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1.
Microbiol Resour Announc ; 13(7): e0033924, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-38860807

RESUMEN

The complete genome of the potential probiotic Lactiplantibacillus plantarum strain beLP1, isolated from kimchi in South Korea, was sequenced using Illumina and PacBio technologies. The genome comprises one circular chromosome and one plasmid without antimicrobial resistance genes.

2.
Bioorg Chem ; 82: 26-32, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30267971

RESUMEN

Inflammation is not only a self-defense response of the innate immune system, but also the pathogenesis mechanism of multiple diseases such as arthritis, neurodegeneration, and cancer. Curcuma zedoaria Roscoe (Zingiberaceae), an indigenous plant of India, has been used traditionally in Ayurveda and folk medicine. As part of our ongoing efforts to screen traditional medicinal plants exhibiting pharmacological potential and to characterize the compounds involved, we examined the anti-inflammatory effects of the MeOH extract of C. zedoaria rhizomes using lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells and found that MeOH extract inhibited the synthesis of nitric oxide (NO) in a dose-dependent manner (IC50: 23.44 ±â€¯0.77 µg/mL). In our efforts to characterize the compounds responsible for these anti-inflammatory effects, bioactivity-guided fractionation of the MeOH extract and chemical investigation of its active hexane-soluble fraction led to the successful isolation of five sesquiterpenes (1-5), the structures of which were elucidated by NMR spectroscopic analysis and LC/MS analysis. Among them, curcuzedoalide (5) exhibited potent inhibitory effects on NO synthesis (IC50: 12.21 ±â€¯1.67 µM) and also suppressed pre-inflammatory protein expression of iNOS and COX-2. Curcuzedoalide (5) was thus determined to be a contributor to the anti-inflammatory effect of C. zedoaria rhizomes and could be a potential candidate for therapeutic applications.


Asunto(s)
Antiinflamatorios/farmacología , Curcuma/química , Rizoma/química , Sesquiterpenos/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/toxicidad , Ciclooxigenasa 2/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Células RAW 264.7 , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/toxicidad
3.
J Ginseng Res ; 42(4): 562-570, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30337817

RESUMEN

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. In this study, we used a bioactivity-guided isolation technique to identify constituents of Korean Red Ginseng (KRG) with antiproliferative activity against human lung adenocarcinoma cells. METHODS: Bioactivity-guided fractionation and preparative/semipreparative HPLC purification were used with LC/MS analysis to separate the bioactive constituents. Cell viability and apoptosis in human lung cancer cell lines (A549, H1264, H1299, and Calu-6) after treatment with KRG extract fractions and constituents thereof were assessed using the water-soluble tetrazolium salt (WST-1) assay and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. Caspase activation was assessed by detecting its surrogate marker, cleaved poly adenosine diphosphate (ADP-ribose) polymerase, using an immunoblot assay. The expression and subcellular localization of apoptosis-inducing factor were assessed using immunoblotting and immunofluorescence, respectively. RESULTS AND CONCLUSION: Bioactivity-guided fractionation of the KRG extract revealed that its ethyl acetate-soluble fraction exerts significant cytotoxic activity against all human lung cancer cell lines tested by inducing apoptosis. Chemical investigation of the ethyl acetatesoluble fraction led to the isolation of six ginsenosides, including ginsenoside Rb1 (1), ginsenoside Rb2 (2), ginsenoside Rc (3), ginsenoside Rd (4), ginsenoside Rg1 (5), and ginsenoside Rg3 (6). Among the isolated ginsenosides, ginsenoside Rg3 exhibited the most cytotoxic activity against all human lung cancer cell lines examined, with IC50 values ranging from 161.1 µM to 264.6 µM. The cytotoxicity of ginsenoside Rg3 was found to be mediated by induction of apoptosis in a caspase-independent manner. These findings provide experimental evidence for a novel biological activity of ginsenoside Rg3 against human lung cancer cells.

4.
Bioorg Chem ; 81: 27-34, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30092384

RESUMEN

Poria cocos Wolf confers edible sclerotia also known as 'Indian bread' in North America, that have been used for the treatment of various diseases in Asian countries. As part of our ongoing aim to identify biologically new metabolites from Korean edible mushrooms, we investigated the ethanol (EtOH) extract of the sclerotia of P. cocos by applying a comparative LC/MS- and bioassay-based analysis approach, since the EtOH extract reciprocally regulated adipocyte and osteoblast differentiation in mouse mesenchymal stem cells (MSCs). Bioassay-based analysis of the EtOH extract led to the successful isolation of two sterols, ergosterol peroxide (1) and 9,11-dehydroergosterol peroxide (2); three diterpenes, dehydroabietic acid (3), 7-oxocallitrisic acid, (4) and pimaric acid (5); and two triterpenes, dehydroeburicoic acid monoacetate (6) and eburicoic acid acetate (7) from the active hexane-soluble fraction. The isolated compounds (1-7) were examined for their effects on the regulation of MSC differentiation. The two sterols (1 and 2) were able to suppress MSC differentiation toward adipocytes. In contrast, the three diterpenes (3-5) showed activity to promote osteogenic differentiation of MSC. These findings demonstrate that the EtOH extract of P. cocos sclerotia is worth consideration as a new potential source of bioactive compounds effective in the treatment of osteoporosis in the elderly, since the extract contains sterols that inhibit adipogenic differentiation as well as diterpenes that promote osteogenic differentiation from MSCs.


Asunto(s)
Adipocitos/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Wolfiporia/química , Abietanos/química , Abietanos/aislamiento & purificación , Abietanos/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Diterpenos/química , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Peróxidos/química , Peróxidos/aislamiento & purificación , Peróxidos/farmacología , Esteroles/química , Esteroles/aislamiento & purificación , Esteroles/farmacología , Relación Estructura-Actividad
5.
J Agric Food Chem ; 66(11): 2677-2684, 2018 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-29444566

RESUMEN

Oryza sativa L. is consumed globally as a staple food, and its roots have been used as a Korean and Chinese medical supplement for protection of the stomach and lungs and for amelioration of vomiting and fever. In our continuing search for biologically effective metabolites from Korean natural materials, we found that an EtOH extract of O. sativa root reciprocally regulated adipocyte and osteoblast differentiation. Chemical analysis of the EtOH extract using a bioassay-guided fractionation protocol led to the isolation and determination of two novel lignans, oryzativols A and B, responsible for these regulatory activities. Using 1D and 2D nuclear magnetic resonance spectroscopic analyses, high-resolution mass spectrometry, and circular dichroism analysis, the structures of the novel compounds were elucidated. We examined their effects on the regulation of mesenchymal stem cell differentiation. Treatment with oryzativol A in the human mesenchymal cell line C3H10T1/2 suppressed gene expression of peroxisome proliferator activated receptor γ, which resulted in a reduction in adipogenesis. Oryzativol A also enhanced the expression of Runx2 and cellular differentiation into osteoblasts in the same mesenchymal stem cell line.


Asunto(s)
Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Productos Biológicos/farmacología , Oryza/química , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Adipocitos/citología , Adipocitos/metabolismo , Animales , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Línea Celular , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Osteoblastos/citología , Osteoblastos/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química
6.
Mol Neurobiol ; 55(4): 3007-3020, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28456941

RESUMEN

The signaling axis of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) has been an important component in overcoming diabetes, and recent reports have uncovered novel beneficial roles of this signaling axis in central nervous system (CNS) disorders, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, accelerating processes for exendin-4 repositioning. Here, we studied whether multiple sclerosis (MS) could be a complement to the CNS disorders that are associated with the GLP-1/GLP-1R signaling axis. Both components of the signaling axis, GLP-1 and GLP-1R proteins, are expressed in neurons, astrocytes, and microglia in the spinal cord of normal mice. In particular, they are abundant in Iba1-positive microglia. Upon challenge by experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the mRNA expression of both GLP-1 and GLP-1R was markedly downregulated in EAE-symptomatic spinal cords, indicating attenuated activity of GLP-1/GLP-1R signaling in EAE. Such a downregulation obviously occurred in LPS-stimulated rat primary microglia, a main cell type to express both GLP-1 and GLP-1R, further indicating attenuated activity of GLP-1/GLP-1R signaling in activated microglia. To investigate whether increased activity of GLP-1R has a therapeutic benefit, exendin-4 (5 µg/kg, i.p.), a GLP-1R agonist, was administered daily to EAE-symptomatic mice. Exendin-4 administration to symptomatic EAE mice significantly improved the clinical signs of the disease, along with the reversal of histopathological sequelae such as cell accumulation, demyelination, astrogliosis, microglial activation, and morphological transformation of activated microglia in the injured spinal cord. Such an improvement by exendin-4 was comparable to that by FTY720 (3 mg/kg, i.p.), a drug for MS. The neuroprotective effects of exendin-4 against EAE were also associated with decreased mRNA expression of proinflammatory cytokines, such as interleukin (IL)-17, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, all of which are usually upregulated in injured sites of the EAE spinal cord. Interestingly, exendin-4 exposure similarly reduced mRNA levels of IL-1ß and TNF-α in LPS-stimulated microglia. Furthermore, exendin-4 administration significantly attenuated activation of NF-κB signaling in EAE spinal cord and LPS-stimulated microglia. Collectively, the current study demonstrates the therapeutic potential of exendin-4 for MS by reducing immune responses in the CNS, highlighting the importance of the GLP-1/GLP-1R signaling axis in the development of a novel therapeutic strategy for MS.


Asunto(s)
Encéfalo/patología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Inflamación/patología , Neuroprotección , Animales , Células Cultivadas , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/genética , Exenatida/administración & dosificación , Exenatida/farmacología , Femenino , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , FN-kappa B/metabolismo , Neuroprotección/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Transducción de Señal , Médula Espinal/patología
7.
Bioorg Med Chem Lett ; 28(2): 122-128, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29223588

RESUMEN

Lespedeza cuneata (Dum. Cours.) G. Don. (Fabaceae), known as Chinese bushclover or sericea lespedeza, has been used in traditional medicine to treat diabetes, hematuria, and insomnia, and it has been reported that bioactive compounds from L. cuneata possess various pharmacological properties. However, there has been no study to determine the active compounds from L. cuneata with potential activity against ovarian cancer. This study aimed to isolate cytotoxic compounds from L. cuneata and identify the molecular mechanisms underlying the apoptosis pathway in ovarian cancer cells. Based on cytotoxic activity identified in the screening test, chemical investigation of the active fraction of L. cuneata led to the isolation of nine compounds including four lignanosides (1-4), three flavonoid glycosides (5-7), and two phenolics (8-9). Cytotoxicity and the molecular mechanism were examined by methyl thiazolyl tetrazolium (MTT) assay and Western blot analysis. Of the isolated compounds, (-)-9'-O-(α-l-rhamnopyranosyl)lyoniresinol (3) demonstrated the strongest effect in suppressing A2780 human ovarian carcinoma cell proliferation in a dose-dependent manner, with an IC50 value of 35.40 ±â€¯2.78 µM. Control A2780 cells had normal morphology, whereas cell blebbing, shrinkage, and condensation were observed after treatment with compound 3. Western blotting analysis showed that compound 3 inhibited A2780 human ovarian cancer cell viability by activating caspase-8, caspase-3, and PARP, which contributed to apoptotic cell death. These results suggest that (-)-9'-O-(α-l-rhamnopyranosyl)lyoniresinol (3) has potent anticancer activities against A2780 human ovarian carcinoma cells through the extrinsic apoptotic pathway. Therefore, (-)-9'-O-(α-l-rhamnopyranosyl)lyoniresinol is an excellent candidate for the development of novel chemotherapeutics.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Lespedeza/química , Monosacáridos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Monosacáridos/química , Monosacáridos/aislamiento & purificación , Relación Estructura-Actividad
8.
Bioorg Chem ; 74: 122-125, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28778013

RESUMEN

Lindera glauca (Sieb. et Zucc.) Blume (Lauraceae) has been used to treat rheumatic arthritis, stroke, and cardiac pain. Phytochemical investigation of twigs of L. glauca (Sieb. et Zucc.) Blume resulted in the isolation and identification of a new cerebroside, glaucerebroside (1). The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR, HR-MS, chemical reactions, and LC/MS analysis. Compound 1 is a relatively rare cerebroside with l-threo-configuration of the sphingosine part. This is the second example of identification of a cerebroside from the family Lauraceae. Compound 1 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV-2 cells, with an IC50 value of 23.84µM without inducing cell toxicity. This study suggests that glaucerebroside (1) can be an excellent candidate for development of novel anti-neuroinflammatory agents.


Asunto(s)
Cerebrósidos/farmacología , Lindera/química , Tallos de la Planta/química , Animales , Supervivencia Celular/efectos de los fármacos , Cerebrósidos/química , Cerebrósidos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Conformación Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Relación Estructura-Actividad
9.
Bioorg Chem ; 70: 94-99, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27912907

RESUMEN

Poria cocos Wolf (Polyporaceae) has been used as a medicinal fungus to treat various diseases since ancient times. This study aimed to investigate the anti-inflammatory chemical constituents of the sclerotia of P. cocos. Based on bioassay-guided fractionation using lipopolysaccharide (LPS)-stimulated Raw264.7 cells, chemical investigation of the EtOH extract of the sclerotia of P. cocos resulted in the isolation and identification of eight compounds including six triterpenoids, namely poricoic acid A (1), 3-O-acetyl-16α-hydroxydehydrotrametenolic acid (2), polyporenic acid C (3), 3ß-hydroxylanosta-7,9(11),24-trien-21-oic acid (4), trametenolic acid (5), and dehydroeburicoic acid (6), as well as (-)-pinoresinol (7) and protocatechualdehyde (8). The structures of the isolated compounds were determined by spectroscopic analysis, including 1H and 13C NMR spectra, and LC/MS analysis. The anti-inflammatory activities of the isolates were evaluated by estimating their effect on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated Raw264.7 as well as on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compounds 1-5 inhibited NO production and iNOS expression in LPS-stimulated Raw264.7 cells. Among them, compound 1 exerted the highest anti-inhibitory activity and reduced PGE2 levels via downregulation of COX-2 protein expression. The findings of this study provide experimental evidence that the sclerotia of P. cocos are a potential source of natural anti-inflammatory agents for use in pharmaceuticals and functional foods. Furthermore, the most active compound 1, seco-lanostane triterpenoid, could be a promising lead compound for the development of novel anti-inflammatory agents.


Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Macrófagos/efectos de los fármacos , Triterpenos/química , Triterpenos/farmacología , Wolfiporia/química , Animales , Antiinflamatorios/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Ciclooxigenasa 2/inmunología , Dinoprostona/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Ratones , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa de Tipo II/inmunología , Células RAW 264.7 , Triterpenos/aislamiento & purificación
10.
Arch Pharm Res ; 39(12): 1628-1634, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27620498

RESUMEN

A new rearranged eudesmane sesquiterpene, named eudeglaucone (1), and five known sesquiterpenes including (+)-faurinone (2) and four eudesmane-type sesquiterpenes (3-6), were isolated from the twigs of Lindera glauca (Sieb. et Zucc.) Blume. The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY) and HR-MS. Compound 1 was a relatively rare rearranged eudesmane sesquiterpene in terpenoids. All isolates were evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15). Compounds 3 and 6 showed significant cytotoxicity against SK-MEL-2 and HCT-15 cell lines with IC50 values ranging from 9.98 to 12.20 µM. We also investigated the anti-neuroinflammatory activities of the isolates (1-6) in the lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cell line by measuring nitric oxide (NO) levels. All isolates significantly inhibited NO production with IC50 values of 3.67-26.48 µM without inducing cell toxicity.


Asunto(s)
Lindera , Tallos de la Planta , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/aislamiento & purificación , Animales , Línea Celular Tumoral , Humanos , Ratones , Microglía/efectos de los fármacos , Microglía/fisiología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos de Eudesmano/farmacología
11.
Chem Biodivers ; 13(10): 1391-1396, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27447684

RESUMEN

A new sesquilignan, euonymolin A (1), and six known lignans, (-)-de-O-methylmagnolin (2), (+)-de-O-methylepimagnolin A (3), (+)-syringaresinol (4), (+)-pinoresinol (5), (+)-medioresinol (6), and (+)-lariciresinol 4'-O-ß-d-glucopyranoside (7), were isolated from the twigs of Euonymus alatus (Thunb.) Siebold (Celastraceae). The structures of the isolated compounds were elucidated based on spectroscopic analyses, including extensive 1D- and 2D-NMR techniques, HR-MS analysis and circular dichroism (CD) data, and the literature data. All of the isolated compounds were evaluated for antiproliferative activity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines and inhibition of nitric oxide (NO) production in a lipopolysaccharide (LPS)-activated BV2 cell line. All compounds showed cytotoxicity against the SK-MEL-2 cell line with IC50 values of 23.24 - 48.14 µm and inhibited NO production in LPS-activated BV-2 cells with IC50 values of 6.75 - 23.53 µm.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Euonymus/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Óxido Nítrico/biosíntesis , Tallos de la Planta/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lignanos/química , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Relación Estructura-Actividad
12.
Mol Neurobiol ; 53(1): 231-239, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25421209

RESUMEN

The neutrophil collagenase matrix metalloproteinase-8 (MMP8) is a recently identified member of MMPs that have important roles in various inflammation-related disorders. Previously, we identified MMP8 as a new neuroinflammatory mediator in activated microglia by regulating TNF-α productivity. Here, we present evidence that MMP8 is a critical factor for brain damage in transient focal cerebral ischemia by modulating neuroinflammation likely microglial activation and TNF-α production. Biochemical analyses showed upregulation of MMP8 expression at mRNA and protein levels in transient middle cerebral artery occlusion/reperfusion (M/R)-challenged brains. Furthermore, double immunolabeling showed that MMP8 expression was upregulated in the activated microglia of M/R-challenged brains. Assessment of infarct volume, neurological score, and survival/death of neural cells revealed that administration of an MMP8 inhibitor (M8I) immediately after reperfusion reduced brain damage. Histological analyses showed that microglial activation and TNF-α expression in ischemic conditions was abrogated by exposure to M8I, as demonstrated in our previous study using cultured microglia. These outcomes from a pharmacological approach were reaffirmed by a genetic approach using a lentiviral system. Intracerebroventricular microinjection of MMP8-specific shRNA lentivirus reduced the extent of ischemia-induced brain damage, as assessed by infarct volume, neurological score, microglial activation, and TNF-α expression. These results suggest a novel pathogenetic role of MMP8 and implicate modulation of its activity as a tractable strategy for therapies against cerebral ischemia.


Asunto(s)
Isquemia Encefálica/enzimología , Metaloproteinasa 8 de la Matriz/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/patología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Claudina-5/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Inflamación/patología , Lentivirus/metabolismo , Masculino , Ratones Endogámicos ICR , ARN Interferente Pequeño/metabolismo , Reperfusión , Regulación hacia Arriba/efectos de los fármacos
13.
Mediators Inflamm ; 2015: 492659, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26576074

RESUMEN

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.


Asunto(s)
Isquemia Encefálica/prevención & control , Lisofosfolípidos/fisiología , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Esfingosina/análogos & derivados , Accidente Cerebrovascular/prevención & control , Animales , Barrera Hematoencefálica , Isquemia Encefálica/etiología , Clorhidrato de Fingolimod/farmacología , Lisofosfolípidos/toxicidad , Masculino , Ratones , Ratones Endogámicos ICR , Microinyecciones , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Transducción de Señal , Esfingosina/fisiología , Esfingosina/toxicidad , Accidente Cerebrovascular/etiología , Factor de Necrosis Tumoral alfa/análisis
14.
Chem Pharm Bull (Tokyo) ; 63(10): 837-42, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26423042

RESUMEN

As part of our ongoing search for bioactive constituents of natural Korean medicinal resources, we found in a preliminary study that the methanol (MeOH) extract from the trunks of Tilia amurensis RUPR. showed an inhibitory effect on nitric oxide (NO) production in an activated murine microglial cell line. A bioassay-guided fractionation and chemical investigation of the MeOH extract resulted in the isolation and identification of a new isoflavonoid glycoside, orobol 4'-O-ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranoside (1) and 16 known compounds (2-17). The structure of the new compound was determined by spectroscopic methods, i.e., one-dimensional (1D) and two-dimensional (2D)-NMR techniques and high resolution (HR)-MS, and chemical methods. The antineuroinflammatory activities of the isolated compounds were determined by measuring NO levels in the medium using murine microglial BV-2 cells. Among them, 12 compounds, including compound 1 (most active with an IC50 value of 23.42 µM), inhibited NO production in lipopolysaccharide-stimulated BV-2 cells. Moreover, compounds 1-4 showed moderate antiproliferative activities against the SK-MEL-2 cell line, with IC50 values ranging from 12.31 to 19.67 µM.


Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Isoflavonas/química , Isoflavonas/farmacología , Tilia/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Glicósidos/química , Glicósidos/farmacología , Humanos , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Microglía/inmunología , Neoplasias/tratamiento farmacológico , Óxido Nítrico/inmunología
15.
J Antibiot (Tokyo) ; 68(6): 414-6, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25627016
16.
J Ethnopharmacol ; 162: 231-7, 2015 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-25582488

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Toxicodendron vernicifluum (Stokes) F.A. Barkley (Anacardiaceae) has traditionally been used as a food supplement and in traditional herbal medicine to treat inflammatory diseases and cancers for centuries in Korea. This study was designed to isolate the bioactive constituents from the ethanol extract of Toxicodendron vernicifluum bark and evaluate their cytotoxic and anti-inflammatory activities. MATERIAL AND METHODS: Bioassay-guided fractionation and chemical investigation of the ethanol extract of Toxicodendron vernicifluum bark resulted in the isolation and identification of three new polyphenols (1-3) and six flavonoids (4-9). The structures of the isolated compounds were elucidated by spectroscopic analysis, including 1D and 2D nuclear magnetic resonance (NMR) ((1)H, (13)C, COSY, HMQC and HMBC experiments), and high resolution (HR)-mass spectrometry, and their absolute configurations were further confirmed by chemical methods and circular dichroism (CD) data analysis. Compounds 1-9 were evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15), and anti-inflammatory activities by measuring nitric oxide (NO) levels in the medium of murine microglia BV-2 cells. RESULTS: The isolated compounds were characterized as in the following: three new polyphenols, rhusopolyphenols G-I (1-3) and six flavonoids including two aurones, 2-benzyl-2,3',4',6-tetrahydroxybenzo[b]furan-3(2H)-one (4), sulfuretin (5), two dihydroflavonols, (+)-(2S,3R)-fustin (6), (+)-epitaxifolin (7), one chalcone, butein (8), and one flavonol, fisetin (9). The published NMR assignments of 4 were corrected by the detailed analysis of spectroscopic data in this study. Among the tested compounds, compounds 4-9 showed antiproliferative activity against the tested cells, with IC50 values of 4.78-28.89 µM. Compounds 5 and 8 significantly inhibited NO production in lipopolysaccharide (LPS)-stimulated BV-2 cells with IC50 values of 23.37 and 11.68 µM, respectively. CONCLUSIONS: Polyphenols including flavonoids were one of the main constituents of Toxicodendron vernicifluum bark, and activities demonstrated by the isolated compounds support the ethnopharmacological use of Toxicodendron vernicifluum as anti-cancer and/or anti-inflammatory agents.


Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos Fitogénicos/farmacología , Corteza de la Planta/química , Toxicodendron/química , Antiinflamatorios/química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Estructura Molecular
17.
J Proteomics ; 117: 70-85, 2015 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-25576851

RESUMEN

Photodamage is extrinsically induced by overexposure to ultraviolet (UV) radiation, and it increases the risk of various skin disorders. Therefore, discovery of novel biomarkers of photodamage is important. In this study, using LC-MS/MS analysis of epidermis from UVB-irradiated hairless mice, we identified 57 proteins whose levels changed after UVB exposure, and selected 7 proteins related to the tricarboxylic acid (TCA) cycle through pathway analysis. Dihydrolipoyl dehydrogenase (DLD) was the only TCA cycle-associated protein that showed a decreased expression after the UVB exposure. We also performed targeted analysis to detect intermediates and products of the TCA cycle using GC-TOF-MS. Interestingly, malic acid and fumaric acid levels significantly decreased in the UVB-treated group. Our results demonstrate that DLD and its associated metabolites, malic acid and fumaric acid, may be candidate biomarkers of UVB-induced skin photoaging. Additionally, we showed that Aloe vera, a natural skin moisturizer, regulated DLD, malic acid and fumaric acid levels in UVB-exposed epidermis. Our strategy to integrate the proteome and targeted metabolite to detect novel UVB targets will lead to a better understanding of skin photoaging and photodamage. Our study also supports that A. vera exerts significant anti-photodamage activity via regulation of DLD, a novel UVB target, in the epidermis. BIOLOGICAL SIGNIFICANCE: This study is the first example of an integration of proteomic and metabolite analysis techniques to find new biomarker candidates for the regulation of the UVB-induced skin photoaging. DLD, malic acid, and fumaric acid can be used for development of cosmeceuticals and nutraceuticals regulating the change of skin metabolism induced by the UVB overexposure. Moreover, this is also the first attempt to investigate the role of the TCA cycle in photodamaged epidermis. Our integration of the proteomic and targeted metabolite analyses will lead to a better understanding of the unidentified photobiological results from UVB-irradiated models and can elicit new diagnostic and treatment strategies based on altered metabolism.


Asunto(s)
Dihidrolipoamida Deshidrogenasa/biosíntesis , Epidermis/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiación , Rayos Ultravioleta , Aloe/química , Animales , Ciclo del Ácido Cítrico/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de la radiación , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Pelados , Proteómica , Envejecimiento de la Piel/efectos de los fármacos , Crema para la Piel/química , Crema para la Piel/farmacología
18.
Bioorg Med Chem Lett ; 25(1): 96-9, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25466198

RESUMEN

A bioassay-guided fractionation and chemical investigation of the MeOH extract of Raphanus sativus seeds resulted in the isolation and identification of eight phenylpropanoid sucrosides (1-8) including two new compounds, named raphasativuside A and B (1-2) from the most active CHCl3-soluble fraction. The structures of these new compounds were elucidated through spectral analysis, including extensive 2D-NMR data, and chemical reaction experiments. We evaluated the anti-inflammatory effects of 1-8 in lipopolysaccharide (LPS)-stimulated murine microglia BV2 cells. Compounds 2 and 5 exhibited significant inhibitory effect on nitric oxide production in LPS-activated BV-2 cells with IC50 values of 21.63 and 26.96 µM, respectively. All isolates were also evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15). Compounds 1-7 showed consistent cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with IC50 values of 6.71-27.92 µM. Additionally, the free-radical scavenging activity of 1-8 was assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay where compounds 1, 3, and 4 scavenged DPPH radical strongly with IC50 values of 23.05, 27.10, and 29.63 µg/mL, respectively.


Asunto(s)
Antiinflamatorios/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Fenilpropionatos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Raphanus , Semillas , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fenilpropionatos/química , Fenilpropionatos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología
19.
Biomol Ther (Seoul) ; 22(5): 445-52, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25414776

RESUMEN

The purpose of this study was to investigate the therapeutic effects of DA-9801, an optimized extract of Dioscorea species, on diabetic peripheral neuropathy in a type 2 diabetic animal model. In this study, db/db mice were treated with DA-9801 (30 and 100 mg/kg, daily, p.o.) for 12 weeks. DA-9801 reduced the blood glucose levels and increased the withdrawal latencies in hot plate tests. Moreover, it prevented nerve damage based on increased nerve conduction velocity and ultrastructural changes. Decrease of nerve growth factor (NGF) may have a detrimental effect on diabetic neuropathy. We previously reported NGF regulatory properties of the Dioscorea genus. In this study, DA-9801 induced NGF production in rat primary astrocytes. In addition, it increased NGF levels in the sciatic nerve and the plasma of type 2 diabetic animals. DA-9801 also increased neurite outgrowth and mRNA expression of Tieg1/Klf10, an NGF target gene, in PC12 cells. These results demonstrated the attenuation of diabetic peripheral neuropathy by oral treatment with DA-9801 via NGF regulation. DA-9801 is currently being evaluated in a phase II clinical study.

20.
Chem Pharm Bull (Tokyo) ; 62(11): 1136-40, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25366316

RESUMEN

A bioassay-guided fractionation and chemical investigation of the MeOH extract from the twigs of Lindera glauca (SIEB. et ZUCC.) BLUME resulted in the isolation and identification of six lignans (1-6) including three new lignan derivatives, named linderuca A (1), B (2), and C (3). The structures of the new compounds (1-3) were determined on the basis of spectroscopic analyses, including two dimensional NMR and circular dichroism (CD) spectroscopy studies. The cytotoxic activities of the isolates (1-6) were evaluated by determining their inhibitory effects on human tumor cell lines. Compounds 1-5 showed antiproliferative activities against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with IC50 values of 7.79-29.42 µM. Based on the understanding that inflammation is a crucial cause of tumor progression, we also investigated the anti-inflammatory activities of the isolates (1-6) in the lipopolysaccharide-stimulated murine microglia BV-2 cell line by measuring nitric oxide (NO) levels. The new lignans (1-3) significantly inhibited NO production with IC50 values of 12.10, 9.48, and 9.87 µM, respectively, without cytotoxicity.


Asunto(s)
Antiinflamatorios/análisis , Antiinflamatorios/farmacología , Antineoplásicos Fitogénicos/análisis , Antineoplásicos Fitogénicos/farmacología , Lignanos/análisis , Lignanos/farmacología , Lindera/química , Animales , Antiinflamatorios/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Lignanos/aislamiento & purificación , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Neoplasias/tratamiento farmacológico , Óxido Nítrico/análisis , Óxido Nítrico/inmunología , Extractos Vegetales/química
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