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1.
BMC Biotechnol ; 24(1): 61, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278901

RESUMO

Nanoporous aluminum metal-organic framework (Al-MOF) was synthesized via solvothermal methods and employed as a carrier matrix for in vitro drug delivery of Umbelliferon (Um). The encapsulated Um was gradually released over seven days at 37 °C, using simulated body fluid phosphate-buffered saline (PBS) at pH 7.4 as the release medium. The drug release profile suggests the potential of Al-MOF nanoparticles as effective drug delivery carriers. Structural and chemical analyses of Um-loaded Al-MOF nanoparticles (Um-Al MOF) were conducted using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), and ultraviolet-visible (UV-Vis) spectroscopy. Thermal gravimetric analysis (TGA) was employed to investigate the thermal stability of the Al-MOF nanoparticles, while Transmission Electron Microscopy (TEM) was utilized to assess their morphological features. Um-Al MOF nanoparticles demonstrated notable antioxidant and anti-inflammatory properties compared to Um and Al-MOF nanoparticles individually. Moreover, they exhibited significant enhancement in wound healing in an earthworm model. These findings underscore the potential of Al-MOF nanoparticles as a promising drug delivery system, necessitating further investigations to explore their clinical applicability.


Assuntos
Alumínio , Anti-Inflamatórios , Antioxidantes , Estruturas Metalorgânicas , Oligoquetos , Umbeliferonas , Cicatrização , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Umbeliferonas/química , Umbeliferonas/farmacologia , Oligoquetos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Alumínio/química , Nanopartículas/química , Liberação Controlada de Fármacos , Portadores de Fármacos/química
2.
BMC Plant Biol ; 24(1): 806, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39187756

RESUMO

BACKGROUND: Scopoletin and umbelliferone belong to coumarins, which are plant specialized metabolites with potent and wide biological activities, the accumulation of which is induced by various environmental stresses. Coumarins have been detected in various plant species, including medicinal plants and the model organism Arabidopsis thaliana. In recent years, key role of coumarins in maintaining iron (Fe) homeostasis in plants has been demonstrated, as well as their significant impact on the rhizosphere microbiome through exudates secreted into the soil environment. Several mechanisms underlying these processes require clarification. Previously, we demonstrated that Arabidopsis is an excellent model for studying genetic variation and molecular basis of coumarin accumulation in plants. RESULTS: Here, through targeted metabolic profiling and gene expression analysis, the gene-metabolite network of scopoletin and umbelliferone accumulation was examined in more detail in selected Arabidopsis accessions (Col-0, Est-1, Tsu-1) undergoing different culture conditions and characterized by variation in coumarin content. The highest accumulation of coumarins was detected in roots grown in vitro liquid culture. The expression of 10 phenylpropanoid genes (4CL1, 4CL2, 4CL3, CCoAOMT1, C3'H, HCT, F6'H1, F6'H2,CCR1 and CCR2) was assessed by qPCR in three genetic backgrounds, cultured in vitro and in soil, and in two types of tissues (leaves and roots). We not only detected the expected variability in gene expression and coumarin accumulation among Arabidopsis accessions, but also found interesting polymorphisms in the coding sequences of the selected genes through in silico analysis and resequencing. CONCLUSIONS: To the best of our knowledge, this is the first study comparing accumulation of simple coumarins and expression of phenylpropanoid-related genes in Arabidopsis accessions grown in soil and in liquid cultures. The large variations we detected in the content of coumarins and gene expression are genetically determined, but also tissue and culture dependent. It is particularly important considering that growing plants in liquid media is a widely used technology that provides a large amount of root tissue suitable for metabolomics. Research on differential accumulation of coumarins and related gene expression will be useful in future studies aimed at better understanding the physiological role of coumarins in roots and the surrounding environments.


Assuntos
Arabidopsis , Escopoletina , Umbeliferonas , Arabidopsis/genética , Arabidopsis/metabolismo , Escopoletina/metabolismo , Umbeliferonas/metabolismo , Glicosídeos/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Raízes de Plantas/metabolismo , Raízes de Plantas/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo
3.
Mol Pharm ; 21(9): 4708-4725, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39115967

RESUMO

This study investigates the interaction between daphnetin and ovalbumin (OVA) as well as its potential to inhibit OVA fibrillation using both spectroscopic and computational analysis. A moderate binding affinity of 1 × 104 M-1 was observed between OVA and daphnetin, with a static quenched mechanism identified during the fluorescence quenching processes. Metal ions' (Cu2+ and Zn2+) presence led to an increase in the binding affinities of daphnetin toward OVA, mirroring a similar trend observed with the pH variation. Synchronous and 3D fluorescence studies indicated an increase in the polarity of the microenvironment surrounding the Trp residues during binding. Interestingly, circular dichroism and Fourier transform infrared studies showed a significant change in the secondary structure of OVA upon binding with daphnetin. The efficacy of daphnetin in inhibiting protein fibrillation was confirmed through thioflavin T and Congo Red binding assays along with fluorescence microscopic imaging analysis. The thermodynamic assessment showed positive ΔH° [+(29.34 ± 1.526) kJ mol-1] and ΔS° [+(181.726 ± 5.465) J mol-1] values, indicating the presence of the hydrophobic forces, while negative ΔG° signifies spontaneous binding interactions. These experimental findings were further correlated with computational analysis, revealing daphnetin dynamics within the binding site of OVA.


Assuntos
Cumarínicos , Ovalbumina , Umbeliferonas , Ovalbumina/metabolismo , Umbeliferonas/química , Umbeliferonas/metabolismo , Concentração de Íons de Hidrogênio , Cumarínicos/química , Cumarínicos/metabolismo , Dicroísmo Circular , Ligação Proteica , Termodinâmica , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Simulação de Acoplamento Molecular , Zinco/química , Zinco/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Fluorescência , Sítios de Ligação , Cobre/química , Estrutura Secundária de Proteína
4.
Fish Shellfish Immunol ; 152: 109767, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39009196

RESUMO

Viral hemorrhagic septicemia virus (VHSV) poses a significant threat to global aquaculture, prompting ongoing efforts to identify potential drug candidates for disease prevention. Coumarin derivatives have recently emerged as a promising class of compounds effective against rhabdoviruses, which severely impact the aquaculture industry. In this study, we assessed the anti-VHSV activity of umbelliferone (7-hydroxycoumarin) in fathead minnow (FHM) cells and olive flounder Paralichthys olivaceus. Umbelliferone exhibited an EC50 of 100 µg/mL by reducing cytopathic effect, with a maximum cytotoxicity of 30.9 % at 750 µg/mL. Mechanistic analyses via a time-course plaque reduction assay revealed that direct incubation with the virus for 1 h resulted in 97.0 ± 1.8 % plaque reduction, showing excellent direct virucidal activity. Pretreatment for 4 h resulted in a 33.5 ± 7.8 % plaque reduction, which increased with longer incubation times. Cotreatment led to a 33.5 ± 2.9 % plaque reduction, suggesting interference with viral binding, whereas postinfection treatment proved less effective. Umbelliferone was prophylactically administered to the olive flounder through short-term (3 days) and long-term (14 days) medicated feeding, followed by a 4-day postinfection period. Short-term administration at 100 mg/kg body weight (bw)/day resulted in the highest relative percent survival (RPS) of 56 %, whereas long-term administration achieved a maximum RPS of 44 % at 30 mg/kg bw/day. Umbelliferone administration delayed mortality at these doses. Additionally, umbelliferone significantly inhibited the expression of the VHSV N gene during viral challenge, with no observed toxic effects in fish up to an administration dose of 30 mg/kg bw/day for 28 days. Our findings suggest that the protective mechanism of short-term administration of 100 mg umbelliferone against VHSV infection may involve the overexpression of TLR2, MDA5, STAT1, and NF-κB at 24 h postinfection (hpi). IL-8 and IFN II expression was upregulated, whereas TNF-α, IL-1ß, and IFN I expression was suppressed at 24 hpi. The upregulation of ISG15 at 48 hpi may contribute to the inhibition of VHSV replication, whereas the downregulation of Caspase 3 expression at 96 hpi suggests a possible inhibition of virus-induced apoptosis at later infection stages. Overall, umbelliferone exhibited anti-VHSV activity through multiple mechanisms, with the added advantage of convenient administration via medicated feed.


Assuntos
Antivirais , Novirhabdovirus , Umbeliferonas , Animais , Umbeliferonas/farmacologia , Antivirais/farmacologia , Novirhabdovirus/fisiologia , Novirhabdovirus/efeitos dos fármacos , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Linguado/imunologia , Septicemia Hemorrágica Viral/virologia , Septicemia Hemorrágica Viral/imunologia , Linhagem Celular
5.
Phytomedicine ; 132: 155876, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39032284

RESUMO

BACKGROUND: Ferroptosis, an emerging nonapoptotic, modulated cell death process characterized by iron accumulation and subsequent lipid peroxidation, has been intimately implicated in the development and progression of ovarian cancer (OC). Daphnetin (Daph), a natural product isolated from Daphne Korean Nakai, exhibits anticancer efficacy against various solid tumors. However, the specific role and potential mechanism underlying Daph-mediated modulation of ferroptosis in OC cells remain elusive. PURPOSE: This study aims to analyze the proferroptotic impacts of Daph on OC cells and to further explore the underlying mechanisms involved. STUDY DESIGN AND METHODS: We used CCK-8, wound healing and Transwell assays to assess whether Daph can inhibit the proliferation and migration of OC cells. Additionally, transmission electron microscopy (TEM), iron measurement, reactive oxygen species (ROS) analysis, lipid peroxidation assays, qRT-PCR and western blotting were utilized to evaluate the impact of Daph on ferroptosis and elucidate the potential underlying mechanism. Furthermore, RNA sequencing analysis, molecular docking analysis, cellular thermal shift assays (CETSAs) and NQO1 activity assays were used to predict and validate the binding and mechanistic interactions between Daph and NQO1. Subcutaneous tumorigenesis models were utilized to examine the effectiveness of Daph (and/or cisplatin) in vivo. RESULTS: Daph exerted antitumor effects by inducing the death and suppressing the migration of A2780 and SKOV3 cells. Further, Daph induced ferroptosis in OC cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), ROS and lipid peroxides, as well as the decreases in the glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio and the expression of ferroptosis indicators (SLC7A11 and GPX4). RNA sequencing and molecular docking analyses revealed that the direct interaction between NQO1 and Daph reduced both the activity and expression of NQO1. Importantly, NQO1 overexpression effectively alleviated the effects of Daph on proliferation, migration, and ferroptosis in vitro and in vivo. Interestingly, we also found that combination treatment with Daph, a negative regulator of NQO1, and cisplatin synergistically induced cytotoxicity in OC cells. CONCLUSION: Our findings are the firstly demonstrated that Daph acts as a novel ferroptosis inducer in OC cells by specifically targeting NQO1 and is thus a promising candidate agent for OC treatment.


Assuntos
Proliferação de Células , Ferroptose , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona) , Neoplasias Ovarianas , Espécies Reativas de Oxigênio , Umbeliferonas , Ferroptose/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Feminino , Humanos , Linhagem Celular Tumoral , Animais , Espécies Reativas de Oxigênio/metabolismo , Umbeliferonas/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Camundongos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Nus , Camundongos Endogâmicos BALB C , Daphne/química , Antineoplásicos Fitogênicos/farmacologia
6.
Eur J Pharmacol ; 979: 176826, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39033840

RESUMO

Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments.


Assuntos
Asma , Janus Quinases , Fator de Transcrição STAT6 , Transdução de Sinais , Umbeliferonas , Animais , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Janus Quinases/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Feminino , Citocinas/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Linhagem Celular , Daphne/química , Fator de Transcrição GATA3/metabolismo , Fator de Transcrição GATA3/genética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Cálcio/metabolismo
7.
Res Vet Sci ; 175: 105314, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38823354

RESUMO

Over the course of the last twenty years, there has been a growing recognition of the pig's potential as a valuable model for studying human drug metabolism. This study aimed to investigate the expression, enzymatic activity, inhibitory susceptibility, and cellular localization of carboxylesterases (CES) in porcine lung tissue not yet explored. Our results showed that CESs hydrolysis activity followed Michaelis-Menten kinetics in both cytosolic and microsomal fractions of porcine lung tissues (N = 8), with comparable hydrolysis rates for tested substrates, namely 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD). We also determined the CESs hydrolysis activity in a representative sample of the porcine liver that, as expected, displayed higher activity than the lung ones. The study demonstrated variable levels of enzyme activities and interindividual variability in both porcine lung fractions. Inhibition studies used to assess the CESs' involvement in the hydrolysis of pNPA, 4-MUA, and FD suggested that CESs may be the enzymes primarily involved in the metabolism of ester compounds in the pig lung tissue. Overall, this study provides insight into the distribution and diversity of CES isoforms involved in substrate hydrolysis across different cellular fractions (cytosol and microsomes) in porcine lungs.


Assuntos
Hidrolases de Éster Carboxílico , Pulmão , Animais , Pulmão/enzimologia , Pulmão/metabolismo , Suínos , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases de Éster Carboxílico/genética , Microssomos/enzimologia , Nitrofenóis/metabolismo , Umbeliferonas/metabolismo , Fluoresceínas , Hidrólise , Citosol/enzimologia , Fígado/enzimologia
8.
Sci Rep ; 14(1): 11450, 2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769394

RESUMO

A mesoporous silica nanoparticle (MSN) coated with polydopamine (PDA) and loaded with umbelliprenin (UMB) was prepared and evaluated for its anti-cancer properties in this study. Then UMB-MSN-PDA was characterized by dynamic light scattering (DLS), Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM) and FTIR methods. UV-visible spectrometry was employed to study the percentage of encapsulation efficiency (EE%). UMB-MSN-PDA mediated cell cytotoxicity and their ability to induce programmed cell death were evaluated by MTT, real-time qPCR, flow cytometry, and AO/PI double staining methods. The size of UMB-MSN-PDA was 196.7 with a size distribution of 0.21 and a surface charge of -41.07 mV. The EE% was 91.92%. FESEM and TEM showed the spherical morphology of the UMB-MSN-PDA. FTIR also indicated the successful interaction of the UMB and MSN and PDA coating. The release study showed an initial 20% release during the first 24 h of the study and less than 40% during 168 h. The lower cytotoxicity of the UMB-MSN-PDA against HFF normal cells compared to MCF-7 carcinoma cells suggested the safety of formulation on normal cells and tissues. The induction of apoptosis in MCF-7 cells was indicated by the upregulation of P53, caspase 8, and caspase 9 genes, enhanced Sub-G1 phase cells, and the AO/PI fluorescent staining. As a result of these studies, it may be feasible to conduct preclinical studies shortly to evaluate the formulation for its potential use in cancer treatment.


Assuntos
Antineoplásicos , Indóis , Nanopartículas , Polímeros , Dióxido de Silício , Humanos , Indóis/química , Indóis/farmacologia , Dióxido de Silício/química , Polímeros/química , Nanopartículas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Porosidade , Células MCF-7 , Umbeliferonas/química , Umbeliferonas/farmacologia , Portadores de Fármacos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos
9.
Eur Rev Med Pharmacol Sci ; 28(8): 3048-3055, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38708463

RESUMO

OBJECTIVE: Despite the multiple available treatment modalities, cervical cancer is one of the leading causes of mortality and morbidity among female gynecological cancers. Endoplasmic Reticulum (ER) is an effective organelle in ensuring cell homeostasis and is closely related to the development of cancer. Esculetin is a coumarin derivative that has anticancer, anti-inflammatory, antioxidant, and neuroprotective effects. Esculetin may have an anticancer effect by inducting apoptosis and ER stress. In this study, we evaluate that esculetin has an anti-tumor effect on human cervical cancer-derived (HeLa) cells via ER stress. MATERIALS AND METHODS: Esculetin was applied to the HeLa cells, and a viability test was performed using the methyl thiazolyl tetrazolium proliferation (MTT) assay. Expression levels of apoptotic genes and anti-apoptotic genes were determined by real-time polymerase chain reaction. The results were statistically evaluated. RESULTS: Analysis of the MTT assay detected that esculetin inhibited HeLa cell viability development. Based on Western blot and quantitative real-time polymerase chain reaction (qPCR) analyses, esculetin destroyed cervical cancer cells via the ER stress pathway. CONCLUSIONS: The results showed that esculetin may have a potent antitumoral effect. It can potentially be utilized in the pharmacological therapy of cervical cancer.


Assuntos
Antineoplásicos , Apoptose , Sobrevivência Celular , Estresse do Retículo Endoplasmático , Umbeliferonas , Humanos , Umbeliferonas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HeLa , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino
10.
Sci Rep ; 14(1): 11770, 2024 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783034

RESUMO

Auraptene (AUR) and umbelliprenin (UMB) are naturally occurring prenylated coumarins that have demonstrated promising anticancer effects across various human cancer cell lines. This meta-analysis aimed to systematically assess, compare, and quantify the anticancer efficacy of AUR and UMB by synthesizing evidence from in vitro studies. A comprehensive literature search identified 27 eligible studies investigating AUR or UMB against cancer cells. Mixed-effects models revealed significant negative associations between coumarin dose and viability for AUR (est. = - 2.27) and UMB (est. = - 3.990), underscoring their dose-dependent cytotoxicity. Meta-regression indicated slightly higher potency for UMB over AUR, potentially due to increased lipophilicity imparted by additional isoprenyl units. Machine learning approaches identified coumarin dose and cancer type as the most influential determinants of toxicity, while treatment duration and the specific coumarin displayed weaker effects. Moderate (AUR) to substantial (UMB) between-study heterogeneity was detected, although the findings proved robust. In summary, this meta-analysis establishes AUR and UMB as promising natural anticancer candidates with clear dose-toxicity relationships across diverse malignancies. The structural insights and quantifications of anticancer efficacy can inform forthcoming efforts assessing therapeutic potential in pre-clinical models and human trials.


Assuntos
Antineoplásicos , Cumarínicos , Umbeliferonas , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Umbeliferonas/farmacologia , Umbeliferonas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Sobrevivência Celular/efeitos dos fármacos
11.
J Mol Med (Berl) ; 102(7): 927-945, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38758435

RESUMO

The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.


Assuntos
Aterosclerose , Hiperglicemia , Resistência à Insulina , Mitocôndrias , Umbeliferonas , Animais , Hiperglicemia/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/etiologia , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Masculino , Células Hep G2 , Sirtuína 1/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Glucose/metabolismo
12.
J Neuropathol Exp Neurol ; 83(8): 670-683, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38819094

RESUMO

The common neurodegenerative disorder Alzheimer disease (AD) is characterized by memory dysfunction and cognitive decline in the elderly. Neuropathological features include aggregated ß-amyloid (Aß) accumulation, neuroinflammation, and oxidative stress in the brain. Daphnetin (DAPH), a natural coumarin derivative, has the potential for inhibiting inflammatory and oxidative responses. We explored neuroprotective roles of DAPH treatment in the APP/PS1 transgenic mouse AD model. DAPH ameliorated spatial learning disabilities in Morris water maze tests and reduced Aß deposition, assessed by immunohistochemistry. It also reduced the Aß content in supernatants of neurons from fetal APP/PS1 mice, assessed by cell-based soluble ELISA. Molecular docking and fluorescence resonance energy transfer-based assay results suggested that DAPH could directly inhibit BACE1 activity. Furthermore, in vitro experiments utilizing isolated rat neurons assessing RNA expression profiling, immunofluorescence, TUNEL assay, and Western-blot analysis, suggested the potential of DAPH for regulating BDNF and GM-CSF expression and mitigating Aß1-42-induced cortical injury, synaptic loss, and apoptosis. HO-1 and Nrf2 mRNA and protein expression were also increased in a dose-dependent manner. These results underscore the potential of DAPH as a neuroprotective agent in reversing memory deficits associated with AD and bolster its candidacy as a multitarget natural small-molecule drug for AD patients.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Modelos Animais de Doenças , Heme Oxigenase-1 , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2 , Neurônios , Fármacos Neuroprotetores , Umbeliferonas , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Umbeliferonas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ratos , Ácido Aspártico Endopeptidases/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Heme Oxigenase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Ratos Sprague-Dawley , Masculino , Proteínas de Membrana
13.
Chemistry ; 30(39): e202401400, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38736421

RESUMO

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.


Assuntos
Antineoplásicos , Cumarínicos , DNA Topoisomerases Tipo I , Inibidores da Topoisomerase I , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/síntese química , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/química , Humanos , Relação Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Oxirredução , Umbeliferonas/química , Umbeliferonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais
14.
J Drug Target ; 32(7): 807-819, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38749010

RESUMO

Short hyperglycaemic episodes trigger metabolic memory (MM) in which managing hyperglycaemia alone is not enough to tackle the progression of Diabetic nephropathy on the epigenetic axis. We used a structural similarity search approach to identify phytochemicals similar to natural epigenetic modifiers and docked with SIRT1 protein and did ADME studies. We found that UMB was 84.3% similar to esculetin. Upon docking, we found that UMB had a binding energy of -9.2 kcal/mol while the standard ligand had -11.8 kcal/mol. ADME showed UMB to be a good lead. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed it to be a good antioxidant with IC50 of 107 µg/mL and MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that it does not promote cell death. Oxidative biomarkers in vitro showed UMB was able to ameliorate glycemic memory induced by high glucose. Western blot revealed decreased histone acetylation under hyperglycaemic conditions and upon treatment with UMB along with DR, its levels increased. This led us to check our hypothesis of whether concomitant diet reversal (DR) together with UMB can alleviate high-fat diet-induced metabolic memory and diabetic nephropathy (DN) in SD rats. UMB was able to decrease blood glucose, lipid, renal, and liver profile concluding UMB was able to ameliorate DN and MM by increasing the histone acetylation level.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Epigênese Genética , Animais , Nefropatias Diabéticas/tratamento farmacológico , Ratos , Epigênese Genética/efeitos dos fármacos , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Antioxidantes/farmacologia , Hiperglicemia/tratamento farmacológico , Sirtuína 1/metabolismo , Sirtuína 1/genética , Simulação de Acoplamento Molecular , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Humanos , Umbeliferonas/farmacologia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/administração & dosagem
15.
J Ethnopharmacol ; 329: 118156, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38583729

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Throughout Chinese history, Hydrangea paniculata Siebold has been utilized as a traditional medicinal herb to treat a variety of ailments associated to inflammation. In a number of immune-mediated kidney disorders, total coumarins extracted from Hydrangea paniculata (HP) have demonstrated a renal protective effect. AIM OF THE STUDY: To investigate renal beneficial effect of HP on experimental Adriamycin nephropathy (AN), and further clarify whether reversing lipid metabolism abnormalities by HP contributes to its renoprotective effect and find out the underlying critical pathways. MATERIALS AND METHODS: After establishment of rat AN model, HP was orally administrated for 6 weeks. Biochemical indicators related to kidney injury were determined. mRNAs sequencing using kidney tissues were performed to clarify the underlying mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, western blot, molecular docking, and drug affinity responsive target stability (DARTS) assay was carried out to further explore and confirm pivotal molecular pathways and possible target by which HP and 7-hydroxylcoumarin (7-HC) played their renal protection effect via modulating lipid metabolism. RESULTS: HP could significantly improve renal function, and restore renal tubular abnormal lipid metabolism and interstitial fibrosis in AN. In vitro study demonstrated that HP and its main metabolite 7-HC could reduce ADR-induced intracellular lipid deposition and fibrosis characteristics in renal tubular cells. Mechanically, HP and 7-HC can activate AMP-activated protein kinase (AMPK) via direct interaction, which contributes to its lipid metabolism modulation effect. Moreover, HP and 7-HC can inhibit fibrosis by inhibiting CCAAT/enhancer binding protein beta (C/EBPß) expression in renal tubular cells. Normalization of lipid metabolism by HP and 7-HC further provided protection of mitochondrial structure integrity and inhibited the nuclear factor kappa-B (NF-κB) pathway. Long-term toxicity using beagle dogs proved the safety of HP after one-month administration. CONCLUSION: Coumarin derivates from HP alleviate adriamycin-induced lipotoxicity and fibrosis in kidney through activating AMPK and inhibiting C/EBPß.


Assuntos
Proteínas Quinases Ativadas por AMP , Proteína beta Intensificadora de Ligação a CCAAT , Cumarínicos , Doxorrubicina , Hydrangea , Animais , Doxorrubicina/toxicidade , Cumarínicos/farmacologia , Cumarínicos/isolamento & purificação , Masculino , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ratos , Hydrangea/química , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Ratos Sprague-Dawley , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/prevenção & controle , Simulação de Acoplamento Molecular , Metabolismo dos Lipídeos/efeitos dos fármacos , Linhagem Celular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Umbeliferonas
16.
Int Immunopharmacol ; 133: 112004, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38613881

RESUMO

Silicosis is a hazardous occupational disease caused by inhalation of silica, characterized by persistent lung inflammation that leads to fibrosis and subsequent lung dysfunction. Moreover, the complex pathophysiology of silicosis, the challenges associated with early detection, and the unfavorable prognosis contribute to the limited availability of treatment options. Daphnetin (DAP), a natural lactone, has demonstrated various pharmacological properties, including anti-inflammatory, anti-fibrotic, and pulmonary protective effects. However, the effects of DAP on silicosis and its molecular mechanisms remain uncover. This study aimed to evaluate the therapeutic effects of DAP against pulmonary inflammation and fibrosis using a silica-induced silicosis mouse model, and investigate the potential mechanisms and targets through network pharmacology, proteomics, molecular docking, and cellular thermal shift assay (CETSA). Here, we found that DAP significantly alleviated silica-induced lung injury in mice with silicosis. The results of H&E staining, Masson staining, and Sirius red staining indicated that DAP effectively reduced the inflammatory response and collagen deposition over a 28-day period following lung exposure to silica. Furthermore, DAP reduced the number of TUNEL-positive cells, increased the expression levels of Bcl-2, and decreased the expression of Bax and cleaved caspase-3 in the mice with silicosis. More importantly, DAP suppressed the expression levels of NLRP3 signaling pathway-related proteins, including NLRP3, ASC, and cleaved caspase-1, thereby inhibiting silica-induced lung inflammation. Further studies demonstrated that DAP possesses the ability to inhibit the epithelial mesenchymal transition (EMT) induced by silica through the inhibition of the TGF-ß1/Smad2/3 signaling pathway. The experimental results of proteomic analysis found that the PI3K/AKT1 signaling pathway was the key targets of DAP to alleviate lung injury induced by silica. DAP significantly inhibited the activation of the PI3K/AKT1 signaling pathway induced by silica in lung tissues. The conclusion was also verified by the results of molecular and CETSA. To further verify this conclusion, the activity of PI3K/AKT1 signaling pathway was inhibited in A549 cells using LY294002. When the A549 cells were pretreated with LY294002, the protective effect of DAP on silica-induced injury was lost. In conclusion, the results of this study suggest that DAP alleviates pulmonary inflammation and fibrosis induced by silica by modulating the PI3K/AKT1 signaling pathway, and holds promise as a potentially effective treatment for silicosis.


Assuntos
Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fibrose Pulmonar , Transdução de Sinais , Dióxido de Silício , Silicose , Umbeliferonas , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , Silicose/tratamento farmacológico , Silicose/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos , Humanos , Pneumonia/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/patologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Masculino , Pulmão/patologia , Pulmão/efeitos dos fármacos , Modelos Animais de Doenças , Simulação de Acoplamento Molecular
17.
Molecules ; 29(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38611695

RESUMO

Oxidative stress plays a crucial role in the pathogenesis of many diseases. Esculetin is a natural coumarin compound with good antioxidant and anti-inflammatory properties. However, whether esculetin can protect HepG2 cells through inhibiting H2O2-induced apoptosis and pyroptosis is still ambiguous. Therefore, this study aimed to investigate the protective effects and mechanisms of esculetin against oxidative stress-induced cell damage in HepG2 cells. The results of this study demonstrate that pretreatment with esculetin could significantly improve the decrease in cell viability induced by H2O2 and reduce intracellular ROS levels. Esculetin not only apparently reduced the apoptotic rates and prevented MMP loss, but also markedly decreased cleaved-Caspase-3, cleaved-PARP, pro-apoptotic protein (Bax), and MMP-related protein (Cyt-c) expression, and increased anti-apoptotic protein (Bcl-2) expression in H2O2-induced HepG2 cells. Meanwhile, esculetin also remarkably reduced the level of LDH and decreased the expression of the pyroptosis-related proteins NLRP3, cleaved-Caspase-1, Il-1ß, and GSDMD-N. Furthermore, esculetin pretreatment evidently downregulated the protein expression of p-JNK, p-c-Fos, and p-c-Jun. Additionally, anisomycin, a specific activator of JNK, blocked the protection of esculetin against H2O2-induced HepG2 cells apoptosis and pyroptosis. In conclusion, esculetin can protect HepG2 cells against H2O2-induced oxidative stress, apoptosis, and pyroptosis via inhibiting the JNK signaling pathway. These findings indicate that esculetin has the potential to be used as an antioxidant that improves oxidative stress-related diseases.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Umbeliferonas , Humanos , Piroptose , Peróxido de Hidrogênio/toxicidade , Antioxidantes/farmacologia , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Apoptose , Estresse Oxidativo
18.
J Biochem Mol Toxicol ; 38(4): e23702, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38567888

RESUMO

Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.


Assuntos
Antioxidantes , Doxorrubicina , Umbeliferonas , Ratos , Animais , Antioxidantes/farmacologia , Ratos Sprague-Dawley , Simulação de Acoplamento Molecular , Doxorrubicina/toxicidade , Estresse Oxidativo , Glutationa/metabolismo , Fígado/metabolismo , Antibióticos Antineoplásicos/farmacologia
19.
Mech Ageing Dev ; 219: 111931, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38554949

RESUMO

Impaired mitochondrial fatty acid ß-oxidation (FAO) plays a role in the onset of several age-associated diseases, including atherosclerosis. In the current work, we investigated the efficacies of mitochondria-targeted esculetin (Mito-Esc) and metformin in enhancing FAO in human aortic endothelial cells (HAECs), and its relevance in the delay of cellular senescence and age-associated atherosclerotic plaque formation in Apoe-/- mice. Chronic culturing of HAECs with either Mito-Esc or metformin increased oxygen consumption rates (OCR), and caused delay in senescence features. Conversely, etomoxir (CPT1 inhibitor) reversed Mito-Esc- and metformin-induced OCR, and caused premature endothelial senescence. Interestingly, Mito-Esc, unlike metformin, in the presence of etomoxir failed to preserve OCR. Thereby, underscoring Mito-Esc's exclusive reliance on FAO as an energy source. Mechanistically, chronic culturing of HAECs with either Mito-Esc or metformin led to AMPK activation, increased CPT1 activity, and acetyl-CoA levels along with a concomitant reduction in malonyl-CoA levels, and lipid accumulation. Similar results were observed in Apoe-/- mice aorta and liver tissue with a parallel reduction in age-associated atherosclerotic plaque formation and degeneration of liver with either Mito-Esc or metformin administration. Together, Mito-Esc and metformin by potentiating FAO, may have a role in the delay of cellular senescence by modulating mitochondrial function.


Assuntos
Aterosclerose , Senescência Celular , Células Endoteliais , Ácidos Graxos , Metformina , Mitocôndrias , Oxirredução , Umbeliferonas , Animais , Metformina/farmacologia , Umbeliferonas/farmacologia , Senescência Celular/efeitos dos fármacos , Camundongos , Oxirredução/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Ácidos Graxos/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/efeitos dos fármacos
20.
Anal Methods ; 16(15): 2256-2266, 2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38517319

RESUMO

A conductive nanocomposite consisting of heparin-stabilized gold nanoparticles embedded in graphene was prepared and characterized to develop an electrochemical sensor for the determination of esculetin in tea and jam samples. The gold nanoparticles were characterized by spectroscopic and microscopic techniques. The different proportions of graphene in the nanocomposite were evaluated and characterized by electrochemical practices. The heterostructure material on the glassy carbon electrode with esculetin showed π-π stacking interactions with an adsorption-controlled process. The voltammetric profile of esculetin using the proposed nanomaterial presented oxidation and reduction peaks at +0.61 and +0.58 V vs. Ag/AgCl, respectively, facilitating the electron transfer with esculetin through the transfer of two moles of protons and two moles of electrons per mole of esculetin. Using optimized conditions and square wave voltammetry, the calibration curve was obtained with two linear ranges, from 0.1 to 20.5 µmol L-1, with a detection limit of 43.0 nmol L-1. The electrochemical sensor showed satisfactory results for repeatability and stability, although interferences were observed in the presence of high concentrations of ascorbic acid or quercetin. The sensor was successfully applied in the determination of esculetin in samples of mulberry jam, white mulberry leaf tea, and white mulberry powder tea, presenting adequate recovery ranges. This directive provides valuable insights for the development of novel electrochemical sensors using heparin-based conductive nanomaterials with improved sensitivity and sensibility.


Assuntos
Grafite , Nanopartículas Metálicas , Toupeiras , Umbeliferonas , Animais , Grafite/química , Ouro/química , Heparina , Nanopartículas Metálicas/química , Chá
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