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1.
Curr Res Toxicol ; 6: 100152, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38327637

RESUMO

Heavy metals (HMs) are environmental pollutants that pose a threat to human health and have been accepted to cause various diseases, including cancer and developmental disorders. DNA replication stress has been identified to be associated with such diseases. However, the effect of HMs exclusively on DNA replication stress is still not well understood. In this study, DNA replication stress induced by thirteen HMs was assessed using a simplified in-vitro DNA replication model. Two parameters, Cte/Ctc reflecting the cycle threshold value alteration and Ke/Kc reflecting the linear phase slope change, were calculated based on the DNA replication amplification curve to evaluate the rate of exponential and linear phases. These parameters were used to detect the replication rate reflecting in-vitro DNA replication stress induced by tested HMs. According to the effective concentrations and rate-limiting degree, HMs were ranked as follows: Hg, Ce > Pb > Zn > Cr > Cd > Co > Fe > Mn, Cu, Bi, Sr, Ni. Additionally, EDTA could relieve the DNA replication stress induced by some HMs. In conclusion, this study highlights the potential danger of HMs themselves on DNA replication and provides new insight into the possible links between HMs and DNA replication-related diseases.

2.
Methods ; 222: 112-121, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215898

RESUMO

Design of molecules for candidate compound selection is one of the central challenges in drug discovery due to the complexity of chemical space and requirement of multi-parameter optimization. Here we present an application scenario-oriented platform (ID4Idea) for molecule generation in different scenarios of drug discovery. This platform utilizes both library or rule based and generative based algorithms (VAE, RNN, GAN, etc.), in combination with various AI learning types (pre-training, transfer learning, reinforcement learning, active learning, etc.) and input representations (1D SMILES, 2D graph, 3D shape, binding site, pharmacophore, etc.), to enable customized solutions for a given molecular design scenario. Besides the usual generation followed screening protocol, goal-directed molecule generation can also be conducted towards predefined goals, enhancing the efficiency of hit identification, lead finding, and lead optimization. We demonstrate the effectiveness of ID4Idea platform through case studies, showcasing customized solutions for different design tasks using various input information, such as binding pockets, pharmacophores, and compound representations. In addition, remaining challenges are discussed to unlock the full potential of AI models in drug discovery and pave the way for the development of novel therapeutics.


Assuntos
Desenho de Fármacos , Descoberta de Drogas , Sítios de Ligação , Algoritmos , Biblioteca Gênica
3.
Free Radic Biol Med ; 204: 20-27, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37094755

RESUMO

Acetylhydrazine (AcHZ), a major human metabolite of the widely-used anti-tuberculosis drug isoniazid (INH), was considered to be responsible for its serious hepatotoxicity and potentially fatal liver injury. It has been proposed that reactive radical species produced from further metabolic activation of AcHZ might be responsible for its hepatotoxicity. However, the exact nature of such radical species remains not clear. Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the initial N-centered radical intermediate can be detected and identified from AcHZ activated by transition metal ions (Mn(III)Acetate and Mn(III) pyrophosphate) and myeloperoxidase. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled AcHZ we synthesized. Additionally, the secondary C-centered radical was identified unequivocally as the reactive acetyl radical by complementary applications of ESR spin-trapping and persistent radical TEMPO trapping coupled with HPLC/MS analysis. This study represents the first detection and unequivocal identification of the initial N-centered radical and its exact location, as well as the reactive secondary acetyl radical. These findings should provide new perspectives on the molecular mechanism of AcHZ activation, which may have potential biomedical and toxicological significance for future research on the mechanism of INH-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hidrazinas , Humanos , Hidrazinas/metabolismo , Isoniazida/metabolismo , Antituberculosos/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres
4.
Int J Biol Macromol ; 231: 123503, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36736975

RESUMO

Evk (ethyl vinyl ketone) is a signal substance for plant defense, but little is known about how evk mediates stomatal closure. Through stomatal biology experiments, we found that evk can mediate stomatal closure, and stomatal closure is weakened when DORN1 (DOES NOT RESPOND TO NUCLEOTIDES 1) and GORK (GATED OUTWARDLY-RECTIFYING K+ CHANNEL) are mutated. In addition, it was found by non-invasive micro-test technology (NMT) that the K+ efflux mediated by evk was significantly weakened when DORN and GORK were mutated. Yeast two-hybrid (Y2H), firefly luciferase complementation imaging (LCI), and in vitro pull-down assays demonstrated that DORN1 and GORK could interact in vitro and in vivo. It was found by molecular docking that evk could combine with MRP (Multidrug Resistance-associated Protein), thus affecting ATP transport, promoting eATP (extracellular ATP) concentration increase and realizing downstream signal transduction. Through inoculation of botrytis cinerea, it was found that evk improved the antibacterial activity of Arabidopsis thaliana. As revealed by reverse transcription quantitative PCR (RT-qPCR), the expression of defense related genes was enhanced by evk treatment. Evk is a potential green antibacterial drug.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Compostos Orgânicos Voláteis , Arabidopsis/metabolismo , Simulação de Acoplamento Molecular , Canais de Potássio/genética , Proteínas de Arabidopsis/metabolismo , Trifosfato de Adenosina/metabolismo
5.
Angew Chem Int Ed Engl ; 62(18): e202301059, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-36815280

RESUMO

Adjuvants stimulate the immune system to vigorously respond to a vaccine. While current adjuvants such as aluminum salts and oil-in-water emulsions have been used for decades, they do not generate broad and long-lasting responses in many vaccines. Consequently, more potent adjuvants are needed. Here, using computer-aided molecule design and machine learning, we discovered 2 new, broad-spectrum adjuvants that can boost vaccine responses. Our library containing 46 toll-like receptor (TLR)-targeting agonist ligands were assembled on Au nanoparticles. Comprehensive in vitro, ex vivo and in vivo studies showed both leads promoted dendritic cell activation via multiple TLRs and enhanced antigen presentation to T cells. When used together with tumor-specific antigens to immunize mice against B16-OVA melanoma and 4T1-PD1 breast cancer, both adjuvants unleashed strong immune responses that suppressed tumor growth and lung metastases. Our results show computer-aided design and screening can rapidly uncover potent adjuvants for tackling waning immunity in current vaccines.


Assuntos
Nanopartículas Metálicas , Neoplasias , Vacinas , Animais , Camundongos , Adjuvantes de Vacinas , Ouro , Adjuvantes Imunológicos/farmacologia , Antígenos de Neoplasias
6.
Adv Sci (Weinh) ; 9(29): e2202679, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36031399

RESUMO

Excess iron accumulation occurs in organs of patients with certain genetic disorders or after repeated transfusions. No physiological mechanism is available to excrete excess iron and iron overload to promote lipid peroxidation to induce ferroptosis, thus iron chelation becomes critical for preventing ion toxicity in these patients. To date, several iron chelators have been approved for iron chelation therapy, such as deferiprone and deferoxamine, but the current iron chelators suffer from significant limitations. In this context, new agents are continuously sought. Here, a library of new deferric amine compounds (DFAs) with adjustable skeleton and flexibility is synthesized by adopting the beneficial properties of conventional chelators. After careful evaluations, compound DFA1 is found to have greater efficacy in binding iron through two molecular oxygens in the phenolic hydroxyl group and the nitrogen atom in the amine with a 2:1 stoichiometry. This compound remarkably ameliorates iron overload in diverse murine models through both oral and intravenous administration, including hemochromatosis, high iron diet-induced, and iron dextran-stimulated iron accumulation. Strikingly, this compound is found to suppress iron-induced ferroptosis by modulating the intracellular signaling that drives lipid peroxidation. This study opens a new approach for the development of iron chelators to treat iron overload.


Assuntos
Ferroptose , Hemocromatose , Sobrecarga de Ferro , Aminas , Animais , Deferiprona , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Dextranos , Humanos , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Camundongos , Nitrogênio , Piridonas/farmacologia , Piridonas/uso terapêutico
7.
Chem Res Toxicol ; 35(6): 1023-1035, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35575305

RESUMO

2,2',4,4'-Tetrabromodiphenyl ether (PBDE 47) is one of the most prominent PBDE congeners detected in the human body, suggesting that the potential health risks of PBDE 47 should be thoroughly considered. However, the cardiovascular toxicity of PBDE 47 remains poorly understood. Here, toxic outcomes of PBDE 47 in human THP-1 macrophages concerning foam cell formation, which play crucial roles in the occurrence and development of atherosclerosis, were elucidated. First, our results indicated that PBDE 47 affected the PPARγ pathway most efficiently in THP-1 macrophages by transcriptomic analysis. Second, the PPARγ target genes CD36 and FABP4, responsible for lipid uptake and accumulation in macrophages, were consistently upregulated both at transcriptional and translational levels in THP-1 macrophages upon PBDE 47. Unexpectedly, PBDE 47 failed to activate the PPARγ target gene LXRα and PPARγ-LXRα-ABCA1/G1 cascade, which is activated by the PPARγ full agonist rosiglitazone and enables cholesterol efflux in macrophages. Thus, coincident with the selective upregulation of the PPARγ target genes CD36 and FABP4, PBDE 47, distinct from rosiglitazone, functionally resulted in more lipid accumulation and oxLDL uptake in THP-1 macrophages through high-content analysis (HCA). Moreover, these effects were markedly abrogated by the addition of the PPARγ antagonist T0070907. Mechanistically, the structural basis of selective activation of PPARγ by PBDE 47 was explored by molecular docking and dynamics simulation, which indicated that PBDE 47 interacted with the PPARγ ligand binding domain (PPARγ-LBD) distinctively from that of rosiglitazone. PBDE 47 was revealed to interact with helix 3 and helix 5 but not helix 12 in the PPARγ-LBD. Collectively, these results unraveled the potential cardiovascular toxicity of PBDE 47 by selective activation of PPARγ to facilitate foam cell formation for the first time.


Assuntos
Células Espumosas , PPAR gama , Antígenos CD36/genética , Linhagem Celular , Colesterol/metabolismo , Éter/metabolismo , Células Espumosas/metabolismo , Éteres Difenil Halogenados , Humanos , Receptores X do Fígado , Macrófagos/metabolismo , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Rosiglitazona
8.
Environ Pollut ; 300: 118965, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35134429

RESUMO

Zero valent iron-loaded biochar (Fe0-BC) has shown promise for the removal of various organic pollutants, but is restricted by reduced specific surface area, low utilization efficiency and limited production of reactive oxygen species (ROS). In this study, iron carbide-loaded activated biochar (Fe3C-AB) with a high surface area was synthesized through the pyrolysis of H3PO4 activated biochar with Fe(NO3)3, tested for removing bisphenol A (BPA) and elucidated the adsorption and degradation mechanisms. As a result, H3PO4 activated biochar was beneficial for the transformation of Fe0 to Fe3C. Fe3C-AB exhibited a significantly higher removal rate and removal capacity for BPA than that of Fe0-BC within a wide pH range of 5.0-11.0, and its performance was maintained even under extremely high salinity and different water sources. Moreover, X-ray photoelectron spectra and density functional theory calculations confirmed that hydrogen bonds were formed between the COOH groups and BPA. 1O2 was the major reactive species, constituting 37.0% of the removal efficiency in the degradation of BPA by Fe3C-AB. Density functional reactivity theory showed that degradation pathway 2 of BPA was preferentially attacked by ROS. Thus, Fe3C-AB with low cost and excellent recycling performance could be an alternative candidate for the efficient removal of contaminants.


Assuntos
Ferro , Poluentes Químicos da Água , Adsorção , Compostos Benzidrílicos , Compostos Inorgânicos de Carbono , Carvão Vegetal/química , Ferro/química , Compostos de Ferro , Fenóis , Poluentes Químicos da Água/análise
9.
Environ Pollut ; 291: 118244, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592327

RESUMO

In this study, N-functionalized biochars with varied structural characteristics were designed by loading poplar leaf with different amounts of urea at 1:1 and 1:3 ratios through pyrolysis method. The addition of urea significantly increased the N content of biochar and facilitated the formation of amine (-NH-, -NH2), imine (-HCNH), benzimidazole (-C7H5N2), imidazole (-C3H3N2), and pyrimidine (-C4H3N2) groups due to substitution reaction and Maillard reaction. The effect of pH on Cr(VI) removal suggested that decrease in solution pH favored the formation of electrostatic attraction between the protonated functional groups and HCrO4-. And, experimental and density functional theory study were used to probe adsorption behaviors and adsorption mechanism which N-functionalized biochars interacted with Cr(VI). The protonation energy calculations indicated that N atoms in newly formed N-containing groups were better proton acceptors. Adsorption kinetics and isotherm experiments exhibited that N-functionalized biochars had greater removal rate and removal capacity for Cr(VI). The removal rate of Cr(VI) on N-functionalized biochar was 10.5-15.5 times that of untreated biochar. Meanwhile, N-functionalized biochar of NB3 with the largest number of adsorption sites for -C7H5N2, -NH2, -OH, -C3H3N2, and phthalic acid (-C8H5O4) exhibited the supreme adsorption capacity for Cr(VI) through H bonds and the highest adsorption energy was -5.01 kcal/mol. These mechanistic findings on the protonation and adsorption capacity are useful for better understanding the functions of N-functionalized biochars, thereby providing a guide for their use in various environmental applications.


Assuntos
Poluentes Químicos da Água , Carvão Vegetal , Cromo/análise , Poluentes Químicos da Água/análise
10.
Mar Drugs ; 19(6)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073769

RESUMO

It is known that bioactivities of chitooligosaccharide (COS) are closely related to the degree of polymerization (DP); therefore, it is essential to prepare COS with controllable DP, such as chitobiose showing high antioxidant and antihyperlipidemia activities. In this study, BLAST, sequence alignment and phylogenetic analysis of characterized glycoside hydrolase (GH) 46 endo-chitosanases revealed that a chitosanase Sn1-CSN from Streptomyces niveus was different from others. Sn1-CSN was overexpressed in E. coli, purified and characterized in detail. It showed the highest activity at pH 6.0 and exhibited superior stability between pH 4.0 and pH 11.0. Sn1-CSN displayed the highest activity at 50 °C and was fairly stable at ≤45 °C. Its apparent kinetic parameters against chitosan (DDA: degree of deacetylation, >94%) were determined, with Km and kcat values of 1.8 mg/mL and 88.3 s-1, respectively. Cu2+ enhanced the activity of Sn1-CSN by 54.2%, whereas Fe3+ inhibited activity by 15.1%. Hydrolysis products of chitosan (DDA > 94%) by Sn1-CSN were mainly composed of chitobiose (87.3%), whereas partially acetylated chitosan with DDA 69% was mainly converted into partially acetylated COS with DP 2-13. This endo-chitosanase has great potential to be used for the preparation of chitobiose and partially acetylated COS with different DPs.


Assuntos
Glicosídeo Hidrolases , Streptomyces/enzimologia , Sequência de Aminoácidos , Quitosana/química , Quitosana/metabolismo , Dissacarídeos/metabolismo , Escherichia coli/genética , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Concentração de Íons de Hidrogênio , Hidrólise , Metais/química , Simulação de Acoplamento Molecular , Filogenia , Temperatura
11.
Org Lett ; 23(9): 3264-3268, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33835803

RESUMO

The stereoselective total synthesis of siladenoserinols A and D has been accomplished using carbohydrate as a chiral template. The feature of this work is to build the medicinally privileged 6,8-DOBCO scaffold through a cascade reaction of hydrogenation/deacetalization/ketalization in a one-pot process, that is, to take advantage of a thermodynamically controlled bicyclization of polyhydroxyketone under HCl/MeOH reaction conditions. The current cost-effective synthetic strategy could facilitate the bioactivity investigation of siladenoserinols.

12.
Sheng Wu Gong Cheng Xue Bao ; 37(1): 178-186, 2021 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-33501799

RESUMO

In order to establish an infectious clone for CDV-3, a commercial vaccine strain of canine distemper virus for mink, to provide reference for the studies of pathogenesis and novel vaccine development of CDV. Thirteen pairs of primers were used to amplify the full-length genome of CDV-3 strain. Five long fragments were obtained based on single restriction site analysis of the whole genome of CDV-3 by RT-PCR. Five fragments were successively inserted into the multiple clone sites in the modified eukaryotic vector of pcDNA3.2 by restriction enzymes and splicing. Meanwhile, the hammerhead ribozyme and hepatitis delta virus ribozyme sequences were added to the beginning of F1 fragment and the ending of F5 fragment, respectively. Then, the full-length cDNA recombinant plasmid of CDV-3 was obtained and named as pcDNA3.2-CDV-3. In addition, three helper plasmids, expressing the N protein, P protein and L protein of the CDV-3 strain respectively, were constructed. The 293T cells were transfected with the full-length cDNA recombinant plasmid and three helper plasmids by Lipofectamine™ 2000. At 3 days post transfection, the supernatant was added to the monolayer of Vero cells to observe the typical syncytium of CDV. Indirect immunofluorescence and artificial label identification of recombinant virus rCDV-3 were conducted after the occurrence of lesions. Finally, the growth characteristics of wtCDV-3 and rCDV-3 were compared after passaging of rCDV-3. The identification of the full-length cDNA recombinant plasmid and three helper plasmids by restriction enzyme digestion and sequencing were consistent with expected. The Vero cells infected with the recombinant rCDV-3 showed typical syncytic. The identification of indirect immunofluorescence and labeled marker, and observation under electron microscope proved that the rCDV-3 was indeed rescued from the recombinant plasmid of pcDNA3.2-CDV-3. In comparison of the virus titers of wtCDV-3, rCDV-3 replicated massively and rapidly and reached the maximize virus titer of 107·667 TCID50/mL within 36 h post infection (p.i.) in Vero cells, while wtCDV-3 grew gradually to 106·667 TCID50/mL at 72 h p.i. in Vero cells. This reverse genetic system of CDV-3 strain has been established successfully, to provide reference for the studies of pathogenesis and novel vaccine development of CDV.


Assuntos
Vírus da Cinomose Canina , Animais , Chlorocebus aethiops , Células Clonais , DNA Complementar , Vírus da Cinomose Canina/genética , Plasmídeos/genética , Células Vero
13.
J Hazard Mater ; 403: 123889, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33264955

RESUMO

In the last years, the synthesis and applications of biochar/Fe composites have been extensively studied, but only few papers have systematically evaluated their removal performances. Herein, we successfully synthesized and structurally characterized Fe0, Fe3C, and Fe3O4-coated biochars (BCs) for the removal of chlortetracycline hydrochloride (CH). Evaluation of their removal rate and affinity revealed that Fe0@BC could achieve better and faster CH removal and degradation than Fe3C@BC and Fe3O4@BC. The removal rate was controlled by the O-Fe content and solution pH after the reaction. The CH adsorption occurred on the O C groups of Fe0@BC and the OC and OFe groups of Fe3C@BC and Fe3O4@BC. Electron paramagnetic resonance analysis and radical quenching experiments indicated that HO and 1O2/ O2- were mainly responsible for CH degradation by biochar/Fe composites. Additional parameters, such as effects of initial concentrations and coexisting anions, regeneration capacity, cost and actual wastewater treatment were also explored. Principal component analysis was applied for a comprehensive and quantitative assessment of the three materials, indicating Fe0@BC is the most beneficial functional material for CH removal.


Assuntos
Clortetraciclina , Poluentes Químicos da Água , Purificação da Água , Adsorção , Carvão Vegetal , Poluentes Químicos da Água/análise
14.
J Hazard Mater ; 404(Pt A): 124162, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33065456

RESUMO

The adsorption of Cr(VI) on biochars can be suppressed by coexisting anions, but the roles of O-containing functional groups and in particular N-containing functional groups are unclear. In this study, we combined spectroscopic and molecular simulation approaches to investigate the selective adsorption of Cr(VI) on the O-rich (PB, UB1) and N-rich (UB3, UB5) biochars under strong competition of anions. The elemental analysis and pyrolysis-gas chromatography/mass spectrometry indicated that the structures of PB and UB1 were similar, and so were the UB3 and UB5. Quantification of functional groups showed that for UB1, 75.3% of Cr(VI) removal was attributed to O-containing groups, while 53.3-72.7% of that was mediated by N-containing groups in UB3 and UB5. X-ray photoelectron spectra and density functional theory calculations confirmed that for O-rich biochars, surface complexation and strong H-bonds between carboxyl/hydroxyl and HCrO4- improved Cr(VI) removal in the presence of anions, while for N-rich biochars, Cr(VI) adsorption was depressed by coexisting anions in the order of Cl->NO3- >SO42- because of the weaker H-bond between protonated amino groups and HCrO4-. This study presents a novel approach for quantitative, molecular-level evaluation of the roles of biochar functional groups in the Cr(VI) removal from complex environmental systems.


Assuntos
Carvão Vegetal , Poluentes Químicos da Água , Adsorção , Cromo/análise , Poluentes Químicos da Água/análise
15.
Adv Sci (Weinh) ; 7(14): 2000609, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32714765

RESUMO

Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α-galactosylceramide (α-GalCer, KRN7000), a well-studied Th1-polarizer, simultaneously induces helper T cell 2 (Th2)-type responses, which is a major drawback for its clinical applications. Based on surflex-docking computation, α-GalCer-diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α-GalCer-diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self-activation, as reflected by tight binding of the T-cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL-12) and interferon-γ (IFN-γ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1-type cytokine profile ex vivo and in vivo. Different from KRN7000, α-GalCer-diol markedly boosts the expansion of the CD11b+ subpopulation and enhances IFN-γ content in CD11b+ cells. These reinforced Th1-type responses collectively endow α-GalCer-diol more robust antitumor activity in a xenograft animal model using B16-F10 melanoma cells. Together, the data demonstrate a new mechanism through which α-GalCer-diol induces stronger Th1-type responses by stimulating CD11b+ leukocyte expansion and DC-conducted CD1d-restricted and TCR-mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.

16.
Carbohydr Res ; 491: 107977, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32169593

RESUMO

Based on structure analyses of butyrylcholinesterase (BChE), a series of 21 acridone glycosides were designed, synthesized and evaluated in vitro for their BChE and acetylcholinesterase (AChE) inhibitory activities. d-ribose derivative 6f exhibited the greatest inhibitory activity on BChE (IC50 = 6.95 µM), and was the most selective inhibitor of BChE with the IC50 ratio of AChE/BChE was 20.59. d-glucose and d-galactose derivatives 6a and 6b showed inhibitory activities against both AChE and BChE. Moreover, compounds 6a, 6b, 6f and 5t were found nontoxic on SHSY5Y neuroblastoma and HepG2 cell and exhibited remarkable neuroprotective activity. Besides, compound 6f showed mixed-type inhibition against BChE (Ki = 1.76 µM), which renders 6f a potential agent for the treatment of Alzheimer's disease. These novel acridone hybrids might be used as efficient probes to reveal the relationship between ligands and BChE and pave the way for developing selective BChE inhibitors to further study the pathogenesis of alzheimer's disease.


Assuntos
Acridonas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Glicosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Acridonas/síntese química , Acridonas/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Glicosídeos/síntese química , Glicosídeos/química , Células Hep G2 , Cavalos , Humanos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 28(1): 115141, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786009

RESUMO

Invariant natural killer T-cells (iNKT-cells) are promising targets for manipulating the immune system, which can rapidly release a large amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipid antigens presented by CD1d. In this paper, we wish to report a novel series of α-GalCer analogues which were synthesized by incorporation of l-amino acid methyl esters in the C-6' position of glycolipid. The evaluation of these synthetic analogues for their capacities to stimulate iNKT-cells into producing Th1 and Th2 cytokines both in vitro and in vivo indicated that they were potent CD1d ligands and could stimulate murine spleen cells into a higher release of the Th1 cytokine IFN-γ in vitro. In vivo, Gly-α-GalCer (1) and Lys-α-GalCer (3) showed more Th1-biased responses than α-GalCer, especially analogue 3 showed the highest selectivity for IFN-γ production (IFN-γ/IL-4 = 5.32) compared with α-GalCer (IFN-γ/IL-4 = 2.5) in vivo. These novel α-GalCer analogues might be used as efficient X-ray crystallographic probes to reveal the relationship between glycolipids and CD1d proteins in α-GalCer/CD1d complexes and pave the way for developing new potent immunostimulating agents.


Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoácidos/farmacologia , Citocinas/biossíntese , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/química , Aminoácidos/química , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Relação Dose-Resposta a Droga , Feminino , Galactosilceramidas/síntese química , Galactosilceramidas/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Células T Matadoras Naturais/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 29(11): 1357-1362, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935793

RESUMO

The binding properties of CD1d/glycolipid/TCR, glycolipid/TCR interactions in particular, have been investigated using docking computation. Accordingly, efficient modification on C-6' of galactose head was recommended in this report to favor the production of Th2 cytokines. The designed glycolipids have been successfully prepared taking advantages of inverse glycosylation procedure, and their abilities to stimulate mouse iNKT cells in vivo have been tested. Compound 9, having p-hydroxyphenylpropionyl amide group on C-6', presented the best result with respect to the selectivity and quantity on Th2-type cytokine IL-4. We found that the increased glycolipid/TCR interaction might be critical in designing new substrate with Th2-biased cytokine production.


Assuntos
Citocinas/biossíntese , Desenho de Fármacos , Galactosilceramidas/farmacologia , Animais , Antígenos CD1d , Relação Dose-Resposta a Droga , Galactosilceramidas/síntese química , Galactosilceramidas/química , Camundongos , Estrutura Molecular , Células T Matadoras Naturais , Relação Estrutura-Atividade , Células Th2
19.
Sci Total Environ ; 670: 67-77, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30903904

RESUMO

"Obesogens" have been widely accepted as chemicals that promote obesity, and there are many environmental pollutants that were functionally identified as obesogens. PBDE 99 is one of the most abundant PBDE congeners detected in human. However, its obesogenic effects are poorly understood. Here, we explore the in vitro effects of PBDE 99 on adipogenesis, which is a key process in obesogenesis. We observed an increase in adipogenesis when differentiating cells were exposed to PBDE 99. Further, the promoting effects of PBDE 99 on adipogenesis were most efficient during the first 4 days of 3T3-L1 differentiation. Consistent with this, early transcriptional factor CCAAT/enhancer-binding proteins ß (C/EBPß) was upregulated at Days 1 and 2 during differentiation, which is accompanied with the acceleration of mitotic clonal expansion (MCE) and the upregulation of terminal transcriptional factors C/EBPα and PPARγ2 from Day 2 or Day 4. Additionally, bisulfite genomic sequencing analysis revealed that PBDE 99 decreased methylation status of the CpG sites at PPARγ promoter region. Collectively, these findings demonstrate that PBDE 99 may be a potential environmental obesogen by promoting adipogenesis through facilitating MCE progression at early differentiation stage and upregulating key adipogenic factor PPARγ2 expression both in direct transcriptional and epigenetic regulation dependent manner.


Assuntos
Adipogenia/efeitos dos fármacos , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Proteína beta Intensificadora de Ligação a CCAAT , Diferenciação Celular , Epigênese Genética , Humanos , Camundongos , Testes de Toxicidade , Ativação Transcricional
20.
ACS Med Chem Lett ; 10(3): 394, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891148

RESUMO

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00640.].

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