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1.
Int J Mol Sci ; 20(7)2019 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-30959963

RESUMEN

Lifestyle choices play a significant role in the etiology of atherosclerosis. Male Apoe-/- mice that develop spontaneous atherosclerotic lesions were fed 0%, 0.3%, and 0.4% mangosteen extracts, composed largely of α-mangostin (MG), for 17 weeks. Body weight gains were significantly decreased in both MG-treated groups compared to the control, but the general condition remained good throughout the study. The levels of total cholesterol (decreased very-low-density lipoprotein in lipoprotein profile) and triglycerides decreased significantly in the MG-treated mice in conjunction with decreased hepatic HMG-CoA synthase and Fatty acid transporter. Additionally, increased serum lipoprotein lipase activity and histopathology further showed a significant reduction in atherosclerotic lesions at both levels of MG exposure. Real-time PCR analysis for macrophage indicators showed a significant elevation in the levels of Cd163, an M2 macrophage marker, in the lesions of mice receiving 0.4% MG. However, the levels of Nos2, associated with M1 macrophages, showed no change. In addition, quantitative immunohistochemical analysis of macrophage subtypes showed a tendency for increased M2 populations (CD68⁺/CD163⁺) in the lesions of mice given 0.4% MG. In further analysis of the cytokine-polarizing macrophage subtypes, the levels of Interleukin13 (Il13), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in Apoe-/- mice, possibly through an M2 macrophage-mediated mechanism.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Macrófagos/metabolismo , Xantonas/uso terapéutico , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/sangre , Aterosclerosis/genética , Colesterol/sangre , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Placa Aterosclerótica/sangre , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Xantonas/química
2.
Cancer Sci ; 109(5): 1660-1671, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29601143

RESUMEN

We previously reported that, in a mouse model of mammary cancer, α-mangostin alone exhibits anti-metastatic properties. To enhance this anti-metastatic effect, we examined the efficacy of synthetic α-mangostin dilaurate (MGD), prepared by adding lauric acid to α-mangostin, in the same experimental system wherein mice bearing mammary tumors are exposed to dietary MGD at 0, 2000 and 4000 ppm. Lauric acid has a high propensity for lymphatic absorption, which is the most common pathway of initial dissemination of many solid malignancies. Both mammary tumor volumes and wide-spectrum organ metastasis were markedly reduced at 2000 and 4000 ppm: furthermore, survival in the 4000-ppm group was significantly greater than in control mice. Apoptosis in mammary carcinomas was also significantly increased in the 4000-ppm group, whereas blood microvessel density and lymphatic vessel invasion were markedly reduced. In real-time PCR analyses of tumor samples, increased p21 and decreased Pcna expression were observed with 4000 ppm but values were not statistically significant when compared to expression in control tumors. However, exposure to 4000 ppm significantly decreased expression of phospho-Akt (Ser473/Thr308) as compared to the control, indicating a role in the anti-tumorigenic effects of MGD. These findings suggest that MGD may be useful for adjuvant therapy and chemoprevention and that conjugated medium-chain fatty acids may enhance the efficacy of certain chemotherapeutic agents.


Asunto(s)
Neoplasias Mamarias Experimentales/tratamiento farmacológico , Xantonas/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Lauratos , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Invasividad Neoplásica , Metástasis de la Neoplasia , Antígeno Nuclear de Célula en Proliferación/análisis , Proteínas Proto-Oncogénicas c-akt/metabolismo
3.
Arch Biochem Biophys ; 529(2): 131-9, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23228597

RESUMEN

Mammalian morphine 6-dehydrogenase (M6DH)(1) converts morphine into a reactive electrophile, morphinone. M6DH belongs to the aldo-keto reductase (AKR) superfamily, but its endogenous substrates and entire amino acid sequence remain unknown. A recent rabbit genomic sequencing predicts three genes for novel AKRs (1C26, 1C27 and 1C28) that share >87% amino acid sequence identity and are similar to the partial sequence of rabbit liver M6DH. We isolated cDNAs for the three AKRs, and compared the properties of their recombinant enzymes. Like M6DH, only AKR1C26 that shares the highest sequence identity with hepatic M6DH oxidized morphine. The three AKRs showed NAD(+)-dependent dehydrogenase activity towards other non-steroidal alicyclic alcohols and 3α/17ß-hydroxy-C(18)/C(19)/C(21)-steroids, and their mRNAs were ubiquitously expressed in rabbit tissues. The kinetic constants for the substrates suggest that at least AKR1C26 and AKR1C28 act as NAD(+)-dependent 3α/17ß-hydroxysteroid dehydrogenases. AKR1C27 differed from AKR1C28 in its high K(m) values for the substrates and low sensitivity towards competitive inhibitors (ikarisoside A, hinokitiol, hexestrol and zearalenone), despite their 95% sequence identity. The site-directed mutagenesis of Tyr118 and Phe310 in AKR1C27 to the corresponding residues (Phe and Ile, respectively) in AKR1C28 produced an enzyme that was similar to AKR1C28, suggesting their key roles in ligand binding.


Asunto(s)
Oxidorreductasas de Alcohol/química , Hidroxiesteroide Deshidrogenasas/química , Morfina/química , NAD/química , Secuencia de Aminoácidos , Animales , Sitios de Unión , Activación Enzimática , Datos de Secuencia Molecular , Unión Proteica , Conejos
4.
Pharmacol Res ; 71: 34-43, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23419834

RESUMEN

Neuroinflammation and oxidative stress are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases and Parkinson's disease. Naturally derived kavalactones isolated from Piper methysticum (Piperaceae) have been shown to exhibit neuroprotective effects. We have previously reported that a chemically synthesized kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain (compound 1) protects against oxidative stress-induced neuronal cell death through activation of Nrf2 signaling. In the present study, we examined the effect of compound 1 on neuroinflammation. In BV2 microglial cells, compound 1 strongly inhibited LPS-stimulated iNOS induction and NO production, but did not affect LPS-stimulated induction of COX2. At 6h after LPS challenge, when iNOS induction was not clearly seen, treatment with LPS or compound 1 alone increased expression of heme oxygenase 1 (HO-1) whose transcription is regulated by Nrf2. When treated with both, compound 1 enhanced LPS-stimulated HO-1 induction, which was more evident at 24h after LPS treatment. Furthermore, LPS-stimulated activation of Nrf2 signaling and nuclear translocation of Nrf2 were potentiated by compound 1. The mechanism by which compound 1 activated Nrf2 signaling was supposed to be a covalent modification of the sulfhydryl groups of Keap1 by an α,ß-unsaturated carbonyl group present in the compound 1. Treatment with hemin, a HO-1 inducer, and with [Ru(CO)3Cl2]2, a CO donor, decreased LPS-stimulated iNOS induction and NO production. In contrast, siRNA-mediated knockdown of HO-1 expression reduced the inhibitory effect of compound 1 on LPS-stimulated iNOS induction and NO production. The compound 1 inhibited LPS-stimulated ERK phosphorylation after LPS treatment. Finally, compound 1 suppressed LPS/IFN-γ-stimulated NO production in primary microglial cells. These results suggest that compound 1 is capable of inhibiting LPS-stimulated iNOS induction and NO production via activation of Nrf2 signaling and HO-1 induction in microglial cells. Taken together, compound 1 has a potential to reduce neuroinflammation as well as oxidative stress in neurodegenerative diseases through activation of Nrf2 signaling.


Asunto(s)
Lactonas/farmacología , Lipopolisacáridos/inmunología , Microglía/citología , Factor 2 Relacionado con NF-E2/inmunología , Óxido Nítrico Sintasa de Tipo II/inmunología , Óxido Nítrico/inmunología , Piper/química , Animales , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/inmunología , Interferón gamma/inmunología , Lactonas/química , Lactonas/aislamiento & purificación , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Factor 2 Relacionado con NF-E2/análisis , Factor 2 Relacionado con NF-E2/metabolismo , Penicilamina/farmacología , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
5.
Biol Pharm Bull ; 36(9): 1448-53, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23995656

RESUMEN

A triterpene saponin, glucoglycyrrhizin, was isolated from a glycyrrhizin-deficient strain 83-555 of Glycyrrhiza uralensis (Leguminosae), and the structure was determined by chemical and spectral data to be 3-O-[ß-D-glucopyranosyl-(1→2)-ß-D-glucuronopyranosyl]-glycyrrhetinic acid. Since this saponin has a 2'-O-ß-D-glucopyranosyl moiety instead of the 2'-O-ß-D-glucuronopyranosyl moiety of glycyrrhizin, the glucuronidation of 3-O-ß-D-glucuronopyranosyl-glycyrrhetinic acid leading to glycyrrhizin is inhibited in this strain. All 4 offspring of the 83-555 strain produced glucoglycyrrhizin. Interestingly, 2 of the offspring produced both glycyrrhizin and glucoglycyrrhizin, and sequence analysis of the pkr gene suggested that these 2 offspring were hybrids of 83-555 strain and glycyrrhizin-producing strains.


Asunto(s)
Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/aislamiento & purificación , Glycyrrhiza uralensis/química , Oxidorreductasas de Alcohol/genética , Proteínas Bacterianas/genética , ADN de Plantas/análisis , Genes de Plantas/genética , Ácido Glicirretínico/química , Glycyrrhiza uralensis/genética , Ácido Glicirrínico , Datos de Secuencia Molecular , Raíces de Plantas/química , Análisis de Secuencia de ADN
6.
Biosci Biotechnol Biochem ; 77(12): 2430-5, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24317060

RESUMEN

We tested the peroxisome proliferator-activated receptor (PPAR)δ agonistic activity of a Garcinia mangostana pericarp extract to develop a treatment for the metabolic syndrome, and demonstrated γ-mangostin to be an active compound on the basis of a luciferase reporter gene assay. γ-Mangostin induced the expression of the uncoupling protein-3 (UCP-3) gene which is related to energy expenditure and fat metabolism in L6 cells. We showed that γ-mangostin is a dual agonist that activates both PPARδ and PPARα. γ-Mangostin also induced the expression of acyl-CoA synthase and carnitine palmitoyl-transferase 1A genes in HepG2 cells. These results suggest the potential of γ-mangostin as a preventive agent of the metabolic syndrome.


Asunto(s)
Frutas/química , Garcinia mangostana/química , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR delta/agonistas , PPAR delta/metabolismo , Xantonas/farmacología , Animales , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Ratas , Proteína Desacopladora 3 , Xantonas/aislamiento & purificación
7.
Chem Pharm Bull (Tokyo) ; 61(5): 551-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23649198

RESUMEN

The acetone-soluble parts of Garcinia subelliptica leaves were analyzed and six new biflavonoids were isolated, i.e., garciniaflavones A-F (1-6), as well as the five known biflavonoids amentoflavone (7), podocarpusflavone A (8), (+)-morelloflavone (9), (+)-morelloflavone-7"-O-ß-glucopyranoside (10), and (+)-4'''-O-methylmorelloflavone (11) and the three triterpenoids oleanan-3-one, ß-amyrin, and cycloartenol. The structures of the isolates were established based on spectroscopic analyses, including a detailed NMR spectroscopic investigation. The new biflavonoids are rare mono-isoprenylated derivatives that have a flavone-(3'-8")-flavone core (1-4: amentoflavone type) and a flavanone-(3-8")-flavone core (5, 6: morelloflavone type). The absolute configurations of the morelloflavone-type biflavonoids (5, 6) were confirmed by circular dichroism to be 2R,3S. The biflavonoids with an isoprenyloxy group (1) and a 2-hydroxy-3-methyl-3-butenyl group (2), and the morelloflavone-type biflavonoids with a C(5) unit are the first examples in nature. We found that 7, one of the major biflavonoids, strongly inhibited hypoxia-inducible factor-1 in human embryonic kidney 293 cells under hypoxic conditions.


Asunto(s)
Biflavonoides/aislamiento & purificación , Garcinia/química , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Biflavonoides/química , Estructura Molecular , Extractos Vegetales/química , Prenilación , Estereoisomerismo
8.
J Biomed Biotechnol ; 2012: 672428, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22577295

RESUMEN

The development of molecularly targeted drugs has greatly advanced cancer therapy, despite these drugs being associated with some serious problems. Recently, increasing attention has been paid to the anticancer effects of natural products. α-Mangostin, a xanthone isolated from the pericarp of mangosteen fruit, has been shown to induce apoptosis in various cancer cell lines and to exhibit antitumor activity in a mouse mammary cancer model. In this study, we investigated the influence of α-mangostin on apoptosis and cell cycle in the human breast cancer cell line MDA-MB231 (carrying a p53 mutation, and HER2, ER, and PgR negative) in order to elucidate its anticancer mechanisms. In α-mangostin-treated cells, induction of mitochondria-mediated apoptosis was observed. On cell-cycle analysis, G1-phase arrest, increased p21(cip1) expression and decreases in cyclins, cdc(s), CDKs and PCNA were observed. In conclusion, α-mangostin may be useful as a therapeutic agent for breast cancer carrying a p53 mutation and having HER2- and hormone receptor-negative subtypes.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Garcinia mangostana/química , Xantonas/farmacología , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Femenino , Frutas/química , Humanos , Extractos Vegetales/farmacología
9.
Arch Virol ; 157(8): 1489-98, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22580497

RESUMEN

The development of therapeutic agents for preventing herpes simplex virus (HSV) infections has become urgently necessary because of the increasing incidence of this virus and its role as a cofactor in the transmission of human immunodeficiency virus infection. We have evaluated the antiviral activities of a series of natural and synthetic flavonoids and found that a synthetic flavonoid, 4'-phenylflavone, showed the highest activity against acyclovir (ACV)-sensitive and ACV-resistant strains of HSV-1, as well as HSV-2, with a selectivity index of 213, 35 and 55, respectively. Although the attachment and penetration of HSV-1 to host cells and the synthesis of viral proteins were not inhibited, the infectivity of the virus and the amount of progeny virus released were reduced by 4'-phenylflavone treatment in a dose-dependent manner. 4'-Phenylflavone plus ACV synergistically inhibited the replication of HSV-1. This flavonoid also showed efficacy in vivo and potentiated the antiherpetic effect of ACV in a mouse model of genital herpes. Our results suggest that 4'-phenylflavone might be useful as a candidate for the development of novel antiherpetic therapeutics.


Asunto(s)
Aciclovir/farmacología , Flavonas/fisiología , Herpes Genital/tratamiento farmacológico , Simplexvirus/efectos de los fármacos , Aciclovir/uso terapéutico , Animales , Línea Celular , Sinergismo Farmacológico , Femenino , Flavonas/uso terapéutico , Herpes Genital/prevención & control , Herpes Genital/virología , Humanos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Simplexvirus/fisiología , Internalización del Virus/efectos de los fármacos , Liberación del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos
10.
J Nat Prod ; 75(4): 563-6, 2012 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-22429094

RESUMEN

ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR). Since ABCA1 plays a pivotal role in cholesterol and HDL metabolism, identification of a compound capable of increasing its expression may be beneficial for the prevention and therapy of atherosclerosis. Firefly luciferase reporter assays were developed for human ABCA1 promoters and LXR enhancers, and an in-house phytochemical library was screened. It was found that a citrus flavonoid, hesperetin (1), increased ABCA1 promoter and LXR enhancer activities in THP-1 macrophages. It was also found that this flavonoid promoted PPAR-enhancing activity. In accordance with these findings, 1 increased mRNA and protein expression of ABCA1 and consequently upregulated ApoA-I-mediated cholesterol efflux. These results provide evidence that 1 promotes ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression through the activation of LXRα and PPARγ.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Hesperidina/farmacología , Macrófagos/efectos de los fármacos , Transportadoras de Casetes de Unión a ATP/metabolismo , Hesperidina/química , Humanos , Lipoproteínas HDL/fisiología , Receptores X del Hígado , Macrófagos/metabolismo , Estructura Molecular , Receptores Nucleares Huérfanos/efectos de los fármacos , PPAR gamma/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética
11.
J Nat Prod ; 75(4): 694-8, 2012 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-22372956

RESUMEN

Seven new terpenoids, including two sesquiterpene dimers (1, 2), two norditerpenoids (3, 4), and three sesquiterpenes (5-7), along with six known sesquiterpene dimers and four known sesquiterpenes were isolated from the whole plant of Chloranthus serratus. Their structures and relative configurations were elucidated on the basis of spectroscopic data analysis. The absolute configuration of 1 was determined by the CD exciton chirality method. These isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Compound 2 and two known compounds, shizukaols B and D, showed significant anti-inflammatory activities, with IC(50) values of 0.22, 0.15, and 7.22 µM, respectively.


Asunto(s)
Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Magnoliopsida/química , Terpenos/aislamiento & purificación , Terpenos/farmacología , Animales , Antiinflamatorios/química , Diterpenos/química , Medicamentos Herbarios Chinos/química , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Sesquiterpenos/química , Sesquiterpenos/farmacología , Terpenos/química
12.
Biol Pharm Bull ; 35(11): 2075-80, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23123477

RESUMEN

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently identified as both diagnostic marker and therapeutic target in the treatment of several types of cancer. In this study, we have examined AKR1B10 inhibition by five xanthone derivatives, components of pericarps of mangosteen, of which α- and γ-mangostins show potential anti-cancer properties. Among the five xanthones, γ-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6 nM), but its 7-methoxy derivative, α-mangostin, was the second potent inhibitor (inhibition constant, 80 nM). Molecular docking of the two mangostins in AKR1B10 and site-directed mutagenesis of the putative binding residues revealed that Phe123, Trp220, Val301 and Gln303 are important for the tight binding of γ-mangostin, and suggested that the 7-methoxy group of α-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Garcinia mangostana , Xantonas/farmacología , Aldehído Reductasa/química , Aldo-Ceto Reductasas , Frutas , Humanos , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica
13.
Chem Biodivers ; 9(10): 2195-202, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23081919

RESUMEN

Two novel zierane-type sesquiterpenes, named melicodenones A and B (1 and 2, resp.), and three new guaiane-type sesquiterpenes, named melicodenones C-E (3-5), were isolated from the root of Melicope denhamii (Seem.) T. G. Hartley together with zierone (6). Their structures were established by extensive NMR-spectroscopic analyses. Compounds 1-6 were tested for cytotoxicity using human colon cancer DLD-1 cells, and melicodenone A (1) was found to exhibit moderate activity.


Asunto(s)
Rutaceae/química , Sesquiterpenos de Guayano/química , Sesquiterpenos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Raíces de Plantas/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/toxicidad
14.
J Asian Nat Prod Res ; 14(7): 708-12, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22574617

RESUMEN

A novel lindenane sesquiterpene with an unprecedented 18-membered triester ring, named chlorafortulide (1), along with one known lindenane sesquiterpene (2) and nine known lindenane sesquiterpene dimers (3-11), was isolated from the whole plant of Chloranthus fortunei. Their structures and relative configurations were elucidated on the basis of spectroscopic analysis. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Henriol D (4), shizukaols E (8), G (9), M (10), and O (11) showed significant anti-inflammatory activities with IC(50) values of 1.90, 3.68, 1.95, 7.01, and 1.95 µM, respectively.


Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Plantas Medicinales/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Medicamentos Herbarios Chinos/química , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear Biomolecular , Sesquiterpenos/química
15.
Oncol Lett ; 23(3): 99, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35154430

RESUMEN

Musa basjoo (MB) is a species of the banana plant belonging to the genus Musa that has been used as a folk medicine. However, evidence-based biological activities and the molecular mechanism of action of MB are unknown. Thus, the aim of the present study was to examine whether the crude dried leaf extracts of MB inhibit the growth of colorectal (HT29 and HCT116) and other types (HepG2, MCF-7 and PC-3) of human cancer cell lines. Crude extracts of MB inhibited the growth of cells with IC50 values of 136 µg/ml (acetone extract, HT29), 51 µg/ml (acetone extract, HCT116), 45 µg/ml (acetone extract, HepG2), 40 µg/ml (acetone extract, MCF-7), 29 µg/ml (acetone extract, PC-3), 175 µg/ml (methanol extract, HT29), 137 µg/ml (methanol extract, HCT116), 102 µg/ml (methanol extract, HepG2), 85 µg/ml (methanol extract, MCF-7), and 85 µg/ml (methanol extract, PC-3) in colony formation assays, and 126 µg/ml (acetone extract, HT29), 68 µg/ml (acetone extract, HCT116), 260 µg/ml (methanol extract, HT29), and 216 µg/ml (methanol extract, HCT116) in MTT assays. Thin layer chromatography analysis revealed the potential existence of aromatic compounds in the acetone extract of MB. Flow cytometric analysis indicated that the percentage of cells in G1 increased, and this was associated with a concomitant decrease of cells in the S and/or G2-M phases of the cell cycle. When colorectal cancer cells were treated with acetone extract of MB, there was a marked decrease in the levels of expression of the cyclin D1, cyclin E, cdk2 and cdk4 proteins and a marked increase in the levels of the expression of the p21CIP1, p27KIP1, and p53 proteins, but those of apoptosis-associated protein PARP did not change. There was a tendency for acetone extract of MB to inhibit xenograft tumor growth in mice. Collectively, the crude extracts of MB contain active components that exert growth inhibition of human cancer cells. This is the first systematic study of the anticancer activity of MB and may broaden insights into the possible clinical approach of specific herbal medicines.

16.
BMC Med ; 9: 69, 2011 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-21639868

RESUMEN

BACKGROUND: The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. METHODS: Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted. RESULTS: Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that α-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308), but not serine 473 (Ser473), in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo. CONCLUSIONS: Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of α-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, α-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Garcinia mangostana/química , Neoplasias Mamarias Animales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Metástasis de la Neoplasia/prevención & control , Neoplasias/tratamiento farmacológico , Xantonas/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Femenino , Humanos , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Mutación , Trasplante Heterólogo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Xantonas/aislamiento & purificación
17.
J Nat Prod ; 74(5): 1201-6, 2011 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-21561086

RESUMEN

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently suggested as a therapeutic target in the treatment of several types of cancer. Due to its high sequence identity with human aldose reductase (AKR1B1), selective inhibition of AKR1B10 compared with AKR1B1 is required for the development of anticancer agents. In this study, we have examined AKR1B10 inhibition by seven pentacyclic triterpenes (1-7) that show potential anticancer properties. Among them, oleanolic acid (1) was found to be the most potent competitive inhibitor (inhibition constant, 72 nM) with the highest AKR1B10/AKR1B1 selectivity ratio of 1370. Molecular docking of 1 with AKR1B10 and AKR1B1 and site-directed mutagenesis studies suggested that the nonconserved residues Val301 and Gln303 in AKR1B10 are important for determining its inhibitory potency and selectivity. Oleanolic acid (1) also inhibited the cellular metabolism by AKR1B10 (IC(50), 4 µM) and decreased mitomycin C tolerance of colon cancer HT29 cells. Thus, the selective and potent inhibition of AKR1B10 by 1 may be related to a possible cancer inhibitory role.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Antineoplásicos Fitogénicos/farmacología , Mitomicina/farmacología , Ácido Oleanólico/farmacología , Triterpenos Pentacíclicos/farmacología , Aldehído Reductasa/genética , Aldo-Ceto Reductasas , Resistencia a Antineoplásicos/efectos de los fármacos , Células HT29 , Células HeLa , Humanos , Modelos Moleculares , Estructura Molecular , Mutación/efectos de los fármacos , Ácido Oleanólico/química , Triterpenos Pentacíclicos/química
18.
Chem Pharm Bull (Tokyo) ; 59(2): 239-48, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21297306

RESUMEN

Investigation of the highly polar chemical constituents in the stem of Hopea parviflora (Dipterocarpaceae) resulted in the isolation of four new resveratrol derivatives, hopeasides A and B (1, 2) (resveratrol pentamers), C (3) (resveratrol trimer), and D (4) (resveratrol dimer) together with nine known resveratrol oligomers (5-13). The new structures have a common partial structure of the 1-hydroxy-1-(3,5-dihydroxy-2-C-glucopyranosylphenyl)-2-(4-hydroxyphenyl)ethane-2-yl group after oxidative condensation of (E)-resveratrol-10-C-ß-glucopyranoside (14). The structures were determined by spectroscopic analysis including 2D-NMR and computer-aided molecular modeling. The biogenetic relationship of the isolates and NMR characteristics caused by steric hindrance are also discussed in this paper.


Asunto(s)
Dipterocarpaceae/química , Glucósidos/química , Corteza de la Planta/química , Extractos Vegetales/química , Estilbenos/química , Glucósidos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Resveratrol
19.
Chem Pharm Bull (Tokyo) ; 59(4): 452-7, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21467673

RESUMEN

Three new stilbene derivatives, albiraminols A (1) (resveratrol hexamer), B (2) (resveratrol dimer), and vatalbinoside F (3) (mono-glucoside of resveratrol dimer), along with malibatol were isolated from acetone soluble portions of the stem of Vatica albiramis. The structures of the isolates were established on the basis of spectroscopic analyses, including a detailed NMR spectroscopic investigation. The biosynthetic aspects of the isolates are discussed in this paper. Compound 1 is composed of tetrameric resveratrol (vaticanol B (1A)) and dimeric resveratrol (1B) and is the first instance of the resveratrol derivative bearing a 5,6,11,12-tetrahydro-5,11-epoxydibenzo[a,e][8]annulene ring system. Compound 2 possesses a novel 4,5-dihydro-13-oxabenzo[3,4]azuleno[7,8,1-jkl]phenanthrene skeleton in the framework.


Asunto(s)
Dipterocarpaceae/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Estilbenos/química , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Conformación Molecular , Tallos de la Planta/química , Resveratrol , Estilbenos/aislamiento & purificación
20.
Int J Oncol ; 58(2): 251-265, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33491745

RESUMEN

The present study, to the best of our knowledge, is the first systematic study of the inhibitory effects of palmitoyl piperidinopiperidine (PPI; Japan Patent no. 5597427), on colon carcinogenesis. PPI exhibited marked growth inhibitory activity in several human colon carcinoma cell lines, with IC50 values of approximately 0.5­2.2 µM. In silico docking analysis indicated that PPI could bind to the SH2 domain of signal transducer and activator of transcription 3 (STAT3). PPI markedly inhibited the transcriptional activity of the SW837 cell line. Flowcytometric analysis demonstrated that PPI induced an increase in the number of cells in the G1 phase of the cell cycle, and induced sub­G1 fractions of cells at a higher concentration level of PPI. In the HT29 and SW837 cells, western blot analyses exhibited that in whole cell lysates, PPI induced a marked decrease in the expression levels of p­STAT3, but not in the levels of STAT3 in these cells. PPI also induced a marked decrease in the expression levels of both STAT3 and p­STAT3 in the chromatin fraction. In addition, PPI affected the protein expression levels of cyclin D1, p53, Bcl­2, Bcl­xL and vascular endothelial growth factor (VEGF). In the HT29 cells, PPI induced a marked and dose­dependent increase in the expression levels of Bax, cleaved caspase­3, cleaved caspase­7, cleaved caspase­8, cleaved caspase­9 and cleaved poly (ADP­ribose) polymerase (PARP). In animal model systems, PPI inhibited the growth of implanted carcinoma cells, and also induced a significant decrease in the multiplicity of colonic aberrant crypt foci. In addition, a marked and dose­dependent inhibition of angiogenesis of the chick chorioallantoic membrane was observed. As regards the possible molecular mechanisms, it is suggested that the inhibition of STAT3 by PPI may affect the function of molecules that are related to apoptosis, angiogenesis and cell cycle progression, eventually contributing to the PPI­induced growth inhibitory effects.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Ácidos Grasos Monoinsaturados/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Azoximetano/administración & dosificación , Azoximetano/toxicidad , Carcinógenos/administración & dosificación , Carcinógenos/toxicidad , Carcinoma/patología , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides , Neoplasias del Colon/patología , Ácidos Grasos Monoinsaturados/química , Ácidos Grasos Monoinsaturados/uso terapéutico , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Simulación del Acoplamiento Molecular , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Neovascularización Patológica/dietoterapia , Neovascularización Patológica/patología , Ratas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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