RESUMEN
This study aims to explore the anti-inflammatory mechanisms of sargachromenol in both RAW 264.7 cells and lipopolysaccharide (LPS)-treated mice, as previous reports have suggested that sargachromenol possesses anti-aging, anti-inflammatory, antioxidant, and neuroprotective properties. Although the precise mechanism behind its anti-inflammatory activity remains unclear, pretreatment with sargachromenol effectively reduced the production of nitric oxide, prostaglandin E2, and interleukin (IL)-1ß in LPS-stimulated RAW 264.7 cells by inhibiting cyclooxygenase-2. Moreover, sargachromenol inhibited the activation of nuclear factor-κB (NF-κB) by preventing the degradation of the inhibitor of κB-α (IκB-α) and inhibiting protein kinase B (Akt) phosphorylation in LPS-stimulated cells. We also found that sargachromenol induced the production of heme oxygenase-1 (HO-1) by activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2). In LPS-treated mice, oral administration of sargachromenol effectively reduced the levels of IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in the serum, suggesting its ability to suppress the production of inflammatory mediators by inhibiting the Akt/NF-κB pathway and upregulating the Nrf2/HO-1 pathway.
Asunto(s)
Lipopolisacáridos , FN-kappa B , Animales , Ratones , FN-kappa B/metabolismo , Células RAW 264.7 , Lipopolisacáridos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antiinflamatorios/farmacología , Hemo-Oxigenasa 1/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
The proteolytic processing of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase releases amyloid-ß peptide (Aß), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aß accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), ß-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPß, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3ß at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3ß. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3ß activation and Aß expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aß production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3ß, resulting in the reduction in Aß levels.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Benzofuranos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Animales , Línea Celular , Cromonas/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Taninos/farmacologíaRESUMEN
A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of Sargassum serratifolium (MES) stimulated adipose tissue browning and inhibited diet-induced obesity and metabolic syndrome. Sargaquinoic acid (SQA) is a major component in MES. We investigated the effects of SQA on the differentiation of preadipocytes to the beige adipocytes. SQA was treated in 3T3-L1 adipocytes differentiated under a special condition that has been reported to induce the browning of adipocytes. SQA at 10 µM reduced lipid accumulation by approximately 23%. SQA at 2.5â-â10 µM induced the differentiation of white adipocytes to beige adipocytes partially by increasing the mitochondrial density and the expression of beige/brown adipocyte markers. In addition, SQA activated lipid catabolic pathways, evidenced by the increased expression levels of perilipin, carnitine palmitoyltransferase 1, and acyl-CoA synthetase long-chain family member 1. As a partial mechanism, biochemical and in silico analyses indicate that SQA activated AMP-activated protein kinase signaling in adipocytes.
Asunto(s)
Adipocitos Marrones/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Alquenos/farmacología , Benzoquinonas/farmacología , Sargassum/química , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos Marrones/citología , Alquenos/aislamiento & purificación , Alquenos/toxicidad , Animales , Benzoquinonas/aislamiento & purificación , Benzoquinonas/toxicidad , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
Aging is a major risk factor for many chronic diseases, such as cancer, cardiovascular disease, and diabetes. The exact mechanisms underlying the aging process are not fully elucidated. However, a growing body of evidence suggests that several pathways, such as sirtuin, AMP-activated protein kinase, insulin-like growth factor, autophagy, and nuclear factor erythroid 2-related factor 2 play critical roles in regulating aging. Furthermore, genetic or dietary interventions of these pathways can extend lifespan by delaying the aging process. Seaweeds are a food source rich in many nutrients, including fibers, polyunsaturated fatty acids, vitamins, minerals, and other bioactive compounds. The health benefits of seaweeds include, but are not limited to, antioxidant, anti-inflammatory, and anti-obese activities. Interestingly, a body of studies shows that some seaweed-derived extracts or isolated compounds, can modulate these aging-regulating pathways or even extend lifespans of various animal models. However, few such studies have been conducted on higher animals or even humans. In this review, we focused on potential anti-aging bioactive substances in seaweeds that have been studied in cells and animals mainly based on their anti-aging cellular and molecular mechanisms.
Asunto(s)
Envejecimiento/efectos de los fármacos , Productos Biológicos/farmacología , Senescencia Celular/efectos de los fármacos , Algas Marinas/metabolismo , Envejecimiento/metabolismo , Animales , Productos Biológicos/aislamiento & purificación , Humanos , Transducción de SeñalRESUMEN
Sargassum species have been reported to be a source of phytochemicals, with a wide range of biological activities. In this study, we evaluated the hepatoprotective effect of a meroterpenoid-rich fraction of the ethanolic extract from Sargassum serratifolium (MES) against tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells. Treatment with MES recovered the cell viability from the t-BHP-induced oxidative damage in a dose-dependent manner. It suppressed the reactive oxygen species production, lipid peroxidation, and glutathione depletion in the t-BHP-treated HepG2 cells. The activity of the antioxidants induced by t-BHP, including superoxide dismutase (SOD) and catalase, was reduced by the MES treatment. Moreover, it increased the nuclear translocation of nuclear factor erythroid 2-related factor 2, leading to the enhanced activity of glutathione S transferase, and the increased production of heme oxygenase-1 and NAD(P)H:quinine oxidoreductase 1 in t-BHP-treated HepG2 cells. These results demonstrate that the antioxidant activity of MES substituted the activity of the SOD and catalase, and induced the production of detoxifying enzymes, indicating that MES might be used as a hepatoprotectant against t-BHP-induced oxidative stress.
Asunto(s)
Etanol/química , Estrés Oxidativo/efectos de los fármacos , Sargassum/química , Terpenos/química , Terpenos/farmacología , terc-Butilhidroperóxido/farmacología , Antioxidantes/metabolismo , Catalasa/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Glutatión/metabolismo , Hemo-Oxigenasa 1/metabolismo , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , NADP/metabolismo , Oxidación-Reducción/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer's disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4µM for BChE; 4.3, 6.9, and 12.5µM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Extractos Vegetales/farmacología , Sargassum/química , Terpenos/farmacología , Sitio Alostérico , Catálisis , Inhibidores Enzimáticos/química , Simulación del Acoplamiento Molecular , Terpenos/químicaRESUMEN
There is a rapid increase in the demand for natural hypopigmenting agents from marine sources for cosmeceutical and pharmaceutical applications. Currently, marine macroalgae are considered as a safe and effective source of diverse bioactive compounds. Many research groups are exploring marine macroalgae to discover and characterize novel compounds for cosmeceutical, nutraceutical, and pharmaceutical applications. Many types of bioactive secondary metabolites from marine algae, including phlorotannins, sulfated polysaccharides, carotenoids, and meroterpenoids, have already been documented for their potential applications in the pharmaceutical industry. Among these metabolites, phlorotannins from brown algae have been widely screened for their pharmaceutical and hypopigmenting effects. Unfortunately, the majority of these articles did not have detailed investigations on molecular targets, which is critical to fulfilling the criteria for their cosmeceutical and pharmaceutical use. Very recently, a few meroterpenoids have been discovered from Sargassum sp., with the examination of their anti-melanogenic properties and mechanisms. Despite the scarcity of in vivo and clinical investigations of molecular mechanistic events of marine algae-derived hypopigmenting agents, identifying the therapeutic targets and their validation in humans has been a major challenge for future studies. In this review, we focused on available data representing molecular mechanisms underlying hypopigmenting properties of potential marine brown alga-derived compounds.
Asunto(s)
Hipopigmentación/inducido químicamente , Phaeophyceae/química , Fitoquímicos/farmacología , Animales , Carotenoides/farmacología , Humanos , Polisacáridos/farmacología , Algas Marinas/química , Sulfatos/farmacología , Taninos/farmacología , Terpenos/farmacologíaRESUMEN
Sargassum serratifolium C. Agardh (Phaeophyceae, Fucales) is a marine brown alga that belongs to the family Sargassaceae. It is widely distributed throughout coastal areas of Korea and Japan. S. serratifolium has been found to contain high concentrations of plastoquinones, which have strong anti-cancer, anti-inflammatory, antioxidant, and neuroprotective activity. This study aims to investigate the anti-diabetic activity of S. serratifolium and its major constituents through inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO--mediated albumin nitration. S. serratifolium ethanolic extract and fractions exhibited broad PTP1B and α-glucosidase inhibitory activity (IC50, 1.83~7.04 and 3.16~24.16 µg/mL for PTP1B and α-glucosidase, respectively). In an attempt to identify bioactive compounds, three plastoquinones (sargahydroquinoic acid, sargachromenol and sargaquinoic acid) were isolated from the active n-hexane fraction of S. serratifolium. All three plastoquinones exhibited dose-dependent inhibitory activity against PTP1B in the IC50 range of 5.14-14.15 µM, while sargachromenol and sargaquinoic acid showed dose-dependent inhibitory activity against α-glucosidase (IC50 42.41 ± 3.09 and 96.17 ± 3.48 µM, respectively). In the kinetic study of PTP1B enzyme inhibition, sargahydroquinoic acid and sargaquinoic acid led to mixed-type inhibition, whereas sargachromenol displayed noncompetitive-type inhibition. Moreover, plastoquinones dose-dependently inhibited ONOO--mediated albumin nitration. Docking simulations of these plastoquinones demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B and α-glucosidase, indicating that these plastoquinones have high affinity and tight binding capacity towards the active site of the enzymes. These results demonstrate that S. serratifolium and its major plastoquinones may have the potential as functional food ingredients for the prevention and treatment of type 2 diabetes.
Asunto(s)
Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Extractos Vegetales/química , Plastoquinona/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Sargassum/química , Animales , Organismos Acuáticos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Plastoquinona/farmacologíaRESUMEN
OBJECTIVE: Microglial activation has been implicated in many neurological disorders for its inflammatory and neurotrophic effects. In this study, we investigated the pharmaceutical properties of 6,6'-bieckol on the regulation of nuclear factor-κB (NF-κB) activation responsible to the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 using lipopolysaccharide (LPS)-stimulated BV2 and murine primary microglial cells. Meterials and methods: The levels of nitric oxide (NO), prostaglandin E2 (PGE)2, and pro-inflammatory cytokines were measured by Griess assay and enzyme-linked immunosorbent assay. The levels of iNOS, COX-2, mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blot. Nuclear translocation and transcriptional activation of NF-κB were determined by immunofluorescence and reporter gene assay, respectively. RESULTS: We found that 6,6'-bieckol decreased the expression of iNOS and COX-2 as well as pro-inflammatory cytokines in LPS-stimulated BV2 and primary microglial cells in a dose-dependent manner. 6,6'-Bieckol inhibited activation of NF-κB by preventing the degradation of inhibitor κB (IκB)-α and led to prevent the nuclear translocation of NF-κB/p65 subunit. Moreover, 6,6'-bieckol inhibited the phosphorylation of Akt, JNK, and p38 MAPK. DISCUSSION AND CONCLUSION: These results indicate that the anti-inflammatory effect of 6,6'-bieckol on LPS-stimulated microglial cells is mainly regulated by the inhibition of IκB-α/NF-κB and JNK/p38 MAPK/Akt pathways, supporting biochemical characteristics of the compound for therapeutic agent against neuroinflammatory diseases caused by microglial activation.
Asunto(s)
Antiinflamatorios/farmacología , Regulación hacia Abajo/efectos de los fármacos , Lipopolisacáridos/toxicidad , MAP Quinasa Quinasa 4/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Microglía/inmunología , FN-kappa B/inmunología , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Animales , Antiinflamatorios/química , Regulación hacia Abajo/inmunología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Excessive pro-inflammatory cytokine production from activated microglia contributes to neurodegenerative diseases, thus, microglial inactivation may delay the progress of neurodegeneration by attenuating the neuroinflammation. Among 5 selected brown algae, we found the highest antioxidant and anti-neuroinflammatory activities from Myagropsis myagroides ethanolic extract (MME) in lipopolysaccharide (LPS)-stimulated BV-2 cells. METHODS: The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess assay and enzyme linked immunesorbent assay. The levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blot. Nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) were determined by immunefluorescence and reporter gene assay, respectively. RESULTS: MME inhibited the expression of iNOS and COX-2 at mRNA and protein levels, resulting in reduction of NO and PGE2 production. As a result, pro-inflammatory cytokines were reduced by MME. MME also inhibited the activation and translocation of NF-κB by preventing inhibitor κB-α (IκB-α) degradation. Moreover, MME inhibited the phosphorylation of extracellular signal regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Main anti-inflammatory compound in MME was identified as sargachromenol by NMR spectroscopy. CONCLUSIONS: These results indicate that the anti-inflammatory effect of sargachromenol-rich MME on LPS-stimulated microglia is mainly regulated by the inhibition of IκB-α/NF-κB and ERK/JNK pathways.
Asunto(s)
Antiinflamatorios/farmacología , Benzopiranos/farmacología , Phaeophyceae/química , Análisis de Varianza , Animales , Antiinflamatorios/química , Benzopiranos/química , Línea Celular , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Eckol isolated from Ecklonia stolonifera was previously reported to exhibit cytoprotective activity with its intrinsic antioxidant activity in in vitro studies. In this study, we characterized the mechanism underlying the eckol-mediated the expression of heme oxygenase-1 (HO-1). Eckol suppressed the production of intracellular reactive oxygen species and increased glutathione level in HepG2 cells. Eckol treatment enhanced the expression of HO-1 at the both level of protein and mRNA in HepG2 cells. Enhanced expression of HO-1 by eckol was presumed to be the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2) demonstrated by its nuclear translocation and increased transcriptional activity. c-Jun NH2-terminal kinases (JNKs) and PI3K/Akt contributed to Nrf2-mediated HO-1 expression. These results demonstrate that the eckol-mediated expression of HO-1 in HepG2 cells is regulated by Nrf2 activation via JNK and PI3K/Akt signaling pathways, suggesting that eckol may be used as a natural antioxidant and cytoprotective agent.
Asunto(s)
Dioxinas/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Antioxidantes/química , Antioxidantes/farmacología , Dioxinas/química , Células Hep G2 , Humanos , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Anthocyanins have been shown to suppress body weight and fat mass in animal studies. However, the effect of anthocyanins on the process of lipid accumulation during adipocyte differentiation is not fully understood and the lipogenic transcription factors regulated by anthocyanins have not been identified. We investigated the effects of anthocyanins on lipogenesis pathways during adipocyte differentiation in 3T3-L1 cells. Anthocyanins reduced triglyceride (TG) accumulation in a dose-dependent manner during adipocyte differentiation. Accumulation of TG was rapidly reversed by anthocyanin withdrawal. Anthocyanins markedly reduced gene and protein expression levels of lipogenic transcription factors such as liver X receptor α, sterol regulatory element-binding protein-1c, peroxisome proliferators-activated receptor-γ, and CCAAT enhancer-binding protein-α. In addition, the target gene and protein expression of these lipogenic transcription factors such as fatty acid synthase, stearoyl-CoA desaturase-1, and acetyl-CoA carboxylase α were markedly suppressed by anthocyanins. Thus, anthocyanins suppress lipid accumulation in adipocytes due to broad inhibition of the transcription factors regulating lipogenesis. This may partially explain the mechanism by which anthocyanins exert their anti-obesity effect.
Asunto(s)
Antocianinas/farmacología , Lipogénesis/efectos de los fármacos , Células 3T3-L1/efectos de los fármacos , Adipocitos/efectos de los fármacos , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Receptores X del Hígado , Ratones , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triglicéridos/metabolismoRESUMEN
PURPOSE: Laminaria japonica is a representative marine brown alga used as a culinary item in East Asia. L. japonica extract was shown to exert various biological activities; however, its anti-inflammatory activity has not been reported. The aim of this study is to investigate the molecular mechanisms underlying its anti-inflammatory action. METHODS: Anti-inflammatory mechanisms of L. japonica n-hexane fraction (LHF) were assessed using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. An anti-inflammatory compound isolated from LHF by reverse-phase chromatography was identified using nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Our results indicate that LHF significantly inhibited LPS-stimulated nitric oxide (NO) and prostaglandin E(2) (PGE(2)) secretion in a dose-dependent manner and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) with no cytotoxicity. As results, levels of pro-inflammatory cytokines were significantly reduced by pretreatment of LHF in LPS-stimulated RAW 264.7 cells. Treatment of LHF strongly suppressed nuclear factor-κB (NF-κB) promoter-driven expression and nuclear translocation of NF-κB by preventing proteolytic degradation of inhibitor of κB (IκB)-α in LPS-stimulated RAW 264.7 cells. Moreover, LHF inhibited the phosphorylation of Akt and mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW 264.7 cells. One of the anti-inflammatory compounds was isolated from LHF and identified as fucoxanthin. CONCLUSIONS: These results indicate that the LHF-mediated inhibition of NO and PGE(2) secretion in LPS-stimulated macrophages is regulated by NF-κB inactivation through inhibition of IκB-α, MAPKs, and Akt phosphorylation. LHF may be considered as a functional food candidate for the prevention or treatment of inflammatory diseases.
Asunto(s)
Antiinflamatorios/farmacología , Productos Biológicos/farmacología , Laminaria/química , Macrófagos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Cromatografía de Fase Inversa , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/análisis , Citocinas/metabolismo , Regulación de la Expresión Génica , Hexanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Lipopolisacáridos/metabolismo , Macrófagos/citología , Espectroscopía de Resonancia Magnética/métodos , Ratones , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Xantófilas/farmacologíaRESUMEN
Antimelanogenic activity has previously been reported in ethyl acetate fraction of Ecklonia stolonifera. In this study, using the isolated dioxinodehydroeckol from the fraction, we sought to investigate an antimelanogenic signalling pathway in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 melanoma cells. Treatment with dioxinodehydroeckol inhibited the cellular melanin contents and expression of melanogenesis-related proteins, including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related proteins TRP-1 and TRP-2. Moreover, dioxinodehydroeckol stimulated phosphorylation of Akt in a dose-dependent manner without affecting phosphorylation of ERK. These data suggest that dioxinodehydroeckol reduces melanin synthesis through the MITF regulation dependent upon PI3K/Akt signalling pathway.
Asunto(s)
Dioxinas/farmacología , Melaninas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Dioxinas/aislamiento & purificación , Melaninas/biosíntesis , Ratones , Phaeophyceae/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , alfa-MSHRESUMEN
BACKGROUND: This study aims to investigate anti-inflammatory effect of ethanolic extract of Myagropsis myagroides (EMM) in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and the phorbol 12-myristate 13-acetate (PMA)-induced ear edema in mice, and to clarify its underlying molecular mechanisms. METHODS: The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess assay and enzyme linked immunosorbent assay. The expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blotting. Nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) were determined by immunocytochemistry and reporter gene assay, respectively. PMA-induced mouse ear edema was used as the animal model of inflammation. Anti-inflammatory compounds in EMM were isolated using high-performance liquid chromatography and identified by nuclear magnetic resonance. RESULTS: EMM significantly inhibited the production of NO, PGE2, and pro-inflammatory cytokines in a dose-dependent manner and suppressed the expression of iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. EMM strongly suppressed nuclear translocation of NF-κB by preventing degradation of inhibitor of κB-α as well as by inhibiting phosphorylation of Akt and MAPKs. EMM reduced ear edema in PMA-induced mice. One of the anti-inflammatory compounds in EMM was identified as 6,6'-bieckol. CONCLUSIONS: These results suggest that the anti-inflammatory properties of EMM are associated with the down-regulation of iNOS, COX-2, and pro-inflammatory cytokines through the inhibition of NF-κB pathway in LPS-stimulated macrophages.
Asunto(s)
Antiinflamatorios/uso terapéutico , Edema/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Inflamación/prevención & control , Phaeophyceae/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antiinflamatorios/análisis , Antiinflamatorios/farmacología , Transporte Biológico , Dioxinas/análisis , Dioxinas/farmacología , Dioxinas/uso terapéutico , Oído , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
Colitis is a colon mucosal disorder characterized by intestinal damage and inflammation. This current study aimed to evaluate the effect of meroterpenoid-rich ethanoic extract of a brown algae, Sargassum macrocarpum (MES) on dextran sulfate sodium (DSS)-induced colitis in mice and explore the possible mechanisms. Mice were given 4% DSS in drinking water for 7 days to induce colitis, followed by 3 days of regular water. MES (12 mg/kg body weight) or celecoxib (10 mg/kg body weight) was administrated orally to mice on a daily basis during these 10 days. Both MES and celecoxib supplementations significantly attenuated DSS-induced weight loss, shortening of colon length, elevated myeloperoxidase activity as well as histomorphological changes of colon. MES and celecoxib reduced the inflammation level of colon tissue, as indicated by its suppression on a panel of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-17, tumor necrosis factor α, and interferon γ, and a group of inflammatory proteins, including intracellular adhesion molecule 1, vascular adhesion molecule 1, matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and inducible nitric oxidase. In addition, their administration down-regulated pro-inflammatory cytokines in serum. Moreover, the supplementation of MES suppressed the DSS-induced hyperactivation of Akt, JNK, and NF-κB signaling pathways. Taken together, our results demonstrate that MES ameliorates DSS-induced colitis in mice, suggesting that MES may have therapeutic implications for the treatment of colitis.
RESUMEN
AIM: The effects of sargahydroquinoic acid (SHQA) on cellular senescence and the underlying mechanisms were investigated using human umbilical vascular endothelial cells (HUVECs). METHODS: SHQA or DMSO was supplemented into the medium. Low dose of H2O2 was used to induce premature senescence. Replicative senescence was achieved by continuously culturing cells until they reached a plateau phase. Senescence biomarkers, including p53, p21, and p16 proteins, and SA-ß-Gal activity were measured. RESULTS: Pretreatment of SHQA significantly suppressed the oxidative stress-induced protein expression of p53, p21, and p16, as well as the activity of SA-ß-Gal. Additionally, SHQA also delayed the replicative senescence as indicated by an increased population doubling number, reduced protein expression of p53, p21, and p16, as well as a decreased SA-ß-Gal activity. SHQA inhibited the phosphorylation of Akt, mTOR, and downstream targets of mTOR, such as p-S6K, which was elevated by premature senescence and replicative senescence. In the absence of senescence stimuli, SHQA also inhibited the Akt/mTOR signaling pathway and promoted autophagy. CONCLUSIONS: SHQA suppressed senescence induced by oxidative stress and replication through inhibiting the Akt/mTOR pathway. With the potential of acting as an Akt/mTOR inhibitor, SHQA might be useful for developing anti-ageing therapy.
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Células Endoteliales , Proteínas Proto-Oncogénicas c-akt , Alquenos , Benzoquinonas , Células Cultivadas , Senescencia Celular , Células Endoteliales/metabolismo , Humanos , Peróxido de Hidrógeno , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Proteína p53 Supresora de TumorRESUMEN
Sargahydroquinoic acid (SHQA) is a major plastoquinone in Sargassum macrocarpum and has shown the capacity to prevent inflammation and oxidative stress. However, the protective mechanisms were unclear. The molecular mechanisms of SHQA on ameliorating inflammation and oxidative stress have been investigated, using lipopolysaccharide (LPS)-stimulated macrophages. SHQA was isolated and purified from S. macrocarpum and the anti-inflammatory mechanisms were explored using LPS-stimulated murine macrophage RAW 264.7 cells. SHQA did not change the expression of cyclooxygenase-2 (COX-2) but inhibited the activity of COX-2. As a result, SHQA significantly diminished the secretions of nitric oxide (NO), prostaglandin E2 (PGE2), and multiple pro-inflammatory cytokines. LPS-induced activation of nuclear factor-κB (NF-κB) was inhibited by SHQA by preventing the degradation of inhibitor κB-α (IκBα). NF-κB activation was also downregulated by the inhibition of Akt phosphorylation in LPS-stimulated cells. Furthermore, SHQA induced the expression of heme oxygenase 1 via Nrf2 activation. These results indicated that SHQA inhibited LPS-induced expressions of inflammatory mediators via suppressing the Akt-mediated NF-κB pathway as well as upregulating the Nrf2/HO-1 pathway. Our findings suggest that SHQA might be a potential therapeutic agent in various inflammatory diseases.
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Alquenos/farmacología , Antiinflamatorios/farmacología , Benzoquinonas/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/antagonistas & inhibidores , Alquenos/aislamiento & purificación , Animales , Antiinflamatorios/aislamiento & purificación , Benzoquinonas/aislamiento & purificación , Inhibidores de la Ciclooxigenasa 2/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Ratones , FN-kappa B/metabolismo , Células RAW 264.7 , SargassumRESUMEN
Forkhead box, class O (FoxO) family members are multifunctional transcription factors that are involved in several metabolic processes, including energy metabolism, apoptosis, DNA repair, and oxidative stress. However, their roles in skin health have not been well-documented. Recent studies have indicated that FoxOs are important factors to control skin homeostasis and health. The activation or deactivation of some FoxO family members is closely related to melanogenesis, wound healing, acne, and melanoma. In this review, we have discussed the recent findings that demonstrate the relationship between FoxOs and skin health as well as the underlying mechanisms associated with their functions.
Asunto(s)
Factores de Transcripción Forkhead , Envejecimiento de la Piel , Apoptosis , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Estrés Oxidativo , Piel/metabolismoRESUMEN
Hyperpigmentation diseases of the skin require topical treatment with depigmenting agents. We investigated the hypopigmented mechanisms of sargahydroquinoic acid (SHQA) in alpha-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells. SHQA reduced cellular tyrosinase (TYR) activity and melanin content in a concentration-dependent manner and attenuated the expression of TYR and tyrosinase-related protein 1 (TRP1), along with their transcriptional regulator, microphthalmia-associated transcription factor (MITF). SHQA also suppressed α-MSH-induced cellular production of cyclic adenosine monophosphate (cAMP), which inhibited protein kinase A (PKA)-dependent cAMP-responsive element-binding protein (CREB) activation. Docking simulation data showed a potential binding affinity of SHQA to the regulatory subunit RIIß of PKA, which may also adversely affect PKA and CREB activation. Moreover, SHQA activated ERK1/2 signaling in B16F10 cells, stimulating the proteasomal degradation of MITF. These data suggest that SHQA ameliorated hyperpigmentation in α-MSH-stimulated B16F10 cells by downregulating MITF via PKA inactivation and ERK1/2 phosphorylation, indicating that SHQA is a potent therapeutic agent against skin hyperpigmentation disorders.