Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 67.997
Filtrar
1.
Ecotoxicol Environ Saf ; 203: 111013, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888588

RESUMO

Multiple pesticides originating from plant protection treatments and the treatment of pests infecting honey bees are frequently detected in beehive matrices. Therefore, winter honey bees, which have a long life span, could be exposed to these pesticides for longer periods than summer honey bees. In this study, winter honey bees were exposed through food to the insecticide imidacloprid, the fungicide difenoconazole and the herbicide glyphosate, alone or in binary and ternary mixtures, at environmental concentrations (0 (controls), 0.1, 1 and 10 µg/L) for 20 days. The survival of the honey bees was significantly reduced after exposure to these 3 pesticides individually and in combination. Overall, the combinations had a higher impact than the pesticides alone with a maximum mortality of 52.9% after 20 days of exposure to the insecticide-fungicide binary mixture at 1 µg/L. The analyses of the surviving bees showed that these different pesticide combinations had a systemic global impact on the physiological state of the honey bees, as revealed by the modulation of head, midgut and abdomen glutathione-S-transferase, head acetylcholinesterase, abdomen glucose-6-phosphate dehydrogenase and midgut alkaline phosphatase, which are involved in the detoxification of xenobiotics, the nervous system, defenses against oxidative stress, metabolism and immunity, respectively. These results demonstrate the importance of studying the effects of chemical cocktails based on low realistic exposure levels and developing long-term tests to reveal possible lethal and adverse sublethal interactions in honey bees and other insect pollinators.


Assuntos
Abelhas/fisiologia , Fungicidas Industriais/toxicidade , Herbicidas/toxicidade , Inseticidas/toxicidade , Praguicidas/toxicidade , Animais , Dioxolanos/toxicidade , Sinergismo Farmacológico , Glicina/análogos & derivados , Glicina/toxicidade , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Polinização/efeitos dos fármacos , Triazóis/toxicidade
2.
Nat Commun ; 11(1): 4522, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908144

RESUMO

A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Parede Celular/efeitos dos fármacos , Parede Celular/genética , Parede Celular/metabolismo , Infecção Hospitalar/microbiologia , Análise Mutacional de DNA , Elementos de DNA Transponíveis/genética , DNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Mutação
3.
Anticancer Res ; 40(9): 5141-5149, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878802

RESUMO

BACKGROUND/AIM: This study investigated the effects of temozolomide (TMZ) and/or checkpoint kinase inhibitor AZD7762 in human glioma cells. MATERIALS AND METHODS: Glioma cells were treated with TMZ and/or AZD7762 for 24 or 48 h, then the cellular survival was studied and the expression of various proteins was investigated. RESULTS: Both TMZ and AZD7762 induced concentration- and time-dependent cytotoxic effects, and combined TMZ and AZD7762 (TMZ+AZD) caused synergistic cytotoxic effects in glioma cells (p<0.05). AZD7762 suppressed the O6-methylguanine-DNA-methyltransferase (MGMT) expression. TMZ+AZD increased the expression of phospho-p53 (p-p53), p-p38 mitogen-activated protein kinase, and phosphatase and tensin homolog; and decreased the expression of p-extracellular signal-regulated kinase 1/2 and p-signal transducer and activator of transcription 3 in glioma cells. CONCLUSION: TMZ and AZD7762 combined induced synergistic cytotoxic effects on human glioma cells and such effects may be related to the AZD7762-induced suppression of MGMT expression and the modulation of multiple signaling pathways.


Assuntos
Antineoplásicos/farmacologia , Temozolomida/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/metabolismo , Humanos , Ureia/farmacologia
4.
Anticancer Res ; 40(9): 5159-5170, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878804

RESUMO

BACKGROUND/AIM: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP). MATERIALS AND METHODS: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests. RESULTS: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters - up-regulation of SLCO1B1 and retention of SN38 in the cells. CONCLUSION: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oxirredução , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Imunofluorescência , Glutationa/metabolismo , Humanos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo
5.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
6.
Anticancer Res ; 40(9): 4913-4919, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878779

RESUMO

BACKGROUND/AIM: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. MATERIALS AND METHODS: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. RESULTS: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 µM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). CONCLUSION: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Quinase 1 de Adesão Focal/metabolismo , Imidazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Estrutura Molecular , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Fosforilação/efeitos dos fármacos , Tiadiazóis/síntese química , Tiadiazóis/química , Células Tumorais Cultivadas
7.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878780

RESUMO

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Camundongos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Fenotiazinas/síntese química , Fenotiazinas/química
8.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Antimicrob Agents ; 56(2): 106020, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32862840

RESUMO

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.


Assuntos
Azitromicina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Gangliosídeo G(M1)/metabolismo , Hidroxicloroquina/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/metabolismo , Ligação Viral/efeitos dos fármacos , Sequência de Aminoácidos , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Sítios de Ligação/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos/efeitos dos fármacos , Alinhamento de Sequência
10.
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
11.
PLoS Biol ; 18(9): e3000856, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941420

RESUMO

Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens. Combination treatment strategies are typically used under the assumption that synergies are conserved across species and strains, even though recent results show that the combined treatment effect is determined by specific drug-strain interactions that can vary extensively and unpredictably, both between and within bacterial species. To address this problem, we present a new method in which antibiotic synergy is rapidly quantified on a case-by-case basis, allowing for improved combination therapy. The novel CombiANT methodology consists of a 3D-printed agar plate insert that produces defined diffusion landscapes of 3 antibiotics, permitting synergy quantification between all 3 antibiotic pairs with a single test. Automated image analysis yields fractional inhibitory concentration indices (FICis) with high accuracy and precision. A technical validation with 3 major pathogens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, showed equivalent performance to checkerboard methodology, with the advantage of strongly reduced assay complexity and costs for CombiANT. A synergy screening of 10 antibiotic combinations for 12 E. coli urinary tract infection (UTI) clinical isolates illustrates the need for refined combination treatment strategies. For example, combinations of trimethoprim (TMP) + nitrofurantoin (NIT) and TMP + mecillinam (MEC) showed synergy, but only for certain individual isolates, whereas MEC + NIT combinations showed antagonistic interactions across all tested strains. These data suggest that the CombiANT methodology could allow personalized clinical synergy testing and large-scale screening. We anticipate that CombiANT will greatly facilitate clinical and basic research of antibiotic synergy.


Assuntos
Antibacterianos/administração & dosagem , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana/métodos , Algoritmos , Andinocilina/administração & dosagem , Andinocilina/farmacologia , Antibacterianos/farmacologia , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Testes de Sensibilidade Microbiana/instrumentação , Nitrofurantoína/administração & dosagem , Nitrofurantoína/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Reprodutibilidade dos Testes , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Trimetoprima/administração & dosagem , Trimetoprima/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia
12.
PLoS One ; 15(8): e0232917, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810161

RESUMO

In human lung cancer progression, the EMT process is characterized by the transformation of cancer cells into invasive forms that migrate to other organs. Targeting to EMT-related molecules is emerging as a novel therapeutic approach for the prevention of lung cancer cell migration and invasion. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as an anti-proliferative target molecule to regulate the Wnt signaling pathway in several types of cancer cells. In the present study, we evaluated the inhibitory effect of a tyrosine kinase inhibitor sunitinib and the integrin-αⅤß3 targeted cyclic peptide (cRGDfK) on EMT in human lung cancer cells. Sunitinib strongly inhibited the TGF-ß1-activated EMT through suppression of Wnt signaling, Smad and non-Smad signaling pathways. In addition, the cRGDfK also inhibited the expression of TGFß1-induced mesenchymal marker genes and proteins. The anti-EMT effect of sunitinib was enhanced when cRGDfK was treated together. When sunitinib was treated with cRGDfK, the mRNA and protein expression levels of mesenchymal markers were decreased compared to the treatment with sunitinib alone. Co-treatment of cRGDfK has shown the potential to improve the efficacy of anticancer agents in combination with therapeutic agents that may be toxic at high concentrations. These results provide new and improved therapies for treating and preventing EMT-related disorders, such as lung fibrosis and cancer metastasis, and relapse.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Sunitinibe/administração & dosagem , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Células A549 , Trifosfato de Adenosina/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Smad/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
13.
Medicine (Baltimore) ; 99(34): e21894, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846852

RESUMO

BACKGROUND: At present, metformin is mainly used in the treatment of type 2 diabetes mellitus (T2DM). When the therapeutic effect is achieved, there are side effects and secondary failure will occur if taken for a long time. It is of great significance to actively explore the clinical scheme of reducing drug use while ensuring the therapeutic effect of T2DM. OBJECTIVE: To evaluate the feasibility of Chinese massage (CM) in the treatment of T2DM. METHODS: Literature retrieval is divided into 2 aspects: Electronic Retrieval and Personal Check. We will search PubMed, EMBASE, CNKI, Cochrane Central, which were registered in international clinical trials registry platform systems, select all eligible studies published before November 2, 2019, and use Personal Check method to retrieve papers, conference papers, ongoing experiments, internal reports, and so on. With fasting blood glucose, 2-hour fasting blood glucose, glycosylated hemoglobin, and insulin index as the main observation indexes, we also pay attention to traditional Chinese medicine syndrome score scale, insulin resisting index, body mass index , serum total cholesterol, Curative effect and the occurrence of all adverse reactions in drug treatment.Of the research group 2 researchers respective selected literature, extracted data, and evaluated the risk of bias. After that we used Revman 5.7 and Stata 12.1 statistical software for meta-analysis. RESULTS: A total of 769 subjects were included in 10 studies for meta-analysis. Compared with metformin hydrochloride tablets, CM plus baseline treatment can reduce fasting plasma glucose (weighted mean difference [WMD] = -0.33, 95% confidence interval [CI] [-0.54, -0.13], Z = 3.15, P = .002), 2 hours postprandial blood glucose (WMD = -0.52, 95% CI [-0.70, -0.34), Z = 5.66, P < .00001], hemoglobin A1c (WMD = 0.12, 95% CI [0.04, 0.20], Z = 2.94, P = .003), fasting insulin (WMD = -3.59, 95% CI [-5.56, -1.42], Z = 10.29,P < .00001), traditional Chinese medicine syndrome score scale (WMD = -4.55, 95% CI [-7.58, -1.51], Z = 2.94, P = .003),homeostasis model assessment of insulin resistance (WMD = -1.76, 95% CI [-2.25, -1.27), Z = 7.08, P < .00001),body mass index (WMD = -1.28, 95% CI [-1.65, -0.92], Z = 6.91, P < .00001), serum total cholesterol (WMD = -1.01, 95% CI [-1.14, -0.83], Z = 15.51, P < .00001), meanwhile, the effective rate was increased (risk ratio [RR] = 1.31, 95% CI [1.21, 1.42], Z = 6.57, P < .00001). CONCLUSION: CM combined with metformin hydrochloride tablet has a synergistic effect. It can not only be used as an auxiliary treatment of T2DM, but also as an important reference way of reducing drug treatment of T2DM, improving Clinical Efficacy and reducing adverse reactions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020158839.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Hipoglicemiantes/uso terapêutico , Massagem/métodos , Metformina/uso terapêutico , Adulto , Idoso , Glicemia/análise , Estudos de Casos e Controles , China/epidemiologia , Terapia Combinada/métodos , Sinergismo Farmacológico , Jejum/sangue , Estudos de Viabilidade , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/sangue , Resistência à Insulina , Massagem/tendências , Metformina/efeitos adversos , Pessoa de Meia-Idade
14.
PLoS Biol ; 18(8): e3000805, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810152

RESUMO

Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.


Assuntos
Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Colistina/farmacologia , Furanos/farmacologia , Gálio/farmacologia , Meropeném/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Biossíntese de Proteínas/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum/efeitos dos fármacos , Virulência
16.
Int J Nanomedicine ; 15: 4739-4752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753862

RESUMO

Purpose: Combined chemotherapeutic drug and protein drug has been a widely employed strategy for tumor treatment. To realize both tumor accumulation and deep tumor penetration for drugs with different pharmacokinetics, we propose a structure-transformable, thermo-pH dual responsive co-delivery system to co-load granzyme B/docetaxel (GrB/DTX). Methods: Thermo-sensitive hydrogels based on diblock copolymers (mPEG-b-PELG) were synthesized through ring opening polymerization. GrB/DTX mini micelles (GDM) was developed by co-loading these two drugs in pH-sensitive mini micelles, and the GDM-incorporated thermo-sensitive hydrogel (GDMH) was constructed. The thermo-induced gelation behavior of diblock copolymers and the physiochemical properties of GDMH were characterized. GDMH degradation and deep tumor penetration of released mini micelles were confirmed. The pH-sensitive disassembly and lysosomal escape abilities of released mini micelles were evaluated. In vitro cytotoxicity was studied using MTT assays and the in vivo antitumor efficacy study was evaluated in B16-bearing C57BL/6 mice. Results: GDMH was gelatinized at body temperature and can be degraded by proteinase to release mini micelles. The mini micelles incorporated in GDMH can achieve deep tumor penetration and escape from lysosomes to release GrB and DTX. MTT results showed that maximum synergistic antitumor efficacy of GrB and DTX was observed at mass ratio of 1:100. Our in vivo antitumor efficacy study showed that GDMH inhibited tumor growth in the subcutaneous tumor model and in the post-surgical recurrence model. Conclusion: The smart-designed transformable GDMH can facilitate tumor accumulation, deep tumor penetration, and rapid drug release to achieve synergistic chemo-protein therapy.


Assuntos
Antineoplásicos/uso terapêutico , Hidrogéis/química , Neoplasias/tratamento farmacológico , Temperatura , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Docetaxel/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Granzimas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Injeções , Camundongos Endogâmicos C57BL , Micelas , Neoplasias/patologia , Polietilenoglicóis/química
17.
Ecotoxicol Environ Saf ; 205: 111163, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32836159

RESUMO

Arthrobacter sp. JQ-1 can completely degrade 500 mg/L of DEHP within 3 days. The minimum inhibitory concentrations (MICs) of Cu2+ could reach 1.56 mM, however, 5.0 mg/L Cu2+ apparently inhibited DEHP degradation and bacterial growth. Consequently, JQ-1 was exposed to the DEHP-copper environment to verify the toxicity mechanism based on the physiological responses of cellular multiple interfaces (cellular surface, membrane and intracellular characteristics). The results showed the combination of 500 mg/L DEHP and 5.0 mg/L Cu2+ significantly decreased cell surface hydrophobicity (CSH) and the absolute value of zeta potential, which implied the bioavailability of DEHP was decreased. The cellular surface changes were mainly due to the interaction between Cu2+ and some functional groups (CH2, CH3, aromatic rings, and amide). The weakened proton-motive force (PMF) across the plasma membrane may interfere the formation and utilization of energy, which is not conducive to the repair process of cellular damages. In this study, Non-invasive micro-test technology (NMT) was applied to the research of combined toxicity of DEHP and heavy metal ions for the first time. DEHP-copper intensified K+ efflux and Ca2+ influx across the plasma membrane, which disturbed ion homeostasis of K+ and Ca2+ and might induce apoptosis and further inhibit DEHP degradation. The decline of intracellular esterase activity indicated that the metabolic capacity is apparently restrained. This study enhances our understanding of cellular different interface processes responding to combined pollutants.


Assuntos
Arthrobacter/efeitos dos fármacos , Cobre/toxicidade , Dietilexilftalato/toxicidade , Poluentes do Solo/toxicidade , Arthrobacter/metabolismo , Arthrobacter/ultraestrutura , Biodegradação Ambiental , Cálcio/metabolismo , Cobre/metabolismo , Dietilexilftalato/metabolismo , Sinergismo Farmacológico , Potássio/metabolismo , Solo/química , Microbiologia do Solo , Poluentes do Solo/metabolismo
18.
Life Sci ; 258: 118155, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735887

RESUMO

AIMS: Aim of the present study was to investigate the effect of co-administration coenzyme Q10 and pioglitazone on the mRNA expression of adipocytokines in white adipose tissues of chemically induced type 2 diabetes mellitus in rats. MAIN METHODS: Diabetes was induced by administration of streptozotocin (65 mg/kg, i.p.), followed by nicotinamide (110 mg/kg, i.p.) 15 min later. The diabetic rats were treated coenzyme Q10 (Q10, 10 mg/kg, p.o.) or pioglitazone (PIO, 20 mg/kg, p.o.) alone and their combination for four weeks. Biochemical parameters like FBS level, insulin and HbA1c along with tissue levels of MDA, SOD, CAT and GSH were estimated. The mRNA levels of ADIPOQ, RBP4, RETN, IL-6 and TNF-α in White Adipose Tissue (WAT) were measured. KEY FINDINGS: Treatment with Q10 + PIO showed a significant reduction in the levels of FBS, HbA1c and a significant increase in insulin levels as compared to normal control group. Additionally, there was a significant change in the levels of biomarkers of oxidative stress after treatment with Q10 + PIO as compared to streptozotocin-nicotinamide group. Treatment with Q10 + PIO also significantly altered the mRNA expression of ADIPOQ, RETN, IL-6 and TNF-α when compared to monotherapy. However, mRNA expression of RBP4 did not alter in Q10 + PIO treated animal as compared to Q10 or PIO alone. SIGNIFICANCE: It is concluded that co-administration of Q10 and PIO has been shown the better therapeutic effect on the mRNA expression of adipocytokines and oxidative stress parameters as compared to either Q10 or PIO.


Assuntos
Adipocinas/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Masculino , Pioglitazona/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Vitaminas/farmacologia
19.
Nat Commun ; 11(1): 3888, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753666

RESUMO

First proposed as antimicrobial agents, histones were later recognized for their role in condensing chromosomes. Histone antimicrobial activity has been reported in innate immune responses. However, how histones kill bacteria has remained elusive. The co-localization of histones with antimicrobial peptides (AMPs) in immune cells suggests that histones may be part of a larger antimicrobial mechanism in vivo. Here we report that histone H2A enters E. coli and S. aureus through membrane pores formed by the AMPs LL-37 and magainin-2. H2A enhances AMP-induced pores, depolarizes the bacterial membrane potential, and impairs membrane recovery. Inside the cytoplasm, H2A reorganizes bacterial chromosomal DNA and inhibits global transcription. Whereas bacteria recover from the pore-forming effects of LL-37, the concomitant effects of H2A and LL-37 are irrecoverable. Their combination constitutes a positive feedback loop that exponentially amplifies their antimicrobial activities, causing antimicrobial synergy. More generally, treatment with H2A and the pore-forming antibiotic polymyxin B completely eradicates bacterial growth.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Estruturas Cromossômicas/efeitos dos fármacos , Histonas/metabolismo , Prótons , Animais , Estruturas Cromossômicas/metabolismo , Cromossomos Bacterianos/metabolismo , DNA Bacteriano/metabolismo , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Imunidade Inata , Mamíferos , Polimixina B/farmacologia , Análise de Sequência de RNA , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo
20.
PLoS One ; 15(8): e0238195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845920

RESUMO

Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (-FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 µg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR- or PDR- A. baumannii.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Clorpromazina/farmacologia , Diclofenaco/farmacologia , Fluoroquinolonas/farmacologia , Propranolol/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Ciprofloxacino/farmacologia , Infecção Hospitalar/microbiologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Egito , Humanos , Levofloxacino/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA