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1.
J Agric Food Chem ; 69(36): 10440-10449, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469128

RESUMO

The widespread application of neonicotinoid insecticides (NEOs) in agriculture causes a series of environmental and ecological problems. Microbial remediation is a popular approach to relieve these negative impacts, but the associated molecular mechanisms are rarely explored. Nitrile hydratase (NHase), an enzyme commonly used in industry for amide production, was discovered to be responsible for the degradation of acetamiprid (ACE) and thiacloprid (THI) by microbes. Since then, research into NHases in NEO degradation has attracted increasing attention. In this review, microbial degradation of ACE and THI is briefly described. We then focus on NHase evolution, gene composition, maturation mechanisms, expression, and biochemical properties with regard to application of NHases in NEO degradation for bioremediation.


Assuntos
Hidroliases , Nitrilas , Neonicotinoides , Tiazinas
2.
BMC Ophthalmol ; 21(1): 319, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470600

RESUMO

BACKGROUND: Long-term use of topical, especially benzalkonium chloride (BAC)-preserved, antiglaucoma medications can cause a negative impact on the ocular surface. The aim of the study was to assess the effect of topical carbonic anhydrase inhibitors (CAIs) on selected oxidative stress biomarkers in the tear film. METHODS: The patients were divided into four sex-matched groups: group C (n = 25) - control group - subjects who did not use topical antiglaucoma medications, group DL (n = 14) - patients using preservative-free dorzolamide, group DL + BAC (n = 16) - patients using topical BAC-preserved dorzolamide, group BL + BAC (n = 17) - patients using BAC-preserved brinzolamide. Subjects in all the study groups have been using the eye drops two times daily for 6-12 months. The oxidative stress biomarkers in the tear film samples were measured: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI). RESULTS: The advanced oxidation protein products content, Total Oxidant Status as well as superoxide dismutase and catalase activities in the group DL + BAC and BL + BAC were higher in comparison with the group C. The total sulfhydryl groups content was lower in the group DL + BAC and BL + BAC when compared to group C. Oxidative Stress Index was higher in the groups DL + BAC and BL + BAC in comparison with the groups DL and C. CONCLUSIONS: Use of topical benzalkonium chloride-preserved carbonic anhydrase inhibitors increases oxidative stress in the tear film.


Assuntos
Compostos de Benzalcônio , Inibidores da Anidrase Carbônica , Compostos de Benzalcônio/farmacologia , Biomarcadores , Humanos , Soluções Oftálmicas , Estresse Oxidativo , Sulfonamidas , Tiazinas , Tiofenos
3.
Water Res ; 203: 117493, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34365194

RESUMO

Developing strategies to identify the origins of contaminants in watersheds is crucial for source water protection. The use of multiple tracers improves the ability to identify contamination events originating from various land use activities. The objective of this study was to evaluate the use of acesulfame and chloride as co-tracers to represent the impact of pollution originating from wastewater and road de-icing on water quality in a municipal drinking water source. The study included a two-year sampling and water quality analysis program in numerous locations within a drinking water reservoir comprising a lake (upstream) and a river (downstream) which supply raw water to a municipal water treatment plant. Results showed that the spatial variability of acesulfame and chloride within the watershed of the lake-river systems depends on the location of contaminant sources, mainly municipal wastewater and septic tank discharges (for acesulfame) and the presence of small tributaries of the lake and river (for chloride). Temporal variability of the tracers under study differed according to the sampling location and was mainly affected by seasonal conditions. Correlation analyses between the two tracers in lake and river waters (in terms of concentrations and loads) made it possible to pinpoint the probable origins of contamination. The assessment of the spatio-temporal variability of these co-tracers within the lake-river watersheds allowed for the delineation of priority intervention zones as a decision-making tool for municipal authorities in improving drinking water source protection.


Assuntos
Água Potável , Poluentes Químicos da Água , Cloretos , Monitoramento Ambiental , Tiazinas , Águas Residuárias , Poluentes Químicos da Água/análise
4.
Environ Pollut ; 289: 117892, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34385134

RESUMO

Thiacloprid is a neonicotinoid insecticide widely exploited in agriculture and easily mobilized towards aquatic environments by atmospheric agents. However, little information about its toxicological effects on aquatic invertebrate bioindicators is available. In this study, specimens of the mussel Mytilus galloprovincialis were exposed to thiacloprid at environmental (4.5 µg L-1) and 100 times higher than environmental (450 µg L-1) concentrations for 20 days. Thiacloprid affected haemolymph biochemical parameters, cell viability in the digestive gland, antioxidant biomarkers and lipid peroxidation in the digestive gland and gills at environmentally relevant concentrations (4.5 µg L-1). In addition, thiacloprid exposure caused histological damage to the digestive gland and gills. Interestingly, the pesticide was detected at levels equal to 0.14 ng g-1 in the soft tissues of sentinels exposed for 20 days to 450 µg L-1 thiacloprid in seawaterµ. Due to its harmful potential and cumulative effects after long-term exposure of M. galloprovincialis, thiacloprid may pose a potential risk to nontarget aquatic organisms, as well as to human health. This aspect requires further in-depth investigation.


Assuntos
Mytilus , Tiazinas , Poluentes Químicos da Água , Animais , Biomarcadores , Brânquias , Humanos , Neonicotinoides/toxicidade , Tiazinas/toxicidade , Poluentes Químicos da Água/toxicidade
5.
Nat Commun ; 12(1): 4671, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344863

RESUMO

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Nitrobenzenos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Tiazinas/química , Tiazinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Vet Intern Med ; 35(5): 2196-2204, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34464464

RESUMO

BACKGROUND: Diagnosis of gastric ulcers by methods other than gastroscopy in dogs has been problematic for many years and biomarkers such as serum gastrin (SG) concentrations have been introduced as a noninvasive way to evaluate gastric diseases. OBJECTIVES: To determine the time course changes in hematology, SG concentrations, and gastroscopic images of meloxicam-induced gastric ulceration in dogs and identify a relationship between SG and gastroscopic image analysis in a clinical setting. ANIMALS: Fifteen crossbreed dogs. METHODS: Two groups: control (n = 5) and meloxicam-treated (n = 10). The meloxicam-treated group received meloxicam 0.2 mg/kg PO for 15 days. Clinical signs, hematology, SG, and image analysis (PI, pixel intensity; ID, integrated density; RA, relative area; and UI, ulcer index) of the gastroscopic examination were evaluated across time (T5, time 5 day; T10, time 10 day; and T15, time 15 day). RESULTS: Significant changes were observed among 3 time points and between the 2 groups in terms of SG, hematology, and gastroscopic image analysis. In the meloxicam-treated group, decreases in hemoglobin concentration, red blood cell count and packed cell volume at T10 and T15 (P = .0001) were observed, whereas SG, ID, and UI increased over time (P < .0001). The PI decreased significantly (P = .0001) in the meloxicam-treated group compared to controls. Significant correlations were found between SG and PI, and ID and ulcer area (r = -0.89, 0.81, 0.64), respectively. CONCLUSION AND CLINICAL IMPORTANCE: Gastroscopy is the gold standard for early descriptive diagnosis of gastric ulcerations in dogs, and SG is a good indicator for meloxicam-induced gastric ulcers in dogs and can predict the gastroscopic score of the lesion.


Assuntos
Doenças do Cão , Hematologia , Úlcera Gástrica , Tiazinas , Animais , Doenças do Cão/induzido quimicamente , Doenças do Cão/diagnóstico , Cães , Gastrinas , Gastroscopia/veterinária , Meloxicam , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/veterinária , Tiazinas/efeitos adversos , Tiazóis/efeitos adversos
7.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360585

RESUMO

New, tricyclic compounds containing a sulfonyl moiety in their structure, as potential safer COX inhibitors, were designed and synthesized. New derivatives have three conjugated rings and a sulfonyl group. A third ring, i.e., an oxazine, oxazepine or oxazocin, has been added to the 1,2-benzothiazine skeleton. Their anti-COX-1/COX-2 and cytotoxic effects in vitro on NHDF cells, together with the ability to interact with model membranes and the influence on reactive oxygen species and nitric oxide, were studied. Additionally, a molecular docking study was performed to understand the binding interaction of the compounds with the active site of cyclooxygenases. For the abovementioned biological evaluation of new tricyclic 1,2-benzothiazine derivatives, the following techniques and procedures were employed: the differential scanning calorimetry, the COX colorimetric inhibitor screening assay, the MTT, DCF-DA and Griess assays. All of the compounds studied demonstrated preferential inhibition of COX-2 compared to COX-1. Moreover, all the examined tricyclic 1,2-thiazine derivatives interacted with the phospholipid model membranes. Finally, they neither have cytotoxic potency, nor demonstrate significant influence on the level of reactive oxygen species or nitric oxide. Overall, the tricyclic 1,2-thiazine derivatives are good starting points for future pharmacological tests as a group of new anti-inflammatory agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Derme/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiazinas/química , Anti-Inflamatórios não Esteroides/química , Células Cultivadas , Inibidores de Ciclo-Oxigenase/química , Derme/citologia , Fibroblastos/citologia , Humanos , Simulação de Acoplamento Molecular , Prostaglandina-Endoperóxido Sintases/química
8.
Molecules ; 26(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34443360

RESUMO

Plasma proteins play a fundamental role in living organisms. They participate in the transport of endogenous and exogenous substances, especially drugs. 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts, have been synthesized as potential anticancer substances used for cancer treatment. Most anticancer substances generate a toxic effect on the human body. In order to check the toxicity and therapeutic dosage of these chemicals, the study of ligand binding to plasma proteins is very relevant. The present work presents the first comparative analysis of the binding of one of the 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium derivatives (Salt1) with human serum albumin (HSA), α-1-acid glycoprotein (AGP) and human gamma globulin (HGG), assessed using fluorescence, UV-Vis and CD spectroscopy. In order to mimic in vivo ligand-protein binding, control normal serum (CNS) was used. Based on the obtained data, the Salt1 binding sites in the tertiary structure of all plasma proteins and control normal serum were identified. Both the association constants (Ka) and the number of binding site classes (n) were calculated using the Klotz method. The strongest complex formed was Salt1-AGPcomplex (Ka = 7.35·104 and 7.86·104 mol·L-1 at excitation wavelengths λex of 275 and 295 nm, respectively). Lower values were obtained for Salt1-HSAcomplex (Ka = 2.45·104 and 2.71·104 mol·L-1) and Salt1-HGGcomplex (Ka = 1.41·104 and 1.33·104 mol·L-1) at excitation wavelengths λex of 275 and 295 nm, respectively, which is a positive phenomenon and contributes to the prolonged action of the drug. Salt1 probably binds to the HSA molecule in Sudlow sites I and II; for the remaining plasma proteins studied, only one binding site was observed. Moreover, using circular dichroism (CD), fluorescence and UV-Vis spectroscopy, no effect on the secondary and tertiary structures of proteins in the absence or presence of Salt1 has been demonstrated. Despite the fact that the conducted studies are basic, from the scientific point of view they are novel and encourage further in vitro and in vivo investigations. As a next part of the study (Part 2), the second new synthetized quinobenzothiazine derivative (Salt2) will be analyzed and published.


Assuntos
Proteínas Sanguíneas/metabolismo , Análise Espectral , Tiazinas/química , Tiazinas/metabolismo , Proteínas Sanguíneas/química , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Termodinâmica
9.
Environ Res ; 200: 111721, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34293312

RESUMO

The coloured dyes released from the textile industrial effluents into water resources cause non-aesthetic pollution and aquatic life toxicity. Thus textile waste water treatment has been studied globally for many years. Photocatalytic properties of lead tungstate (PbWO4) nanoparticles (NPs) were analyzed for thiazine dyes and textile waste water under ultraviolet light conditions. XRD result showed the tetragonal scheelite structure of PbWO4 NPs. The crystallinity of the sample was confirmed from the SAED and XRD pattern. The existence of stretch vibration of Pb-O and O-W-O confirmed from FTIR results. EDAX displays optical absorption signals of Pb, W and O, and confirm the formation of PbWO4. Optical studies reveal that the band gap of the obtained nanoparticles increases with respect to their bulk counterparts that may be attributed to reduction in particle size. TEM images of PbWO4 powder consists of hexagonal particles and relatively uniform and smooth surface rod shaped prism-like structures. The photocatalytic activity of the prepared nanoparticles was analyzed through the degradation of textile waste water under UV light irradiation. The photocatalytic reaction rate constant was found to be 0.014/min. The small sized PbWO4 particles can adsorb more OH groups and oxidatively degrade the pollutants in the textile waste water.


Assuntos
Nanopartículas , Tiazinas , Poluentes Químicos da Água , Catálise , Corantes , Têxteis , Águas Residuárias , Poluentes Químicos da Água/análise
10.
Water Res ; 202: 117454, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34332189

RESUMO

The artificial sweetener Acesulfame (ACE) has been frequently detected in wastewater treatment plants (WWTPs) and is regarded as an emerging pollutant due to its low biodegradability. However, recent observations of ACE biodegradation in WWTPs have stimulated interest in the ACE-degrading bacteria and mineralization pathways. In this study, next-generation sequencing methods, Illumina and Nanopore sequencing, were combined to explore the ACE-degrading communities enriched from the activated sludge of six municipal wastewater treatment plants. Metagenomic investigations indicated that all enrichments were similarly dominated by the phyla Proteobacteria and Planctomycetes. Notably, at the species level, four metagenome-assembled genomes (MAGs) were shared by six enriched communities with considerable abundances, indicating that they may be responsible for ACE biodegradation in the enrichments. Besides, two ACE-degrading pure strains, affiliated to the genus Chelatococcus, were isolated from the enrichment. The genomic analysis showed that these two isolates were the new species that were genetically distinct from their relatives. Two type strains, Chelatococcus asaccharovorans DSM 6462 and Chelatococcus composti DSM 101465, could not degrade ACE, implying that the ACE-degrading capability was not shared among the different species in the genus Chelatococcus. The results of the degradation experiment showed that the two isolates could use ACE as the sole carbon source and mineralize ~90% of the total organic carbon. Three biotransformation products (TP96, TP180B, and TP182B) were demonstrated by UPLC-QTOF-MS. The results of this study provide valuable insights into ACE biodegradation and its biotransformation products.


Assuntos
Genômica , Edulcorantes , Alphaproteobacteria , Biodegradação Ambiental , Cinética , Tiazinas
11.
Int Ophthalmol ; 41(9): 3191-3198, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34114138

RESUMO

PURPOSE: To evaluate the effect of topical prophylaxis with brinzolamide-brimonidine fixed combination on short-term intraocular pressure (IOP) elevation after intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF). METHODS: This prospective comparative study included 56 eyes of 47 patients treated with intravitreal injections of anti-VEGF, and they were randomly divided into two groups. In control group (25 eyes), no prophylactic medication was used, whereas in case group (31 eyes) one drop of a fixed combination of brinzolamide-brimonidine was instilled two hours before the injection. IOP was measured before the injection and at 1 min, 10 min and 30 min post-injection in all eyes. RESULTS: The mean IOP before injection at 1 min, 10 min and 30 min post-injection was 16,6 ± 2,8 mmHg, 53,4 ± 12 mmHg, 26,4 ± 5,5 mmHg and 17,9 ± 4 mmHg, respectively, in control group and 15,1 ± 3,4 mmHg, 42,6 ± 8,4 mmHg, 21,4 ± 5,5 mmHg and 12,4 ± 3,5 mmHg, respectively, in case group. At 1 min, 10 min and 30 min post-injection, the mean IOP was significantly lower in case group compared with control group (p < 0,001, p = 0,0014 and p < 0,0001, respectively), but no difference at the pre-injection IOP between the two groups was found (p = 0,09). CONCLUSIONS: The prophylactic administration of one drop of brinzolamide-brimonidine fixed combination significantly reduces the IOP spikes during the first 30 min after the intravitreal anti-VEGF injection.


Assuntos
Pressão Intraocular , Hipertensão Ocular , Tartarato de Brimonidina/uso terapêutico , Humanos , Injeções Intravítreas , Hipertensão Ocular/tratamento farmacológico , Estudos Prospectivos , Sulfonamidas , Tiazinas
12.
Molecules ; 26(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065194

RESUMO

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.


Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Acetamidas/química , Acetamidas/uso terapêutico , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazinas/síntese química
13.
J Am Vet Med Assoc ; 259(1): 84-87, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34125605

RESUMO

OBJECTIVE: To determine the pharmacokinetics of meloxicam in Wyandotte hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg [0.45 mg of meloxicam/lb]) and compare results with those previously published for White Leghorn hens. ANIMALS: 8 healthy adult Wyandotte hens. PROCEDURES: Hens were administered 1 mg of meloxicam/kg, PO, once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma and egg whites (albumen) and yolks were analyzed with high-performance liquid chromatography. RESULTS: Mean ± SD terminal half-life, maximum concentration, and time to maximum concentration were 5.53 ± 1.37 hours, 6.25 ± 1.53 µg/mL, and 3.25 ± 2.12 hours, respectively. Mean ± SD number of days meloxicam was detected in egg whites and yolks after drug administration was 4.25 ± 2 days and 9.0 ± 1.5 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with White Leghorn hens, meloxicam in Wyandotte hens had a longer terminal half-life, greater area under the plasma concentration-versus-time curve from time 0 to infinity, a smaller elimination rate constant, and a longer mean residence time-versus-time curve from time 0 to infinity, and drug persisted longer in their egg yolks. Therefore, the oral dosing interval of meloxicam may be greater for Wyandotte hens. Results may aid veterinarians on appropriate dosing of meloxicam to Wyandotte hens and inform regulatory agencies on appropriate withdrawal times.


Assuntos
Galinhas , Tiazinas , Administração Oral , Animais , Anti-Inflamatórios não Esteroides , Área Sob a Curva , Feminino , Meia-Vida , Meloxicam , Óvulo , Tiazóis
14.
Acta Chim Slov ; 68(1): 151-158, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057526

RESUMO

Phytoalexins are substances with antimicrobial properties produced by plants after being attacked by microorganisms, especially phytopathogenic fungi and viruses. They are also currently being studied for their antitumor effect. We aimed to study the apoptosis-stimulating effect of homobrassinin and thiazino[6,5-b]indol in human ovarian adenocarcinoma A2780 and A2780cis cells via flow cytometric analysis of annexin V/PI, caspase 3 and 9 activity, cytochrome C release, and smac-diablo accumulation. Using the western blot technique, we also monitored the effect of both indoles on the response of heat shock proteins in these cells. Thiazino[6,5-b]indol showed more pronounced sensitizing and/or pro-apoptotic effect compared to homobrassinin accompanied by increased smac-diablo accumulation at earlier time intervals and pronounced externalization of phosphatidylserine at 72 h in A2780cis compared to A2780 cells. The apoptosis stimulating effect of thiazino[6,5-b]indol in A2780cis cells was associated with significant irreversible downregulation of HSP70 and HSP90 and partly with a decrease of HSP40. On the other hand, cisplatin-induced the apoptosis of sensitive A2780 cells with reversible downregulation of HSP40 and HSP57. In conclusion, the effect of thiazino[6,5-b]indol on resistant A2780cis cells could have a great utility in both the potential prevention and the treatment of other cisplatin-resistant tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Indóis/farmacologia , Tiazinas/farmacologia , Tiocarbamatos/farmacologia , Anexina A5/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo
15.
Food Chem ; 359: 129936, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957328

RESUMO

In this work, new selective and sensitive dual-template molecularly imprinted polymer nanoparticles (MIPs) were synthesized and characterized. Sorbent MIPs were investigated for simultaneous extraction and clean-up of thiamethoxam and thiacloprid from light and dark honey samples. In this study, ultra-high-performance liquid chromatography-tandem mass spectrometry triple-quadrupole (UHPLC-MS/MS) (QQQ) was used to detect and quantify the pesticides. The kinetic model with adsorption kinetics of sorbent was investigated. The optimal adsorption conditions were 80 mg of polymer MIPs, a 30-min extraction time, and a pH of 7. The detection limit (LOD) and the quantification limit (LOQ) varied from 0.045 to 0.070 µg kg-1 and from 0.07 to 0.10 µg kg-1, respectively. The intra-day and inter-day precision (RSD, %) ranged from 1.3 to 2.0% and from 8.2 to 12.0%, respectively. The recovery of thiamethoxam and thiacloprid ranged from 96.8 to 106.5% and 95.3 to 104.4%, respectively, in light and dark honey samples.


Assuntos
Mel/análise , Fenômenos Magnéticos , Impressão Molecular/métodos , Nanopartículas/química , Neonicotinoides/isolamento & purificação , Praguicidas/isolamento & purificação , Polímeros/química , Tiametoxam/isolamento & purificação , Tiazinas/isolamento & purificação , Adsorção , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Magnetismo , Polímeros Molecularmente Impressos , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
16.
Eur J Med Chem ; 218: 113398, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33823392

RESUMO

A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016 µg/mL), and good safety index (CC50: >64 µg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazina/farmacologia , Tiazinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazina/química , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química
17.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918322

RESUMO

In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N-(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo-pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno-pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo-quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- triazolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- methylthieno[2,3-d]pyrimidin-4(3H)-one (3). The chemical structures were confirmed using many spectroscopic ways (IR, 1H, 13C, -NMR and MS) and elemental analyses. A series of thiazine, imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20, 19, 17, 16 and 11 showed significant cytotoxicity against types of human cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Pirimidinas/síntese química , Pirróis/química , Quinoxalinas/síntese química , Tiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia
18.
J Med Chem ; 64(8): 4677-4696, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844524

RESUMO

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aß levels in mice, rats, and dogs in acute and chronic treatment regimens.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/síntese química , Ácidos Picolínicos/síntese química , Tiazinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Oxazinas/química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
19.
Phys Med Biol ; 66(7)2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33657537

RESUMO

Purpose. Radiation dose delivered to targets located near the upper-abdomen or in the thorax are significantly affected by respiratory-motion. Relatively large-margins are commonly added to compensate for this motion, limiting radiation-dose-escalation. Internal-surrogates of target motion, such as a radiofrequency (RF) tracking system, i.e. Calypso®System, are used to overcome this challenge and improve normal-tissue sparing. RF tracking systems consist of implanting transponders in the vicinity of the tumor to be tracked using radiofrequency-waves. Unfortunately, although the manufacture provides a universal quality-assurance (QA) phantom, QA-phantoms specifically for lung-applications are limited, warranting the development of alternative solutions to fulfil the tests mandated by AAPM's TG142. Accordingly, our objective was to design and develop a motion-phantom to evaluate Calypso for lung-applications that allows the Calypso®Beacons to move in different directions to better simulate truelung-motion.Methods and Materials.A Calypso lung QA-phantom was designed, and 3D-printed. The design consists of three independent arms where the transponders were attached. A pinpoint-chamber with a buildup-cap was also incorporated. A 4-axis robotic arm was programmed to drive the motion-phantom to mimic breathing. After acquiring a four-dimensional-computed-tomography (4DCT) scan of the motion-phantom, treatment-plans were generated and delivered on a Varian TrueBeam®with Calypso capabilities. Stationary and gated-treatment plans were generated and delivered to determine the dosimetric difference between gated and non-gated treatments. Portal cine-images were acquired to determine the temporal-accuracy of delivery by calculating the difference between the observed versus expected transponders locations with the known speed of the transponders' motion.Results.Dosimetric accuracy is better than the TG142 tolerance of 2%. Temporal accuracy is greater than, TG142 tolerance of 100 ms for beam-on, but less than 100 ms for beam-hold.Conclusions.The robotic QA-phantom designed and developed in this study provides an independent phantom for performing Calypso lung-QA for commissioning and acceptance testing of Calypso for lung treatments.


Assuntos
Procedimentos Cirúrgicos Robóticos , Humanos , Pulmão/diagnóstico por imagem , Neonicotinoides , Imagens de Fantasmas , Impressão Tridimensional , Tiazinas
20.
Ecotoxicol Environ Saf ; 215: 112143, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33740489

RESUMO

Risk assessment of pesticides involves ecotoxicological testing. In case pesticide exposure to bees is likely, toxicity tests are performed with honey bees (Apis mellifera), with a tiered approach, for which validated and internationally accepted test protocols exist. However, concerns have grown regarding the protection of non-Apis bees [bumble bees (Bombus spp.), solitary and stingless bees], given their different life cycles and therefore distinct exposure routes. Larvae of solitary bees of the genus Osmia feed on unprocessed pollen during development, yet no toxicity test protocol is internationally accepted or validated to assess the impact of pesticide exposure during this stage of their life cycle. Therefore, the purpose of this study is to further validate a test protocol with two solitary bee species (O. cornuta and O. bicornis) to assess lethal and sublethal effects of pesticide exposure on larval development. Larvae were exposed to thiacloprid (neonicotinoid insecticide) mixed in a new, artificial pollen provision. Both lethal (developmental and winter mortality) and sublethal endpoints (larval development time, pollen provision consumption, cocoon weight, emergence time and adult longevity) were recorded. Effects of lower, more environmentally realistic doses were only reflected in sublethal endpoints. In both bee species, thiacloprid treatment was associated with increased developmental mortality and larval development time, and decreased pollen provision consumption and cocoon weight. The test protocol proved valid and robust and showed that for higher doses of thiacloprid the acute endpoint (larval mortality) is sufficient. In addition, new insights needed to develop a standardized test protocol were acquired, such as testing of a positive control for the first time and selection of male and female individuals at egg level.


Assuntos
Abelhas/fisiologia , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Tiazinas/toxicidade , Animais , Feminino , Himenópteros , Larva/efeitos dos fármacos , Estágios do Ciclo de Vida , Praguicidas/toxicidade , Pólen , Testes de Toxicidade
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