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1.
Molecules ; 27(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36080485

RESUMO

Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 µM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU's antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8-100 µM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.


Assuntos
Angelica , Diabetes Mellitus , Furocumarinas , Angelica/química , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , alfa-Glucosidases/metabolismo
2.
J Ethnopharmacol ; 298: 115648, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35987408

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea involucrata Kar.et Kir. (S.I.) has long been used as a precious national medicine and clinically proven to be an effective treatment for rheumatoid arthritis (RA) and cardiovascular diseases. In clinical practice, two extraction methods of S.I., including water decoction and alcohol extraction, are prescribed to treat the same conditions. Nevertheless, no study has been performed on the exposure differences of the pharmacodynamic material basis in vivo caused by different extraction methods. AIM OF THE STUDY: Based on the integrated strategy of metabolism, network pharmacology, and pharmacokinetics, we aimed to reveal exposure differences in pharmacodynamic substances caused by different extraction methods. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) was employed to identify the chemical constituents of S.I. extracts and the metabolites in vivo after administration. Based on the analysis of prototype components in vivo, the major exposure active constituents, potential therapeutic targets and possible pharmacological mechanisms in RA treatment were investigated using network pharmacological analysis. Seven critical active components, including quercetin, hispidulin, apigenin, chlorogenic acid, arctigenin, syringin, and umbelliferone, were quantitatively compared between the alcohol, and aqueous extraction methods, which had been confirmed by the reference substance. RESULTS: The chemical comparison demonstrated that the types of chemicals in the two extracts were identical, mainly flavonoids, phenylpropanoids, coumarins, lignins, sesquiterpene lactones, and others, but the contents of the primary constituents in the aqueous extract were lower than those of the alcohol extract. A total of 30 prototype components and 174 metabolites were analyzed and identified in rat plasma, urine, fecal, and bile samples. Twenty-three prototype components were analyzed by network pharmacology, and seven critical active components were selected as representative markers for the pharmacokinetic study. Pharmacokinetic studies had shown that the Tmax values of apigenin, hispidulin, chlorogenic acid, arctigenin, and syringin after the oral administration of the alcohol extract were lower than those after the oral administration of the aqueous extract, and the above components in the alcohol extract could increase the absorption. Compared with the aqueous extract group, the Tmax and T1/2 of quercetin and umbelliferone were longer; it was suggested that alcohol extraction might have a slow-release and long-term effect on these two components. The relative bioavailability of apigenin, hispidulin, quercetin, chlorogenic acid, and umbelliferone in the alcohol extract group were higher than those in the aqueous extract group, which was consistent with the traditional clinical experience that alcohol extract could improve the efficacy of S.I. CONCLUSIONS: The major exposure active constituents in vivo were screened. The representative components that could be used in pharmacokinetics were determined by integrating network pharmacology and metabolism studies. The critical active compounds were quantitatively compared between the alcohol and aqueous extraction methods. This study clarified that flavonoids, coumarin, and phenylpropanoids might be the primary material basis that caused the exposure differences between aqueous and alcoholic extracts from S.I.. This research aimed to provide the basis of metabolism in vivo for further studying these pharmacodynamic differences.


Assuntos
Medicamentos de Ervas Chinesas , Saussurea , Animais , Apigenina , Ácido Clorogênico , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides , Farmacologia em Rede , Extratos Vegetais/uso terapêutico , Quercetina , Ratos , Saussurea/química , Umbeliferonas
3.
Atherosclerosis ; 356: 28-40, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35961209

RESUMO

BACKGROUND AND AIMS: Age is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression. METHODS: We recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe-/- mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects. RESULTS: A chronic low-dose administration of Mito-Esc to Apoe-/- mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe-/- mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe-/- mice and in HAECs. CONCLUSIONS: Overall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function.


Assuntos
Aterosclerose , MicroRNAs , Idoso , Envelhecimento , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/prevenção & controle , Senescência Celular , Células Endoteliais/metabolismo , Humanos , Camundongos , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Sirtuína 1/metabolismo , Umbeliferonas
4.
Sheng Li Xue Bao ; 74(4): 555-562, 2022 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-35993207

RESUMO

This study aimed to investigate the effects of hypoxia on RhoA/Rho-kinase (ROCK) signaling pathway and autophagy in pulmonary artery smooth muscle cells (PASMCs), and to explore the underlying mechanism of Umbelliferone (Umb) in ameliorating chronic hypoxic pulmonary hypertension. PASMCs were cultured from Sprague-Dawley (SD) rats and randomly divided into control group, hypoxia group, hypoxia + Umb intervention group and normoxia + Umb intervention group. Alpha smooth muscle actin (α-SMA) and LC3 were assessed by immunofluorescence staining. Protein expression of RhoA, ROCK2, p-MYPT1, LC3-II, Beclin-1, p62, C-Caspase 3, Bax and Bcl-2 was analyzed by Western blotting. In in vivo study, SD rats were divided into control group, hypoxia group and hypoxia + Umb intervention group. Weight ratio of the right ventricle (RV)/left ventricle plus septum (LV+S) was detected, and pulmonary arterial morphological features were examined by HE staining. The results indicated that compared with the control group, the LC3-II/LC3-I ratio and expression of Beclin-1 were significantly increased, while p62 expression was significantly decreased, and the expressions of RhoA, ROCK2 and p-MYPT1 were significantly increased in PASMCs of hypoxia group (P < 0.05). The changes of LC3-II/LC3-I ratio, the expressions of Beclin-1, p62, RhoA, ROCK2 and p-MYPT1 in PASMCs were reversed by Umb treatment (P < 0.05). Consistently, the pulmonary arterial wall was thickened and the RV/(LV+S) ratio was increased in hypoxic rats, which were significantly improved by Umb treatment (P < 0.05). These results suggest that Umb can improve hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy in PASMCs.


Assuntos
Hipertensão Pulmonar , Animais , Autofagia , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Umbeliferonas/metabolismo , Umbeliferonas/farmacologia , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/farmacologia
5.
Chem Biodivers ; 19(9): e202200261, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35880614

RESUMO

Coumarins is a huge family of phenolic compounds containing a common structure of 2H-1-benzopyran-2-one. Nowadays, more than 1,300 natural-based coumarins have been identified in a variety of plants, bacteria and fungi, many of them exhibited promising biomedical performance. Daphnetin (7,8-dihydroxycoumarin), a typical coumarin, showed a couple of bioactivities such as anti-cancer, antibacterial, anti-inflammatory and anti-arthritis. In the treatment of diseases, it has been verified that daphnetin has outstanding therapeutic effects on diabetes, arthritis, transplant rejection, cancer and even on central nervous system diseases. In China, it is being used for clinical applications, about 93 patent publications were associated with daphnetin. Due to its wide therapeutic potentials in clinical applications, numerous research on the action mechanisms and synthetic methods of daphnetin have been performed to support the future developments. Herein, we summarized the chemical synthetic methodologies, bioactivities, therapeutic potentials and structure-activity relationships of daphnetin and its derivatives. Moreover, the state-of-the-arts in current daphnetin study and future perspective in this field were discussed. Hopefully, this review would be beneficial for the discovery of new coumarin-based biomedicine in the near future.


Assuntos
Anti-Inflamatórios , Cumarínicos , Antibacterianos , Anti-Inflamatórios/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Umbeliferonas
6.
Biomed Pharmacother ; 153: 113387, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35834991

RESUMO

BACKGROUND: Although therapeutic antibodies against immune checkpoints such as PD-1/PD-L1 have achieved unprecedented success in clinical tumor patients, there are still many patients who are ineffective or have limited responses to immune checkpoint blockade (ICB). Discovery of novel strategies for cancer immunotherapy including natural small molecules is needed. METHODS: Owing to its extremely low content in Epimedium genus, we firstly constructed a microbial cell factory to enzymatically biosynthesize icariside I, a natural flavonoid monosaccharide from Herbal Epimedium. Using a combination of targeted MS-based metabolomics, flow cytometric analysis, and biological assays, the therapeutic potentials of icariside I were subsequently investigated in vivo and in vitro. RESULTS: We find that icariside I markedly downregulates a series of intermediate metabolites such as kynurenine, kynurenic acid and xanthurenic acid and corresponding key enzymes involved in kynurenine-AhR pathway in both tumor cells and tumor-bearing mice. In vivo, oral administration of icariside I downregulates SLC7A8 and PAT4 transporters and AhR, thus inhibiting nuclear PD-1 in CTLs. Moreover, icariside I significantly upregulates CD8 + T cells in both peripheral blood and tumor tissues of tumor-bearing mice. Consequently, interferon-γ (IFN-γ) secreted by CD8 + T cells suppresses tumor growth through activation of JAK1-STAT1 signaling, thus inducing tumor cell apoptosis. CONCLUSIONS: These results suggest that icariside I could be an effective small molecule drug for tumor immunotherapy by blocking kynurenine-AhR pathway and tumor immune escape.


Assuntos
Cinurenina , Neoplasias , Animais , Linhagem Celular Tumoral , Flavonas , Imunoterapia , Camundongos , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , Evasão Tumoral , Microambiente Tumoral , Umbeliferonas
7.
Arch Biochem Biophys ; 728: 109366, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35878680

RESUMO

An impressive body of evidence has been accumulated now on sound beneficial effects of mitochondrial uncouplers in struggling with the most dangerous pathologies such as cancer, infective diseases, neurodegeneration and obesity. To increase their efficacy while gaining further insight in the mechanism of the uncoupling action has been remaining a challenge. Encouraged by our previous promising results on lipophilic derivatives of 7-hydroxycoumarin-4-acetic acid (UB-4 esters), here, we use a 7-hydroxycoumarin-3-carboxylic acid scaffold to synthesize a new series of 7-hydroxycoumarin (umbelliferone, UB)-derived uncouplers of oxidative phosphorylation - alkyl esters of umbelliferone-3-carboxylic acid (UB-3 esters) with varying carbon chain length. Compared to the UB-4 derivatives, UB-3 esters proved to be stronger uncouplers: the most effective of them caused a pronounced increase in the respiration rate of isolated rat heart mitochondria (RHM) at submicromolar concentrations. Both of these series of UB derivatives exhibited a striking difference between their uncoupling patterns in mitochondria isolated from liver and heart or kidney, namely: a pronounced but transient decrease in membrane potential, followed by its recovery, was observed after the addition of these compounds to isolated rat liver mitochondria (RLM), while the depolarization of RHM and rat kidney mitochondria (RKM) was rather stable under the same conditions. Interestingly, partial reversal of this depolarization in RHM and RKM was caused by carboxyatractyloside, an inhibitor of ATP/ADP translocase, thereby pointing to the involvement of this mitochondrial membrane protein in the uncoupling activity of both UB-3 and UB-4 esters. The fast membrane potential recovery in RLM uncoupled by the addition of the UB esters was apparently associated with hydrolysis of these compounds, catalyzed by mitochondrial aldehyde dehydrogenase (ALDH2), being in high abundance in liver compared to other tissues. Protonophoric properties of the UB derivatives in isolated mitochondria were confirmed by measurements of RHM swelling in the presence of potassium acetate. In model bilayer lipid membranes (liposomes), proton-carrying activity of UB-3 esters was demonstrated by measuring fluorescence response of the pH-dependent dye pyranine. Electrophysiological experiments on identified neurons from Lymnaea stagnalis demonstrated low neurotoxicity of UB-3 esters. Resazurin-based cell viability assay showed low toxicity of UB-3 esters to HEK293 cells and primary human fibroblasts. Thus, the present results enable us to consider UB-3 esters as effective tissue-specific protonophoric mitochondrial uncouplers.


Assuntos
Translocases Mitocondriais de ADP e ATP , Fosforilação Oxidativa , Trifosfato de Adenosina , Aldeído-Desidrogenase Mitocondrial , Animais , Ésteres , Células HEK293 , Humanos , Mitocôndrias Cardíacas , Mitocôndrias Hepáticas , Ratos , Umbeliferonas , Desacopladores
8.
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
9.
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
10.
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
11.
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
12.
Free Radic Biol Med ; 186: 17-30, 2022 06.
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
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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