RESUMEN
Agarobiose (AB; d-galactose-ß-1,4-AHG), produced by one-step acid hydrolysis of agarose of red seaweed, is considered a promising cosmetic ingredient due to its skin-moisturizing activity. In this study, the use of AB as a cosmetic ingredient was found to be hampered due to its instability at high temperature and alkaline pH. Therefore, to increase the chemical stability of AB, we devised a novel process to synthesize ethyl-agarobioside (ethyl-AB) from the acid-catalyzed alcoholysis of agarose. This process mimics the generation of ethyl α-glucoside and glyceryl α-glucoside by alcoholysis in the presence of ethanol and glycerol during the traditional Japanese sake-brewing process. Ethyl-AB also showed in vitro skin-moisturizing activity similar to that of AB, but showed higher thermal and pH stability than AB. This is the first report of ethyl-AB, a novel compound produced from red seaweed, as a functional cosmetic ingredient with high chemical stability.
Asunto(s)
Bebidas Alcohólicas , Algas Marinas , Sefarosa/química , Fermentación , Algas Marinas/química , GlucósidosRESUMEN
Numerous health benefits of diets containing red seaweeds or agar-derived sugar mixtures produced by enzymatic or acid hydrolysis of agar have been reported. However, among various agar-derived sugars, the key components that confer health-beneficial effects, such as prebiotic and anti-colon cancer activities, remain unclear. Here, we prepared various agar-derived sugars by multiple enzymatic reactions using an endo-type and an exo-type of ß-agarase and a neoagarobiose hydrolase and tested their in vitro prebiotic and anti-colon cancer activities. Among various agar-derived sugars, agarotriose exhibited prebiotic activity that was verified based on the fermentability of agarotriose by probiotic bifidobacteria. Furthermore, we demonstrated the anti-colon cancer activity of 3,6-anhydro-l-galactose, which significantly inhibited the proliferation of human colon cancer cells and induced their apoptosis. Our results provide crucial information regarding the key compounds derived from red seaweeds that confer beneficial health effects, including prebiotic and anti-colon cancer activities, to the host.
Asunto(s)
Agar/metabolismo , Antineoplásicos/farmacología , Bifidobacterium/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Galactosa/análogos & derivados , Prebióticos , Rhodophyta/metabolismo , Algas Marinas/metabolismo , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Fermentación , Galactosa/aislamiento & purificación , Galactosa/farmacología , Células HCT116 , Humanos , HidrólisisRESUMEN
3,6-Anhydro-l-galactose (l-AHG) is a bioactive sugar that is a major component of agarose. Recently, l-AHG was reported to have anti-melanogenic potential in human epidermal melanocytes (HEMs) and B16F10 melanoma cells; however, its underlying molecular mechanisms remain unknown. At noncytotoxic concentrations, l-AHG has been shown to inhibit alpha-melanocyte-stimulating hormone-induced melanin synthesis in various cell models, including HEMs, melan-a cells, and B16F10 cells. Although l-AHG did not inhibit tyrosinase activity in vitro, reverse transcription-polymerase chain reaction results demonstrated that the anti-melanogenic effect of l-AHG was mediated by transcriptional repression of melanogenesis-related genes, including tyrosinase, tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and microphthalmia-associated transcription factor (MITF) in HEMs. Western blot analysis showed that l-AHG effectively attenuated α-melanocyte-stimulating hormone-induced melanogenic proteins by inhibiting cyclic adenosine monophosphate/cyclic adenosine monophosphate-dependent protein kinase, mitogen-activated protein kinase, and Akt signaling pathways in HEMs. Topical application of l-AHG significantly ameliorated melanin production in a 3D pigmented human skin model. Collectively, these results suggest that l-AHG could be utilized as novel cosmetic compounds with skin-whitening efficacy.
Asunto(s)
Galactosa/análogos & derivados , Melaninas/metabolismo , Melanocitos/citología , alfa-MSH/metabolismo , Administración Tópica , Animales , Línea Celular Tumoral , Supervivencia Celular , Células Cultivadas , Galactosa/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Oxidorreductasas Intramoleculares/genética , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Factor de Transcripción Asociado a Microftalmía/genética , Modelos Biológicos , Oxidorreductasas/genéticaRESUMEN
Marine algae are considered to be an abundant sources of bioactive compounds with cosmeceutical potential. Recently, a great deal of interest has focused on the health-promoting effects of marine bioactive compounds. Carbohydrates are the major and abundant constituent of marine algae and have been utilized in cosmetic formulations, as moisturizing and thickening agents for example. In addition, marine carbohydrates have been suggested as promising bioactive biomaterials for their various properties beneficial to skin, including antioxidant, anti-melanogenic and skin anti-aging properties. Therefore, marine algae carbohydrates have potential skin health benefits for value-added cosmeceutical applications. The present review focuses on the various biological capacities and potential skin health benefits of bioactive marine carbohydrates.
Asunto(s)
Organismos Acuáticos , Carbohidratos/farmacología , Cosmecéuticos/farmacología , Microalgas/química , Algas Marinas/química , Piel/efectos de los fármacos , Animales , Cosmecéuticos/química , Cosmecéuticos/aislamiento & purificación , HumanosRESUMEN
3,6-Anhydro-l-galactose (AHG), a major monomeric constituent of red macroalgae (Rhodophyta), was recently reported to possess skin whitening activity. Moreover, AHG-containing oligosaccharides, such as agarooligosaccharides (AOSs) and neoagarooligosaccharides (NAOSs), have various physiological activities, including anti-inflammatory, antioxidant, and skin moisturizing effects. In this study, AHG and NAOSs were produced from agarose by enzymatic reactions catalyzed by an endo-type ß-agarase, an exo-type ß-agarase, and a neoagarobiose hydrolase. In a cell proliferation assay, AHG, AOSs, and NAOSs at 12.5, 25, and 50 µg/mL concentrations did not exhibit cytotoxicity toward murine B16 melanoma cells or human epidermal melanocytes. In an in vitro skin whitening activity assay of AHG, AOSs, and NAOSs at 50 µg/mL, AHG showed the highest skin whitening activity in both murine B16 melanoma cells and human epidermal melanocytes; this activity was mediated by the inhibition of melanogenesis. Neoagarotetraose and neoagarohexaose also exhibited in vitro skin whitening activity, whereas neoagarobiose and AOSs with degrees of polymerization of 3 (agarotriose), 5 (agaropentaose), and 7 (agaroheptaose) did not. Therefore, AHG is responsible for the skin whitening activity of agar-derived sugars, and the structural differences among the AHG-containing oligosaccharides may be responsible for their different skin whitening activities.
Asunto(s)
Galactosa/análogos & derivados , Galactósidos/farmacología , Oligosacáridos/farmacología , Rhodophyta/química , Algas Marinas/química , Preparaciones para Aclaramiento de la Piel/farmacología , Pigmentación de la Piel/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Disacaridasas/química , Células Epidérmicas , Epidermis/efectos de los fármacos , Epidermis/fisiología , Galactosa/química , Galactosa/farmacología , Galactósidos/química , Glicósido Hidrolasas/química , Humanos , Melaninas/biosíntesis , Melanocitos , Ratones , Oligosacáridos/química , Sefarosa/química , Preparaciones para Aclaramiento de la Piel/química , Relación Estructura-ActividadRESUMEN
Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling.
Asunto(s)
Chlorophyta/química , Glycine max/química , Extractos Vegetales/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Administración Oral , Animales , Senescencia Celular/efectos de los fármacos , Senescencia Celular/efectos de la radiación , Colágeno/metabolismo , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Epidermis/efectos de la radiación , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Ratones , Ratones Desnudos , Extractos Vegetales/administración & dosificación , Proteolisis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Ginsenoside F1 (GF1) is a metabolite produced by hydrolysis of the ginsenoside Re and Rg1 in Panax ginseng. According to various studies, high amounts of ginseng components are absorbed in the metabolized form, which are key constituents responsible for the biological effects of P. ginseng. Recently, GF1 was reported to have beneficial effects on skin. However, there has not been a sound understanding of its antimelanogenic effect and underlying molecular mechanisms. In this study, GF1 reduced α-melanocyte-stimulating hormone-induced melanin secretion in B16F10 cell culture media by 60%. However, it did not suppress intracellular melanin levels, tyrosinase activity and expression. Immunofluorescence assay showed that GF1 had no effect on melanosome transport, but significantly induced dendrite retraction. Pull-down assay demonstrated that GF1 primarily modulates the Rho family GTPases resulting in dendrite retraction. Collectively, these data suggest that GF1 could act as a potent skin-whitening agent.
Asunto(s)
Dendritas/metabolismo , Ginsenósidos/química , Hiperpigmentación/metabolismo , Melanoma/metabolismo , Neoplasias Cutáneas/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , AMP Cíclico/metabolismo , GTP Fosfohidrolasas/química , Hidrólisis , Melaninas/química , Melaninas/metabolismo , Melanocitos/citología , Melanoma Experimental , Melanosomas/metabolismo , Ratones , Neuropéptidos/metabolismo , Transducción de Señal , Piel/metabolismo , alfa-MSH/química , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Various health effects have been attributed to the ginsenoside metabolite 20-O-ß-D-glucopyranosyl-20(S)-protopanaxadiol (GPD); however, its effect on ultraviolet (UV)-induced matrix metalloproteinase (MMP)-1 expression and the mechanism underlying this effect are unknown. We examined the inhibitory effect of GPD on UV-induced MMP-1 expression and its mechanisms in human dermal fibroblasts (HDFs). GPD attenuated UV-induced MMP-1 expression in HDFs and suppressed the UV-induced phosphorylation of mammalian target of rapamycin (mTOR) and p70(S6K) without inhibiting the activity of phosphatidylinositol 3-kinase and Akt, which are well-known upstream kinases of mTOR. GPD augmented the phosphorylation of liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK), which are inhibitors of mTOR, to a greater extent than UV treatment alone. Similar to GPD, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranosyl 5'-monophosphate (AICAR), an activator of AMPK, augmented UV-induced AMPK phosphorylation to a greater extent than UV treatment alone, resulting in the inhibition of MMP-1 expression. AICAR also decreased the phosphorylation of mTOR and p70(S6K). However, compound C, an antagonist of AMPK, increased MMP-1 expression. In HDF cells with AMPK knock-down using shRNA, MMP-1 expression was increased. These results indicate that AMPK activation plays a key role in MMP-1 suppression. Additionally, the cAMP-dependent protein kinase (PKA) inhibitor, H-89, antagonized GPD-mediated MMP-1 suppression via the inhibition of LKB1. Our results suggest that the suppressive activity of GPD on UV-induced MMP-1 expression is due to the activation of AMPK as a downstream of the PKA-LKB1 pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP/biosíntesis , Ginsenósidos/farmacología , Metaloproteinasa 1 de la Matriz/biosíntesis , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP/genética , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Línea Celular , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fibroblastos , Humanos , Isoquinolinas/farmacología , Oxazinas/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Ribonucleótidos/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Sulfonamidas/farmacología , Rayos UltravioletaRESUMEN
3,6-Anhydro-L-galactose (L-AHG) constitutes 50% of agarose, which is the main component of red macroalgae. No information is currently available on the mass production, metabolic fate, or physiological effects of L-AHG. Here, agarose was converted to L-AHG in the following three steps: pre-hydrolysis of agarose into agaro-oligosaccharides by using acetic acid, hydrolysis of the agaro-oligosaccharides into neoagarobiose by an exo-agarase, and hydrolysis of neoagarobiose into L-AHG and galactose by a neoagarobiose hydrolase. After these three steps, L-AHG was purified by adsorption and gel permeation chromatographies. The final product obtained was 95.6% pure L-AHG at a final yield of 4.0% based on the initial agarose. In a cell proliferation assay, L-AHG at a concentration of 100 or 200 µg/ mL did not exhibit any significant cytotoxicity. In a skin whitening assay, 100 µg/ mL of L-AHG showed significantly lower melanin production compared to arbutin. L-AHG at 100 and 200 µg/ mL showed strong anti-inflammatory activity, indicating the significant suppression of nitrite production. This is the first report on the production of high-purity L-AHG and its physiological activities.
Asunto(s)
Ácido Acético/metabolismo , Antiinflamatorios/farmacología , Disacaridasas/metabolismo , Galactosa/análogos & derivados , Glicósido Hidrolasas/metabolismo , Sefarosa/metabolismo , Preparaciones para Aclaramiento de la Piel/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/metabolismo , Antiinflamatorios/toxicidad , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Galactosa/aislamiento & purificación , Galactosa/metabolismo , Galactosa/farmacología , Galactosa/toxicidad , Hidrólisis , Macrófagos/efectos de los fármacos , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Ratones , Preparaciones para Aclaramiento de la Piel/aislamiento & purificación , Preparaciones para Aclaramiento de la Piel/metabolismo , Preparaciones para Aclaramiento de la Piel/toxicidadRESUMEN
Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Glycine max/metabolismo , Isoflavonas/química , Isoflavonas/farmacología , MAP Quinasa Quinasa 4/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Neoplasias Inducidas por Radiación/prevención & control , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Cutáneas/prevención & control , Animales , Ciclooxigenasa 2/metabolismo , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal , Rayos UltravioletaRESUMEN
Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease. Environmental sanitization, modern lifestyles, advanced medicines, ethnic origins, host genetics and immune systems, mucosal barrier function, and the gut microbiota have been delineated to explain how they cause mucosal inflammation. However, the pathogenesis of IBD and its therapeutic targets remain elusive. Recent studies have highlighted the importance of the human gut microbiota in health and disease, suggesting that the pathogenesis of IBD is highly associated with imbalances of the gut microbiota or alterations of epithelial barrier function in the gastrointestinal (GI) tract. Moreover, diet-induced alterations of the gut microbiota in the GI tract modulate immune responses and perturb metabolic homeostasis. This review summarizes recent findings on IBD and its association with diet-induced changes in the gut microbiota; furthermore, it discusses how diets can modulate host gut microbes and immune systems, potentiating the impact of personalized diets on therapeutic targets for IBD.
RESUMEN
Licorice (Glycyrrhiza) has been used as preventive and therapeutic material for hyperpigmentation disorders. Previously, we isolated noble compounds including dehydroglyasperin C (DGC), dehydroglyasperin D (DGD) and isoangustone A (IAA) from licorice hexane/ethanol extracts. However, their anti-melanogenic effects and underlying molecular mechanisms are unknown. The present study compared effects of DGC, DGD and IAA on pigmentation in melan-a melanocytes and human epidermal melanocytes (HEMn). DGD exerted the most excellent anti-melanogenic effect, followed by DGC and IAA at non-cytotoxic concentrations. In addition, DGD significantly inhibited tyrosinase activity in vitro cell-free system and cell system. Western blot result showed that DGD decreased expression of microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein-1 (TRP-1) in melan-a cells and HEMn cells. DGD induced phosphorylation of MITF, ERK and Akt signal pathway promoting MITF degradation system. However, DGD did not influence p38 and cAMP-dependent protein kinase (PKA)/CREB signal pathway in melan-a cells. These result indicated that DGD inhibited melanogenesis not only direct regulation of tyrosinase but also modulating intracellular signaling related with MITF level. Collectively, these results suggested a protective role for DGD against melanogenesis.
Asunto(s)
Melaninas , Factor de Transcripción Asociado a Microftalmía , Flavonoides , Humanos , Antígeno MART-1 , Melanocitos , Monofenol MonooxigenasaRESUMEN
Food-derived bioactive peptides (BPs) have received considerable attention as postbiotics for human gut health. Here we used a genomics-based semirational approach to expand the postbiotic potential of collagen peptides (CPs) produced from probiotic fermentation. In silico digestion revealed distinct BPs embedded in fish collagen in a protease-dependent manner. Anaerobic digestion of collagen by representative Lactobacillaceae species revealed differential substrate utilization and collagen degradation patterns. Nanoliquid chromatography-mass spectrometry analysis of CPs showed that each species exhibited different cleavage patterns and unique peptide profiles. Remarkably, the 1-10 kDa CPs produced by Lacticaseibacillus paracasei showed agonistic activities toward G protein-coupled receptor 35 (GPR35). These CPs could repair intestinal epithelium through the GPR35-mediated extracellular signal-regulated protein kinase (ERK) 1/2 signaling pathway, suggesting that probiotic-aided collagen hydrolysates can serve as postbiotics for host-microbe interactions. Therefore, this study provides an effective strategy for the rapid screening of CPs for gut health in the gastrointestinal tract.
Asunto(s)
Colágeno , Lactobacillaceae , Animales , Antioxidantes/química , Colágeno/química , Genómica , Humanos , Lactobacillaceae/metabolismo , Péptidos/químicaRESUMEN
The gut microbiome influences the development of allergic diseases during early childhood. However, there is a lack of comprehensive understanding of microbiome-host crosstalk. Here, we analyzed the influence of gut microbiome dynamics in early childhood on atopic dermatitis (AD) and the potential interactions between host and microbiome that control this homeostasis. We analyzed the gut microbiome in 346 fecal samples (6-36 months; 112 non-AD, 110 mild AD, and 124 moderate to severe AD) from the Longitudinal Cohort for Childhood Origin of Asthma and Allergic Disease birth cohort. The microbiome-host interactions were analyzed in animal and in vitro cell assays. Although the gut microbiome maturated with age in both AD and non-AD groups, its development was disordered in the AD group. Disordered colonization of short-chain fatty acids (SCFA) producers along with age led to abnormal SCFA production and increased IgE levels. A butyrate deficiency and downregulation of GPR109A and PPAR-γ genes were detected in AD-induced mice. Insufficient butyrate decreases the oxygen consumption rate of host cells, which can release oxygen to the gut and perturb the gut microbiome. The disordered gut microbiome development could aggravate balanced microbiome-host interactions, including immune responses during early childhood with AD.
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Dermatitis Atópica , Microbioma Gastrointestinal , Microbiota , Animales , Butiratos , Ácidos Grasos Volátiles , Microbioma Gastrointestinal/genética , Humanos , RatonesRESUMEN
Epidemiological studies suggest that coffee consumption reduces the risk of cancers, including colon cancer, but the molecular mechanisms and target(s) underlying the chemopreventive effects of coffee and its active ingredient(s) remain unknown. Based on serving size or daily units, coffee contains larger amounts of phenolic phytochemicals than tea or red wine. Coffee or chlorogenic acid inhibited CT-26 colon cancer cell-induced lung metastasis by blocking phosphorylation of ERKs. Coffee or caffeic acid (CaA) strongly suppressed mitogen-activated MEK1 and TOPK activities and bound directly to either MEK1 or TOPK in an ATP-noncompetitive manner. Coffee or CaA, but not caffeine, inhibited ERKs phosphorylation, AP-1 and NF-κB transactivation and subsequently inhibited TPA-, EGF- and H-Ras-induced neoplastic transformation of JB6 P+ cells. Coffee consumption was also associated with a significant attenuation of ERKs phosphorylation in colon cancer patients. These results suggest that coffee and CaA target MEK1 and TOPK to suppress colon cancer metastasis and neoplastic cell transformation.
Asunto(s)
Adenocarcinoma/prevención & control , Café , Neoplasias del Colon/prevención & control , Neoplasias Pulmonares/prevención & control , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fenoles/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Western Blotting , Adhesión Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Ácido Clorogénico/uso terapéutico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Humanos , Técnicas para Inmunoenzimas , Luciferasas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Quinasas de Proteína Quinasa Activadas por Mitógenos/química , Modelos Moleculares , Estudios Prospectivos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Numerous in vitro and in vivo studies have shown that isoflavones exhibit anti-proliferative activity against epidermal growth factor (EGF) receptor-positive malignancies of the breast, colon, skin, and prostate. 7,3',4'-Trihydroxyisoflavone (7,3',4'-THIF) is one of the metabolites of daidzein, a well known soy isoflavone, but its chemopreventive activity and the underlying molecular mechanisms are poorly understood. In this study, 7,3',4'-THIF prevented EGF-induced neoplastic transformation and proliferation of JB6 P+ mouse epidermal cells. It significantly blocked cell cycle progression of EGF-stimulated cells at the G(1) phase. As shown by Western blot, 7,3',4'-THIF suppressed the phosphorylation of retinoblastoma protein at Ser-795 and Ser-807/Ser-811, which are the specific sites of phosphorylation by cyclin-dependent kinase (CDK) 4. It also inhibited the expression of G(1) phase-regulatory proteins, including cyclin D1, CDK4, cyclin E, and CDK2. In addition to regulating the expression of cell cycle-regulatory proteins, 7,3',4'-THIF bound to CDK4 and CDK2 and strongly inhibited their kinase activities. It also bound to phosphatidylinositol 3-kinase (PI3K), strongly inhibiting its kinase activity and thereby suppressing the Akt/GSK-3beta/AP-1 pathway and subsequently attenuating the expression of cyclin D1. Collectively, these results suggest that CDKs and PI3K are the primary molecular targets of 7,3',4'-THIF in the suppression of EGF-induced cell proliferation. These insights into the biological actions of 7,3',4'-THIF provide a molecular basis for the possible development of new chemoprotective agents.
Asunto(s)
Quinasas Ciclina-Dependientes/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Isoflavonas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Anticarcinógenos/farmacología , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , Proteína de Retinoblastoma/metabolismo , Serina/química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/prevención & controlRESUMEN
Targeting tumor necrosis factor (TNF)-α-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-α-mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-α-induced COX-2 expression by down-regulating the transactivation of nuclear factor-κB and activator protein-1. Furthermore, luteolin inhibited TNF-α-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/ERK/p90(RSK), mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/c-Jun, and Akt/p70(S6K). However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-α-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2.
Asunto(s)
Ciclooxigenasa 2/biosíntesis , Epidermis/metabolismo , Expectorantes/farmacología , Luteolina/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Unión Competitiva/efectos de los fármacos , Western Blotting , Supervivencia Celular/efectos de los fármacos , Células Epidérmicas , Epidermis/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Silenciador del Gen , Inmunoprecipitación , Luciferasas/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Moleculares , FN-kappa B/biosíntesis , FN-kappa B/genética , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño , Factor de Transcripción AP-1/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Resveratrol (RES) and oxyresveratrol (OXYRES) are considered and utilized as active ingredients of anti-aging skin cosmetics. However, these compounds are susceptible to oxidative discoloration and unpleasant odor in solutions, limiting their use in cosmetics. Accordingly, RES and OXYRES were chemically modified to acetylated derivatives with enhanced stability, and their anti-aging effect on the skin and detailed molecular mechanism of their acetylated derivatives were investigated. Acetylated RES and OXYRES lost their acetyl group and exerted an inhibitory effect on H2O2-induced ROS levels in human dermal fibroblast (HDF) cells. In addition, RES, OXYRES, and their acetylated derivatives suppressed UVB-induced matrix metalloproteinase (MMP)-1 expression via inhibition of mitogen-activated protein kinases (MAPKs) and Akt/mTOR signaling pathways. Furthermore, RES, OXYRES, and their acetylated derivatives suppressed type I collagen in TPA-treated HDF cells. Collectively, these results suggest the beneficial effects and underlying molecular mechanisms of RES, OXYRES, and their acetylated derivatives for anti- skin aging applications.
RESUMEN
Cocoa polyphenols have antioxidant and anti-inflammatory effects. TNF-α is a pro-inflammatory cytokine that has a vital role in the pathogenesis of inflammatory diseases such as cancer and psoriasis. Vascular endothelial growth factor (VEGF) expression is associated with tumorigenesis, CVD, rheumatoid arthritis and psoriasis. We tested whether cocoa polyphenol extract (CPE) inhibited TNF-α-induced VEGF expression in promotion-sensitive JB6 mouse epidermal cells. CPE significantly inhibited TNF-α-induced up-regulation of VEGF via reducing TNF-α-induced activation of the nuclear transcription factors activator protein-1 (AP-1) and NF-κB, which are key regulators of VEGF expression. CPE also inhibited TNF-α-induced phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase. CPE blocked activation of their downstream kinases, p70 kDa ribosomal protein S6 kinase and p90 kDa ribosomal protein S6 kinase. CPE suppressed phosphoinositide 3-kinase (PI3K) activity via binding PI3K directly. CPE did not affect TNF-α-induced phosphorylation of mitogen-activated protein kinase kinase-1 (MEK1) but suppressed TNF-α-induced MEK1 activity. Collectively, these results indicate that CPE reduced TNF-α-induced up-regulation of VEGF by directly inhibiting PI3K and MEK1 activities, which may contribute to its chemopreventive potential.
Asunto(s)
Antioxidantes/farmacología , Cacao/química , Epidermis/efectos de los fármacos , Flavonoides/farmacología , Fenoles/farmacología , Extractos Vegetales/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular , Células Epidérmicas , Epidermis/enzimología , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3 , Extractos Vegetales/química , Polifenoles , SemillasRESUMEN
We evaluated the effects of the two main kiwifruit cultivars (gold kiwifruit (GOK) and green kiwifruit (GRK)) and their active phenolic compound, quercetin, on H2O2-induced inhibition of gap-junction intercellular communication (GJIC) in WB-F344 rat liver epithelial cells. We found that both GOK and GRK protect WB-F344 cells from H2O2-induced inhibition of GJIC. The extracellular signal-regulated protein kinase 1/2 (ERK1/2)-connexin 43 (Cx43) signalling pathway is crucial for the regulation of GJIC, and both GOK and GRK blocked the H2O2-induced phosphorylation of Cx43 and ERK1/2 in WB-F344 cells. Quercetin alone attenuated the H2O2-mediated ERK1/2-Cx43 signalling pathway and consequently reversed H2O2-mediated inhibition of GJIC in WB-F344 cells. A free radical-scavenging assay using 1,1-diphenyl-2-picrylhydrazyl showed that the scavenging activity of quercetin was higher than that of a synthetic antioxidant, butylated hydroxytoluene, per mol, suggesting that the chemopreventive effect of quercetin on H2O2-mediated inhibition of ERK1/2-Cx43 signalling and GJIC may be mediated through its free radical-scavenging activity. Since the carcinogenicity of reactive oxygen species such as H2O2 is attributable to the inhibition of GJIC, GOK, GRK and quercetin may have chemopreventive potential by preventing the inhibition of GJIC.