RESUMEN
Mounting evidence supporting the negative impacts of exposure to neonicotinoids on bees has prompted the registration of novel 'bee-friendly' insecticides for agricultural use. Flupyradifurone (FPF) is a butenolide insecticide that shares the same mode of action as neonicotinoids and has been assessed to be 'practically non-toxic to adult honeybees' using current risk assessment procedures. However, these assessments overlook some routes of exposure specific to wild bees, such as contact with residues in soil for ground-nesters. Co-exposure with other pesticides may also lead to detrimental synergistic effects. In a fully crossed experiment, we assessed the possible lethal and sublethal effects of chronic exposure to two pesticides used on Cucurbita crops, the insecticide Sivanto Prime (FPF) and the fungicide Quadris Top (azoxystrobin and difenoconazole), alone or combined, on solitary ground-nesting squash bees (Xenoglossa pruinosa). Squash bees exposed to Quadris Top collected less pollen per flower visit, while Sivanto-exposed bees produced larger offspring. Pesticide co-exposure induced hyperactivity in female squash bees relative to both the control and single pesticide exposure, and reduced the number of emerging offspring per nest compared to individual pesticide treatments. This study demonstrates that 'low-toxicity' pesticides can adversely affect squash bees under field-realistic exposure, alone or in combination.
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4-Butirolactona/análogos & derivados , Insecticidas , Plaguicidas , Piridinas , Pirimidinas , Estrobilurinas , Abejas , Femenino , Animales , Plaguicidas/toxicidad , Insecticidas/toxicidad , Neonicotinoides/toxicidadRESUMEN
Obesity is often accompanied by increased adipose tissue inflammation, a process that is partially driven by adipose tissue-resident macrophages. In this study, we explored the potential for plant-derived dietary compounds to exert anti-inflammatory effects in macrophages that alleviate obesity-associated adipocyte dysfunction. Capsaicin (CAP), schisandrin A (SA), enterodiol (END), and enterolactone (ENL) treatment polarized J774 macrophages to an "M2" or anti-inflammatory phenotype and inhibited responses to stimulation with lipopolysaccharide (LPS). Furthermore, these compounds blocked inflammasome activation when administered just before ATP-induced NLRP3 activation, as evidenced by the abrogation of IL-1ß release in mouse macrophages and human peripheral blood monocytes. The addition of CAP, SA, or ENL during the differentiation of bone marrow-derived macrophages was also sufficient to inhibit LPS-induced IL-6 and TNFα production. Finally, CAP, END, and ENL treatment during differentiation of 3T3-L1 adipocytes induced an adiponectin-high phenotype accompanied by increases in thermogenic gene expression, and conditioned media from these adipocytes inhibited LPS-induced production of IL-1ß, IL-6, and TNFα from J774 macrophages. These polarizing effects were partially mediated by the elevated adiponectin and decreased syndecan-4 in the adipocyte-conditioned media. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.NEW & NOTEWORTHY The utility of food-based products to prevent or alleviate chronic conditions such as obesity and its associated comorbidities is an attractive approach. Capsaicin, schisandrin A, enterodiol, and enterolactone, phytochemicals present in traditional medicinal food, decreased proinflammatory cytokine production from macrophages that, in turn, reduced obesity-associated adipocyte dysfunction. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.
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4-Butirolactona/análogos & derivados , Capsaicina , Ciclooctanos , Lignanos , Compuestos Policíclicos , Factor de Necrosis Tumoral alfa , Animales , Ratones , Humanos , Capsaicina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Adiponectina , Lipopolisacáridos/toxicidad , Medios de Cultivo Condicionados/metabolismo , Medios de Cultivo Condicionados/farmacología , Obesidad/complicaciones , Obesidad/metabolismo , Inflamación/metabolismo , Antiinflamatorios , Macrófagos/metabolismoRESUMEN
Computational design advances enzyme evolution and their use in biocatalysis in a faster and more efficient manner. In this study, a synergistic approach integrating tunnel engineering, evolutionary analysis, and force-field calculations has been employed to enhance the catalytic activity of D-lactonohydrolase (D-Lac), which is a pivotal enzyme involved in the resolution of racemic pantolactone during the production of vitamin B5. The best mutant, N96S/A271E/F274Y/F308G (M3), was obtained and its catalytic efficiency (kcat/KM) was nearly 23-fold higher than that of the wild-type. The M3 whole-cell converted 20 % of DL-pantolactone into D-pantoic acid (D-PA, >99 %â e.e.) with a conversion rate of 47 % and space-time yield of 107.1â g L-1 h-1, demonstrating its great potential for industrial-scale D-pantothenic acid production. Molecular dynamics (MD) simulations revealed that the reduction in the steric hindrance within the substrate tunnel and conformational reconstruction of the distal loop resulted in a more favourable"catalytic" conformation, making it easier for the substrate and enzyme to enter their pre-reaction state. This study illustrates the potential of the distal residue on the pivotal loop at the entrance of the D-Lac substrate tunnel as a novel modification hotspot capable of reshaping energy patterns and consequently influencing the enzymatic activity.
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4-Butirolactona/análogos & derivados , Simulación de Dinámica Molecular , Ingeniería de Proteínas , Ingeniería de Proteínas/métodos , CatálisisRESUMEN
Within bioplastics, natural poly(3-hydroxybutyrate) (PHB) stands out as fully biocompatible and biodegradable, even in marine environments; however, its high isotacticity and crystallinity limits its mechanical properties and hence its applications. PHB can also be synthesized with different tacticities via a catalytic ring-opening polymerization (ROP) of rac-ß-butyrolactone (BBL), paving the way to PHB with better thermomechanical and processability properties. In this work, the catalyst family is extended based on aluminum phenoxy-imine methyl catalyst [AlMeL2], that reveals efficient in the ROP of BBL, to the halogeno analogous complex [AlClL2]. As well, the impact on the ROP mechanism of different initiators is further explored with a particular focus in dimethylaminopyridine (DMAP), a hardly studied initiator for the ROP of BBL. A thorough mechanistic study is performed that evidences the presence of two concomitant DMAP-mediated mechanisms, that lead to either a DMAP or a crotonate end-capping group. Besides, in order to increase the possibilities of PHB post-polymerization functionalization, the introduction of a side-chain functionality is explored, establishing the copolymerization of BBL with ß-allyloxymethylene propiolactone (BPLOAll), resulting in well-defined P(BBL-co-BPLOAll) copolymers.
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4-Butirolactona , Aluminio , Polihidroxialcanoatos , Polimerizacion , Catálisis , 4-Butirolactona/química , 4-Butirolactona/análogos & derivados , Polihidroxialcanoatos/química , Aluminio/química , Estructura Molecular , Hidroxibutiratos/química , PolihidroxibutiratosRESUMEN
AIM: The increased availability of genome sequences has enabled the development of valuable tools for the prediction and identification of bacterial natural products. Burkholderia catarinensis 89T produces siderophores and an unknown potent antifungal metabolite. The aim of this work was to identify and purify natural products of B. catarinensis 89T through a genome-guided approach. MATERIALS AND METHODS: The analysis of B. catarinensis 89T genome revealed 16 clusters putatively related to secondary metabolism and antibiotics production. Of particular note was the identification of a nonribosomal peptide synthetase (NRPS) cluster related to the production of the siderophore ornibactin, a hybrid NRPS-polyketide synthase Type 1 cluster for the production of the antifungal glycolipopeptide burkholdine, and a gene cluster encoding homoserine lactones (HSL), probably involved in the regulation of both metabolites. We were able to purify high amounts of the ornibactin derivatives D/C6 and F/C8, while also detecting the derivative B/C4 in mass spectrometry investigations. A group of metabolites with molecular masses ranging from 1188 to 1272 Da could be detected in MS experiments, which we postulate to be new burkholdine analogs produced by B. catarinensis. The comparison of B. catarinensis BGCs with other Bcc members corroborates the hypothesis that this bacterium could produce new derivatives of these metabolites. Moreover, the quorum sensing metabolites C6-HSL, C8-HSL, and 3OH-C8-HSL were observed in LC-MS/MS analysis. CONCLUSION: The new species B. catarinensis is a potential source of new bioactive secondary metabolites. Our results highlight the importance of genome-guided purification and identification of metabolites of biotechnological importance.
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4-Butirolactona/análogos & derivados , Productos Biológicos , Complejo Burkholderia cepacia , Burkholderia , Lipopéptidos , Sideróforos/metabolismo , Antifúngicos/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Burkholderia/genética , Burkholderia/metabolismo , Complejo Burkholderia cepacia/metabolismo , Productos Biológicos/metabolismo , Proteínas Bacterianas/genéticaRESUMEN
Total syntheses of two γ-butenolide natural products, asperjinone (1) and asperimide C (2) in both racemic and chiral forms have been accomplished utilizing Basavaiah's one-pot Friedel-Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of 1 proposed by Williams et al. and the structure and absolute configuration of 2 reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of 1. Synthetic 1 exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 under LPS-induced renal inflammation condition and was superior to (S)-1, rac-2, 2, and a positive drug control, indomethacin. Moreover, compound 1 inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (1) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.
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Antiinflamatorios , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Estructura Molecular , Animales , Ciclooxigenasa 2/metabolismo , Lipopolisacáridos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , 4-Butirolactona/análogos & derivadosRESUMEN
The activated sludge process faces challenges in achieving adequate nitrification ability under low-temperature conditions. Therefore, we investigated the effects of different concentrations of exogenous N-butyryl-homoserine lactone (C4-HSL) on nitrogen removal in lab-scale sequencing batch reactors (SBRs) at 10 °C. The results revealed that both 10 and 100 µg/L of C4-HSL could improve NH4+-N removal efficiency by 26% and reduce the effluent TN concentration to below 15 mg/L. Analysis of extracellular polymeric substances (EPS) revealed that adding C4-HSL (especially 100 µg/L) reduced the protein-like substance content while increasing the humic and fulvic acid-like substance content in EPS. Protein-like substances could serve as carbon sources for denitrifiers, thus promoting denitrification. Moreover, exogenous C4-HSL increased the abundance of bacteria and genes associated with nitrification and denitrification. Further analysis of quorum sensing (QS) of microorganisms indicated that exogenous C4-HSL (especially 100 µg/L) promoted regulation, transportation, and decomposition functions in the QS process. Furthermore, CS, sdh, fum, and mdh gene expressions involved in the tricarboxylic acid (TCA) cycle were enhanced by 100 µg/L C4-HSL. Exogenous C4-HSL promoted microbial communication, microbial energy metabolism, and nitrogen metabolism, thereby improving the nitrogen removal efficiency of activated sludge systems at low temperatures. This study provides a feasible strategy for enhancing denitrogenation performance at low temperatures through exogenous C4-HSL.
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4-Butirolactona/análogos & derivados , Percepción de Quorum , Aguas del Alcantarillado , Aguas del Alcantarillado/microbiología , Temperatura , Nitrógeno , DesnitrificaciónRESUMEN
Pseudomonas aeruginosa (P. aeruginosa) biofilm formation is a crucial cause of enhanced antibiotic resistance. Quorum sensing (QS) is involved in regulating biofilm formation; QS inhibitors block the QS signaling pathway as a new strategy to address bacterial resistance. This study investigated the potential and mechanism of L-HSL (N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide) as a QS inhibitor for P. aeruginosa. The results showed that L-HSL effectively inhibited the biofilm formation and dispersed the pre-formed biofilm of P. aeruginosa. The production of extracellular polysaccharides and the motility ability of P. aeruginosa were suppressed by L-HSL. C. elegans infection experiment showed that L-HSL was non-toxic and provided protection to C. elegans against P. aeruginosa infection. Transcriptomic analysis revealed that L-HSL downregulated genes related to QS pathways and biofilm formation. L-HSL exhibits a promising potential as a therapeutic drug for P. aeruginosa infection. KEY POINTS: ⢠Chemical synthesis of N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide, named L-HSL. ⢠L-HSL does not generate survival pressure on the growth of P. aeruginosa and can inhibit the QS system. ⢠KEGG enrichment analysis found that after L-HSL treatment, QS-related genes were downregulated.
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4-Butirolactona , Biopelículas , Caenorhabditis elegans , Pseudomonas aeruginosa , Percepción de Quorum , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Pseudomonas aeruginosa/genética , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Percepción de Quorum/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Animales , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacología , 4-Butirolactona/metabolismo , Antibacterianos/farmacología , Perfilación de la Expresión Génica , Homoserina/análogos & derivados , Homoserina/metabolismo , Homoserina/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND Retinopathy of prematurity (ROP), originally described as retrolental fibroplasia, represents an abnormal growth of blood vessels in the premature retina that can occur in response to oxygen therapy. The association between ROP and invasive mechanical ventilation has been widely studied in the literature; however, the relationships between different types of ventilation and ROP have not been as well documented. This study aimed to compare the association of ROP incidence with mechanical ventilation (MV), nasal continuous positive airway pressure (nCPAP), and high-flow nasal cannula (HFNC) therapies in 130 pre-term infants with gestational ages <32 weeks. MATERIAL AND METHODS The study includes 130 premature newborns, out of which 54 underwent MV therapy, either alone or in combination with nCPAP or HFNC therapy, 63 underwent nCPAP therapy, either alone or in combination with MV or HFNC therapy, and 23 underwent HFNC therapy, either alone or in combination with MV or nCPAP therapy. The relationships between ROP and the 3 types of ventilation were analyzed by univariate followed by multivariate logistic regression. RESULTS When adjusting for covariates, only nCPAP and birth weight were significantly associated with ROP, the former being a strong risk factor, with an adjusted odds ratio (AOR) of 7.264 (95% CI, 2.622-20.120; P<0.001), and the latter being a weak protective factor, with an AOR of 0.998 (95% CI, 0.996-0.999; P<0.05). CONCLUSIONS The results showed nCPAP was a strong ROP risk factor, birth weight was a weak ROP protective factor, and MV and HFNC were not significantly associated with increased ROP risk.
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4-Butirolactona/análogos & derivados , Respiración Artificial , Retinopatía de la Prematuridad , Recién Nacido , Lactante , Humanos , Respiración Artificial/efectos adversos , Presión de las Vías Aéreas Positiva Contínua , Retinopatía de la Prematuridad/terapia , Peso al Nacer , CánulaRESUMEN
Acyl-homoserine lactones (AHLs) are quorum-sensing signaling molecules in Gram-negative bacteria and positively regulate biofilm formation in Salmonella under specific conditions. In this study, biofilm formation in Salmonella enterica was evaluated at 28 and 37 °C, under aerobic and anaerobic conditions. Additionally, the influence of the N-dodecanoyl-DL-homoserine lactone (C12-HSL) on biofilm formation and the expression of genes related to the synthesis of structural components, regulation, and quorum sensing was assessed under anaerobiosis at 28 and 37 °C. Biofilm formation was found not to be influenced by the atmospheric conditions at 28 °C. However, it was reduced at 37 °C under anaerobiosis. C12-HSL enhanced biofilm formation at 37 °C under anaerobiosis and increased the expression of the adrA and luxS genes, suggesting an increase in c-di-GMP, a second messenger that controls essential physiological functions in bacteria. These results provide new insights into the regulation of biofilm formation in Salmonella under anaerobic conditions.
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Percepción de Quorum , Salmonella enteritidis , Percepción de Quorum/genética , Salmonella enteritidis/genética , Biopelículas , Anaerobiosis , 4-Butirolactona/farmacología , 4-Butirolactona/metabolismo , Acil-ButirolactonasRESUMEN
Flaxseed is the richest source of secoisolariciresinol diglucoside, which is converted by ruminal microorganisms primarily to the mammalian lignan enterolactone. Our objective was to investigate the effect of diets containing soybean meal or flaxseed meal (FM) supplemented with sucrose, flaxseed oil, or both, on milk enterolactone concentration yield, diversity, and relative abundance of ruminal bacterial taxa, ruminal fermentation profile, production performance, milk fatty acids (FA) yield, and nutrient utilization in dairy cows. Sixteen Holstein cows (8 multiparous [4 ruminally cannulated] and 8 primiparous) averaging (mean ± SD) 134 ± 54.1 DIM and 679 ± 78.9 kg of BW in the beginning of the study were assigned to treatment sequences in a replicated 4 × 4 Latin square design. Each experimental period lasted 25 d, with 18 d for diet adaptation and 7 d for data and sample collection. Diets were formulated to contain a 60:40 forage:concentrate ratio and included the following (DM basis): (1) 8% soybean meal and 23% ground corn (SBM); (2) 15% FM, 10.7% ground corn, and 5% sucrose (FLX+S); (3) 15% FM, 15.4% ground corn, and 3% flaxseed oil (FLX+O); and (4) 15% FM, 10.2% ground corn, 5% sucrose, and 3% flaxseed oil (FLX+SO). Compared with SBM, the concentration and yield of milk enterolactone increased in cows fed the FM diets but did not differ among FLX+S, FLX+O, and FLX+SO. The relative abundances of the phyla Firmicutes, Verrucomicrobiota, and Actinobacteriota, and those of the bacterial genera Lachnospiraceae NK3A20 group, Eubacterium coprostanoligenes group, Anaeromusa-Anaeroarcus, WCHB1-41, and p-251-o5 decreased, whereas Prevotella and NK4A214 group increased when comparing SBM against at least 1 diet containing FM. Furthermore, the relative abundances of Firmicutes and Actinobacteriota and those of Prevotella, Lachnospiraceae NK3A20 group, Eubacterium coprostanoligenes group, Acetitomaculum, Lachnospiraceae unclassified, NK4A214 group, and Anaeromusa-Anaeroarcus changed (increased or decreased) across the FLX+S, FLX+O, and FLX+SO diets. However, all these changes in the relative abundance of the ruminal bacterial taxa were not conclusively associated with the effect of diets on milk enterolactone. Diets did not affect ruminal pH and concentrations of NH3-N and total VFA. Dry matter intake and yields of milk, milk fat, and milk true protein all decreased in cows fed FLX+O or FLX+SO. Yields of milk total odd-chain FA, branched-chain FA, total <16C FA, and total 16C FA decreased with feeding FLX+O and FLX+SO. The apparent total-tract digestibilities of DM and OM were lowest in the FLX+S and FLX+O diets, with CP and ADF digestibilities lowest in cows receiving FLX+S or FLX+O, respectively. Urinary excretion of total N was lowest with feeding SBM. Contrarily, diets did not affect the urinary excretion of total purine derivatives. In brief, despite the effect of diets on the relative abundance of several ruminal microbiota phyla and genera, we were unable to conclusively associate these changes with increased milk enterolactone in FM-containing diets versus SBM.
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Alimentación Animal , Dieta , Lino , Lactancia , Aceite de Linaza , Leche , Rumen , Sacarosa , Animales , Bovinos , Femenino , Leche/química , Dieta/veterinaria , Rumen/metabolismo , Rumen/microbiología , Sacarosa/metabolismo , Aceite de Linaza/farmacología , Alimentación Animal/análisis , Lignanos , Suplementos Dietéticos , Microbiota , Fermentación , 4-Butirolactona/análogos & derivadosRESUMEN
Aphis gossypii, a globally distributed and economically significant pest of several crops, is known to infest a wide range of host plants. Heat shock proteins (Hsps), acting as molecular chaperones, are essential for the insect's environmental stress responses. The present study investigated the molecular characteristics and expression patterns of AgHsp70, a heat shock protein gene, in Aphis gossypii. Our phylogenetic analysis revealed that AgHsp70 shared high similarity with homologs from other insects, suggesting a conserved function across species. The developmental expression profiles of AgHsp70 in A. gossypii showed that the highest transcript levels were observed in the fourth instar nymphs, while the lowest levels were detected in the third instar nymphs. Heat stress and exposure to four different xenobiotics (2-tridecanone, tannic acid, gossypol, and flupyradifurone (4-[(2,2-difluoroethyl)amino]-2(5H)-furanone)) significantly up-regulated AgHsp70 expression. Knockdown of AgHsp70 using RNAi obviously increased the susceptibility of cotton aphids to 2-tridecanone, gossypol and flupyradifurone. Dual-luciferase reporter assays revealed that gossypol and flupyradifurone significantly enhanced the promoter activity of AgHsp70 at a concentration of 10 mg/L. Furthermore, we identified the transcription factor heat shock factor (HSF) as a regulator of AgHsp70, as silencing AgHSF reduced AgHsp70 expression. Our results shed light on the role of AgHsp70 in xenobiotic adaptation and thermo-tolerance.
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4-Butirolactona/análogos & derivados , Áfidos , Gosipol , Cetonas , Polifenoles , Piridinas , Animales , Áfidos/genética , Áfidos/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Gosipol/metabolismo , Filogenia , Xenobióticos/farmacología , Xenobióticos/metabolismoRESUMEN
The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.
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Compuestos de Espiro , Animales , Compuestos de Espiro/farmacología , Compuestos de Espiro/metabolismo , Acaricidas/farmacología , Propionatos/farmacología , Propionatos/metabolismo , Tetranychidae/efectos de los fármacos , Tetranychidae/genética , Tetranychidae/metabolismo , Simulación del Acoplamiento Molecular , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/metabolismo , Resistencia a Medicamentos/genética , 4-Butirolactona/análogos & derivadosRESUMEN
Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC50 = 20.4 µM) and U-251 MG non-CSCs (IC50 = 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γ-butyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,ß-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.
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4-Butirolactona/análogos & derivados , Antineoplásicos , Neoplasias , Sesquiterpenos , Humanos , Antineoplásicos/farmacología , Lactonas/farmacología , Sesquiterpenos/farmacología , Células Madre Neoplásicas , Sesquiterpenos de Guayano/farmacología , Línea Celular TumoralRESUMEN
The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via 1H-NMR, 13C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC50 values of 6.187â mg â L-1 and 3.269â mg â L-1, respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC50=15.743â mg â L-1). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compoundâ (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization.
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4-Butirolactona , Teoría Funcional de la Densidad , Insecticidas , Simulación del Acoplamiento Molecular , Mariposas Nocturnas , Insecticidas/química , Insecticidas/farmacología , Insecticidas/síntesis química , Animales , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacología , 4-Butirolactona/síntesis química , Mariposas Nocturnas/efectos de los fármacos , Cristalografía por Rayos X , Estructura Molecular , Xantinas/farmacología , Xantinas/química , Xantinas/síntesis química , Áfidos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Marine fungi represent a huge untapped resource of natural products. The bio-activity of a new asperbutenolide A from marine fungus Aspergillus terreus was not well known. In the present study, the minimum inhibitory concentration (MIC) and RNA-Sequencing were used to analyze the bio-activity and sterilization mechanism of asperbutenolide A against clinical pathogenic microbes. The results showed that the MICs of asperbutenolide A against methicillin-resistant Staphylococcus aureus (MRSA) were 4.0-8.0â µg/mL. The asperbutenolide A present poor bio-activity against with candida. The sterilization mechanism of asperbutenolide A against MRSA showed that there were 1426 differentially-expressed genes (DEGs) between the groups of MRSA treated with asperbutenolide A and negative control. Gene Ontology (GO) classification analysis indicated that the DEGs were mainly involved in cellular process, metabolic process, cellular anatomical entity, binding, catalytic activity, etc. Kyoto Encyclopedia of Genes and Genomes (KEGG) classification analysis showed that these DEGs were mainly enriched in amino acid metabolism, carbohydrate metabolism, membrane transport, etc. Moreover, qRT-PCR showed similar trends in the expressions of argF, ureA, glmS and opuCA with the RNA-Sequencing. These results indicated that asperbutenolide A was with ideal bio-activity against with MRSA and could be as a new antibacterial agent.
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4-Butirolactona/análogos & derivados , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Hongos , ARNRESUMEN
Sea cucumber-derived fungi have attracted much attention due to their capacity to produce an incredible variety of secondary metabolites. Genome-wide information on Aspergillus micronesiensis H39 obtained using third-generation sequencing technology (PacBio-SMRT) showed that the strain contains nonribosomal peptide synthetase (NRPS)-like gene clusters, which aroused our interest in mining its secondary metabolites. 11 known compounds (1-11), including two γ-aromatic butenolides (γ-AB) and five cytochalasans, were isolated from A. micronesiensis H39. The structures of the compounds were determined by NMR and ESIMS, and comparison with those reported in the literature. From the perspective of biogenetic origins, the γ-butyrolactone core of compounds 1 and 2 was assembled by NRPS-like enzyme. All of the obtained compounds showed no inhibitory activity against drug-resistant bacteria and fungi, as well as compounds 1 and 2 had no anti-angiogenic activity against zebrafish.
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4-Butirolactona , 4-Butirolactona/análogos & derivados , Aspergillus , Familia de Multigenes , Péptido Sintasas , Péptido Sintasas/genética , Estructura Molecular , 4-Butirolactona/farmacología , 4-Butirolactona/química , Aspergillus/enzimología , Aspergillus/química , Aspergillus/genética , Animales , Pez CebraRESUMEN
During gastrulation and neurulation, the chordamesoderm and overlying neuroectoderm of vertebrate embryos converge under the control of a specific genetic programme to the dorsal midline, simultaneously extending along it. However, whether mechanical tensions resulting from these morphogenetic movements play a role in long-range feedback signaling that in turn regulates gene expression in the chordamesoderm and neuroectoderm is unclear. In the present work, by using a model of artificially stretched explants of Xenopus midgastrula embryos and full-transcriptome sequencing, we identified genes with altered expression in response to external mechanical stretching. Importantly, mechanically activated genes appeared to be expressed during normal development in the trunk, i.e., in the stretched region only. By contrast, genes inhibited by mechanical stretching were normally expressed in the anterior neuroectoderm, where mechanical stress is low. These results indicate that mechanical tensions may play the role of a long-range signaling factor that regulates patterning of the embryo, serving as a link coupling morphogenesis and cell differentiation.
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4-Butirolactona , Animales , Estrés Mecánico , Xenopus laevis/genética , Expresión GénicaRESUMEN
N-acyl homoserine lactones (AHLs) function as signaling molecules influencing microbial community dynamics. This study investigates the impact of exogenously applied AHLs on methane production during waste-activated sludge (WAS) anaerobic digestion (AD). Nine AHL types, ranging from 10-4 to 10 µg/g VSS, were applied, comparing microbial community composition under optimal AHL concentrations. Firmicutes, Bacteroidetes, Chloroflexi, and Proteobacteria were identified in anaerobic digesters with C4-HSL, C6-HSL, and C8-HSL. Compared to the control, Halobacterota increased by 19.25%, 20.87%, and 9.33% with C7-HSL, C10-HSL, and C12-HSL. Exogenous C7-HSL enhanced the relative abundance of Methanosarcina, Romboutsia, Sedimentibacter, Proteiniclasticum, Christensenellaceae_R-7_group. C10-HSL increased Methanosarcina abundance. C4-HSL, C6-HSL, C8-HSL, C10-HSL, and C12-HSL showed potential to increase unclassified_Firmicutes. Functional Annotation of Prokaryotic Taxa (FAPROTAX) predicted AHLs' impact on related functional genes, providing insights into their role in AD methanogenesis regulation. This study aimed to enhance the understanding of the influence of different types of exogenous AHLs on AD and provide technical support for regulating the methanogenesis efficiency of AD by exogenous AHLs.
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4-Butirolactona , 4-Butirolactona/análogos & derivados , Acil-Butirolactonas , Acil-Butirolactonas/farmacología , Anaerobiosis , 4-Butirolactona/farmacología , Aguas del Alcantarillado , LactonasRESUMEN
Lignan-rich beans, nuts, and various seeds are the main foods with antioxidative and hormone-modulating activities. Although the role of lignans in mediating hormone-dependent cancers and cardiovascular diseases is well characterized, the function of lignans in anti-arthritic activity and its underlying mechanisms remain unknown. Three new lignan derivatives, (-)-nortrachelogenin, trachelogenin, and matairesinol, were extracted from Loranthus parasiticus. After establishing the collagen-induced arthritis (CIA) model by intradermal injection of collagen, rats were treated with three new lignan derivatives ((-)-nortrachelogenin: 37%; trachelogenin: 27%; matairesinol: 25.7%) at a concentration of 50 mg/kg and 100 mg/kg, or methotrexate at 0.3 mg/kg. Mixed lignan derivatives significantly attenuated the immune responses in the joints of CIA rats, leading to lower levels of proinflammatory cytokines (IL-6 and TNF-α) and higher levels of free androgen in the serum compared to the CIA model. The results of molecular docking using AutoDock Vina showed that the lignan derivative (-)-nortrachelogenin was the most effective compound for binding to sex hormone-binding globulin (SHBG), thus inhibiting the activity of NFκB in LPS-stimulated macrophages. In this study, (-)-nortrachelogenin was identified as a novel natural lignan derivative with previously unrecognized anti-inflammatory activity. Its molecular mechanism appears related to the regulation of the NFκB/SHBG pathway. Our findings suggest that further application of sex hormone-like compounds in the treatment of rheumatoid arthritis and the potential clinical applications of (-)-nortrachelogenin are promising.