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1.
Anticancer Res ; 40(5): 2675-2685, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366412

RESUMO

BACKGROUND/AIM: To evaluate the anti-cancer mechanism of N-Farnesyl-norcantharimide (NC15). MATERIALS AND METHODS: The viability of NC15-treated human leukemic Jurkat T (JKT) cells was assessed using the Kit-8 cell counting method. Flow cytometry analysis, human apoptosis antibody array assay, and whole genome sequencing were adopted to investigate the mechanism underlying the anti-cancer activity of NC15 in JKT cells. RESULTS: The growth inhibition rates of NC15 in JKT cells were about 80% and 95% after treatment with 8 µmol/l NC15 for 24 and 48 h, respectively. The percentages of NC15-treated JKT cells in the sub-G1 phase at 24 and 48 h were 22.0% and 34.3%, respectively, in contrast to the 1.5% in the control. Next-generation sequencing showed that many tumor suppressor genes (TSG) were up-regulated, while many genes associated with steroid biosynthesis, metabolic pathways, and fatty acid metabolism were down-regulated. CONCLUSION: NC15 can reduce the cell viability and increase the percentage of JKT cells in the sub-G1 phase by up-regulating TSG and related genes, and down-regulating the genes for steroid biosynthesis, metabolic pathways and fatty acid metabolism, instead of through apoptosis.


Assuntos
Cantaridina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Genes Supressores de Tumor , Redes e Vias Metabólicas/genética , Esteroides/biossíntese , Linfócitos T/citologia , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Cantaridina/química , Cantaridina/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação para Baixo/genética , Humanos , Células Jurkat , Redes e Vias Metabólicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Regulação para Cima/genética
2.
PLoS One ; 15(2): e0229490, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107496

RESUMO

Application of plant growth regulators has become one of the most important means of improving yield and quality of medicinal plants. To understand the molecular basis of phytohormone-regulated oleanolic acid metabolism, RNA-seq was used to analyze global gene expression in Achyranthes bidentata treated with 2.0 mg/L 1-naphthaleneacetic acid (NAA) and 1.0 mg/L 6-benzyladenine (6-BA). Compared with untreated controls, the expression levels of 20,896 genes were significantly altered with phytohormone treatment. We found that 13071 (62.5%) unigenes were up-regulated, and a lot of differentially expressed genes involved in hormone or terpenoid biosynthesis, or transcription factors were significantly up-regulated. These results suggest that oleanolic acid biosynthesis induced by NAA and 6-BA occurs due to the expression of key genes involved in jasmonic acid signal transduction. This study is the first to analyze the production and hormonal regulation of medicinal A. bidentata metabolites at the molecular level. The results herein contribute to a better understanding of the regulation of oleanane-type triterpenoid saponins accumulation and define strategies to improve the yield of these useful metabolites.


Assuntos
Achyranthes/efeitos dos fármacos , Achyranthes/metabolismo , Compostos de Benzil/farmacologia , Ciclopentanos/metabolismo , Ácidos Naftalenoacéticos/farmacologia , Ácido Oleanólico/biossíntese , Oxilipinas/metabolismo , Purinas/farmacologia , Achyranthes/crescimento & desenvolvimento , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Medicina Tradicional Chinesa , Filogenia , Reguladores de Crescimento de Planta/metabolismo , Plantas Medicinais/efeitos dos fármacos , Plantas Medicinais/genética , Plantas Medicinais/metabolismo , RNA-Seq , Saponinas/metabolismo
3.
Gut ; 69(1): 177-186, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954949

RESUMO

OBJECTIVE: Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DESIGN: We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. RESULTS: Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. CONCLUSION: Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/biossíntese , Ácido Graxo Sintase Tipo I/metabolismo , Ácidos Graxos/biossíntese , Neoplasias Hepáticas/metabolismo , Animais , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Genômica , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipidômica , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Transcriptoma
4.
J Pharm Biomed Anal ; 177: 112878, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31561062

RESUMO

Trans-crocin 4 (TC4) is an important carotenoid constituent of saffron showing potential activity against Alzheimer's Disease (AD) due to its antioxidant and antiamyloidogenic properties. Metabolomics is an emerging scientific field that enhances biomarker discovery and reveals underlying biochemical mechanisms aiming towards the early subclinical diagnosis of diseases. To date, there are no reports on the changes induced to mice plasma metabolome after TC4 administration. We report a novel untargeted UHPLC-ESI HRMS metabolomics strategy to determine the alteration of the metabolic fingerprint following i.p. administration of TC4 in male and female mice. Blood samples from fiftysix mice treated with TC4 as well as from control animals were analyzed with UHPLC-ESI HRMS. Statistical evaluation of the results was achieved by multivariate analysis (MVA), i.e., principal component analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA) in order to discover the variables that contributed to the discrimination between treated and untreated groups which were identified by online database searching (e.g., Metlin, HMDB, KEGG) aided by chemometric processing, e.g., covariance searching etc. Due to the high variability imposed by various factors, e.g., sex of the animals participating in the study, administration dose and time-points of sacrifice, multilevel sparse PLS-DA analysis, e.g., splitting variation to each individual component, has been employed as a more efficient approach for such designs. This methodology allowed the identification of the time sequence of metabolome changes due to the administration of TC4, whereas a sex-related effect on the metabolome is indicated, denoting that the administration in both sexes is indispensable in order to acquire safe conclusions as reliable metabolome pictures. The results demonstrated a number of annotated metabolites playing a potential role in neuroprotection while they are closely related to AD. Moreover, five additional annotated metabolites were involved in the steroid biosynthesis pathway while two of them may be considered as putative neuroprotective agents.


Assuntos
Carotenoides/farmacocinética , Crocus/química , Metabolômica/métodos , Fármacos Neuroprotetores/farmacocinética , Animais , Vias Biossintéticas/efeitos dos fármacos , Carotenoides/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Injeções Intraperitoneais , Masculino , Espectrometria de Massas/métodos , Camundongos , Modelos Animais , Fármacos Neuroprotetores/administração & dosagem , Fatores Sexuais , Esteroides/biossíntese
5.
Enzyme Microb Technol ; 131: 109381, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31615662

RESUMO

Phytohormones are chemical messengers that have a positive effect at low concentrations on the biosynthesis of high-value compounds. Therefore, the effects of phytohormones on lipid and arachidonic acid (ARA) biosynthesis in Mortierella alpina were investigated in this study. At proper concentrations, the stimulatory effects of phytohormones on lipid production were determined to be as follows: 6-benzyl adenine (BA) > indole-3-acetic acid (IAA) > furfuryl adenine (KT) > gibberellin (GA) > indole-3-butyric acid (IBA) > abscisic acid (ABA). The results show that in the presence of 15 mg L-1 BA, the best positive effect was obtained, in which the lipid and ARA yields of M. alpina increased by 20.34% and 29.17%, respectively. Surprisingly, there was no synergy between the addition of two cytokinins (KT and BA), while adding cytokinins (KT or BA) and auxin (IAA) inhibited the growth of M. alpina and the ARA yield decreased by approximately 64%. Additional studies, such as those involving enzyme activity detection and quantitative real time polymerase chain reaction were carried out to check the fatty acid and lipid biosynthesis when the phytohormones were present. The activity of the main NADPH-supplying enzyme, 6-phosphoglucose dehydrogenase (G6PDH), increased by 19.52%. Moreover, the transcription levels of fatty acid synthase (FAS), Δ9-desaturase, and diacylglycerolacyltransferase (DGAT) increased by 9.3, 9.6 and 7.7 times, respectively, when only one type of phytohormone was present, indicating the enhancement of fatty acid and lipid biosynthesis in M. alpina. This study demonstrates the potential application of phytohormones for improving ARA yields of M. alpina.


Assuntos
Ácido Araquidônico/biossíntese , Vias Biossintéticas/efeitos dos fármacos , Mortierella/efeitos dos fármacos , Mortierella/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos
6.
Int J Mol Sci ; 20(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561511

RESUMO

The organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) has various biological activities. We previously reported that THGP forms a complex with cis-diol structures. L-3,4-Dihydroxyphenylalanine (L-DOPA), a precursor of melanin, contains a cis-diol structure in its catechol skeleton, and excessive melanin production causes skin darkening and staining. Thus, the cosmetic field is investigating substances that suppress melanin production. In this study, we investigated whether THGP inhibits melanin synthesis via the formation of a complex with L-DOPA using mushroom tyrosinase and B16 4A5 melanoma cells. The ability of THGP to interact with L-DOPA was analyzed by 1H-NMR, and the influence of THGP and/or kojic acid on melanin synthesis was investigated. We also examined the effect of THGP on cytotoxicity, tyrosinase activity, and gene expression and found that THGP interacted with L-DOPA, a precursor of melanin with a cis-diol structure. The results also showed that THGP inhibited melanin synthesis, exerted a synergistic effect with kojic acid, and did not affect tyrosinase activity or gene expression. These results suggest that THGP is a useful substrate that functions as an inhibitor of melanogenesis and that its effect is enhanced by combination with kojic acid.


Assuntos
Agaricales/enzimologia , Levodopa/química , Levodopa/farmacologia , Melaninas/biossíntese , Monofenol Mono-Oxigenase/antagonistas & inibidores , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Vias Biossintéticas/efeitos dos fármacos , Melanoma Experimental , Camundongos
7.
Nat Commun ; 10(1): 3546, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391464

RESUMO

Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host-guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin αvß3-overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 105-106 M-1. We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Poliaminas/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Vias Biossintéticas/efeitos dos fármacos , Neoplasias da Mama/patologia , Calixarenos/química , Calixarenos/farmacologia , Calixarenos/uso terapêutico , Cátions/química , Cátions/metabolismo , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Poliaminas/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
PLoS Genet ; 15(8): e1008284, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31437147

RESUMO

Several important human pathogens are represented in the Corynebacterineae suborder, including Mycobacterium tuberculosis and Corynebacterium diphtheriae. These bacteria are surrounded by a multilayered cell envelope composed of a cytoplasmic membrane, a peptidoglycan (PG) cell wall, a second polysaccharide layer called the arabinogalactan (AG), and finally an outer membrane-like layer made of mycolic acids. Several anti-tuberculosis drugs target the biogenesis of this complex envelope, but their efficacy is declining due to resistance. New therapies are therefore needed to treat diseases caused by these organisms, and a better understanding of the mechanisms of envelope assembly should aid in their discovery. To this end, we generated the first high-density library of transposon insertion mutants in the model organism C. glutamicum. Transposon-sequencing was then used to define its essential gene set and identify loci that, when inactivated, confer hypersensitivity to ethambutol (EMB), a drug that targets AG biogenesis. Among the EMBs loci were genes encoding RipC and the FtsEX complex, a PG cleaving enzyme required for proper cell division and its predicted regulator, respectively. Inactivation of the conserved steAB genes (cgp_1603-1604) was also found to confer EMB hypersensitivity and cell division defects. A combination of quantitative microscopy, mutational analysis, and interaction studies indicate that SteA and SteB form a complex that localizes to the cytokinetic ring to promote cell separation by RipC-FtsEX and may coordinate its PG remodeling activity with the biogenesis of other envelope layers during cell division.


Assuntos
Antituberculosos/farmacologia , Divisão Celular/genética , Corynebacterium glutamicum/fisiologia , Farmacorresistência Bacteriana/genética , /efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas/efeitos dos fármacos , Corynebacterium glutamicum/efeitos dos fármacos , Elementos de DNA Transponíveis/genética , Etambutol/farmacologia , Galactanos/biossíntese , Loci Gênicos , Mutação , Ácidos Micólicos/metabolismo , Peptidoglicano/metabolismo
9.
Biotechnol Lett ; 41(10): 1213-1222, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451996

RESUMO

OBJECTIVES: In order to elucidate the antibacterial activity and mechanism of S. alboflavus TD-1 active metabolites, the minimal inhibitory concentration of R. solanacearum and other effects on cell wall, cell membrane, nucleic acid, protein and cell morphology were studied. Besides, based on LCMS-IT-TOF, the active metabolites of S. alboflavus TD-1 were preliminarily analyzed. RESULTS: In this study, We found that the active metabolites had obvious inhibitory effect on R. solanacearum, and the minimal inhibitory concentration (MIC) of R. solanacearum was 3.125 mg/mL. And the treatment of 10 mg/mL active metabolites can increase the permeability of R. solanacearum membranes, destroy the cell wall integrity, inhibit the synthesis of bacterial nucleic acids and proteins, and cause leakage of bacterial nucleic acids and proteins, obstruct the normal expression of proteins and destroy their bacterial morphology. At the same time, We speculated the molecular weights corresponding to the six compounds were 618, 615, 615, 615, 646, 646, respectively among the active metabolites, and it was found that were highly unstable. CONCLUSIONS: The active metabolites produced by S. alboflavus TD-1 liquid fermentation contain components that can significant inhibitory effects on R. solanacearum. It had the potential to develop biocontrol agents against bacterial wilt and be a kind potential sources for the preparation of functional anti-pathogenic microbial agents.


Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacologia , Ralstonia solanacearum/efeitos dos fármacos , Ralstonia solanacearum/crescimento & desenvolvimento , Streptomyces/metabolismo , Antibacterianos/química , Antibacterianos/isolamento & purificação , Vias Biossintéticas/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Meios de Cultura/química , DNA Bacteriano/biossíntese , Fermentação , Testes de Sensibilidade Microbiana , Peso Molecular , Biossíntese de Proteínas/efeitos dos fármacos , Ralstonia solanacearum/citologia
10.
Future Med Chem ; 11(10): 1137-1155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31280672

RESUMO

Aim: To study a new series of [1,2,3]triazolo[1,5-α]pyridine derivatives as trypanocidal agents because current antichagasic pharmacologic therapy is only partially effective. Materials & methods: The effect of the series upon Trypanosoma cruzi epimastigotes and murine macrophages viability, cell cycle, cell death and on the metabolites of the sterol biosynthesis pathway was measured; also, docking in 14α-demethylase was analyzed. Results: Compound 16 inhibits 14α-demethylase producing an imbalance in the cholesterol/ergosterol synthesis pathway, as suggested by a metabolic control and theoretical docking analysis. Consequently, it prevented cell proliferation, stopping the cellular cycle at the G2/M phase, inducing cell death. Conclusion: Although the exact cell death mechanism remained elusive, this series can be used for the further rational design of novel antiparasitic molecules.


Assuntos
Piridinas/farmacologia , Esteróis/metabolismo , Triazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Vias Biossintéticas/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Humanos , Camundongos , Piridinas/química , Células RAW 264.7 , Triazóis/química , Tripanossomicidas/química , Trypanosoma cruzi/metabolismo
11.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336931

RESUMO

The abnormal regulation of melanin synthesis leads to a wide range of pigmentary disorders. Although various melanin biosynthesis inhibitors have been developed, their efficacy and long-term safety needs to be further improved, and thus the goal of this study is to develop promising natural compound inhibitors of melanin biosynthesis. Here, we obtained aglycone flavonoid extract through the microwave-assisted hydrolysis of glycoside extract from Korean mistletoe in acidic condition. The aglycone extract inhibited tyrosinase activity more efficiently with better antioxidant activity than glycoside extract in vitro. The microwave-assisted aglycone extract of mistletoe was further analyzed for in vivo activity, and the results showed the aglycone extract inhibited both early melanocyte development and melanin synthesis more efficiently in zebrafish embryo in a dose-dependent manner. Our in vivo toxicity assay quantitatively measured cell death in zebrafish embryos and showed that the microwave-assisted aglycone extract of mistletoe had no significant effect on cell death (p < 0.001), indicating that aglycone extract is more biocompatible than glycoside extract. Furthermore, our in vitro and in vivo analyses successfully identified and characterized velutin, an aglycone of a homoflavoyadorinin B glycoside, as a major inhibitory component in the microwave-assisted mistletoe extract. Ultimately, this study showed that the novel natural compound inhibitor velutin, which was generated through microwave-assisted extraction from mistletoe, improved the efficacy of melanin biosynthesis inhibition with little toxicity.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Flavonas/farmacologia , Melaninas/biossíntese , Erva-de-Passarinho/química , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/farmacologia , Glicosídeos/química , Hidrólise , Melanócitos/metabolismo , Micro-Ondas , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Peixe-Zebra
12.
Molecules ; 24(14)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337014

RESUMO

Ochratoxin A (OTA) is a mycotoxin with a serious impact on human health. In Mediterranean countries, the black Aspergilli group, in particular Aspergillus carbonarius, causes the highest OTA contamination. Here we describe the synthesis of three polyphenolic flavonoids: 5-hydroxy-6,7-dimethoxy-flavone (MOS), 5,6-dihydroxy-7-methoxy-flavone (NEG), and 5,6 dihydroxy-flavone (DHF), as well as their effect on the prevention of OTA biosynthesis and lipoxygenase (LOX) activity in A. carbonarius cultured in a conducive liquid medium. The best control effect on OTA biosynthesis was achieved using NEG and DHF. In fungal cultures treated with these compounds at 5, 25, and 50 µg/mL, OTA biosynthesis significantly decreased throughout the 8-day experiment. NEG and DHF appear to have an inhibiting effect also on the activity of LOX, whereas MOS, which did not significantly inhibit OTA production, had no effect on LOX activity. The presence of free hydroxyls in catecholic position in the molecule appears to be a determining factor for significantly inhibiting OTA biosynthesis. However, the presence of a methoxy group in C-7 in NEG could slightly lower the molecule's reactivity increasing OTA inhibition by this molecule at 5 µg/mL. Polyphenolic flavonoids present in edible plants may be easily synthesized and used to control OTA biosynthesis.


Assuntos
Aspergillus/efeitos dos fármacos , Aspergillus/metabolismo , Flavonoides/síntese química , Flavonoides/farmacologia , Ocratoxinas/biossíntese , Vias Biossintéticas/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Flavonoides/química , Lipoxigenase/metabolismo , Micotoxinas
13.
Aquat Toxicol ; 213: 105213, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31200332

RESUMO

Atrazine is a widely used pesticide which acts as an endocrine disruptor in various organisms. The aim of this study was to investigate adverse effects of atrazine on life parameters, oxidative stress, and ecdysteroid biosynthetic pathway in the marine copepod Tigriopus japonicus. In T. japonicus, no mortality was shown in response to atrazine up to 20 mg/L in acute toxicity assessment. In nauplii, retardation in the growth and prolonged molting and metamorphosis resulted under chronic exposure of atrazine at 20 mg/L. In addition, body sizes of T. japonicus nauplii were significantly decreased (P < 0.01 in length and P < 0.001 in width) in response to 20 mg/L of atrazine. Furthermore, atrazine induced oxidative stress by the generation of reactive oxygen species at all concentrations compared to the control in the nauplii. Also, significant increase in glutathione-S transferase activity was observed in adult T. japonicus at low concentration of atrazine. To understand effects of atrazine on ecdysteroid biosynthetic pathway-involved genes (e.g., neverland, CYP307E1, CYP306A1, CYP302A1, CYP3022A1 [CYP315A1], CYP314A1, and CYP18D1) were examined with mRNA expressions of ecdysone receptor (EcR) and ultraspiracle (USP) in response to 20 mg/L atrazine in nauplii and adults. In the nauplii, these genes were significantly downregulated (P < 0.05) in response to atrazine, compared to the control but not in the adult T. japonicus. These results suggest that atrazine can interfere in vivo life parameters by oxidative stress-induced retrogression and ecdysteroid biosynthetic pathway in this species.


Assuntos
Organismos Aquáticos/metabolismo , Atrazina/toxicidade , Vias Biossintéticas/efeitos dos fármacos , Copépodes/efeitos dos fármacos , Ecdisteroides/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Animais , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/genética , Atrazina/química , Vias Biossintéticas/genética , Tamanho Corporal/efeitos dos fármacos , Copépodes/genética , Copépodes/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/metabolismo , Estresse Oxidativo/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade
14.
Nat Commun ; 10(1): 2733, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227716

RESUMO

Cell wall antibiotics are crucial for combatting the emerging wave of resistant bacteria. Yet, our understanding of antibiotic action is limited, as many strains devoid of all resistance determinants display far higher antibiotic tolerance in vivo than suggested by the antibiotic-target binding affinity in vitro. To resolve this conflict, here we develop a comprehensive theory for the bacterial cell wall biosynthetic pathway and study its perturbation by antibiotics. We find that the closed-loop architecture of the lipid II cycle of wall biosynthesis features a highly asymmetric distribution of pathway intermediates, and show that antibiotic tolerance scales inversely with the abundance of the targeted pathway intermediate. We formalize this principle of minimal target exposure as intrinsic resistance mechanism and predict how cooperative drug-target interactions can mitigate resistance. The theory accurately predicts the in vivo efficacy for various cell wall antibiotics in different Gram-positive bacteria and contributes to a systems-level understanding of antibiotic action.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Parede Celular/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Modelos Biológicos , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurâmico/biossíntese
15.
J Steroid Biochem Mol Biol ; 191: 105372, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31042565

RESUMO

Cardiotonic steroids such as ouabain are potent inhibitors of the sodium pump and have been widely used for centuries in the treatment of congestive heart failure. In recent decades, however, they have also been identified as hormone-like molecules that trigger signaling cascades of physiological relevance by using the various sodium pump α subunit isoforms as receptors. The murine Leydig cell line MLTC-1 expresses both the ubiquitous, relatively ouabain-insensitive α1 isoform of the sodium pump and the ouabain-sensitive α3 isoform that is normally found in neuronal cells. The physiological relevance of the simultaneous presence of the two isoforms in Leydig cells has not been previously addressed. MLTC-1 Leydig cells contain lipid droplets (LDs) and are capable of progesterone biosynthesis when stimulated by luteinizing hormone (LH). When exposed to low nanomolar concentrations of ouabain, they respond with stimulation of Erk1/2, CREB, and ATF-1 phosphorylation, LD enlargement, and perilipin2 mobilization to the LDs. As a result, progesterone biosynthesis is augmented. Abrogation of α3 isoform expression by siRNA prevents all of the above responses, indicating that it is the hormone/receptor-like interaction of ouabain exclusively with this isoform that triggers the signaling events that normally occur when LH binds to its receptor. Considering that ouabain is produced endogenously and is found in seminal fluid, one can speculate that effects of this substance on germ and somatic cells of the testis might play a role in male reproductive physiology.


Assuntos
Cardiotônicos/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Ouabaína/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Esteroides/metabolismo , Animais , Vias Biossintéticas/efeitos dos fármacos , Linhagem Celular , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Progesterona/metabolismo , Isoformas de Proteínas/metabolismo
16.
BMC Plant Biol ; 19(1): 189, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068143

RESUMO

BACKGROUND: Chinese jujube (Ziziphus jujuba Mill.) is a non-climacteric fruit; however, the underlying mechanism of ripening and the role of abscisic acid involved in this process are not yet understood for this species. RESULTS: In the present study, a positive correlation between dynamic changes in endogenous ABA and the onset of jujube ripening was determined. Transcript analyses suggested that the expression balance among genes encoding nine-cis-epoxycarotenoid dioxygenase (ZjNCED3), ABA-8'-hydroxylase (ZjCYP707A2), and beta-glucosidase (ZjBG4, ZjBG5, ZjBG8, and ZjBG9) has an important role in maintaining ABA accumulation, while the expression of a receptor (ZjPYL8), protein phosphatase 2C (ZjPP2C4-8), and sucrose nonfermenting 1-related protein kinase 2 (ZjSnRK2-2 and ZjSnRK2-5) is important in regulating fruit sensitivity to ABA applications. In addition, white mature 'Dongzao' fruit were harvested and treated with 50 mg L- 1 ABA or 50 mg L- 1 nordihydroguaiaretic acid (NDGA) to explore the role of ABA in jujube fruit ripening. By comparative transcriptome analyses, 1103 and 505 genes were differentially expressed in response to ABA and NDGA applications on the 1st day after treatment, respectively. These DEGs were associated with photosynthesis, secondary, lipid, cell wall, and starch and sugar metabolic processes, suggesting the involvement of ABA in modulating jujube fruit ripening. Moreover, ABA also exhibited crosstalk with other phytohormones and transcription factors, indicating a regulatory network for jujube fruit ripening. CONCLUSIONS: Our study further elucidated ABA-associated metabolic and regulatory processes. These findings are helpful for improving strategies for jujube fruit storage and for gaining insights into understand complex non-climacteric fruit ripening processes.


Assuntos
Ácido Abscísico/metabolismo , Frutas/crescimento & desenvolvimento , Frutas/genética , Regulação da Expressão Gênica de Plantas , Ziziphus/crescimento & desenvolvimento , Ziziphus/genética , Biomassa , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Etilenos/biossíntese , Frutas/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Ontologia Genética , Genes de Plantas , Masoprocol/farmacologia , Reguladores de Crescimento de Planta/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Ziziphus/efeitos dos fármacos
17.
Elife ; 82019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964003

RESUMO

Penicillin and related antibiotics disrupt cell wall synthesis to induce bacteriolysis. Lysis in response to these drugs requires the activity of cell wall hydrolases called autolysins, but how penicillins misactivate these deadly enzymes has long remained unclear. Here, we show that alterations in surface polymers called teichoic acids (TAs) play a key role in penicillin-induced lysis of the Gram-positive pathogen Streptococcus pneumoniae (Sp). We find that during exponential growth, Sp cells primarily produce lipid-anchored TAs called lipoteichoic acids (LTAs) that bind and sequester the major autolysin LytA. However, penicillin-treatment or prolonged stationary phase growth triggers the degradation of a key LTA synthase, causing a switch to the production of wall-anchored TAs (WTAs). This change allows LytA to associate with and degrade its cell wall substrate, thus promoting osmotic lysis. Similar changes in surface polymer assembly may underlie the mechanism of antibiotic- and/or growth phase-induced lysis for other important Gram-positive pathogens.


Assuntos
Antibacterianos/farmacologia , Bacteriólise/efeitos dos fármacos , Vias Biossintéticas/efeitos dos fármacos , Penicilinas/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Ácidos Teicoicos/biossíntese
18.
Appl Microbiol Biotechnol ; 103(11): 4565-4574, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31011774

RESUMO

Biosurfactants are amphiphilic compounds that composed of hydrophilic and hydrophobic moieties, which possess the ability of self-organizing between phases, reducing the interfacial tension, and forming aggregates such as micelles. This spontaneous process results in significant changes in surface properties that directly influence the adherence of microorganisms. In this study, the ability of surfactin, a biosurfactant produced by Bacillus subtilis in reducing adhesion and disrupting the presence of biofilm of Staphylococcus aureus (S. aureus) on several surfaces, was investigated. Significant biofilm removal was observed on glass, polystyrene, and stainless steel surfaces. Furthermore, we explored the probable mechanism about how surfactin affected S. aureus biofilm formation. Based on our findings, surfactin had a significant effect on the polysaccharides production and especially decreased the percentage of alkali-soluble polysaccharide in biofilms. It also down-regulated the expression of icaA and icaD significantly, which are necessary for the important constituents to take shape of staphylococcal biofilm. In addition, it was found that the lipopeptide affected the quorum sensing (QS) system in S. aureus through regulating the auto inducer 2 (AI-2) activity, which has been reported to be negative for biofilm formation in S. aureus. These above properties could be applied in developing surfactin as a potential pre-coating agent on material surfaces to prevent S. aureus biofilm formation.


Assuntos
Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Lipopeptídeos/metabolismo , Peptídeos Cíclicos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Bacillus subtilis/química , Vias Biossintéticas/efeitos dos fármacos , Microbiologia Ambiental , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Lipopeptídeos/isolamento & purificação , Peptídeos Cíclicos/isolamento & purificação , Polissacarídeos/biossíntese , Percepção de Quorum/efeitos dos fármacos , Propriedades de Superfície/efeitos dos fármacos
19.
J Pharm Biomed Anal ; 172: 126-138, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31035094

RESUMO

Salvia miltiorrhiza Bunge is a traditional Chinese medicine, and its water-soluble phenolic acid active compounds have very important medicinal value; however, the synthesis pathways of the main active ingredients remain unknown. Here, we employed nuclear magnetic resonance (NMR)-based metabolomics and transcriptomics techniques to study the biosynthesis mechanism of salvianolic acids. High-performance liquid chromatography (HPLC) combined with NMR showed an improvement over traditional techniques, and 54 metabolites were detected. The results of the multivariate statistical analysis showed that salvianolic acid B (SAB), rosmarinic acid (RA), caffeic acid, succinate, and citrate were among the multiple compounds that were increased in the methyl jasmonate (MeJA)-elicited group; the levels of sucrose, fructose, glutamine, and tyrosine were decreased. Combined with the differentially expressed genes (DEGs) found by transcriptome sequencing, we speculate that the synthesis of RA after MeJA treatment mostly occurred through caffeic acid and bypassed 4-hydroxyphenyllactic acid. This provides useful information for the study of salvianolic acids synthesis.


Assuntos
Benzofuranos/metabolismo , Cinamatos/metabolismo , Depsídeos/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Salvia miltiorrhiza/metabolismo , Acetatos/farmacologia , Vias Biossintéticas/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Ciclopentanos/farmacologia , Perfilação da Expressão Gênica/métodos , Metabolômica/métodos , Oxilipinas/farmacologia , Fenilpropionatos/metabolismo , Raízes de Plantas/citologia
20.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934786

RESUMO

Silybum marianum (L.) Gaertn. is a well-known medicinal herb, primarily used in liver protection. Light strongly affects several physiological processes along with secondary metabolites biosynthesis in plants. Herein, S. marianum was exploited for in vitro potential under different light regimes in the presence of melatonin. The optimal callogenic response occurred in the combination of 1.0 mg/L α-naphthalene acetic acid and 0.5 mg/L 6-benzylaminopurine under photoperiod. Continuous light associated with melatonin treatment increased total flavonoid content (TFC), total phenolic content (TPC) and antioxidant potential, followed by photoperiod and dark treatments. The increased level of melatonin has a synergistic effect on biomass accumulation under continuous light and photoperiod, while an adverse effect was observed under dark conditions. More detailed phytochemical analysis showed maximum total silymarin content (11.92 mg/g dry weight (DW)) when placed under continuous light + 1.0 mg/L melatonin. Individually, the level of silybins (A and B), silydianin, isolsilychristin and silychristin was found highest under continuous light. Anti-inflammatory activities were also studied and highest percent inhibition was recorded against 15-lipoxygenase (15-LOX) for cultures cultivated under continuous light (42.33%). The current study helps us to better understand the influence of melatonin and different light regimes on silymarin production as well as antioxidant and anti-inflammatory activities in S. marianum callus extracts.


Assuntos
Anti-Inflamatórios/farmacologia , Vias Biossintéticas/efeitos dos fármacos , Luz , Melatonina/farmacologia , Cardo-Mariano/química , Cardo-Mariano/metabolismo , Silimarina/biossíntese , Anti-Inflamatórios/química , Antioxidantes/química , Antioxidantes/farmacologia , Biomassa , Metabolismo Secundário/efeitos dos fármacos
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