RESUMO
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
Assuntos
Antineoplásicos , Ácidos Cafeicos , Álcool Feniletílico , Humanos , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/síntese química , Células HeLa , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Álcool Feniletílico/química , Álcool Feniletílico/síntese química , Água/química , Linhagem Celular Tumoral , Amidas/farmacologia , Amidas/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
Caffeic acid (CA), a hydrophobic polyphenol with various pharmacological activities, exhibits a low aqueous solubility and sensitivity to light. In order to improve its chemical properties and overcome the limits in its application, the compound was loaded in P123 micelles (MCs) prepared using two polymer concentrations (10 and 20% w/w, MC10 and MC20). The micelles were characterised in terms of the size distribution, zeta potential, drug encapsulation efficiency, rheology, and cumulative drug release. Micellar formulations exhibited sizes in the range of 11.70 and 17.70 nm and a good polydispersion, indicating the formation of relatively small-sized micelles, which is favourable for drug delivery applications. Additionally, the stability and antioxidant profiles of the free CA and the CA loaded in micelles were studied. The results obtained on the free CA showed the formation of photodegradation products endowed with higher DPPH scavenging activity with respect to the pure compound. Instead, it was found that the incorporation of CA into the micelles significantly increased its solubility and decreased the photodegradation rate. Overall, the results indicate the successful formation of P123 micelles loaded with CA, with promising characteristics such as a small size, good encapsulation efficiency, sustained release profile, and improved light stability. These findings suggest the potentiality of these micelles as a delivery system for CA, thus enhancing its bioavailability.
Assuntos
Ácidos Cafeicos , Micelas , Polímeros , Solubilidade , Ácidos Cafeicos/química , Polímeros/química , Antioxidantes/química , Estabilidade de Medicamentos , Liberação Controlada de Fármacos , Composição de Medicamentos , Tamanho da Partícula , Portadores de Fármacos/químicaRESUMO
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
Assuntos
Analgésicos , Anticonvulsivantes , Ácidos Cafeicos , Cinamatos , Convulsões , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Camundongos , Masculino , Convulsões/tratamento farmacológico , Cinamatos/farmacologia , Cinamatos/química , Cinamatos/síntese química , Cinamatos/uso terapêutico , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Ácidos Cafeicos/síntese química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Peptídeos/uso terapêutico , Simulação de Acoplamento Molecular , IsomerismoRESUMO
The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, Rg, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.
Assuntos
Neoplasias do Colo , Histona Desacetilase 2 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Humanos , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Propionatos/química , Propionatos/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Ligação de Hidrogênio , Teoria da Densidade FuncionalRESUMO
Corni fructus (CF) is always subjected to wine processing before prescription in clinic, for an enhancing effect of nourishing liver and kidney. While, the underlying mechanism for this processing on CF remains obscure. In this study, a sensitive ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method combined multi-dimensional analyses was established to monitor chemical characterizations of raw and wine-processed CF (WCF) and hence reveal the effects and underlying mechanism of wine processing on CF. As indicated, a total of 216 compounds were tentatively identified, including 98 structurally complex and variable home/hetero-polymers, that were composed of iridoid glucosides, gallic acids, caffeic acid and/or 5-HMF. Interestingly, 53 of these compounds probably characterized potential novel, including 35 iridoid glucosides or their dimers, 9 iridoid glucoside-gallic acid dimers, 7 gallic acids derivatives and 2 gallic acid-caffeic acid dimers, which provides ideas for natural product researchers. Meanwhile, the multi-dimensional analyses including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and linear regression analysis were used to explore the differences between CF and WCF. The results showed that 23 compounds as chemical markers greatly contributing to the distinction were screened out, and 3 of which (7α/ß-O-ethyl-morroniside, gallic acid and 5-HMF) in WCF indicated an increasing trend in intensities in relative to those in CF. Additionally, linear regression analysis showed that in WCF 53 compounds exhibited an increasing in intensities, while 132 ones did a decreasing trend, compared with those in CF. As our investigation demonstrated, acetal reaction of morroniside, ester hydrolysis in different organic acid derivatives as well as glycoside bond cleavage during wine processing probably resulted in the distinctions. The findings of this study provide a further understanding of the effect and mechanism of wine processing on CF.
Assuntos
Cornus , Análise de Componente Principal , Espectrometria de Massas em Tandem , Vinho , Vinho/análise , Cromatografia Líquida de Alta Pressão/métodos , Cornus/química , Espectrometria de Massas em Tandem/métodos , Ácidos Cafeicos/análise , Ácidos Cafeicos/química , Ácido Gálico/química , Ácido Gálico/análise , Frutas/química , Análise dos Mínimos QuadradosRESUMO
Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population and, to date, there is no approved drug therapy for this condition. Individuals with type 2 diabetes mellitus (T2DM) are at a significantly elevated risk of developing NAFLD, underscoring the urgency of identifying effective NAFLD treatments for T2DM patients. Salvianolic acid A (SAA) is a naturally occurring phenolic acid that is an important component of the water-soluble constituents isolated from the roots of Salvia miltiorrhiza Bunge. SAA has been demonstrated to possess anti-inflammatory and antioxidant stress properties. Nevertheless, its potential in ameliorating diabetes-associated NAFLD has not yet been fully elucidated. In this study, diabetic ApoE-/- mice were employed to establish a NAFLD model via a Western diet. Following this, they were treated with different doses of SAA (10 mg/kg, 20 mg/kg) via gavage. The study demonstrated a marked improvement in liver injury, lipid accumulation, inflammation, and the pro-fibrotic phenotype after the administration of SAA. Additionally, RNA-seq analysis indicated that the primary pathway by which SAA alleviates diabetes-induced NAFLD involves the cascade pathways of lipid metabolism. Furthermore, SAA was found to be effective in the inhibition of lipid accumulation, mitochondrial dysfunction and ferroptosis. A functional enrichment analysis of RNA-seq data revealed that SAA treatment modulates the AMPK pathway and IGFBP-1. Further experimental results demonstrated that SAA is capable of inhibiting lipid accumulation through the activation of the AMPK pathway and IGFBP-1.
Assuntos
Proteínas Quinases Ativadas por AMP , Ácidos Cafeicos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Lactatos , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Camundongos , Lactatos/farmacologia , Lactatos/uso terapêutico , Lactatos/química , Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos KnockoutRESUMO
In the search for pharmaceutically active compounds from natural products, it is crucial and challenging to develop separation or purification methods that target not only structurally similar compounds but also those with specific pharmaceutical functions. The adsorption-based method is widely employed in this field and holds potential for this application, given the diverse range of functional monomers that can be chosen based on structural or functional selectivity. In this work, an imidazolium ionic liquid (IL) modified paper membrane was synthesized via microwave reaction. Caffeic acid (CA), with potential interactions with imidazolium IL and a representative component of phenolic acids in Taraxaci Herba, was chosen as a target compound. After optimization of synthesis and extraction parameters, the resulting extraction membrane could be used to quantitatively analyze CA at ng/ml level, and to extract CA's analogues from the sample matrix. Cheminformatics confirmed the presence of structural and functional similarity among these extracted compounds. This study offers a novel approach to preparing a readily synthesized extraction membrane capable of isolating compounds with structural and functional analogies, as well as developing a membrane solid-phase extraction-based analytical method for natural products.
Assuntos
Ácidos Cafeicos , Imidazóis , Líquidos Iônicos , Membranas Artificiais , Ácidos Cafeicos/química , Ácidos Cafeicos/isolamento & purificação , Líquidos Iônicos/química , Imidazóis/química , Papel , Extração em Fase Sólida/métodos , Limite de Detecção , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Reprodutibilidade dos TestesRESUMO
Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.
Assuntos
Ácidos Cafeicos , Osteoclastos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/síntese química , Animais , Relação Estrutura-Atividade , Camundongos , Estrutura Molecular , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Osteoporose/tratamento farmacológico , Reabsorção Óssea/tratamento farmacológico , Células RAW 264.7 , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese químicaRESUMO
This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase-substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase-substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture.
Assuntos
Ácidos Cafeicos , Proliferação de Células , Dopamina , Lacase , Melaninas , Melanócitos , Poliestirenos , Humanos , Lacase/metabolismo , Melanócitos/metabolismo , Melanócitos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Poliestirenos/química , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Dopamina/metabolismo , Melaninas/metabolismo , Adesão Celular/efeitos dos fármacos , Levodopa/farmacologia , Levodopa/metabolismo , Levodopa/química , Propriedades de Superfície , Linhagem Celular Tumoral , Células-Tronco de Carcinoma Embrionário/metabolismo , Células-Tronco de Carcinoma Embrionário/efeitos dos fármacosRESUMO
2-(2-Phenylethyl)chromones (PECs) are the primary constituents responsible for the promising pharmacological activities and unique fragrance of agarwood. However, the O-methyltransferases (OMTs) involved in the formation of diverse methylated PECs have not been reported. In this study, we identified one Mg2+-dependent caffeoyl-CoA-OMT subfamily enzyme (AsOMT1) and three caffeic acid-OMT subfamily enzymes (AsOMT2-4) from NaCl-treated Aquilaria sinensis calli. AsOMT1 not only converts caffeoyl-CoA to feruloyl-CoA but also performs nonregioselective methylation at either the 6-OH or 7-OH position of 6,7-dihydroxy-PEC. On the other hand, AsOMT2-4 preferentially utilizes PECs as substrates to produce structurally diverse methylated PECs. Additionally, AsOMT2-4 also accepts nonPEC-type substrates such as caffeic acid and apigenin to generate methylated products. Protein structure prediction and site-directed mutagenesis revealed that residues of L313 and I318 in AsOMT3, as well as S292 and F313 in AsOMT4 determine the distinct regioselectivity of these two OMTs toward apigenin. These findings provide important biochemical evidence of the remarkable structural diversity of PECs in agarwood.
Assuntos
Metiltransferases , Proteínas de Plantas , Thymelaeaceae , Metiltransferases/genética , Metiltransferases/química , Metiltransferases/metabolismo , Thymelaeaceae/enzimologia , Thymelaeaceae/química , Thymelaeaceae/genética , Proteínas de Plantas/genética , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Madeira/química , Especificidade por Substrato , Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Metilação , FlavonoidesRESUMO
Phenolic acids still gain significant attention due to their potential antimicrobial and cytotoxic properties. In this study, we have investigated the antimicrobial of six phenolic acids, namely chlorogenic, caffeic, p-coumaric, rosmarinic, gallic and tannic acids in the concentration range 0.5-500 µM, against Escherichia coli and Lactobacillus rhamnosus. The antimicrobial activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Additionally, the cytotoxic effects of these phenolic acids on two cancer cell lines, the colorectal adenocarcinoma Caco-2 cell line and Dukes' type C colorectal adenocarcinoma DLD-1 cell line was examined. To further understand the molecular properties of these phenolic acids, quantum chemical calculations were performed using the Gaussian 09W program. Parameters such as ionization potential, electron affinity, electronegativity, chemical hardness, chemical softness, dipole moment, and electrophilicity index were obtained. The lipophilicity properties represented by logP parameter was also discussed. This study provides a comprehensive evaluation of the antimicrobial and cytotoxic activity of six phenolic acids, compounds deliberately selected due to their chemical structure. They are derivatives of benzoic or cinnamic acids with the increasing number of hydroxyl groups in the aromatic ring. The integration of experimental and computational methodologies provides a knowledge of the molecular characteristics of bioactive compounds and partial explanation of the relationship between the molecular structure and biological properties. This knowledge aids in guiding the development of bioactive components for use in dietary supplements, functional foods and pharmaceutical drugs.
Assuntos
Hidroxibenzoatos , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Testes de Sensibilidade Microbiana , Ácido Gálico/química , Ácido Gálico/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologiaRESUMO
Herein, we describe the synthesis of the proposed structure of the caffeamide alkaloid bassiamide A. The amide moiety of bassiamide A was readily formed via an amide coupling reaction between caffeic acid and the known N-(3-aminopropyl)-3-methylbutanamide. However, the spectral data of the synthesized bassiamide A did not agree with that of a previous study. The structure of the synthesized bassiamide A was confirmed using combined two-dimensional NMR analysis. Extended analyses of the bioactivity of the synthesized bassiamide A revealed its efficacy in protecting dopaminergic neurons from MPP+-induced neurotoxicity in Caenorhabditis elegans. Additionally, treatment with bassiamide A notably ameliorated the impaired food-sensing ability and locomotion of Caenorhabditis elegans, suggesting a protective effect on the functionality of dopaminergic neurons.
Assuntos
Caenorhabditis elegans , Ácidos Cafeicos , Fármacos Neuroprotetores , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/isolamento & purificação , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/síntese química , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Estrutura Molecular , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Relação Estrutura-Atividade , 1-Metil-4-fenilpiridínioRESUMO
Dendrimers have emerged as an important group of nanoparticles to transport drugs, DNA, or RNA into target cells in cancer and other diseases. Various functional modifications can be imposed on dendrimers to increase the efficacy and specificity in delivering their cargo to the target cells and decrease their toxicity. In the present work, we evaluated the potential of carbosilane polyphenolic dendrimers modified with caffeic acid (CA) and polyethylene glycol (PEG) to deliver proapoptotic Mcl-1 and Bcl-2 siRNAs to A549 cancer cells. Dendrimers formed stable complexes with siRNAs as assessed by transmission electron microscopy and gel electrophoresis. Modification of dendrimers with PEG reduced the size and the zeta potential of dendrimer/siRNA complexes. The presence of PEG caused a red shift of the CD spectrum, and this effect was the more pronounced, the higher the dendrimer/siRNA ratio was. The nanocomplexes were internalized by A549. All studied dendrimer/siRNA formulations inhibited tumor cell migration and adhesion and caused an increase in the population of early apoptotic cells. Among four tested dendrimers, the polyphenolic compound containing two caffeic acid moieties complexed with siRNA demonstrated the lowest polydispersity index and showed an excellent transfection profile. In conclusion, this dendrimer are a promising candidate for the delivery of siRNA into cancer cells in further in vivo studies.
Assuntos
Apoptose , Dendrímeros , Polietilenoglicóis , Polifenóis , RNA Interferente Pequeno , Humanos , Dendrímeros/química , Dendrímeros/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , Células A549 , Apoptose/efeitos dos fármacos , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/administração & dosagem , Polietilenoglicóis/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/administração & dosagem , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Silanos/química , Transfecção/métodos , Linhagem Celular TumoralRESUMO
Chronic nonhealing wounds are serious complications of diabetes with a high morbidity, and they can lead to disability or death. Conventional drug therapy is ineffective for diabetic wound healing because of the complex environment of diabetic wounds and the depth of drug penetration. Here, we developed a self-healing, dual-layer, drug-carrying microneedle (SDDMN) for diabetic wound healing. This SDDMN can realize transdermal drug delivery and broad-spectrum sterilization without drug resistance and meets the multiple needs of the diabetic wound healing process. Quaternary ammonium chitosan cografted with dihydrocaffeic acid (Da) and l-arginine and oxidized hyaluronic acid-dopamine are the main parts of the self-healing hydrogel patch. Methacrylated poly(vinyl alcohol) (methacrylated PVA) and phenylboronic acid (PBA) were used as the main part of the MN, and gallium porphyrin modified with 3-amino-1,2 propanediol (POGa) and insulin were encapsulated at its tip. Under hyperglycaemic conditions, the PBA moiety in the MN reversibly formed a glucose-boronic acid complex that promoted the rapid release of POGa and insulin. POGa is disguised as hemoglobin through a Trojan-horse strategy, which is then taken up by bacteria, allowing it to target bacteria and infected lesions. Based on the synergistic properties of these components, SDDMN-POGa patches exhibited an excellent biocompatibility, slow drug release, and antimicrobial properties. Thus, these patches provide a potential therapeutic approach for the treatment of diabetic wounds.
Assuntos
Ácidos Borônicos , Diabetes Mellitus Experimental , Glucose , Cicatrização , Cicatrização/efeitos dos fármacos , Animais , Ácidos Borônicos/química , Glucose/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Agulhas , Insulina/administração & dosagem , Camundongos , Quitosana/química , Álcool de Polivinil/química , Ratos , Ácido Hialurônico/química , Masculino , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Sistemas de Liberação de Medicamentos , Ratos Sprague-Dawley , Humanos , Hidrogéis/químicaRESUMO
The copigmentation effect between malvidin-3-O-glucoside and caffeic acid was comprehensive inquiry on the model wine solution, theoretical simulation and real wine. Thermodynamic parameters were determined by UV/Visible spectroscopy and Isothermal titration calorimetry (ITC). Theoretical data were obtained employing a dispersion-corrected density functional approach. The effects in real wines were investigated by adding the caffeic acid during different fermentation periods. Results shown that the copigmentation reaction between caffeic acid and malvidin-3-O-glucoside is a spontaneous exothermic reaction driven by hydrogen bonding and dispersions forces. Computations show that the polyhydroxyl sugar moiety and phenolic hydroxyl groups are the key active sites. The addition of caffeic acid in post-alcohol fermentation samples evidences an improving color characteristics in the wine.
Assuntos
Antocianinas , Ácidos Cafeicos , Cor , Glucosídeos , Termodinâmica , Vinho , Ácidos Cafeicos/química , Vinho/análise , Glucosídeos/química , Antocianinas/química , Ligação de Hidrogênio , Estrutura Molecular , FermentaçãoRESUMO
Caffeic acid phenethyl ester (CAPE) is a naturally occurring phenolic compound with various biological activities. However, poor water solubility and storage stability limit its application. In this context, sorghum peptides were used to encapsulate CAPE. Sorghum peptides could self-assemble into regularly spherical nanoparticles (SPNs) by hydrophobic interaction and hydrogen bonds. Solubility of encapsulated CAPE was greatly increased, with 9.44 times higher than unencapsulated CAPE in water. Moreover, the storage stability of CAPE in aqueous solution was significantly improved by SPNs encapsulation. In vitro release study indicated that SPNs were able to delay CAPE release during the process of gastrointestinal digestion. Besides, fluorescence quenching analysis showed that a static quenching existed between SPNs and CAPE. The interaction between CAPE and SPNs occurred spontaneously, mainly driven by hydrophobic interactions. The above results suggested that SPNs encapsulation was an effective approach to improve the water solubility and storage stability of CAPE.
Assuntos
Ácidos Cafeicos , Nanopartículas , Peptídeos , Álcool Feniletílico , Solubilidade , Sorghum , Ácidos Cafeicos/química , Sorghum/química , Peptídeos/química , Nanopartículas/química , Álcool Feniletílico/química , Álcool Feniletílico/análogos & derivados , Interações Hidrofóbicas e Hidrofílicas , Estabilidade de Medicamentos , Composição de Medicamentos , Ligação de Hidrogênio , Tamanho da PartículaRESUMO
Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein-protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 µM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3ß/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3ß/Nrf2 signaling pathway.
Assuntos
Ácidos Cafeicos , Hemorragia Cerebral , Ferroptose , Lactatos , Fármacos Neuroprotetores , Animais , Ferroptose/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ratos , Lactatos/farmacologia , Lactatos/química , Lactatos/uso terapêutico , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Fator 2 Relacionado a NF-E2/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.
Assuntos
Antifúngicos , Ácidos Cafeicos , Imidazóis , Antifúngicos/farmacologia , Antifúngicos/química , Imidazóis/química , Imidazóis/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Sais/química , Teoria Quântica , Modelos Moleculares , Testes de Sensibilidade Microbiana , Cristalografia por Raios X , Ligação de Hidrogênio , Eletricidade EstáticaRESUMO
In order to broaden the application range of squash polysaccharide (WESP/SWESP) and caffeic acid (CAA) and improve the quality of potato starch (PS) products, the effects of WESP/SWESP and CAA on the gelatinization, rheology, thermodynamics, microstructure and in vitro digestion of PS were investigated. Meanwhile, the synergistic effect of WESP/SWESP and CAA on PS was further analyzed. Differently, due to WESP and SWESP had different monosaccharide composition and structure, they had different effects on the system. Pasting properties results showed that the presence of WESP/SWESP and CAA significantly reduced the peak viscosity, trough viscosity, breakdown viscosity and final viscosity of PS, especially under the combined action. In rheological tests, all sample gels belonged to the pseudoplastic fluids and weak gel system (tan δ < 1). Besides, thermodynamic properties revealed that WESP/SWESP and CAA synergistic effect had better retrogradation delay effect. In the ternary system, WESP/SWESP, CAA and PS can form a new network structure and improve the stability of the gel system. In addition, the results of infrared spectroscopy, Raman spectroscopy, x-ray diffraction and scanning electron microscopy exhibited that the ternary system can promote the accumulation and winding of the spiral structure of PS chain, and make the structure of PS gel network more orderly and stable. Furthermore, compared with PS gel, the ternary system had lower RDS and higher SDS and RS content, suggesting that the addition of WESP/SWESP and CAA at the same time was more conducive to reducing the hydrolysis rate of PS. This work revealed the interaction between WESP/SWESP, CAA and PS, which improved the physicochemical and digestive properties of PS. It will provide a theoretical basis for improving the quality of potato starch-related products and developing functional foods.
Assuntos
Ácidos Cafeicos , Polissacarídeos , Reologia , Solanum tuberosum , Amido , Água , Ácidos Cafeicos/química , Solanum tuberosum/química , Amido/química , Polissacarídeos/química , Água/química , Viscosidade , Termodinâmica , Temperatura , Géis/químicaRESUMO
Chicoric acid (CA) is a natural nutrient found in plants, showcasing diverse biological activities, including anti-inflammatory and antioxidant properties. Despite its valuable properties, CA faces limitations in bioavailability and susceptibility to oxidative breakdown during utilization. Previous research introduced synthesized dihydrocaffeic acid grafted chitosan self-assembled nanomicelles (DA-g-CS), demonstrating its potential to enhance CA absorption. This study aims to investigate the pharmacokinetics, tissue distribution, and antioxidant activity of both CA and DA-g-CS loaded CA (DA-g-CS/CA) in broilers. An IPEC-J2 cell model was established and evaluated to delve deeper into the transport mechanism and antioxidant potential. The in vivo pharmacokinetic analysis in broilers highlighted a substantial difference: the maximum plasma concentration (Cmax) of DA-g-CS/CA exceeded CA by 2.6-fold, yielding a notable increased relative bioavailability to 214%. This evidence underscores the significant enhancement in CA's oral absorption, facilitated by DA-g-CS. The collective evaluation outcomes affirm the successful development of the cell model, indicating its suitability for drug transporter experiments. The findings from the intestinal transit analysis revealed that both CA and DA-g-CS/CA underwent passive entry into IPEC-J2 cells. Notably, the cellular uptake rate of DA-g-CS loaded with CA was significantly amplified, reaching 2.1 times higher than that of CA alone. Intracellular transport mechanisms involved microtubules, lysosomes, and the endoplasmic reticulum, with an additional pathway involving the endoplasmic reticulum observed specifically for DA-g-CS/CA, distinguishing it from CA. Moreover, the results from both in vivo and in vitro antioxidant assessments highlight the potent antioxidant activity of DA-g-CS/CA, showcasing its efficacy in preventing and treating cellular damage induced by oxidative stress. In summary, these findings underscore the significant enhancement of CA's efficacy facilitated by DA-g-CS, establishing a robust theoretical foundation for the prospective application of CA within livestock and poultry farming.