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1.
Chemosphere ; 245: 125623, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31855759

RESUMO

Glyphosate (GLY)-dicamba (DIC) and GLY-flurochloridone (FLC) are herbicide mixtures which are widely used for treating fallow containing glyphosate resistant weeds. The aim of this study was to evaluate the acute toxic effects and the prevailing interactions on stage 36 tadpoles of the anuran species Rhinella arenarum when exposed to equitoxic and non-equitoxic combinations of these herbicide combinations. Experiments were realized using the following combinations of commercial formulations: 48% GLY-based Credit® + 57.71% DIC-based Banvel® and 48% GLY-based Credit® + 25% FLC-based Twin Pack Gold®. GLY-DIC and GLY-FLC equitoxic mixtures were assayed mixing each constituent with an equivalent individual toxicity able to induce the same lethality effect. After 96 h of exposure, GLY-DIC and GLY-FLC equitoxic mixtures presented toxic unit 50 values (TU50 96h) of 1.74 (confidence interval: 1.58-1.92) and 1.54 (confidence interval: 1.46-1.62) respectively, indicating the presence of a weak antagonistic interaction as TU values were greater than 1. For their part, most non-equitoxic combinations of GLY-DIC and GLY-FLC tested did not significantly differ from additivity, the only exception being when DIC and FLC were fixed at 0.33 TUs, where a weak antagonism was observed. Overall, results indicate that the toxicity of both GLY-DIC and GLY-FLC mixtures to R. arenarum tadpoles vary from additive to slightly antagonistic, depending on the proportion of constituting herbicide formulations present in the mixture.


Assuntos
Bufonidae , Dicamba/toxicidade , Glicina/análogos & derivados , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Animais , Anuros , Misturas Complexas/toxicidade , Antagonismo de Drogas , Glicina/toxicidade , Pirrolidinonas/toxicidade
2.
BMC Complement Altern Med ; 19(1): 292, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685022

RESUMO

BACKGROUND: The herbal medicine Bryophyllum pinnatum has been used as a tocolytic agent in anthroposophic medicine and, recently, in conventional settings alone or as an add-on medication with tocolytic agents such as atosiban or nifedipine. We wanted to compare the inhibitory effect of atosiban and nifedipine on human myometrial contractility in vitro in the absence and in the presence of B. pinnatum press juice (BPJ). METHODS: Myometrium biopsies were collected during elective Caesarean sections. Myometrial strips were placed under tension into an organ bath and allowed to contract spontaneously. Test substances alone and at concentrations known to moderately affect contractility in this setup, or in combination, were added to the organ bath, and contractility was recorded throughout the experiments. Changes in the strength (measured as area under the curve (AUC) and amplitude) and frequency of contractions after the addition of all test substances were determined. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1-41 cell lines. RESULTS: BPJ (2.5 µg/mL), atosiban (0.27 µg/mL), and nifedipine (3 ng/mL), moderately reduced the strength of spontaneous myometrium contractions. When BPJ was added together with atosiban or nifedipine, inhibition of contraction strength was significantly higher than with the tocolytics alone (p = 0.03 and p < 0.001, respectively). In the case of AUC, BPJ plus atosiban promoted a decrease to 48.8 ± 6.3% of initial, whereas BPJ and atosiban alone lowered it to 70.9 ± 4.7% and to 80.9 ± 4.1% of initial, respectively. Also in the case of AUC, BPJ plus nifedipine promoted a decrease to 39.9 ± 4.6% of initial, at the same time that BPJ and nifedipine alone lowered it to 78.9 ± 3.8% and 71.0 ± 3.4% of initial. Amplitude data supported those AUC data. The inhibitory effects of BPJ plus atosiban and of BPJ plus nifedipine on contractions strength were concentration-dependent. None of the test substances, alone or in combination, decreased myometrial cell viability. CONCLUSIONS: BPJ enhances the inhibitory effect of atosiban and nifedipine on the strength of myometrial contractions, without affecting myometrium tissue or cell viability. The combination treatment of BPJ with atosiban or nifedipine has therapeutic potential.


Assuntos
Kalanchoe/química , Miométrio/efeitos dos fármacos , Nifedipino/antagonistas & inibidores , Extratos Vegetais/farmacologia , Nascimento Prematuro/prevenção & controle , Tocolíticos/antagonistas & inibidores , Contração Uterina/efeitos dos fármacos , Vasotocina/análogos & derivados , Adulto , Antagonismo de Drogas , Feminino , Humanos , Técnicas In Vitro , Miométrio/fisiopatologia , Nifedipino/farmacologia , Gravidez , Tocolíticos/farmacologia , Vasotocina/antagonistas & inibidores , Vasotocina/farmacologia , Adulto Jovem
3.
Clin Appl Thromb Hemost ; 25: 1076029619863493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31298056

RESUMO

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.


Assuntos
Antagonismo de Drogas , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Proteínas Recombinantes/farmacologia , Trombina/biossíntese , Anticoagulantes/farmacologia , Benzamidas/farmacologia , Testes de Coagulação Sanguínea , Inibidores do Fator Xa/química , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Rivaroxabana/farmacologia , Tiazóis/farmacologia , Trombina/efeitos dos fármacos
4.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357442

RESUMO

The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)-valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro. The combination of CDDP/SAHA and CDDP/VPA in the MDA-MB-231 triple negative breast cancer (TNBC) cells with increased activity of Notch1, as well as CDDP/VPA in the MDA-MB-231 cells with decreased activity of Notch1, yielded an additive interaction, whereas additivity with a tendency towards antagonism was observed for the combination of CDDP/SAHA in MDA-MB-231 cells with the decreased activity of Notch1. Our studies demonstrated that SAHA and VPA might be considered as potential therapeutic agents in combination therapy with CDDP against TNBC with altered Notch1 activity.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Receptor Notch1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Interações Medicamentosas , Sinergismo Farmacológico , Feminino , Expressão Gênica , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Estrutura Molecular , Receptor Notch1/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Prod Rep ; 36(6): 869-888, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31187844

RESUMO

Covering: 2000 to 2019 According to a 2012 survey from the Centers for Disease Control and Prevention, approximately 18% of the U.S. population uses natural products (including plant-based or botanical preparations) for treatment or prevention of disease. The use of plant-based medicines is even more prevalent in developing countries, where for many they constitute the primary health care modality. Proponents of the medicinal use of natural product mixtures often claim that they are more effective than purified compounds due to beneficial "synergistic" interactions. A less-discussed phenomenon, antagonism, in which effects of active constituents are masked by other compounds in a complex mixture, also occurs in natural product mixtures. Synergy and antagonism are notoriously difficult to study in a rigorous fashion, particularly given that natural products chemistry research methodology is typically devoted to reducing complexity and identifying single active constituents for drug development. This report represents a critical review with commentary about the current state of the scientific literature as it relates to studying combination effects (including both synergy and antagonism) in natural product extracts. We provide particular emphasis on analytical and Big Data approaches for identifying synergistic or antagonistic combinations and elucidating the mechanisms that underlie their interactions. Specific case studies of botanicals in which synergistic interactions have been documented are also discussed. The topic of synergy is important given that consumer use of botanical natural products and associated safety concerns continue to garner attention by the public and the media. Guidance by the natural products community is needed to provide strategies for effective evaluation of safety and toxicity of botanical mixtures and to drive discovery in botanical natural product research.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Antagonismo de Drogas , Combinação de Medicamentos , Sinergismo Farmacológico , Echinacea/microbiologia , Endotoxinas/farmacologia , Humanos , Metabolômica/métodos , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética
6.
Molecules ; 24(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167480

RESUMO

Lauridia tetragona (L.f) R.H. Archer is routinely used in traditional medicine; however, its hepatoprotective property is yet to be scientifically proven. To this effect, the hepatoprotective activity of the polyphenolic-rich fractions (PPRFs) was investigated against acetaminophen (APAP) injured HepG2 cells. The ability of the PPRF to scavenge free radicals was tested against 2,2-diphenyl-1-picrylhydrazyl (DPPH), and [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonicacid)] (ABTS). The ferric ion reducing power (FRAP) was also evaluated as a cell-free antioxidant assay. The hepatoprotective activity was then investigated by observing the effect of PPRFs against APAP-induced reduction in cell viability of HepG2 cells. The concentrations of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and lactate dehydrogenase (LDH) released into the medium were evaluated while the underlying mechanism was further explored through western blot analysis. Thereafter, the isolated PPRFs were identified using UHPLC-QToF-MS. All six fractions of the PPRFs isolated showed significant antioxidant properties that were evident by the effective scavenging of DPPH, ABTS, and higher FRAP. The results indicated that PPRF pretreatments ameliorated APAP-induced hepatocellular injury by significantly inhibiting the leakage of AST, ALT, and LDH into the medium. The most active fractions for hepatoprotection were PPRF4 and PPRF6 with IC50 of 50.243 ± 8.03 and 154.59 ± 1.9 µg/mL, respectively. PPRFs markedly increased activities of liver superoxide dismutase, total antioxidant capacity, and liver glutathione concentration. Both PPRF4 and PPRF6 significantly increased the expression of Nrf2 and translocation. The LC-MS analysis revealed the presence of a wide variety of polyphenolics such as coumarin, ferulic acid, and caffeine among the dominant constituents. In conclusion, this study demonstrates that the isolated PPRFs have potential hepatoprotective activity that may be due to the increased expression of antioxidative genes dependent on Nrf2.


Assuntos
Acetaminofen/efeitos adversos , Celastraceae/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Alanina Transaminase/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Aspartato Aminotransferases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Células Hep G2 , Humanos , Concentração Inibidora 50 , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Polifenóis/química , Substâncias Protetoras/química
7.
Nat Commun ; 10(1): 2674, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209238

RESUMO

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biologia Computacional/métodos , Neoplasias/tratamento farmacológico , Farmacogenética/métodos , Proteína ADAM17/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benchmarking , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional/normas , Conjuntos de Dados como Assunto , Antagonismo de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Genômica/métodos , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias/genética , Farmacogenética/normas , Fosfatidilinositol 3-Quinases/genética , Resultado do Tratamento
8.
Molecules ; 24(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242703

RESUMO

The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Mentha/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Vemurafenib/efeitos adversos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Camundongos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia
9.
Phytother Res ; 33(6): 1658-1669, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945389

RESUMO

Doxorubicin (Dox) is a first-line drug for breast cancer chemotherapy. However, with the prolongation of chemotherapy cycle, breast cancer cells are increasingly tempt to resist Dox, and meanwhile, high cumulative dose of Dox brings enhancing toxic side effects, and these effects may lead to chemotherapy failure. Hence, it is necessary to search an agent in combination medication with Dox, which can not only enhance the chemosensitivity of Dox but also reduce the toxic side effects. Tanshinone IIA (Tan IIA) is reported to have antitumor activity in addition to its cardiovascular protective effects. We employed human breast cancer MCF-7 and MCF-7/dox cells in order to assess whether Tan IIA might perform such function. Our in vitro studies showed that Tan IIA could enhance the sensitivity of breast cancer cells to Dox through inhibiting the PTEN/AKT pathway and downregulating the expression of efflux ABC transporters including P-gp, BCRP, and MRP1. In addition, our in vivo studies showed Tan IIA enhanced the chemotherapeutic effect of Dox against breast cancer while reducing its toxic side effects including weight loss, myelosuppression, cardiotoxicity, and nephrotoxicity. Therefore, Tan IIA could be used as a novel agent combined with Dox in breast cancer therapy.


Assuntos
/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Antagonismo de Drogas , Interações Medicamentosas , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Inflammation ; 42(4): 1426-1440, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30937838

RESUMO

In the present study, we demonstrated the anti-catabolic effects of formononetin, a phytoestrogen derived from herbal plants, against interleukin-1ß (IL-1ß)-induced severe catabolic effects in primary rat chondrocytes and articular cartilage. Formononetin did not affect the viability of primary rat chondrocytes in both short- (24 h) and long-term (21 days) treatment periods. Furthermore, formononetin effectively antagonized the IL-1ß-induced catabolic effects including the decrease in proteoglycan content, suppression of pericellular matrix formation, and loss of proteoglycan through the decreased expression of cartilage-degrading enzymes like matrix metalloproteinase (MMP)-13, MMP-1, and MMP-3 in primary rat chondrocytes. Moreover, catabolic oxidative stress mediators like nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin E2 were significantly downregulated by formononetin in primary rat chondrocytes treated with IL-1ß. Sequentially, the upregulation of pro-inflammatory cytokines (like IL-1α, IL-1ß, IL-6, and tumor necrosis factor α), chemokines (like fractalkine, monocyte chemoattractant protein-1, and macrophage inflammatory protein-3α), and vascular endothelial growth factor were significantly downregulated by formononetin in primary rat chondrocytes treated with IL-1ß. These data suggest that formononetin may suppress IL-1ß-induced severe catabolic effects and osteoarthritic condition. Furthermore, formononetin may be a promising candidate for the treatment and prevention of osteoarthritis.


Assuntos
Condrócitos/patologia , Antagonismo de Drogas , Inflamação/tratamento farmacológico , Interleucina-1beta/farmacologia , Isoflavonas/farmacologia , Metabolismo/efeitos dos fármacos , Animais , Cartilagem Articular/efeitos dos fármacos , Células Cultivadas , Interleucina-1beta/antagonistas & inibidores , Isoflavonas/antagonistas & inibidores , Osteoartrite/prevenção & controle , Fitoestrógenos/farmacologia , Ratos
11.
J Microbiol Biotechnol ; 29(4): 538-547, 2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-30939634

RESUMO

The aim of the present study was to evaluate the effects of two well-known natural antioxidants vitamin C (VC) and vitamin E (VE) on the antifungal activity of honokiol against Candida albicans. The broth microdilution method was employed to test the antifungal activities of honokiol with or without antioxidants in the medium against C. albicans strain. Intracellular reactive oxygen species (ROS) and lipid peroxidation were determined by fluorescence staining assay. Mitochondrial dysfunction was assessed by detecting the mitochondrial DNA and the mitochondrial membrane potential. We observed that VC could significantly potentiate the antifungal activities of honokiol while VE reduced the effectiveness of honokiol against C. albicans. In addition, VC accelerated honokiol-induced mitochondrial dysfunction and inhibited glycolysis leading to a decrease in cellular ATP. However, VE could protect against mitochondrial membrane lipid peroxidation and rescue mitochondrial function after honokiol treatment. Our research provides new insight into the understanding of the action mechanism of honokiol and VC combination against C. albicans.


Assuntos
Antifúngicos/farmacologia , Ácido Ascórbico/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Candida albicans/efeitos dos fármacos , Antagonismo de Drogas , Lignanas/farmacologia , Vitamina E/antagonistas & inibidores , Antioxidantes/farmacologia , Candida albicans/citologia , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/isolamento & purificação , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
12.
Medicina (Kaunas) ; 55(4)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999703

RESUMO

Synergy is a process in which some substances cooperate to reach a combined effect that is greater than the sum of their separate effects. It can be considered a natural "straight" strategy which has evolved by nature to obtain more efficacy at low cost. In this regard, synergistic effects may be observed in the interaction between herbal products and conventional drugs or biochemical compounds. It is important to identify and exploit these interactions since any improvement brought by such kind of process can be advantageously used to treat human disorders. Even in a complex disease such as cancer, positive synergistic plant-drug interactions should be investigated to achieve the best outcomes, including providing a greater benefit to patients or avoiding adverse side effects. This review analyzes and summarizes the current knowledge on the synergistic effects of plant-drug interactions with a focus on anticancer strategies.


Assuntos
Antineoplásicos/uso terapêutico , Sinergismo Farmacológico , Interações Ervas-Drogas , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Fitoterapia , Animais , Antagonismo de Drogas , Humanos , Camundongos , Óleos Voláteis/uso terapêutico , Polifenóis/uso terapêutico , Ratos
13.
Inflammation ; 42(4): 1441-1455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31028577

RESUMO

Paraquat (PQ), a widely used potent herbicide, generates superoxide anions and other free radicals, leading to severe toxicity and acute lung injury. PQ induces pulmonary fibrosis through epithelial to mesenchymal transition (EMT) characterized by increased number of myofibroblasts. Time-dependent PQ-induced EMT has been evaluated in present investigation where intracellular ROS levels were significantly enhanced after 24 h of PQ intoxication. Anti-inflammatory effects of curcumin have been studied where alveolar epithelial cells (A549 cells) were incubated with curcumin (30 µΜ) for 1 and 3 h before PQ intoxication (700 µM). Western blot and immunocytochemistry studies revealed that pretreatment of A549 cells with curcumin for 3 h before PQ exposure has maintained E-cadherin expression and inhibited PQ induced α-smooth-muscle actin (α-SMA) expression. Transforming growth factor-ß (TGF-ß) that seems to be involved in PQ-induced EMT was enhanced after PQ intoxication, but curcumin pretreatment has effectively inhibited its expression. Immunostaining studies have shown that curcumin pretreatment has significantly reduced matrix metalloproteinase-9 (MMP-9) expressions, which were elevated after PQ intoxication. These results demonstrate that curcumin can regulate PQ-induced EMT by regulating the expression of TGF-ß.


Assuntos
Curcumina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Paraquat/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Células A549 , Caderinas/metabolismo , Antagonismo de Drogas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Herbicidas , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Paraquat/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo
14.
Chemosphere ; 224: 751-764, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851527

RESUMO

Microcystin-LR (MC-LR) and Cylindrospermopsin (CYN) are produced by cyanobacteria. Although being considered as a hepatotoxin and a cytotoxin, respectively, different studies have revealed neurotoxic properties for both of them. The aim of the present work was to study their cytotoxic effects, alone and in combination, in the SH-SY5Y cell line. In addition, toxicity mechanisms such as oxidative stress and acetylcholinesterase (AChE) activity, and morphological studies were carried out. Results showed a cytotoxic response of the cells after their exposure to 0-100 µg/mL of MC-LR or 0-10 µg/mL CYN in both differentiated and undifferentiated cells. Thus, CYN resulted to be more toxic than MC-LR. Respect to their combination, a higher cytotoxic effect than the toxins alone in the case of undifferentiated cells, and almost a similar response to the presented by MC-LR in differentiated cells were observed. However, after analyzing this data with the isobolograms method, an antagonistic effect was mainly obtained. The oxidative stress study only showed an affectation of glutathione levels at the highest concentrations assayed of MC-LR and the combination in the undifferentiated cells. A significant increase in the AChE activity was observed after exposure to MC-LR in undifferentiated cells, and after exposure to the combination of both cyanotoxins on differentiated cells. However, CYN decreased the AChE activity only on differentiated cultures. Finally, the morphological study revealed different signs of cellular affectation, with apoptotic processes at all the concentrations assayed. Therefore, both cyanotoxins isolated and in combination, have demonstrated to cause neurotoxic effects in the SH-SY5Y cell line.


Assuntos
Toxinas Bacterianas/toxicidade , Microcistinas/toxicidade , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Uracila/análogos & derivados , Acetilcolinesterase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Antagonismo de Drogas , Combinação de Medicamentos , Humanos , Neuroblastoma/tratamento farmacológico , Uracila/toxicidade
15.
Biotech Histochem ; 94(5): 381-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822167

RESUMO

We investigated the effects of quercetin (Q) on some hematological parameters and determined the percentage of alpha-naphthyl acetate esterase (ANAE) positive lymphocytes in rats that had been exposed to cadmium (Cd). Thirty male Wistar albino rats were divided into four groups: control (C), quercetin (Q), cadmium (Cd) and Q + Cd (CdQ). Blood samples were taken to assess erythrocytes (RBC), leukocytes (WBC), hemoglobin levels (Hb), hematocrit values (Hct), platelets (PLT), alpha-naphthyl acetate esterase (ANAE) positive lymphocytes. RBC, Hb, Hct; the number of PLT significantly decreased in the Cd group. To the contrary, these parameters were increased significantly in the CdQ group compared to the Cd group. Although we found a significant increase in total WBC count and neutrophil percentage, the number of lymphocytes decreased in the Cd group compared to the other three groups. Also, the percentage of peripheral blood ANAE positive lymphocytes decreased significantly in the Cd group (p < 0.05). Q exhibits positive effects on some hematological characteristics and the percentage of ANAE positive lymphocyte in cases of acute CD toxicity.


Assuntos
Antioxidantes/farmacologia , Cádmio/toxicidade , Quercetina/farmacologia , Animais , Antioxidantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Contagem de Células , Antagonismo de Drogas , Hematócrito , Testes Hematológicos , Leucócitos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Masculino , Naftol AS D Esterase/sangue , Quercetina/uso terapêutico , Ratos , Ratos Wistar
16.
Med Oral Patol Oral Cir Bucal ; 24(2): e195-e203, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818312

RESUMO

BACKGROUND: The aim of this study was to determine if the treatment with bisphosphonates other anti-resorptive and antiangiogenic agents influences the success of regenerative and / or implant treatments. MATERIAL AND METHODS: We reviewed the literature from the last 5 years in the PubMed database, using the following words: "Sinus Floor Augmentation"[Mesh] OR "Dental Implants"[Mesh]) OR "Guided Tissue Regeneration"[Mesh]) AND "Osteonecrosis"[Mesh]. The articles were selected following the inclusion and exclusion criteria and were evaluated using the 22 items of the STROBE declaration. The following PICO clinical question was applied: Does the treatment with agents associated with drug osteonecrosis influence the success of regenerative and implant treatments? RESULTS: The initial search resulted in a total of 27 articles. After eliminating those that did not refer to the topic, were duplicated or did not meet the inclusion / exclusion criteria, a full reading of the articles was made evaluating their methodological quality, obtaining six studies with high methodological quality and two with moderate. CONCLUSIONS: The literature regarding this topic is scarce, randomized clinical trials would be necessary to establish protocols relative to implant treatment in patients on antiresorptive treatments. The risk of developing an osteonecrosis associated with the regeneration / implant placement in patients with benign bone diseases is scarce, but it exists and it should not be underestimated. Especially, in the posterior areas of the jaw, if the duration of treatment with BP is greater than 3 years, and if the patient is under therapy with systemic corticosteroids.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Implantes Dentários , Difosfonatos/efeitos adversos , Osteonecrose/induzido quimicamente , Animais , Anticorpos Monoclonais , Bases de Dados Factuais , Implantação Dentária Endo-Óssea , Falha de Restauração Dentária , Antagonismo de Drogas , Humanos , Levantamento do Assoalho do Seio Maxilar
17.
Ecotoxicol Environ Saf ; 173: 225-234, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30772712

RESUMO

Neutrophils represent an important part of the body's innate immunity and can resist the invasion of pathogenic microorganisms by releasing neutrophil extracellular traps (NETs). In this study, we investigated the toxic effects of lead (Pb) on the release of NETs, the antagonism of selenium (Se) on Pb toxicity and the potential molecular mechanisms. Our model was an in vitro exposure model for the addition of Se, Pb or both in the culture medium and was based on the separation of neutrophils from the peripheral blood of healthy chickens. Phorbol-myristate-acetate (PMA) was used as a stimulant. The scanning electron microscopy and fluorescence microscopy results showed that Pb weakened the PMA-induced formation of NETs. Exposure to Pb reduced the expression of the extracellular regulated protein kinase (ERK) pathway and the respiratory burst. Exposure to Pb also attenuated the release of Ca2+ in the endoplasmic reticulum mediated by the inositol 1,4,5-trisphosphate receptor (IP3R). These are two ways by which Pb decreases the formation of NETs. Pb also attenuates the expression levels of myeloperoxidase (MPO) and neutrophil elastase (NE), and attenuates histone removal by affecting the expression of different protein kinase C (PKC) isoforms. In contrast, Se can reduce the toxic damage caused by Pb. These results indicate that exposure to Pb decreases the formation of NETs, while Se can antagonize the toxicity of Pb to allow the formation of NETs.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Chumbo/toxicidade , Neutrófilos/efeitos dos fármacos , Selênio/farmacologia , Animais , Cálcio/metabolismo , Células Cultivadas , Galinhas , Antagonismo de Drogas , Histonas/metabolismo , Elastase de Leucócito/metabolismo , Neutrófilos/fisiologia , Peroxidase/metabolismo , Acetato de Tetradecanoilforbol
18.
Biotech Histochem ; 94(5): 313-319, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30777790

RESUMO

Exposure to high doses of acetaminophen is the most common cause of drug induced liver injury. We investigated the protective effects of Hedera helix extract against acetaminophen induced oxidative stress and hepatotoxicity using a mouse model. We used two control groups: group A was given 0.9% NaCl, group B was an acetaminophen control that was given a single injection of 600 mg/kg acetaminophen. T1-T4 groups were pretreated orally with different doses of H. helix extract. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin. Liver samples also were used for histopathological studies. We found that acetaminophen significantly increased the levels of serum ALP, ALT, AST and MDA, and also significantly reduced the antioxidant factors, CAT, GPX and SOD. H. helix extract treatment produced a significant reduction in the levels of ALP, ALT, AST and MDA in serum and restored the levels of CAT, GPX and SOD to control levels. The histopathological findings were consistent with the biochemical findings. H. helix extract exhibited antioxidant and hepatoprotective effects against acetaminophen induced liver damage.


Assuntos
Acetaminofen/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hedera , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetaminofen/envenenamento , Alanina Transaminase/metabolismo , Animais , Antioxidantes/uso terapêutico , Aspartato Aminotransferases/metabolismo , Antagonismo de Drogas , Glutationa Peroxidase/metabolismo , Interações Ervas-Drogas , Fígado/enzimologia , Fígado/fisiopatologia , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Superóxido Dismutase/metabolismo
19.
Fitoterapia ; 134: 14-22, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30731149

RESUMO

Apigenin and protoapigenone that both have the activities against various cancer cell lines co-exist in Macrothelypteris torresiana, while the extracts of M. torresiana couldn't achieve the fine anti-tumor effects for the existence of potent anti-tumor compounds. This study disclosed an antagonism between the two compounds on the protein level to elucidate the paradox. First, the study established the fingerprint for M. torresiana extract. The following anti-proliferation assay verified that the antagonism occurs between protoapigenone and apigenin. And then Western blot and qt-PCR were applied to evaluate the expression and transcription level of the Akt phosphorylation related targets to validate the antagonism at the protein level. Moreover, CETSA further validated the binding of PDK-1 with apigenin and protoapigenone, as well as the antagonism between the two compounds. Finally, the compound-protein complexes predicted by SYBYL-X gave the visual results for the antagonism. The results demonstrated that: Due to the structural similarity and close binding coefficients to the identical targets, when the cells were treated with apigenin and protoapigenone simultaneously, the Akt phosphorylation inhibition induced by protoapigenone would attenuate significantly. The antagonism disclosed in this paper could be a new explanation for the unsatisfied efficacy of M. torresiana extract.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apigenina/farmacologia , Cicloexanonas/farmacologia , Gleiquênias/química , Flavonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Antagonismo de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fosforilação , Plantas Medicinais/química , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rizoma/química
20.
Nat Rev Microbiol ; 17(3): 141-155, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30683887

RESUMO

Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chemical, biological and pharmacological requisites for effective antibiotic drugs. Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compounds offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, we outline a theoretical and practical framework for the development of effective antibiotic combinations.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Ensaios Clínicos como Assunto , Antagonismo de Drogas , Sinergismo Farmacológico , Humanos
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