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1.
Appl Microbiol Biotechnol ; 108(1): 418, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39012538

RESUMO

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.


Assuntos
4-Butirolactona , Biofilmes , Caenorhabditis elegans , Pseudomonas aeruginosa , Percepção de Quorum , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/genética , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Percepção de Quorum/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/metabolismo , Antibacterianos/farmacologia , Perfilação da Expressão Gênica , Homosserina/análogos & derivados , Homosserina/metabolismo , Homosserina/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos
2.
J Agric Food Chem ; 72(28): 15474-15486, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38949855

RESUMO

Corn ear rot and fumonisin caused by Fusarium verticillioides pose a serious threat to food security. To find more highly active fungicidal and antitoxic candidates with structure diversity based on naturally occurring lead xanthatin, a series of novel spiropiperidinyl-α-methylene-γ-butyrolactones were rationally designed and synthesized. The in vitro bioassay results indicated that compound 7c showed broad-spectrum in vitro activity with EC50 values falling from 3.51 to 24.10 µg/mL against Rhizoctonia solani and Alternaria solani, which was more active than the positive controls xanthatin and oxathiapiprolin. In addition, compound 7c also showed good antitoxic efficacy against fumonisin with a 48% inhibition rate even at a concentration of 20 µg/mL. Fluorescence quenching and the molecular docking validated both 7c and oxathiapiprolin targeting at FvoshC. RNA sequencing analysis discovered that FUM gene cluster and protein processing in endoplasmic reticulum were downregulated. Our studies have discovered spiropiperidinyl-α-methylene-γ-butyrolactone as a novel FvoshC target-based scaffold for fungicide lead with antitoxin activity.


Assuntos
Alternaria , Fungicidas Industriais , Fusarium , Simulação de Acoplamento Molecular , Rhizoctonia , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/síntese química , Alternaria/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade , Doenças das Plantas/microbiologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Receptores de Esteroides/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/química , Descoberta de Drogas , Zea mays/química , Zea mays/microbiologia , Estrutura Molecular
3.
Int J Med Mushrooms ; 26(8): 41-57, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38967210

RESUMO

Bone metastasis in metastatic breast cancer commonly results in osteolytic lesions due to osteoclast activity, promoting bone destruction and tumor progression. The bioactive fungal isolates, 4-acetyl-antroquinonol B (4-AAQB) and erinacine A, have diverse pharmacological and biological activities. However, their effects on breast cancer bone metastasis treatment remain unclear. Our study aimed to examine the impact of 4-AAQB or erinacine A on breast cancer metastases in bone. The effects of 4-AAQB and erinacine A on breast cancer-induced osteoclastogenesis, breast cancer migration, production of prometastatic cytokine (TGF-ß) and marker (MMP-9), as well as potential MAPK signaling transductions were assessed. The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-ß and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.


Assuntos
Neoplasias da Mama , Metaloproteinase 9 da Matriz , Osteoclastos , Osteogênese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Animais , Fator de Crescimento Transformador beta/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Cicloexanonas , 4-Butirolactona/análogos & derivados
4.
Food Funct ; 15(14): 7305-7313, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38874113

RESUMO

Aims: Plant-derived lignans may protect against obesity, while their bioactivity needs gut microbial conversion to enterolignans. We used repeated measures to identify enterolignan-predicting microbial species and investigate whether enterolignans and enterolignan-predicting microbial species are associated with obesity. Methods: Urinary enterolignans, fecal microbiota, body weight, height, and circumferences of the waist (WC) and hips (HC) were repeatedly measured at the baseline and after 1 year in 305 community-dwelling adults in Huoshan, China. Body composition and liver fat [indicated by the controlled attenuation parameter (CAP)] were measured after 1 year. Multivariate-adjusted linear models and linear mixed-effects models were used to analyze single and repeated measurements, respectively. Results: Enterolactone and enterodiol levels were both inversely associated with the waist-to-hip ratio, body fat mass (BFM), visceral fat level (VFL), and liver fat accumulation (all P < 0.05). Enterolactone levels were also associated with lower WC (ß = -0.0035 and P = 0.013) and HC (ß = -0.0028 and P = 0.044). We identified multiple bacterial genera whose relative abundance was positively associated with the levels of enterolactone (26 genera) and enterodiol (22 genera, all P false discovery rate < 0.05), and constructed the enterolactone-predicting microbial score and enterodiol-predicting microbial score to reflect the overall enterolignan-producing potential of the host gut microbiota. Both these scores were associated with lower body weight and CAP (all P < 0.05). The enterolactone-predicting microbial score was also inversely associated with the BFM (ß = -0.1128 and P = 0.027) and VFL (ß = -0.1265 and P = 0.044). Conclusion: Our findings support that modulating the host gut microbiome could be a potential strategy to prevent obesity by enhancing the production of enterolignans.


Assuntos
Microbioma Gastrointestinal , Lignanas , Obesidade , Humanos , Lignanas/urina , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Obesidade/microbiologia , Obesidade/metabolismo , Obesidade/urina , China , Bactérias/classificação , Bactérias/metabolismo , Bactérias/isolamento & purificação , Fezes/microbiologia , Biomarcadores/urina , 4-Butirolactona/análogos & derivados , 4-Butirolactona/urina , 4-Butirolactona/metabolismo , Fígado/metabolismo
5.
Environ Sci Pollut Res Int ; 31(31): 43927-43940, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38913262

RESUMO

The caterpillar Anticarsia gemmatalis (Lepidoptera: Noctuidae) is a prevalent pest in soybean plantations, managed using both natural and synthetic chemical products. However, the emergence of resistance in some populations emphasizes the need to explore alternative insecticides. Flupyradifurone, a neurotoxic insecticide, has not been previously used for controlling A. gemmatalis. This study evaluated the potential of flupyradifurone in the management of A. gemmatalis. Initially, the toxicity and anti-feeding effects, as well as histopathological and cytotoxic impacts, of flupyradifurone on A. gemmatalis were evaluated. Subsequently, the indirect effects of flupyradifurone on the midgut and fat body of the predator Podisus nigrispinus (Hemiptera: Pentatomidae) were verified. The results indicate the susceptibility of caterpillars to flupyradifurone, with an LC50 of 5.10 g L-1. Furthermore, the insecticide adversely affects survival, induces an anti-feeding response, and inflicts damage on the midgut of the caterpillars. However, flupyradifurone also leads to side effects in the predator P. nigrispinus through indirect intoxication of the caterpillars, including midgut and fat body damage. While flupyradifurone demonstrates toxicity to A. gemmatalis, suggesting its potential for the chemical control of this pest, the indirect negative effects on the predator indicate the need for its controlled use in integrated pest management programs with the insecticide and the predator.


Assuntos
Inseticidas , Animais , Inseticidas/toxicidade , Larva/efeitos dos fármacos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/toxicidade , Heterópteros/efeitos dos fármacos , Mariposas/efeitos dos fármacos , Lepidópteros/efeitos dos fármacos , Piridinas
6.
Pestic Biochem Physiol ; 202: 105952, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879306

RESUMO

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.


Assuntos
Compostos de Espiro , Animais , Compostos de Espiro/farmacologia , Compostos de Espiro/metabolismo , Acaricidas/farmacologia , Propionatos/farmacologia , Propionatos/metabolismo , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/metabolismo , Simulação de Acoplamento Molecular , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Resistência a Medicamentos/genética , 4-Butirolactona/análogos & derivados
7.
PLoS One ; 19(5): e0302254, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38743749

RESUMO

The gut microbiome may affect overall cardiometabolic health. Enterolactone is an enterolignan reflective of dietary lignan intake and gut microbiota composition and diversity that can be measured in the urine. The purpose of this study was to examine the association between urinary enterolactone concentration as a reflection of gut health and blood pressure/risk of hypertension in a large representative sample from the US population. This analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) collected from January 1999 through December 2010. Variables of interest included participant characteristics (including demographic, anthropometric and social/environmental factors), resting blood pressure and hypertension history, and urinary enterolactone concentration. 10,637 participants (45 years (SE = 0.3), 51.7% (SE = 0.6%) were female) were included in analyses. In multivariable models adjusted for demographic, socioeconomic and behavioral/environmental covariates, each one-unit change in log-transformed increase in enterolactone was associated with a 0.738 point (95% CI: -0.946, -0.529; p<0.001) decrease in systolic blood pressure and a 0.407 point (95% CI: -0.575, -0.239; p<0.001) decrease in diastolic blood pressure. Moreover, in fully adjusted models, each one-unit change in log-transformed enterolactone was associated with 8.2% lower odds of hypertension (OR = 0.918; 95% CI: 0.892, 0.944; p<0.001). Urinary enterolactone, an indicator of gut microbiome health, is inversely associated with blood pressure and hypertension risk in a nationally representative sample of U.S. adults.


Assuntos
4-Butirolactona , Pressão Sanguínea , Hipertensão , Lignanas , Inquéritos Nutricionais , Humanos , Hipertensão/epidemiologia , Hipertensão/urina , Feminino , Masculino , Pessoa de Meia-Idade , 4-Butirolactona/análogos & derivados , 4-Butirolactona/urina , Lignanas/urina , Microbioma Gastrointestinal , Adulto , Fatores de Risco , Estados Unidos/epidemiologia
8.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2290-2298, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812129

RESUMO

Ligustilide is the main active component of the volatile oil from Angelica sinensis and Ligusticum chuanxiong in the Umbelliferae family. It is a phthalein compound with anti-inflammatory, analgesic, antioxidant, anti-tumor, anti-atherosclerosis, neuroprotective, and other pharmacological effects. It can improve the permeability of the blood-brain barrier and has important potential in the treatment of neurodegenerative diseases and other nervous system diseases, such as Alzheimer's disease, ischemic stroke, Parkinson's disease, vascular dementia, and depression. Therefore, the mechanism of ligustilide in the treatment of nervous system diseases was summarized to provide a reference for drug development and clinical application.


Assuntos
4-Butirolactona , Doenças do Sistema Nervoso , Humanos , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/química , Doenças do Sistema Nervoso/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
9.
Fitoterapia ; 176: 106039, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38801896

RESUMO

Five undescribed γ-butyrolactones harzianolides BF (1-5), one precursor harzianolide G (6) along with two known analogues, were isolated and identified from the EtOAc extract of the liquid fermentation of Trichoderma harzianum ZN-4, which was obtained from the sediment of Zhoushan coastal area. Notably, compound 1 featured an unusual carbon skeleton with methylene-bridged furan rings system. Their structures were determined by detailed interpretation of NMR and mass spectroscopic data, and the absolute configurations were unambiguously established based on ECD quantum chemical calculations. In bioassay, 1 and 7 showed inhibitory activity against Pestalotiopsis theae, with MIC values of 25 and 50 µg/mL, respectively.


Assuntos
4-Butirolactona , Hypocreales , Estrutura Molecular , 4-Butirolactona/análogos & derivados , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , 4-Butirolactona/química , Hypocreales/química , Pestalotiopsis , China , Testes de Sensibilidade Microbiana , Animais
10.
Sci Total Environ ; 935: 173418, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-38788938

RESUMO

Flupyradifurone (FPF) has been reported to have a potential risk to terrestrial and aquatic ecosystems. In the present study, the effects of chronic FPF exposure on bees were systematically investigated at the individual behavioral, tissue, cell, enzyme activity, and the gene expression levels. Chronic exposure (14 d) to FPF led to reduced survival (12 mg/L), body weight gain (4 and 12 mg/L), and food utilization efficiency (4 and 12 mg/L). Additionally, FPF exposure (12 mg/L) impaired sucrose sensitivity and memory of bees. Morphological analysis revealed significant cellular and subcellular changes in brain neurons and midgut epithelial cells, including mitochondrial damage, nuclear disintegration, and apoptosis. FPF exposure (4 and 12 mg/L) led to oxidative stress, as evidenced by increased lipid peroxidation and alterations in antioxidant enzyme activity. Notably, gene expression analysis indicated significant dysregulation of apoptosis, immune, detoxification, sucrose responsiveness and memory-related genes, suggesting the involvement of different pathways in FPF-induced toxicity. The multiple stresses and potential mechanisms described here provide a basis for determining the intrinsic toxicity of FPF.


Assuntos
Estresse Oxidativo , Animais , Abelhas/efeitos dos fármacos , Abelhas/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Fisiológico , 4-Butirolactona/toxicidade , 4-Butirolactona/análogos & derivados
11.
J Environ Sci Health B ; 59(7): 417-424, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38804855

RESUMO

The choice of effective crop protection technologies is a key factors in the economical production of oilseed rape. Insecticides belonging to the group of active substances butenolides and diamides are active substances available as seed treatments in oilseed rape and promising control tools in the crop protection technologies. Our laboratory experiment demonstrated that the experimental insecticides flupyradifurone and cyantraniliprole are both effective against Eurydema ventralis (Hemiptera: Pentatomidae) when used as a seed and in-crop treatments, but there is a fundamental difference in their insect mortality inducing effects. Flupyradifurone was found to have a total mortality 96 h after application based on basipetal translocation. In the case of cyantraniliprole, the insecticidal effect of the same treatment was 27% less. The experiment showed that the acropetal translocation of the tested active substances after seed treatment did not induce efficacy comparable to that of the basipetal translocation. The study of the biophoton emission of the plants demonstrated a verifiable correlation between the different application methods of the insecticides and the photon emission intensity per unit plant surface area. In conclusion, the systematic insecticides tested, in addition to having the expected insecticidal effect, interfere with plant life processes by enhancing photosynthetic activity.


Assuntos
Inseticidas , Fotossíntese , Animais , Inseticidas/farmacologia , Fotossíntese/efeitos dos fármacos , Hemípteros/efeitos dos fármacos , Hemípteros/fisiologia , Brassica napus/efeitos dos fármacos , Pirazóis/farmacologia , Sementes/efeitos dos fármacos , Proteção de Cultivos/métodos , Piridinas/farmacologia , ortoaminobenzoatos/farmacologia , Controle de Insetos/métodos , 4-Butirolactona/análogos & derivados
12.
Environ Toxicol Chem ; 43(7): 1497-1508, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38819074

RESUMO

After regulation of pesticides, determination of their persistence in the environment is an important indicator of effectiveness of these measures. We quantified concentrations of two types of systemic insecticides, neonicotinoids (imidacloprid, acetamiprid, clothianidin, thiacloprid, and thiamethoxam) and butenolides (flupyradifurone), in off-crop nontarget media of hummingbird cloacal fluid, honey bee (Apis mellifera) nectar and honey, and wildflowers before and after regulation of imidacloprid on highbush blueberries in Canada in April 2021. We found that mean total pesticide load increased in hummingbird cloacal fluid, nectar, and flower samples following imidacloprid regulation. On average, we did not find evidence of a decrease in imidacloprid concentrations after regulation. However, there were some decreases, some increases, and other cases with no changes in imidacloprid levels depending on the specific media, time point of sampling, and site type. At the same time, we found an overall increase in flupyradifurone, acetamiprid, thiamethoxam, and thiacloprid but no change in clothianidin concentrations. In particular, flupyradifurone concentrations observed in biota sampled near agricultural areas increased twofold in honey bee nectar, sevenfold in hummingbird cloacal fluid, and eightfold in flowers after the 2021 imidacloprid regulation. The highest residue detected was flupyradifurone at 665 ng/mL (parts per billion [ppb]) in honey bee nectar. Mean total pesticide loads were highest in honey samples (84 ± 10 ppb), followed by nectar (56 ± 7 ppb), then hummingbird cloacal fluid (1.8 ± 0.5 ppb), and least, flowers (0.51 ± 0.06 ppb). Our results highlight that limited regulation of imidacloprid does not immediately reduce residue concentrations, while other systemic insecticides, possibly replacement compounds, concurrently increase in wildlife. Environ Toxicol Chem 2024;43:1497-1508. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Assuntos
Inseticidas , Neonicotinoides , Nitrocompostos , Neonicotinoides/análise , Animais , Inseticidas/análise , Nitrocompostos/análise , Piridinas/análise , Abelhas , Monitoramento Ambiental , Aves , Néctar de Plantas/química , Mel/análise , Tiametoxam , Flores/química , Guanidinas , Tiazinas , Tiazóis , 4-Butirolactona/análogos & derivados
13.
Chem Biodivers ; 21(7): e202400823, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38687255

RESUMO

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 6.187 mg ⋅ L-1 and 3.269 mg ⋅ L-1, respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC50=15.743 mg ⋅ L-1). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compound (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.


Assuntos
4-Butirolactona , Teoria da Densidade Funcional , Inseticidas , Simulação de Acoplamento Molecular , Mariposas , Inseticidas/química , Inseticidas/farmacologia , Inseticidas/síntese química , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , 4-Butirolactona/síntese química , Mariposas/efeitos dos fármacos , Cristalografia por Raios X , Estrutura Molecular , Xantinas/farmacologia , Xantinas/química , Xantinas/síntese química , Afídeos/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Sci Total Environ ; 931: 172617, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38653409

RESUMO

Lady beetles play a crucial role in natural ecosystems and agricultural settings. Unfortunately, these insects and more specifically the two-spotted lady beetle (Adalia bipunctata) are currently facing a severe decline in populations due to various stressors, with pesticide exposure being a significant threat. Flupyradifurone is a relatively newly introduced insecticide and as existing research is mainly elucidating its effects on bees there remains a limited understanding of its effects on non-hymenopteran insects, including lady beetles. In this study we investigated the impact of acute orally applied flupyradifurone doses on survival and sublethal parameters such as physical condition and mobility on A. bipunctata. Our findings revealed a significant increase in mortality among individuals subjected to flupyradifurone doses of 19 ng/individual (corresponding to >1.5-2.0 ng active substance (a.s.)/mg body weight (bw). The calculated LD50 of flupyradifurone at 48 h was 2.11 ng a.s./mg bw corresponding to an amount of 26.38 ng/individual. Sublethal consequences were observable immediately after pesticide application. Even at doses as low as 2 ng/individual (corresponding to >0.0-0.5 ng a.s./mg bw), flupyradifurone induced trembling and temporary immobility in treated animals. Furthermore, pesticide intoxication led to hypoactivity, with less distance covered and a decline in straightness of locomotion. In conclusion, our study underscores the harmful effects of flupyradifurone on the two-spotted lady beetle at doses notably lower than those affecting bees. These findings stress the importance of additional research to attain a more holistic understanding of pesticide impacts not only on a broader range of non-target arthropods species, but also on various exposure routes as well as lethal and sublethal effects.


Assuntos
Besouros , Inseticidas , Animais , Besouros/efeitos dos fármacos , Besouros/fisiologia , Inseticidas/toxicidade , 4-Butirolactona/análogos & derivados , 4-Butirolactona/toxicidade , Piridinas/toxicidade
15.
J Med Chem ; 67(9): 7504-7515, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38640354

RESUMO

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration-time curve (AUC0-∞) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.


Assuntos
4-Butirolactona , Antialérgicos , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/química , 4-Butirolactona/farmacocinética , 4-Butirolactona/administração & dosagem , Administração Oral , Ratos , Humanos , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Antialérgicos/química , Antialérgicos/administração & dosagem , Relação Estrutura-Atividade , Masculino , Ratos Sprague-Dawley , Disponibilidade Biológica , Hipersensibilidade Alimentar/tratamento farmacológico , Camundongos
16.
J Nat Med ; 78(3): 608-617, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38587582

RESUMO

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-ß-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies.


Assuntos
4-Butirolactona , Estereoisomerismo , Estrutura Molecular , 4-Butirolactona/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , Relação Estrutura-Atividade , Conformação Molecular
17.
J Ethnopharmacol ; 330: 118217, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-38641072

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The natural anodyne Ligustilide (Lig), derived from Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort., has been traditionally employed for its analgesic properties in the treatment of dysmenorrhea and migraine, and rheumatoid arthritis pain. Despite the existing reports on the correlation between TRP channels and the analgesic effects of Lig, a comprehensive understanding of their underlying mechanisms of action remains elusive. AIM OF THE STUDY: The objective of this study is to elucidate the mechanism of action of Lig on the analgesic target TRPA1 channel. METHODS: The therapeutic effect of Lig was evaluated in a rat acute soft tissue injury model. The analgesic target was identified through competitive inhibition of TRP channel agonists at the animal level, followed by Fluo-4/Ca2+ imaging on live cells overexpressing TRP proteins. The potential target was verified through in-gel imaging, colocalization using a Lig-derived molecular probe, and a drug affinity response target stability assay. The binding site of Lig was identified through protein spectrometry and further analyzed using molecular docking, site-specific mutation, and multidisciplinary approaches. RESULTS: The administration of Lig effectively ameliorated pain and attenuated oxidative stress and inflammatory responses in rats with soft tissue injuries. Moreover, the analgesic effects of Lig were specifically attributed to TRPA1. Mechanistic studies have revealed that Lig directly activates TRPA1 by interacting with the linker domain in the pre-S1 region of TRPA1. Through metabolic transformation, 6,7-epoxyligustilide (EM-Lig) forms a covalent bond with Cys703 of TRPA1 at high concentrations and prolonged exposure time. This irreversible binding prevents endogenous electrophilic products from entering the cysteine active center of ligand-binding pocket of TRPA1, thereby inhibiting Ca2+ influx through the channel opening and ultimately relieving pain. CONCLUSIONS: Lig selectively modulates the TRPA1 channel in a bimodal manner via non-electrophilic/electrophilic metabolic conversion. The epoxidized metabolic intermediate EM-Lig exerts analgesic effects by irreversibly inhibiting the activation of TRPA1 on sensory neurons. These findings not only highlight the analgesic mechanism of Lig but also offer a novel nucleophilic attack site for the development of TRPA1 antagonists in the pre-S1 region.


Assuntos
4-Butirolactona , Analgésicos , Canal de Cátion TRPA1 , Animais , Feminino , Humanos , Masculino , Ratos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/química , Analgésicos/farmacologia , Analgésicos/química , Sítios de Ligação , Cisteína/farmacologia , Cisteína/química , Células HEK293 , Simulação de Acoplamento Molecular , Dor/tratamento farmacológico , Ratos Sprague-Dawley , Canal de Cátion TRPA1/metabolismo
18.
Nutrients ; 16(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38613077

RESUMO

The aim of the study was to develop and evaluate a novel dietary index for gut microbiota (DI-GM) that captures dietary composition related to gut microbiota profiles. We conducted a literature review of longitudinal studies on the association of diet with gut microbiota in adult populations and extracted those dietary components with evidence of beneficial or unfavorable effects. Dietary recall data from the National Health and Nutrition Examination Survey (NHANES, 2005-2010, n = 3812) were used to compute the DI-GM, and associations with biomarkers of gut microbiota diversity (urinary enterodiol and enterolactone) were examined using linear regression. From a review of 106 articles, 14 foods or nutrients were identified as components of the DI-GM, including fermented dairy, chickpeas, soybean, whole grains, fiber, cranberries, avocados, broccoli, coffee, and green tea as beneficial components, and red meat, processed meat, refined grains, and high-fat diet (≥40% of energy from fat) as unfavorable components. Each component was scored 0 or 1 based on sex-specific median intakes, and scores were summed to develop the overall DI-GM score. In the NHANES, DI-GM scores ranged from 0-13 with a mean of 4.8 (SE = 0.04). Positive associations between DI-GM and urinary enterodiol and enterolactone were observed. The association of the novel DI-GM with markers of gut microbiota diversity demonstrates the potential utility of this index for gut health-related studies.


Assuntos
4-Butirolactona/análogos & derivados , Microbioma Gastrointestinal , Lignanas , Adulto , Feminino , Masculino , Humanos , Inquéritos Nutricionais , Dieta Hiperlipídica , Carne
19.
Med Sci Monit ; 30: e943486, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613144

RESUMO

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.


Assuntos
4-Butirolactona/análogos & derivados , Respiração Artificial , Retinopatia da Prematuridade , Recém-Nascido , Lactente , Humanos , Respiração Artificial/efeitos adversos , Pressão Positiva Contínua nas Vias Aéreas , Retinopatia da Prematuridade/terapia , Peso ao Nascer , Cânula
20.
Biomolecules ; 14(3)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38540801

RESUMO

Since the growing number of fungi resistant to the fungicides used is becoming a serious threat to human health, animals, and crops, there is a need to find other effective approaches in the eco-friendly suppression of fungal growth. One of the main mechanisms of the development of resistance in fungi, as well as in bacteria, to antimicrobial agents is quorum sensing (QS), in which various lactone-containing compounds participate as signaling molecules. This work aimed to study the effectiveness of action of enzymes exhibiting lactonase activity against fungal signaling molecules. For this, the molecular docking method was used to estimate the interactions between these enzymes and different lactone-containing QS molecules of fungi. The catalytic characteristics of enzymes such as lactonase AiiA, metallo-ß-lactamase NDM-1, and organophosphate hydrolase His6-OPH, selected for wet experiments based on the results of computational modeling, were investigated. QS lactone-containing molecules (butyrolactone I and γ-heptalactone) were involved in the experiments as substrates. Further, the antifungal activity of the enzymes was evaluated against various fungal and yeast cells using bioluminescent ATP-metry. The efficient hydrolysis of γ-heptalactone by all three enzymes and butyrolactone I by His6-OPH was demonstrated for the first time. The high antifungal efficacy of action of AiiA and NDM-1 against most of the tested fungal cells was revealed.


Assuntos
4-Butirolactona/análogos & derivados , Antifúngicos , Percepção de Quorum , Animais , Humanos , Antifúngicos/farmacologia , Simulação de Acoplamento Molecular , Lactonas/farmacologia
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