RESUMEN
Background: Colletotrichum fructicola is a predominant anthracnose species in Camellia oleifera, causing various adverse effects. Traditional intercropping Vernicia fordii with C. oleifera may enhance anthracnose resistance, but the mechanism remains elusive. Methods: We utilized UPLC-MS/MS and acid-base detection to identify the major antimicrobial alkaloid components in the V. fordii leaf extract. Subsequently, by adding different concentrations of V. fordii leaf extract for cultivating C. fructicola, with untreated C. fructicola as a control, we investigated the impact of the V. fordii leaf extract, cell wall integrity, cell membrane permeability, MDA, and ROS content changes. Additionally, analysis of key pathogenic genes of C. fructicola confirmed that the V. fordii leaf extract inhibits the growth of the fungus through gene regulation. Results: This study discovered the alkaloid composition of V. fordii leaf extract by UPLC-MS/MS and acid-base detection, such as trigonelline, stachydrine, betaine, and O-Phosphocholine. V. fordii leaf extract successfully penetrated C. fructicola mycelia, damaged cellular integrity, and increased ROS and MDA levels by 1.75 and 2.05 times respectively, thereby inhibiting C. fructicola proliferation. By analyzing the key pathogenic genes of C. fructicola, it was demonstrated that the antifungal function of V. fordii leaf extract depends mainly on the regulation of RAB7 and HAC1 gene expression. Therefore, this study elucidates the mechanism of V. fordii -C. oleifera intercropping in strengthening anthracnose resistance in C. oleifera, contributing to efficient C. oleifera cultivation.
Asunto(s)
Colletotrichum , Enfermedades de las Plantas , Extractos Vegetales , Hojas de la Planta , Especies Reactivas de Oxígeno , Extractos Vegetales/farmacología , Extractos Vegetales/química , Colletotrichum/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hojas de la Planta/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Camellia/química , Alcaloides/farmacología , Regulación hacia Abajo/efectos de los fármacos , Espectrometría de Masas en TándemRESUMEN
Extensive research has been conducted on Camellia oleifera Abel., a cultivar predominantly distributed in China, to investigate its phytochemical composition, owning to its potential as an edible oil crop. Pentacyclic triterpene saponins, as essential active constituents, play a significant role in contributing to the pharmacological effects of this cultivar. The saponins derived from C. oleifera (CoS) offer a diverse array of bioactivity benefits, including antineoplastic/bactericidal/inflammatory properties, cardiovascular protection, neuroprotection, as well as hypoglycemic and hypolipidemic effects. This review presents a comprehensive analysis of the isolation and pharmacological properties of CoS. Specially, we attempt to reveal the antitumor structure-activity relationship (SAR) of CoS-derived triterpenoids. The active substitution sites of CoS, namely, C-3, C-15, C-16, C-21, C-22, C-23, and C-28 pentacyclic triterpenoids, make it a unique and highly valuable substance with significant medicinal and culinary applications. As such, CoS can play a critical role in transforming people's lives, providing unique medicinal benefits, and contributing to the advancement of both medicine and cuisine.
Asunto(s)
Camellia , Saponinas , Triterpenos , Humanos , Triterpenos/química , Camellia/química , Relación Estructura-Actividad , Semillas/química , Saponinas/farmacología , Saponinas/químicaRESUMEN
Psoriasis is an inflammatory skin disease accompanied with chronic papulosquamous lesions and multiple comorbidities that considerably affect patients' quality of life. In order to develop an enhanced therapeutic strategy for psoriasis, 5-demethylnobiletin (5-DN), a kind of polymethoxyflavones (PMFs) with high anti-inflammatory activity, was delivered in vitro and in vivo by the nanocarrier of mesoporous silica nanoparticles (MSNs) both in the human keratinocytes HaCaT cell line and the mouse model with psoriasis-like lesions. The drug-loaded nanocarrier system (MSNs@5-DN) significantly improved the biocompatibility and bioavailability of 5-DN. Investigations at cell biological, histopathological, and molecular levels revealed the pharmacological mechanism of the drug delivery system, including the inhibition of inflammatory responses by downregulating the proinflammatory cytokine levels of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). The upregulation of antiinflammatory cytokine of transforming growth factor-ß1 (TGF-ß1) and microRNA-17-5p, a critical regulator of the PTEN/AKT pathway, was also observed. The psoriasis-like lesions were markedly ameliorated in the mouse models treated with MSNs@5-DN. The designed drug-loading system shows an enhanced therapeutic outcome for psoriasis-like lesion compared with free 5-DN. This study revealed the synergistic effect of functionalized MSNs loaded with PMFs on the clinical treatment of human psoriasis.
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MicroARNs , Nanopartículas , Psoriasis , Animales , Ratones , Humanos , Especies Reactivas de Oxígeno , Dióxido de Silicio/química , Calidad de Vida , Nanopartículas/química , Psoriasis/tratamiento farmacológico , Citocinas , Antiinflamatorios/farmacología , Concentración de Iones de Hidrógeno , PorosidadRESUMEN
In this study, Toxicodendron vernicifluum fisetin chelated silver nanoparticles (FT-AgNPs) with outstanding antioxidant and antimicrobial activities were constructed via self-assembly. To surprise, 0.6 wt% FT-AgNPs was compatibly dispersed into the 1:1 chitosan/pullulan (CS/PUL, CP) matrix. The hydrogen bonding and electrostatic interaction between FT-AgNPs and CP, slightly increased the CP thermal stability, and greatly enhanced the tensile strength to 61.2 MPa, water vapor permeability below 20 kg/m2â¢d. Furthermore, after treated with the composite hydrocolloid film (FT-AgNPs/CP), the reactive oxygen species level of the treated Aspergillus niger cells was significantly increased, and the membrane permeability was enhanced. It effectively slowed down the decay of litchi fruit induced by microbial infection under the storage at 25 °C (15 d of the 0.6 % FT-AgNPs/CP treatment vs 9 d of the control). In addition, 0.024 µg/kg Ag+ residual in lichi pulp verified the qualified safety of the application of the 0.6 % FT-AgNPs/CP.
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Quitosano , Litchi , Nanopartículas del Metal , Frutas , Plata/farmacología , Antibacterianos/farmacologíaRESUMEN
Inflammatory bowel disease (IBD) is a global chronic disease with a long duration and repeated relapse. Currently, there is still a lack of effective approaches to prevent IBD. Food-derived oryzanol (ORY) possesses extensive biological activities, such as ameliorating bowel diseases, antioxidation, and antiobesity. However, the mechanism of ORY in preventing colitis remains unclear. The present research aims to explore the potential mechanism of ORY in dextran sulfate sodium (DSS)-stimulated colitis in a rat model. The results showed that the symptoms of colitis were significantly improved with the administration of ORY. Mechanismly, the expression levels of Zonula occludens-1 (ZO-1), Claudin-1, Occludin, MUC2, and TFF3 were elevated through ORY treatment, suggesting that oral ORY relieved the degree of gut barrier damage of colitis rats. Meanwhile, 16S sequencing results found that ORY supplementation increased the abundances of Alloprevotella, Roseburia, Treponema, Muribaculaceae, and Ruminococcus, which are associated with the synthesis of short-chain fatty acids (SCFAs). Moreover, GC-MS results confirmed that ORY supplementation reversed the DSS-induced reduction of acetic acid, butyric acid, and total acid. Further research indicated that ORY intervention downregulated the TLR4/NF-κB/NLRP3 pathway, which is closely linked to the expression of proinflammatory cytokines and colon injury. Taken together, ORY ameliorates DSS-stimulated gut barrier damage and inflammatory responses via the gut microbiota-TLR4/NF-κB/NLRP3 signaling axis.
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Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Animales , Ratas , Ácido Butírico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/genética , Colon , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , FN-kappa B/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptor Toll-Like 4/genéticaRESUMEN
High-fat diet (HFD) is closely related to the formation of metabolic diseases. Studies have confirmed that neohesperidin dihydrochalcone (NHDC) possesses the biological activity of preventing glycolipid metabolism disorder. To explore the mechanism of its preventive activity against glucolipid metabolism disorder, HFD-treated rats were orally administered with NHDC for 12 weeks continuously. The results showed that, compared with the HFD group, the intervention of 40-80 mg/kg body weight of NHDC effectively downregulated the level of fasting blood glucose. Western blot analysis revealed that the treatment of NHDC alleviated the inhibitory effect of HFD on the expression of hepatic GLUT-4 and IRS-1. Further studies confirmed that NHDC reduced the degree of HFD-stimulated inflammation of ileum through the TLR4/MyD88/NF-κB signaling pathway. Moreover, ileum intestinal flora analysis showed that intragastric administration of NHDC reversed the change of Proteobacteria abundance and the Firmicutes/Bacteroidetes (F/B) ratio caused by HFD. At the generic level, NHDC promoted the relative abundance of Coprococcus, Bifidobacterium, Clostridium, Oscillospira, and [Eubacterium], while reducing the relative abundance of Defluviitalea and Prevotella. Taken together, these findings suggest that NHDC possesses the biological activity of improving HFD-induced glycolipid metabolism disorder.
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Hesperidina , Enfermedades Metabólicas , Animales , Chalconas , Dieta Alta en Grasa/efectos adversos , Glucolípidos , Hesperidina/análogos & derivados , Hesperidina/farmacología , Ratones , Ratones Endogámicos C57BL , RatasRESUMEN
Theasaponin derivatives, which are reported to exert antitumor activity, have been widely reported to exist in edible plants, including in the seed cake of Camellia oleifera (C.), which is extensively grown in south of China. The purpose of this study was to isolate new theasaponin derivatives from C. seed cake and explore their potential antitumor activity and their underlying molecular mechanism. In the present study, we first isolated and identified four theasaponin derivatives (compounds 1, 2, 3, and 4) from the total aglycone extract of the seed cake of Camellia oleifera by utilizing a combination of pre-acid-hydrolysis treatment and activity-guided isolation. Among them, compound 1 (C1) and compound 4 (C4) are newly discovered theasaponins that have not been reported before. The structures of these two new compounds were characterized based on comprehensive 1D and 2D NMR spectroscopy and high-resolution mass spectrometry, as well as data reported in the literature. Secondly, the cytotoxicity and antitumor property of the above four purified compounds were evaluated in selected typical tumor cell lines, Huh-7, HepG2, Hela, A549, and SGC7901, and the results showed that the ED50 value of C4 ranges from 1.5 to 11.3 µM, which is comparable to that of cisplatinum (CDDP) in these five cell lines, indicating that C4 has the most powerful antitumor activity among them. Finally, a preliminary mechanistic investigation was performed to uncover the molecular mechanism underlying the antitumor property of C4, and the results suggested that C4 may trigger apoptosis through the Bcl-2/Caspase-3 and JAK2/STAT3 pathways, and stimulate cell proliferation via the NF-κB/iNOS/COX-2 pathway. Moreover, it was surprising to find that C4 can inhibit the Nrf2/HO-1 pathway, which indicates that C4 has the potency to overcome the resistance to cancer drugs. Therefore, C1 and C4 are two newly identified theasaponin derivatives with antitumor activity from the seed cake of Camellia oleifera, and C4 is a promising antitumor candidate not only for its powerful antitumor activity, but also for its ability to function as an Nrf2 inhibitor to enhance the anticancer drug sensitivity.
RESUMEN
To valorise olive mill wastewater phenols (OPs) potentially applied in food preservation, a novel stable and regularly spherical OPs-AgNPs (Davg = 78 nm) were successfully assembled in aqueous solution under the optimized conditions (pH 8.0, 5 mM AgNO3, 35C and 30 min). The results of antimicrobial zone diameters indicated that 50 µg/mL of promising OPs-AgNPs presented excellent antimicrobial effects. Especially, the cell wall damages of E. coli ATCC 23,815 were caused when OPs-AgNPs concentration was exceeded its MIC (8.58 µg/mL). Also, a significant down-regulating of the Ca2+-ATPase activity in E. coli was revealed, and the intracellular Ca2+ concentrations were thus decreased from 12.5 to 1.35 µg/mL after a treatment for 3 h. The apoptosis level of E. coli was significantly increased more than the control (55.13% of OPs-AgNPs vs 9.90% of control). In sum, OPs exerts enhanced antimicrobial function via penetrating cell membrane and targeting Ca2+-ATPase after chelated with AgNPs.
RESUMEN
Studies have revealed that a novel anti-inflammatory mediatorâmaresin-1 (MaR1)âcan reduce the level of inflammatory factors. There is evidence that physical exercise (PE) promotes the biosynthesis of MaR1, leading to the prevention of rheumatoid arthritis (RA). Previously, we have proven that resveratrol can mitigate the formation of RA. Pterostilbene (Pte) is an analogue of resveratrol, but it is around four times more bioavailable. Hence, we hypothesize that Pte could be more effective in preventing RA, in particular, when accompanied by moderate PE. Based on this hypothesis, we explored the preventive effect of Pte combined with PE on a bovine type II collagen (BIIC)-stimulated rat RA model and its underlying molecular mechanism. Compared with the BIIC-stimulated group, the serum content of MaR1 with continuous intervention of Pte plus PE for 8 weeks was significantly increased to 46.3 pg/mL from 7.2 pg/mL in BIIC-treated alone. Besides, the variation in the relative expression levels of p-NF-κB and p-Akt was reversed with the administration of Pte plus PE. More importantly, the in vitro results confirmed that the treatment of Pte plus MaR1 inhibited proliferation and apoptosis and promoted the autophagy of the interleukin (IL)-1ß-stimulated primary rat synovial cells through the PI3K/Akt/NF-κB signal pathway. Collectively, the oral administration of Pte plus moderate PE helped to ameliorate the pathological process of RA by correcting the PI3K/Akt/NF-κB signal pathway.
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Artritis Experimental/prevención & control , Artritis Reumatoide/prevención & control , FN-kappa B , Proteínas Proto-Oncogénicas c-akt , Estilbenos/administración & dosificación , Animales , Bovinos , Colágeno , FN-kappa B/genética , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Condicionamiento Físico Animal , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de SeñalRESUMEN
Theaflavins (TFs), formed by the dimerization of green tea catechins during "fermentation" to prepare black tea, possess antioxidant and anti-inflammatory effects. Reported efficacious effects of black tea (â¼2% of TFs) or related products come from catechins unless TFs are assayed. The present study aimed to target the preparation of black tea extract (BTE) enriched with theaflavin mono- and digallates majorly from dry tea leaves in aqueous media versus traditional fermentation of fresh leaves. We further investigated the protective function of the produced BTE on rat liver and kidney injury induced by CCl4 and its underlying molecular mechanisms. The results showed that BTE suppressed the activation level of hepatic stellate cells (HSCs), and the secretion of collagen was induced by CCl4. The relative expression levels of TGF-ß, p-ERK1/ERK1, p-ERK2/ERK2, p-Smad1/Smad1, and p-Smad2/Smad2 were reduced to 56, 68, 56, 44, and 32%, respectively, compared with those of CCl4-treated rats. Therefore, BTE enriched with TFs prevented rat hepatic fibrosis through the TGF-ß/Smad/ERK signaling pathway and kidney injury by inhibiting the expression of TGF-ß and proinflammatory cytokines in rats. We predict the broad application of TFs and related products because of their strong antioxidant and inhibitory effects on chronic inflammation.
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Antioxidantes , Té , Animales , Biflavonoides , Catequina , Riñón , Hígado , Extractos Vegetales , RatasRESUMEN
Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A-1F, in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B, connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC50 value of 0.23 ~ 0.39 µM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
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Antineoplásicos/farmacología , Diseño de Fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Talidomida/farmacología , Triterpenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Talidomida/química , Triterpenos/químicaRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease characterized by long duration and repeated relapse. This study explored the preventive effect of tangeretin (TAN) and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF) on RA, and the underlying molecular mechanism based on a rat model stimulated by bovine type II collagen (BIIC). After the intervention of TAN or 5-HPMF (TAN/5-HPMF) for 5 weeks, the RA lesions and autophagy levels of the synovial tissue were significantly reduced, and the ROS content and HO-1 expression level were down-regulated simultaneously. The relative expression levels of p-AKT and p-mTOR were down-regulated after TAN/5-HPMF feeding. Meanwhile, the relative expression level of p62 increased by more than two-fold for TAN/5-HPMF treated rats at 200 mg/kg BW comparing with those in BIIC group. Results of immunofluorescence staining and Western blotting further confirmed that TAN/5-HPMF treatment reduced BIIC-induced conversion from LC3I to LC3II. Observations under transmission electron microscope also demonstrated that the autophagy level was reduced upon TAN/5-HPMF intervention. Collectively, these results revealed that TAN and 5-HPMF prevented the pathological process of BIIC-stimulated arthritis through inhibiting the autophagy of synovial cells, achieved via the ROS-AKT/mTOR signal axis. Thus, our findings confirmed the protective potential of TAN and 5-HPMF for RA disease.
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Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Flavonas/administración & dosificación , Sustancias Protectoras/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/efectos de los fármacos , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Autofagia/efectos de los fármacos , Bovinos , Proliferación Celular/efectos de los fármacos , Colágeno Tipo II/efectos adversos , Femenino , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Both as a food and an herbal plant, Polygonum multiflorum (PM) has long been used in food and prescriptions for several centuries in Southeast Asia. trans-2,3,5,4'-tetrahydroxystilbene 2-O-ß-d-glucopyranoside (trans-THSG) is one of the major compounds derived from PM and has been reported to exhibit multiple biological activities such as antioxidation and anti-obesity activities among others. The current study was aimed at investigating the effects of trans-THSG on liver fibrosis and renal injury in a carbon tetrachloride (CCl4) induced rodent model via oral feeding. Research results have demonstrated that administration of trans-THSG (100 and 300 mg kg-1) significantly ameliorated liver fibrosis, manifested by reduced expression of desmin and α-smooth muscle actin (α-SMA) plus collagen deposition. Specifically, treatment with trans-THSG effectively decreased the levels of transforming growth factor-ß (TGF-ß) and reduced the phosphorylation of Smad1/2 (p-Smad1/2) and extracellular signal-regulated kinases 1/2 (p-ERK1/2). Furthermore, we found that trans-THSG significantly down-regulated CCl4-induced excessive collagen secretion and increased the levels of desmin, MMP2 and MMP9 in rat liver tissues, suggesting that trans-THSG prevents liver fibrosis by attenuating the activation of hepatic stellate cells (HSCs) through the inhibition of Smad and ERK signaling pathways. Hence, the present findings demonstrate that trans-THSG is an effective antifibrotic agent in protecting liver from CCl4-induced toxicity.
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Medicamentos Herbarios Chinos/administración & dosificación , Fallopia multiflora/química , Glucósidos/administración & dosificación , Enfermedades Renales/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Estilbenos/administración & dosificación , Animales , Tetracloruro de Carbono/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/lesiones , Riñón/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Hígado/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Polymethoxyflavones (PMFs) are widely found in Citri Reticulatae Pericarpium (CRP) and have been investigated with a broad spectrum of biological activities as well as health promoting properties. However, separation of the PMFs from a complex sample, especially preparative separation of these PMFs with high purity, remains challenging. In the present study, an efficient method based on supercritical fluid extraction (SFE) and continuous high-speed counter-current chromatography (HSCCC) has been developed for extracting and preparative purification PMFs from CRP. Various experimental conditions were investigated to optimize the SFE and HSCCC processes. Under these optimized conditions, crude extract of CRP (extract I) was obtained with a maximum contents of nobiletin, 3,5,6,7,8,3',4'-heptamethoxyflavone and tangeretin. Further extraction of crude extract I was carried out to obtain crude extract II, which was further isolated and purified by HSCCC. It was worth mentioned that continuous injection HSCCC process were realized without lost of separation efficiency, which allowed for multiple purification cycles and therefore saved a lot of labor and time. Furthermore, high-performance liquid chromatography (HPLC) was employed to analyze the fractions separated by HSCCC, which revealed that the purities of the three PMFs were all above 98%. The structures of the three PMFs were identified by LC-MS and 1H NMR spectroscopy.
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Cromatografía con Fluido Supercrítico/métodos , Citrus/química , Distribución en Contracorriente/métodos , Flavonas/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Dióxido de Carbono/química , Flavonas/química , Espectroscopía de Resonancia Magnética , Extractos Vegetales/químicaRESUMEN
Dietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways.
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Flavonas/administración & dosificación , Quinasas de Proteína Quinasa Activadas por Mitógenos/inmunología , Factor de Transcripción ReIA/inmunología , Enfermedades Vasculares/prevención & control , Animales , Aorta/efectos de los fármacos , Aorta/inmunología , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hígado/efectos de los fármacos , Hígado/inmunología , Masculino , Metilaminas/efectos adversos , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Ratas , Ratas Sprague-Dawley , Factor de Transcripción ReIA/genética , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/genética , Enfermedades Vasculares/inmunologíaRESUMEN
Successful isolation of polymethoxyflavones (PMFs) from citrus peels has led to numerous evaluations of PMFs in a broad spectrum of biological activities, such as inhibition of chronic inflammation, cancer prevention and anti-atherogenic properties. Recent reports associated with the health promoting properties of PMFs in citrus fruits have dramatically increased. However, the limiting factor in animal and human study of PMFs is still the supply of pure PMFs, such as tangeretin, nobiletin, sinensetin and 3,5,6,7,3',4'-hexamethoxyflavone. Herein, we introduce the newly developed efficient separation method using high-performance counter-current chromatography (HPCCC) in isolating multiple pure single PMFs simultaneously in one cycle process. With the smallest preparation loop on the semi-preparative HPCCC instrument, the optimized solvent system of hexanes/ethyl acetate/methanol/water resulted in the isolation of pure sinensetin, tangeretin, nobiletin, 3,5,6,7,3',4'-hexamethoxyflavone, 5,6,7,4'-tetramethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone directly from crude sweet orange peel extract in one cycle of separation process by HPCCC in the mode of reverse phase. The purity of each of the six isolated PMFs is greater than 96.6% analyzed by high-performance liquid chromatography and proton nuclear magnetic resonance. Scale-up and high purity of individual PMFs can be separated by using a large separation loop in preparative HPCCC model. The renovated HPCCC methodology can be practically used in natural product isolation and consequent biological property evaluation.
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Cromatografía Líquida de Alta Presión/métodos , Citrus sinensis/química , Flavonas/química , Citrus sinensis/metabolismo , Distribución en Contracorriente , Flavonas/aislamiento & purificación , Flavonoides/química , Flavonoides/aislamiento & purificación , Humanos , Extractos Vegetales/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Polyphenols derived from green tea have been reported to have a wide range of profound functions. Tea catechins, including epicatechin, epigallocatechin (EGC), epicatechin-3- O-gallate (ECG), and epigallocatechin-3- O-gallate (EGCG), are considered as the major bioactive polyphenols in tea. The present study was designed to elucidate the potential antifibrogenic role of three abundant tea catechins (ECG, EGC, and EGCG) in a CCl4-induced fibrotic rat and their underlying molecular mechanisms. Tea catechins, especially groups of ECG, EGC, and EGCG, effectively induced several beneficial alterations of liver injury markers, oxidative status, and liver histology. Furthermore, catechins ameliorated liver fibrosis, as evidenced by the reduced expression of desmin, α-smooth muscle actin, transforming growth factor ß (TGF-ß), and downstream ERK1/2 and Smad1/2 phosphorylation. The most significant inhibitory effect on those proteins was observed in ECG (300 mg/kg) and EGCG (300 mg/kg) groups. In addition, catechins conferred their protective role by downregulating the proinflammation cytokines TGF-ß, tumor necrosis factor α, and interleukin 17. It is postulated that tea catechins, particularly ECG and EGCG, are potential therapeutic candidates in antifibrotic therapy.
Asunto(s)
Catequina/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Animales , Camellia sinensis/química , Catequina/química , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Fosforilación/efectos de los fármacos , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley , Proteína Smad1/genética , Proteína Smad2/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting joints and is featured by chronic synovial inflammation and angiogenesis. We employed a bovine type-II collagen (BIIC)-induced Sprague-Dawley rat arthritis model and an in vitro RA model based on interleukin (IL)-1ß-stimulated rat synovial cells (RSC-364) to explore the preventive effect of resveratrol on RA and the underlying mechanisms. We found that resveratrol ameliorated BIIC-elicited synovitis and RA-related pathological hallmarks such as inflammatory cell infiltration and angiogenesis in the synovial tissue. Also, BIIC-stimulated rats displayed increased serum levels of proinflammatory cytokines and reactive oxygen species (ROS), as manifested by elevated serum malonaldehyde contents combined with reduced superoxide dismutase activity. It is noteworthy that resveratrol abolished BIIC-induced ROS and inflammation, confirming the antioxidative and anti-inflammatory actions of resveratrol in the context of RA. Furthermore, immunoblotting indicated that resveratrol downregulated the increase in the levels of hypoxia-inducible factor-1α (HIF-1α) and that of the activated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in IL-1ß-stimulated RSC-364 cells. Moreover, we observed that resveratrol-treated RSC-364 cells displayed both G0/G1 cell-cycle arrest and enhanced levels of apoptosis. Altogether, the present evidence established the preventive role of resveratrol in RA progression. Mechanistically, resveratrol inhibits MAPK signaling pathways, likely by reducing ROS accumulation, to suppress the inflammatory response and cell proliferation and to provoke cell apoptosis in the synovial tissue, along with mitigation of HIF-1α-mediated angiogenesis. Thus resveratrol appears to hold great potential for clinical translation as a novel RA therapeutic.
Asunto(s)
Artritis Reumatoide/prevención & control , Inflamación/prevención & control , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Neovascularización Patológica/prevención & control , Especies Reactivas de Oxígeno/sangre , Resveratrol/administración & dosificación , Animales , Antiinflamatorios , Antioxidantes , Artritis Reumatoide/inducido químicamente , Línea Celular , Proliferación Celular/efectos de los fármacos , Colágeno Tipo II/administración & dosificación , Citocinas/sangre , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inflamación/sangre , Interleucina-1beta/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Membrana Sinovial/irrigación sanguínea , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/patología , Sinovitis/patología , Sinovitis/prevención & controlRESUMEN
Macrophages can polarize into two different states (M1 and M2), which play contrasting roles during pathogenesis or tissue damage. M1 polarized macrophages produce pro-inflammatory cytokines and mediators resulting in inflammation, while M2 macrophages have an anti-inflammatory effect. Secretion of appropriate cytokines and chemokines from macrophages can lead to the modification of the microenvironment for bridging innate and adaptive immune responses. Increasing evidence suggests that polarized macrophages are pivotal for disease progression, and the regulation of macrophage polarization may provide a new approach in therapeutic treatment of inflammation-related diseases, including cancer, obesity and metabolic diseases, fibrosis in organs, brain damage and neuron injuries, and colorectal disease. Polarized macrophages affect the microenvironment by secreting cytokines and chemokines while cytokines or mediators that are produced by resident cells or tissues may also influence macrophages behavior. The interplay of macrophages and other cells can affect disease progression, and therefore, understanding the activation of macrophages and the interaction between polarized macrophages and disease progression is imperative prior to taking therapeutic or preventive actions. Manipulation of macrophages can be an entry point for disease improvement, but the mechanism and potential must be understood. In this review, some advanced studies regarding the role of macrophages in different diseases, potential mechanisms involved, and intervention of drugs or phytochemicals, which are effective on macrophage polarization, will be discussed.
Asunto(s)
Inflamación/complicaciones , Inflamación/prevención & control , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Fitoquímicos/farmacología , Animales , Polaridad Celular/efectos de los fármacos , Citocinas/inmunología , Humanos , Inflamación/inmunología , Macrófagos/citología , Macrófagos/inmunología , Fitoquímicos/uso terapéuticoRESUMEN
Psoriasis is a chronic and benign proliferative skin disease. Flavonoids in chenpi (aged tangerine peel) from tangerine ( Citrus reticulate Blanco), such as nobiletin (Nob), tangeretin, and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF), possess anti-inflammation and regulation of immune activity among others. In this study, psoriasis-like skin lesions were induced by 12- O-tetradecanoylphorbol-13-acetate (TPA), and the preventive effect of Nob and 5-HPMF on psoriasis-like skin lesions was evaluated. Results showed that skin lesions were dramatically reduced by Nob and 5-HPMF. Levels of cytokines, including interleukin (IL)-1ß, IL-17, IL-4, IL-6, tumor necrosis factor-α, and interferon-γ, were also reduced after Nob and 5-HPMF treatment. The expression levels of p-ERK1/2 and p-p38 mitogen-activated protein kinase (MAPK) in the TPA group were 5.3, 4.8, and 5.7 but downregulated to 2.7, 2.9, and 2.3 in the Nob group and 2.4, 2.7, and 1.2 in the 5-HPMF group, respectively ( p ≤ 0.05). The expression of transcription factors Ki-67 and proliferating cell nuclear antigen (PCNA) and the differentiation of CD4+ T cells were reduced by downregulating the expression of the MAPK signaling pathways. The expression levels in TPA, Nob, and 5-HPMF groups were 0.649 ± 0.094, 0.218 ± 0.034, and 0.193 ± 0.042 for Ki-67 and 0.753 ± 0.114, 0.315 ± 0.094, and 0.294 ± 0.035 for PCNA, respectively. Moreover, 5-HPMF showed stronger reduction activity in the prevention of psoriasis than Nob, indicating that the 5-hydroxyl group facilitated the suppression of psoriasis.