RESUMEN
Background: : This study aimed to investigate the efficacy of P. oleracea in the management of patients with functional constipation. Methods: : A total of 60 patients with functional constipation as defined by the Rome IV criteria were enrolled in this randomized, double-blind, placebo-controlled study; 70% ethanol extracts of the aerial parts of P. oleracea were used for the intervention. Patients were randomly assigned to the P. oleracea or placebo groups. Treatment response, quality of life, and changes in colonic transit time (CTT) were evaluated. Results: : Complete spontaneous bowel movement (CSBM) improved significantly in the P. oleracea group compared with that in the placebo group over 8 weeks of treatment (P = 0.003). Overall Patient Assessment of Constipation Quality of Life (PAC-QOL) and Patient Assessment of Constipation Symptoms (PAC-SYM) score improvements were observed in the P. oleracea group (P < 0.05). Moreover, CTT decreased from 44.5 ± 22.0 h to 33.7 ± 22.7 h in the P. oleracea group after 7 weeks of treatment (P = 0.04). There were no significant differences in the Bristol Stool Form Scale (BSFS) or adverse events between the groups. Conclusions: : Compared to placebo, the use of P. oleracea in patients with functional constipation significantly improved CSBM, severity of symptoms, and quality of life. Further large studies are required to assess the benefits of P. oleracea in the treatment of functional constipation.
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Portulaca , Calidad de Vida , Estreñimiento/tratamiento farmacológico , Método Doble Ciego , Humanos , Resultado del TratamientoRESUMEN
Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.
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Sistemas de Liberación de Medicamentos , Ubiquinona , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo , Emulsiones , Excipientes , Ratas , Solubilidad , TensoactivosRESUMEN
The pharmacological effects of BST204-a fermented ginseng extract-on several types of cancers have been reported. However, the effects of ginseng products or single ginsenosides against cancer stem cells are still poorly understood. In this study, we identified the anti-tumorigenic and anti-invasive activities of BST204 through the suppression of the cancer stem cell marker, CD133. The treatment of embryonic carcinoma cells with BST204 induced the expression of the tumor suppressor protein, p53, which decreased the expression of cell cycle regulatory proteins and downregulated the expression of CD133 and several stemness transcription factors. These changes resulted in both the inhibition of tumor cell proliferation and tumorigenesis. The knockdown of CD133 suggests that it has a role in tumorigenesis, but not in cancer cell proliferation or cell cycle arrest. Treatment with BST204 resulted in the reduced expression of the mesenchymal marker, N-cadherin, and the increased expression of the epithelial marker, E-cadherin, leading to the suppression of tumor cell migration and invasion. The knockdown of CD133 also exhibited an anti-invasive effect, indicating the role of CD133 in tumor invasion. The single ginsenosides Rg3 and Rh2-major components of BST204-exhibited limited effects against cancer stem cells compared to BST204, suggesting possible synergism among several ginsenoside compounds.
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Carcinogénesis , Carcinoma Embrionario , Movimiento Celular/efectos de los fármacos , Células Madre Neoplásicas , Extractos Vegetales/farmacología , Antígeno AC133/biosíntesis , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Embrionario/tratamiento farmacológico , Carcinoma Embrionario/metabolismo , Carcinoma Embrionario/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
BACKGROUND: The biological and pharmacological effects of BST204, a fermented ginseng extract, have been reported in various disease conditions. However, its molecular action in metabolic disease remains poorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from its inhibition of the S6 kinase 1 (S6K1) signaling pathway. METHODS: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclear fractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated by measuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitative real-time polymerase chain reaction analysis. RESULTS: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, further decreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently, phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing an increase in the mRNA expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiation and promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatment during adipogenic commitment suppressed the expression of adipogenic marker genes and lipid drop formation. CONCLUSION: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through the inhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeutic strategy using BST204 to combat obesity and musculoskeletal diseases.
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E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.
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Carcinogénesis/patología , Núcleo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Regulación hacia Abajo/genética , Proteínas Oncogénicas Virales/metabolismo , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Transporte Activo de Núcleo Celular , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Doxiciclina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Carioferinas/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Isoformas de Proteínas/metabolismo , Proteolisis , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Riesgo , Proteína p53 Supresora de Tumor/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitinación , Proteína Exportina 1RESUMEN
BACKGROUND: The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer. METHODS: Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis. RESULTS: RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis. CONCLUSIONS: Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin.
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Antineoplásicos/farmacología , Cinamatos/farmacología , Depsidos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cinamatos/química , Cisplatino/farmacología , Depsidos/química , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas S6 Ribosómicas 70-kDa/química , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Neoplasias del Cuello UterinoRESUMEN
Brown adipocytes are characterized by a high number of uncoupling protein 1 (UCP1)-positive mitochondrial content and increased thermogenic capacity. As UCP1-enriched cells can consume lipids by generating heat, browning of white adipocytes is now highlighted as a promising approach for the prevention of obesity and obesity-associated metabolic diseases. Upon cold exposure or ß-adrenergic stimuli, downregulation of microRNA-133 (miR-133) elevates the expression levels of PR domain containing 16 (Prdm16), which has been shown to be a brown adipose determination factor, in brown adipose tissue and subcutaneous white adipose tissues (WAT). Here, we show that treatment of reversine to white adipocytes induces browning via suppression of miR-133a. Reversine treatment promoted the expression of brown adipocyte marker genes, such as Prdm16 and UCP1, increasing the mitochondrial content, while decreasing the levels of miR-133a and white adipocyte marker genes. Ectopic expression of miR-133a mimic reversed the browning effects of the reversine treatment. Moreover, intraperitoneal administration of reversine in mice upregulated thermogenesis and resulted in resistance to high-fat diet-mediated weight gain as well as browning of subcutaneous and epididymal WAT. Taken together, we found a novel way to promote browning of white adipocytes through downregulation of miR-133a followed by activation of Prdm16, with a synthetic chemical, reversine.
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Adipocitos Blancos/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Fármacos Antiobesidad/farmacología , MicroARNs/metabolismo , Morfolinas/farmacología , Obesidad/prevención & control , Purinas/farmacología , Aumento de Peso/efectos de los fármacos , Células 3T3-L1 , Adipocitos Blancos/metabolismo , Adipocitos Blancos/patología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Regulación hacia Abajo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Fenotipo , Transducción de Señal , Termogénesis/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Eudesmin has been reported to possess diverse therapeutic effects, including anti-tumor, anti-inflammatory, and anti-bacterial activities. However, its molecular action has not been implicated in metabolic disease. In this study, we show that treatment of mesenchymal stem cells (MSCs) with eudesmin disturbs adipogenesis via suppression of S6K1 signaling pathway. Eudesmin treatment inhibited activation and nuclear translocation of S6K1. Consequently, S6K1-mediated phosphorylation of H2B at serine 36 (H2BS36p) was reduced upon eudesmin treatment, further inducing the expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiation. Moreover, eudesmin promoted myogenic and osteogenic gene expression in MSCs. Taken together, we found a novel small molecule, eudesmin, to block adipogenesis through down-regulation of S6K1-H2BS36p axis, followed by regulation of cell fate determination genes. This study suggests a promising therapeutic approach with eudesmin to cure obesity and metabolic diseases.
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Adipogénesis/efectos de los fármacos , Furanos/farmacología , Lignanos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Línea Celular , Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Células Musculares/citología , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/genéticaRESUMEN
The failure of insulin production by pancreatic ß cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes-derived complications, endogenous α to ß cell transition can be an attractive alternative. Although decreased ß cell size and hypoinsulinaemia have been observed in S6K1-deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1-deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production. First, we observed that increased expression of α cell marker genes and decreased expression of ß cell marker genes in pancreas tissues from S6K1-deficient mice. Furthermore, S6K1 was highly activated in murine ß cell line, ßTC6, compared to murine α cell line αTC1. In both α and ß cells, active S6K1 promoted the transcription of ß cell marker genes, including insulin, whereas S6K1 inhibition increased the transcription of α cell marker genes. Moreover, S6K1 mediated pancreatic gene regulation by modifying two histone marks (activating H3K4me3 and repressing H3K27me3) on gene promoters. These results suggest that S6K1 drives the α to ß transition through the epigenetic regulation of cell-specific genes, including insulin and glucagon. This novel role of S6K1 in islet cells provides basic clues to establish therapeutic strategies against T1DM.
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Antígenos de Diferenciación/biosíntesis , Epigénesis Genética , Células Secretoras de Glucagón/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transcripción Genética , Animales , Antígenos de Diferenciación/genética , Células Secretoras de Glucagón/citología , Células Secretoras de Insulina/citología , Ratones , Ratones Mutantes , Proteínas Quinasas S6 Ribosómicas 90-kDa/genéticaRESUMEN
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder. The present study investigated the effects of Amomum xanthioides extract (AXE) on ADlike skin inflammation using a Dermatophagoides farinae extract (DFE) and 2,4dinitrochlorobenzene (DNCB)induced mouse AD model. Hematoxylin and eosin staining results demonstrated that repeated DFE/DNCB exposure markedly increased the thickening of the dermis and epidermis, in addition to the infiltration of eosinophils and mast cells. However, oral administration of AXE reduced these histopathological alterations in a dosedependent manner. Elevated serum histamine, total and DFEspecific immunoglobulin E (IgE), and IgG2a were also decreased by treatment with AXE. In addition, reverse transcriptionquantitative polymerase chain reaction (RTqPCR) results demonstrated that the mRNA expression of tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)4, IL13, IL31 and IL17A was reduced in ear skin following AXE administration in AD mice. Fluorescenceactivated cell sorting demonstrated that the population of CD4+/IL4+, CD4+/IFNγ+ and CD4+/IL17A+ cells in draining lymph nodes was also significantly decreased in AXEtreated mice compared with AD mice without AXE treatment. Furthermore, keratinocytes that were stimulated with TNFα and IFNγ exhibited increased gene expression of proinflammatory cytokines and chemokines, including TNFα, IL1ß, IL6, IL8, CC motif chemokine ligand (CCL)17 and CCL22, as determined by RTqPCR. However, upregulation of these genes was reduced by AXE pretreatment. Based on these results, we hypothesize that AXE may be useful in the treatment of allergic skin inflammation, particularly AD.
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Amomum/química , Antiinflamatorios/farmacología , Dermatitis Atópica/inmunología , Extractos Vegetales/farmacología , Animales , Línea Celular , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Histamina/sangre , Histamina/inmunología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Piel/metabolismo , Piel/patologíaRESUMEN
We previously reported the inhibitory effect of chrysin, a natural flavonoid plentifully contained in propolis, vegetables and fruits, on the mast cell-mediated allergic reaction. In this study, we evaluated the effect of chrysin on atopic dermatitis (AD) and defined underlying mechanisms of action. We used an AD model in BALB/c mice by the repeated local exposure of 2,4-dinitrochlorobenzene (DNCB) and house dust mite (Dermatophagoides farinae extract, DFE) to the ears. Repeated alternative treatment of DNCB/DFE caused AD-like skin lesions. Oral administration of chrysin diminished AD symptoms such as ear thickness and histopathological analysis, in addition to serum IgE and IgG2a levels. Chrysin decreased infiltration of mast cells, and reduced serum histamine level. Chrysin also suppressed AD by inhibiting the inflammatory responses of Th1, Th2, and Th17 cells in mouse lymph node and ear. Interestingly, chrysin significantly inhibited the production of cytokines, Th2 chemokines, CCL17 and CCL22 by the down-regulation of p38 MAPK, NF-κB, and STAT1 in tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT). Chrysin also inhibited TNF-α/IFN-γ-stimulated IL-33 expression in HaCaT cells and mouse primary keratinocytes. Taken together, the results indicate that chrysin suppressed AD symptoms, suggesting that chrysin might be a candidate for the treatment of AD and skin allergic diseases.
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Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Flavonoides/administración & dosificación , Queratinocitos/efectos de los fármacos , Animales , Citocinas/genética , Citocinas/inmunología , Dermatitis Atópica/genética , Femenino , Histamina/inmunología , Humanos , Inmunoglobulina E/inmunología , Queratinocitos/inmunología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
This study investigated the chemical composition changes of Salvia plebeia R.Br. cultivated under different light sources, including florescent light and sunlight. The plants were exposed to fluorescent light for four months and sunlight and then examined for the next 5-7 months. Plants were harvested monthly during the seven months, and we examined whether the difference in light source affected the phenolic and flavonoid contents and antioxidant activity. A simple and reliable HPLC method using a PAH C18 column was applied for the quantitative analysis of two triterpenoids from the S. plebeia groups. Oleanolic acid (OA) and ursolic acid (UA) showed good linearity (R² > 0.9999) within the test ranges (0.005-0.05 mg/mL), and the average percentage recoveries of the OA and UA were 95.1-104.8% and 97.2-107.1%, respectively. The intra- and inter-day relative standard deviations (RSDs) were less than 2.0%. After exposure to sunlight, the phenolic contents, including rosmarinic acid, showed a reduced tendency, whereas the flavonoid contents, including homoplantaginin and luteolin 7-glucoside, were increased. The content of the triterpenoids also showed an increased tendency under sunlight irradiation, but the variance was not larger than those of the phenolic and flavonoid contents. Among experimental groups, the group harvested at six months, having been exposed to sunlight for two months, showed the most potent antioxidant activity. Therefore, these results showed that the chemical composition and antioxidant activities of S. plebeia R.Br. was affected from environmental culture conditions, such as light source. Our studies will be useful for the development of functional materials using S. plebeia R.Br.
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Extractos Vegetales/química , Salvia/efectos de la radiación , Luz Solar , Animales , Antioxidantes/química , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión , Flavonoides/química , Humanos , Ratones , Estructura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Fenoles/química , Fotosíntesis , Células RAW 264.7 , Salvia/química , Salvia/crecimiento & desarrollo , Triterpenos/química , Triterpenos/farmacología , Ácido UrsólicoRESUMEN
The interleukin-6 (IL-6) family of cytokines plays a key role in the pathogenesis of rheumatoid arthritis and osteoporosis through the regulation of bone formation and resorption. In this study, it was observed that ethanol extract of Salvia plebeia R.Br. (S.P-EE) inhibited IL-6-induced signaling cascade including phosphorylation of JAK2/STAT3 and ERK. Subsequently, it was examined whether S.P-EE treatment could recover bone loss in ovariectomized (OVX) mice. Indeed, S.P-EE exhibited both preventive and therapeutic effect on OVX-induced bone loss in trabecular microarchitecture along with significant increase in bone mineral density and content. To understand the mechanism of action of S.P-EE in bone metabolism, the effect of S.P-EE on osteoclast differentiation and activity was investigated. S.P-EE significantly inhibited RANKL-induced osteoclast differentiation by suppressing phosphorylation of MAPK and Akt, and expression of NFATc1 and osteoclast marker genes. S.P-EE also inhibited bone-resorbing activity of osteoclasts. Furthermore, isolation and identification of the active compounds which are responsible for the inhibitory effect of S.P-EE on osteoclast differentiation was carried out. Six major flavonoids and plebeiolide A-C were isolated and examined their effects on osteoclast differentiation. Luteolin and hispidulin, and plebeiolide A and C, not B exhibited potent inhibitory activity on RANKL-induced osteoclast formation.
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Resorción Ósea/prevención & control , Interleucina-6/antagonistas & inhibidores , Osteogénesis/efectos de los fármacos , Ovariectomía/efectos adversos , Extractos Vegetales/uso terapéutico , Salvia , Animales , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Osteogénesis/fisiología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Salvia plebeia R. Br. has been used to treat a variety of inflammatory diseases and as an antioxidant in many countries, including Korea and China. In this study, we investigated the effects of S. plebeia extract (SPE) on inflammatory arthritis and the underlying mechanisms of action. We used a collagen-induced arthritis (CIA) mouse model. TNF-α-stimulated rheumatoid arthritis (RA) synovial fibroblasts were used to elucidate the underlying mechanisms of action. Oral administration of SPE improved the clinical arthritis score, footpad thickness, and histologic changes, as well as serum IgG1 and IgG2a levels. SPE administration inhibited Th1/Th2/Th17 phenotype CD4(+) T lymphocyte expansion in inguinal lymph node and expression of inflammatory mediators such as cytokines, MMP-1, and MMP-3 in the ankle joint tissue. SPE significantly suppressed the expression of cytokines and MMP-1 by down-regulating NF-κB, Akt, and mitogen-activated protein kinases in RA synovial fibroblasts. Taken together, these results indicate that SPE is therapeutically efficacious against chronic inflammatory arthritis, suggesting that SPE is a candidate for treating RA.
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Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Fibroblastos/efectos de los fármacos , Salvia/química , Animales , Artritis Reumatoide/tratamiento farmacológico , Linfocitos T CD4-Positivos/inmunología , Canfanos , Células Cultivadas , Citocinas/inmunología , Humanos , Inmunoglobulina G/sangre , Masculino , Metaloproteinasas de la Matriz/inmunología , Ratones , Ratones Endogámicos BALB C , Panax notoginseng , Componentes Aéreos de las Plantas/química , Salvia miltiorrhizaRESUMEN
Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydropipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.
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Adhesión Celular/efectos de los fármacos , Piper nigrum/metabolismo , Piper/metabolismo , Extractos Vegetales/farmacología , Bioensayo , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Etanol/farmacología , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Piper/química , Piper nigrum/química , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría/métodosRESUMEN
We tested the effects of SI000413, a new formula, consisting of Pyrolae herba and Trachelospermi caulis, on type II collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by immunization with bovine type II collagen (CII) on days 1 and 21. SI000413 was orally administered 3 times per week throughout the experiment and indomethacin was served as a positive control. Clinical scores, the count of arthritic legs, levels of interleukin 6 (IL-6) and anti-CII antibody, and lymphocyte subsets in blood were examined. SI000413 suppressed CIA development in a dose dependent manner and reduced the incidence of arthritic legs in mice. Histological analysis showed administration of SI000413 reduced inflammatory signs and cartilage destruction. Serum levels of IL-6 and anti-CII antibody were significantly decreased in SI000413-treated mice and the percentages of CD4 T cell, CD8 T cell and B cell in blood were restored to normal levels. In conclusion, we demonstrate that SI000413 ameliorates CIA both clinically and histologically and inhibits the production of anti-CII antibody and pro-inflammatory cytokine in the CIA mouse. These findings suggest that SI000413 is a potential new therapeutic herbal formula for the treatment of RA.
Asunto(s)
Antirreumáticos/farmacología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/prevención & control , Colágeno Tipo II , Extractos Vegetales/farmacología , Preparaciones de Plantas/farmacología , Animales , Antirreumáticos/química , Artritis Reumatoide/patología , Autoanticuerpos/análisis , Autoanticuerpos/biosíntesis , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Cartílago/patología , Cromatografía Líquida de Alta Presión , Colágeno Tipo II/inmunología , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Furanos/análisis , Furanos/aislamiento & purificación , Glucósidos/análisis , Glucósidos/aislamiento & purificación , Interleucina-6/análisis , Interleucina-6/biosíntesis , Articulaciones/patología , Subgrupos Linfocitarios/inmunología , Masculino , Ratones , Ratones Endogámicos DBA , Extractos Vegetales/química , Preparaciones de Plantas/químicaRESUMEN
The mushroom Paecilomyces japonica, grown on the silkworm larvae, has been used in Asia as a nutraceutical, tea, and Chinese medicine. In the present study, a sialic acid-specific lectin has been purified from the mushroom P. japonica using affinity chromatography on a fetuin-agarose column. Electrophoretical analyses indicated that this lectin, designated P. japonica agglutinin (PJA), is an acidic protein with a molecular mass of 16 kDa, and has no intermolecular disulfide bonds. PJA induced hemagglutination activity in human ABO, mouse, rat, and rabbit erythrocytes. This activity was inhibited by sialic acid and sialoglycoproteins, but not by any other carbohydrates. PJA was stable at pH 4.0-8.0, and at temperatures below 55 degrees C. The activity of PJA was independent of EDTA and divalent cations. In addition, PJA exerts cytotoxic effects on the following cancer cell lines: human stomach cancer SNU-1, human pancreas cancer AsPc-1, and human breast cancer MDA-MB-231.