptotecina/metabolismo , Camptotecina/toxicidade , Clorambucila/síntese química , Clorambucila/metabolismo , Clorambucila/toxicidade , Dissulfetos/síntese química , Dissulfetos/metabolismo , Dissulfetos/farmacologia , Dissulfetos/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Glutationa/metabolismo , Humanos , Células MCF-7 , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/toxicidade , Solubilidade , Água/química
20.
Appl Microbiol Biotechnol ; 102(17): 7555-7564, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29951860

RESUMO

Garlic oil can disrupt the quorum sensing (QS) pathways of the opportunistic pathogen Pseudomonas aeruginosa; however, the underlying mechanisms for this effect are unclear. Diallyl disulfide (DADS) is one of the most abundant sulfur-containing compounds in garlic oil. This study investigated the effects of DADS on the growth, virulence factor production (elastase, pyocyanin, biofilm, and swarming motility), and essential gene expression of P. aeruginosa PAO1, particularly as they apply to QS and virulence. DADS at 1.28 mg/mL did not affect P. aeruginosa PAO1 growth, although it decreased elastase and pyocyanin production, biofilm formation, and swarming motility. Each of these phenomena is regulated by the three QS systems of P. aeruginosa PAO1 (las, rhl, and pqs). Real-time q-PCR revealed that DADS down-regulated the transcription levels of several important QS genes (lasI, lasR, rhlI, rhlR, pqsA, and pqsR) in the three systems. Furthermore, the transcription levels of QS-regulated virulence genes were also down-regulated. The lasB gene, encoding LasB elastase, is co-regulated by the las, rhl, and pqs systems, and thus the down-regulation of genes across the three systems further down-regulated lasB. Additionally, phzM (encoding pyocyanin), pslB (responsible for the production of a biofilm matrix polysaccharide), and chiC (encoding chitinase) were positively activated by LasR, and a decrease in lasR transcription further down-regulated the transcription of phzM, pslB, and chiC. Hence, DADS inhibits P. aeruginosa PAO1 virulence factors by inactivating the transcription of key genes across three different QS systems.


Assuntos
Compostos Alílicos/química , Compostos Alílicos/farmacologia , Proteínas de Bactérias/genética , Dissulfetos/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/genética , Sulfetos/química , Fatores de Virulência/genética , Antibacterianos/farmacologia , Biofilmes
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