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1.
J Mass Spectrom ; 59(8): e5069, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38989730

RESUMO

Cinnamomi ramulus (CR) is a common Chinese herbal medicine with a long history. It is often used to treat exogenous wind-cold diseases in clinic, but its chemical compositions remain to be studied. In this study, CR was extracted with 75% ethanol, and UPLC-Q-Orbitrap-MS combined with data post-processing method was used to identify the chemical components in the extract. Through this technology, the components in CR can be separated and accurately identified. A total of 61 compounds were identified, including 14 simple phenylpropanoids, 3 coumarins, 5 lignans, 14 flavonoids, 10 benzoic acids, 8 organic acids, and 7 others. This study confirmed the existence of these compounds in CR and speculated the cleavage pathways of each compound, which enriched the mass spectrometry data and cleavage rules. This study can provide a reference for CR and other research.


Assuntos
Cumarínicos , Medicamentos de Ervas Chinesas , Flavonoides , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Cumarínicos/química , Cumarínicos/análise , Flavonoides/análise , Flavonoides/química , Lignanas/análise , Lignanas/química , Espectrometria de Massas/métodos , Cinnamomum/química , Espectrometria de Massas em Tandem/métodos
2.
Sci Rep ; 14(1): 15706, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977770

RESUMO

Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.


Assuntos
Colite , Cumarínicos , Mucosa Intestinal , Fator 2 Relacionado a NF-E2 , Receptores de Hidrocarboneto Arílico , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Camundongos , Mucosa Intestinal/metabolismo , Cumarínicos/farmacologia , Colite/metabolismo , Colite/induzido quimicamente , Mucina-2/metabolismo , Mucina-2/genética , Humanos , Colo/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Masculino , Microbioma Gastrointestinal , Camundongos Knockout , Sulfato de Dextrana , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Função da Barreira Intestinal
3.
Molecules ; 29(13)2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38998955

RESUMO

The chromenopyridine scaffold represents an important class of heterocyclic compounds exhibiting a broad spectrum of biological properties. This review describes novel and efficient procedures for the synthesis of this scaffold. Herein, several methods were detailed and grouped according to their starting material (e.g., salicylaldehydes, chromones, chromanones and coumarins) and respective biological activity, when reported. This review highlights the potential of the reported synthetic strategies for preparing chromenopyridine derivatives with promising biological activity, paving the way for further developments in drug discovery.


Assuntos
Desenho de Fármacos , Piridinas , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Humanos , Estrutura Molecular , Cromonas/química , Cromonas/síntese química , Cromonas/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Relação Estrutura-Atividade
4.
Cell Commun Signal ; 22(1): 361, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39010083

RESUMO

BACKGROUND: Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. METHODS: A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. RESULTS: We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. CONCLUSIONS: Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.


Assuntos
Neoplasias da Mama , Cumarínicos , Histona Desacetilase 1 , Ácidos Hidroxâmicos , Transdução de Sinais , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Histona Desacetilase 1/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Animais , Transdução de Sinais/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/uso terapêutico , Fator de Transcrição Sp1/metabolismo , Camundongos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Camundongos Endogâmicos BALB C , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Descoberta de Drogas
5.
Luminescence ; 39(7): e4825, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38961763

RESUMO

Herein, we have reported a red-emitting 4-methyl coumarin fused barbituric acid azo dye (4-MCBA) synthesized by conventional method. Density functional theory (DFT) studies of tautomer compounds were done using (B3LYP) with a basis set of 6-31G(d,p). NLO analysis has shown that tautomer has mean first-order hyperpolarisabilities (ß) value of 1.8188 × 10-30 esu and 1.0470 × 10-30 esu for azo and hydrazone forms, respectively, which is approximately nine and five times greater than the magnitude of urea. 4-MCBA exhibited two absorption peaks in the range of 290-317 and 379-394 nm, and emission spectra were observed at 536 nm. CV study demonstrated that the modified 4-MCBA/MGC electrode exhibited excellent electrochemical sensitivity towards the detection of catechol and the detection limit is 9.39 µM under optimum conditions. The 4-MCBA employed as a fluorescent probe for the visualisation of LFPs on various surfaces exhibited Level-I to level-II LFPs, with low background interference.


Assuntos
Barbitúricos , Catecóis , Cumarínicos , Técnicas Eletroquímicas , Barbitúricos/química , Catecóis/química , Catecóis/análise , Técnicas Eletroquímicas/instrumentação , Cumarínicos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Teoria da Densidade Funcional , Eletrodos
6.
Food Funct ; 15(14): 7518-7533, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38920000

RESUMO

The increasing prevalence of obesity and type 2 diabetes (T2D) signifies the failure of conventional treatments for these diseases. The gut microbiota has been proposed as a key player in the pathophysiology of diet-induced T2D. Urolithin B (Uro B), a gut microbiota-derived polyphenol metabolite, exerts several beneficial health effects. In this study, we investigated the metabolic effects of Uro B on high-fat/high-sucrose (HFHS)-fed mice and determined whether its antidiabetic effects are related to the modulation of the gut microbiota. C57BL/6J mice were fed either a chow or HFHS diet. HFHS-fed mice were administered daily with either a vehicle (water) or different doses of Uro B (100 or 200 mg kg-1) for eight weeks. The composition of the gut microbiota was assessed by 16S rRNA sequencing. The results showed that Uro B treatment reduced HFHS-induced weight gain and visceral obesity and decreased liver weight and triglyceride accumulation associated with blunted hepatic oxidative stress and inflammation. Furthermore, Uro B administration improved insulin sensitivity as revealed by improved insulin tolerance, a lower homeostasis model assessment of insulin resistance, and decreased glucose-induced hyperinsulinemia during the oral glucose tolerance test. Uro B treatment was found to lower the intestinal triglyceride content and alleviate intestinal inflammation and oxidative stress. Remarkably, Uro B treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in metagenomic samples. In conclusion, Uro B exerts beneficial metabolic effects by alleviating HFHS diet-induced features of metabolic syndrome, which is associated with a proportional increase in the population of Akkermansia spp.


Assuntos
Cumarínicos , Dieta Hiperlipídica , Microbioma Gastrointestinal , Resistência à Insulina , Camundongos Endogâmicos C57BL , Obesidade , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/metabolismo , Camundongos , Masculino , Dieta Hiperlipídica/efeitos adversos , Cumarínicos/farmacologia , Cumarínicos/administração & dosagem , Inflamação , Estresse Oxidativo/efeitos dos fármacos
7.
Anal Methods ; 16(27): 4551-4560, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38912555

RESUMO

In this paper, a coumarin-based Schiff base chemosensor has been synthesized and developed to detect Cu2+ and Zn2+ ions in nanomolar concentrations. The probe selectively distinguishes Cu2+ and Zn2+ from among several metal ions in DMF : H2O (7 : 3, v/v, pH 7.4) HEPES buffer. The structure of the probe and its sensing behavior were investigated by FT-IR, UV-vis, fluorescence, HRMS, and NMR analyses, along with X-ray crystallography and computational studies. CIH detects Zn2+ and Cu2+ using different strategies: CHEF-induced fluorescence enhancement and paramagnetic fluorescence quenching, respectively. Job's plots show a 1 : 1 binding interaction between CIH and Cu2+ or Zn2+ ions. The binding constant values for Cu2+ (1.237 × 105 M-1) and Zn2+ (1.24 × 104 M-1) suggest a better ability for Cu2+ to interact with CIH than Zn2+. An extremely high sensitivity of the probe was highlighted by its very low detection limits (LOD) of 5.36 nM for Cu2+ and 3.49 nM for Zn2+. The regeneration of the probe with the addition of EDTA in its complexes allows the formation of molecular logic gates. CIH has been successfully employed in mitotracking and intracellular detection of Zn2+ and Cu2+ in SiHa cells.


Assuntos
Cobre , Cumarínicos , Corantes Fluorescentes , Bases de Schiff , Zinco , Zinco/análise , Zinco/química , Cumarínicos/química , Cobre/análise , Cobre/química , Humanos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Bases de Schiff/química , Limite de Detecção , Espectrometria de Fluorescência/métodos , Imagem Óptica/métodos
8.
BMC Complement Med Ther ; 24(1): 226, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858650

RESUMO

OBJECTIVE: Previous studies have shown that fraxetin has antitumor activity in a variety of tumors, but its role in acute myeloid leukemia (AML) remains unclear. In this study, we aimed to evaluate the anti-AML effect of fraxetin through cell experiments and network pharmacology analysis. METHODS: The inhibitory and apoptotic effects of fraxetin on AML cells were determined by CCK-8 and flow cytometry experiments. Potential targets of fraxetin and AML-related targets were screened using public databases. PPI network, GO functional enrichment and KEGG pathway enrichment analyses were performed to predict the hub targets and signaling pathways by which fraxetin alleviates AML. Molecular docking was used to determine the fraxetin binding sites on hub targets. Using the GEPIA database, the expression of hub targets was analyzed in relation to the overall survival of AML patients. RESULTS: Cell experiments showed that fraxetin inhibits AML cell proliferation and induces apoptosis. To explore the potential mechanism of fraxetin, 29 shared targets of fraxetin and AML were obtained through screening online public databases. Among them, AKT1, TNF, SRC, etc., are related to AML cell apoptosis. The expression levels of SRC, NOS3, VAV1, LYN, and PTGS1 were associated with the overall survival of AML patients (p value < 0.05). The enrichment analysis results identified the main pathways, namely, focal adhesion and the PI3K-AKT signaling pathway, that affected the proliferation and apoptosis of AML cells. The analysis of hub targets of the PPI network showed that AKT1, TNF, CTNNB1, etc., were hub targets, which were related to the proliferation and apoptosis of AML cells. The results of molecular docking showed that the hub targets had good binding with fraxetin. CONCLUSION: Fraxetin may inhibit AML cell proliferation and induce AML cell apoptosis through multiple targets, such as AKT1, SRC, and EGFR, and multiple pathways, such as focal adhesion and the PI3K-AKT signaling pathway.


Assuntos
Apoptose , Proliferação de Células , Leucemia Mieloide Aguda , Simulação de Acoplamento Molecular , Farmacologia em Rede , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/farmacologia , Transdução de Sinais/efeitos dos fármacos
9.
Gigascience ; 132024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38837945

RESUMO

BACKGROUND: Traditional Chinese medicine has used Peucedanum praeruptorum Dunn (Apiaceae) for a long time. Various coumarins, including the significant constituents praeruptorin (A-E), are the active constituents in the dried roots of P. praeruptorum. Previous transcriptomic and metabolomic studies have attempted to elucidate the distribution and biosynthetic network of these medicinal-valuable compounds. However, the lack of a high-quality reference genome impedes an in-depth understanding of genetic traits and thus the development of better breeding strategies. RESULTS: A telomere-to-telomere (T2T) genome was assembled for P. praeruptorum by combining PacBio HiFi, ONT ultra-long, and Hi-C data. The final genome assembly was approximately 1.798 Gb, assigned to 11 chromosomes with genome completeness >98%. Comparative genomic analysis suggested that P. praeruptorum experienced 2 whole-genome duplication events. By the transcriptomic and metabolomic analysis of the coumarin metabolic pathway, we presented coumarins' spatial and temporal distribution and the expression patterns of critical genes for its biosynthesis. Notably, the COSY and cytochrome P450 genes showed tandem duplications on several chromosomes, which may be responsible for the high accumulation of coumarins. CONCLUSIONS: A T2T genome for P. praeruptorum was obtained, providing molecular insights into the chromosomal distribution of the coumarin biosynthetic genes. This high-quality genome is an essential resource for designing engineering strategies for improving the production of these valuable compounds.


Assuntos
Apiaceae , Cumarínicos , Genoma de Planta , Telômero , Cumarínicos/metabolismo , Apiaceae/genética , Apiaceae/metabolismo , Telômero/genética , Telômero/metabolismo , Evolução Molecular , Filogenia , Genômica/métodos , Vias Biossintéticas/genética
10.
Int J Mol Sci ; 25(12)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38928509

RESUMO

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.


Assuntos
Cumarínicos , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Triazóis , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/síntese química , Triazóis/química , Triazóis/farmacologia , Monoaminoxidase/metabolismo , Monoaminoxidase/química , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular , Teoria da Densidade Funcional
11.
Molecules ; 29(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38930806

RESUMO

Pterocaulon polystachyum is a species of pharmacological interest for providing volatile and non-volatile extracts with antifungal and amebicidal properties. The biological activities of non-volatile extracts may be related to the presence of coumarins, a promising group of secondary metabolites. In the present study, leaves and inflorescences previously used for the extraction of essential oils instead of being disposed of were subjected to extraction with supercritical CO2 after pretreatment with microwaves. An experimental design was followed to seek the best extraction condition with the objective function being the maximum total extract. Pressure and temperature were statistically significant factors, and the optimal extraction condition was 240 bar, 60 °C, and pretreatment at 30 °C. The applied mathematical models showed good adherence to the experimental data. The extracts obtained by supercritical CO2 were analyzed and the presence of coumarins was confirmed. The extract investigated for cytotoxicity against bladder tumor cells (T24) exhibited significant reduction in cell viability at concentrations between 6 and 12 µg/mL. The introduction of green technology, supercritical extraction, in the exploration of P. polystachyum as a source of coumarins represents a paradigm shift with regard to previous studies carried out with this species, which used organic solvents. Furthermore, the concept of circular bioeconomy was applied, i.e., the raw material used was the residue of a steam-distillation process. Therefore, the approach used here is in line with the sustainable exploitation of native plants to obtain extracts rich in coumarins with cytotoxic potential against cancer cells.


Assuntos
Dióxido de Carbono , Cromatografia com Fluido Supercrítico , Cumarínicos , Extratos Vegetais , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Dióxido de Carbono/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Humanos , Cromatografia com Fluido Supercrítico/métodos , Componentes Aéreos da Planta/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação
12.
Molecules ; 29(12)2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38930816

RESUMO

3,4-Fused pyrrolocoumarins, synthetically prepared or naturally occurring, possess interesting biological properties. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological activities. Two routes are followed for that synthesis. In one, the pyrrole ring is formed from coumarin derivatives, such as aminocoumarins or other coumarins. In the other approach, the pyranone moiety is built from an existing pyrrole derivative or through the simultaneous formation of coumarin and pyrrole frameworks. The above syntheses are achieved via 1,3-dipolar cycloaddition reactions, Michael reaction, aza-Claisen rearrangement reactions, multi-component reactions (MCR), as well as metal-catalyzed reactions. Pyrrolocoumarins present cytotoxic, antifungal, antibacterial, α-glucosidase inhibition, antioxidant, lipoxygenase (LOX) inhibition, and fluorescent activities, as well as benzodiazepine receptor ability.


Assuntos
Cumarínicos , Pirróis , Cumarínicos/química , Cumarínicos/síntese química , Pirróis/química , Pirróis/síntese química , Humanos , Antioxidantes/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Estrutura Molecular , Reação de Cicloadição
13.
Int J Biol Macromol ; 273(Pt 2): 133045, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38942666

RESUMO

This work was to investigate the effect of four prebiotic saccharides gum arabic (GA), fructooligosaccharide (FOS), konjac glucomannan (KGM), and inulin (INU) incorporation on the encapsulation efficiency (EE), physicochemical stability, and in vitro digestion of urolithin A-loaded liposomes (UroA-LPs). The regulation of liposomes on gut microbiota was also investigated by in vitro colonic fermentation. Results indicated that liposomes coated with GA showed the best EE, bioaccessibility, storage and thermal stability, the bioaccessibility was 1.67 times of that of UroA-LPs. The UroA-LPs coated with FOS showed the best freeze-thaw stability and transformation. Meanwhile, saccharides addition remarkably improved the relative abundance of Bacteroidota, reduced the abundances of Proteobacteria and Actinobacteria. The UroA-LPs coated with FOS, INU, and GA exhibited the highest beneficial bacteria abundance of Parabacteroides, Monoglobus, and Phascolarctobacterium, respectively. FOS could also decrease the abundance of harmful bacteria Collinsella and Enterococcus, and increase the levels of acetic acid, butyric acid and iso-butyric acid. Consequently, prebiotic saccharides can improve the EE, physicochemical stability, gut microbiota regulation of UroA-LPs, and promote the bioaccessibility of UroA, but the efficiency varied based on saccharides types, which can lay a foundation for the application of UroA in foods industry and for the enhancement of its bio-activities.


Assuntos
Microbioma Gastrointestinal , Lipossomos , Prebióticos , Microbioma Gastrointestinal/efeitos dos fármacos , Lipossomos/química , Polimerização , Cumarínicos/química , Cumarínicos/metabolismo , Fermentação
14.
Parasitol Res ; 123(6): 246, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896311

RESUMO

Human toxocariasis is a neglected anthropozoonosis with global distribution. Treatment is based on the administration of anthelmintics; however, their effectiveness at the tissue level is low to moderate, necessitating the discovery of new drug candidates. Several groups of synthetic compounds, including coumarin derivatives, have demonstrated bioactivity against fungi, bacteria, and even parasites, such as Dactylogyrus intermedius, Leishmania major, and Plasmodium falciparum. The aim of this study was to evaluate the effect of ten coumarin-derived compounds against Toxocara canis larvae using in vitro, cytotoxicity, and in silico tests for selecting new drug candidates for preclinical tests aimed at evaluating the treatment of visceral toxocariasis. The compounds were tested in vitro in duplicate at a concentration of 1 mg/mL, and compounds with larvicidal activity were serially diluted to obtain concentrations of 0.5 mg/mL; 0.25 mg/mL; 0.125 mg/mL; and 0.05 mg/mL. The tests were performed in a microculture plate containing 100 T. canis larvae in RPMI-1640 medium. One compound (COU 9) was selected for cytotoxicity analysis using J774.A1 murine macrophages and it was found to be non-cytotoxic at any concentration tested. The in silico analysis was performed using computational models; the compound presented adequate results of oral bioavailability. To confirm the non-viability of the larvae, the contents of the microplate wells of COU 9 were inoculated intraperitoneally (IP) into female Swiss mice at 7-8 weeks of age. This confirmed the larvicidal activity of this compound. These results show that COU 9 exhibited larvicidal activity against T. canis larvae, which, after exposure to the compound, were non-viable, and that COU 9 inhibited infection in a murine model. In addition, COU 9 did not exhibit cytotoxicity and presented adequate bioavailability in silico, similar to albendazole, an anthelmintic, which is the first choice for treatment of human toxocariasis, supporting the potential for future investigations and preclinical tests on COU 9.


Assuntos
Cumarínicos , Larva , Toxocara canis , Animais , Larva/efeitos dos fármacos , Toxocara canis/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/química , Anti-Helmínticos/farmacologia , Anti-Helmínticos/química , Disponibilidade Biológica , Camundongos , Simulação por Computador , Toxocaríase/tratamento farmacológico , Toxocaríase/parasitologia
15.
J Agric Food Chem ; 72(26): 14653-14662, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38860840

RESUMO

The damage to the mechanical barrier of the intestinal mucosa is the initiating factor and the core link of the progression of ulcerative colitis (UC). Protecting the mechanical barrier of the intestinal mucosa is of great significance for improving the health status of UC patients. ZO-1 is a key scaffold protein of the mechanical barrier of the intestinal mucosa, and its fusion with the membrane of the intestinal epithelium is a necessary condition to maintain the integrity of the mechanical barrier of the intestinal mucosa. Enteric glial cells (EGCs) play an important role in the maintenance of intestinal homeostasis and have become a new target for regulating intestinal health in recent years. In this study, we found that glycyrol (GC), a representative coumarin compound isolated from Licorice (Glycyrrhiza uralensis Fisch, used for medicine and food), can alleviate UC by promoting the production of neurotrophic factor GDNF in mice EGCs. Specifically, we demonstrated that GC promotes the production of GDNF, then activates its receptor RET, promotes ZO-1 fusion with cell membranes, and protects the intestinal mucosal mechanical barrier. The results of this study can provide new ideas for the prevention and treatment of UC.


Assuntos
Colite Ulcerativa , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Mucosa Intestinal , Neuroglia , Proteína da Zônula de Oclusão-1 , Animais , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Camundongos , Humanos , Proteína da Zônula de Oclusão-1/metabolismo , Proteína da Zônula de Oclusão-1/genética , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Camundongos Endogâmicos C57BL , Cumarínicos/farmacologia , Cumarínicos/química , Transdução de Sinais/efeitos dos fármacos , Glycyrrhiza/química
16.
ACS Appl Mater Interfaces ; 16(24): 30900-30914, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38848495

RESUMO

Coumarins have great pharmacotherapeutic potential, presenting several biological and pharmaceutical applications, like antibiotic, fungicidal, anti-inflammatory, anticancer, anti-HIV, and healing activities, among others. These molecules are practically insoluble in water, and for biological applications, it became necessary to complex them with cyclodextrins (CDs), which influence their bioavailability in the target organism. In this work, we studied two coumarins, and it was possible to conclude that there were structural differences between 4,7-dimethyl-2H-chromen-2-one (DMC) and 7-methoxy-4-methyl-2H-chromen-2-one (MMC)/ß-CD that were solubilized in ethanol, frozen, and lyophilized (FL) and the mechanical mixtures (MM). In addition, the inclusion complex formation improved the solubility of DMC and MMC in an aqueous medium. According to the data, the inclusion complexes were formed and are more stable at a molar ratio of 2:1 coumarin/ß-CD, and hydrogen bonds along with π-π stacking interactions are responsible for the better stability, especially for (MMC)2@ß-CD. In vivo wound healing studies in mice showed faster re-epithelialization and the best deposition of collagen with the (DMC)2@ß-CD (FL) and (MMC)2@ß-CD (FL) inclusion complexes, demonstrating clearly that they have potential in wound repair. Therefore, (DMC)2@ß-CD (FL) deserves great attention because it presented excellent results, reducing the granulation tissue and mast cell density and improving collagen remodeling. Finally, the protein binding studies suggested that the anti-inflammatory activities might exert their biological function through the inhibition of MEK, providing the possibility of development of new MEK inhibitors.


Assuntos
Cumarínicos , Cicatrização , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Cumarínicos/química , Cumarínicos/farmacologia , Animais , Cicatrização/efeitos dos fármacos , Camundongos , Humanos , Solubilidade , Masculino
17.
Mol Neurodegener ; 19(1): 49, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890703

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. METHODS: A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. RESULTS: UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. CONCLUSIONS: Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.


Assuntos
Cumarínicos , Animais , Camundongos , Cumarínicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Retina/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Proteína Sequestossoma-1/metabolismo , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Iodatos/toxicidade
18.
Chem Pharm Bull (Tokyo) ; 72(6): 574-583, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38866495

RESUMO

In Vietnam, the stems and roots of the Rutaceous plant Paramignya trimera (Oliv.) Burkill (known locally as "Xáo tam phân") are widely used to treat liver diseases such as viral hepatitis and acute and chronic cirrhosis. In an effort to search for Vietnamese natural compounds capable of inhibiting coronavirus based on molecular docking screening, two new dimeric coumarin glycosides, namely cis-paratrimerin B (1) and cis-paratrimerin A (2), and two previously identified coumarins, the trans-isomers paratrimerin B (3) and paratrimerin A (4), were isolated from the roots of P. trimera and tested for their anti-angiotensin-converting enzyme 2 (ACE-2) inhibitory properties in vitro. It was discovered that ACE-2 enzyme was inhibited by cis-paratrimerin B (1), cis-paratrimerin A (2), and trans-paratrimerin B (3), with IC50 values of 28.9, 68, and 77 µM, respectively. Docking simulations revealed that four biscoumarin glycosides had good binding energies (∆G values ranging from -10.6 to -14.7 kcal/mol) and mostly bound to the S1' subsite of the ACE-2 protein. The key interactions of these natural ligands include metal chelation with zinc ions and multiple H-bonds with Ser128, Glu145, His345, Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots occur naturally in both cis- and trans-diastereomeric forms. The biscoumarin glycosides Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots hold potential for further studies as natural ACE-2 inhibitors for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Assuntos
Enzima de Conversão de Angiotensina 2 , Cumarínicos , Glicosídeos , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/isolamento & purificação , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/química , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/isolamento & purificação , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , COVID-19/virologia , Rutaceae/química , Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Raízes de Plantas/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação
19.
Gut Microbes ; 16(1): 2367342, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38889450

RESUMO

Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.


Assuntos
Cumarínicos , Estresse do Retículo Endoplasmático , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Fígado , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Disbiose/microbiologia , Humanos , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação
20.
Int Immunopharmacol ; 136: 112330, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823180

RESUMO

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.


Assuntos
Cumarínicos , Citocinas , Depressão , Hipocampo , Lipopolissacarídeos , Microglia , Estresse Psicológico , Animais , Microglia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Depressão/tratamento farmacológico , Depressão/imunologia , Depressão/induzido quimicamente , Camundongos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/imunologia , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/imunologia , Camundongos Endogâmicos C57BL , Mediadores da Inflamação/metabolismo
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