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1.
Mol Immunol ; 120: 13-22, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045770

RESUMO

OBJECTIVE: To investigate the impact of death-associated protein kinase 1 (Dapk1) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) via p38MAPK/NF-κB pathway. METHODS: Dapk1+/+ and Dapk1-/- mice were randomized into Control, LPS, SB203580 (a p38MAPK pathway inhibitor) + LPS, and PDTC (a NF-κB pathway inhibitor) + LPS groups. Cell counts, lung wet to dry weight ratio (W/D weight ratio), as well as indicators of oxidative stress were determined followed by the detection with HE staining, ELISA, qRT-PCR, Western blotting and Immunofluorescence. Besides, to explore whether the effect of Dapk1 on ALI directly mediated via p38MAPK/NF-κB pathway, mice were injected with TC-DAPK 6 (a Dapk1 inhibitor) with or without SB203580/PDTC before LPS administration. RESULTS: LPS induced lung injury with increased lung W/D weight ratio, which could be partly reversed by SB203580 and PDTC in LPS-induced mice with activated p38MAPK/NF-κB pathway in lung tissues, especially in Dapk1-/- mice. SB203580 and PDTC reduced total cells and neutrophils in BALF in LPS-induced mice, accompanying with decreased levels of TNF-α, IL-6, MPO, LPO and MDA and the expressions of beclin-1, Atg5 and LC3II, but with the up-regulated activities of SOD and GSH-Px, as well as p62 protein expression. Besides, TC-DAPK 6 aggravated the pathologic injury in LPS-induced ALI with more serious inflammatory response, oxidative stress and autophagy as well as the activated p38MAPK/NF-κB pathway, which were reversed by SB203580 or PDTC. CONCLUSION: Dapk1 improved oxidative stress, inhibited autophagy, and reduce inflammatory response of LPS-induced ALI mice by inhibiting p38MAPK/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteínas Quinases Associadas com Morte Celular/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Autofagia , Proteínas Quinases Associadas com Morte Celular/deficiência , Proteínas Quinases Associadas com Morte Celular/genética , Imidazóis/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo , Piridinas/farmacologia , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiocarbamatos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Food Chem ; 314: 126165, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972405

RESUMO

There are few studies for risk assessment of cartap and its metabolites, although cartap is easily transformed into metabolites which could induce higher toxicity. This study aimed to investigate the dissipation pattern of cartap and its metabolites during tea planting, manufacturing and brewing for evaluating the safety of cartap pesticide. Cartap metabolites were identified using Q-Exactive Orbitrap mass spectrometry. Half-lives of cartap in fresh tea leaves ranged from 0.49 to 0.59 days. Cartap decreased rapidly with time, and it was degraded into nereistoxin and cartap monothiol during tea production chain. Cartap monothiol residues dissipated rapidly by 98% in three days during tea planting. Nereistoxin had a longer residual period than cartap and it dominated the total residue in made tea after tea manufacturing. Transfer rates of nereistoxin during tea brewing ranged from 78.24% to 121.56%. Therefore, we suggested sum of cartap and nereistoxin residues as maximum residual limits in tea.


Assuntos
Resíduos de Praguicidas/análise , Chá/química , Tiocarbamatos/análise , Análise de Perigos e Pontos Críticos de Controle , Espectrometria de Massas , Estrutura Molecular , Tiocarbamatos/química
3.
Molecules ; 25(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935863

RESUMO

Herein, we report the development of chitosan (CH)-based bio-composite modified with acrylonitrile (AN) in the presence of carbon disulfide. The current work aimed to increase the Lewis basic centers on the polymeric backbone using single-step three-components (chitosan, carbon disulfide, and acrylonitrile) reaction. For a said purpose, the thiocarbamate moiety was attached to the pendant functional amine (NH2) of chitosan. Both the pristine CH and modified CH-AN bio-composites were first characterized using numerous analytical and imaging techniques, including 13C-NMR (solid-form), Fourier-transform infrared spectroscopy (FTIR), elemental investigation, thermogravimetric analysis, and scanning electron microscopy (SEM). Finally, the modified bio-composite (CH-AN) was deployed for the decontamination of cations from the aqueous media. The sorption ability of the CH-AN bio-composite was evaluated by applying it to lead and copper-containing aqueous solution. The chitosan-based CH-AN bio-composite exhibited greater sorption capacity for lead (2.54 mmol g-1) and copper (2.02 mmol g-1) than precursor chitosan from aqueous solution based on Langmuir sorption isotherm. The experimental findings fitted better to Langmuir model than Temkin and Freundlich isotherms using linear regression method. Different linearization of Langmuir model showed different error functions and isothermal parameters. The nonlinear regression analysis showed lower values of error functions as compared with linear regression analysis. The chitosan with thiocarbamate group is an outstanding material for the decontamination of toxic elements from the aqueous environment.


Assuntos
Cátions/química , Quitosana/química , Descontaminação/métodos , Tiocarbamatos/química , Acrilonitrila/química , Adsorção , Dissulfeto de Carbono/química , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Água/química
4.
DNA Cell Biol ; 39(4): 513-521, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31999475

RESUMO

The apoptosis of human lens epithelial cells (HLECs) is a characteristic change that occurs during the development of cataracts. Ultraviolet B (UVB) is known to induce the generation of reactive oxygen species (ROS) and apoptosis in HLECs, and thus cause cataracts. Previously, we reported the functions of cartilage acidic protein 1 (CRTAC1) in UVB-treated HLECs. However, the underlying mechanism was not known. In this study, we found that CRTAC1 expression and nuclear factor-kappa B (NF-κB) p65 nuclear translocation were elevated in capsule tissues of cataract patients in comparison with normal controls. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), alleviated UVB-induced apoptosis in HLECs; while activation of NF-κB suppressed the effects of the ROS inhibitor, N-acetyl-L-cysteine (NAC), on UVB-treated HLECs. The expression and promoter activity of CRTAC1 was inhibited by PDTC and NAC. Moreover, the suppressed effects of CRTAC1 knockdown on UVB-induced ROS generation, cell apoptosis, nuclear translocation of NF-κB p65, and p38 phosphorylation were attenuated by a p38 agonist. In contrast, the p38 inhibitor abolished the promotional effects of CRTAC1 overexpression on HLECs. Taken together, our results for the first time show that NF-κB is a potential transcription factor for CRTAC1. The regulatory network involving NF-κB, CRTAC1, and p38 may therefore play an important role in cataract formation.


Assuntos
Apoptose/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Catarata/patologia , Cristalino/patologia , Fator de Transcrição RelA/metabolismo , Acetilcisteína/farmacologia , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Células Epiteliais/patologia , Humanos , Cristalino/citologia , Pirrolidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiocarbamatos/farmacologia , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Enzyme Inhib Med Chem ; 35(1): 118-128, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694418

RESUMO

A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 µM for eeAChE; IC50 = 0.16 µM for hAChE), and it was also the best inhibitor to AChE-induced Aß aggregation (29.02% at 100 µM) and an efficient inhibitor to self-induced Aß aggregation (30.67% at 25 µM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Quinolonas/química , Tiocarbamatos/química , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos
8.
Nature ; 573(7772): 37-38, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31485062
9.
Chem Biodivers ; 16(11): e1900370, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31523926

RESUMO

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Ftalimidas/farmacologia , Tiocarbamatos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Electrophorus , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cavalos , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Ftalimidas/química , Tiocarbamatos/química
10.
Chem Asian J ; 14(24): 4717-4724, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31502759

RESUMO

The emergence of hydrogen sulfide (H2 S) as an important signalling molecule in redox biology with therapeutic potential has triggered interest in generating this molecule within cells. One strategy that has been proposed is to use carbonyl sulfide (COS) as a surrogate for hydrogen sulfide. Small molecules that generate COS have been shown to produce hydrogen sulfide in the presence of carbonic anhydrase, a widely prevalent enzyme. However, other studies have indicated that COS may have biological effects which are distinct from H2 S. Thus, it would be useful to develop tools to compare (and contrast) effects of COS and H2 S. Here we report enzyme-activated COS donors that are capable of inducing protein persulfidation, which is symptomatic of generation of hydrogen sulfide. The COS donors are also capable of mitigating stress induced by elevated reactive oxygen species. Together, our data suggests that the effects of COS parallel that of hydrogen sulfide, laying the foundation for further development of these donors as possible therapeutic agents.


Assuntos
Substâncias Protetoras/farmacologia , Proteínas/metabolismo , Óxidos de Enxofre/metabolismo , Tiocarbamatos/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sulfeto de Hidrogênio/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Tiocarbamatos/síntese química , Tiocarbamatos/metabolismo
11.
Carbohydr Polym ; 224: 115155, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472825

RESUMO

Plant-parasitic nematodes cause substantial crop losses annually; however, current nematicides are environmentally unfriendly and highly toxic to nontarget organisms. The development of green efficient nematicides from multifunctional natural bioactive substances such as chitin oligosaccharide (COS) is promising. In this paper, COS dithiocarbamate derivatives (COSDTC, COSDTA, COSDTB) were synthesized to increase nematicidal activity (against Meloidogyne incognita), and their structures were characterized by FTIR, NMR, TGA/DTG and elemental analysis. Furthermore, the nematicidal activities, egg hatching inhibitory activities, plant growth adjustment abilities, cytotoxicity and phytotoxicity of the derivatives were evaluated. The primary mechanism was assessed by heavy metal ion absorption and GSH-binding assays. The results showed COS dithiocarbamate derivatives could possess multiple efficacies, including high nematicidal activities and egg hatching inhibitory activities, plant growth regulating effects, low cell toxicities and phytotoxicities. Additionally, it was inferred that nematicidal activity may be correlated with GSH-binding activity but not heavy metal ion complexation. COS modification has immense potential for controlling plant-parasitic nematodes.


Assuntos
Antinematódeos/química , Antinematódeos/farmacologia , Quitina/química , Quitina/farmacologia , Oligossacarídeos/química , Tiocarbamatos/química , Tylenchoidea/efeitos dos fármacos , Animais , Antinematódeos/metabolismo , Antinematódeos/toxicidade , Caenorhabditis elegans/efeitos dos fármacos , Quitina/metabolismo , Quitina/toxicidade , Glutationa/metabolismo , Humanos , Células MCF-7
12.
Am J Physiol Renal Physiol ; 317(4): F1058-F1067, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411073

RESUMO

Nitric oxide inhibition with Nω-nitro-l-arginine methyl ester (l-NAME), along with salt overload, leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia, and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere have suggested that activation of at least two pathways of innate immunity, Toll-like receptor 4 (TLR4)/NF-κB and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome/IL-1ß, occurs in several experimental models of CKD and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-κB or NLRP3/IL-1ß pathway, is involved in the pathogenesis of renal injury in chronic nitric oxide inhibition with the salt-overload model. Adult male Munich-Wistar rats that received l-NAME in drinking water with salt overload (HS + N group) were treated with allopurinol (ALLO) as an NLRP3 inhibitor (HS + N + ALLO group) or pyrrolidine dithiocarbamate (PDTC) as an NF-κB inhibitor (HS + N + PDTC group). After 4 wk, HS + N rats developed hypertension, albuminuria, and renal injury along with renal inflammation, oxidative stress, and activation of both the NLRP3/IL-1ß and TLR4/NF-κB pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria, and interstitial inflammation/fibrosis but not glomerular injury. PDTC inhibited the renal NF-κB system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1ß and TLR4/NF-κB pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection.


Assuntos
Imunidade Inata , Óxido Nítrico/antagonistas & inibidores , Insuficiência Renal Crônica/fisiopatologia , Cloreto de Sódio na Dieta/farmacologia , Alopurinol/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Hipertensão/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tiocarbamatos/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo
13.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374887

RESUMO

Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.


Assuntos
Antiparasitários/uso terapêutico , Leishmaniose/tratamento farmacológico , Tiocarbamatos/uso terapêutico , Trypanosoma/efeitos dos fármacos , Animais , Antiparasitários/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Tiocarbamatos/química , Trypanosoma/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
14.
Anal Chim Acta ; 1078: 135-141, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31358211

RESUMO

Hypochlorous acid (HOCl)/hypochlorite (OCl-), important reactive oxygen species, play essential roles in many physiological and pathological progresses. Accordingly, we developed a novel dicyanomethylene-4H-pyran (DCM)-based probe DCM-OCl for colorimetric and near-infrared fluorescent turn-on detection of OCl-. The probe exhibited excellent selectivity and sensitivity for OCl- over other bio-related analytes with a detection limit of 80 nM. The excellent selectivity of DCM-OCl for OCl- was ascribed to specific oxidative cleavage of the dimethylthiocarbamate (DMTC) recognition unit by OCl-. Moreover, DCM-OCl exhibited an ultrafast turn-on response (<3 s) to OCl-, potentially allowing real-time detection of OCl-. Furthermore, DCM-OCl was successfully used to image endogenous/exogenous OCl- in living cells.


Assuntos
Benzopiranos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Tiocarbamatos/química , Benzopiranos/síntese química , Benzopiranos/toxicidade , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Tiocarbamatos/síntese química , Tiocarbamatos/toxicidade
15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 313-319, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167690

RESUMO

Objective To explore the mechanism of transdifferentiation of human renal tubular epithelial cells induced by high glucose based on reactive oxygen species (ROS)/NF-κB signaling pathway. Methods HK-2 normal human proximal tubular epithelial cells were randomly divided into blank control group, osmotic pressure control group, high glucose group and pyrrolidine dithiocarbamate (PDTC) group. Cell morphology was observed by phase contrast microscope. Cell viability was measured by MTT assay. Flow cytometry was used to detect intracellular ROS content. Malondialdehyde (MDA) content and superoxide dismutase activity were tested by ELISA. Western blot analysis was used to examine the protein levels of NF-κBp65, phosphorylated IκBα (p-IκBα) and IKKα, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1). The expressions of NF-κBp65, epithelial cadherin (E-cadherin) and alpha smooth muscle actin (α-SMA) were assessed by immunocytochemistry. Results In high glucose group, the cells became spindle-shaped or irregular, with radial edges, enlarged intercellular space, decreased refractive index and irregular arrangement. At the same time, the cell activity decreased with the prolongation of treatment time, and the cell activity in PDTC group was higher than that in high glucose group. Compared with the blank control group, the content of ROS and MDA increased and the activity of SOD decreased in the high glucose group, while the content of ROS and MDA decreased and the activity of SOD increased in the PDTC group compared with the high glucose group. Compared with the blank group, the protein levels of NF-κBp65, p-IκBα, IKKα, MCP-1 and ICAM-1 increased in the high glucose group, while the protein levels above decreased in the PDTC group compared with the high glucose group. Compared with the blank group, the proportion of positive cells of NF-κBp65 and α-SMA increased and the proportion of positive cells of E-cadherin decreased in the high glucose group. Compared with the high glucose group, the proportion of positive cells of NF-κBp65 and α-SMA decreased and the proportion of positive cells of E-cadherin increased in the PDTC group. Conclusion High glucose can induce epithelial-mesenchymal transition in HK-2 cells. Activation of NF-κB signaling pathway mediated by ROS participates in the above process, which can be blocked by PDTC.


Assuntos
Transdiferenciação Celular , Células Epiteliais/citologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Linhagem Celular , Meios de Cultura , Glucose , Humanos , Túbulos Renais/citologia , Pirrolidinas , Tiocarbamatos
16.
J Chromatogr A ; 1600: 148-157, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31060785

RESUMO

Risk assessment of cartap residue in tea should include the exposure of cartap and its metabolite due to rapid degradation of cartap into nereistoxin. Herein, a reliable method for determination of cartap and nereistoxin in tea was developed by hydrophilic interaction chromatography tandem mass spectrometry. Target compounds were extracted with water containing 1% formic acid and 5 mM ammonium formate. The use of dichloromethane effectively removed caffeine. Tea extracts were cleaned up by dispersive adsorbents of octadecylsilane and strong anion exchanger, then further purified using hydrophilic lipophilic balanced solid phase extraction cartridge. Isotopic internal standard was employed to calibrate the loss of analytes during sample preparation and compensate matrix effects. Method validation illustrated excellent linearity, with correlation coefficients (R2) higher than 0.999. Satisfactory recoveries of target compounds spiked in green tea, black tea and oolong tea ranged from 87.6% to 119.9% with intra- and inter-day precisions below 20%. Limits of quantification of cartap and nereistoxin were 10.0 µg kg-1, and limits of detection were 2.0 µg kg-1 for cartap and 4.0 µg kg-1 for nereistoxin. The developed method was applied to determine cartap and nereistoxin in thirty tea samples.


Assuntos
Extração em Fase Sólida , Espectrometria de Massas em Tandem , Chá/química , Tiocarbamatos/análise , Cromatografia Gasosa-Espectrometria de Massas , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção , Toxinas Marinhas/análise , Tiocarbamatos/metabolismo
17.
Balkan Med J ; 36(4): 245-250, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31140237

RESUMO

Background: Nuclear factor-kB is highly activated in cardiovascular disorders. However, few articles have targeted at the role of nuclear factor-kB inhibitor in heart failure. Aims: To evaluate the effects of nuclear factor-kB inhibitor pyrrolidine dithiocarbamate on cardiocyte apoptosis and cardiac function in a rat heart failure model. Study Design: Animal experiment. Methods: A stable and reproducible rat heart failure model (n=64) was prepared by injecting homologous microthrombotic particles into the left ventricle of Sprague­Dawley rats while obstructing the ascending aorta to produce coronary microembolization. Rats with heart failure were randomized into untreated (HFu) and pyrrolidine dithiocarbamate-treated (HFp) groups; the latter received an intraperitoneal injection of pyrrolidine dithiocarbamate (100 mg/kg/day) 1 h prior to surgery as well as on postoperative days 1-7. The sham group comprised 32 Sprague­Dawley rats. Eight rats from each group were sacrificed on days 1, 3, 7, and 14 postoperatively. Masson's trichrome staining was used to determine the micro-fibrotic area to indicate the severity of myocardial loss. Terminal transferase uridine triphosphate nick end labeling staining was used to detect apoptotic cardiomyocytes. Echocardiography and hemodynamics were performed to evaluate left ventricular function. Results: Rats with heart failure exhibited pathological changes evidenced by patchy myocardial fibrosis, remarkably elevated severity of myocardial loss, and persistently reduced left ventricular function. At the end of the study, compared with the HFu group, myocardial infarct size was reduced by 28% (p=0.001), cardiocyte apoptosis was suppressed (7.17%±1.47% vs 2.83%±0.75%, p<0.001), cardiac function parameters such as left ventricular ejection fraction (80%±4% vs 61%±6%), left ventricular + dP/dt max (4828±289 vs 2918±76 mmHg.s−1), left ventricular - dP/dt max (4398±269 vs 2481±365 mmHg.s−1), and left ventricular systolic pressure (126±13 vs 100±10 mmHg) were significantly increased, and left ventricular end-diastolic pressure was reduced (18±2 vs 13±1 mmHg) (p<0.001, for all) in the HFu group. Conclusion: Our rat model can adequately mimic heart failure via coronary vessel embolization. Moreover, pyrrolidine dithiocarbamate treatment can reduce cardiocyte apoptosis and improve cardiac function, which may be beneficial for patients with heart failure secondary to myocardial infarction.


Assuntos
Apoptose/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , NF-kappa B/efeitos dos fármacos , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Embolia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , NF-kappa B/análise , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos/genética , Ratos/metabolismo , Ratos Sprague-Dawley , Tiocarbamatos/metabolismo , Tiocarbamatos/uso terapêutico
18.
Colloids Surf B Biointerfaces ; 181: 185-197, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132609

RESUMO

Chemotherapeutic drugs have a series of limitations in the conventional clinical treatments, mainly including serious adverse effects and multidrug resistance (MDR). Herein, we developed a pH-sensitive polymeric nanoparticle with using poly(ortho ester urethanes) copolymers for co-delivering doxorubicin (DOX) and pyrrolidinedithiocarbamate (PDTC) to settle these problems. Dual-drug-loaded nanoparticles were nano-sized (˜220 nm) with the spherical morphology and excellent physiological stability. Both drugs both could be quickly released in the mild acidic conditions due to the cleavage of ortho ester bonds. Monolayer cultured cells (2D) and multicellular spheroids (3D) experiments proved that PDTC could reverse multidrug resistance (MDR), improve intracellular drugs accumulation and enhance tumor penetration by down-regulating the expression of P-gp, then resulting in higher DOX-induced cytotoxicity and apoptosis in MCF-7 and MCF-7/ADR cells. Besides, in vivo experiments further demonstrated that co-encapsulated nanoparticles had higher DOX accumulation and superiorer tumor growth inhibition (TGI 82.9%) than free drugs or single-drug-loaded nanoparticles on MCF-7/ADR bearing-mice. Accordingly, the pH-sensitive co-delivery systems possess a promising potential to overcome MDR in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HEK293 , Humanos , Hidrodinâmica , Concentração de Íons de Hidrogênio , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Polímeros/química , Pirrolidinas/química , Propriedades de Superfície , Tiocarbamatos/química
19.
Chem Biol Interact ; 307: 136-146, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059705

RESUMO

Since reproductive toxicity is associated with oxidative stress, nuclear factor κB (NFκB), a redox-sensitive transcription factor, may be involved in the reproductive dysfunction induced by the abusive drug, such as cocaine. In the present study, we investigated whether NFκB mediates cocaine-induced reproductive dysfunction in male mice, and whether glutathione peroxidase (GPx)-1, a well-known enzymatic antioxidant, modulates NFκB activity to affect this reproductive dysfunction. Cocaine treatment significantly increased nuclear translocation of NFκB and its DNA binding activity in the testis of mice. Treatment with cocaine resulted in a significant increase in sperm abnormality, and in significant decreases in the sperm viability and sperm level. Furthermore, cocaine significantly reduced hypothalamic gonadotropin-releasing-hormone expression and plasma testosterone level. These alterations were more pronounced in the GPx-1 knockout (GPx-1 KO) than wild type (WT) mice, and they were less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than in non-transgenic (non-TG) mice. Pyrrolidine dithiocarbamate (PDTC), an NFκB inhibitor, was more effective in attenuating cocaine-induced reproductive toxicity in GPx-1 KO than in WT mice. Although PDTC treatment was also significantly protective against the reproductive toxicity in non-TG mice, PDTC did not show additional positive effects against the protective potential mediated by GPx-1 overexpression in mice. Therefore, our results suggest that GPx-1 gene is a protective factor in response to reproductive dysfunction induced by cocaine in male mice, and that NFκB is a critical mediator of protective activity of GPx-1 gene in our experimental conditions.


Assuntos
Cocaína/toxicidade , Glutationa Peroxidase/metabolismo , NF-kappa B/metabolismo , Animais , Núcleo Celular/metabolismo , Glutationa Peroxidase/deficiência , Glutationa Peroxidase/genética , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , Pirrolidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/sangue , Tiocarbamatos/farmacologia
20.
Eur J Med Chem ; 177: 32-46, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129452

RESUMO

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC50 values from 0.001 µM to 0.06 µM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC50 = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiocarbamatos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiocarbamatos/toxicidade
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