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1.
Anticancer Res ; 39(11): 6057-6062, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704832

RESUMO

BACKGROUND/AIM: The prognosis of patients with osteosarcoma is poor; therefore, new treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of the 11 families (PDE1-PDE11) of the phosphodiesterase superfamily that regulates the intracellular concentrations and effects of cAMP and cGMP. This in vitro study was performed to investigate the role of PDE2 in human oral osteosarcoma HOSM-1 cells. MATERIALS AND METHODS: PDE2 expression was measured by a cAMP-PDE assay and real-time-PCR. The effects of the PDE2-specific inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 8-bromo-cAMP, and 8-bromo-cGMP on cell proliferation and migration were assessed. RESULTS: PDE2 activity and PDE2A mRNA expression were detected in HOSM-1 cells. Cell proliferation was inhibited by EHNA and 8-bromo-cAMP but not by 8-bromo-cGMP. Cell migration was stimulated by EHNA and 8-bromo-cGMP, but it was inhibited by 8-bromo-cAMP. CONCLUSION: Cell proliferation is regulated by PDE2-cAMP signaling and cell migration is regulated by PDE2-cGMP signaling in HOSM-1 cells.


Assuntos
Neoplasias Ósseas/patologia , Movimento Celular , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Neoplasias Bucais/patologia , Osteossarcoma/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose , Compostos de Benzil/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Ciclo Celular , AMP Cíclico/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/enzimologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Transdução de Sinais , Células Tumorais Cultivadas
2.
Expert Opin Investig Drugs ; 28(12): 1051-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31603362

RESUMO

Introduction: Multiple sclerosis (MS) causes focal lesions of immune-mediated demyelinating events followed by slow progressive accumulation of disability. Over the past 2 decades, multiple medications have been studied and approved for use in MS. Most of these agents work by modulating or suppressing the peripheral immune system. Siponimod is a newer-generation sphingosine 1 phosphate (S1P) receptor modulator that internalizes S1P1 receptors, thereby inhibiting efflux of lymphocytes from lymph nodes and thymus. There are promising data suggesting that it may also have a direct neuroprotective property independent of peripheral lymphocytopenia.Areas covered: We reviewed the pharmacology and the clinical and radiological effects of siponimod.Expert opinion: The selective effect of siponimod on the S1P1 and S1P5 receptors offers a favorable side-effect profile and transient bradycardia can be avoided by dose titration. A phase-II study showed that siponomod has dose-dependent beneficial effects in patients with relapsing remitting disease. The results of a phase-III study suggest that siponimod may be beneficial in secondary progressive MS, at least in patients with disease activity.


Assuntos
Azetidinas/administração & dosagem , Compostos de Benzil/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , /administração & dosagem , Animais , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Compostos de Benzil/efeitos adversos , Compostos de Benzil/farmacologia , Relação Dose-Resposta a Droga , Humanos , Esclerose Múltipla/fisiopatologia , /farmacologia , /metabolismo
3.
C R Biol ; 342(5-6): 220-229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31400945

RESUMO

The in vitro cultivation of date palm staminodes (vestigial stamens) at different stages of female floral ontogenesis confirms the persistence at an immature state of such organs at all the floral differentiation stages. This is evidenced even in fully mature female flowers. Our study revealed the advanced developmental patterns of these rudimentary structures, which bear diverse morphogenetic potentialities. In vitro cultivation of staminodes provides new opportunities for in vitro regeneration of date palm. Such developmental processes were found to be modulated by the stage of floral differentiation, which closely reflected the level of staminode maturity. Development was also impacted by the composition and concentration in plant growth regulators (NAA, BAP and 2,4-D) of the culture media. The large morphogenetic plasticity of the staminodes disposed them to evolutionary variations of the date palm reproduction system. The practical benefits (micropropagation) and the fundamental interests (evolutionary process) of our investigation are discussed.


Assuntos
Evolução Biológica , Phoeniceae/fisiologia , Ácido 2,4-Diclorofenoxiacético/farmacologia , Compostos de Benzil/farmacologia , Meios de Cultura , Flores/crescimento & desenvolvimento , Flores/fisiologia , Herbicidas/farmacologia , Morfogênese , Ácidos Naftalenoacéticos/farmacologia , Reguladores de Crescimento de Planta/farmacologia , Purinas/farmacologia
4.
J Plant Res ; 132(5): 617-627, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31432295

RESUMO

The timing of the transition between developmental phases is a critical determinant of plant form. In the moss Physcomitrella patens, the transition from protonema to gametophore is a particularly important step as it results in a change from two-dimensional to three-dimensional growth of the plant body. It is well known that this transition is promoted by cytokinin (CK), however, the underlying mechanisms are poorly understood. Previously, it was reported that P. patens orthologs of BLADE-ON-PETIOLE (BOP) genes (PpBOPs) work downstream of CK to promote the transition to gametophore. To further understand the role of PpBOPs in the control of this transition, we performed functional analyses of PpBOP genes. We simultaneously disrupted the function of all three PpBOP genes in P. patens using CRISPR technology, however, no abnormal phenotypes were observed in the triple mutant during either the gametophytic or the sporophytic growth stages. CK treatment did not alter the phase change in the triple mutant. We conclude that PpBOP genes are unnecessary in the control of P. patens development under normal conditions. We propose that BOP genes are not involved in the control of developmental processes in bryophytes and other basal land plants, but may function in physiological processes such as in the defense response.


Assuntos
Compostos de Benzil/farmacologia , Bryopsida/crescimento & desenvolvimento , Células Germinativas Vegetais/crescimento & desenvolvimento , Reguladores de Crescimento de Planta/farmacologia , Proteínas de Plantas/genética , Purinas/farmacologia , Bryopsida/genética , Expressão Gênica/efeitos dos fármacos , Células Germinativas Vegetais/efeitos dos fármacos , Proteínas de Plantas/metabolismo
5.
Eur J Med Chem ; 180: 213-223, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306908

RESUMO

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type [MII(Fedtc)2] (M = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, 1H NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and [NiII(Fedtc)2] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. [PdII(Fedtc)2] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI = 48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the [NiII(Fedtc)2] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate.


Assuntos
Compostos de Benzil/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Metalocenos/farmacologia , NADPH Desidrogenase/antagonistas & inibidores , Níquel/farmacologia , Paládio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Hidrazinas/química , Macaca mulatta , Metalocenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , NADPH Desidrogenase/química , NADPH Desidrogenase/metabolismo , Níquel/química , Níquel/metabolismo , Paládio/química , Paládio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Trypanosoma cruzi/metabolismo
7.
Stroke ; 50(5): 1224-1231, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31009359

RESUMO

Background and Purpose- The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods- Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions- For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Acidente Vascular Cerebral/tratamento farmacológico , Fatores Etários , Animais , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento
8.
Nature ; 568(7753): 566-570, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944472

RESUMO

ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA1-5. The acetyl-CoA product is crucial for the metabolism of fatty acids6,7, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation2,5,11. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials4,5. Many inhibitors of ACLY have been reported, but most of them have weak activity5. Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors.


Assuntos
ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/ultraestrutura , Compostos de Benzil/farmacologia , Microscopia Crioeletrônica , Inibidores Enzimáticos/farmacologia , ATP Citrato (pro-S)-Liase/química , ATP Citrato (pro-S)-Liase/metabolismo , Difosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Compostos de Benzil/química , Sítios de Ligação/efeitos dos fármacos , Ácido Cítrico/metabolismo , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Domínios Proteicos , Multimerização Proteica , Relação Estrutura-Atividade
9.
Contact Dermatitis ; 81(3): 174-183, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30957232

RESUMO

BACKGROUND: Over 4000 small chemicals have been identified as allergens capable of inducing skin sensitization. Many sensitizers are hypothesized to act as haptens producing novel antigens, which can be presented to T cells by human leukocyte antigens (HLAs). Recent studies suggest that some chemical allergens use hapten-independent mechanisms. OBJECTIVE: To determine whether molecular docking can identify HLA molecules that bind skin-sensitizing chemical allergens. METHODS: Structural models of HLA molecules were used as the basis for molecular docking of 22 chemical allergens. Allergens predicted to bind HLA-B*57:01 were tested for their ability to stimulate T cells by the use of proliferation and interferon-gamma enzyme-linked immunospot assays. RESULTS: Chemical allergens that did not satisfy the criteria for hapten activity in vitro were predicted to bind more strongly to common HLA isoforms than those with known hapten activity. HLA-B*57:01, which is an HLA allele required for drug hypersensitivity reactions, was predicted to bind several allergens, including benzyl benzoate, benzyl cinnamate, and benzyl salicylate. In in vitro T cell stimulation assays, benzyl salicylate and benzyl cinnamate were found to stimulate T cell responses from HLA-B*57:01 carriers. CONCLUSIONS: These data suggest that small-molecule skin sensitizers have the potential to interact with HLA, and show that T cell-based in vitro assays may be used to evaluate the immunogenicity of skin-sensitizing chemicals.


Assuntos
Alérgenos/química , Dermatite Alérgica de Contato/imunologia , Antígenos HLA-B/química , Haptenos/química , Perfumes/química , Alérgenos/imunologia , Alérgenos/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Proliferação de Células , Células Cultivadas , Cinamatos/química , Cinamatos/farmacologia , Antígenos HLA-B/imunologia , Haptenos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Perfumes/farmacologia , Salicilatos/química , Salicilatos/farmacologia , Linfócitos T/fisiologia
10.
J Agric Food Chem ; 67(19): 5560-5570, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901205

RESUMO

The phytohormone 6-benzylaminopurine (6-BAP) significantly improves lipid synthesis of oleaginous microorganisms with the great potential applied in lipid production. In the current study, the lipid and DHA productions in oleaginous Aurantiochytrium sp. were found to be improved by 48.7% and 55.3%, respectively, induced by 6-BAP treatments. Then, using high-throughput RNA-seq technology, the overall de novo assembly of the cDNA sequence data generated 53871 unigenes, and 15902 of these were annotated in at least one database. The comparative transcriptomic profiles of cells with and without 6-BAP treatments revealed that a total of 717 were differently expressed genes (DE), with 472 upregulated and 245 downregulated. Further annotation and categorization indicated that some DE genes were involved in pathways crucial to lipid and DHA productions, such as fatty acid synthesis, central carbon metabolism, transcriptional factor, signal transduction, and mevalonate pathway. A regulation mode of 6-BAP, in turn, perception and transduction of 6-BAP signal, transcription factor, expression regulations of the downstream genes, and metabolic changes, respectively, was put forward for the first time in the present study. This research illuminates the transcriptomic mechanism of phytohormone stimulation of lipid and DHA production in an oleaginous microorganism and provides the potential targets modified using genetic engineering for improving lipid and DHA productivity.


Assuntos
Compostos de Benzil/farmacologia , Ácidos Docosa-Hexaenoicos/biossíntese , Metabolismo dos Lipídeos/efeitos dos fármacos , Reguladores de Crescimento de Planta/farmacologia , Purinas/farmacologia , Estramenópilas/efeitos dos fármacos , Estramenópilas/genética , Compostos de Benzil/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Reguladores de Crescimento de Planta/química , Purinas/química , Estramenópilas/metabolismo
11.
Mar Drugs ; 17(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875760

RESUMO

The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and α-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (3). All compounds inhibited the target enzymes by 50% at concentrations below 10 µM. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 µM); however, 3 was more potent (IC50; 5.29 ± 0.08 µM) against PTP1B. Interestingly, the activity of 1⁻3 against α-glucosidase was 30⁻110 times higher than acarbose (IC50; 212.66 ± 0.35 µM). Again, 3 was the most potent α-glucosidase inhibitor (IC50; 1.92 ± 0.02 µM). Similarly, 1⁻3 showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7⁻OH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from S. latiuscula, especially highly brominated 3, are inhibitors of PTP1B and α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.


Assuntos
Compostos de Benzil/farmacologia , Diabetes Mellitus/tratamento farmacológico , Éteres/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rodófitas/química , alfa-Glucosidases/metabolismo , Compostos de Benzil/química , Compostos de Benzil/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Éteres/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Resistência à Insulina , Simulação de Acoplamento Molecular
12.
BMC Plant Biol ; 19(1): 93, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841918

RESUMO

BACKGROUND: Insufficient production of flower buds is an intractable problem in 'Fuji' apple orchards. Although cytokinin (CK) promotes flower bud formation in apple trees, little is known about the mechanisms regulating this phenomenon. RESULTS: In the present study, high-throughput RNA sequencing (RNA-Seq) of 'Nagafu No. 2' buds was conducted to characterize the transcriptional response to 6-BA treatment during key period of floral transition. A weighted gene co-expression network analysis (WGCNA) of the differentially expressed genes identified hormone signal transduction pathways, totaling 84 genes were highly correlated with the expression pattern of flowering-time genes. The up-regulation of CK signal components and a gibberellin (GA) signal repressor were found to contribute to the promotion of floral transition. In relative comparison to non-treated buds, a series of sugar metabolism- and signal- related genes were associated with relatively high levels of sucrose, fructose, and glucose during floral induction in the 6-BA treated buds. Several transcription factors (i.e. SPLs, SOC1, FD, and COL) that are involved in GA, aging, and photoperiod-regulated flowering pathways were also upregulated by the 6-BA treatment. In addition, potential transcription factors integrating CK signaling to trigger floral induction in apple were also assessed; including PHYTO-CHROME-INTERACTING FACTOR (PIF1,3), WUSCHEL-related homeobox (WOX3,13), and CK response regulators (ARR2). CONCLUSIONS: The present study provides insight into the response of flowering and development-related pathways and transcription factors to 6-BA during the period of floral transition in apple. It extends our knowledge of the fundamental mechanisms associated with CK-regulated floral transition in apple trees.


Assuntos
Compostos de Benzil/farmacologia , Perfilação da Expressão Gênica/métodos , Malus/genética , Reguladores de Crescimento de Planta/farmacologia , Purinas/farmacologia , Flores/efeitos dos fármacos , Flores/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Proteínas de Plantas/metabolismo
13.
Mar Drugs ; 17(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736380

RESUMO

In this study, as part of our continuous search for environmentally-friendly antifoulants from natural resources, subergorgic acid (SA) was identified from the gorgonian coral Subergorgia suberosa, demonstrating non-toxic, significant inhibitory effects (EC50 1.25 µg/mL, LC50 > 25 µg/mL) against the settlement of Balanus amphitrite. To further explore the bioactive functional groups of SA and synthesize more potent antifouling compounds based on the lead SA, the structure-activity relationships of SA were studied, followed by rational design and synthesis of two series of SA derivatives (one being benzyl esters of SA and another being SA derivatives containing methylene chains of various lengths). Our results indicated that (1) both the double bond and ketone carbonyl are essential elements responsible for the antifouling effect of SA, while the acid group is not absolutely necessary for maintaining the antifouling effect; (2) all benzyl esters of SA displayed good antifouling effects (EC50 ranged from 0.30 to 2.50 µg/mL) with the most potent compound being 5 (EC50 0.30 µg/mL, LC50 > 25 µg/mL), which was over four-fold more potent than SA; and (3) the introduction of a methylene chain into SA reduces the antifouling potency while the length of the methylene chain may differently influence the antifouling effect, depending on the functional group at the opposite site of the methylene chain. Not only has this study successfully revealed the bioactive functional groups of SA, contributing to the mechanism of SA against the settlement of B. amphitrite, but it has also resulted in the identification of a more potent compound 5, which might represent a non-toxic, high-efficiency antifoulant.


Assuntos
Antozoários/química , Incrustação Biológica/prevenção & controle , Sesquiterpenos/química , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Thoracica/efeitos dos fármacos
14.
Plant Physiol Biochem ; 137: 154-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784987

RESUMO

Steviol glycosides (SGs) and gibberellic acids share a part of their biosynthesis pathways. Despite the widespread studies on the effect of gibberellic acid 3 (GA3), the effect of gibberellic acid 4 and 7 (GA4/7) on Stevia rebaudiana has never been studied. This study aimed at a comparative evaluation of different hormone effects, i.e., 1 mg L-1 GA4/7, 1 mg L-1 GA3, or 0.5 mg L-1 kinetin and 0.5 mg L-1 6-benzylaminopurine (BAP) (KB 0.5), on in vitro propagation, growth, morphological properties, and content of SGs in leaf samples of stevia. In comparison with the control group (hormone-free), the treatments of KB 0.5 or GA3 produced the highest biomasses and largest leaf areas. The three hormonal treatments produced a similar number of leaves, the ratio of fresh to dry weight, and leaf length. GA4/7-treated explants produced the highest ratio of leaf area to leaf length. The effect of GA4/7 on shoot elongation was greater than that of the control or even GA3. While the effect of GA3 on rebaudioside-A (Reb-A) production was similar to that of the control (16.2 and 18.04 mg g-1, respectively), GA4/7 resulted in a lower amount of it (13.31 mg g-1). Except for GA4/7, which induced more stevioside accumulation, the treatments' effects were comparable to that of the control. The ratio of stevioside to Reb-A was the highest for GA4/7 (2.62), followed by GA3 (1.93), and then the two others. Sum of Reb-A and stevioside content was not changed by the use of any of the treatments.


Assuntos
Citocininas/farmacologia , Diterpenos de Caurano/metabolismo , Giberelinas/farmacologia , Glucosídeos/metabolismo , Stevia/efeitos dos fármacos , Stevia/fisiologia , Compostos de Benzil/farmacologia , Cinetina/farmacologia , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Purinas/farmacologia
15.
Eur J Pharmacol ; 847: 103-112, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710549

RESUMO

The effects on the vasculature produced by ethanol withdrawal include both vasodilatation and hypocontractility, although a detailed biochemical understanding of these processes is yet to be accomplished. Here, we sought to investigate some of the mechanisms underlying vascular hypocontractility induced by ethanol withdrawal. Male Wistar rats were treated with increasing doses of 3-9% ethanol (v/v) for 21 days and the impact of ethanol withdrawal on the vascular function was assessed 48 h after immediate ethanol suspension. Endothelium-denuded rat aortic rings showed a reduced contractile response to phenylephrine, angiotensin II, serotonin and KCl after ethanol withdrawal, but the same phenomenon was not observed in endothelium-intact rings. Indomethacin, but not L-NAME, tiron, PEG-catalase and SC560, restored the contractile response to phenylephrine of endothelium-denuded aortas from abstinent rats. Hyporeactivity to phenylephrine induced by ethanol withdrawal was reversed by SC236, a selective cyclooxygenase (COX)-2 inhibitor. Similarly, Ro1138452, a selective prostacyclin IP receptor antagonist, reversed vascular hypocontractility induced by ethanol withdrawal. Increased concentrations of 6-keto-prostaglandin (PG)F1α, a stable product of PGI2, was detected in endothelium-denuded aortas from abstinent rats, and this response was prevented by indomethacin. However, no changes in aortic PGE2 levels were detected after ethanol withdrawal. In situ quantification of hydrogen peroxide (H2O2) and nitric oxide (NO) using fluorescent dyes revealed that ethanol withdrawal decreased the levels of these two compounds in the tunica media. Our studies show that the vascular hypocontractility induced by ethanol withdrawal is independent of the endothelium and it is mediated by PGI2 derived from COX-2.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Epoprostenol/metabolismo , Etanol/efeitos adversos , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Compostos de Benzil/farmacologia , Catalase/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Endotélio Vascular/metabolismo , Peróxido de Hidrogênio/farmacologia , Imidazóis/farmacologia , Indometacina/farmacologia , Masculino , Fenilefrina/farmacologia , Polietilenoglicóis/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
16.
Biol Res ; 52(1): 3, 2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30660192

RESUMO

BACKGROUND: Gymnema sylvestre is a medicinal woody perennial vine known for its sweetening properties and anti-diabetic therapeutic uses in the modern and traditional medicines. Its over-exploitation for the therapeutic uses and to meet the demand of pharmaceutical industry in raw materials supply for the production of anti-diabetic drugs has led to considerable decline in its natural population. RESULTS: An efficient system of shoot bud sprouting from nodal segment explants and indirect plant regeneration from apical meristem-induced callus cultures of G. sylvestre have been developed on Murashige and Skoog (MS) medium amended with concentrations of cytokinins. Of the three growth regulators tested, N6-benzylaminopurine (BAP) was the most efficient and 2.0 mg L-1 gave the best shoot formation efficiency. This was followed by thidiazuron (TDZ) and kinetin (Kin) but, most of the TDZ-induced micro shoots showed stunted growth. Multiple shoot formation was observed on medium amended with BAP or TDZ at higher concentrations. The produced micro shoots were rooted on half strength MS medium amended with auxins and rooted plantlets acclimatized with 87% survival of the regenerates. CONCLUSIONS: The developed regeneration system can be exploited for genetic transformation studies, particularly when aimed at producing its high yielding cell lines for the anti-diabetic phytochemicals. It also offers opportunities for exploring the expression of totipotency in the anti-diabetic perennial vine.


Assuntos
Gymnema sylvestre/crescimento & desenvolvimento , Morfogênese/efeitos dos fármacos , Reguladores de Crescimento de Planta/farmacologia , Brotos de Planta/crescimento & desenvolvimento , Regeneração/efeitos dos fármacos , Compostos de Benzil/farmacologia , Gymnema sylvestre/efeitos dos fármacos , Cinetina/farmacologia , Compostos de Fenilureia/farmacologia , Brotos de Planta/efeitos dos fármacos , Purinas/farmacologia , Tiadiazóis/farmacologia
17.
PLoS One ; 14(1): e0209804, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629611

RESUMO

The last fifteen years have seen the emergence and overflow into the drug scene of "superpotent" N-benzylated phenethylamines belonging to the "NBOMe" series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT2A or 5-HT2C receptors suggesting that a few of them, with affinities in the 10-100 nanomolar range for 5-HT2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT2C receptor full agonists while most of them showed low efficacy at the 5-HT2A subtype. Furthermore, several showed moderate-to-strong preferences for activation of the 5-HT2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophrenia.


Assuntos
Receptores 5-HT2 de Serotonina/metabolismo , Triptaminas/farmacologia , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/farmacologia , Animais , Compostos de Benzil/farmacologia , Células CHO , Cricetulus , Células HeLa , Humanos , Estrutura Molecular , Fenetilaminas , Ensaio Radioligante , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Triptaminas/síntese química
18.
Cells ; 8(1)2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30621015

RESUMO

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.


Assuntos
Anti-Inflamatórios/farmacologia , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Adolescente , Adulto , Anti-Inflamatórios/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Sistema Nervoso Central/patologia , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Adulto Jovem
19.
Planta ; 249(2): 407-416, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30225671

RESUMO

MAIN CONCLUSION: Cucumber fruit trichomes could be classified into eight types; all of them are multicellular with complex and different developmental processes as compared with unicellular trichomes in other plants. The fruit trichomes or fruit spines of cucumber, Cucumis sativus L., are highly specialized structures originating from epidermal cells with diverse morphology, which grow perpendicular to the fruit surface. To understand the underlying molecular mechanisms of fruit trichome development, in this study, we conducted morphological characterization and classification of cucumber fruit trichomes and their developmental processes. We examined the fruit trichomes among 200 cucumber varieties, which could be classified into eight morphologically distinct types (I-VIII). Investigation of the organogenesis of the eight types of trichomes revealed two main developmental patterns. The development of glandular trichomes had multiple stages including initiation and expansion of the trichome precursor cell protuberating out of the epidermal surface, followed by periclinal bipartition to two cells (top and bottom) which later formed the head region and the stalk, respectively, through subsequent cell divisions. The non-glandular trichome development started with the expansion of the precursor cell perpendicularly to the epidermal plane followed by cell periclinal division to form a stalk comprising of some rectangle cells and a pointed apex cell. The base cell then started anticlinal bipartition to two cells, which then underwent many cell divisions to form a multicellular spherical structure. In addition, phytohormones as environmental cues were closely related to trichome development. We found that GA and BAP were capable of increasing trichome number per fruit with distinct effects under different concentrations.


Assuntos
Cucumis sativus/anatomia & histologia , Frutas/anatomia & histologia , Reguladores de Crescimento de Planta/farmacologia , Tricomas/classificação , Compostos de Benzil/farmacologia , Cucumis sativus/crescimento & desenvolvimento , Cucumis sativus/ultraestrutura , Frutas/crescimento & desenvolvimento , Frutas/ultraestrutura , Giberelinas/farmacologia , Microscopia Eletrônica de Varredura , Purinas/farmacologia , Tricomas/efeitos dos fármacos , Tricomas/crescimento & desenvolvimento , Tricomas/ultraestrutura
20.
Nat Prod Res ; 33(19): 2731-2737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30124345

RESUMO

A new benzylated alkamide, N-(3,4-dimethoxybenzyl)-9Z-oleamide (1), along with two known ones (2 and 3) were isolated from the roots of Lepidium meyenii collected from Lijiang, Yunnan Province of China. Their structures were elucidated by extensive spectroscopic analyses and the new compound further confirmed by a one-step synthesis. All the isolated alkamides were evaluated for their cytotoxicity against five human cancer cell lines. However, no significant activities were detected at concentrations up to 40 µM.


Assuntos
Compostos de Benzil/isolamento & purificação , Lepidium/química , Alcamidas Poli-Insaturadas/isolamento & purificação , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Linhagem Celular Tumoral , China , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/farmacologia
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