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1.
Life Sci ; 285: 119996, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34597607

RESUMO

AIMS: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting µ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. MAIN METHODS: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. KEY FINDINGS: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. SIGNIFICANCE: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.


Assuntos
Analgésicos Opioides/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dor Nociceptiva/tratamento farmacológico , Pentazocina/farmacologia , Receptores Opioides mu/agonistas , Tapentadol/farmacologia , Tetra-Hidronaftalenos/farmacologia , Inibidores da Captação Adrenérgica/química , Inibidores da Captação Adrenérgica/farmacologia , Analgésicos Opioides/química , Analgésicos Opioides/uso terapêutico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Agonismo de Drogas , Antagonismo de Drogas , Células HEK293 , Humanos , Camundongos , Pentazocina/química , Pentazocina/uso terapêutico , Receptores Adrenérgicos/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Tapentadol/química , Tapentadol/uso terapêutico , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/uso terapêutico
2.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445277

RESUMO

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino , Antagonismo de Drogas , Inibidores de Histona Desacetilases/farmacologia , Modelos Biológicos , Naftalenos , Pirimidinonas , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Feminino , Humanos , Células MCF-7 , Naftalenos/antagonistas & inibidores , Naftalenos/farmacologia , Pirimidinonas/antagonistas & inibidores , Pirimidinonas/farmacologia
3.
Am J Physiol Gastrointest Liver Physiol ; 321(4): G367-G377, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34261364

RESUMO

Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. So, this study aimed to investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid-state catheter. Data were analyzed from three series of bolus swallows, baseline, during study medication exposure, and 15 min after methylnaltrexone. Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.NEW & NOTEWORTHY In this randomized controlled trial, we used the "Swallow Gateway" online platform to analyze the effects of remifentanil on pharyngeal and esophageal swallowing. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. By using methylnaltrexone, we demonstrated that effects of remifentanil on pharyngeal swallowing were predominantly centrally mediated, whereas its effects on the distal esophagus may be mediated by both central and peripheral mechanisms.


Assuntos
Analgésicos Opioides/farmacologia , Deglutição , Esôfago/efeitos dos fármacos , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Faringe/efeitos dos fármacos , Remifentanil/farmacologia , Adulto , Analgésicos Opioides/administração & dosagem , Antagonismo de Drogas , Esôfago/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Masculino , Contração Muscular , Relaxamento Muscular , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Faringe/fisiologia , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/farmacologia , Remifentanil/administração & dosagem
4.
PLoS One ; 16(6): e0251731, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34181666

RESUMO

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.


Assuntos
Hidroxicloroquina/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Receptor de Morte Celular Programada 1/imunologia , Animais , Azitromicina/farmacologia , Linhagem Celular Tumoral , Antagonismo de Drogas , Inibidores de Checkpoint Imunológico/imunologia , Melanoma/patologia , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
5.
BMC Cancer ; 21(1): 356, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823841

RESUMO

BACKGROUND: Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain. METHODS: We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using a neutral cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software. RESULTS: Four of the ten chemotherapy drugs - tamoxifen, doxorubicin, methotrexate and rapamycin - exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Two drug pairs, lovastatin combined with tamoxifen or cisplatin, were also assayed in human cell lines as proof of principle. CONCLUSIONS: The synergistic interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin - because they suggest the possibility of clinical utility - merit further exploration and validation in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to any chemotherapeutic regimen. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.


Assuntos
Anticolesterolemiantes/uso terapêutico , Antagonismo de Drogas , Sinergismo Farmacológico , Lovastatina/uso terapêutico , Saccharomyces cerevisiae/efeitos dos fármacos , Anticolesterolemiantes/farmacologia , Humanos , Lovastatina/farmacologia , Preparações Farmacêuticas
6.
J Antibiot (Tokyo) ; 74(6): 370-380, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33580212

RESUMO

The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to national healthcare systems. Most pressing is an immediate need for the development of novel antibacterial agents to treat Gram-negative multi-drug resistant infections, including the opportunistic, hospital-derived pathogen, Acinetobacter baumannii. Herein we report a naturally occurring 1,2-benzisoxazole with minimum inhibitory concentrations as low as 6.25 µg ml-1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a new chemotype for antibacterial agents against A. baumannii and is easily accessed in two steps via de novo synthesis. In vitro testing of structural analogs suggest that the natural compound may already be optimized for activity against this pathogen. Our results demonstrate that supplementation of 4-hydroxybenzoate in minimal media was able to reverse 1,2-benzisoxazole's antibacterial effects in A. baumannii. A search of metabolic pathways involving 4-hydroxybenzoate coupled with molecular modeling studies implicates two enzymes, chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyltransferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Bradyrhizobium/metabolismo , Antagonismo de Drogas , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxo-Ácido-Liases/antagonistas & inibidores , Oxo-Ácido-Liases/química , Oxo-Ácido-Liases/metabolismo , Parabenos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos
7.
Sci Rep ; 11(1): 177, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420288

RESUMO

Infections caused by Staphylococcus aureus are a serious global threat, and with the emergence of antibiotic resistance, even more difficult to treat. One of the possible complications in antistaphylococcal therapy represents negative interactions of antibiotics with food. In this study, the in vitro interaction between oxacillin and crude palm seed oil from Astrocaryum vulgare, Cocos nucifera, and Elaeis guineensis against nine strains of S. aureus was determined using the checkerboard method. Lauric acid was identified as a major constituent of all tested oils by gas chromatography. The results showed strong concentration dependent antagonistic interactions between palm oils and oxacillin with values of fractional inhibitory concentrations indices ranging from 4.02 to 8.56 at concentrations equal or higher than 1024 µg/mL of the tested oils. Similarly, lauric acid in combination with oxacillin produced antagonistic action with fractional inhibitory concentration indices ranging from 4.01 to 4.28 at 1024 µg/mL. These findings suggest that interference between oxacillin and palm oils and their constituents can negatively affect the treatment of staphylococcal infections in humans and other animals.


Assuntos
Antibacterianos/farmacologia , Ácidos Láuricos/farmacologia , Oxacilina/antagonistas & inibidores , Oxacilina/farmacologia , Petróleo/análise , Staphylococcus aureus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Testes de Sensibilidade Microbiana , Oxacilina/análogos & derivados
8.
Food Chem Toxicol ; 147: 111918, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33301842

RESUMO

Methylmercury (MeHg) is a neurotoxic pollutant widely present in the environment. Initial symptoms of MeHg may include loss of body weight. However, the mechanisms by which MeHg induces body weight changes have yet to be fully elucidated. Body weight is regulated by multiple mechanisms. Whereas multiple peripheral peptides lead to food intake cessation, ghrelin is the only recognized peripheral hormone that stimulates food intake. It exerts its action on Neuropeptide Y/Agouti-related peptide neurons in the hypothalamus. To test if MeHg affects ghrelin signaling C57BL/6J mice (males and females) were exposed to 5 ppm MeHg via drinking water during a month. On days 15 and 30 of MeHg exposure ghrelin was administered intraperitoneally and changes in body weight and food intake were recorded. In addition, changes in ghrelin-induced signaling pathways in hypothalamus were also analyzed. Here, we show that in males, MeHg enhanced ghrelin-induced body weight gain by activating the AMP-activated Kinase (AMPK)/Uncoupled protein 2 (UCP2) signaling pathway. In contrast, in females, MeHg inhibited ghrelin-induced mTOR signaling activation and decreased Npy mRNA expression, thus mitigating the ghrelin-induced weight gain. Combined, our novel results demonstrate, for the first time, that MeHg disrupts the physiological functions of ghrelin differently in males and females.


Assuntos
Grelina/farmacologia , Grelina/farmacocinética , Compostos de Metilmercúrio/farmacocinética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Esquema de Medicação , Antagonismo de Drogas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Compostos de Metilmercúrio/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Ganho de Peso
9.
Molecules ; 25(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182506

RESUMO

Ovarian cancer is the leading cause of death from gynecologic malignancies. Some estrogens, as well as xenoestrogens, such as chromium (VI) (Cr(VI)), are indicated as important pathogenic agents. The objective of this study was to evaluate the role of estradiol and some its metabolites upon exposure to the metalloestrogen Cr(VI) in an in vitro model. The changes in cell viability of malignant ovarian cancer cells (SKOV-3 resistant to cisplatin) exposed to 17ß-estradiol (E2) and its two metabolites, 2-methoxyestradiol (2-MeOE2) and 16α-hydroxyestrone (16α-OHE1), upon exposure to potassium chromate (VI) and its interactions were examined. The single and mixed models of action, during short and long times of incubation with estrogens, were applied. The different effects (synergism and antagonism) of estrogens on cell viability in the presence of Cr(VI) was observed. E2 and 16α-OHE1 caused a synergistic effect after exposure to Cr(VI). 2-MeOE2 showed an antagonistic effect on Cr(VI). The examined estrogens could be ranked according to the most protective effect or least toxicity in the order: 2-MeOE2 > E2 > 16α-OHE1. Early pre-incubation (24 h or 7 days) of cells with estrogens caused mostly an antagonistic effect-protective against the toxic action of Cr(VI). The beneficial action of estrogens on the toxic effect of Cr(VI), in the context of the risk of ovarian cancer, seems to be important and further studies are needed.


Assuntos
2-Metoxiestradiol/farmacologia , Cromatos/farmacologia , Cromo/farmacologia , Estradiol/farmacologia , Hidroxiestronas/farmacologia , Neoplasias Ovarianas/patologia , Compostos de Potássio/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Antagonismo de Drogas , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico
10.
PLoS Genet ; 16(11): e1009198, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33137124

RESUMO

The level of antibiotic resistance exhibited by bacteria can vary as a function of environmental conditions. Here, we report that phenazine-methosulfate (PMS), a redox-cycling compound (RCC) enhances resistance to fluoroquinolone (FQ) norfloxacin. Genetic analysis showed that E. coli adapts to PMS stress by making Fe-S clusters with the SUF machinery instead of the ISC one. Based upon phenotypic analysis of soxR, acrA, and micF mutants, we showed that PMS antagonizes fluoroquinolone toxicity by SoxR-mediated up-regulation of the AcrAB drug efflux pump. Subsequently, we showed that despite the fact that SoxR could receive its cluster from either ISC or SUF, only SUF is able to sustain efficient SoxR maturation under exposure to prolonged PMS period or high PMS concentrations. This study furthers the idea that Fe-S cluster homeostasis acts as a sensor of environmental conditions, and because its broad influence on cell metabolism, modifies the antibiotic resistance profile of E. coli.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/genética , Escherichia coli/fisiologia , Proteínas Ferro-Enxofre/metabolismo , Fatores de Transcrição/metabolismo , Antibacterianos/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Antagonismo de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Metilfenazônio Metossulfato/farmacologia , Testes de Sensibilidade Microbiana , Norfloxacino/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética
11.
Oncol Rep ; 44(6): 2581-2594, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33125153

RESUMO

Pancreatic cancer is one of the most aggressive, heterogeneous and fatal type of human cancers for which more effective therapeutic agents are urgently needed. Here, we investigated the sensitivity of a panel of seven human pancreatic cancer cell lines (HPCCLs) to treatment with various tyrosine kinase inhibitors (TKIs), cyclin­dependent kinase (CDK) inhibitors, an inhibitor of STAT3 stattic, and a cytotoxic agent gemcitabine both as single agents and in combination. The membranous expression of various receptors and the effect of selected agents on cell cycle distribution, cell signaling pathways and migration was determined using flow cytometry, western blot analysis and scratch wound healing assays, respectively. While the expression of both HER­3 and HER­4 was low or negative, the expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC50 values of ≤10 nM, followed by SRC targeting TKI dasatinib (IC50 of ≤258 nM), gemcitabine (IC50 of ≤330 nM), stattic (IC50 of ≤2 µM) and the irreversible pan­HER TKI afatinib (IC50 of ≤2.95 µM). Treatment with afatinib and dasatinib inhibited the ligand­induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were found between HER2 expression and response to treatment with the ALK/IGF­IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF­IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), and c­MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan­HER TKI afatinib and SRC targeting TKI dasatinib were most effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/metabolismo , Antagonismo de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento/metabolismo , Projetos de Pesquisa
12.
Ecotoxicol Environ Saf ; 205: 111334, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961486

RESUMO

In order to investigate and model toxicity and interactions between metals in mixtures, inhibition of wheat root elongation in response to additions of single-metals of copper (Cu), zinc (Zn), and nickel (Ni) and of binary mixed-metal combinations of Cu-Ni and Zn-Ni was tested, using water culture experiments under different Mg concentrations and pH values. A biotic ligand model (BLM) of single-metal Cu, Zn, and Ni was established. The results showed that the toxicity of Cu, Zn or Ni in isolation decreased with increasing Mg concentration whereas the effects of pH on Cu, Zn, or Ni toxicity were related not only to free Cu2+, Zn2+, and Ni2+ concentrations, but also to inorganic metal complexes. In binary mixtures, the two metals in the Cu-Ni mixture showed a weakly antagonistic effect, whereas the two metals in the Zn-Ni mixture showed greater antagonism. Using data from single-metal Cu, Zn, and Ni BLMs, combined with the toxicity index and the overall amounts of metal ions bound to the biotic ligands, one simple model was developed. This model consisted of the toxic unit (TUM, no competition included) and two extended BLMs, BLM-TUf (f as a function of TU, including competition between Mg2+ and metal ions) and BLM-fmix (including the competition between Mg2+ and metal ions, as well as between free metal ions). They were then used to predict the joint toxicity of Cu-Ni and Zn-Ni binary mixtures to wheat. Both of the extended BLMs could provide more accurate predictions of toxic effects of Cu-Ni and Zn-Ni than TUM. BLM-fmix performed best for the Zn-Ni binary mixture (r2 = 0.93; root-mean-square error, RMSE = 9.87). On the other hand, for the Cu-Ni mixture, the predictive effect based on BLM-TUf (r2 = 0.93; RMSE = 9.60) was similar to that of BLM-fmix (r2 = 0.93; RMSE = 9.56). The results provide a theoretical basis for the evaluation and remediation of soils contaminated with mixtures of heavy metals.


Assuntos
Cobre/toxicidade , Modelos Biológicos , Níquel/toxicidade , Poluentes do Solo/toxicidade , Triticum/efeitos dos fármacos , Zinco/toxicidade , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Ligantes , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Triticum/crescimento & desenvolvimento
13.
Ecotoxicol Environ Saf ; 205: 111300, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961492

RESUMO

Bacterial resistance caused by the abuse of antibiotics has attracted worldwide attention. However, there are few studies exploring bacterial resistance under the environmental exposure condition of antibiotics that is featured by low-dose and mixture. In this study, sulfonamides (SAs), sulfonamide potentiators (SAPs) and tetracyclines (TCs) were used to determine the effects of antibiotics on plasmid RP4 conjugative transfer of Escherichia coli (E. coli) under single or combined exposure, and the relationship between the effects of antibiotics on conjugative transfer and growth was investigated. The results show that the effects of single or binary antibiotics on plasmid RP4 conjugative transfer all exhibit a hormetic phenomenon. The linear regression reveals that the concentrations of the three antibiotics promoting conjugative transfer are correlated with the concentrations promoting growth and the physicochemical properties of the compounds. The combined effects of SAs-SAPs and SAs-TCs on plasmid conjugative transfer are mainly synergistic and antagonistic. While SAPs provide more effective concentrations for the promotion of conjugative transfer in SAs-SAPs mixtures, SAs play a more important role in promoting conjugative transfer in SAs-TCs mixtures. Mechanism explanation shows that SAs, SAPs and TCs inhibit bacterial growth by acting on their target proteins DHPS, DHFR and 30S ribosomal subunit, respectively. This study indicates that toxic stress stimulates the occurrence of conjugative transfer and promotes the development of bacterial resistance, which will provide a reference for resistance risk assessment of antibiotic exposure.


Assuntos
Antibacterianos/toxicidade , Conjugação Genética/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Escherichia coli/efeitos dos fármacos , Hormese , Plasmídeos , Antagonismo de Drogas , Sinergismo Farmacológico , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Plasmídeos/efeitos dos fármacos , Plasmídeos/genética , Sulfonamidas/toxicidade , Tetraciclinas/toxicidade
14.
mBio ; 11(4)2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753497

RESUMO

The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a few studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real-time microtiter plate readout with a matrix-like heat map of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of extraintestinal pathogenic Escherichia coli (ExPEC) with antibiotic levels blanketing the MIC across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, two different related phages that differed in their burst sizes produced drastically different synograms. Collectively, these data suggest lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria while also synergizing with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.IMPORTANCE Bacteriophage (phage) therapy is a promising approach to combat the rise of multidrug-resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bacteriófagos/fisiologia , Escherichia coli/efeitos dos fármacos , Antagonismo de Drogas , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Terapia por Fagos
15.
Antiviral Res ; 181: 104878, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32679055

RESUMO

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 µM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pandemias , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Berberina/farmacologia , COVID-19 , Chlorocebus aethiops , Cloroquina/farmacologia , Infecções por Coronavirus/virologia , Ciclosporina/farmacologia , Antagonismo de Drogas , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , Lopinavir/farmacologia , Pneumonia Viral/virologia , SARS-CoV-2 , Células Vero
16.
Nat Commun ; 11(1): 3350, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620767

RESUMO

Odor landscapes contain complex blends of molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we find widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions are stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a common feature of odor mixture encoding in OSNs and helps in normalizing activity to reduce saturation and increase information transfer.


Assuntos
Misturas Complexas/farmacologia , Odorantes , Percepção Olfatória/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Olfato/fisiologia , Animais , Antagonismo de Drogas , Feminino , Ligantes , Masculino , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Bulbo Olfatório/citologia , Bulbo Olfatório/diagnóstico por imagem , Bulbo Olfatório/fisiologia , Mucosa Olfatória/citologia , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/metabolismo , Percepção Olfatória/efeitos dos fármacos , Neurônios Receptores Olfatórios/efeitos dos fármacos , Terminações Pré-Sinápticas/fisiologia , Receptores Odorantes/metabolismo , Respiração , Olfato/efeitos dos fármacos
17.
Int J Biol Macromol ; 163: 232-239, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32561283

RESUMO

5-Fluorouracil (5-Fu) is an effective anticarcinogenic agent, however, continuous use of 5-Fu may cause severe side effects. The goal of this study was to investigate the effectiveness of Sarcodon aspratus polysaccharides (SATP) in alleviating 5-Fu-induced toxicity in Lewis tumor-bearing mice. Lewis tumor-bearing mice were treated with saline, SATP, 5-Fu or 5-Fu + SATP. The results indicated that compared to the 5-Fu group, the 5-Fu + SATP group showed effective amelioration of the liver, kidney and small intestine injury caused by 5-Fu and decreases in the levels of related biochemical indicators, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea nitrogen (BUN). Additionally, the combination therapy enhanced the quality of life and immune organ indexes of mice. Further mechanistic studies indicated that the 5-Fu + SATP group showed a decrease in hepatotoxicity caused by 5-Fu via a reduction in the levels of interleukin-1ß (IL-1ß), an increase in the expression of Bcl-2 and decreases in the expression of p-p38, p-JNK and Bax. Collectively, the results indicated that SATP could significantly alleviate the toxicity of 5-Fu in Lewis tumor-bearing mice and showed the hepatoprotective capability of SATP via its effect on the expression levels of inflammatory factors and components of the MAPK/P38/JNK pathway, which shows that it may be a potential adjuvant for the chemotherapeutic drug 5-Fu in cancer treatment.


Assuntos
Basidiomycota/química , Fluoruracila/farmacologia , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Animais , Carcinoma Pulmonar de Lewis , Linhagem Celular Tumoral , Modelos Animais de Doenças , Antagonismo de Drogas , Imuno-Histoquímica , Interleucina-1beta/sangue , Masculino , Camundongos , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Anesthesiology ; 133(3): 583-594, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32541553

RESUMO

BACKGROUND: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1ß3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist. METHODS: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1ß3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1ß3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model. RESULTS: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold. CONCLUSIONS: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist.


Assuntos
Diazepam/farmacologia , Etomidato/antagonistas & inibidores , Hipnóticos e Sedativos/farmacologia , Receptores de GABA/efeitos dos fármacos , Animais , Antagonismo de Drogas , Hipnóticos e Sedativos/antagonistas & inibidores , Modelos Animais , Peixe-Zebra
19.
Biol Pharm Bull ; 43(5): 774-781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378556

RESUMO

The role of morphine, an opioid analgesic drug, in cancer biology has increasingly garnered attention due to its frequent usage in postoperative period for pain management in cancer patients. In this work, we demonstrated that morphine, at clinically relevant concentrations, stimulated migration and growth, and alleviated chemo drugs' efficacy in esophageal carcinoma cells. Although morphine did not affect survival, it protected esophageal carcinoma cells from chemo drugs-induced apoptosis. Mechanistical studies showed that morphine increased RhoA but not Rac1 activity. In addition, morphine activated AMP-activated protein kinase (AMPK) pathway, induced epithelial-mesenchymal transition (EMT) via upregulating Snail and Slug levels, and increased oxidative stress in esophageal carcinoma cells. Rescue studies further demonstrated that the stimulatory effects of morphine in esophageal carcinoma cells are through activation of AMPK pathway but not RhoA or opioid receptor. In addition, morphine induced EMT in an AMPK-dependent manner whereas increased RhoA activity in an AMPK-independent manner. Our work demonstrates the protective role of morphine on esophageal carcinoma cells via AMPK activation, which may provide a new guide in clinical use of morphine for patients with esophageal carcinoma.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Analgésicos Opioides/farmacologia , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Morfina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino , Antagonismo de Drogas , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Fluoruracila/farmacologia , Humanos , Paclitaxel/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
20.
Elife ; 92020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32367801

RESUMO

Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap2 method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with Cryptococcus neoformans meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.


Assuntos
Antifúngicos/uso terapêutico , Antagonismo de Drogas , Sinergismo Farmacológico , Micoses/tratamento farmacológico , Animais , Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Ensaios de Triagem em Larga Escala , Humanos , Meningite Criptocócica/tratamento farmacológico , Camundongos , Relação Estrutura-Atividade
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