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2.
Environ Monit Assess ; 192(4): 253, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32222945

RESUMO

This study describes the development of a sensitive and accurate dispersive liquid-liquid microextraction strategy for the preconcentration and determination of selected pesticides in wastewater and lake water samples by gas chromatography-mass spectrometry. Determination of these pesticides at high accuracy and precision is important because they can be still be found in environmental samples. The type of extraction solvent and type of disperser solvent were optimized using the univariate approach. Furthermore, a Box-Behnken experimental design was used to set up a working model made up of 18 combinations of three variables, tested at three levels. The parameters fitted into the design model were volume of extraction solvent, disperser solvent volume, and mixing period. Analysis of variance was used to evaluate the experimental data to determine the significance of extraction variables and their interactions, before selecting optimum extraction conditions. The method was then applied to aqueous standard solutions between 2.0 and 500 µg L-1, and the limit of detection (LOD) and quantification (LOQ) values obtained for the analytes were between 0.37-2.8 and 1.2-9.4 µg L-1, respectively. The percent recoveries were calculated in the range of 92-114 and 96-110% for wastewater and lake water, respectively. These results validated the accuracy and applicability of the method to the selected matrices.


Assuntos
Monitoramento Ambiental , Microextração em Fase Líquida , Praguicidas/análise , Poluentes Químicos da Água , Clorpirifos , Endossulfano , Cromatografia Gasosa-Espectrometria de Massas , Lagos/química , Fenilcarbamatos , Tiadiazóis/análise , Águas Residuárias/química
3.
Nat Commun ; 11(1): 498, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980651

RESUMO

Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.


Assuntos
Glutamina/metabolismo , Sarcoma/metabolismo , Sarcoma/patologia , Aloenxertos/efeitos dos fármacos , Aloenxertos/metabolismo , Animais , Benzenoacetamidas/farmacologia , Benzenoacetamidas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glutaminase/antagonistas & inibidores , Glutaminase/genética , Glutaminase/metabolismo , Camundongos , Nucleosídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Tomografia Computadorizada por Raios X
4.
Chem Commun (Camb) ; 56(7): 1093-1096, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894764

RESUMO

We prepared novel conjugated polymer based NIR-II nanoparticles, which display extremely high photothermal conversion efficiency (65%). Both in vitro and in vivo investigations revealed that the as-prepared nanoparticles exhibit excellent theranostic properties including an extremely high cancer cell killing ability, admirable tumor elimination efficiency (100%) and a remarkable photoacoustic imaging contrast enhancing ability.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Compostos de Organossilício/uso terapêutico , Polímeros/uso terapêutico , Tiadiazóis/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Células Hep G2 , Humanos , Hipertermia Induzida/métodos , Raios Infravermelhos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Compostos de Organossilício/química , Compostos de Organossilício/efeitos da radiação , Técnicas Fotoacústicas/métodos , Polímeros/química , Polímeros/efeitos da radiação , Nanomedicina Teranóstica/métodos , Tiadiazóis/química , Tiadiazóis/efeitos da radiação
5.
Eur J Med Chem ; 188: 112022, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901744

RESUMO

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 µg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 µg/mL vs. 1-64 µg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.


Assuntos
Antibacterianos/farmacologia , Quinolonas/farmacologia , Tiadiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , DNA Girase/metabolismo , Desenho de Fármacos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Feminino , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/toxicidade , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/toxicidade
6.
BMC Plant Biol ; 20(1): 31, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959097

RESUMO

BACKGROUND: Daylilies are a lucrative crop used for its floral beauty, medicinal proprieties, landscaping, fire prevention, nutritional value, and research. Despite the importance, daylilies remain extremely challenging for multiplying in vitro. The response difficulty is exacerbated because a few good protocols for daylilies micropropagation are generally difficult to reproduce across genotypes. An efficient strategy, currently applied at Langston University, is to systematically explore individual tissues or organs for their potential to micropropagation. This article is a partial report of the investigation carried out under room environmental conditions and focuses on developing an efficient daylilies in vitro propagation protocol that uses the stem tissue as the principal explant. RESULTS: In less than three months, using thidiazuron, the use of the stem tissue as the in vitro experimental explant was successful in inducing multiple shoots several folds greater than current daylilies shoot organogenesis protocols. The study showed that tissue culture can be conducted successfully under unrestricted room environmental conditions as well as under the controlled environment of a growth chamber. It also showed that splitting lengthwise stem explants formed multiple shoots several folds greater than cross-sectioned and inverted explants. Shoot conversion rate was mostly independent of the number of shoots formed per explants. The overall response was explant and genotype-dependent. Efficient responses were observed in all thidiazuron treatments. CONCLUSION: An efficient protocol, which can be applied for mass multiple shoots formation using the daylilies stem tissue as the main explant, was successfully developed. This could lead to a broad and rapid propagation of the crop under an array of environmental conditions to meet the market demand and hasten exogenous gene transfer and breeding selection processes.


Assuntos
Hemerocallis/fisiologia , Compostos de Fenilureia/farmacologia , Reguladores de Crescimento de Planta/farmacologia , Brotos de Planta/fisiologia , Regeneração , Tiadiazóis/farmacologia , Técnicas de Cultura de Tecidos
7.
Eur J Med Chem ; 186: 111897, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761382

RESUMO

Diosgenin, a naturally occurring steroidal saponin, has been confirmed to possess potent anticancer properties. In the current work, two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (6a-6e and 7a-7e) or 1,3,4-thiadiazole (8a-8e and 9a-9e) moieties were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, A549, MCF-7 and HCT-116) and normal human gastric epithelial cells (GES-1) using the MTT assay in vitro. The results showed that compounds 8d and 9d exhibited significant cytotoxic activities against the HepG2 and A549 cells, being more potent than their parent compound diosgenin. Furthermore, the 1,3,4-thiadiazole series of compounds generally exhibited stronger cytotoxicity compared with the 1,3,4-oxadiazole series against HepG2 and A549 cells, and the substitution of 3-pyridyl group at the C5 position of the 1,3,4-thiadiazole ring was the preferred option for these compounds to display significant cytotoxic activities. Compound 8d showed potent cytotoxic activity against A549 cell line (IC50 = 3.93 µM) and was 6.7-fold more potent than diosgenin (IC50 = 26.41 µM). Moreover, compound 8d displayed low toxicity against GES-1 cells (IC50 = 420.4 µM), showing specificity between normal and tumor cells. Further cellular mechanism studies in A549 cells indicated that compound 8d triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential, which was associated with up-regulation of Bax, down-regulation of Bcl-2 and activation levels of the caspase cascade. The above results indicated that compound 8d may be used as a promising skeleton for antitumor agents with improved efficacy.


Assuntos
Antineoplásicos/farmacologia , Diosgenina/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diosgenina/síntese química , Diosgenina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-Atividade , Tiadiazóis/química
8.
Expert Opin Investig Drugs ; 29(1): 5-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31815551

RESUMO

Introduction: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect in vitro, however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).Areas covered: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.Expert opinion: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.


Assuntos
Antimitóticos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Tiadiazóis/administração & dosagem , Animais , Antimitóticos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Desenvolvimento de Medicamentos , Humanos , Cinesina/antagonistas & inibidores , Mieloma Múltiplo/patologia , Tiadiazóis/farmacologia
9.
Food Chem ; 308: 125663, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31655474

RESUMO

Apple exocarp was used to investigate the effect of acibenzolar-S-methyl (ASM) and dehydroepiandrosterone (DHEA) treatments on reaction oxygen species (ROS) metabolism. The results indicated that ASM enhanced the hydrogen peroxide (H2O2) content, the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PDH). ASM also increased the contents of ascorbic acid (AsA), reduced glutathione (GSH) and nicotinamide ademine dinucleotidephosphate (NADPH), MdSOD and MdAPX expression, but decreased MdMDHAR and dehydroascorbate reductase (MdDHAR) expression. DHEA suppressed H2O2 accumulation and POD, APX, MDHAR, G6PDH activities, but increased SOD, CAT and GR activities compared to the control. ASM and DHEA treatments suppressed the contents of AsA, GSH and NADPH, and expression of MdSOD, MdAPX and MdMDHAR. These results suggest that DHEA treatment prevented ROS metabolism induced by ASM which showed the important role of G6PDH in maintaining redox homeostasis in apple exocarp.


Assuntos
Glucosefosfato Desidrogenase/metabolismo , Malus/enzimologia , Espécies Reativas de Oxigênio/metabolismo , Ascorbato Peroxidases/metabolismo , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Peróxido de Hidrogênio/metabolismo , NADH NADPH Oxirredutases/metabolismo , Oxirredução , Oxirredutases/metabolismo , Superóxido Dismutase/metabolismo , Tiadiazóis/metabolismo
10.
Food Chem ; 302: 125288, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419774

RESUMO

The effects of benzothiadiazole (BTH) on Penicillium expansum development, mitochondria energy metabolism, and changes in the number and structure of mitochondria in apple fruit were investigated after the fruit were immersed in 100 mg L-1 BTH for 10 min and then stored at 22 °C. The results indicated that BTH treatment significantly decreased the lesion diameter of fruit challenged with P. expansum; further, treatment enhanced the activities of mitochondrial respiratory metabolism-related enzymes, such as succinate dehydrogenase, cytochrome oxidase, H+-ATPase and Ca2+-ATPase, along with high ATP level and energy status in apple fruit during storage. Moreover, transmission electron microscopy results indicated that BTH treatment was beneficial for maintaining the number and structure of mitochondria during storage. The results suggested that BTH treatment enhanced ATP levels via mitochondrial energy metabolism, which might contribute to the induced resistance in apple fruit during storage.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Armazenamento de Alimentos , Frutas/metabolismo , Malus/efeitos dos fármacos , Malus/metabolismo , Mitocôndrias/efeitos dos fármacos , Tiadiazóis/farmacologia , Frutas/microbiologia , Malus/microbiologia , Mitocôndrias/metabolismo , Penicillium/fisiologia
11.
Food Chem ; 309: 125608, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31678673

RESUMO

Benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH) can improve wound healing of potato tubers; however, how the chemical regulates reactive oxygen species (ROS) generation and scavenging during wound healing is not completely understood. BTH at 100 mg·L-1 regulated changes in ROS generation and scavenging in healing tissues of potato tubers. A higher H2O2 content was presented in healing tissues of potato tubers, while cell membrane permeability and malondialdehyde content declined due to BTH treatment. Additionally, the activities and transcript level of enzymes related with ROS generation, including NADPH oxidase, peroxidase and polyamine oxidase, as well as enzymes involved in ROS scavenging, such as superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, were significantly enhanced by BTH treatment. It is suggested that ROS metabolism might play a crucial role in wound healing of potato tubers mediated by BTH during postharvest.


Assuntos
Tubérculos/efeitos dos fármacos , Tubérculos/metabolismo , Solanum tuberosum/efeitos dos fármacos , Solanum tuberosum/metabolismo , Tiadiazóis/farmacologia , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Enzimas/genética , Enzimas/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Malondialdeído/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Eur J Med Chem ; 185: 111808, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683103

RESUMO

Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 µM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 µM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Tiadiazóis/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
13.
Chem Commun (Camb) ; 56(5): 707-710, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31850402

RESUMO

Visual detection of the methylglyoxal (MGO) level in the brain is critical for understanding its role in the onset and progression of AD. Herein, we disclosed a NIR fluorescent probe, DBTPP, for detecting MGO by utilizing a thiadiazole-fused o-phenylenediamine moiety as a MGO-specific sensing unit. DBTPP exhibits a series of distinct advantages, such as NIR emission, high selectivity and sensitivity, excellent acid-stability, and a huge off-on ratio. The probe could accurately monitor both exogenous and endogenous MGO variations in SH-SY5Y cells. Besides, it was able to image the endogenous MGO in a transgenic AD mouse model successfully, suggesting the great potential of MGO as a biomarker for early AD diagnosis.


Assuntos
Doença de Alzheimer/metabolismo , Corantes Fluorescentes/química , Fenilenodiaminas/química , Aldeído Pirúvico/análise , Tiadiazóis/química , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Fenilenodiaminas/síntese química , Presenilina-1/genética , Aldeído Pirúvico/metabolismo , Tiadiazóis/síntese química
14.
Org Biomol Chem ; 18(3): 495-499, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31850447

RESUMO

A robust lipophilic dye, based on the structures of the benzothiadiazole heterocycle, was shown to be a potent fluorescent stain for the selective imaging of lipid droplets (LDs) within both live and fixed human cells. Its small molecular framework, large Stokes shift, and vastly improved photostability over that of the current status quo, Nile Red, highlight its tremendous potential as a versatile chemical tool for facilitating LD imaging and research.


Assuntos
Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Tiadiazóis/química , Células HeLa , Humanos , Gotículas Lipídicas/química , Coloração e Rotulagem/métodos
15.
Anticancer Res ; 39(12): 6723-6730, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810937

RESUMO

BACKGROUND/AIM: Phosphoserine aminotransferase 1 (PSAT1) is an enzyme implicated in serine biosynthesis, and its overexpression has been linked to cancer cell proliferation. Therefore, targeting PSAT1 is considered to be an anticancer strategy. MATERIALS AND METHODS: The viability of non-small cell lung cancer (NSCLC) cells was measured by MTT assay. Protein and mRNA expression were determined by western blot and reverse transcription polymerase chain reaction, respectively. RESULTS: Glutamine-limiting conditions were generated through glutamine deprivation or CB-839 treatment, which induced PSAT1 expression in NSCLC cells. PSAT1 expression induced by glutamine-limiting conditions was regulated by activating transcription factor 4. Knock-down of PSAT1 enhanced the sensitivity of NSCLC cells to glutamine-limiting conditions. Interestingly, ionizing radiation induced PSAT1 expression, and knocking down PSAT1 increased cell sensitivity to ionizing radiation. CONCLUSION: Inhibiting PSAT1 might aid in the treatment of lung cancer, and PSAT1 may be a therapeutic target for lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Glutamina/metabolismo , Neoplasias Pulmonares/metabolismo , Transaminases/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Benzenoacetamidas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Introdução de Genes , Glutaminase/antagonistas & inibidores , Glutamina/antagonistas & inibidores , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , RNA Mensageiro/metabolismo , Tolerância a Radiação , Tiadiazóis/farmacologia , Transaminases/genética
16.
Int J Mol Sci ; 21(1)2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877772

RESUMO

Myotonic dystrophy type 1 (DM1) is a complex genetic disease affecting many tissues. DM1 is caused by an expansion of CTG repeats in the 3'-UTR of the DMPK gene. The mechanistic studies of DM1 suggested that DMPK mRNA, containing expanded CUG repeats, is a major therapeutic target in DM1. Therefore, the removal of the toxic RNA became a primary focus of the therapeutic development in DM1 during the last decade. However, a cure for this devastating disease has not been found. Whereas the degradation of toxic RNA remains a preferential approach for the reduction of DM1 pathology, other approaches targeting early toxic events downstream of the mutant RNA could be also considered. In this review, we discuss the beneficial role of the restoring of the RNA-binding protein, CUGBP1/CELF1, in the correction of DM1 pathology. It has been recently found that the normalization of CUGBP1 activity with the inhibitors of GSK3 has a positive effect on the reduction of skeletal muscle and CNS pathologies in DM1 mouse models. Surprisingly, the inhibitor of GSK3, tideglusib also reduced the toxic CUG-containing RNA. Thus, the development of the therapeutics, based on the correction of the GSK3ß-CUGBP1 pathway, is a promising option for this complex disease.


Assuntos
Proteínas CELF1/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Distrofia Miotônica/tratamento farmacológico , Miotonina Proteína Quinase/genética , Animais , Inibidores Enzimáticos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Miotonina Proteína Quinase/metabolismo , Transdução de Sinais , Tiadiazóis/uso terapêutico
17.
Bull Exp Biol Med ; 168(2): 247-249, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776948

RESUMO

Emopag, a new drug, preventively administered in doses of 10 and 30 mg/kg/day over 4 days produced a pronounced neuroprotective effect in the model of brain ischemia caused by gravitational overload and reduced animal mortality from 17 to 0%. The preparation more effectively corrected neurological deficit than the reference drugs Mexidol (in considerably larger doses of 30 and 90 mg/kg/day) and antihypoxic drug amtizol (30 mg/kg/day). Moreover, Emopag exhibited considerable antiamnestic activity comparable to that of Mexidol (in 3-fold higher doses); in a dose of 30 mg/kg/day Emopag was more effective than Mexidol and amtizol in the same dose. Thus, Emopag showed marked neuroprotective and antiamnestic effects in the model of gravitational overload in rats.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Amnésia/prevenção & controle , Animais , Isquemia Encefálica/mortalidade , Isquemia Encefálica/prevenção & controle , Modelos Animais de Doenças , Masculino , Picolinas/farmacologia , Piridinas/farmacologia , Ratos , Tiadiazóis/farmacologia
18.
Molecules ; 24(22)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718083

RESUMO

New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5a), 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5b)), (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6a), and 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6b)), were prepared and screened in vitro for their antimicrobial activity against various pathogenic microbes. In addition, two compounds (5a and 6a) were examined for their in vivo genotoxicity using rats and an 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay. Compounds 5a and 5b were found to be highly active against Gram-positive and Gram-negative bacteria. In addition, a significant inhibition of urinary 8-OHdG level (50.2%) was observed upon treatment of animals with 500 mg/kg body weight (b.w.) of compound 6a (p < 0.0001). However, compound 5a increased urinary 8-OHdG levels. The lethal dose (LD50) values for compounds 5a and 6a were determined by an up-and-down procedure (OECD 425; OECD 1998), which showed that these compounds are safe, since the LD50 was >5000 mg/kg b.w. Thus, the tested compounds might have the potential for use as antibiotics, since they have low genotoxicity and strong antimicrobial activity.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Mutagênicos/síntese química , Mutagênicos/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Anti-Infecciosos/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos , Dose Letal Mediana , Testes de Sensibilidade Microbiana , Mutagênicos/química , Tiadiazóis/química
19.
Int J Mol Sci ; 20(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690061

RESUMO

The below article presents the results of spectroscopic research, theoretical (time-dependent density functional theory (TD-DFT)), microbiological, and antioxidative calculations for three compounds from the group of 1,3,4-thiadiazoles: 2-amino-5-phenyl-1,3,4-thiadiazole (TB), 2-amino-5-(2-hydroxyphenyl)-1,3,4-thiadiazole (TS), 2-amino-5-(2-hydroxy-5-sulfobenzoyl)-1,3,4-thiadiazole (TSF). In the fluorescence emission spectra (TS) of solutions with varying concentrations of hydrogen ions, a particularly interesting effect of dual fluorescence was observed. The aforementioned effect was observed even more clearly in the environment of butan-1-ol, relative to the compound's concentration. Depending on the modification of the resorcylic substituent (TS and TSF), we observed the emergence of two separate, partially overlapping, fluorescence emission spectra or a single emission spectrum. Interpretation of the obtained spectra using stationary and time-resolved spectroscopy allowed the correlation of the effect's emergence with the phenomenon of molecular aggregation (of a particular type) as well as, above all, the structure of the substituent system. The overlap of said effects most likely induces the processes related to the phenomenon of charge transfer (in TS) and is responsible for the observed fluorescence effects. Also, the position of the -OH group (in the resorcylic ring) is significant and can facilitate the charge transfer (CT). The determinations of the changes in the dipole moment and TD-DFT calculations further corroborate the above assumption. The following paper presents the analysis (the first for this particular group of analogues) of the fluorescence effects relative to the changes in the structure of the resorcylic group combined with pH effects. The results of biological studies also indicate the highest pharmacological potential of the analogue in the case where the effects of dual fluorescence emission are observed, which predisposes this particular group of fluorophores as effective fluorescence probes or potential pharmaceuticals with antimycotic properties.


Assuntos
Antifúngicos/química , Tiadiazóis/química , Absorção de Radiação , Antifúngicos/farmacologia , Antifúngicos/efeitos da radiação , Candida/efeitos dos fármacos , Fluorescência , Tiadiazóis/farmacologia , Tiadiazóis/efeitos da radiação , Raios Ultravioleta
20.
Molecules ; 24(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690062

RESUMO

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , RNA Helicases DEAD-box/antagonistas & inibidores , Tiadiazóis/química , Antivirais/química , HIV-1/efeitos dos fármacos , Humanos , Replicação Viral/efeitos dos fármacos
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