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1.
J Nat Prod ; 79(4): 1097-104, 2016 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-27064730

RESUMEN

The antitumor activity of spicatoside A (1), a steroidal saponin isolated from the tuber of Liriope platyphylla, and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. Compound 1 induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with 1 for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1 (LAMP 1), and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase (MAPK) signaling, and increasing p53 levels. However, a prolonged exposure to 1 resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide (PI)-positive cell population. Apoptosis induced by 1 was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly-ADP-ribose polymerase (PARP). Further study revealed that cleavage of beclin 1 by caspases plays a critical role in the 1-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of 1 in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of 1 as a novel candidate in the treatment of human colorectal cancer cells.


Asunto(s)
Autofagia/efectos de los fármacos , Liliaceae/química , Saponinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Beclina-1 , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales , Células HCT116 , Humanos , Proteínas de la Membrana , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Saponinas/química , Saponinas/aislamiento & purificación , Transducción de Señal/efectos de los fármacos
2.
J Nat Prod ; 77(4): 917-24, 2014 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-24689881

RESUMEN

The anti-inflammatory activity of handelin (1), a guaianolide dimer from Chrysanthemum boreale flowers, was evaluated in vivo, and the effects on mediators nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) and the nuclear factor-κB (NF-κB) and ERK/JNK signaling pathways were investigated in vitro. Compound 1 inhibited lipopolysaccharide (LPS)-induced production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compound 1 also suppressed the induction of pro-inflammatory cytokines TNF-α and IL-1ß in LPS-stimulated RAW 264.7 cells. To further clarify the transcriptional regulatory pathway in the expression of iNOS and COX-2 by 1, the role of NF-κB was determined in RAW 264.7 cells. Compound 1 inhibits the binding activity of NF-κB into the nuclear proteins. The transcriptional activity of NF-κB stimulated with LPS was also suppressed by 1, which coincided with the inhibition of IκB degradation. Compound 1 also suppressed the activation of mitogen-activated protein kinases, including ERK and JNK signaling. In addition, the LPS-stimulated upregulation of miRNA-155 expression was suppressed by 1. The oral administration of 1 inhibited acute inflammation in carrageenan-induced paw and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema models. The serum level of IL-1ß was also inhibited by 1 in a carrageenan-induced paw edema model. These findings suggest that the suppression of NF-κB activation and pro-inflammatory cytokine production may be a plausible mechanism of action for the anti-inflammatory activity of handelin.


Asunto(s)
Antiinflamatorios/farmacología , Chrysanthemum/química , Citocinas/metabolismo , Proteínas I-kappa B/metabolismo , FN-kappa B/efectos de los fármacos , Terpenos/farmacología , Animales , Antiinflamatorios/química , Ciclooxigenasa 2 , Dinoprostona/metabolismo , Regulación hacia Abajo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Proteínas I-kappa B/efectos de los fármacos , Interleucina-1beta/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Animales , Estructura Molecular , Inhibidor NF-kappaB alfa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fitoterapia , Transducción de Señal/efectos de los fármacos , Terpenos/química , Factor de Necrosis Tumoral alfa/efectos de los fármacos
3.
Chem Biodivers ; 11(5): 749-59, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24827684

RESUMEN

Anemarrhena asphodeloides is widely used in traditional Chinese medicine, and is known to possess antidiabetic and anti-inflammatory properties. Because inducible nitric oxide synthase (iNOS) plays an important role in inflammation, we investigated the inhibitory effects of two known phenolic compounds, nyasol (1) and broussonin A (2), from A. asphodeloides, on iNOS and its plausible mechanism of action. Compounds 1 and 2 exhibited inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Compounds 1 and 2 also suppressed the expressions of iNOS protein and mRNA. Moreover, compounds 1 and 2 suppressed the expression of inflammatory cytokines such as interleukin-1ß (IL-1ß) and interferon-ß (IFN-ß). They also inhibited the transcriptional activity of NF-κB and degradation of IκB-α, as well as the activation of Akt and ERK in LPS-stimulated RAW 264.7 cells. In in vivo animal model, compounds 1 and 2 significantly inhibited TPA-induced mouse ear edema. These results suggest that 1 and 2 suppress LPS-stimulated iNOS expression at the transcriptional level through modulating NF-κB and down-regulation of the Akt and ERK signaling pathways. Taken together, these findings indicate that the suppressive effects of 1 and 2 on iNOS expression might provide one possible mechanism for their anti-inflammatory activities.


Asunto(s)
Anemarrhena/química , Antiinflamatorios/farmacología , Proteínas I-kappa B/genética , Lignanos/farmacología , Macrófagos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/genética , Fenoles/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Proteínas I-kappa B/inmunología , Lignanos/aislamiento & purificación , Lignanos/uso terapéutico , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Inhibidor NF-kappaB alfa , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa de Tipo II/inmunología , Fenoles/aislamiento & purificación , Fenoles/uso terapéutico , Activación Transcripcional/efectos de los fármacos
4.
Mar Drugs ; 11(3): 611-22, 2013 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-23442790

RESUMEN

In the chemical investigation of marine unicellular bacteria, a new peptide, thalassospiramide G (1), along with thalassospiramides A and D (2-3), was discovered from a large culture of Thalassospira sp. The structure of thalassospiramide G, bearing γ-amino acids, such as 4-amino-5-hydroxy-penta-2-enoic acid (AHPEA), 4-amino-3,5-dihydroxy-pentanoic acid (ADPA), and unique 2-amino-1-(1H-indol-3-yl) ethanone (AIEN), was determined via extensive spectroscopic analysis. The absolute configuration of thalassospiramide D (3), including 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), was rigorously determined by 1H-1H coupling constant analysis and chemical derivatization. Thalassospiramides A and D (2-3) inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells, with IC(50) values of 16.4 and 4.8 µM, respectively.


Asunto(s)
Macrófagos/efectos de los fármacos , Péptidos Cíclicos/farmacología , Péptidos/farmacología , Rhodospirillaceae/química , Animales , Línea Celular , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Ratones , Óxido Nítrico/biosíntesis , Péptidos/química , Péptidos/aislamiento & purificación , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/aislamiento & purificación , Análisis Espectral
5.
Bioorg Med Chem ; 20(13): 4109-16, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22633122

RESUMEN

A chlorinated methyl jasmonate analog (J7) was elaborated as an in vitro anti-inflammatory lead. However, its in vitro efficacy profile was not reproduced in a subsequent in vivo evaluation, presumably due to its rapid enzymatic hydrolysis in a biological system. In an attempt to improve the metabolic stability of the lead J7 by replacement of its labile methyl ester with reasonable ester groups, several analogs resistant to enzymatic hydrolysis were synthesized. In vivo evaluation of the stability-improved analogs showed that these compounds displayed higher efficacy than the lead J7, suggesting that these new jasmonate analogs may serve as potential anti-inflammatory leads.


Asunto(s)
Antiinflamatorios/síntesis química , Ciclopentanos/química , Ciclopentanos/síntesis química , Ácidos Grasos Insaturados/síntesis química , Oxilipinas/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclopentanos/farmacología , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Ratones , Óxido Nítrico/metabolismo , Oxilipinas/síntesis química , Oxilipinas/farmacología , Relación Estructura-Actividad
6.
Chin Med ; 11: 17, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27069504

RESUMEN

BACKGROUND: SHINBARO is a refined herbal formulation used to treat inflamed lesions and bone diseases. This study aimed to investigate the anti-osteoarthritic activities of intra-articular administration of SHINBARO and determine its underlying molecular mechanism in a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. METHODS: Male Sprague-Dawley rats received a single intra-articular injection of MIA into the infrapatellar ligament of the right knee. Subsequently, the rats were treated with normal saline, SHINBARO, and diclofenac once daily for 21 days. Rats treated with normal saline, but not MIA, comprised the control group. Histological changes in the femur of the MIA-induced osteoarthritis rat model were observed by micro-computed tomography scanning and staining with hematoxylin and eosin, and safranin-O fast green. Serum levels of PGE2 and anti-type II collagen antibodies in the MIA-induced osteoarthritis rat model were measured using commercial kits. Protein levels of inflammatory enzymes (iNOS, COX-2), pro-inflammatory cytokines (TNF-α, IL-1ß), and inflammatory mediators (NF-κB, IκB) in cartilaginous tissues were determined by western blot analysis. RESULTS: Intra-articular administration of SHINBARO (IAS) at 20 mg/kg remarkably restrained the decrease in bone volume/total volume, being 28 % (P = 0.0001) higher than that in the vehicle-treated MIA group. IAS (2, 10, and 20 mg/kg) treatment significantly recovered the mean number of objects values with increased percentage changes of 13.5 % (P = 0.147), 27.5 % (P = 0.028), and 44.5 % (P = 0.031), respectively, compared with the vehicle-treated MIA group. The serum level of PGE2 in the IAS group at 20 mg/kg was markedly inhibited by 60.6 % (P = 0.0007) compared with the vehicle-treated MIA group, and the anti-collagen type II antibody level in the IAS group was reduced in a dose-dependent manner. IAS (20 mg/kg) effectively suppressed the induction of inflammation-mediated enzymes (iNOS and COX-2) and pro-inflammatory cytokines (TNF-α and IL-1ß). IAS treatment also downregulated the NF-κB level and increased the IκB-α level in the MIA- induced osteoarthritis rat model. CONCLUSION: SHINBARO inhibited PGE2 and anti-type II collagen antibody production and modulated the balance of inflammatory enzymes, mediators, and cytokines in the MIA-induced osteoarthritis rat model.

7.
J Med Chem ; 55(1): 342-56, 2012 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-22142423

RESUMEN

Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.


Asunto(s)
Agonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A3/síntesis química , Adenosina/análogos & derivados , Adenosina/síntesis química , Receptor de Adenosina A3/metabolismo , Receptores de Adenosina A2/metabolismo , Tiofenos/síntesis química , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A3/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Masculino , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacología
8.
Food Chem Toxicol ; 49(11): 2942-6, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21782877

RESUMEN

The fruit of Poncirus trifoliata (Rutaceae) has been used a medicinal food and traditional medicine. Recently we reported the isolation of 25-methoxyhispidol A (25-MHA) as a novel triterpenoid from the immature fruit of P. trifoliata with the potential growth inhibition of cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells remain to be elucidated. In the present study, we investigated the anti-proliferative activity and mechanisms of actions mediated by 25-MHA in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. 25-MHA exhibited the growth inhibitory activity against MDA-MB-231 cells with the cell cycle arrest in the G0/G1 phase. The cell cycle arrest in the G0/G1 by 25-MHA was well correlated with the downregulation of cyclin D1, cyclin dependent kinase (CDK4), CDK2, cyclin A, phosphorylated retinoblastoma protein (pRb), and induction of cdk inhibitor p21(WAF1/Cip1) protein. 25-MHA also suppressed the activation of c-Src/epidermal growth factor receptor (EGFR)/Akt signaling, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that 25-MHA-mediated inhibitory activity of human breast cancer cell growth might be related with the cell cycle arrest and modulation of signal transduction pathways.


Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores ErbB/metabolismo , Poncirus/química , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Proteína Tirosina Quinasa CSK , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estructura Molecular , Proteínas Tirosina Quinasas/genética , Triterpenos/química , Familia-src Quinasas
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