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1.
Phytother Res ; 38(4): 1815-1829, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38349045

RESUMEN

Triple-negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype and lacks effective targeted therapies at present. Isobavachalcone (IBC), the main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor and characterized the potential mechanisms underlying the inhibition of TNBC. Molecular dynamics analysis, enzyme activity assay, and cellular thermal shift assay were performed to evaluate the combination of IBC and SIRT2. The therapeutic effects, mechanism, and safety of IBC were analyzed in vitro and in vivo using cellular and xenograft models. IBC effectively inhibited SIRT2 enzyme activity with an IC50 value of 0.84 ± 0.22 µM by forming hydrogen bonds with VAL233 and ALA135 within its catalytic domain. In the cellular environment, IBC bound to and stabilized SIRT2, consequently inhibiting cellular proliferation and migration, and inducing apoptosis and cell cycle arrest by disrupting the SIRT2/α-tubulin interaction and inhibiting the downstream Snail/MMP and STAT3/c-Myc pathways. In the in vivo model, 30 mg/kg IBC markedly inhibited tumor growth by targeting the SIRT2/α-tubulin interaction. Furthermore, IBC exerted its effects by inducing apoptosis in tumor tissues and was well-tolerated. IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/ß-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.


Asunto(s)
Chalconas , Sirtuina 2 , Neoplasias de la Mama Triple Negativas , Humanos , Sirtuina 2/farmacología , Línea Celular Tumoral , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Tubulina (Proteína)/farmacología , Tubulina (Proteína)/uso terapéutico , Proliferación Celular , Apoptosis
2.
Phytochemistry ; 207: 113558, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36521584

RESUMEN

Six undescribed alkaloids together with 15 known alkaloids were isolated from the aerial parts of Aconitum carmichaelii. Their structures were elucidated extensively by NMR and HRESIMS spectroscopy. The absolute configurations of N-formyllaurotetanine, and the known compounds glaucine-ß-N-oxide and glaucine-α-N-oxide were established by electronic circular dichroism (ECD) spectra. Notably, it was the discovery of rare indole alkaloids from the genus Aconitum, and biosynthetic pathway of compounds 1 and 6 was deduced. Evaluation of the antiproliferative activity of these alkaloids demonstrated that costemline exhibited significant anti-proliferation effects against HCT116, SKOV3, and A549 cells with IC50 values of 5.6, 14.2, and 6.8 µM, respectively. Costemline could also inhibit the cell invasion activity of HCT116 cells. Mechanistic studies in HCT116 cells suggested that the antiproliferative activity of costemline was attributable to SIRT1/ROCK1/P-STAT3 pathways regulation. This study revealed the potential for developing and utilizing the aerial parts of Aconitum carmichaelii.


Asunto(s)
Aconitum , Alcaloides , Diterpenos , Aconitum/química , Alcaloides/química , Diterpenos/química , Estructura Molecular , Componentes Aéreos de las Plantas/metabolismo , Raíces de Plantas/química , Sirtuina 1/metabolismo , Factor de Transcripción STAT3/metabolismo , Quinasas Asociadas a rho/metabolismo
3.
Nat Prod Res ; 35(21): 3535-3539, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31979990

RESUMEN

As part of our search for compounds with cytotoxicity from endophytes of traditional Chinese medicines, two novel nor-sesquiterpenoids (1-2) with a new skeleton containing a tetrahydrofuran moiety were isolated form a rice medium of Fusarium tricinctum, an endophytic fungus isolated from the root of Ligusticum chuanxiong. The structures of these two previously undescribed compounds were elucidated by interpretation of the spectroscopic evidences including NMR correlations as well as MS data. The absolute configurations of these two compounds were confirmed by TD-DFT-ECD calculations. An MTT assay indicated that compound 1 exhibited moderate cytotoxic activity against MV4-11 with an IC50 value of 22.29 µM.


Asunto(s)
Fusarium , Ligusticum , Sesquiterpenos , Endófitos , Hongos
4.
FASEB J ; 34(8): 10182-10190, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32543003

RESUMEN

Erlotinib has potential therapeutic effect on acute myeloid leukemia (AML) in patients, but the mechanism is not clear. Effective tumor biomarkers for erlotinib in the treatment of AML remain poorly defined. Here, we demonstrate that erlotinib in vitro significantly inhibits the growth of the FLT3-ITD mutant AML cell MV4-11 and Ba/F3-FLT3-ITD cell via targeting FLT3, a certified valid target for the effective treatment of AML. In vivo, oral administration of erlotinib at 100 mg/kg/day induced rapid MV4-11 tumor regression and significantly prolonged the survival time of bone marrow engraftment AML mice via inhibiting the FLT3 signal. Thus, the therapeutic benefits of erlotinib on AML are due to its ability to target FLT3. FLT3-ITD mutation is an effective biomarker for erlotinib during AML treatment. In addition, we also demonstrate that erlotinib inhibits the activity of AML cell KG-1 (no FLT3 expression) by targeting Lyn. Recently, single cell analysis demonstrated that intratumoral heterogeneity are one of the contributors in the relapse and FLT3 inhibitor resistance. Erlotinib could effectively inhibit the MV4-11 cells via targeting FLT3, and inhibit KG-1 cells via targeting Lyn. Therefore, Erlotinib also has the potential to overcome intratumoral heterogeneity via targeting FLT3 and Lyn.


Asunto(s)
Clorhidrato de Erlotinib/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación/efectos de los fármacos , Secuencias Repetidas en Tándem/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/genética , Familia-src Quinasas/genética , Animales , Biomarcadores de Tumor/genética , Médula Ósea/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación/genética , Células THP-1 , Secuencias Repetidas en Tándem/genética
5.
Fitoterapia ; 141: 104484, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31954180

RESUMEN

The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, has been reported oncogenic tyrosine phosphatase associated with various tumors and played critical roles in many cell signaling events. Targeting SHP2 by small molecules may be a promising way for cancer therapy. Herein, a new abietane diterpenoid, named 3-acetoxylteuvincenone G (3-AG), was isolated from the whole plants of Ajuga ovalifolia var. calantha. The structure of the new compound was elucidated by means of extensive spectroscopic analyses. Using recombinant enzyme activity assay and cellular thermal shift assay, we found that 3-AG was a selective inhibitor of SHP2. Molecular docking suggested 3-AG displayed an orientation favorable to nucleophilic attack in the catalytic domain of SHP2. 3-AG suppressed A549 cell proliferation (IC50 = 10.79 ± 0.14 µM), invasion and induced cell apoptosis through SHP2/ERK1/2 and SHP2/AKT pathways. In summary, 3-AG, a potent, selective, and efficacious SHP2 inhibitor, may be a promising small molecule to treat human lung epithelial cancer.


Asunto(s)
Abietanos/farmacología , Apoptosis/efectos de los fármacos , Diterpenos/química , Diterpenos/farmacología , Lamiaceae/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células A549 , Abietanos/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética
6.
Nat Prod Res ; 34(7): 958-964, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30600715

RESUMEN

Chemical epigenetic manipulation was applied to explore secondary metabolite of an endophytic fungus Penicillium herquei, which was obtained from the fruiting body of Cordyceps sinensis, and three previously undescribed polyketides with pyran-2-one scaffold were isolated from its fermentation broth containing 10 mg/L 5-aza-2-deoxycytidine (a frequently-used DNA methyltransferase inhibitor). The structures of these new compounds were identified by extensive spectroscopic analyses, and their absolute configurations were elucidated by quantum chemical ECD calculations.


Asunto(s)
Cordyceps/química , Epigénesis Genética , Penicillium/química , Pironas/aislamiento & purificación , Fermentación , Estructura Molecular , Penicillium/genética , Penicillium/aislamiento & purificación , Policétidos/química , Policétidos/aislamiento & purificación , Análisis Espectral
7.
J Asian Nat Prod Res ; 22(2): 138-143, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30450959

RESUMEN

Two previously undescribed sesquiterpenes along with nine known compounds were isolated from the fermentation broth of Aspergillus fumigatus, an endophyte of Ligusticum wallichii. Their structures were elucidated through extensive spectroscopic analysis combined with quantum chemical ECD calculations. Two new compounds exhibited moderate growth inhibition against MV4-11 and MDA-MB-231 cell lines.


Asunto(s)
Ligusticum , Sesquiterpenos , Aspergillus fumigatus , Endófitos , Estructura Molecular
8.
Mol Pharmacol ; 96(5): 589-599, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31462456

RESUMEN

Licorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3-internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.


Asunto(s)
Chalconas/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Glycyrrhiza , Leucemia Mieloide Aguda/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Simulación del Acoplamiento Molecular/métodos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Tirosina Quinasa 3 Similar a fms/metabolismo
9.
Molecules ; 24(16)2019 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-31405117

RESUMEN

Two new terpene glycosides (1-2) along with two known analogs (3-4) were obtained from the root of Sanguisorba officinalis, which is a common traditional Chinese medicine (TCM). Their structures were elucidated by nuclear magnetic resonance (NMR), electrospray ionization high resolution mass spectrometry (HRESIMS), and a hydrolysis reaction, as well as comparison of these data with the literature data. Compounds 1-4 exhibited anti-inflammatory properties in vitro by attenuating the production of inflammatory mediators, such as nitric oxide (NO) as well as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). An anti-inflammatory assay based on the zebrafish experimental platform indicated that compound 1 had good anti-inflammatory activity in vivo by not only regulating the distribution, but also by reducing the amount of the macrophages of the zebrafish exposed to copper sulfate.


Asunto(s)
Antiinflamatorios , Glicósidos , Sanguisorba/química , Terpenos , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Glicósidos/química , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7 , Terpenos/química , Terpenos/aislamiento & purificación , Terpenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra
10.
Artículo en Inglés | MEDLINE | ID: mdl-31118959

RESUMEN

Geniposide is a well-known iridoid glycoside compound and is an essential component of a wide variety of traditional phytomedicines, for example, Gardenia jasminoides Elli (Zhizi in Chinese), Eucommia ulmoides Oliv. (Duzhong in Chinese), Rehmannia glutinosa Libosch. (Dihuang in Chinese), and Achyranthes bidentata Bl. (Niuxi in Chinese). It is also the main bioactive component of Gardeniae Fructus, the dried ripe fruit of Gardenia jasminoides Ellis. Increasing pharmacological evidence supports multiple medicinal properties of geniposide including neuroprotective, antidiabetic, hepatoprotective, anti-inflammatory, analgesic, antidepressant-like, cardioprotective, antioxidant, immune-regulatory, antithrombotic, and antitumoral effects. It has been proposed that geniposide may be a drug or lead compound for the prophylaxis and treatment of several diseases, such as Alzheimer's disease, Parkinson's disease, diabetes and diabetic complications, ischemia and reperfusion injury, and hepatic disorders. The aim of the present review is to give a comprehensive summary and analysis of the pharmacological properties of geniposide, supporting its use as a medicinal agent.

11.
Bioorg Chem ; 87: 136-141, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30884307

RESUMEN

Chlorovaltrates U-W (1-3), three previously undescribed iridoids, together with four known analogues were isolated from the roots of Valeriana jatamansi. Their structures were elucidated by means of spectroscopic analyses (HRESIMS, NMR). The cytotoxicity of all isolates was evaluated. Compounds 5-7 exhibited selective cytotoxicity against HCT116 cells, with IC50 values of 9.3, 1.7 and 2.2 µM, respectively. The preliminary mechanistic study revealed that, the cytotoxicity effect of 6 was attributed to Akt/mTOR activation blockade via inhibition of PDK1 phosphorylation. Meanwhile, compound 6 could induce autophagosome formation in HCT116 cells via suppressing its downstream Akt/mTOR. These findings show that compound 6 could be of great importance to the development of anti-colon cancer agents.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Autofagia/efectos de los fármacos , Iridoides/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Valeriana/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Iridoides/química , Iridoides/aislamiento & purificación , Modelos Moleculares , Estructura Molecular , Raíces de Plantas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo
12.
Nat Prod Res ; 33(13): 1870-1875, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29792356

RESUMEN

Four previously undescribed isochromanes were isolated from the fermentation broth of an endophytic fungus Aspergillus fumigatus, which was obtained from the fruiting body of Cordyceps sinensis. Their structures were elucidated through extensive spectroscopic analyses. One racemic isochromane was further purified by chiral HPLC to yield a pair of enantiomers and their absolute configurations were determined by quantum chemical ECD calculations. These isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-ME-231) and the result showed that compounds 1a and 2 exhibited moderate growth inhibition against MV4-11 cell line.


Asunto(s)
Aspergillus fumigatus/química , Cromanos/aislamiento & purificación , Cordyceps , Línea Celular , Proliferación Celular/efectos de los fármacos , Cromanos/química , Cromanos/farmacología , Citotoxinas/aislamiento & purificación , Inhibidores de Crecimiento/aislamiento & purificación , Humanos , Estructura Molecular , Análisis Espectral , Estereoisomerismo
13.
J Asian Nat Prod Res ; 21(10): 999-1004, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29945462

RESUMEN

Three aryl-tetralin-type lignans, including 2 previously undescribed compounds, were isolated from the root of Sanguisorba officinalis. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analyses and mass spectrometry. Experimental and calculated ECD were used to determine the absolute configurations. The isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-MB-231) and compound 1 exhibited moderate growth inhibition against MDA-MB-231 cell line with IC50 value of 15.76 µM.


Asunto(s)
Lignanos/farmacología , Sanguisorba/química , Antineoplásicos Fitogénicos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lignanos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química
14.
J Nat Prod ; 81(9): 1992-2003, 2018 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-30212198

RESUMEN

Twenty-two new sesquiterpenoids with four skeletal types and 15 known analogues were isolated from the whole plants of Ligularia rumicifolia. The structures of the isolates were elucidated based on comprehensive spectroscopic data analysis. Compound 1 is a C14 nor-sesquiterpenoid featuring a 6/6/6 tricyclic skeleton with a 9,13-ether bridge. The absolute configuration of 2 was established through single-crystal X-ray diffraction data. Compounds 13-16 exhibited in vitro antiproliferative activity against the four human tumor cell lines A-549, HGC-27, HeLa, and MV4-11. Specifically, compounds 13 and 16 showed antiproliferative activity against the MV4-11 cell line with IC50 values of 0.5 ± 0.2 and 1.1 ± 0.5 µM, respectively.


Asunto(s)
Asteraceae/química , Sesquiterpenos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Extractos Vegetales/farmacología , Sesquiterpenos/química , Sesquiterpenos/farmacología , Difracción de Rayos X
15.
Molecules ; 23(7)2018 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-30011828

RESUMEN

Five new polyketides, including two pairs of enantiomers and a racemate, were isolated from the fermentation broth of Aspergillus fumigatus, an endophytic fungus isolated from Cordyceps sinensis. Their structures were identified using one-dimensional (1D) and two-dimensional (2D) NMR experiments, and the absolute configurations of the enantiomers were confirmed using electronic circular dichroism (ECD) calculations. Compounds 1a and 2a exhibited inhibitory activity against the MV4-11 cell line in vitro, with IC50 values of 23.95 µM and 32.70 µM, respectively.


Asunto(s)
Aspergillus fumigatus/química , Cordyceps , Policétidos/química , Aspergillus fumigatus/metabolismo , Policétidos/metabolismo
16.
Oncotarget ; 8(61): 103087-103099, 2017 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-29262547

RESUMEN

Targeted therapies for the treatment of acute myeloid leukemia (AML), specifically the FLT3 inhibitors, have shown promising results. Nevertheless, it is very unlikely that inhibitors which target a single pathway will provide long-term disease control. Here, we report the characterization of crotonoside, a natural product extracted from Chinese medicinal herb, Croton, for the treatment of AML via inhibition of FLT3 and HDAC3/6. In vitro, crotonoside exhibited selective inhibition in AML cells. In vivo, crotonoside treatment at 70 and 35 mg/kg/d produced significant AML tumor inhibition rates of 93.5% and 73.6%, respectively. Studies on the anti-AML mechanism of crotonoside demonstrated a significant inhibition of FLT3 signaling, cell cycle arrest in G0/G1 phase, and apoptosis. In contrast to classic FLT3 inhibitor; sunitinib, crotonoside was able to selectively suppress the expression of HDAC3 and HDAC6 without altering the expression of other HDAC isoforms. Inhibitors of HDAC3 and HDAC6; RGFP966 and HPOB, respectively, also exhibited selective inhibition in AML cells. Furthermore, we established novel signaling pathways including HDAC3/NF-κB-p65 and HDAC6/c-Myc besides FLT3/c-Myc which are aberrantly regulated in the progression of AML. In addition, crotonoside alone or the combination of sunitinib/RFP966/HPOB exhibited a significant post-inhibition effect in AML cells by the inhibition of FLT3 and HDAC3/6. Inhibitors targeting the FLT3 and HDAC3/6 might provide a more effective treatment strategy for AML. Taken together, the present study suggests that crotonoside could be a promising candidate for the treatment of AML, and deserves further investigations.

17.
Phytochemistry ; 141: 156-161, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28623738

RESUMEN

Five iridoids, named as chlorovaltrate P-T, together with six known analogues, (4ß,8ß)-8-methoxy-3-methoxy-10-methylene-2,9-dioxatricyclo[4.3.1.03,7]decan-4-ol, chlorovaltrate A, (1R,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-ethyl-5-hydroxyvalechlorine, 8-methoxy-4-acetoxy-3-chlormethyl-10-methylen-2,9-dioxa-tricyclo[4.3.1.03,7]decan, (1S,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-ethyl-5-hydroxyvalechlorine, (1R,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-methyl-5-hydroxyvalechlorine were isolated from the roots of Valeriana jatamansi (syn. Valeriana wallichii). Their structures were elucidated by extensive analysis of 1D, 2D NMR and HRESIMS spectroscopic. The absolute configuration of chlorovaltrate P-T were established by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. 3,8-epoxy iridoids exhibited weak cytotoxicity against the lung adenocarcinoma (A 549) and gastric carcinoma cells (SGC 7901). Some also showed moderate neuroprotective effects against CoCl2-induced neuronal cell death in PC12 cells.


Asunto(s)
Iridoides/química , Fármacos Neuroprotectores/química , Raíces de Plantas/química , Valeriana/química , Células A549 , Animales , Muerte Celular/efectos de los fármacos , Humanos , Iridoides/aislamiento & purificación , Estructura Molecular , Fármacos Neuroprotectores/aislamiento & purificación , Células PC12 , Ratas
18.
J Ethnopharmacol ; 202: 20-27, 2017 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-27416805

RESUMEN

ETHNOPHAMACOLOGICAL RELEVANCE: Pogostemon cablin is a medicinal herb widely used to treat gastrointestinal diseases in many Asian countries. Pogostone is an important constituent of Pogostemon cablin, and possesses various bioactivitys. In this study, we performed to investigate the anti-colorectal tumor property of Pogostone by inducing aurophagy and apoptosis in human colorectal cancer cells, and to define the potential molecular mechanisms. MATERIALS AND METHODS: In vitro, The anti-tumor activity of pogostone was assessed using MTT assay. Autophagy was monitored by transmission electron microscopy observation and mRFP-GFP-LC3 fluorescence analysis in colorectal tumor cell line. Apoptosis was measured by flow cytometry and annexinV-FITC/PI staining. The protein expressions or activition of LC3-Ⅱ, AKT, mTOR, caspase-3 and caspase-7 were detected through western blotting. In vivo, the anti-tumor effect of pogostone was tested with HCT116 colorectal tumor cells transplantation tumor model. The expression of Ki-67 was determined by Immunohistochemistry staining and the apoptosis was evaluated using TUNEL assay. RESULTS: In vitro, pogostone exhibits significant anti-tumor activity against human cancer cell lines, especially for HCT116 (18.7±1.93µg/ml). Transmission electron microscopy observation, mRFP-GFP-LC3 fluorescence analysis, flow cytometry and assay and western blotting detection revealed that the anti-colorectal tumor activity of pogostone was dependent on inducing autophagy and apoptosis through up-regulating the expression of LC3-Ⅱ, cleaved caspase-7 and caspase-3, and decreasing the phosphorylation of AKT/mTOR. In vivo, 150mg/kg pogostone inhibited the HCT116 tumor growth in immunodeficient mice with an inhibitory rate of 43.3%, decreased the expression of Ki67, and induced apoptosis in three days. CONCLUSION: Pogostone showed anti-colorectal tumor effects by inducing autophagy and apoptosis involving PI3K/Akt/mTOR axis. Thus, pogostone may be a promising lead compound to be further developed for cancer therapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Aceites Volátiles/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales , Femenino , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Oncogénica v-akt/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Serina-Treonina Quinasas TOR/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Food Chem Toxicol ; 97: 141-149, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27597133

RESUMEN

The carcinogenicity prediction has become a significant issue for the pharmaceutical industry. The purpose of this investigation was to develop a novel prediction model of carcinogenicity of chemicals by using a naïve Bayes classifier. The established model was validated by the internal 5-fold cross validation and external test set. The naïve Bayes classifier gave an average overall prediction accuracy of 90 ± 0.8% for the training set and 68 ± 1.9% for the external test set. Moreover, five simple molecular descriptors (e.g., AlogP, Molecular weight (MW), No. of H donors, Apol and Wiener) considered as important for the carcinogenicity of chemicals were identified, and some substructures related to the carcinogenicity were achieved. Thus, we hope the established naïve Bayes prediction model could be applied to filter early-stage molecules for this potential carcinogenicity adverse effect; and the identified five simple molecular descriptors and substructures of carcinogens would give a better understanding of the carcinogenicity of chemicals, and further provide guidance for medicinal chemists in the design of new candidate drugs and lead optimization, ultimately reducing the attrition rate in later stages of drug development.


Asunto(s)
Teorema de Bayes , Pruebas de Carcinogenicidad/métodos , Carcinógenos/clasificación , Carcinógenos/toxicidad , Modelos Estadísticos , Neoplasias/inducido químicamente , Animales , Carcinógenos/química , Simulación por Computador , Bases de Datos de Compuestos Químicos , Ratas
20.
Melanoma Res ; 26(2): 117-24, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26684062

RESUMEN

Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metastatic, highlighting the need for discovery of novel potent agents. In this investigation, we adopted a zebrafish embryonic pigmentation model to identify antimelanoma agents by screening an in-house small molecule library. With this assay, we found that a small molecule compound, SKLB226, blocked zebrafish pigmentation and pigment cell migration. Mechanism of action studies showed that SKLB226 downregulated MITF mRNA level in both zebrafish embryos and mammalian melanoma cells. Further studies showed that it could efficiently suppress the viability and migration of mammalian melanoma cells. In summary, SKLB226 can be used as a chemical tool to study melanocyte development as well as an antimelanoma lead compound that should be subjected to further structural optimization.


Asunto(s)
Antineoplásicos/farmacología , Melanoma/tratamiento farmacológico , Factor de Transcripción Asociado a Microftalmía/biosíntesis , Neoplasias Cutáneas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Ratones , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Pez Cebra
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