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1.
Chem Commun (Camb) ; 56(11): 1661-1664, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31939463

RESUMO

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Compostos de Sulfônio/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Derivados de Benzeno/toxicidade , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Escherichia coli/efeitos dos fármacos , Humanos , Lipídeos/síntese química , Lipídeos/farmacologia , Lipídeos/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfônio/síntese química , Compostos de Sulfônio/toxicidade
2.
Chem Commun (Camb) ; 56(8): 1179-1182, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31868184

RESUMO

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Carboxílicos/farmacologia , Fulerenos/farmacologia , Água/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Fulerenos/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Solubilidade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-31521749

RESUMO

The aim of this study was to determine whether purinergic signaling is a pathway associated with fumonisin B1 (FB1)-induced impairment of immune and hemostatic responses. We also determined whether dietary supplementation with diphenyl diselenide (Ph2Se2) prevents or reduces these effects. Splenic nucleoside triphosphate diphosphohydrolase (NTPDase) activity for adenosine triphosphate (ATP) and adenosine diphosphate (ADP) as substrates and total blood thrombocytes counts were significant lower in silver catfish fed with FB1-contaminated diets than in fish fed with a basal diet, while splenic adenosine deaminase (ADA) activity and metabolites of nitric oxide (NOx) levels were significant higher. Also, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significant lower in silver catfish fed with FB1-contaminated diets than in fish fed with a basal diet. Dietary supplementation with 3 mg Ph2Se2/kg of feed effectively modulated splenic NTPDase (ATP as substrate), ADA, GPx and SOD activities, as well as NOx levels, and was partially effective in the modulation of spleen NTPDase activity (ADP as substrate) and total blood thrombocytes count. These data suggest that splenic purinergic signaling of silver catfish fed with FB1-contaminated diets generates a pro-inflammatory profile that contributes to impairment of immune and inflammatory responses, via reduction of splenic ATP hydrolysis followed possible ATP accumulation in the extracellular environment. Reduction of ADP hydrolysis associated with possible accumulation in the extracellular environment can be a pathophysiological response that restricts the hemorrhagic process elicited by FB1 intoxication. Supplementation with Ph2Se2 effectively modulated splenic enzymes associated with control of extracellular nucleotides (except ADP; that was partially modulated) and nucleosides, thereby limiting inflammatory and hemorrhagic processes.


Assuntos
Ração Animal/análise , Derivados de Benzeno/farmacologia , Peixes-Gato , Doenças dos Peixes/induzido quimicamente , Fumonisinas/toxicidade , Compostos Organosselênicos/farmacologia , Baço/efeitos dos fármacos , Animais , Plaquetas , Dieta/veterinária , Contaminação de Alimentos , Glutationa Peroxidase/metabolismo , Nitratos/sangue , Nitritos/sangue , Transdução de Sinais , Superóxido Dismutase/metabolismo
4.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
5.
EBioMedicine ; 47: 578-589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474553

RESUMO

BACKGROUND: Long term low-dose benzene exposure leads to the inhibition of haematopoiesis. However, the underlying mechanisms remained poorly defined, especially mediated by early effector molecules. METHODS: Here, we first found in mRNA microarray that pyroptotic classic genes (Casp1, 4, 5, and IL1ß) were up-regulated and represented dose-dependent differential expression in controls, low-dose benzene-exposed and chronic benzene-poisoned workers, and the expression of Casp1 and IL1ß were confirmed in low-dose benzene-exposed workers and was accompanied with elevated potent proinflammatory IL1ß. In vitro studies showed that benzene metabolites induced AHH-1 cell pyroptosis through activating Aim2/Casp1 pathway with the increased expression of GSDMD. Meanwhile, TET2 overexpression was elevated in vivo and in vitro and it was positively correlated with IL1ß. Further, we verified that pyroptosis caused by 1,4-BQ could be ameliorated in vitro by RNAi or pretreatment with Dimethyloxalylglycine (DMOG), the inhibitor of TET2. FINDINGS: Exposure to benzene can trigger pyroptosis via TET2 directly regulating the Aim2/Casp1 signaling pathway to cause haematotoxicity. INTERPRETATION: Benzene metabolites induced pyroptotic cell death through activation of the Aim2/Casp1 pathway which can be regulated by Tet2 overexpression. Tet2 may be a potential risk factor and is implicated in the development of benzene-related diseases. FUND: National Natural Science Foundation of China; the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan; Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education.


Assuntos
Derivados de Benzeno/farmacologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hematopoese/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Piroptose/efeitos dos fármacos , Transdução de Sinais , Biomarcadores , Morte Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Proteínas Proto-Oncogênicas/genética
6.
Chem Biodivers ; 16(12): e1900313, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31545879

RESUMO

Cissampelos sympodialis Eichler is well studied and investigated for its antiasthmatic properties, but there are no data in the literature describing antibacterial properties of alkaloids isolated from this botanical species. This work reports the isolation and characterization of phanostenine obtained from roots of C. sympodialis and describes for the first time its antimicrobial and antibiotic modulatory properties. Phanostenine was first isolated from Cissampelos sympodialis and its antibacterial activities were determined. Chemical structures of the alkaloid isolate were determined using spectroscopic and chemical analyses. Phanostenine was also tested for its antibacterial activity against standard strains and clinical isolates of Escherichia coli and Staphylococcus aureus. Minimal inhibitory concentration (MIC) was determined in a microdilution assay and for the evaluation of antibiotic resistance-modifying activity. MIC of the antibiotics was determined in the presence or absence of phanostenine at sub-inhibitory concentrations. The evaluation of antibacterial activity by microdilution assay showed activity for all strains with better values against S. aureus ATCC 12692 and E. coli 27 (787.69 mm). The evaluation of aminoglycoside antibiotic resistance-modifying activity showed reduction in the MIC of the aminoglycosides (amikacin, gentamicin and neomycin) when associated with phanostenine, MIC reduction of antibiotics ranging from 21 % to 80 %. The data demonstrated that phanostenine possesses a relevant ability to modify the antibiotic activity in vitro. We can suggest that phanostenine presents itself as a promising tool as an adjuvant for novel antibiotics formulations against bacterial resistance.


Assuntos
Alcaloides/química , Antibacterianos/química , Derivados de Benzeno/química , Cissampelos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Derivados de Benzeno/isolamento & purificação , Derivados de Benzeno/farmacologia , Cissampelos/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Staphylococcus aureus/efeitos dos fármacos
7.
Chem Commun (Camb) ; 55(69): 10214-10217, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380528

RESUMO

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.


Assuntos
Azóis/química , Azóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cisteína/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
8.
J Oleo Sci ; 68(9): 931-937, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31413242

RESUMO

The essential oil extracted from roots and rhizomes of Ligusticum jeholense Nakai et Kitagawa was investigated for its chemical composition by GC-MS analysis, and evaluated for its contact toxicity and repellency against Tribolium castaneum and Lasioderma serricorne, along with some of its individual components. The essential oil was rich in aromatics (65.34%) with low molecular weight. Major components included sedanolide (33.95%), 3-butylidenephthalide (18.76%), spathulenol (8.90%) and myristicin (6.76%). The results of bioassays indicated that the essential oil of L. jeholense and 3-butylidenephthalide possessed significant repellent activities against T. castaneum at 2 and 4 h post-exposure. Meanwhile, 3-butylidenephthalide had potent contact toxicity against L. serricorne (LD50 = 13.64 µg/adult). The minor component n-butylbenzene in the oil was highly toxic to T. castaneum (LD50 = 23.99 µg/adult) and L. serricorne (LD50 = 7.86 µg/adult) in contact assays, but failed to repel these beetles at all testing concentrations. Spathulenol and myristicin exerted good insecticidal and repellent effects on the two target insects. This work suggests that the essential oil of L. jeholense has promising potential for development as natural insecticide or repellent to control pest damage in warehouses.


Assuntos
Derivados de Benzeno/farmacologia , Repelentes de Insetos/farmacologia , Inseticidas/farmacologia , Óleos Voláteis/farmacologia , Anidridos Ftálicos/farmacologia , Tribolium/efeitos dos fármacos , Animais , Ligusticum/química , Óleos Voláteis/análise , Óleos Voláteis/toxicidade
9.
Eur J Med Chem ; 181: 111573, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394463

RESUMO

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: KIs, 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (KIs, 8.9-51.5 nM); they were almost equally potent to AAZ (KI, 12.0 nM) and had superior potency to SLC-0111 (KI, 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with KI values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with KI values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization.


Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Sulfonamidas/síntese química
10.
J Trace Elem Med Biol ; 55: 180-189, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345356

RESUMO

BACKGROUND: Gliomas are the most aggressive malignant tumors of the central nervous system. The diphenyl diselenide [(PhSe)2] is an organoselenium compound that has multiple pharmacological properties. Previous reports showed that (PhSe)2 nanoencapsulation potentiates its in vitro antitumoral action and reduces its toxicity. OBJECTIVE: In this sense, the current study was designed to further evaluate the (PhSe)2 antitumoral effect by a set of in vitro techniques using a glioma cell line as well as by an animal model of gliobastoma. METHODS: For the in vitro tests, the cell viability, propidium iodide uptake and nitrite levels of rat glioma C6 cells were determined after incubation with free (PhSe)2 or (PhSe)2-loaded nanocapsules (NC). The glioblastoma model was induced by implantation of C6 glioma cells in the right striatum of rats. Following, animals were submitted to a repeated intragastric administration treatment with (PhSe)2 or NC (PhSe)2 (1 mg/kg/day for 15 days) to assess the possible antitumor effect. MAIN FINDINGS: Both compound forms decreased the C6 glioma cells viability without causing any effect in astrocytes cells (healthy control). Importantly, the NC (PhSe)2 had superior cytotoxic effect than its free form and increased the nitrite content. Independent of the (PhSe)2 forms, the intragastric treatment reduced brain tumor size and caused neither alteration in the plasma renal and hepatic markers of function nor in the parameters of oxidative balance in brain, liver and kidneys. PRINCIPAL CONCLUSIONS: The (PhSe)2 nanoencapsulation improved its cytotoxic effect against C6 glioma cells and both compound forms attenuated the tumor development.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Nanocápsulas/química , Compostos Organosselênicos/farmacologia , Animais , Antineoplásicos/química , Astrócitos/efeitos dos fármacos , Derivados de Benzeno/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Masculino , Nitritos/análise , Compostos Organosselênicos/química , Ratos , Ratos Wistar
11.
Int J Oncol ; 55(2): 499-512, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268156

RESUMO

Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose­limiting toxicities in patients with multiple myeloma (MM). The present study investigated the interaction between the HDAC6 inhibitor, A452, and immunomodulatory drugs (IMiDs) on dexamethasone (Dex)­sensitive and ­resistant MM cells compared with the current clinically tested HDAC6 inhibitor, ACY­1215. It was shown that the combination of the HDAC6­selective inhibitor, A452, with either of the IMiDs tested (lenalidomide or pomalidomide) led to the synergistic inhibition of cell growth, a decrease in the viability of MM cells and in an increase in the levels of apoptosis. Furthermore, enhanced cell death was associated with the inactivation of AKT and extracellular signal­regulated kinase (ERK)1/2. Of note, A452 in combination with IMiDs induced synergistic MM cytotoxicity without altering the expression of cereblon and thereby, the synergistic downregulation of IKAROS family zinc finger (IKZF)1/3, c­Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD­L1. More importantly, this combination treatment was effective in the Dex­resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY­1215. Taken together, these findings suggest that a combination of the HDAC6­selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.


Assuntos
Sinergismo Farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fatores Imunológicos/farmacologia , Mieloma Múltiplo/patologia , Apoptose , Derivados de Benzeno/farmacologia , Proliferação de Células , Humanos , Lenalidomida/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Células Tumorais Cultivadas
12.
Cells ; 8(6)2019 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31181844

RESUMO

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation.


Assuntos
Antineoplásicos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/radioterapia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Raios gama , Engenharia Genética , Camundongos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia
13.
Cell Mol Life Sci ; 76(23): 4745-4768, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31129858

RESUMO

Peroxiredoxins are antioxidant enzymes that use redox active Cys residues to reduce H2O2 and various organic hydroperoxides to less reactive products, and thereby protect cells against oxidative stress. In yeasts and mammals, the Prx1 proteins are sensitive to hyperoxidation and consequent loss of their peroxidase activity whereas in most bacteria they are not. In this paper we report the characterization of the Prx1 family in the non-parasitic protist Tetrahymena thermophila. In this organism, four genes potentially encoding Prx1 have been identified. In particular, we show that the mitochondrial Prx1 protein (Prx1m) from T. thermophila is relatively robust to hyperoxidation. This is surprising given that T. thermophila is a eukaryote like yeasts and mammals. In addition, the proliferation of the T. thermophila cells was relatively robust to inhibition by H2O2, cumene hydroperoxide and plant natural products that are known to promote the production of H2O2. In the presence of these agents, the abundance of the T. thermophila Prx1m protein was shown to increase. This suggested that the Prx1m protein may be protecting the cells against oxidative stress. There was no evidence for any increase in Prx1m gene expression in the stressed cells. Thus, increasing protein stability rather than increasing gene expression may explain the increasing Prx1m protein abundance we observed.


Assuntos
Peroxirredoxinas/metabolismo , Proteínas de Protozoários/metabolismo , Tetrahymena thermophila/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Antioxidantes/metabolismo , Derivados de Benzeno/metabolismo , Derivados de Benzeno/farmacologia , Produtos Biológicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/classificação , Peroxirredoxinas/genética , Filogenia , Proteínas de Protozoários/classificação , Proteínas de Protozoários/genética , Alinhamento de Sequência , Tetrahymena thermophila/genética , Tetrahymena thermophila/crescimento & desenvolvimento
14.
Free Radic Res ; 53(7): 737-747, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31130017

RESUMO

Dermal exposure to cumene hydroperoxide (CumOOH) during manufacturing processes is a toxicological issue for the industry. Its genotoxicity, mutagenic action, ability to promote skin tumour, capacity to induce epidermal hyperplasia, and aptitude to induce allergic and irritant skin contact dermatitis are well known. These toxic effects appear to be mediated through the activation to free radical species such as hydroxyl, alkoxyl, and alkyl radicals characterised basically by electron paramagnetic resonance (EPR) and spin-trapping (ST) techniques. To be a skin sensitiser CumOOH needs to covalently bind to skin proteins in the epidermis to form the antigenic entity triggering the immunotoxic reaction. Cleavage of the O-O bond allows formation of unstable CumO•/CumOO• radicals rearranging to longer half-life specific carbon-centred radicals R• proposed to be at the origin of the antigen formation. Nevertheless, it is not still clear which R• is precisely formed in the epidermis and thus involved in the sensitisation process. The aim of this work was to elucidate in conditions closer to real-life sensitisation which specific R• are formed in a 3D reconstructed human epidermis (RHE) model by using 13C-substituted CumOOH at carbon positions precursors of potentially reactive radicals and EPR-ST. We demonstrated that most probably methyl radicals derived from ß-scission of CumO• radicals occur in RHE through a one-electron reductive pathway suggesting that these could be involved in the antigen formation inducing skin sensitisation. We also describe a coupling between nitroxide radicals and ß position 13C atoms that could be of an added value to the very few examples existing for the coupling of radicals with 13C atoms.


Assuntos
Derivados de Benzeno/uso terapêutico , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Epiderme/efeitos dos fármacos , Radicais Livres/química , Detecção de Spin/métodos , Derivados de Benzeno/farmacologia , Humanos
15.
Mol Med Rep ; 19(6): 5015-5022, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059088

RESUMO

Sweet taste receptors (STRs) expressed on ß­cells stimulate insulin secretion in response to an increase in the circulating level of glucose, maintaining glucose homeostasis. 3­Deoxyglucosone (3DG), a highly reactive α­dicarbonyl compound, has been previously described as an independent factor associate with the development of prediabetes. In our previous study, pathological plasma levels of 3DG were induced in normal rats with a single intravenous injection of 50 mg/kg 3DG, and an acute rise in circulating 3DG induced glucose intolerance by impairing the function of pancreatic ß­cells. The present study aimed to investigate whether the deleterious effects of pathological plasma levels of 3DG on ß­cell function and insulin secretion were associated with STRs. INS­1 cells, an in vitro model to study rat ß­cells, were treated with various concentrations of 3DG (1.85, 30.84 and 61.68 mM) or lactisole (5 mM). Pancreatic islets were collected from rats 2 h after a single intravenous injection of 50 mg/kg 3DG + 0.5 g/kg glucose. The insulin concentration was measured by ELISA. The protein expression levels of components of the STR signaling pathways were determined by western blot analysis. Treatment with 3DG and 25.5 mM glucose for 1 h significantly reduced insulin secretion by INS­1 cells, which was consistent with the phenotype observed in INS­1 cells treated with the STR inhibitor lactisole. Accordingly, islets isolated from rats treated with 3DG exhibited a significant reduction in insulin secretion following treatment with 25.5 mM glucose. Furthermore, acute exposure of INS­1 cells to 3DG following treatment with 25.5 mM glucose for 1 h significantly reduced the protein expression level of the STR subunit taste 1 receptor member 3 and its downstream factors, transient receptor potential cation channel subfamily M member 5 and glucose transporter 2. Notably, islet tissues collected from rats treated with 3DG exhibited a similar downregulation of these factors. The present results suggested that acute exposure to pathologically relevant levels of 3DG in presence of high physiological levels of glucose decreased insulin secretion from ß­cells by, at least in part, downregulating the STR signaling pathway.


Assuntos
Desoxiglucose/análogos & derivados , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Derivados de Benzeno/farmacologia , Células Cultivadas , Desoxiglucose/farmacologia , Regulação para Baixo/efeitos dos fármacos , Transportador de Glucose Tipo 2/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo
16.
J Enzyme Inhib Med Chem ; 34(1): 999-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072143

RESUMO

This study explored the possible bioactive ingredients and target protein of Rostellularia procumbens (L.) Nees. The results of optical turbidimetry revealed that the ethyl acetate extraction obtained from R. procumbens (L.) Nees could inhibit platelet aggregation. Gene chip was used to investigate differentially expressed genes. According to the results of the gene chip, the targets of compounds isolated from the ethyl acetate extraction were predicted by network pharmacology. Computational studies revealed that chinensinaphthol methyl ether and neojusticin B may target the integrin αIIbß3 protein. The results of Prometheus NT.48 and microscale thermophoresis suggested that the molecular interactions between the two compounds with purified integrin αIIbß3 protein in the optimal test conditions were coherent with the docking results. To our best knowledge, this is the first report to state that chinensinaphthol methyl ether and neojusticin B target the integrin αIIbß3 protein.


Assuntos
Acanthaceae/química , Derivados de Benzeno/farmacologia , Dioxolanos/farmacologia , Éteres/farmacologia , Lignanas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Dioxolanos/química , Dioxolanos/isolamento & purificação , Relação Dose-Resposta a Droga , Éteres/química , Éteres/isolamento & purificação , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Testes de Função Plaquetária , Relação Estrutura-Atividade
17.
Curr Top Med Chem ; 19(10): 847-860, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977451

RESUMO

BACKGROUND: Due to the limited availability of antibiotics, Gram-negative bacteria (GNB) acquire different levels of drug resistance. It raised an urgent need to identify such agents, which can reverse the phenomenon of drug resistance. OBJECTIVE: To understand the mechanism of drug resistance reversal of glycosides; niaziridin and niazirin isolated from the pods of Moringa oleifera and ouabain (control) against the clinical isolates of multidrug-resistant Escherichia coli. METHODS: The MICs were determined following the CLSI guidelines for broth micro-dilution. In-vitro combination studies were performed by broth checkerboard method followed by Time-Kill studies, the efflux pump inhibition assay, ATPase inhibitory activity, mutation prevention concentration and in-silico studies. RESULTS: The results showed that both glycosides did not possess antibacterial activity of their own, but in combination, they reduced the MIC of tetracycline up to 16 folds. Both were found to inhibit efflux pumps, but niaziridin was the best. In real time expression pattern analysis, niaziridin was also found responsible for the down expression of the two important efflux pump acrB & yojI genes alone as well as in combination. Niaziridin was also able to over express the porin forming genes (ompA & ompX). These glycosides decreased the mutation prevention concentration of tetracycline. CONCLUSION: This is the first ever report on glycosides, niazirin and niaziridin acting as drug resistance reversal agent through efflux pump inhibition and modulation of expression pattern drug resistant genes. This study may be helpful in preparing an effective antibacterial combination against the drug-resistant GNB from a widely growing Moringa oleifera.


Assuntos
Complexos de ATP Sintetase/antagonistas & inibidores , Acetonitrilos/farmacologia , Antibacterianos/farmacologia , Derivados de Benzeno/farmacologia , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Complexos de ATP Sintetase/metabolismo , Acetonitrilos/química , Acetonitrilos/isolamento & purificação , Antibacterianos/química , Antibacterianos/isolamento & purificação , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Moringa oleifera/química
18.
J Pharmacol Exp Ther ; 370(3): 864-875, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30996033

RESUMO

Castration-resistant prostate cancer that has become resistant to docetaxel (DTX) represents one of the greatest clinical challenges in the management of this malignancy. There is an urgent need to develop novel therapeutic agents to overcome chemoresistance and improve the overall survival of patients. We have designed a novel microtubule destabilizer (2-(4-hydroxy-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (QW-296) and combined it with a newly synthesized hedgehog (Hh) signaling pathway inhibitor 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4- bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) to treat taxane-resistant (TXR) prostate cancer. The combination of QW-296 and MDB5 exhibited stronger anticancer activity toward DU145-TXR and PC3-TXR cells and suppressed tumor colony formation when compared with single-drug treatment. Because these drugs are hydrophobic, we synthesized the mPEG-p(TMC-MBC) [methoxy-poly(ethylene glycol)-block-poly(trimethylene carbonate-co-2-methyl-2-benzoxycarbonyl-propylene carbonate)] copolymer, which could self-assemble into micelles with loading capacities of 8.13% ± 0.75% and 9.12% ± 0.69% for QW-296 and MDB5, respectively. Further, these micelles provided controlled the respective drug release of 58% and 42% release of QW-296 and MDB5 within 24 hours when dialyzed against PBS (pH 7.4). We established an orthotopic prostate tumor in nude mice using stably luciferase expressing PC3-TXR cells. There was maximum tumor growth inhibition in the group treated with the combination therapy of QW-296 and MDB5 in micelles compared with their monotherapies or combination therapy formulated in cosolvent. The overall findings suggest that combination therapy with QW-296 and MDB5 has great clinical potential to treat TXR prostate cancer, and copolymer mPEG-p(TMC-MBC) could serve as an effective delivery vehicle to boost therapeutic efficacy in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Microtúbulos/química , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Nus , Micelas , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Taxoides/uso terapêutico
19.
PLoS One ; 14(4): e0205626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31034521

RESUMO

2,2'-diselenyldibenzoic acid (DSBA) is a chemical probe produced to explore the pharmacological properties of diphenyldiselenide-derived agents with seleno-hormetic activity undergoing preclinical development. The present study was designed to verify in vivo the drug's properties and to determine mechanistically how these may mediate the protection of tissues against stress conditions, exemplified by ionizing radiation induced damage in mouse bone marrow. In murine bone marrow hematopoietic cells, the drug initiated the activation of the Nrf2 transcription factor resulting in enhanced expression of downstream stress response genes. This type of response was confirmed in human liver cells and included enhanced expression of glutathione S-transferases (GST), important in the metabolism and pharmacological function of seleno-compounds. In C57 BL/6 mice, DSBA prevented the suppression of bone marrow hematopoietic cells caused by ionizing radiation exposure. Such in vivo prevention effects were associated with Nrf2 pathway activation in both bone marrow cells and liver tissue. These findings demonstrated for the first time the pharmacological properties of DSBA in vivo, suggesting a practical application for this type of Se-hormetic molecules as a radioprotective and/or prevention agents in cancer treatments.


Assuntos
Derivados de Benzeno/farmacologia , Raios gama/efeitos adversos , Células-Tronco Hematopoéticas/metabolismo , Compostos Organosselênicos/farmacologia , Protetores contra Radiação/farmacologia , Animais , Derivados de Benzeno/química , Células-Tronco Hematopoéticas/patologia , Células Hep G2 , Humanos , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organosselênicos/química , Protetores contra Radiação/química
20.
Artigo em Inglês | MEDLINE | ID: mdl-31028929

RESUMO

This study aimed to evaluate whether dietary supplementation with diphenyl diselenide (Ph2Se2) would prevent the impaired immune and inflammatory responses elicited by methylmercury chloride (CH3HgCl) via protective effects on purinergic signaling in fish immune organs. Tissue and lymphocytic nucleoside triphosphate diphosphohydrolase (NTPDase) activity for adenosine triphosphate (ATP) and adenosine diphosphate (ADP) was downregulated in the head kidney and spleen of grass carp (Ctenopharyngodon idella) exposed to CH3HgCl. Concomitantly, adenosine deaminase (ADA) activity was upregulated. Further, nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome gene expression was upregulated in the spleen and head kidney of CH3HgCl-exposed grass carp. Dietary supplementation with Ph2Se2 ameliorated these CH3HgCl-mediated alterations on purinergic enzymes, and their activities returned to baseline levels (except NTPDase activity for ADP). Based on these results, purinergic signaling in immune organs and lymphocytes can be considered a pathway linked to pro-inflammatory effects during exposure to environmental CH3HgCl concentrations, which may contribute to mortality of the affected fish. Since dietary supplementation with 3 mg Ph2Se2/kg in the feed prevented the CH3HgCl-induced alterations, it can be considered a potential suitable treatment to prevent impaired immune and inflammatory responses caused by Hg.


Assuntos
Derivados de Benzeno/farmacologia , Carpas , Doenças dos Peixes/induzido quimicamente , Rim Cefálico/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Compostos Organosselênicos/farmacologia , Baço/efeitos dos fármacos , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais , Doenças dos Peixes/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
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