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1.
Inorg Chem ; 59(2): 968-971, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31891256

RESUMO

A dithiolate/hydride bridged Fe-Ni complex, [(CN)(CO)2FeII(µ-pdt)(µ-H)NiII(CN)(PCy3)]- (2, pdt = propane-1,3-dithiolate) has been synthesized by the reaction of [(CN)2(CO)2FeII(pdt)]2- with [NiII(Cl)(H)(PCy3)2] as a synthetic analogue of the Ni-R state of the active site of the [Ni-Fe] hydrogenase. X-ray crystallography of this model complex suggests that the hydride unsymmetrically binds to Ni and Fe similar to natural [Ni-Fe] hydrogenases.


Assuntos
Monóxido de Carbono/química , Complexos de Coordenação/química , Cianetos/química , Hidrogenase/química , Tolueno/análogos & derivados , Monóxido de Carbono/metabolismo , Domínio Catalítico , Complexos de Coordenação/metabolismo , Cianetos/metabolismo , Hidrogenase/metabolismo , Ferro/química , Ferro/metabolismo , Modelos Moleculares , Conformação Molecular , Níquel/química , Níquel/metabolismo , Tolueno/química , Tolueno/metabolismo
2.
Chem Commun (Camb) ; 55(83): 12487-12490, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31566647

RESUMO

CF2H-Pseudoprolines obtained from difluoroacetaldehyde hemiacetal and serine are stable proline surrogates. The consequence of the incorporation of the CF2H group is an important decrease of the trans to cis amide bond isomerization energy and a remarkable stabilisation of the cis conformer by an hydrogen bond.


Assuntos
Peptídeos/química , Prolina/análogos & derivados , Tiazóis/química , Tolueno/análogos & derivados , Ligações de Hidrogênio , Metilação , Conformação Molecular , Prolina/química , Estereoisomerismo , Tolueno/química
3.
Chemistry ; 25(50): 11641-11645, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31338883

RESUMO

Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C-H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO2 , isolating 2.3 g for 10 min of operation time.


Assuntos
Ibuprofeno/química , Metais/química , Xilenos/química , Carbono/química , Hidrogênio/química , Ibuprofeno/síntese química , Tolueno/análogos & derivados , Tolueno/química
4.
Neurotox Res ; 36(2): 347-356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069753

RESUMO

Methamphetamine (Meth) is a widely abused stimulant. High-dose Meth induces degeneration of dopaminergic neurons through p53-mediated apoptosis. A recent study indicated that treatment with the p53 inhibitor, pifithrin-alpha (PFT-α), antagonized Meth-mediated behavioral deficits in mice. The mechanisms underpinning the protective action of PFT-α against Meth have not been identified, and hence, their investigation is the focus of this study. Primary dopaminergic neuronal cultures were prepared from rat embryonic ventral mesencephalic tissue. High-dose Meth challenge reduced tyrosine hydroxylase immunoreactivity and increased terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling. PFT-α significantly antagonized these responses. PFT-α also reduced Meth-activated translocation of p53 to the nucleus, an initial step before transcription. Previous studies have indicated that p53 can also activate cell death through transcription-independent pathways. We found that PFT-α attenuated endoplasmic reticulum (ER) stressor thapsigargin (Tg)-mediated loss of dopaminergic neurons. ER stress was further monitored through the release of Gaussia luciferase (GLuc) from SH-SY5Y cells overexpressing GLuc-based Secreted ER Calcium-Modulated Protein (GLuc-SERCaMP). Meth or Tg significantly increased GLuc release in to the media, with PFT-α significantly reducing GLuc release. Additionally, PFT-α significantly attenuated Meth-induced CHOP expression. In conclusion, our data indicate that PFT-α is neuroprotective against Meth-mediated neurodegeneration via transcription-dependent nuclear and -independent cytosolic ER stress pathways.


Assuntos
Benzotiazóis/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Metanfetamina/toxicidade , Tolueno/análogos & derivados , Animais , Linhagem Celular Tumoral , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Gravidez , Ratos , Tolueno/farmacologia
5.
Methods Mol Biol ; 1967: 295-304, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069779

RESUMO

Conjugates of 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO) with optical or radionuclide probes are able to image cell death in vivo. GSAO conjugates are retained in the cytosol of dying and dead cells via the formation of covalent bonds between the As(III) ion and the thiol groups of proximal cysteine residues. Here we describe the method for preparing a NODAGA-GSAO conjugate and its radiolabeling with gallium-68 (68Ga-NODAGA-GSAO) for positron-emission tomography (PET) imaging of cell death.


Assuntos
Morte Celular/genética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Tolueno/análogos & derivados , Acetatos/química , Acetatos/uso terapêutico , Animais , Arsenicais/química , Arsenicais/uso terapêutico , Radioisótopos de Gálio/química , Radioisótopos de Gálio/uso terapêutico , Glutationa/análogos & derivados , Glutationa/química , Glutationa/uso terapêutico , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Radioisótopos/administração & dosagem , Radioisótopos/química , Compostos Radiofarmacêuticos/uso terapêutico , Tolueno/química
6.
Methods Mol Biol ; 1967: 305-321, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069780

RESUMO

Flow cytometry assessment of platelets using the combination of GSAO [4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid], a dithiol-reactive probe, and P-selectin, a platelet activation marker, is a novel and powerful assay in the identification and quantification of the procoagulant subpopulation of platelets that has the capacity to support thrombin generation. In this chapter, we provide the flow cytometry protocols aimed at the study of procoagulant platelets under resting and agonist-stimulated conditions in whole blood and washed platelets of both human and murine (mouse) samples.


Assuntos
Plaquetas/química , Citometria de Fluxo/métodos , Tolueno/análogos & derivados , Animais , Humanos , Camundongos , Selectina-P/química , Selectina-P/genética , Ativação Plaquetária/efeitos dos fármacos , Trombina/química , Tolueno/química
7.
Environ Monit Assess ; 191(5): 309, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028555

RESUMO

To enhance our understanding on environmental conditions of the Maowei Sea in Guangxi province, China, the concentration and distribution of 22 chlorobenzene compounds (CBs) in the surface sediment were determined by gas chromatography-mass spectrometry (GC-MS). The relationship of the sediment between CBs and total organic carbon (TOC) was also investigated. The results showed that a total of eight kinds of CBs compounds were detected in the sediment samples which were collected from the coastal environment of the Maowei Sea, with an average concentration of 15.3 ng·g-1 (the concentration range, 2.5-61.5 ng·g-1). The rank of their average concentrations was as follows: 2,3,4,5,6-pentachlorotoluene > hexachlorobenzene, 2-chlorotoluene, 3-chlorotoluene and 2,3-dichlorotoluene > 2,4-dichlorotoluene > 4-chlorotoluene > pentachlorobenzene. Most CBs were distributed in sediments along the east coast of the Maowei Sea. For total TOC content in sediments, the concentration in the sampling locations was similar, with a mean concentration of 8.83 g·kg-1 (the concentration range, 4.87-20.13 g·kg-1). However, there was no significant correlation between the concentration of TOC and total CBs. Compared to the corresponding CBs in the sediment of other coastal areas in mainland China and other countries, the value of CBs in the Maowei Sea was low.


Assuntos
Clorobenzenos/análise , Monitoramento Ambiental , Sedimentos Geológicos/química , Compostos Orgânicos/análise , Poluentes Químicos da Água/análise , China , Ecologia , Cromatografia Gasosa-Espectrometria de Massas , Hexaclorobenzeno/análise , Oceanos e Mares , Tolueno/análogos & derivados , Tolueno/análise
8.
Vet Microbiol ; 232: 1-12, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31030832

RESUMO

Porcine epidemic diarrhea virus (PEDV) is a member of Coronavirus, which causes severe watery diarrhea in piglets with high morbidity and mortality. ROS and p53 play key roles in regulating many kinds of cell process during viral infection, however, the exact function in PEDV-induced apoptosis remains unclear. In this study, the pro-apoptotic effect of PEDV was examined in Vero cells and we observed that PEDV infection increased MDM2 and CBP, promoted p53 phosphorylation at serine 20 and, promoted p53 nuclear translocation, leading to p53 activation in Vero cells. Treatment with the p53 inhibitor PFT-α could significantly inhibit PEDV-induced apoptosis. We also observed PEDV infection induced time-dependent ROS accumulation. Treatment with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited PEDV-induced apoptosis. Moreover, further inhibition tests were established to prove that p53 was regulated by ROS in PEDV-induced apoptosis. In addition, we also found that p38 MAPK and SAPK/JNK were activated in PEDV-infected Vero cells. However, treatment with the p38 MAPK inhibitor SB203580, and the SAPK/JNK inhibitor SP600125 reversed PEDV-induced apoptosis. Taken together, the results of this study demonstrate that activated p53 and accumulated ROS participated in PEDV-induced apoptosis and p53 could be regulated by ROS during PEDV infection. Activated p38 MAPK and SAPK/JNK exerted no influence on PEDV-induced apoptosis. These findings provide new insights into the function of p53 and ROS in the interaction of PEDV with Vero cells.


Assuntos
Apoptose , Sistema de Sinalização das MAP Quinases , Vírus da Diarreia Epidêmica Suína/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilcisteína/farmacologia , Animais , Benzotiazóis/farmacologia , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Tolueno/análogos & derivados , Tolueno/farmacologia , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
J Parasitol ; 105(1): 146-154, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30807708

RESUMO

To evaluate the effect of mitogen-activated protein kinase (MAPK) signal transduction pathway inhibitors against alveolar echinococcosis in vitro and in vivo, Echinococcus multilocularis metacestode cysts and protoscolices were obtained from infected mice. Protein chip technology was utilized to screen for key highly expressed target proteins in the MAPK pathway in this parasite and their corresponding inhibitors. Four-week-old Balb/c female mice used for the in vivo experiment underwent inoculation of E. multilocularis by intraperitoneal injection, as well as intragastric administration of MAPK inhibitors for 6 wk. We included 6 groups of mice: a phosphate-buffered saline (PBS) group (negative control); an albendazole-treated group (positive group); and 4 experimental groups treated with TRx0237 mesylate, GDC-0994, pifithrin-ß hydrobromide, or Selonsertib. Echinococcus multilocularis protoscolices were collected and cultured in 1066 medium with penicillin/streptomycin and 10% fetal bovine serum. The in vitro experiment included a PBS group (negative control), a dimethyl sulfoxide-treated group (solvent group), and 4 inhibitor-treated groups as in the in vivo experiment (experimental groups). Each inhibitor group received 4 drug concentrations (5, 30, 55, and 80 µM), and the experiment was performed in triplicate per sample. Fluorescence microscopy was used to evaluate the survival rate of the protoscolices every 48 hr beginning from the first 24 hr. The same grouping was used to evaluate cytotoxicity on E. multilocularis germinal cells and L02 cells. The average weights of E. multilocularis metacestode cyst tissue from each group of the in vivo experiment were 873 mg (PBS), 335 mg (albendazole), 323 mg (TRx0237 mesylate), 420 mg (GDC-0994), 340 mg (pifithrin-ß hydrobromide), and 642 mg (Selonsertib). Results showed albendazole, TRx0237 mesylate, and pifithrin-ß hydrobromide had significant inhibitory effects on inhibition of E. multilocularis. We found a positive correlation between drug concentrations and the inhibitory effects seen in the in vitro experiment, with the differences in contrast with the control group becoming statistically significant after 72 hr of treatment ( P < 0.05). The inhibition rates of TRx0237 mesylate to germinal cells by drug concentration were 23.73, 46.59, 74.71, and 77.44%. Other drugs had no effect on germinal cells. All the inhibitors had low toxicity on L02 cells. Inhibitors of the MAPK signal transduction pathway showed significant inhibitory effects on E. multilocularis, suggesting these may be potential candidates for the treatment of alveolar echinococcosis.


Assuntos
Anti-Helmínticos/farmacologia , Equinococose/tratamento farmacológico , Echinococcus multilocularis/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Albendazol/farmacologia , Albendazol/uso terapêutico , Animais , Anti-Helmínticos/química , Anti-Helmínticos/uso terapêutico , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Equinococose/enzimologia , Feminino , Hepatócitos/parasitologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Azul de Metileno/análogos & derivados , Azul de Metileno/química , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Análise Serial de Proteínas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Tolueno/análogos & derivados , Tolueno/química , Tolueno/farmacologia , Tolueno/uso terapêutico
10.
Am J Physiol Renal Physiol ; 316(4): F674-F681, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698046

RESUMO

The cyclin kinase inhibitor p21 is acutely upregulated during acute kidney injury (AKI) and exerts cytoprotective effects. A proposed mechanism is oxidant stress-induced activation of p53, the dominant p21 transcription factor. Glycerol-induced rhabdomyolysis induces profound renal oxidant stress. Hence, we studied this AKI model to determine whether p53 activation corresponds with p21 gene induction and/or whether alternative mechanism(s) might be involved. CD-1 mice were subjected to glycerol-induced AKI. After 4 or 18 h, plasma, urinary, and renal cortical p21 protein and mRNA levels were assessed. Renal p53 activation was gauged by measurement of both total and activated (Ser15-phosphorylated) p53 and p53 mRNA levels. Glycerol evoked acute, progressive increases in renal cortical p21 mRNA and protein levels. Corresponding plasma (~25-fold) and urinary (~75-fold) p21 elevations were also observed. Renal cortical ratio of total to phosphorylated (Ser15) p53 rose three- to fourfold. However, the p53 inhibitor pifithrin-α failed to block glycerol-induced p21 gene induction, suggesting that an alternative p21 activator might also be at play. To this end, it was established that glycerol-induced AKI 1) dramatically increased plasma (~5-fold) and urinary (~75-fold) cortisol levels, 2) the glucocorticoid receptor antagonist mifepristone blocked glycerol-induced p21 mRNA and protein accumulation, and 3) dexamethasone or cortisol injections markedly increased p21 protein and mRNA in both normal and glycerol-treated mice, although no discernible p53 protein or mRNA increases were observed. We conclude that AKI-induced "systemic stress" markedly increases plasma and urinary cortisol, which can then activate renal p21 gene expression, at least in part, via a glucocorticoid receptor-dependent signaling pathway. Discernible renal cortical p53 increases are not required for this dexamethasone-mediated p21 response.


Assuntos
Lesão Renal Aguda/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Glucocorticoides/metabolismo , Transdução de Sinais , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/fisiopatologia , Animais , Benzotiazóis/uso terapêutico , Dexametasona/uso terapêutico , Glicerol , Antagonistas de Hormônios/uso terapêutico , Hidrocortisona/sangue , Hidrocortisona/uso terapêutico , Hidrocortisona/urina , Córtex Renal/metabolismo , Masculino , Camundongos , Mifepristona/uso terapêutico , Tolueno/análogos & derivados , Tolueno/uso terapêutico , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
11.
Biosens Bioelectron ; 129: 284-291, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30245166

RESUMO

Silica nanopores have electron channels and ion channels interpenetrating each other, which prompt the use of this structure for creating efficient electronic devices. In this study, silica nanopores membrane modified screen printed electrodes were applied in a smartphone-based electrochemiluminescence system for nitroaromatic explosives detection. Universal serial bus-on the go (USB-OTG) and camera on smartphone were used as the electrical stimulation and luminescence capture, respectively. ⎕Multimode methods including (red-green-blue) RGB, (hue-saturation-brightness) HSB, and Gray were proposed for luminescence analysis. Specific polypeptides were immobilized on the nanopores modified electrodes for nitroaromatic explosives sensing. With positive-charged tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)32+) as electrochemiluminescence label, the increase in luminescence was associated with the selective ion channels and the well-conductive electron channels in the negative-charged nanopores. Besides, on account of the large specific surface area, nanopores modified screen printed electrodes showed stable and uniform luminescence. Results showed that the nanopores-enhanced electrochemiluminescence on smartphone covered a linear dynamic range from 10-7 mg/mL to 10-3 mg/mL for nitroaromatic explosives detection with the detection limit of 2.3 × 10-9 mg/mL. Therefore, high-efficient photo-electricity conversion capabilities of nanopores made it a kind of promising platform for sensitive and stable electrochemiluminescence. Furthermore, smartphone-based electrochemiluminescence with disposable screen printed electrodes could facilitate the mobile monitoring of biochemical analytes in the fields of environment, security, and health.


Assuntos
Técnicas Biossensoriais/instrumentação , Dinitrobenzenos/análise , Substâncias Explosivas/análise , Nanoporos/ultraestrutura , Dióxido de Silício/química , Tolueno/análogos & derivados , Trinitrotolueno/análise , Técnicas Eletroquímicas/instrumentação , Eletrodos , Desenho de Equipamento , Limite de Detecção , Medições Luminescentes/instrumentação , Peptídeos/química , Smartphone , Tolueno/análise
12.
FASEB J ; 33(1): 844-856, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052487

RESUMO

Aging of white adipose tissue (WAT) is associated with reduced insulin sensitivity, which contributes to whole-body glucose intolerance. WAT aging in mice impairs cold-induced beige adipocyte recruitment (beiging), which has been attributed to the senescence of adipose progenitor cells. Tumor suppressor p53 has also been implicated in WAT aging. However, whether p53-related cellular aging in mature white adipocytes is causative of age-impaired WAT beiging remains unknown. It is also unclear whether transient p53 inhibition can rescue WAT beiging. Herein, we report that p53 increased in adipose tissues of 28-wk-old (aged) mice with impaired beiging capability. Cold exposure decreased p53 in beiging WAT of young mice but not in aged mice. In aged mice, inducible p53 ablation in differentiated adipocytes restored cold-induced WAT beiging and augmented whole-body energy expenditure and insulin sensitivity. Transient pharmacological inhibition of p53 led to the same beneficial effects. Mechanistically, cold exposure repressed autophagy in beiging WAT of young mice yet increased autophagy in aged WAT. p53-ablation reduced microtubule-associated protein light chain 3-mediated mitochondria clearance (mitophagy) and hence facilitated the increase of mitochondria during beiging. These findings suggest that p53-induced mitophagy in aged white adipocytes impedes WAT beiging and may be therapeutically targeted to improve insulin sensitivity in aged WAT.-Fu, W., Liu, Y., Sun, C., Yin, H. Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy.


Assuntos
Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/efeitos dos fármacos , Adiponectina/genética , Adiposidade , Animais , Benzotiazóis/farmacologia , Células Cultivadas , Temperatura Baixa , Metabolismo Energético , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Sirolimo/farmacologia , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores
13.
Biomater Sci ; 7(2): 607-617, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30462102

RESUMO

Stimuli-responsive nanogels are important drug and gene carriers that mediate the controlled release of therapeutic molecules. Herein, we report the synthesis of fully degradable disulfide cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2'-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA). Because the poly(EDDET) backbone repeat structure and cross-linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Cross-linked nanogels were synthesized using controlled microfluidic mixing in the presence of a nonionic Pluronic surfactant PLU-127 to increase the nanogel stability. Adjusting the monomer to cross-linker ratio from 5 : 1 to 100 : 1 (mol/mol) tuned the cross-linking density, resulting in swelling ratios from 1.65 to >3. Increasing the amount of stabilizing Pluronic surfactant resulted in a decrease of nanogel diameter, as expected due to increased surface area of the resulting nanogels. The monomer to cross-linker ratio in the feed had no effect on the formed nanogel diameter, providing a way to control cross-linking density with constant nanogel size but tunable drug release kinetics. Nanogels exhibited an entrapment efficiency of up to 75% for loading of Rhodamine B dye. In vitro studies showed low cytotoxicity, quick uptake, and fast degradation kinetics. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer potential for use in a variety of drug delivery applications.


Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Nanoestruturas/química , Polimerização , Tolueno/análogos & derivados , Transporte Biológico , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Géis , Células HeLa , Humanos , Cinética , Oxirredução , Tensoativos/química , Tolueno/química
14.
Eur J Pharm Sci ; 128: 61-72, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472223

RESUMO

p53 is generally known as an effective anti-cancer molecular, but it is lost or mutated in more than 50% of human tumors. It is still a controversial issue whether the activity of p53 really benefits for treating cancers, we wondered what would happen if the endogenous p53 was inhibited before treated with topotecan (TPT) on p53 positive tumor cells. In this study, pifithrin-α (PFTα), a p53 inhibitor, was used 2 h before treated with TPT on three kinds of cancer cell lines including MCF7, BGC823 and HepG2 cells. The IC50s of TPT for MCF7, BGC823 and HepG2 cells after 10 µΜ PFTα pretreated, was 4.8 to 14.4 folds lower than the effect of TPT alone. It was demonstrated that PFTα decreases the p-p53 levels and p-p53 activity, not affects p53 expression in p53 positive tumor cells. PFTα enhanced anticancer effect of TPT on cells was found mainly by two ways. Firstly, it increased the TPT accumulation in cells and nucleus and promoted the inhibition of TPT on activity of Topo I, and induced more DNA damage. Secondly, PFTα decreased formation of p53/mdm2 complex responsible for p53 degradation by inhibiting the protein expression of mdm2, so p53 degradation was decreased in cytoplasm and p53 accumulation was increased in nucleus, which induced more cells undergo apoptosis. So, the crosstalk between p53 and TPT played a pivotal role for enhancing anticancer effects of PFTα and TPT on p53 positive cancer cells. These findings provide a new idea for drug design and combination chemotherapy of cancers.


Assuntos
Benzotiazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Tolueno/análogos & derivados , Topotecan/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Tolueno/administração & dosagem , Tolueno/química , Tolueno/farmacologia , Proteína Supressora de Tumor p53/genética
15.
Ecotoxicol Environ Saf ; 170: 306-313, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30530183

RESUMO

Novel brominated flame retardants (NBFRs), which are lipophilic compounds that have been widely applied after the phasing-out of legacy BFRs, can bioaccumulate through the food chain. However, information on NBFRs in animal feeds, the beginning of farm-to-fork pathway, is very limited. Fishmeal is one of the most widely applied feedstuff worldwide. The present study identified eleven NBFRs from ninety-two globally collected fishmeal samples with levels in the range of 0.13-822 (mean: 15.1 ±â€¯85.5) ng/g lipid weight (lw). Hexabromobenzene (HBB) and pentabromotoluene (PBT) were the most prevalent contributors (detection frequencies: 95.7% and 73.9%, respectively), and decabromodiphenylethane (DBDPE) was the weightiest contributor (accounted for 67.1% of the ΣNBFRs, mean: 12.1 ±â€¯84.8 ng/g lw). From a geographical view, the highest NBFR level was found in Chinese fishmeal. The NBFRs fell within an order of magnitude in South America, Southeast Asia, Europe and United States. DBDPE was predominant in the fishmeal collected from China, South America and United States, but it was not detected in European fishmeal. The NBFR levels are significantly lower compared to the polybrominated diphenyl ethers (PBDEs) (p < 0.01), indicating that the distribution of NBFRs was not as wide as PBDEs in fishmeal. DBDPE was significantly correlated with BDE209 (r = 0.557, p < 0.01), which implies that the two chemicals might have similar sources. Quantitative structure-activity relationship (QSAR)results imply that the NBFRs might have similar persistence and biomagnification potential as legacy lipophilic POPs.


Assuntos
Ração Animal/análise , Bromobenzenos/análise , Monitoramento Ambiental/métodos , Retardadores de Chama/análise , Contaminação de Alimentos/análise , Tolueno/análogos & derivados , Animais , China , Europa (Continente) , Cadeia Alimentar , Relação Quantitativa Estrutura-Atividade , América do Sul , Tolueno/análise
16.
J Adhes Dent ; 20(6): 541-547, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564801

RESUMO

PURPOSE: To evaluate the effect of a polymerization accelerator on the microtensile bond strength (µTBS) of etch-and-rinse and self-etch adhesives to eugenol-contaminated dentin. MATERIALS AND METHODS: Sixty flat dentin surfaces were prepared from human molars. Half of the specimens were restored with zinc oxide eugenol temporary cement (IRM) (eugenol-contaminated group) and the other half remained without restoration (control group). After 24-h storage, the cement was mechanically removed. Then the specimens in each group were further divided into three subgroups based on the application procedure of a polymerization accelerator (p-toluenesulfinic acid sodium salt; Accel): no application, 10-s application, or 30-s application. After air drying, the dentin surfaces were bonded with either a three-step etch-and-rinse adhesive (OptiBond FL) or a two-step self-etch adhesive (Clearfil SE Bond) and restored with composite. After 24-h water storage, the bonded specimens were subjected to the µTBS test. Data were analyzed by three-way ANOVA and Dunnett's T3 test (p < 0.05). RESULTS: The eugenol-contaminated groups had significantly lower µTBS than the control groups with both types of adhesives (p < 0.05), and the application of Accel significantly increased the compromised µTBS to eugenol-contaminated dentin. Optibond FL presented significantly higher µTBS to eugenol-contaminated dentin than did Clearfil SE Bond (p < 0.05). CONCLUSION: The application of a polymerization accelerator on eugenol-contaminated dentin prior to adhesive resin application increased the µTBS of both the three-step etch-and-rinse and two-step self-etch adhesive.


Assuntos
Luzes de Cura Dentária , Colagem Dentária , Cimentos Dentários , Eugenol , Resistência à Tração , Ataque Ácido Dentário , Cimentos Dentários/química , Cimentos Dentários/efeitos da radiação , Dentina/efeitos da radiação , Eugenol/análise , Humanos , Polimerização/efeitos da radiação , Tolueno/análogos & derivados
17.
Cell Physiol Biochem ; 51(1): 452-469, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30453300

RESUMO

BACKGROUND/AIMS: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4+ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. METHODS: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4+ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53-/-) mice or the specific inhibitor pifithrin-α (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real-time PCR, and cytokine levels in culture supernatants were determined by enzyme-linked immunosorbent assay. RESULTS: Splenic CD4+ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53-/-) maintained CD4+ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4+ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. CONCLUSION: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Sepse/patologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Células Jurkat , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Taxa de Sobrevida , Tolueno/análogos & derivados , Tolueno/farmacologia , Tolueno/uso terapêutico , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Regulação para Cima/efeitos dos fármacos
20.
J Am Chem Soc ; 140(40): 12808-12818, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30200760

RESUMO

The large family of mononuclear molybdenum and tungsten enzymes all possess the special ligand molybdopterin (MPT), which consists of a metal-binding dithiolene chelate covalently bound to a pyranopterin group. MPT pyran cyclization/scission processes have been proposed to modulate the reactivity of the metal center during catalysis. We have designed several small-molecule models for the Mo-MPT cofactor that allow detailed investigation into how pyran cyclization modulates electronic communication between the dithiolene and pterin moieties and how this cyclization alters the electronic environment of the molybdenum catalytic site. Using a combination of cyclic voltammetry, vibrational spectroscopy (FT-IR and rR), electronic absorption spectroscopy, and X-ray absorption spectroscopy, distinct changes in the Mo≡O stretching frequency, Mo(V/IV) reduction potential, and electronic structure across the pterin-dithiolene ligand are observed as a function of pyran ring closure. The results are significant, for they reveal that a dihydropyranopterin is electronically coupled into the Mo-dithiolene group due to a coplanar conformation of the pterin and dithiolene units, providing a mechanism for the electron-deficient pterin to modulate the Mo environment. A spectroscopic signature identified for the dihydropyranopterin-dithiolene ligand on Mo is a strong dithiolene → pterin charge transfer transition. In the absence of a pyran group bridge between pterin and dithiolene, the pterin rotates out of plane, largely decoupling the system. The results support a hypothesis that pyran cyclization/scission processes in MPT may function as a molecular switch to electronically couple and decouple the pterin and dithiolene to adjust the redox properties in certain pyranopterin molybdenum enzymes.


Assuntos
Coenzimas/química , Metaloproteínas/química , Pteridinas/química , Pterinas/química , Piranos/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Conformação Molecular , Oxirredução , Espectroscopia de Infravermelho com Transformada de Fourier , Tolueno/análogos & derivados , Tolueno/química
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