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1.
Food Chem Toxicol ; 135: 110991, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765699

RESUMO

The goal of this research was to study the selective pro-apoptotic effect of ligustilide on prostate-cancer-associated fibroblast in the tumor microenvironment and the related molecular mechanisms. The effects of ligustilide on cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs) isolated from the prostate were determined by MTT assay. Flow cytometry and cellular immunofluorescence were used to detect the effects of ligustilide on the cell cycle and apoptosis. Western blotting was used to detect the expression of apoptosis-related proteins after the action of ligustilide on CAFs. In the investigation, ligustilide had a selective pro-apoptotic effect on prostate-CAFs. After ligustilide treatment, the proportion of CAFs in the G2-M phase of the cell cycle increased, and the expression of apoptosis-related proteins (p-P53, Bcl-2, Caspase9 and Cytochrome C) changed. Ligustilide blocks the CAF cell cycle and induces the apoptosis of CAFs.


Assuntos
4-Butirolactona/análogos & derivados , Apoptose/efeitos dos fármacos , Fibroblastos Associados a Câncer/efeitos dos fármacos , Neoplasias da Próstata/patologia , Receptor 4 Toll-Like/metabolismo , 4-Butirolactona/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/genética , Microambiente Tumoral
2.
Eur J Med Chem ; 187: 111969, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865018

RESUMO

Compounds inducing adiponectin production have therapeutic potential for metabolic diseases. During screening, heme oxygenase-1-inducing marliolide derivatives were identified as adiponectin-inducing compounds. Although some marliolide derivatives were directly bound to peroxisome proliferator-activated receptor γ (PPARγ), the adiponectin-inducing activity did not correlate with the PPARγ binding affinity. The most potent adiponectin inducing compound, (E,4S,5S)-3-butylidene-dihydro-4-hydroxy-5-methylfuran-2(3H)-one (1a), exhibited the weakest PPARγ binding activity. A docking simulation suggested that two 1a molecules can be present in two different sites within the PPARγ-ligand-binding pocket (LBP). Based on the docking model, novel linked butanolide dimer compounds were synthesized. A linked butanolide dimer compound, (3E,3'E,4S,4'S,5S,5'S)-3,3'-(decane-1,10-diylidene)bis(4-hydroxy-5-methyldihydrofuran-2(3H)-one) (3a), promoted adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs) as a novel PPARγ full agonist (EC50, 4.34 µM). This linked butanolide dimer study provides novel insight into PPARγ biology, suggesting that small molecules can form multiple ligand interactions within the PPARγ-LBP and thereby affect the functional outcomes of PPARγ activation.


Assuntos
4-Butirolactona/farmacologia , Adipogenia/efeitos dos fármacos , Adiponectina/biossíntese , Células-Tronco Mesenquimais/efeitos dos fármacos , PPAR gama/agonistas , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Células Cultivadas , Dimerização , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Mesenquimais/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/metabolismo , Relação Estrutura-Atividade
3.
Chem Pharm Bull (Tokyo) ; 67(10): 1088-1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582628

RESUMO

In this study, we synthesized four series of novel L-homoserine lactone analogs and evaluated their in vitro quorum sensing (QS) inhibitory activity against two biomonitor strains, Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Studies of the structure-activity relationships of the set of L-homoserine lactone analogs indicated that phenylurea-containing N-dithiocarbamated homoserine lactones are more potent than (Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (C30), a positive control for biofilm formation. In particular, compared with C30, QS inhibitor 11f significantly reduced the production of virulence factors (pyocyanin, elastase and rhamnolipid), swarming motility, the formation of biofilm and the mRNA level of QS-related genes regulated by the QS system of PAO1. These results reveal 11f as a potential lead compound for developing novel antibacterial quorum sensing inhibitors.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pseudomonas aeruginosa/crescimento & desenvolvimento , Percepção de Quorum/genética , Relação Estrutura-Atividade
4.
Nat Commun ; 10(1): 4129, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511505

RESUMO

Synthetic biology and metabolic engineering have expanded the possibilities for engineered cell-based systems. The addition of non-native biosynthetic and regulatory components can, however, overburden the reprogrammed cells. In order to avoid metabolic overload, an emerging area of focus is on engineering consortia, wherein cell subpopulations work together to carry out a desired function. This strategy requires regulation of the cell populations. Here, we design a synthetic co-culture controller consisting of cell-based signal translator and growth-controller modules that, when implemented, provide for autonomous regulation of the consortia composition. The system co-opts the orthogonal autoinducer AI-1 and AI-2 cell-cell signaling mechanisms of bacterial quorum sensing (QS) to enable cross-talk between strains and a QS signal-controlled growth rate controller to modulate relative population densities. We further develop a simple mathematical model that enables cell and system design for autonomous closed-loop control of population trajectories.


Assuntos
Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Técnicas de Cocultura/métodos , Transdução de Sinais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Proliferação de Células/efeitos dos fármacos , Homosserina/análogos & derivados , Homosserina/farmacologia , Lactonas/farmacologia , Modelos Biológicos , Percepção de Quorum/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Artigo em Inglês | MEDLINE | ID: mdl-31434344

RESUMO

Despite the adverse effects of emerging ZnO nanoparticles (nano-ZnO) on wastewater biological nitrogen removal (BNR) systems being widely documented, strategies for mitigating nanoparticle (NP) toxicity impacts on nitrogen removal have not been adequately addressed. Herein, N-acyl-homoserine lactone (AHL)-based quorum sensing (QS) was investigated for its effects against nano-ZnO toxicity to a model nitrifier, Nitrosomonas europaea. The results indicated that AHL-attenuated nano-ZnO toxicity, which was inversely correlated with the increasing dosage of AHL from 0.01 to 1 µM. At 0.01 µM, AHL notably enhanced the tolerance of N. europaea cells to nano-ZnO stress, and the inhibited cell proliferation, membrane integrity, ammonia oxidation rate, ammonia monooxygenase activity and amoA gene expression significantly increased by 18.2 ± 2.1, 2.4 ± 0.9, 58.7 ± 7.1, 32.3 ± 1.7, and 7.3 ± 5.9%, respectively, after 6 h of incubation. However, increasing the AHL dosage compromised the QS-mediated effects and even aggravated the NPs' toxicity effects. Moreover, AHLs, at all tested concentrations, significantly increased superoxide dismutase activity, indicating the potential of QS regulations to enhance cellular anti-oxidative stress capacities when facing NP invasion. These results provide novel insights into the development of QS regulation strategies to reduce the impact of nanotoxicity on BNR systems.


Assuntos
4-Butirolactona/análogos & derivados , Nanopartículas Metálicas/química , Nitrosomonas europaea/efeitos dos fármacos , Transdução de Sinais , Óxido de Zinco/química , 4-Butirolactona/farmacologia , Nitrosomonas europaea/metabolismo , Oxirredução , Percepção de Quorum
6.
Molecules ; 24(14)2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330867

RESUMO

Three new γ-hydroxyl butenolides (1-3), a pair of new enantiomeric spiro-butenolides (4a and 4b), a pair of enantiomeric cyclopentenones (5a new and 5b new natural), and six known compounds (6-11), were isolated from Aspergillus sclerotiorum. Their structures were established by spectroscopic data and electronic circular dichroism (ECD) spectra. Two pairs of enantiomers [(+)/(-)-6c and (+)/(-)-6d] obtained from the reaction of 6 with acetyl chloride (AcCl) confirmed that 6 was a mixture of two pairs of enantiomers. In addition, the X-ray data confirmed that 7 was also a racemate. The new metabolites (1-5) were evaluated for their inhibitory activity against cancer and non-cancer cell lines. As a result, compound 1 exhibited moderate cytotoxicity to HL60 and A549 with IC50 values of 6.5 and 8.9 µM, respectively, and weak potency to HL-7702 with IC50 values of 17.6 µM. Furthermore, compounds 1-9 were screened for their antimicrobial activity using the micro-broth dilution method. MIC values of 200 µg/mL were obtained for compounds 2 and 3 towards Staphylococcus aureus and Escherichia coli, while compound 8 exhibited a MIC of 50 µ/mL towards Candida albicans.


Assuntos
4-Butirolactona/análogos & derivados , Aspergillus/química , Ciclopentanos/química , Microbiologia do Solo , Solo/química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
7.
Biomed Pharmacother ; 117: 109074, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177061

RESUMO

Atherosclerosis is initiated by the local inflammation response to lipid deposition, and the most commonly administered antiatherogenic drugs are statins. Based on traditional Chinese medicine (TCM) evidence, we aimed to find effective therapeutic agents other than statins. A TCM, Suxiao Jiuxin Pill (SX), has been widely used in curing cardiovascular diseases for thirty years. In this paper, a combination of pharmacologic studies and RNA-Seq transcriptomics were employed to explore the pharmacodynamic advantages of SX over atorvastatin in the ApoE-/- mouse. 113 differentially expressed genes that were modulated by SX to a greater degree than atorvastatin were primarily involved in immunomodulation. The expression of BTK, AKT1, c-jun and CD137 was effectively regulated by SX with better effect than atorvastatin. Then a dual-luciferase reporter assay for NF-κB inhibition was applied to identify active components in SX. As a result, Senkyunolide A (Sen A) and Ligustilide (Lig), the key immunomodulatory ingredients in SX, were found to inhibit the expression of CD137 which is a diagnostic biomarker in atherosclerosis. It was further confirmed that Lig effectively suppressed the expression of AP-1 and NF-κB and the phosphorylation of AKT. Therefore, Lig achieved its CD137 inhibition through suppressing the expression of AP-1 and AKT/NF-κB signaling pathway, which partly explains the immunomodulation of SX in atherosclerosis. Above all, phthalides may be the primary components of SX improving immune and inflammation response in atherosclerosis.


Assuntos
4-Butirolactona/análogos & derivados , Aterosclerose/tratamento farmacológico , Benzofuranos/farmacologia , Fatores Imunológicos/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , 4-Butirolactona/química , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Benzofuranos/química , Benzofuranos/uso terapêutico , Células HEK293 , Humanos , Fatores Imunológicos/sangue , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
8.
Blood Cells Mol Dis ; 79: 102340, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31207554

RESUMO

Acyl-homoserine lactones (AHLs), are the key autoinducer molecules that mediate Pseudomonas aeruginosa associated quorum sensing. P. aeruginosa produces two types of AHLs; N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12 HSL) and N-butyryl-L-homoserine lactone (C4 HSL). AHLs are not only regulating the virulence gene of bacteria but also influence the host cell functions by interkingdom signaling. In this study, we explored the mechanism of AHLs induced calcium mobilization in human platelets. We found that 3-oxo-C12 HSL but not C4 HSL induces intracellular calcium release. 3-oxo-C12 HSL induced calcium mobilization was majorly contributed from the dense tubular system (DTS). Furthermore, 3-oxo-C12 HSL also stimulates the store-operated Ca2+ entry (SOCE) in platelet. Intracellular calcium rise was significantly lowered in rotenone, and bafilomycin pre-treated platelets suggesting partial involvement of mitochondria and acidic vacuoles. The significant effect of 3-oxo-C12 HSL on calcium mobilization can alter the platelet functions that might results in thrombotic disorders in individuals infected with P. aeruginosa.


Assuntos
4-Butirolactona/análogos & derivados , Plaquetas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Homosserina/análogos & derivados , Pseudomonas aeruginosa/patogenicidade , 4-Butirolactona/farmacologia , Plaquetas/efeitos dos fármacos , Cálcio/metabolismo , Homosserina/farmacologia , Humanos , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos , Virulência
9.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163670

RESUMO

Three new butenolide derivatives, namely aspernolides N-P (1-3), together with six known analogues (4-9), were isolated from the ethyl acetate (EtOAc) extract of the deep sea-derived fungus Aspergillus terreus YPGA10. The structures of compounds 1-3 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compound 1 represents the rare example of Aspergillus-derived butenolide derivatives featured by a monosubstituted benzene ring. Compounds 6-9 exhibited remarkable inhibitory effects against α-glucosidase with IC50 values of 3.87, 1.37, 6.98, and 8.06 µM, respectively, being much more active than the positive control acarbose (190.2 µM).


Assuntos
4-Butirolactona/análogos & derivados , Organismos Aquáticos/química , Aspergillus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Acetatos/química , Dicroísmo Circular , Ativação Enzimática/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
10.
Pestic Biochem Physiol ; 157: 204-210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153470

RESUMO

Sulfoxaflor is the first commercially available sulfoximine insecticide, which exhibits highly efficacy against many sap-feeding insect pests and has been applied as an alternative insecticide against cotton aphid in China. This study was conducted to investigate the risk of resistance development, the cross-resistance pattern and the potential resistance mechanisms of sulfoxaflor in Aphis gossypii. A colony (SulR strain) of A. gossypii with 245-fold resistance, originated from Xinjiang field population, was established by continuous selection using sulfoxaflor. The SulR strain has developed cross-resistance to imidacloprid (80.8-fold), acetamiprid (19.3-fold), thiamethoxam (10.0-fold), and flupyradifurone (107.5-fold), while no cross-resistance was detected to malathion, omethoate, bifenthrin, methomyl, and carbosulfan. Piperonyl butoxide and S, S, S-tributyl phosphorotrithioate could significantly increase the toxicity of sulfoxaflor to the SulR strain by 5.99- and 4.18-fold, respectively, whereas no synergistic effect with diethyl maleate was observed. The activities of P450s and carboxylesterase were significantly higher in the SulR strain than that in the SS strain. Further gene expression determination demonstrated that nine P450 genes were significantly increased in SulR strain and suppression the expression of CYP6CY13 and CYP6CY19 by RNAi significantly increased the susceptibility of SulR adult aphids to sulfoxaflor. These results demonstrated that the enhancing detoxification by cytochrome P450 monooxygenase may be involved in A.gossypii resistance to sulfoxaflor.


Assuntos
Afídeos/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Piridinas/farmacologia , Compostos de Enxofre/farmacologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Afídeos/genética , Afídeos/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Piretrinas/farmacologia
11.
Mol Med Rep ; 20(1): 198-204, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115578

RESUMO

The present study aimed to investigate the antibacterial activity of striatisporolide A (SA) against Escherichia coli (E. coli) and the underlying mechanism. Antibacterial activity was evaluated according to the inhibitory rate and zone of inhibition. The antibacterial mechanism was investigated by analyzing alkaline phosphatase (AKP) activity and ATP leakage, protein expression, cell morphology and intracellular alterations in E. coli. The results demonstrated that SA exerted bacteriostatic effects on E. coli in vitro. AKP activity and ATP leakage analysis revealed that SA damaged the cell wall and cell membrane of E. coli. SDS­PAGE analysis indicated that SA notably altered the level of 10 and 35 kDa proteins. Scanning electron microscopy and transmission electron microscopy analyses revealed marked alterations in the morphology and ultrastructure of E. coli following treatment with SA. The mechanism underlying the antimicrobial effects of SA against E. coli may be attributed to its actions of disrupting the cell membrane and cell wall and regulation of protein level. The findings of the present study provide novel insight into the antimicrobial activity of SA as a potential natural antibacterial agent.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Traqueófitas/química , 4-Butirolactona/química , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologia , Trifosfato de Adenosina/química , Fosfatase Alcalina/genética , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Escherichia coli/ultraestrutura , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Extratos Vegetais/química , Extratos Vegetais/farmacologia
12.
Planta Med ; 85(9-10): 719-728, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31137047

RESUMO

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet-induced hepatic steatosis in mice as well as oleic acid-induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid-induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.


Assuntos
4-Butirolactona/análogos & derivados , Angelica/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Anidridos Ftálicos/farmacologia , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/farmacologia , Anidridos Ftálicos/isolamento & purificação , Componentes Aéreos da Planta/química , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
13.
Reprod Biol ; 19(1): 100-111, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30929911

RESUMO

Prostaglandins (PGs) are important regulators of the early corpus luteum (CL) in the dog. Whereas, initially, CL is gonadotropin independent, in the second half of its lifespan, hypophyseal support is required. The transition period is marked by decreased availability of PGs, in particular of PGE2. We previously reported that inhibition of COX2/PTGS2 in vivo suppressed luteal production of PGE2, lowered circulating progesterone and negatively affected luteal development. Therefore, bitches were treated with a COX2-specific blocker, firocoxib, for 5, 10, 20 and 30 days after ovulation, leading to suppression of the steroidogenic machinery. Control groups received a placebo for the same periods. Considering the wide range of possible modulatory roles of PGs shown in different organ systems, this follow-up project aimed to understand further possible PG-mediated effects in early canine CL. Thirty-four (34) factors related predominantly to vascularization and immune response were screened (mRNAs and proteins) on samples from the above described in vivo study. Most of the effects were observed during the transitional period (days 20 and 30). The inhibition of COX2 diminished the expression of angiopoietin family members ANGPT1, -2, Tie1 and -2 receptors. The expression of endothelin (ET)-1 was increased. Concerning the immune system, increased expression of the pro-inflammatory cytokines, IL1ß, IL6 and IL12a, and elevated expression levels of CD4, was observed. Cumulatively, besides its involvement in regulating steroidogenesis, our results indicate a broader role of PGs in the canine CL, including modulation of angiogenesis, vascular stabilization and local immunomodulation. Possible cross-species translational effects are strongly implied.


Assuntos
4-Butirolactona/análogos & derivados , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Fatores Imunológicos/metabolismo , Prostaglandinas/farmacologia , Sulfonas/farmacologia , 4-Butirolactona/farmacologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Cães , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/genética , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Transcriptoma
14.
Toxicol In Vitro ; 58: 207-214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30930231

RESUMO

Lipid droplets (LD) are newly characterized dynamic cytoplasmic organelle which is the storehouse of different immunosuppressive cytokines and enzymes like cyclooxygenase and lipoxygenase. Tumors are known to modulate the immune system by immune-editing the microenvironment. Immuno-editing comprises of three steps namely cancer immune-surveillance, tumor dormancy and finally escape leading to tumor development. The latency of the tumor microenvironment is greatly contributed by the M2 polarized macrophages and TGF-ß is a prime culprit. Modulating M2 macrophages to M1 can be a strategy against tumor progression. We found that tumor-conditioned medium or recombinant TGF-ß was efficient to induce LD formation in Raw264.7 cells and the inhibition of LD was associated with the switch of M2 to M1 phenotype involving MEK1/2 axis. Signature molecules of M2 polarized macrophages like CD206 were also downregulated while co-stimulatory molecules like CD80, CD86 were up-regulated along with enhanced surface expression of MHCII when these macrophages were subjected to C75 treatment to reduce the LD formation. The level of pro-inflammatory cytokine, as well as ROS and NO generation, were also increased when TGF-ß treated macrophages were subjected to C75 treatment. This study is probably the first report of this kind and can be used in the future in cancer treatment.


Assuntos
Citocinas/imunologia , Gotículas Lipídicas/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fenótipo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Microambiente Tumoral/imunologia
15.
Ecotoxicol Environ Saf ; 176: 339-345, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30953999

RESUMO

The acaricidal bioactivity of an oxymatrine-based commercial formulation against Brevipalpus yothersi Baker (Acari: Tenuipalpidae), a vector mite of the Citrus leprosis virus (CiLV), and its impact on predatory mites were assessed. For this purpose, laboratory and field assays using bioacaricide concentrations ranging from 0.5 to 2.0 mg L-1 of oxymatrine were performed during the years from 2015 to 2016. Laboratory results showed that the oxymatrine-based commercial formulation does not cause deleterious effects on B. yothersi eggs; however, it causes high larval mortality. For adult females, the bioacaricide caused high acute toxicity and residual effect for at least 5 days after application. In the field, the bioacaricide exhibited high acaricidal activity against B. yothersi, with efficacy levels similar to that of synthetic acaricide spirodiclofen (48 mg L-1) until 49 days after the application. The application of the bioacaricide did not negatively affect the population levels of phytoseiid predatory mites. Therefore, our results suggest that the oxymatrine-based commercial formulation is an important tool for management of the citrus leprosis mite in citrus groves.


Assuntos
Acaricidas/farmacologia , Alcaloides/farmacologia , Vetores Aracnídeos/efeitos dos fármacos , Citrus/virologia , Ácaros/efeitos dos fármacos , Quinolizinas/farmacologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Vetores Aracnídeos/virologia , Feminino , Larva/efeitos dos fármacos , Larva/virologia , Ácaros/virologia , Compostos de Espiro/farmacologia
16.
Phytochemistry ; 163: 187-194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31014820

RESUMO

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR1 displayed the most encouraging activity returning IC50 values of 13.75 ±â€¯0.001 µM and 0.03 ±â€¯0.02 µM for monoamine oxidase A and B and 0.08 ±â€¯0.006 µM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases.


Assuntos
4-Butirolactona/análogos & derivados , Transtorno Depressivo/tratamento farmacológico , Furanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piranos/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Acetilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piranos/síntese química , Piranos/química , Relação Estrutura-Atividade
17.
Molecules ; 24(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987115

RESUMO

A series of novel 3-aryl-4-hydroxy-2(5H) furanone-acrylate hybrids were designed and synthesized based on the natural butenolides and acrylates scaffolds. The structures of the prepared compounds were characterized by ¹H-NMR, 13C-NMR and electrospray ionization mass spectrometry (ESI-MS), and the bioactivity of the target compounds against twelve phytopathogenic fungi was investigated. The preliminary in vitro antifungal activity screening showed that most of the target compounds had moderate inhibition on various pathogenic fungi at the concentration of 100 mg·L-1, and presented broad-spectrum antifungal activities. Further studies also indicated that compounds 7e and 7k still showed some inhibitory activity against Pestallozzia theae, Sclerotinia sclerotiorum and Gibberella zeae on rape plants at lower concentrations, which could be optimized as a secondary lead for further research.


Assuntos
4-Butirolactona/análogos & derivados , Acrilatos/síntese química , Acrilatos/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Acrilatos/química , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
18.
Molecules ; 24(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893785

RESUMO

Aspernolide A, a butyrolactone secondary metabolite, was purified from the endophytic fungus Cladosporium cladosporioides derived from roots of Camptotheca acuminata Decne. In this study, the antitumor activity and mechanisms of aspernolide A on human laryngeal cancer Hep-2 and TU212 cells were studied by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, morphological observation and Western blotting. The results showed that aspernolide A significantly inhibited the proliferation of Hep-2 and TU212 cells in dose- and time-dependent manners. Morphological changes of apoptotic cells could be observed under an inverted microscope, such as irregular margins, decreased adherence ability and chromatin condensation. The expressions of Bax, Caspase-9, Caspase-3 and PARP (poly ADP-ribose polymerase) increased with the increase of dosage while Bcl-2 decreased, suggesting that the apoptotic mechanism might be related to the mitochondrial apoptotic pathway. Moreover, the expression of the phosphorylation of STAT3 decreased with the increase of dosage, suggesting that the apoptotic mechanism might be related to the STAT3 signaling pathway. All these conclusions indicated that aspernolide A has the potential anti-laryngocarcinoma effects.


Assuntos
4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Laríngeas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
19.
Chin J Nat Med ; 17(2): 149-154, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30797421

RESUMO

Two new isomeric modified tripeptides, aspergillamides C and D (compounds 1 and 2), together with fifteen known compounds (compounds 3-17), were obtained from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008. The structures of the new compounds, including absolute configurations, were determined by extensive analyses of spectroscopic data (NMR, MS, UV, and IR) and comparisons between the calculated and experimental electronic circular dichroism (ECD) spectra. Butyrolactone I (compound 11) exhibited strong inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 being 5.11 ± 0.53 µmol·L-1, and acted as a noncompetitive inhibitor based on kinetic analysis.


Assuntos
Aspergillus/química , Peptídeos/isolamento & purificação , Policetídeos/isolamento & purificação , Poríferos/microbiologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Técnicas de Química Analítica , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Dipeptídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Indóis/química , Indóis/isolamento & purificação , Indóis/farmacologia , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Policetídeos/química , Policetídeos/farmacologia , Proteínas Tirosina Fosfatases/química
20.
Chem Biol Interact ; 302: 143-148, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30779908

RESUMO

N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule, affects intracellular Zn2+ concentration ([Zn2+]i) and cellular levels of nonprotein thiols ([NPT]i) of rat thymic lymphocytes, both of which are assumed to affect cell vulnerability to oxidative stress. Therefore, it is interesting to examine the effects of ODHL on the cells under oxidative stress. ODHL augmented the cytotoxicity of H2O2, but not calcium ionophore A23187. ODHL potentiated the H2O2-induced elevation of [Zn2+]i, wherein, it greatly attenuated the H2O2-induced increase in intracellular Ca2+ concentration. ODHL did not affect [NPT]i in the presence of H2O2. Therefore, we conclude that the elevation of [Zn2+]i is involved in the ODHL-induced potentiation of H2O2 cytotoxicity. Our findings suggest that ODHL modifies cell vulnerability to oxidative stress in host cells.


Assuntos
4-Butirolactona/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Timócitos/efeitos dos fármacos , 4-Butirolactona/farmacologia , Animais , Calcimicina/farmacologia , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Masculino , Percepção de Quorum/efeitos dos fármacos , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Zinco/metabolismo
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