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1.
Int J Nanomedicine ; 15: 2971-2986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431496

RESUMO

Background: Due to their extraordinary physical and chemical properties, MoS2 nanosheets (MSNs) are becoming more widely used in nanomedicine. However, their influence on immune systems remains unclear. Materials and Methods: Two few-layered MSNs at sizes of 100-250 nm (S-MSNs) and 400-500 nm (L-MSNs) were used in this study. Bone marrow-derived dendritic cells (DCs) were exposed to both MSNs at different doses (0, 8, 16, 32, 64, 128 µg/mL) for 48 h and subjected to analyses of surface marker expression, cytokine secretion, lymphoid homing and in vivo T cell priming. Results: Different-sized MSNs of all doses did not affect the viability of DCs. The expression of CD40, CD80, CD86 and CCR7 was significantly higher on both S-MSN- and L-MSN-treated DCs at a dose of 128 µg/mL. As the dose of MSN increased, the secretion of IL-12p70 remained unchanged, the secretion of IL-1ß decreased, and the production of TNF-α increased. A significant increase in IL-6 was observed in the 128 µg/mL L-MSN-treated DCs. In particular, MSN treatment dramatically improved the ex vivo movement and in vivo homing ability of both the local resident and blood circulating DCs. Furthermore, the cytoskeleton rearrangement regulated by ROS elevation was responsible for the enhanced homing ability of the MSNs. More robust CD4+ and CD8+ T cell proliferation and activation (characterized by high expression of CD107a, CD69 and ICOS) was observed in mice vaccinated with MSN-treated DCs. Importantly, exposure to MSNs did not interrupt LPS-induced DC activation, homing and T cell priming. Conclusion: Few-layered MSNs ranging from 100 to 500 nm in size could play an immunostimulatory role in enhancing DC maturation, migration and T cell elicitation, making them a good candidate for vaccine adjuvants. Investigation of this study will not only expand the applications of MSNs and other new transition metal dichalcogenides (TMDCs) but also shed light on the in vivo immune-risk evaluation of MSN-based nanomaterials.


Assuntos
Diferenciação Celular , Movimento Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Dissulfetos/farmacologia , Molibdênio/farmacologia , Nanopartículas/química , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Células Dendríticas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos
3.
Int J Oncol ; 56(3): 772-782, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32124958

RESUMO

Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)­induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL­60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL­60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS­induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS­induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho­associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL­60 cells, while 8 µM DADS enhanced the effects of the Rac1­ROCK1­LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL­60 cells. These results suggest that the anticancer function of DADS on HL­60 leukemia cells is regulated by the Rac1­ROCK1­LIMK1­cofilin 1 pathway, indicating that DADS could be a promising anti­leukemia therapeutic compound.


Assuntos
Compostos Alílicos/farmacologia , Antineoplásicos/farmacologia , Cofilina 1/genética , Cofilina 1/metabolismo , Dissulfetos/farmacologia , Leucemia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Quinases Lim/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
4.
Appl Microbiol Biotechnol ; 104(7): 3121-3131, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32060693

RESUMO

Antibiotic resistance in pathogenic bacteria is a major health challenge, as Infectious Diseases Society of America (IDSA) has recognized that the past simply drugs susceptible pathogens are now the most dangerous pathogens due to their nonstop growing resistance towards conventional antibiotics. Therefore, due to the emergence of multi-drug resistance, the bacterial infections have become a serious global problem. Acute infections feasibly develop into chronic infections because of many factors; one of them is the failure of effectiveness of antibiotics against superbugs. Modern research of two-dimensional nanoparticles and biopolymers are of great interest to attain the intricate bactericidal activity. In this study, we fabricated an antibacterial nanocomposite consisting of representative two-dimensional molybdenum disulfide (2D MoS2) nanoparticles. Polyhydroxyalkanoate (PHA) and chitosan (Ch) are used to encapsulate MoS2 nanoparticles into their matrix. This study reports the in vitro antibacterial activity and host cytotoxicity of novel PHA-Ch/MoS2 nanocomposites. PHA-Ch/MoS2 nanocomposites were subjected to time-dependent antibacterial assays at various doses to examine their antibacterial activity against multi-drug-resistant Escherichia coli K1 (Malaysian Type Culture Collection 710859) and methicillin-resistant Staphylococcus aureus (MRSA) (Malaysian Type Culture Collection 381123). Furthermore, the cytotoxicity of nanocomposites was examined against spontaneously immortalized human keratinocyte (HaCaT) cell lines. The results indicated significant antibacterial activity (p value < 0.05) against E. coli K1 and MRSA. In addition, PHA-Ch/MoS2 showed significant host cytocompatibility (p < 0.05) against HaCaT cells. The fabricated PHA-Ch/MoS2 nanocomposites have demonstrated effective antibacterial activity against both Gram-positive and -negative bacteria and exhibited better biocompatibility. Finally, PHA-Ch/MoS2 nanocomposites are shown to be suitable for antibacterial applications and also hold potential for further biomedical studies. Graphical Abstract.


Assuntos
Antibacterianos/farmacologia , Biopolímeros/farmacologia , Dissulfetos/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Molibdênio/farmacologia , Poli-Hidroxialcanoatos/farmacologia , Antibacterianos/química , Biopolímeros/química , Linhagem Celular , Quitosana/química , Dissulfetos/química , Farmacorresistência Bacteriana Múltipla/fisiologia , Humanos , Nanopartículas Metálicas/química , Molibdênio/química , Nanocompostos/química , Poli-Hidroxialcanoatos/síntese química , Poli-Hidroxialcanoatos/química
5.
J Agric Food Chem ; 68(6): 1571-1578, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927886

RESUMO

Diallyl trisulfide (DATS) is a secondary metabolite of allicin, a volatile organosulfur flavoring compound generated by the crushing of garlic. These compounds have various medicinal effects such as antiplatelet activity. In this study, we demonstrated for the first time the cellular mechanism involved in the inhibition of platelet aggregation by DATS and dipropyl trisulfide (DPTS), which is a saturated analogue of DATS. Washed murine platelets were incubated with these sulfides, and platelet aggregation was evaluated by light transmission aggregometry. The amount of reaction products produced by DATS, DPTS, and glutathione (GSH) was measured using liquid chromatography-mass spectrometry. Compared with DPTS, DATS potently inhibited platelet aggregation induced by thrombin, U46619, and collagen. N-Ethylmaleimide (NEM), which is commonly used to modify sulfhydryl groups, also suppressed platelet aggregation. The reactivity of DATS with GSH was higher than that of DPTS. These data suggested that DATS inhibited platelet aggregation through the reaction of sulfhydryl groups.


Assuntos
Compostos Alílicos/química , Compostos Alílicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Compostos de Sulfidrila/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Dissulfetos/química , Dissulfetos/farmacologia , Alho/química , Glutationa/química , Camundongos , Agregação Plaquetária/efeitos dos fármacos , Compostos de Sulfidrila/química
6.
Med Sci Monit ; 25: 8920-8927, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31760404

RESUMO

BACKGROUND Several factors found in foods are beneficial to human health and they may contribute to radiation protection. Taking food factors could be an easy way to reduce the effects of radiation after nuclear accidents, as well as secondary radiation risks after cancer radiotherapy or space missions. Here, diallyl disulfide (DADS), a component of garlic oil, was studied for its ability to mitigate radiation damage. MATERIAL AND METHODS We investigated the effects of DADS on micronucleus (MN) formation and apoptosis in HepG2 cells by use of 4-Gy X-ray irradiation. We also assessed the effects of DADS on radiation damage in vivo by evaluating MN formation in bone marrow cells in mice (BALB/c, 8-week-old females) after oral intake of DADS prior to irradiation with 4 Gy. Several tissue effects were also investigated. RESULTS The presence of DADS inhibited MN formation, whereas DADS had no influence on the radiation-induced inhibition of cell cycle progression in HepG2 cells. An increase in apoptosis in HepG2 cells was induced after irradiation, and this effect was stronger in the presence of DADS than in its absence. In mice, when DADS was administered daily for 3 days prior to irradiation, MN formation in irradiated mice was decreased. The decrease in MN formation in mice was greater with 0.5% DADS compared to 1% DADS. Moreover, an increase in spleen weight observed 3 weeks after irradiation was suppressed in mice administered DADS. CONCLUSIONS DADS is a potential radiation-protective agent that effectively mitigates DNA damage, and its effects in the spleen observed after irradiation may be related to inflammation and carcinogenesis.


Assuntos
Compostos Alílicos/farmacologia , Dissulfetos/farmacologia , Lesões por Radiação/prevenção & controle , Compostos Alílicos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Dissulfetos/metabolismo , Feminino , Células Hep G2/efeitos da radiação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Protetores contra Radiação/farmacologia , Baço/efeitos da radiação
7.
Nutrients ; 11(11)2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31717643

RESUMO

Skeletal muscle atrophy is one of the major symptoms of cancer cachexia. Garlic (Allium sativum), one of the world's most commonly used and versatile herbs, has been employed for the prevention and treatment of diverse diseases for centuries. In the present study, we found that ajoene, a sulfur compound found in crushed garlic, exhibits protective effects against muscle atrophy. Using CT26 tumor-bearing BALB/c mice, we demonstrate in vivo that ajoene extract alleviated muscle degradation by decreasing not only myokines secretion but also janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) and SMADs/forkhead box (FoxO) signaling pathways, thereby suppressing muscle-specific E3 ligases. In mouse skeletal myoblasts, Z-ajoene enhanced myogenesis as evidenced by increased expression of myogenic markers via p38 mitogen-activated protein kinase (MAPK) activation. In mature myotubes, Z-ajoene protected against muscle protein degradation induced by conditioned media from CT26 colon carcinoma cells, by suppressing expression of muscle specific E3 ligases and nuclear transcription factor kappa B (NF-κB) phosphorylation which contribute to muscle atrophy. Moreover, Z-ajoene treatment improved myofiber formation via stimulation of muscle protein synthesis. These findings suggest that ajoene extract and Z-ajoene can attenuate skeletal muscle atrophy induced by cancer cachexia through suppressing inflammatory responses and the muscle wasting as well as by promoting muscle protein synthesis.


Assuntos
Caquexia/metabolismo , Dissulfetos/farmacologia , Alho/química , Atrofia Muscular , Substâncias Protetoras/farmacologia , Animais , Caquexia/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/fisiopatologia , Dissulfetos/isolamento & purificação , Dissulfetos/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Extratos Vegetais/química , Substâncias Protetoras/uso terapêutico
8.
Colloids Surf B Biointerfaces ; 184: 110551, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622812

RESUMO

The treatment of cancer has always been a worldwide problem. The combination of chemotherapy and other therapies would be a promising therapy strategy. Photothermal therapy (PTT) does not cause serious side effects and has dual control of time and space, which was considered to be a good method for combination with chemotherapy. Here, we modified multifunctional nanosheets based on in-situ gold nanoparticles (Au NPs) grown molybdenum disulfide (MoS2) to combine their excellent photothermal conversion and drug loading capabilities. More importantly, the target peptide cRGD modified nanosheets have good selectivity to tumor cells rich in integrin receptors, and drug loading and drug release tests showed that it could carry enough chemotherapeutic drugs and had excellent photo controlled release performance. In vitro cell experiments showed that the drug-loaded multifunctional nanosheets had good anti-tumor effect under 808 nm laser irradiation. Therefore, the multifunctional nanosheets designed in this paper have great potential in the study of targeted drug release and chemo-photothermal therapy combined therapy, and are of great significance for in vivo and clinical research.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Dissulfetos/farmacologia , Doxorrubicina/farmacologia , Ouro/farmacologia , Molibdênio/farmacologia , Nanoestruturas/química , Fotoquimioterapia , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Células Hep G2 , Humanos , Molibdênio/química , Tamanho da Partícula , Propriedades de Superfície , Temperatura , Células Tumorais Cultivadas
9.
Ecotoxicol Environ Saf ; 186: 109781, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31622879

RESUMO

Nanomaterials of Al2O3 and TiO2 have been proved to promote the spread of antibiotic resistance genes (ARGs) by horizontal gene transfer. In this work, we found that Fe2O3@MoS2 nanocomposite inhibited the horizontal gene transfer (HGT) by inhibiting the conjugative transfer mediated by RP4-7 plasmid. To discover the mechanism of Fe2O3@MoS2 inhibiting HGT, the bacterial cells were collected under the optimal mating conditions. The collected bacterial cells were used for analyzing the expression levels of genes unique to the plasmid and the bacterial chromosome in the conjugation system by qPCR. The results of genes expression demonstrated that the mechanism of Fe2O3@MoS2 inhibited conjugation by promoting the expression of global regulatory gene (trbA) and inhibiting the expression of conjugative transfer genes involved in mating pair formation (traF, trbB) and DNA replication (trfA). The risk assessment of Fe2O3@MoS2 showed that it had very low toxicity to organisms. The findings of this paper showed that Fe2O3@MoS2, as an inhibitor of horizontal gene transfer, is an environment-friendly material.


Assuntos
Conjugação Genética/efeitos dos fármacos , Dissulfetos/química , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Compostos Férricos/química , Transferência Genética Horizontal/efeitos dos fármacos , Molibdênio/química , Nanocompostos/química , Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Conjugação Genética/genética , Dissulfetos/farmacologia , Resistência Microbiana a Medicamentos/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Compostos Férricos/farmacologia , Genes Microbianos , Molibdênio/farmacologia , Plasmídeos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética
10.
DNA Repair (Amst) ; 82: 102690, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31479843

RESUMO

Combining natural products with chemotherapy and/or radiotherapy may increase the efficacy of cancer treatment. It has been hypothesized that natural products may inhibit DNA repair and sensitize cancer cells to DNA damage-based cancer therapy. However, the molecular mechanisms underlying these activities remain unclear. In this study, we found that diallyl disulfide (DADS), an organosulfur compound, increased the sensitivity of yeast cells to DNA damage and has potential for development as an adjuvant drug for DNA damage-based cancer therapy. We induced HO endonuclease to generate a specific DNA double-strand break (DSB) by adding galactose to yeast and used this system to study how DADS affects DNA repair. In this study, we found that DADS inhibited DNA repair in single-strand annealing (SSA) system and sensitized SSA cells to a single DSB. DADS impaired DNA repair by inhibiting the protein levels of the DNA resection-related proteins Sae2 and Exo1. We also found that the recruitment of MRX and the Mec1-Ddc2 complex to a DSB was prevented by DADS. This result suggests that DADS counteracts G2/M DNA damage checkpoint activation in a Mec1 (ATR)- and Tel1 (ATM)-dependent manner. Only by elucidating the molecular mechanisms by which DADS influences DNA repair will we be able to discover new adjuvant drugs to improve chemotherapy and/or radiotherapy.


Assuntos
Compostos Alílicos/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Dissulfetos/farmacologia , Endonucleases/metabolismo , Exodesoxirribonucleases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Morte Celular Autofágica/efeitos dos fármacos , Morte Celular Autofágica/genética , Sinergismo Farmacológico , Proteólise/efeitos dos fármacos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
11.
Molecules ; 24(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500271

RESUMO

Garlic and formulations containing allicin are used widely as fungicides in modern agriculture. However, limited reports are available on the allelopathic mechanism of green garlic volatile organic compounds (VOCs) and its component allelochemicals. The aim of this study was to investigate VOCs of green garlic and their effect on scavenging of reactive oxygen species (ROS) in cucumber. In this study, green garlic VOCs were collected by HS-SPME, then analyzed by GS-MS. Their biological activity were verified by bioassays. The results showed that diallyl disulfide (DADS) is the main allelochemical of green garlic VOCs and the DADS content released from green garlic is approximately 0.08 mg/g. On this basis, the allelopathic effects of green garlic VOCs in vivo and 1 mmol/L DADS on scavenging of ROS in cucumber seedlings were further studied. Green garlic VOCs and DADS both reduce superoxide anion and increase the accumulation of hydrogen peroxide of cucumber seedlings. They can also regulate active antioxidant enzymes (SOD, CAT, POD), antioxidant substances (MDA, GSH and ASA) and genes (CscAPX, CsGPX, CsMDAR, CsSOD, CsCAT, CsPOD) responding to oxidative stress in cucumber seedlings.


Assuntos
Compostos Alílicos/farmacologia , Cucumis sativus/metabolismo , Dissulfetos/farmacologia , Alho/química , Espécies Reativas de Oxigênio/análise , Compostos Alílicos/isolamento & purificação , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/genética , Dissulfetos/isolamento & purificação , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Peróxido de Hidrogênio/análise , Estresse Oxidativo/efeitos dos fármacos , Feromônios/isolamento & purificação , Feromônios/farmacologia , Proteínas de Plantas/genética , Plântula/efeitos dos fármacos , Plântula/metabolismo , Superóxidos/análise , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/isolamento & purificação
12.
Pharmacol Res Perspect ; 7(5): e00518, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31516713

RESUMO

P21-activated kinase-1 (PAK-1) is a serine/threonine kinase involved in multiple signaling pathways that mediate cellular functions such as cytoskeletal motility, cell proliferation, and survival. PAK-1 expression is altered in various cancers, including prostate and breast. Our recent studies showed that prostate cancer cells expressing higher levels of PAK-1 were resistant to the cytotoxic effects of the PAK-1 inhibitor, inhibitor targeting PAK-1 activation-3 (IPA-3), compared to those with lower expression. This study expanded these findings to other cancers (breast and melanoma) by testing the hypothesis that genetic and pharmacological inhibition of PAK-1 alters cell growth, migration, and invasion in prostate, breast, and skin cancer cell lines. We also tested the specificity of IPA-3 for PAK-1 and the hypothesis that gene silencing of PAK-1 altered the efficacy of sterically stabilized liposomes (SSL) containing IPA-3 (SSL-IPA-3). PAK-1 expression was identified in four different breast cancer cell lines, and in a melanoma cell line. The expression of PAK-1 correlated to the IC50 of IPA-3 as measured by MTT staining. PAK-1 inhibition using shRNA correlated with decreased cell migration and invasion in prostate cancer DU-145 and breast cancer MCF-7 cells. Decreased migration and invasion also correlated to decreased expression of E-cadherin and alterations in C-X-C Chemokine Receptor type 4 and Homing Cell Adhesion Molecule expression. PAK-1 inhibition increased the cytotoxicity of IPA-3, and the cytotoxicity of SSL-IPA-3 to levels comparable to that of free drug. These data demonstrate that both pharmacological and molecular inhibition of PAK-1 decreased growth in prostate, breast, and melanoma cancer cell lines, and increased the toxicity of IPA-3 and its liposomal formulation. These data also show the specificity of IPA-3 for PAK-1, are some of the first data suggesting that IPA-3 is a therapeutic treatment for breast cancer and melanoma, and demonstrate the efficacy of liposome-encapsulated IPA-3 in breast cancer cells.


Assuntos
Neoplasias da Mama/enzimologia , Dissulfetos/farmacologia , Melanoma/enzimologia , Naftóis/farmacologia , RNA Interferente Pequeno/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Lipossomos , Células MCF-7 , Masculino , Melanoma/tratamento farmacológico , Quinases Ativadas por p21/genética
13.
Pharmacol Res Perspect ; 7(4): e00509, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31372229

RESUMO

The novel clopidogrel conjugate, DT-678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT-678 and currently approved P2Y12 antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT-678. Ninety-one New Zealand white rabbits were randomized to one of 13 treatment groups (n = 7). Platelet activation was assessed by flow cytometry and light transmission aggregometry before and after the administration of various doses of DT-678, clopidogrel, and ticagrelor. Tongue template bleeding times were also measured before and after drug treatment. Treatment with P2Y12 receptor antagonists caused a dose-dependent reduction in markers of platelet activation (P-selectin and integrin αIIbß3) and aggregation in response to adenosine diphosphate stimulation. At the same doses required for platelet inhibition, clopidogrel and ticagrelor significantly prolonged bleeding times, while DT-678 did not. DT-678 and the FDA-approved P2Y12 antagonists clopidogrel and ticagrelor are effective inhibitors of platelet activation and aggregation. However, unlike clopidogrel and ticagrelor, DT-678 did not prolong bleeding times at equally effective antiplatelet doses. The results suggest a more favorable benefit/risk ratio for DT-678 and potential utility as part of a dual antiplatelet therapy regimen.


Assuntos
Dissulfetos/administração & dosagem , Ativação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Animais , Tempo de Sangramento , Clopidogrel/administração & dosagem , Clopidogrel/química , Clopidogrel/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Relação Dose-Resposta a Droga , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Coelhos , Distribuição Aleatória , Ticagrelor/administração & dosagem , Ticagrelor/farmacologia
14.
ACS Appl Mater Interfaces ; 11(37): 34364-34375, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31442020

RESUMO

In this study, a multifunctional hybrid coating composed of AgBr nanoparticles (AgBrNPs) and two-dimensional molybdenum sulfide (MoS2) nanosheets (AgBr@MoS2) was constructed on Ti implant materials using an in situ growth method for the first time. With 660 nm light and visible light irradiation, the electrons were rapidly excited from the valence band of MoS2 to its conduction band, at the same time, AgBrNPs was used as a photoelectric receiver, which exhibited an enhanced photocatalytic activity due to the rapid transfer of photoelectrons from MoS2 nanosheets to AgBrNPs and the suppression of the recombination of electron-hole pairs. This contributed to the rapid production of reactive oxygen species under 660 nm light irradiation, thus the AgBr@MoS2 system killed bacteria and degraded organic matter quickly and efficiently in a short time. Meanwhile, the AgBr@MoS2 system showed excellent stability due to the strong covalent binding between S and Ag in the system, thus preventing AgBrNPs from being reduced to metal Ag.


Assuntos
Antibacterianos , Bactérias/crescimento & desenvolvimento , Brometos , Desinfecção , Dissulfetos , Luz , Molibdênio , Nanopartículas/química , Compostos de Prata , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Brometos/química , Brometos/farmacologia , Linhagem Celular , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/efeitos da radiação , Molibdênio/química , Molibdênio/farmacologia , Ratos , Ratos Sprague-Dawley , Compostos de Prata/química , Compostos de Prata/farmacologia
15.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340526

RESUMO

Diallyl disulfide (DADs), a natural organic compound, is extracted from garlic and scallion and has anti-tumor effects against various tumors. This study investigated the anti-tumor activity of DADs in human osteosarcoma cells and the mechanisms. MG-63 cells were exposed to DADs (0, 20, 40, 60, 80, and 100 µM) for different lengths of time (24, 48, and 72 h). The CCK8 assay results showed that DADs inhibited osteosarcoma cell viability in a dose-and time-dependent manner. FITC-Annexin V/propidium iodide staining and flow cytometry demonstrated that the apoptotic ratio increased and the cell cycle was arrested at the G2/M phase as the DADs concentration was increased. A Western blot analysis was employed to detect the levels of caspase-3, Bax, Bcl-2, LC3-II/LC3-I, and p62 as well as suppression of the mTOR pathway. High expression of LC3-II protein revealed that DADs induced formation of autophagosome. Furthermore, DADs-induced apoptosis was weakened after adding 3-methyladenine, demonstrating that the DADs treatment resulted in autophagy-mediated death of MG-63 cells. In addition, DADs depressed p-mTOR kinase activity, and the inhibited PI3K/Akt/mTOR pathway increased DADs-induced apoptosis and autophagy. In conclusion, our results reveal that DADs induced G2/M arrest, apoptosis, and autophagic death of human osteosarcoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway.


Assuntos
Compostos Alílicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Dissulfetos/farmacologia , Regulação Neoplásica da Expressão Gênica , Osteoblastos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Compostos Alílicos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dissulfetos/isolamento & purificação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Alho/química , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
16.
Acta Derm Venereol ; 99(11): 1022-1028, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304555

RESUMO

Cutaneous T-cell lymphoma (CTCL) represents a rare group of extranodal T-cell lymphoproliferative diseases. Due to poor clinical outcome of CTCL, there is an urgent need for new and improved therapies. A small molecule, IPA-3, which inhibits p21-activated kinase 1 (PAK1), has shown therapeutic potential in various types of malignancies. In the present study, the anti-tumor effect of IPA-3 and its underlying molecular mechanism was evaluated. High expression of phosphorylated-PAK1 (pho-PAK1) was seen in CTCL lesional skin compared to benign inflammatory dermatoses. IPA-3 could significantly inhibit the proliferation of 3 CTCL lines in a dose- and time-dependent manner. The percentage of apoptotic cells was higher in the treatment group. Further, IPA-3 treatment caused increased EGR1 protein levels and decreased apoptosis-related BCL-2 and pho-BAD protein levels. In summary, inhibition of pho-PAK1 has significant anti-tumor effects in CTCL cells and it can be explored as a future therapeutic option.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dissulfetos/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Naftóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Quinases Ativadas por p21/antagonistas & inibidores , Adulto , Idoso , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Linfoma Cutâneo de Células T/enzimologia , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Proteína de Morte Celular Associada a bcl/metabolismo , Quinases Ativadas por p21/metabolismo
17.
Mar Drugs ; 17(7)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252563

RESUMO

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon-sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Dissulfetos/farmacologia , Poríferos/química , Tirosina/análogos & derivados , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/química , Linhagem Celular Tumoral , Dissulfetos/química , Eriptose/efeitos dos fármacos , Humanos , Inseticidas/química , Inseticidas/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Tirosina/química , Tirosina/farmacologia
18.
PLoS One ; 14(6): e0218507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216348

RESUMO

Bovine NK-lysins are cationic antimicrobial proteins found predominantly in the cytosolic granules of T lymphocytes and NK-cells. NK-lysin-derived peptides show antimicrobial activity against both Gram positive and Gram negative bacteria. Mature NK-lysin protein has six well-conserved cysteine residues. This study was performed to assess whether synthetic bovine NK-lysin-derived peptide (bNK2A) forms disulfide bonds and whether disulfide bonds were essential for bNK2A antimicrobial activity. Two 30-mer bNK2A peptides were synthesized: one with two original cysteines and an analog with cysteines substituted with two serines. Mass spectrometry revealed lack of disulfide bonds in original peptide while CD spectrophotometry showed both peptides have similar α-helical structures. Since both peptides were equally inhibitory to Histophilus somni, disulfide bonds appeared dispensable for synthetic bNK2A peptide antibacterial activity.


Assuntos
Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Animais , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bovinos , Dissulfetos/química , Dissulfetos/farmacologia , Hemólise/efeitos dos fármacos , Pasteurellaceae/efeitos dos fármacos , Conformação Proteica em alfa-Hélice , Relação Estrutura-Atividade
19.
Mol Med Rep ; 20(2): 1363-1372, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173200

RESUMO

Non­alcoholic steatohepatitis (NASH) is a common clinicopathological condition. Currently, the pathogenesis of NASH remains unknown, and no optimal therapy option currently exists. It has previously been demonstrated that diallyl disulfide (DADS) was capable of attenuating liver dysfunction, as DADS supplementation had a positive impact on liver regeneration, proliferation and oxidative damage. Thus, DADS could serve as a potential therapeutic agent that can protect against the effects of NASH. The present study aimed to evaluate the effect of DADS on NASH and to understand the associated underlying molecular mechanisms. A methionine­ and choline­deficient diet (MCD) and high­fat diet (HFD) are the two common animal models that induce NASH. C57BL/6J mice were fed an MCD for 4 weeks, or an HFD for 20 weeks, in the present study. The mice were treated with or without DADS (20, 50 and 100 mg/kg) for 4 or 20 weeks. For the histopathological examination, hematoxylin and eosin staining, oil red O staining and immunohistochemical analyses were performed using the liver sections. Biochemical assays and ELISA were performed to measure the serum biochemical indicators of hepatic function and inflammatory indicators, respectively. Reverse transcription­quantitative PCR, immunofluorescence and western blotting were used to detect expression levels of the genes involved in the molecular mechanisms underlying DADS protection. MCD or HFD induced the histological features of NASH in mice, including significant vacuolated hepatocytes, marked inflammatory cell infiltration and severe micro­ and macro­vesicular steatosis. Serum alanine transferase and aspartate aminotransferase levels, as well as the contents of liver triglyceride and total cholesterol, were significantly increased in these two models. DADS attenuated these histological and biochemical changes. DADS ameliorated hepatic steatosis by regulating sterol regulatory element­binding transcription factor 1, apolipoprotein A1, cyclic AMP­responsive element­binding protein H and fibroblast growth factor 21. Furthermore, DADS was revealed to prevent lipotoxicity via peroxisome proliferator­activated receptor α elevation and stearoyl­coenzyme A desaturase 1 inhibition in HFD­fed mice. In addition, DADS markedly inhibited lipid peroxidation by modulating malondialdehyde and superoxide dismutase, and it also decreased tumor necrosis factor­α production, interleukin­6 production and macrophage influx, as well as suppressing nuclear factor­κB activation, indicating suppression of MCD­induced hepatic inflammation. Taken together, the results have shown that DADS exerts beneficial effects on MCD­ or HFD­induced NASH by suppressing key regulators of lipid metabolism, lipid peroxidation and inflammation.


Assuntos
Compostos Alílicos/uso terapêutico , Dissulfetos/uso terapêutico , Inflamação/metabolismo , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Compostos Alílicos/farmacologia , Animais , Modelos Animais de Doenças , Dissulfetos/farmacologia , Inflamação/complicações , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transdução de Sinais
20.
Neurochem Res ; 44(8): 1878-1892, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31190314

RESUMO

Parkinson's disease (PD) is a prevalent, progressive, neurodegenerative disorder with no known cure. Oxidative stress has been found to play a significant role in its etiology, and the search for novel neuroprotective compounds that actively prevent disease progression is currently ongoing. Dithiolethiones are a group of sulfur-containing heterocyclic compounds found in cruciferous vegetables. Using the 6-hydroxydopamine (6-OHDA) model of PD, we tested a previously identified disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) for its neuroprotective potential. Pretreatment of SH-SY5Y cells with ACDT led to a time- and concentration-dependent induction of the antioxidant glutathione (GSH). ACDT also diminished 6-OHDA-induced cell death, lactate dehydrogenase release, elevation of caspase 3/7 activity, and increase in levels of reactive oxygen species. Inhibition of the GSH-synthesizing enzyme glutamate-cysteine ligase catalytic subunit (GCLC) led a corresponding dissipation of ACDT's neuroprotective effects, hence underlining the importance of GSH in ACDT's neuroprotective response. ACDT caused the stabilization and nuclear translocation of nuclear factor erythroid-2 related factor (Nrf2), resulting in increased protein expression of the phase II enzyme NADPH:quinone oxidoreductase 1 (NQO1), and the excitatory amino acid cysteine membrane transporter (EAAT3). Interestingly, no changes in the levels of other Nrf2-dependent molecules including GCLC were observed, indicating the possible involvement of additional alternate mechanisms behind ACDT's GSH-inducing property. Collectively, the data demonstrated ACDT to be a promising new dithiolethione for the treatment of PD, with two modifiable functional groups offering additional avenues for enhanced pharmacological application.


Assuntos
Dissulfetos/farmacologia , Ésteres/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia , Tionas/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
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