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1.
J Agric Food Chem ; 70(23): 7130-7138, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35657168

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is clinically characterized by the impairment of memory and cognition. Accumulation of ß-amyloid (Aß) in the brain is considered as a key process in the development of AD because it impairs the synapses' function to impair memory formation. Recent research studies have indicated that a group of edible plant-derived Thymelaeaceae compounds known as coumarin may exert particularly powerful actions on alleviating learning and memory impairment. 7,8-Dithydroxycoumarin (7,8-DHC), a bioactive component of coumarin derived from Thymelaeaceae, showed its function in neuroprotection before. In this study, we found that 7,8-DHC was able to mitigate Aß accumulation via reducing the level of BACE1 and increasing the level of ADAM17 and ADAM10. More importantly, we found that 7,8-DHC could mitigate memory impairment, promote the dendrite branch density, and increase synaptic protein expression via activating PI3K-Akt-CREB-BDNF signaling. Hence, these results suggested that 7,8-DHC represented a novel bioactive therapeutic agent in mitigating Aß deposition and synaptic loss in the process of treating AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cumarínicos/farmacologia , Modelos Animais de Doenças , Transtornos da Memória/tratamento farmacológico , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Umbeliferonas
2.
Phytomedicine ; 103: 154230, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35724612

RESUMO

BACKGROUND: Phytoestrogens are found in many plants used in traditional medicines. Increasingly, plant extracts (botanicals) are also being added to foods or marketed as dietary supplements. Especially such powder formulations are susceptible to adulteration and falsification, given the global processing chain. To detect estrogen-like compounds in such multicomponent mixtures, non-target screening for hormonally active or endocrine disrupting compounds in plant products is becoming more important. Unfortunately, the current planar yeast estrogen screen (pYES) is prone to zone diffusion on the normal-phase high-performance thin-layer chromatography (NP-HPTLC) plate due to long incubation times in the aqueous bioassay. PURPOSE: The present study aimed to reduce zone diffusion on NP plates, which provides the basis for extending pYES to a multiplex bioassay, offering 4 different biological activity principles, followed by targeted identification of active zones. STUDY DESIGN AND METHODS: The reduction of substance diffusion via a polyisobutyl methacrylate polymer coating was studied. After successful zone fixation (fix), a multiplex bioassay was developed, in which a 17ß-estradiol-strip was applied along each sample track to detect synergists and antagonists (A), and for verification (V), a 4-methyl umbelliferone-strip to exclude false-positives. After multiplex bioassay screening of 68 botanicals, the zones with hormonal activities were heart-cut eluted to reversed-phase high-performance liquid chromatography-diode array detection-high-resolution tandem mass spectrometry (RP-HPLC-DAD-HESI-HRMS/MS). RESULTS: The separated substances were successfully fixed by the chromatogram coating. The zone sharpness (achieved after the bioassay) made it possible to add two strips, the 17ß-estradiol-strip for antagonistic and synergistic, and the 4-methyl umbelliferone-strip for false-positive effect detection, resulting in a multiplex bioassay. Using the 12D hyphenation NP-HPTLCfix-UV/Vis/FLD-pYAVES-FLD heart-cut RP-HPLC-DAD-HESI-HRMS/MS, it was possible to obtain information on estrogens, antiestrogens, false-positives, and synergists, and (tentatively) assign 17 hormonally active compounds, of which only 7 have been known to affect the human estrogen receptor, while another 4 had structural similarity to common phytoestrogens and antiestrogens. CONCLUSIONS: The streamlined 12D hyphenation including a multiplex bioassay has been shown to differentiate hormonal effects, leading to new insights and better understanding. It can generally be used to identify unknown hormonally active compounds in complex samples.


Assuntos
Moduladores de Receptor Estrogênico , Estrogênios , Bioensaio/métodos , Cromatografia em Camada Delgada/métodos , Estradiol , Humanos , Fitoestrógenos/farmacologia , Umbeliferonas , Leveduras
3.
Biomed Pharmacother ; 150: 113001, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35658220

RESUMO

Atherosclerosis is one of the potential causes of death in patients with cardiovascular disease. With the discovery of new anti atherosclerotic drugs becoming the pursuit of the pharmaceutical industry, natural products have attracted more and more attention because of their unique efficacy in the treatment of atherosclerosis. More and more studies have shown that esculetin, a coumarin mainly found in cortex fraxini, can improve atherosclerosis by participating in cellular antioxidant responses and reducing inflammation related pathogenesis. This paper summarizes the researches of esculetin on anti-atherosclerosis in the past two decades. Esculetin plays an anti atherosclerotic role through reducing blood triglyceride level, preventing the proliferation of vascular smooth muscle cells (VSMC) and the production of matrix metallopeptidase 9 (MMP-9), inhibiting the oxidation of low density lipoprotein (LDL) and the secretion of adhesion factors and chemokines, and increasing the outflow level of high density lipoprotein cholesterol (HDL-C). Esculetin is safe and reliable, easy to be absorbed by the body and can be synthesized in a variety of ways. Although there are still few clinical studies on anti-atherosclerosis, in vivo experiments have proved that esculetin has high bioavailability. From the current research, the anti-atherosclerotic effect of esculetin is positive and encouraging. However, much work remains to be done to clarify the molecular mechanism of esculetin in the treatment of atherosclerosis.


Assuntos
Aterosclerose , Músculo Liso Vascular , Aterosclerose/tratamento farmacológico , Humanos , Miócitos de Músculo Liso , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico
4.
J Ethnopharmacol ; 296: 115489, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35728711

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aesculetin (6,7-dihydroxy-2H-1-benzopyran-2-one) has been reported to exhibit potent anti-inflammatory property both in vitro and in vivo. AIMS OF THIS STUDY: In this study, we evaluated the anti-inflammatory effect and investigated underlying molecular mechanisms of aesculetin in LPS-induced RAW264.7 macrophages and DSS-induced colitis. MATERIALS AND METHODS: In this study, the production of NO, TNF-α, and IL-6 were measured to identify the aesculetin with potent anti-inflammatory effect. Then, the underlying anti-inflammatory mechanisms were explored by western blotting in LPS-induced cells. Next, we verify the anti-inflammatory potential of aesculetin in DSS-induced colitis in vivo. The clinical symptoms of colitis, including weight loss, DAI, colon length and MPO activity, and the secretion of TNF-α and IL-6 were evaluated. Finally, Western blot analysis was applied to further investigate underlying mechanism in DSS-induced colitis model. RESULTS: Our studies showed that aesculetin exhibited anti-inflammatory potential by inhibiting NO, TNF-α, and IL-6 production and reducing iNOS and NLRP3 expression in LPS-induced RAW264.7 cells. Mechanically, we found that aesculetin significantly inhibited LPS-induced activation of NF-κB and MAPKs signaling pathways. In DSS-induced mouse model, the colitis-related symptoms were relieved by treatment with aesculetin. Besides, aesculetin also inhibited the secretion of TNF-α and IL-6, and the activation of NF-κB and MAPKs signaling pathways in DSS-induced colitis. CONCLUSIONS: The anti-inflammatory effect of aesculetin was connected with its inhibition on the activation of NF-κB and MAPKs signaling pathways both in vitro and in vivo. Therefore, aesculetin was expected to be developed as an anti-inflammatory drug.


Assuntos
Colite , NF-kappa B , Umbeliferonas , Animais , Anti-Inflamatórios/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas , Sulfato de Dextrana , Interleucina-6 , Lipopolissacarídeos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico
5.
Phys Chem Chem Phys ; 24(21): 13015-13025, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35583143

RESUMO

This study investigated the effect of 2-methylimidazole (2-MIM) addition on the fluorescence of ethyl-7-hydroxy-2-oxo-2H-chromene-3-carboxylate using low-cost density functional theory (DFT) and Time-Dependent DFT calculations on single crystal X-ray geometries of ethyl-7-hydroxy-2-oxo-2H-chromene-3-carboxylate hydrate (1), 2-MIM (2), and the 1 : 1 co-crystal of (1) and (2), (3). At low concentrations (1 : 1-1 : 10) of 2-MIM, the fluorophore shows a decrease in the fluorescence intensity, but at higher concentrations (above 1 : 10) the fluorescence excitation maximum shifted from 354 nm to 405 nm, with a significant emission intensity increase. The changed excitation and emission profile at high concentrations is due to the deprotonation of the coumarin's phenolic group, which was confirmed by the increased shielding of the aromatic protons in the titration 1H NMR spectra. The experimental fluorescence data between the 1 : 1 and 1 : 10 ratios agreed with the theoretical fluorescence data, with a redshift and decreased intensity when comparing (1) and (3). The data indicated that combining the fluorophore with 2-MIM increased levels of vibronic coupling between 2-MIM and the fluorophore decreasing de-excitation efficiency. These increased vibronic changes were due to charge transfer between the fluorophore and 2-MIM in (3). The subtle movement of the proton, H(5) toward N(2') (0.07 Å) caused a significant decrease in fluorescence due to electron density distribution (EDD) changes. This was identified by comparison of the EDD in the excited (S1) and ground (S0) states plotted as an isosurface of EDD difference. For the higher concentrations, an alternative excitation pathway was explored by modifying the crystal geometry of (3) based on 1H NMR spectroscopy data to resemble excitoplexes. Theses excitoplex geometries reflected the fluorescence profile of the fluorophore with high concentrations of 2-MIM; there were dramatic changes in the theoretical fluorescence pathway, which was 100% vibronic coupling compared to 15.31% in the free fluorophore. At this concentration, the de-excitation pathway causes remodelling of the lactone ring via stretching/breaking the CO bond in the S1 causing increased fluorescence by movement of the transition dipole moment. These results reflect previous studies, but the methods used are less experimentally and computationally expensive. This study is among the first to explain charge transfer fluorescence using crystalline geometries. This study will be of interest to the fields of crystal engineering and fluorescence spectroscopy.


Assuntos
Prótons , Teoria Quântica , Corantes Fluorescentes , Imidazóis , Umbeliferonas , Difração de Raios X
6.
Free Radic Biol Med ; 186: 17-30, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35513128

RESUMO

Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-ß1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang-II)-stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-ß1/Smad2/3 signaling axis.


Assuntos
Heme Oxigenase-1 , Proteínas de Membrana , Fator 2 Relacionado a NF-E2 , Proteína Smad2 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Umbeliferonas , Angiotensina II/metabolismo , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Colágeno/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/antagonistas & inibidores , Proteína Smad2/metabolismo , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismo , Umbeliferonas/farmacologia , Regulação para Cima , Remodelação Ventricular/efeitos dos fármacos
7.
Int J Mol Sci ; 23(7)2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35408852

RESUMO

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.


Assuntos
Anticonvulsivantes , Umbeliferonas , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque , Lacosamida/uso terapêutico , Camundongos , Fenobarbital/farmacologia , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico
8.
J Oleo Sci ; 71(4): 575-585, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370216

RESUMO

Hepatocellular carcinoma (HCC) is the 5th most common cancer disease and the 3rd cause of cancer related disease. Oxidative stress and inflammatory reactions are increases due to the expansion of hepatic cancer. Daphnetin is a well-known antioxidant and anti-inflammatory drug. The current experimental study was exploring the chemoprotective effect of daphnetin against diethylnitrosamine (DEN) induced HCC in rats and scrutinizing the possible mechanism. In this experimental study, Swiss Wistar rats were used for the current protocol and intraperitoneal injection of DEN (200 mg/kg) and phenobarbital (8 mg/kg) were used for the induction and progression of HCC and after induction the HCC, the rats were received the oral administration of different doses of daphnetin. Body weight was estimated at regular time intervals. Macroscopical evaluation was done at the end of the experimental study for the confirmation of hepatic nodules. Hepatic markers, antioxidant and inflammatory mediators were estimated in the serum of experimental rats. Daphnetin treatment successfully attenuated the hepatic injury induced by DEN/Pb as shown by the suppressed the levels of biochemical parameters including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (T-Bil) and total protein (TP). Daphnetin significantly (p < 0.001) enhanced the level of glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and decreased the malonaldehyde (MDA) level. Daphnetin treatment significantly altered the level of phase I and phase II enzymes and also significantly (p < 0.001) decreased the level of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α); inflammatory mediators include cyclooxygenase-2 (COX-2), nuclear kappa B factor (NF-κB) and prostaglandin (PGE2). Collectively, we can say that daphnetin suggestively suppressed the hepatic cancer via suppression of antioxidant and inflammatory reactions.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Inflamação/tratamento farmacológico , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Estresse Oxidativo , Ratos , Ratos Wistar , Umbeliferonas
9.
Biomed Pharmacother ; 149: 112900, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35378502

RESUMO

The role of oxidative injury and inflammatory response in cardiovascular diseases and heart failure has been well-acknowledged. This study evaluated the protective effect of umbelliferone (UMB), a coumarin with promising radical scavenging and anti-inflammatory activities, on myocardial injury induced by isoproterenol (ISO) in rats. Rats received 50 mg/kg UMB orally for 14 days and 85 mg/kg ISO twice at an interval of 24 h. Administration of ISO elevated serum troponin I, creatine kinase-MB and lactate dehydrogenase, and caused histopathological alterations, including degeneration, fatty vacuolation, myolysis, and atrophy of myocardial fibers. Malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß were increased, whereas reduced glutathione (GSH), superoxide dismutase (SOD), and catalase were decreased in ISO-administered rats. UMB effectively ameliorated myocardial injury, alleviated cardiac function markers, MDA, NO, NF-κB p65, and the inflammatory mediators, and enhanced cellular antioxidants. Bax, caspase-3, and 8-OHdG were decreased, and Bcl-2 was increased in ISO-administered rats treated with UMB. In addition, UMB upregulated nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 in the heart of ISO-administered rats. In conclusion, UMB can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants.


Assuntos
Antioxidantes , Fator 2 Relacionado a NF-E2 , Animais , Antioxidantes/metabolismo , Morte Celular , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Inflamação/metabolismo , Isoproterenol/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico
10.
Molecules ; 27(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35458645

RESUMO

Tuberculosis remains a global threat to public health, and dormant Mycobacterium tuberculosis leads to long-term medication that is harmful to the human body. M. tuberculosis isocitrate lyase (MtICL), which is absent in host cells, is a key rate-limiting enzyme of the glyoxylic acid cycle and is essential for the survival of dormant M. tuberculosis. The aim of this study was to evaluate natural compounds as potential MtICL inhibitors through docking and experimental verification. Screening of the TCMSP database library was done using Discovery Studio 2019 for molecular docking and interaction analysis, with the putative inhibitors of MtICL, 3-BP, and IA as reference ligands. Daphnetin (MOL005118), with a docking score of 94.8 and -CDOCKER interaction energy of 56 kcal/mol, was selected and verified on MtICL in vitro and M. smegmatis; daphnetin gave an IC50 of 4.34 µg/mL for the MtICL enzyme and an MIC value of 128 µg/mL against M. smegmatis, showing enhanced potential in comparison with 3-BP and IA. The interactions and essential amino acid residues of the protein were analyzed. In summary, natural daphnetin may be a promising new skeleton for the design of inhibitors of MtICL to combat dormant M. tuberculosis.


Assuntos
Isocitrato Liase , Mycobacterium tuberculosis , Tuberculose , Umbeliferonas , Antituberculosos/química , Humanos , Isocitrato Liase/antagonistas & inibidores , Ligantes , Simulação de Acoplamento Molecular , Tuberculose/tratamento farmacológico , Umbeliferonas/química
11.
Pharmacol Res ; 180: 106227, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35452800

RESUMO

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-ß peptide 1-40 (Aß40) and 1-42 (Aß42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aß deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Presenilina-1/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Umbeliferonas
12.
Oxid Med Cell Longev ; 2022: 7795602, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432722

RESUMO

Rheumatoid arthritis (RA) is a well-known autoimmune disorder that affects 1% of the global population. Zinc (Zn) is crucial for bone homeostasis, when compared with normal human bone, Zn level found to be decreased in RA patients and collagen-induced arthritis (CIA) rats. Notably, Zn-based medicinal products play a prominent role in reducing disease symptoms and acute side effects of patients with bone-related diseases. In this study, we report the clinical efficiency of gelatin- (Gel-) coated ZnO-ZnS core-shell nanoparticles (CSNPs) with umbelliferon (Uf) drug (Uf-Gel-ZnO-ZnS CSNPs) on the normal and CIA-induced Wistar rats. The formed ZnO-ZnS CSNPs are spherical in shape, with an average particle diameter of 150 ± 7 nm. It showed strong cytocompatibility when tested on L929 and foreskin fibroblasts (BJ) cells by MTT assay. While comparing with free Uf, various doses (2.5 and 5 mg) of Uf-Gel-ZnO-ZnS CSNPs showed strong inhibition of CIA by attenuated proinflammatory cytokines such as interleukin-1ß, IL-6, PEG2, and IL-17. The Uf-Gel-ZnO-ZnS CSNPs show more effectiveness in reducing joint swelling and also increase the level of antioxidant enzymes. In addition, CSNPs significantly reduced the infiltration of inflammatory cells in the knee joint. Thus, the current study concludes that Uf-Gel-ZnO-ZnS CSNPs feasibly reduce the incidence of arthritis in a dose-dependent manner by attenuation of inflammation.


Assuntos
Artrite Experimental , Artrite Reumatoide , Nanopartículas , Óxido de Zinco , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Gelatina , Humanos , Ratos , Ratos Wistar , Sulfetos , Umbeliferonas , Zinco/uso terapêutico , Compostos de Zinco , Óxido de Zinco/farmacologia , Óxido de Zinco/uso terapêutico
13.
Anal Chim Acta ; 1202: 339664, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35341516

RESUMO

Electrode sensitivity and selectivity in complex biological matrices are major challenges in the development of electrochemical sensors. Bimetallic nanoparticles provide a new perspective for enhancing electrocatalytic property because of some specific synergetic effects. In this work, platinum nanoparticles (PtNPs) and gold nanoparticles (AuNPs) modified carbon fiber microelectrode (PtNPs/AuNPs/CFME) was fabricated to determine aesculin and aesculetin simultaneously. Differential pulse voltammetry (DPV) method was conducted for the electrochemical sensing of aesculin and aesculetin, the modified electrode displayed high electrocatalytic activity for the redox of these two drugs. The linear ranges of aesculin and aesculetin were 0.4-10 µM and 0.04-1 µM, with the detection limits of 41 nM and 3.6 nM, respectively, which were the lowest values achieved. Furthermore, an electrochemical investigation of the interactions of these two drugs with Calf thymus double stranded DNA (dsDNA) was investigated by PtNPs/AuNPs/CFME, the decrease in peak currents is proportional to DNA concentration and can be used to detect DNA. The electrode was successfully used to measure aesculin and aesculetin in mouse serum and urine with 98.0-104.8% recovery. The novel electrochemical probe possessed excellent performances of high sensitivity, good reproducibility, and simplicity of fabrication, which will facilitate effective detection of aesculin and aesculetin for metabolic kinetics study.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Animais , Técnicas Biossensoriais/métodos , Fibra de Carbono , DNA/química , Esculina , Ouro/química , Nanopartículas Metálicas/química , Camundongos , Microeletrodos , Platina/química , Reprodutibilidade dos Testes , Umbeliferonas
14.
Biosci Biotechnol Biochem ; 86(5): 596-609, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35325017

RESUMO

Daphnetin is a dehydroxylated derivative of coumarin isolated from Daphne species. However, the effect of daphnetin on melanogenesis has not been elucidated. This study aims to investigate the inhibitory effect of daphnetin on melanogenesis in α-melanocyte stimulating hormone (α-MSH)-treated B16F10 cells and its potential mechanism. Melanin content analysis and cellular tyrosinase activity assay showed that daphnetin inhibited melanin biosynthesis in α-MSH-treated B16F10 cells. Immunoblotting and qRT-PCR also indicated that daphnetin suppressed the expression of microphthalmia-associated transcription factor, a mastering transcription factor of melanogenesis and its downstream melanogenic enzymes including tyrosinase and tyrosinase-related proteins. Moreover, daphnetin downregulated the phosphorylation of PKA, ERK, MSK1, and CREB. Additionally, daphnetin inhibited melanin synthesis in UVB-irradiated HaCaT conditioned medium system suggesting that daphnetin has potential as an antipigmentation activity in a physiological skin condition. Our data propose that daphnetin inhibits melanogenesis via modulating both the PKA/CREB and the ERK/MSK1/CREB pathways.


Assuntos
Melanoma Experimental , Melanoma , Animais , Linhagem Celular Tumoral , Melaninas , Melanoma/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase , Transdução de Sinais , Umbeliferonas , alfa-MSH/farmacologia
15.
Food Chem Toxicol ; 163: 112892, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35278496

RESUMO

BACKGROUND: Ferroptosis is a novel form of lipid reactive oxygen species and iron dependent cell death, and it has been shown to be involved in renal tubular injury in diabetic mice. Nrf2 plays an important role in regulating lipid peroxidation and is closely related to ferroptosis. Umbelliferone has antioxidant, anti-glycation and protective effects on diabetic mice. However, the potential mechanisms and underlying effects of these effects in diabetic nephropathy (DN) remain to be investigated. METHODS: 10-week-old male C57BLKS/J db/db, C57BLKS/J db/m mice and HK-2 cells cultured with high glucose were used as experimental objects in this study. ROS levels, GSH, MDA and iron content were detected. RESULTS: We found that Umbelliferone can significantly improve the renal pathological damage and ROS accumulation of db/db mice, and inhibit ferroptosis, such as the down-regulation of ACSL4 and the up-regulation of GPX4. Meanwhile, Nrf2 and HO-1 expression were up-regulated. We demonstrated that knockdown of Nrf2 blocked the inhibitory effect of Umbelliferone on ferroptosis in renal tubule cells induced by high glucose. CONCLUSION: These results suggest that Umbelliferone has a protective effect on DN, possibly by activating the Nrf2/HO-1 pathway, thus attenuating the level of high glucose-induced ferroptosis.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ferroptose , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Feminino , Glucose/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Ferro , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Umbeliferonas
16.
Arch Biochem Biophys ; 720: 109173, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35300940

RESUMO

The effect of Esculetin on pyroptosis and its possible mechanism in endothelium were explored. 10 µg/mL LPS and 0.5 mM ATP were used to stimulate the rat intestinal microvascular endothelial cells. Then add different concentrations of Esculetin (20µM, 40 µM) to the culture medium containing LPS and ATP culturing for 24 h. The expression of p-NF-κB p65, NF-κB p65, I-κB, p-I-κB, NLRP3, ASC, caspase-1, and gasdermin-D were detected by Western blot, and the release level of IL-18 and IL-1ß were measured by ELISA. The NLRP3 inhibitor MCC950 was used at the concentration of 10 µM for 4 h to disentangle the potential mechanism of the influence of Esculetin on pyroptosis. In our experiments, the expression of gasdermin-d and important proteins of NF-κB and NLRP3 signaling pathways were inhibited by Esculetin. Besides, Esculetin also attenuated the morphological changes like swelling rupture and pores on the membrane caused by pyroptosis thereby protecting cells from being damaged by pyroptosis. Combining with the effect of Esculetin on proteins above and its protective effect on cell morphology, we believe that Esculetin has an anti-pyroptosis effect. The inhibiting pyroptosis effects mentioned above are similar to MCC950, which means the anti-pyroptosis effects of Esculetin are associated with the NLRP3 signaling pathway. In conclusion, Esculetin inhibits the pyroptosis of microvascular endothelial cells through the NF-κB/NLFP3 signaling pathway and is expected to be conducive in treating pyroptosis-related diseases.


Assuntos
Células Endoteliais , Microvasos , NF-kappa B , Piroptose , Umbeliferonas , Trifosfato de Adenosina , Animais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Lipopolissacarídeos/farmacologia , Microvasos/citologia , Microvasos/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Ratos , Transdução de Sinais , Umbeliferonas/farmacologia
17.
Drug Dev Res ; 83(4): 952-960, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35132666

RESUMO

Evidence has demonstrated that Daphnetin has antiangiogenesis activity, indicating it might be a new multi-targeted medication for cancer therapy. Here, we aimed to reveal Daphnetin role in hepatocellular carcinoma (HCC) progression and the underlying mechanism. Huh7 and SK-HEP-1, two human HCC cell lines were used in this study. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), colony formation, flow cytometry, and tumor-bearing experiments were applied to evaluate the effects of different concentrations of Daphnetin on cell viability, apoptosis, cell cycle, and in vivo tumor formation, respectively. Real-time PCR (Polymerase Chain Reaction)and western blotting were applied to measure the mRNA and protein levels of ß-catenin. We observed that Daphnetin inhibited cell viability and tumorigenesis, promoted cell apoptosis, and induced a G1 phase arrest in a dose-dependent manner in both Huh7 and SK-HEP-1 cells, which were rescued by SKL2001, an activator of the Wnt/ß-catenin signaling. Taken together, this study reveals that Daphnetin exerts an antitumor role in HCC through the inactivation of Wnt/ß-catenin signaling.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Umbeliferonas , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacologia
18.
J Mol Biol ; 434(8): 167498, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35183558

RESUMO

Fatty acids play critical roles in biological processes, such as energy storage, metabolism, signal transduction, and immune regulation. Therefore, it is necessary to develop in-vitro fluorescent sensors to detect free fatty acids. By genetically incorporating a synthetic fluorescent amino acid (L-(7-hydroxycoumarin-4-yl) ethylglycine, Cou) into fatty acid-binding protein (FABP), we obtained a fluorescent sensor that has a turn-on signal in the presence of the fatty acids. Its response to medium-chain and long-chain fatty acids can be increased by 5.8-fold within several minutes, highlighting its potential applications in fatty acids-related biological processes. Our newly developed fatty acid detection system based on genetic expansion technology has extended the molecular toolboxes available for important biological molecular analysis.


Assuntos
Técnicas Biossensoriais , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos , Glicina/análogos & derivados , Umbeliferonas , Aminoácidos/genética , Aminoácidos/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/análise , Ácidos Graxos não Esterificados/análise , Corantes Fluorescentes/metabolismo , Glicina/química , Glicina/genética , Fígado/metabolismo , Umbeliferonas/química
19.
Talanta ; 243: 123331, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35220079

RESUMO

The extracellular microenvironments play a key role in tumor metabolism. To online dynamic monitoring the efficacy of 7-hydroxycoumarin (7-OHC) to cells cultured on microfluidics in acidic microenvironment, we developed an integrated multi-channel chip-mass spectrometry system. This system has six drug-loading units, cell culture chamber, metabolite collection, filtration, HPLC separation and MS detection. The cells in each microchannel will be incubated with continuous flow of culture medium, metabolites will be collected by the fixed card slot, automatic sampling needle will be precise positioned and sampled. Through this new system, the 7-hydroxycoumarin-sulfonate (7-OHC-sulfonate) and 7-hydroxycoumarin-glucuronide (7-OHC-glucuronide) can be determined in real-time. The results revealed that the addition of lactic acid promoted the formation of inactive 7-OHC-sulfonate and 7-OHC-glucuronide metabolites. Besides, acidic extracellular environment amplified cancer cell proliferation, indicating the anticancer effect of 7-OHC was weakened by low extracellular pH.


Assuntos
Microfluídica , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , Espectrometria de Massas/métodos , Microfluídica/métodos , Umbeliferonas
20.
Talanta ; 242: 123295, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35151080

RESUMO

As a new type of carbon nanomaterial, graphdiyne (GDY) has unique sp hybridized carbon atom, which makes it possible to develop new nitrogen-doped configurations. In this paper, sp-hybridized nitrogen atom doped ultrathin graphdiyne (NUGDY) was prepared based on graphdiyne oxide and melamine by carbonization at high temperature. NUGDY not only preserves the typical folded and wrinkled two-dimensional morphology of GDY, but also presents a three-dimensional porous network structure, which provides sufficient interface and capacity for the loading of target analyte. Meanwhile, N doping increases the GDY defects with more active sites and higher conductivity. Then, NUGDY was modified on the surface of carbon ionic liquid electrode and the modified electrode was applied to 6,7-dihydroxycoumarin (6,7-DHC) analysis. Cyclic voltammetry, electrochemical impedance spectroscopy and chronocoulometry results show that NUGDY has good promotive effect to the electrode performances. Differential pulse voltammetric experiments show that this electrochemical sensor has a low detection limit as 2.3 nM (3S0/S) for 6,7-DHC with high sensitivity. In addition, the modified electrode has the characteristics of excellent anti-interference ability and stability, and been successfully used in the real samples determination, which provides a promising method for the sensitive detection of drug molecules.


Assuntos
Grafite , Nitrogênio , Técnicas Eletroquímicas/métodos , Grafite/química , Nitrogênio/química , Umbeliferonas
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