RESUMEN
Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2-3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond dermatological manifestations to impact joints and nails and is often associated with systemic disorders. Although traditional treatments provide relief, their use is limited by potential side effects and the chronic nature of the disease. This review aims to discuss the therapeutic potential of keratinocyte-targeting natural products in psoriasis and highlight their efficacy and safety in comparison with conventional treatments. This review comprehensively examines psoriasis pathogenesis within keratinocytes and the various related signaling pathways (such as JAK-STAT and NF-κB) and cytokines. It presents molecular targets such as high-mobility group box-1 (HMGB1), dual-specificity phosphatase-1 (DUSP1), and the aryl hydrocarbon receptor (AhR) for treating psoriasis. It evaluates the ability of natural compounds such as luteolin, piperine, and glycyrrhizin to modulate psoriasis-related pathways. Finally, it offers insights into alternative and sustainable treatment options with fewer side effects.
Asunto(s)
Productos Biológicos , Queratinocitos , Psoriasis , Transducción de Señal , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Receptores de Hidrocarburo de Aril/metabolismo , Terapia Molecular DirigidaRESUMEN
Blackberries (Rubus fruticosus), which are known to include a variety of bioactive substances, have been extensively studied for their antioxidant properties. Blackberries possess multiple health beneficial effects, including anti-inflammation, anti-atherosclerosis, anti-tumor and immunomodulatory activity. However, the potential biological effects and precise molecular mechanisms of the fermented extracts remain largely unexplored. In this research, we demonstrate the effect of blackberries fermented with Lactobacillus for addressing obesity. We investigated the effect of blackberries fermented by Lactobacillus on mice fed a high-fat (60% kcal) diet for 12 weeks. Fermented blackberry administration reduced the body weight and epididymal fat caused by a high-fat diet compared to the obese group. The triglyceride and total cholesterol, which are blood lipid indicators, and the levels of leptin, which is an insulin resistance indicator, were significantly increased in the obese group but were significantly decreased in the fermented blackberries-treated group. Additionally, the expression of adipogenesis marker proteins, such as CEBPα, PPAR-γ and SREBP-1, was significantly increased in the obese group, whereas it was decreased in the fermented blackberries-treated group. These results suggest that fermented blackberries have a protective effect against high-fat-diet-induced obesity by inhibiting adipogenesis and are a potential candidate for the treatment of obesity.
Asunto(s)
Adipogénesis , Fármacos Antiobesidad , Dieta Alta en Grasa , Fermentación , Lactobacillus plantarum , Obesidad , PPAR gamma , Rubus , Transducción de Señal , Animales , Adipogénesis/efectos de los fármacos , Rubus/química , Ratones , Obesidad/metabolismo , Fármacos Antiobesidad/farmacología , Masculino , Dieta Alta en Grasa/efectos adversos , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Ratones Endogámicos C57BL , Leptina/metabolismo , Leptina/sangre , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Triglicéridos/sangre , Triglicéridos/metabolismo , Peso Corporal/efectos de los fármacosRESUMEN
Excessive exposure to ultraviolet (UV) radiation from sunlight accelerates skin aging, leading to various clinical manifestations such as wrinkles, dryness, and loss of elasticity. This study investigated the protective effects of porcine placenta peptide (PPP) against UVB-induced skin photoaging. Female hairless SKH-1 mice were orally administered PPP for 12 weeks, followed by UVB irradiation. PPP significantly reduced wrinkle formation, improved skin moisture levels, and prevented collagen degradation. Mechanistically, PPP inhibited the expression of matrix metalloproteinases (MMPs) and upregulated collagen production. Moreover, PPP elevated hyaluronic acid levels, contributing to enhanced skin hydration. Additionally, PPP demonstrated antioxidant properties by increasing the expression of the antioxidant enzyme GPx-1, thereby reducing UVB-induced inflammation. Further molecular analysis revealed that PPP suppressed the activation of p38 MAP kinase and JNK signaling pathways, crucial mediators of UV-induced skin damage. These findings highlight the potential of porcine placental peptides as a natural and effective intervention against UVB-induced skin photoaging. The study provides valuable insights into the mechanisms underlying the protective effects of PPP, emphasizing its potential applications in skincare and anti-aging formulations.
Asunto(s)
Sistema de Señalización de MAP Quinasas , Envejecimiento de la Piel , Femenino , Embarazo , Ratones , Porcinos , Animales , Antioxidantes/farmacología , Deshidratación , Placenta , Transducción de Señal , Ratones Pelados , Péptidos/farmacología , ColágenoRESUMEN
Doxorubicin (DOX), an effective chemotherapeutic drug, causes cardiotoxicity in a cumulative and dose-dependent manner. The aim of this study is to investigate the effects of hot-water extract of Capsella bursa-pastoris (CBW) on DOX-induced cardiotoxicity (DICT). We utilized H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells to evaluate the effects of CBW on DOX-induced cell death. Superoxide dismutase (SOD) levels, reactive oxygen species (ROS) production, and oxygen consumption rate were measured in H9c2 cells. C57BL/6 mice were treated with DOX and CBW to assess their impact on various cardiac parameters. Human-induced pluripotent stem-cell-derived cardiomyocytes were also used to investigate DOX-induced electrophysiological changes and the potential ameliorative effects of CBW. UPLC-TQ/MS analysis identified seven flavonoids in CBW, with luteolin-7-O-glucoside and isoorientin as the major compounds. CBW inhibited DOX-induced death of H9c2 rat cardiomyocytes but did not affect DOX-induced death of MDA-MB-231 human breast cancer cells. CBW increased SOD levels in a dose-dependent manner, reducing ROS production and increasing the oxygen consumption rate in H9c2 cells. The heart rate, RR interval, QT, and ST prolongation remarkably recovered in C57BL/6 mice treated with the combination of DOX and CBW compared to those in mice treated with DOX alone. Administration of CBW with DOX effectively alleviated collagen accumulation, cell death in mouse heart tissues, and reduced the levels of creatinine kinase (CK) and lactate dehydrogenase (LDH) in serum. Furthermore, DOX-induced pathological electrophysiological features in human-induced pluripotent stem-cell-derived cardiomyocytes were ameliorated by CBW. CBW may prevent DICT by stabilizing SOD and scavenging ROS. The presence of flavonoids, particularly luteolin-7-O-glucoside and isoorientin, in CBW may contribute to its protective effects. These results suggest the potential of CBW as a traditional therapeutic option to mitigate DOX-induced cardiotoxicity.
Asunto(s)
Neoplasias de la Mama , Capsella , Ratas , Ratones , Animales , Humanos , Femenino , Antioxidantes/metabolismo , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Capsella/metabolismo , Estrés Oxidativo , Ratones Endogámicos C57BL , Doxorrubicina/toxicidad , Doxorrubicina/metabolismo , Miocitos Cardíacos/metabolismo , Flavonoides/farmacología , Superóxido Dismutasa/metabolismo , Neoplasias de la Mama/metabolismo , ApoptosisRESUMEN
We sought to investigate the effect of rose petal extract (RPE) on the proliferation, migration, and invasion of cancer cells. RPE significantly inhibited the growth of lung and colorectal cancer cell lines, with rapid suppression of A549 lung cancer cells at low concentrations. These effects occurred concomitantly with downregulation of the cell proliferation mediators PCNA, cyclin D1, and c-myc. In addition, RPE suppressed the migration and invasion of A549 cells by inhibiting the expression and activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and -9). We hypothesize that the suppressive activity of RPE against lung cancer cell proliferation and early metastasis occurs via the EGFR-MAPK and mTOR-Akt signaling pathways. These early results highlight the significant potency of RPE, particularly for lung cancer cells, and warrant further investigation.
Asunto(s)
Adenocarcinoma del Pulmón , Antineoplásicos Fitogénicos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Flores/química , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Extractos Vegetales , Rosa/química , Transducción de Señal/efectos de los fármacos , Células A549 , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
Red ginseng has been reported to elicit various therapeutic effects relevant to cancer, diabetes, neurodegenerative diseases, and inflammatory diseases. However, the effect of red ginseng on exercise endurance and skeletal muscle function remains unclear. Herein, we sought to investigate whether red ginseng could affect exercise endurance and examined its molecular mechanism. Mice were fed with red ginseng extract (RG) and undertook swimming exercises to determine the time to exhaustion. Animals fed with RG had significantly longer swimming endurance. RG treatment was also observed to enhance ATP production levels in myoblasts. RG increased mRNA expressions of mitochondrial biogenesis regulators, NRF-1, TFAM, and PGC-1α, which was accompanied by an elevation in mitochondrial DNA, suggesting an enhancement in mitochondrial energy-generating capacity. Importantly, RG treatment induced phosphorylation of p38 and AMPK and upregulated PGC1α expression in both myoblasts and in vivo muscle tissue. In addition, RG treatment also stimulated C2C12 myogenic differentiation. Our findings show that red ginseng improves exercise endurance, suggesting that it may have applications in supporting skeletal muscle function and exercise performance.
Asunto(s)
Mitocondrias/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Mioblastos/efectos de los fármacos , Panax/química , Resistencia Física/efectos de los fármacos , Extractos Vegetales/farmacología , Adenosina Trifosfato/biosíntesis , Animales , Diferenciación Celular/efectos de los fármacos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Ratones , Ratones Endogámicos ICR , Mitocondrias/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Factor Nuclear 1 de Respiración/genética , Factor Nuclear 1 de Respiración/metabolismo , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Resistencia Física/fisiología , Extractos Vegetales/aislamiento & purificación , Natación/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs.
Asunto(s)
Ácidos Cafeicos/farmacología , Fibroblastos/enzimología , Histona Acetiltransferasas/antagonistas & inhibidores , Metaloproteinasa 1 de la Matriz/genética , Alcohol Feniletílico/análogos & derivados , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Regulación de la Expresión Génica , Histona Acetiltransferasas/metabolismo , Humanos , Alcohol Feniletílico/farmacología , Piel/efectos de los fármacos , Piel/enzimología , Piel/metabolismo , Piel/efectos de la radiación , Rayos UltravioletaRESUMEN
Quercetin is a naturally occurring polyphenol present in various fruits and vegetables. The bioactive properties of quercetin include anti-oxidative, anti-cancer, anti-inflammatory, and anti-diabetic effects. However, the effect of quercetin on skin aging and the direct molecular targets responsible have remained largely unknown. Herein, we investigated the protective effect of quercetin against UV-mediated skin aging and the molecular mechanisms responsible. Treatment with quercetin suppressed UV-induced matrix metalloproteinase-1 (MMP-1) and cyclooxygenase-2 (COX-2) expression and prevented UV-mediated collagen degradation in human skin tissues. Quercetin exerted potent inhibitory effects towards UV-induced activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) activity. Further examination of the upstream signaling pathways revealed that quercetin can attenuate UV-mediated phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N terminal kinases (JNK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Kinase assays using purified protein demonstrated that quercetin can directly inhibit protein kinase C delta (PKCδ) and Janus kinase 2 (JAK2) kinase activity. Quercetin was observed to bind to PKCδ and JAK2 in pull-down assays. These findings suggest that quercetin can directly target PKCδ and JAK2 in the skin to elicit protective effects against UV-mediated skin aging and inflammation. Our results highlight the potential use of quercetin as a natural agent for anti-skin aging applications.
Asunto(s)
Antioxidantes/farmacología , Janus Quinasa 2/metabolismo , Proteína Quinasa C-delta/metabolismo , Quercetina/farmacología , Envejecimiento de la Piel , Piel/efectos de los fármacos , Línea Celular , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Metaloproteinasa 1 de la Matriz/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Piel/metabolismo , Piel/efectos de la radiación , Factor de Transcripción AP-1/metabolismo , Rayos Ultravioleta/efectos adversosRESUMEN
In this study, we investigated changes in the structural and immunological features of polysaccharides (S1-PLE0, S2-PLE0, and S3-PLE0) extracted from persimmon leaves at three different growth stages. Physicochemical analyses revealed that their chemical compositions, molecular weight distributions, and linkage types differed. High-performance size-exclusion chromatograms showed that the molecular weights of the polysaccharides increased during successive growth stages. In addition, seasonal variation of persimmon leaves affected the sugar compositions and glycosidic linkages in the polysaccharides. S2-PLE0 was composed of comparatively more galactose, arabinose, rhamnose, xylose, and galacturonic acid, showing the presence of ß-glucopyranoside linkages. Significant differences also occurred in their immunostimulatory effects on RAW264.7 macrophages, with respect to which their activities could be ordered as S2-PLE0 > S3-PLE0 > S1-PLE0. Evidently, S2-PLE0 showed the greatest immunostimulatory activity by enhancing the phagocytic capacity and promoting nitric oxide (NO) and cytokines secretion through the upregulation of their gene expression in macrophages. These results suggest that differences in the structural features of polysaccharides according to the different maturity of persimmon leaves might impact their immunostimulatory properties. The results also provide a basis for optimizing persimmon leaf cultivation strategies for food and medical uses of the polysaccharides.
Asunto(s)
Diospyros/química , Extractos Vegetales/química , Hojas de la Planta/química , Polisacáridos/química , Polisacáridos/inmunología , Adyuvantes Inmunológicos/química , Animales , Citocinas/metabolismo , Frutas/química , Ácidos Hexurónicos/química , Ratones , Peso Molecular , Células RAW 264.7 , Azúcares/químicaRESUMEN
The soy isoflavone daidzein is bioconverted to 7,8,4'-trihydroxyisoflavone (7,8,4'-THIF) by microorganisms. Here, we investigated the matrix metalloproteinase (MMP)-1 inhibitory properties of 7,8,4'-THIF that arise through the suppression of UVB-induced MMP-1 expression. 7,8,4'-THIF reduced UVB-induced MMP-1 expression at the transcriptional level in primary human dermal fibroblasts and inhibited UVB-induced transcriptional activity of AP-1, a major activator of MMP-1 expression. Additionally, it was observed that the mitogen-activated protein kinase (MAPK) pathway, a crucial signalling cascade for MMP-1 expression, was suppressed by 7,8,4'-THIF. Protein kinase C iota (PKCι) was suspected to be a direct target of 7,8,4'-THIF. The direct interaction between 7,8,4'-THIF and PKCι was confirmed using pull-down assays and immobilized metal ion affinity-based fluorescence polarization assays. Finally, we observed that 7,8,4'-THIF inhibited UVB-induced MMP-1 expression in a human skin equivalent model. Taken together, these results suggest that 7,8,4'-THIF, a bioconversion product of daidzein, suppresses UVB-induced MMP-1 expression.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Isoflavonas/farmacología , Metaloproteinasa 1 de la Matriz/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Envejecimiento de la Piel/efectos de los fármacos , Rayos UltravioletaRESUMEN
Opuntia humifusa is a type of cactus whose fruits have been used in folk medicine for the treatment of several diseases. In the present study, we aimed to determine whether O. humifusa fruit water extract (OHE) has inhibitory effects against solar ultraviolet (sUV)-induced matrix metalloproteinase-1 (MMP-1) expression. In ex vivo human skin, we found that OHE suppressed sUV radiation-induced MMP-1 expression. The inhibitory effect of OHE was confirmed in human dermal fibroblasts. OHE treatment reduced sUV-induced MMP-1 expression by suppressing reactive oxygen species (ROS) generation and phosphorylation of c-Jun, a component of transcription factor activator protein 1 (AP-1). On the other hand, OHE recovered the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and type 1 collagen production attenuated by sUV. As upstream signaling pathways for AP-1, MKK4-JNK, MEK-ERK, and MKK3/6-p38 phosphorylation were downregulated by OHE treatment. In addition, OHE exhibited DPPH radical scavenging activity. These findings demonstrate that OHE has a preventive effect against sUV-induced skin damage via suppression of pathways triggered by ROS.
Asunto(s)
Frutas/química , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Metaloproteinasa 1 de la Matriz/genética , Opuntia/química , Extractos Vegetales/farmacología , Luz Solar , Rayos Ultravioleta , Biomarcadores , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Cromatografía Líquida de Alta Presión , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Espectrometría de Masa por Ionización de Electrospray , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Ginsenosides are major pharmacologically active compounds present in ginseng (Panax ginseng). Among the ginsenosides, 20-O-ß-D-glucopyranosyl-20(S)-protopanaxadiol (GPPD) and ginsenoside Rb1 (Rb1) have previously been reported to exhibit anti-wrinkle effects. In this study, 20(S)-protopanaxadiol (20(S)-PPD), an aglycone derivative of the Rb1 metabolite was investigated for its anti-wrinkle benefit and compared to GPPD and Rb1. The anti-wrinkle effect of 20(S)-PPD during solar UV light was investigated using a human skin equivalent model and human keratinocytes. 20(S)-PPD attenuated solar UV-induced matrix metalloproteinase (MMP)-1 expression to a greater extent than GPPD and Rb1. 20(S)-PPD treatment modulated MMP-1 mRNA expression and the transcriptional activity of activator protein (AP)-1, a major transcription factor of MMP-1. Two upstream signaling pathways for AP-1, the MEK1/2-ERK1/2-p90RSK and MEK3/6-p38 pathways, were also suppressed. Taken together, these findings highlight the potential of 20(S)-PPD for further development as a preventative agent for sunlight-induced skin wrinkle. J. Cell. Biochem. 118: 3756-3764, 2017. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Queratinocitos/enzimología , Sistema de Señalización de MAP Quinasas , Metaloproteinasa 1 de la Matriz/biosíntesis , Sapogeninas/farmacología , Rayos Ultravioleta/efectos adversos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de la radiación , Ginsenósidos/química , Ginsenósidos/farmacología , Humanos , Queratinocitos/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Sapogeninas/químicaRESUMEN
We recently reported the immune-enhancing effects of a high-molecular-weight fraction (HMF) of CW in macrophages and immunosuppressed mice, and this effect was attributed to a crude polysaccharide. As polysaccharides may also have anti-inflammatory functions, we investigated the anti-inflammatory effects and related molecular mechanisms of a crude polysaccharide (HMFO) obtained from HMF of CW in mice with dextran sulfate sodium- (DSS-) induced colitis and in lipopolysaccharide-induced RAW 264.7 macrophages. HMFO ameliorated the pathological characteristics of colitis and significantly reduced production of proinflammatory cytokines in the serum. Histological analysis indicated that HMFO improved the signs of histological damage such as abnormal crypts, crypt loss, and inflammatory cell infiltration induced by DSS. In addition, HMFO inhibited iNOS and COX-2 protein expression, as well as phosphorylated NF-κB p65 levels in the colon tissue of mice with DSS-induced colitis. In macrophages, HMFO inhibited several cytokines and enzymes involved in inflammation such as prostaglandin E2, nitric oxide, tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 by attenuating nuclear factor-κB (NF-κB) and mitogen-activated protein kinases. HMFO attenuated inflammation both in vitro and in vivo, primarily by inhibiting NF-κB activation. Our findings indicate that HMFO is a promising remedy for treating inflammatory bowel diseases, such as colitis.
Asunto(s)
Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Cynanchum/química , Sulfato de Dextran/toxicidad , Macrófagos/metabolismo , Polisacáridos/química , Polisacáridos/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Ciclooxigenasa 2/metabolismo , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Ratones , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7RESUMEN
Targeting epigenetic changes in gene expression in cancer cells may offer new strategies for the development of selective cancer therapies. In the present study, we investigated coumestrol, a natural compound exhibiting broad anti-cancer effects against skin melanoma, lung cancer and colon cancer cell growth. Haspin kinase was identified as a direct target protein of coumestrol using kinase profiling analysis. Histone H3 is a direct substrate of haspin kinase. We observed haspin kinase overexpression as well as greater phosphorylation of histone H3 at threonine 3 (Thr-3) in the cancer cells compared to normal cells. Computer modeling using the Schrödinger Suite program identified the binding interface within the ATP binding site. These findings suggest that the anti-cancer effect of coumestrol is due to the direct targeting of haspin kinase. Coumestrol has considerable potential for further development as a novel anti-cancer agent.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Cumestrol/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Células A549 , Sitios de Unión , Línea Celular Tumoral , Células HCT116 , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Simulación del Acoplamiento Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de ProteínaRESUMEN
Bioactive natural compounds from plant-derived sources have received substantial interest due to their potential therapeutic and preventive effects toward various human diseases. Licorice (Glycyrrhiza), a frequently-used component in traditional oriental medicines, has been incorporated into recipes not only to enhance taste, but also to treat various conditions including inflammation, chronic fatigue syndrome, and even cancer. Dehydroglyasperin C (DGC) is a major isoflavone found in the root of licorice. In the present study, we investigated the cancer chemopreventive effect of DGC and the underlying molecular mechanisms involved, by analyzing its effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation and cyclooxygenase (COX)-2 expression in JB6 P+ mouse epidermal cells. DGC treatment attenuated TPA-induced activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) transcriptional activation, two major regulators of TPA-induced cell transformation, and COX-2 expression. TPA-induced phosphorylation of p38, JNK1/2 and Akt was also suppressed by DGC. Kinase assay data revealed that DGC inhibited the kinase activity of MKK4 and PI3K and this outcome was due to direct physical binding with DGC. Notably, DGC bound directly to MKK4 and PI3K in an ATP-competitive manner. Taken together, these results suggest that DGC exhibits cancer chemopreventive potential via its inhibitory effect on TPA-induced neoplastic cell transformation and COX-2 modulation through regulation of the MKK4 and PI3K pathways.
Asunto(s)
Benzopiranos/farmacología , Carcinógenos/toxicidad , Transformación Celular Neoplásica/efectos de los fármacos , MAP Quinasa Quinasa 4/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Acetato de Tetradecanoilforbol/toxicidad , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Ciclooxigenasa 2/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , FN-kappa B/metabolismo , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor de Transcripción AP-1/metabolismoRESUMEN
Dehydroglyasperin D (DHGA-D), a compound present in licorice, has been found to exhibit anti-obesity, antioxidant and anti-aldose reductase effects. However, the direct molecular mechanism and molecular targets of DHGA-D during skin inflammation remain unknown. In the present study, we investigated the effect of DHGA-D on inflammation and its mechanism of action on UVB-induced skin inflammation in HaCaT human keratinocytes and SKH-1 hairless mice. DHGA-D treatment strongly suppressed UVB-induced COX-2 expression, PGE2 generation and AP-1 transactivity in HaCaT cells without affecting cell viability. DHGA-D also inhibited phosphorylation of the mitogen-activated protein kinase kinase (MKK) 3/6/p38, MAPK/Elk-1, MKK4/c-Jun N-terminal kinase (JNK) 1/2/c-Jun/mitogen, and stress-activated protein kinase (MSK), whereas phosphorylation of the mixed-lineage kinase (MLK) 3 remained unaffected. Kinase and co-precipitation assays with DHGA-D Sepharose 4B beads showed that DHGA-D significantly suppressed MLK3 activity through direct binding to MLK3. Knockdown of MLK3 suppressed COX-2 expression as well as phosphorylation of MKK4/p38 and MKK3/6/JNK1/2 in HaCaT cells. Furthermore, Western blot assay and immunohistochemistry results showed that DHGA-D pre-treatment significantly inhibits UVB-induced COX-2 expression in vivo. Taken together, these results indicate that DHGA-D may be a promising anti-inflammatory agent that mediates suppression of both COX-2 expression and the MLK3 signalling pathway through direct binding and inhibition of MLK3.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Flavonoides/farmacología , Quinasas Quinasa Quinasa PAM/metabolismo , Rayos Ultravioleta , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Dinoprostona/biosíntesis , Femenino , Flavonoides/química , Técnicas de Silenciamiento del Gen , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/enzimología , Queratinocitos/efectos de la radiación , MAP Quinasa Quinasa 3/metabolismo , MAP Quinasa Quinasa 6/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Ratones Pelados , Fosforilación/efectos de los fármacos , Fosforilación/efectos de la radiación , Unión Proteica/efectos de los fármacos , Unión Proteica/efectos de la radiación , Factor de Transcripción AP-1/metabolismo , Proteina Quinasa Quinasa Quinasa 11 Activada por MitógenoRESUMEN
Non-small-cell lung cancer (NSCLC) is associated with diverse genetic alterations including mutation of epidermal growth factor receptor (EGFR). Isoliquiritigenin (ILQ), a chalcone derivative, possesses anticancer activities. In the present study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor (TKI)-sensitive and -resistant NSCLC cells and elucidated its underlying mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both TKI-sensitive and -resistant NSCLC cells. ILQ-induced apoptosis was associated with the cleavage of caspase-3 and poly-(ADP-ribose)-polymerase, increased expression of Bim, and reduced expression of Bcl-2. In vitro kinase assay results revealed that ILQ inhibited the catalytic activity of both wild type and double mutant (L858R/T790M) EGFR. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wild type or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells, and attenuated the kinase activity of Akt1 and ERK2 in vitro. ILQ directly interacted with both wild type and double-mutant EGFR in an ATP-competitive manner. A docking model study showed that ILQ formed two hydrogen bonds (Glu-762 and Met-793) with wild type EGFR and three hydrogen bonds (Lys-745, Met-793, and Asp-855) with mutant EGFR. ILQ attenuated the xenograft tumor growth of H1975 cells, which was associated with decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Chalconas/farmacología , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular , Receptores ErbB/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Mutación Missense , Células 3T3 NIH , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lung cancer is a leading cause of death worldwide and MET amplification is a major therapeutic limitation in acquired-resistance lung cancer. We hypothesized that butein, a phytochemical, can overcome gefitinib-induced resistance by targeting both EGFR and MET in non-small cell lung cancer (NSCLC). To investigate the ability of butein to target EGFR and MET, we used in silico docking, a library of natural compounds and kinase assays. The effects of butein on growth, induction of apoptosis and expression of EGFR/MET signaling targets were examined in HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) NSCLC cells. Results were confirmed in vivo by a HCC827 or HCC827GR cell xenograft mouse model, each treated with vehicle, butein or gefitinib. Butein inhibited phosphorylation and kinase activity of EGFR and MET as well as soft agar colony formation and decreased viability of HCC827 and HCC827GR cells. Butein increased apoptosis-related protein expression in these cells. Results were confirmed by co-treatment with inhibitors of EGFR/MET or double knock-down. Finally, xenograft study results showed that butein strongly suppressed HCC827 and HCC827GR tumor growth. Immunohistochemical data suggest that butein inhibited Ki-67 expression. These results indicate that butein has potent anticancer activity and targets both EGFR and MET in acquired-resistance NSCLC.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Chalconas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Quinazolinas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Receptores ErbB/metabolismo , Gefitinib , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Desnudos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4â µM and 12.2â µM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6â µM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cromonas/química , Cromonas/farmacología , Proteína Quinasa 8 Activada por Mitógenos/química , Factores Biológicos , Cromonas/metabolismo , Diseño de Fármacos , Flavonas , Humanos , Concentración 50 Inhibidora , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Rayos UltravioletaRESUMEN
Skin hydration is one of the primary aims of beauty and anti-aging treatments. Barley (Hordeum vulgare) and soybean (Glycine max) are major food crops, but can also be used as ingredients for the maintenance of skin health. We developed a natural product-based skin treatment using a barley and soybean formula (BS) incorporating yeast fermentation, and evaluated its skin hydration effects as a dietary supplement in a clinical study. Participants ingested a placebo- (n = 33) or BS- (3 g/day) containing drink (n = 32) for 8 weeks. A significant increase in hydration in the BS group as compared to the placebo group was observed on the faces of subjects after 4 and 8 weeks, and on the forearm after 4 weeks. Decreases in stratum corneum (SC) thickness were also observed on the face and forearm. BS enhanced hyaluronan (HA) and skin barrier function in vitro and reduced Hyal2 expression in human dermal fibroblasts (HDF). BS also recovered ultraviolet (UV) B-induced downregulation of HA in HaCaT cells. These results suggest that BS has promising potential for development as a health functional food to enhance skin health.