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1.
Phytother Res ; 38(6): 2800-2817, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38526171

RESUMEN

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.


Asunto(s)
Melanoma Experimental , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor de Transcripción STAT3 , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Factor de Transcripción STAT3/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Humanos , Furanos/farmacología , Simulación del Acoplamiento Molecular , Supervivencia Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Autofagia/efectos de los fármacos , Sesquiterpenos
2.
Int J Mol Sci ; 23(19)2022 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-36233191

RESUMEN

Polyphyllin II (PPII) is a natural steroidal saponin occurring in Rhizoma Paridis. It has been demonstrated to exhibit anti-cancer activity against a variety of cancer cells. However, the anti-colorectal cancer (CRC) effects and mechanism of action of PPII are rarely reported. In the present study, we showed that PPII inhibited the proliferation of HCT116 and SW620 cells. Moreover, PPII induced G2/M-phase cell cycle arrest and apoptosis, as well as protective autophagy, in CRC cells. We found that PPII-induced autophagy was associated with the inhibition of PI3K/AKT/mTOR signaling. Western blotting results further revealed that PPII lowered the protein levels of phospho-Src (Tyr416), phospho-JAK2 (Tyr1007/1008), phospho-STAT3 (Tyr705), and STAT3-targeted molecules in CRC cells. The overactivation of STAT3 attenuated the cytotoxicity of PPII against HCT116 cells, indicating the involvement of STAT3 inhibition in the anti-CRC effects of PPII. PPII (0.5 mg/kg or 1 mg/kg, i.p. once every 3 days) suppressed HCT116 tumor growth in nude mice. In alignment with the in vitro results, PPII inhibited proliferation, induced apoptosis, and lowered the protein levels of phospho-STAT3, phospho-AKT, and phospho-mTOR in xenografts. These data suggest that PPII could be a potent therapeutic agent for the treatment of CRC.


Asunto(s)
Neoplasias Colorrectales , Saponinas , Animales , Apoptosis , Autofagia , Neoplasias Colorrectales/patología , Humanos , Ratones , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Saponinas/farmacología , Saponinas/uso terapéutico , Esteroides , Serina-Treonina Quinasas TOR/metabolismo
3.
Biol Pharm Bull ; 43(8): 1267-1271, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32741948

RESUMEN

Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N (GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K-Akt pathway and regulates the mTOR-ULK1 pathway in liver cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Homólogo de la Proteína 1 Relacionada con la Autofagia/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Lignanos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/fisiología , Compuestos Policíclicos/farmacología , Proteínas Proto-Oncogénicas c-akt/fisiología , Serina-Treonina Quinasas TOR/fisiología , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Línea Celular Tumoral , Ciclooctanos/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos
4.
Pharmacol Res ; 142: 115-126, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30797070

RESUMEN

A traditional Chinese medicine (TCM) formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was used for treating melanoma in ancient China. We have previously shown that an ethanolic extract of SL (SLE) possesses anti-melanoma effects and suppresses STAT3 signaling in vitro and in vivo. STAT3 has been linked to the development of melanoma immunosuppressive microenvironment. In this work, we investigated whether SLE inhibits melanoma growth by reprogramming the tumor microenvironment in mouse and co-culture cell models. In B16F10 melanoma-bearing mice, we found that intragastric administration of SLE (1.2 g/kg) dramatically inhibited tumor growth. This observation was associated with the downregulation of protein levels of phospho-STAT3 (Tyr 705) and STAT3-regulated immunosuppressive cytokines, and mRNA levels of STAT3-targeted genes involved in tumor growth and immune evasion. We also observed increased Th, Tc and dendritic cells in the melanomas and spleens in SLE-treated mice compared to that in control mice. In a co-culture system composed of B16F10 cells and mouse primary splenic lymphocytes, it was found that SLE not only inhibited STAT3 activation in B16F10 cells, but also downregulated mRNA levels of STAT3-targeted genes in the splenic lymphocytes. In this co-culture setting, SLE decreased the levels of STAT3-regulated immunosuppressive cytokines, increased the percentages of Th, Tc and dendritic cells as well. Furthermore, effects of SLE on STAT3 phosphorylation, cytokine levels and immune cell subtype percentages were significantly weaker in the B16STAT3C cells (stable cells harboring a constitutively active STAT3 variant STAT3C)/splenic lymphocytes co-culture system than in the B16V cells (cells stably transfected with the empty vector)/splenic lymphocytes co-culture system, indicating that STAT3 over-activation diminishes SLE's effects. In summary, our findings indicate that reprograming the immune microenvironment, partially mediated by inhibiting STAT3 signaling, contributes to the anti-melanoma mechanisms of SLE. This study provides further pharmacological groundwork for developing SLE as a modern agent for melanoma prevention/treatment, and supports the notion that reprograming immunosuppressive microenvironment is a viable anti-melanoma strategy.


Asunto(s)
Antineoplásicos/farmacología , Melanoma Experimental/inmunología , Extractos Vegetales/farmacología , Factor de Transcripción STAT3/inmunología , Neoplasias Cutáneas/inmunología , Sophora , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Técnicas de Cocultivo , Flores , Lonicera , Linfocitos , Masculino , Medicina Tradicional China , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Extractos Vegetales/uso terapéutico , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Microambiente Tumoral/inmunología
5.
Exp Dermatol ; 27(2): 201-204, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29078004

RESUMEN

In this study, we aimed to investigate the anti-melanoma effects and the JAK2/STAT3 pathway-related mechanism of action of atractylenolide I in human melanoma cells. Our results showed that atractylenolide I effectively reduced viability, induced apoptosis and inhibited migration of melanoma cells. Meanwhile, atractylenolide I decreased the protein expression levels of phospho-JAK2 and phospho-STAT3, and in turn downregulated the mRNA levels of STAT3-targeted genes, including Bcl-xL, MMP-2 and MMP-9. Furthermore, the cytotoxic effect of atractylenolide I was attenuated in STAT3-overactivated A375 cells. These findings indicate that inhibition of JAK2/STAT3 signalling contributes to the anti-melanoma effects of atractylenolide I.


Asunto(s)
Apoptosis , Janus Quinasa 2/metabolismo , Lactonas/farmacología , Melanoma/metabolismo , Factor de Transcripción STAT3/metabolismo , Sesquiterpenos/farmacología , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Fosforilación , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos
6.
BMC Complement Altern Med ; 18(1): 141, 2018 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-29720145

RESUMEN

BACKGROUND: Herba Siegesbeckiae (HS, Xixiancao in Chinese) is a commonly used traditional Chinese medicinal herb for soothing joints. In ancient materia medica books, HS is recorded to be the aerial part of Siegesbeckia pubescens Makino (SP) which is also the only origin of HS in the 1963 edition of the Chinese Pharmacopeia (ChP). The aerial parts of Siegesbeckia orientalis L. (SO) and Siegesbeckia glabrescens Makino (SG) have been included as two additional origins for HS in each edition of ChP since 1977. However, chemical and pharmacological comparisons among these three species have not been conducted. METHODS: An HPLC with diode array detector (HPLC-DAD) method combined with similarity analysis, hierarchical cluster analysis (HCA) and principal component analysis (PCA) was developed for comparing the fingerprint chromatograms of the three species. The inhibitory effects of the three species on NO production and IL-6 secretion in LPS-stimulated RAW264.7 macrophages were compared. RESULTS: Fingerprint chromatograms of the three species showed different profiles, but had 13 common peaks. Results from HCA and PCA of the common peaks demonstrated that all 14 herbal samples of the three species tended to be grouped and separated species dependently. The extents of inhibition on NO production and IL-6 secretion of the three species were different, with SG being the most and SP the least potent. CONCLUSIONS: Both chemical profiles and inflammatory mediator-inhibitory effects of the three species were different. These findings provide a chemical and pharmacological basis for determining whether the three species can all serve as the origins of HS.


Asunto(s)
Asteraceae/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Interleucina-6/análisis , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Células RAW 264.7 , Reproducibilidad de los Resultados
7.
Lipids Health Dis ; 16(1): 8, 2017 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-28086886

RESUMEN

BACKGROUND: It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly. METHODS: Male ICR mice were given a single oral dose of Sch B (0.25-2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12-120 h after Sch B treatment. RESULTS: Serum and hepatic TG levels were increased by 1.0-4.3 fold and 40-158% at 12-72 h and 12-96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 103 µm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18-60% and 42-71% at 12-120 h and 24-72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice. CONCLUSION: Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.


Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Hígado Graso/metabolismo , Hepatomegalia/metabolismo , Hipertrigliceridemia/metabolismo , Lignanos/efectos adversos , Hígado/efectos de los fármacos , Compuestos Policíclicos/efectos adversos , Adipocitos/metabolismo , Adipocitos/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Apolipoproteína B-48/sangre , Tamaño de la Célula , Colesterol/sangre , VLDL-Colesterol/sangre , Ciclooctanos/efectos adversos , Ácidos Grasos no Esterificados/sangre , Hígado Graso/inducido químicamente , Hígado Graso/patología , Factor de Crecimiento de Hepatocito/sangre , Hepatomegalia/inducido químicamente , Hepatomegalia/patología , Hipertrigliceridemia/inducido químicamente , Hipertrigliceridemia/patología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos ICR , Mitocondrias/metabolismo , Mitocondrias/patología , Schisandra/química , Triglicéridos/sangre
8.
Lipids Health Dis ; 14: 93, 2015 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-26303027

RESUMEN

BACKGROUND: At the present, a shift from drug therapy, especially herbal therapy, to dietary supplementation is a trend in the management of dyslipidemia and related diseases. Therefore, the optimal utilization of herbal resource is important for a sustainable development of herbal medicine. Here, we compared the effects of dietary supplementation with Chinese medicine Schisandrae Chinensis Fructus seed (FSC-S) and the post-ethanol extraction residue of FSC-S (FSC-SpEt) on normal diet-fed (normal) and experimental hypercholesterolemic (HCL) mice. METHODS: Male ICR mice (n = 10 in each group), weighing 17-21 g, were fed with normal diet (ND) or high cholesterol/bile salt (1/0.3 %, w/w) diet (HCBD) with or without supplemented with FSC-S, FSC-SpEt), or lipid-lowering agent fenofibrate (FF). Ten days later, serum/hepatic lipid and glucose (GLU) levels, body weight, organ/epididymal fat masses, and food/water intake were measured. Lipid level measurements included those of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), HDL/LDL ratio, LDL/HDL ratio, and non-HDL (N-HDL). RESULTS: Supplementation with FSC-S and FSC-SpEt increased serum TC (by 64 and 25 %, respectively) and LDL (by 60 and 27 %, respectively) in normal mice. FSC-S supplementation elevated serum TC, TG, HDL, LDL, and LDL/HDL ratio (up to 64, 118, 77, 197, and 51 %, respectively) in HCL mice. FSC-SpEt supplementation reduced serum TG (by 15 %) and LDL/HDL ratio (by 18 %), as well as increased serum HDL (by 22 %) and HDL/LDL ratio (by 21 %) in HCBD-fed mice. FSC-S decreased hepatic TC (by 19 %) contents and increased hepatic TG contents by 14 % in normal mice. FSC-S reduced hepatic GLU level in both normal and HCL mice by 24 and 22 %, respectively. Hepatic TC and TG contents were lowered in FSC-SpEt-supplemented normal mice by 16 and 20 %, respectively. The body/fatty masse and food intake were lowered, but the feed efficiency index (FEI), weight gain per unit of food ingested, was increased in FSC-S-supplemented normal and HCL mice. FF supplements reduced serum/hepatic lipids, hepatic GLU contents, and epididymal fat mass, but it induced hepatomegaly and high serum alanine aminotransferase (ALT) activity in normal and/or HCL mice. CONCLUSION: The ensemble of results indicated that while FSC-SpEt supplementation is beneficial for the treatment of hyperlipidemia/fatty liver, FSC-S is potentially useful for the management of overweight/obesity.


Asunto(s)
Anticolesterolemiantes/farmacología , Hígado Graso/tratamiento farmacológico , Hipercolesterolemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Schisandra/química , Semillas/química , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Anticolesterolemiantes/aislamiento & purificación , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol en la Dieta/administración & dosificación , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Etanol , Hígado Graso/etiología , Hígado Graso/metabolismo , Hígado Graso/patología , Fenofibrato/farmacología , Hipercolesterolemia/etiología , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Solventes , Triglicéridos/metabolismo
9.
Lipids Health Dis ; 13: 46, 2014 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-24621253

RESUMEN

BACKGROUND: Recently, it has been found that Fructus Schisandra Chinensis (FSC), a Chinese herbal medicine, and its related compounds have a profound impact on lipid metabolism process. FSC can be divided into two parts, i.e., seed and pulp. The current study aimed to examine the effect of aqueous extracts of FSC pulp (AqFSC-P) on serum/hepatic lipid and glucose levels in mice fed with a normal diet (ND) or a high cholesterol/bile salt diet (HCBD). METHODS: The AqFSC-P used in the present study was fractionated into supernatant (SAqFSC-P) and precipitate (PAqFSC-P) separated by centrifugation. Male ICR mice were fed with ND or HCBD, without or with supplementation of 1%, 3%, or 9% (w/w) SAqFSC-P or PAqFSC-P for 10 days. Biomarkers were determined according to the manufacturer's instruction. RESULTS: Supplementation with SAqFSC-P or PAqFSC-P significantly reduced serum and hepatic triglyceride levels (approximately 40%) in ND- and/or HCBD-fed mice. The supplementation with SAqFSC-P or PAqFSC-P reduced hepatic total cholesterol levels (by 27-46%) in HCBD-fed mice. Supplementation with SAqFSC-P or PAqFSC-P markedly lowered hepatic glucose levels (by 13-30%) in ND- and HCBD-fed mice. SAqFSC-P decreased serum alanine aminotransferase (ALT) activity, but PAqFSC-P increased hepatic protein contents in ND-fed mice. Bicylol, as a positive control, reduced ALT activity. In addition, mice supplemented with FSC-P or bicylol showed a smaller body weight gain and adipose tissue mass as compared to the respective un-supplemented ND- or HCBD-fed mice. CONCLUSION: The results indicate that SAqFSC-P and PAqFSC-P produce hepatic lipid- and glucose-lowering as well as serum TG-lowering effects in hypercholesterolemic mice. FSC pulp may provide a safe alternative for the management of fatty liver and/or lipid disorders in humans.


Asunto(s)
Anticolesterolemiantes/administración & dosificación , Suplementos Dietéticos , Medicamentos Herbarios Chinos/administración & dosificación , Hipercolesterolemia/sangre , Hígado/metabolismo , Schisandra/química , Adiposidad , Animales , Ácidos y Sales Biliares/efectos adversos , Compuestos de Bifenilo/farmacología , Glucemia , Colesterol en la Dieta/efectos adversos , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Evaluación Preclínica de Medicamentos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/etiología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Triglicéridos/sangre , Aumento de Peso
10.
J Pharmacol Sci ; 123(2): 110-9, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24096833

RESUMEN

Hyperlipidemia is referred to as hypercholesterolemia, hypertriglyceridemia, or both in combined hyperlipidemia. Here, a novel mouse model of combined hyperlipidemia is described. Mice were orally given a single dose of a modeling agent (MA) made of a mixture of schisandrin B/cholesterol/bile salts (1/2/0.5 g/kg) suspended in olive oil. MA treatment increased serum triglycerides (TG) and total cholesterol (TC) (up to 422% and 100% at 12 - 96 h post-treatment, respectively) and hepatic TG and TC (up to 220% and 26%, respectively) in a time- and dose-dependent manner, associated with elevation of high-density lipoprotein and low-density lipoprotein levels. Serum alanine/aspartate aminotransferase activities, indicators of liver cell damage, were also elevated (up to 198%) at 48 and 72 h post-MA treatment. Fenofibrate blocks MA-induced hyperlipidemia, lipid accumulation in the liver, as well as liver injury. Oral administration of a mixture of schisandrin B, cholesterol, and bile salt could generate an interesting mouse model of combined hyperlipidemia associated with hepatic steatosis and steatohepatitis.


Asunto(s)
Ácidos y Sales Biliares , Enfermedad Hepática Inducida por Sustancias y Drogas , Colesterol , Modelos Animales de Enfermedad , Hígado Graso , Hiperlipidemias , Lignanos , Compuestos Policíclicos , Administración Oral , Animales , Ácidos y Sales Biliares/administración & dosificación , Ácidos y Sales Biliares/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Colesterol/administración & dosificación , Colesterol/efectos adversos , Ciclooctanos/administración & dosificación , Ciclooctanos/efectos adversos , Relación Dosis-Respuesta a Droga , Hígado Graso/inducido químicamente , Hígado Graso/prevención & control , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Hiperlipidemias/sangre , Hiperlipidemias/inducido químicamente , Hiperlipidemias/prevención & control , Lignanos/administración & dosificación , Lignanos/efectos adversos , Lipoproteínas/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/efectos adversos , Factores de Tiempo , Triglicéridos/sangre
11.
Phytomedicine ; 108: 154526, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36334389

RESUMEN

BACKGROUND: Melanoma is an aggressive cancer. Gracillin has been reported to treat various types of cancer, such as colorectal and lung cancer. However, there is a paucity of research on the anti-melanoma effects of gracillin. PURPOSE: The aim of this study was to assess the anti-melanoma effects and mechanisms of action of gracillin in vitro and in vivo. METHODS: Cell viability was detected using MTT and crystal violet staining assays. Cell proliferation was examined by EdU staining assays. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Autophagic flux was monitored under a confocal microscope. Protein levels were determined by immunoblotting. LY294002 and rapamycin (Rapa) were used to determine the involvement of PI3K/AKT/mTOR signaling in gracillin-mediated autophagy. Signal transducer and activator of transcription 3 (STAT3) was overactivated to explore the contribution of the STAT3 signaling pathway in the anti-melanoma effects of gracillin. A B16F10 allograft mouse model was developed to evaluate the anti-melanoma effects of gracillin in vivo. RESULTS: We demonstrated that in melanoma cells, gracillin inhibited proliferation, induced G0/G1 phase cell cycle arrest, evoked apoptosis, and triggered autophagic cell death. Gracillin induced DNA damage in melanoma cells. Moreover, it suppressed the phosphorylation/activation of PI3K, AKT, mTOR, and 4E-BP1 in melanoma cells. Inhibiting PI3K/AKT and mTOR activity using LY294002 and Rapa, respectively, increased the protein level of LC3B-II in gracillin-treated melanoma cells. Furthermore, gracillin downregulated the protein levels of p-JAK2 (Tyr1007/1008), p-Src (Tyr416), and p-STAT3 (Tyr705) in melanoma cells. Over-expression of STAT3 in A375 cells significantly mitigated the cytotoxic and apoptotic effects of gracillin. In vivo studies showed that gracillin (1 mg/kg or 8 mg/kg, administered intraperitoneally for 16 consecutive days) suppressed B16F10 tumor growth and Src/STAT3 and AKT/mTOR signaling in tumors. No overt toxicity was observed in mice. CONCLUSION: Induction of DNA damage, inhibition of PI3K/AKT/mTOR signaling and suppression of STAT3 signaling are involved in gracillin-mediated cell cycle arrest, autophagic cell death and apoptosis, respectively, in melanoma cells. These findings provide novel insights into the anti-melanoma molecular mechanisms of gracillin, and suggest a potential role of gracillin in melanoma management.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis , Autofagia , Serina-Treonina Quinasas TOR/metabolismo , Melanoma/tratamiento farmacológico , Proliferación Celular , Daño del ADN , Línea Celular Tumoral
12.
J Ethnopharmacol ; 312: 116548, 2023 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-37100264

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) poses a growing challenge to global health efforts. The 5-year survival rate of HCC patients is still dismal. A traditional prescription Qi-Wei-Wan (QWW) comprising Astragali Radix and Schisandra chinensis Fructus has traditionally been used for HCC treatment according to traditional Chinese medicine theory, but the pharmacological basis is not clear. AIM OF THE STUDY: This study aims to investigate the anti-HCC effects of an ethanolic extract of QWW (hereafter, QWWE) and the mechanism of action. MATERIALS AND METHODS: An UPLC-Q-TOF-MS/MS method was developed to control the quality of QWWE. Two human HCC cell lines (HCCLM3 and HepG2) and a HCCLM3 xenograft mouse model were employed to investigate the anti-HCC effects of QWWE. The anti-proliferative effect of QWWE in vitro was determined by MTT, colony formation and EdU staining assays. Apoptosis and protein levels were examined by flow cytometry and Western blotting, respectively. Nuclear presence of signal transducer and activator of transcription 3 (STAT3) was examined by immunostaining. Transient transfection of pEGFP-LC3 and STAT3C plasmids was performed to assess autophagy and determine the involvement of STAT3 signaling in QWWE's anti-HCC effects, respectively. RESULTS: We found that QWWE inhibited the proliferation of and triggered apoptosis in HCC cells. Mechanistically, QWWE inhibited the activation of SRC and STAT3 at Tyr416 and Tyr705, respectively; inhibited the nuclear translocation of STAT3; lowered Bcl-2 protein levels, while increased Bax protein levels in HCC cells. Over-activating STAT3 attenuated the cytotoxic and apoptotic effects of QWWE in HCC cells. Moreover, QWWE induced autophagy in HCC cells by inhibiting mTOR signaling. Blocking autophagy with autophagy inhibitors (3-methyladenine and chloroquine) enhanced the cytotoxicity, apoptotic effect and the inhibitory effect on STAT3 activation of QWWE. Intragastric administration of QWWE at 10 mg/kg and 20 mg/kg potently repressed tumor growth and inhibited STAT3 and mTOR signaling in tumor tissues, but did not significantly affect mouse body weight. CONCLUSION: QWWE exhibited potent anti-HCC effects. Inhibiting the STAT3 signaling pathway is involved in QWWE-mediated apoptosis, while blocking mTOR signaling contributes to QWWE-mediated autophagy induction. Blockade of autophagy enhanced the anti-HCC effects of QWWE, indicating that the combination of an autophagy inhibitor and QWWE might be a promising therapeutic strategy for HCC management. Our findings provide pharmacological justifications for the traditional use of QWW in treating HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Schisandra , Humanos , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Línea Celular Tumoral , Espectrometría de Masas en Tándem , Apoptosis , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Proliferación Celular
13.
Chin Med ; 17(1): 27, 2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35193642

RESUMEN

BACKGROUND: Tea trees originated in southwest China 60 million or 70 million years ago. Written records show that Chinese ancestors had begun drinking tea over 3000 years ago. Nowadays, with the aging of populations worldwide and more people suffering from non-communicable diseases or poor health, tea beverages have become an inexpensive and fine complementary and alternative medicine (CAM) therapy. At present, there are 3 billion people who like to drink tea in the world, but few of them actually understand tea, especially on its development process and the spiritual and cultural connotations. METHODS: We searched PubMed, Google Scholar, Web of Science, CNKI, and other relevant platforms with the key word "tea", and reviewed and analyzed tea-related literatures and pictures in the past 40 years about tea's history, culture, customs, experimental studies, and markets. RESULTS: China is the hometown of tea, tea trees, tea drinking, and tea culture. China has the oldest wild and planted tea trees in the world, fossil of a tea leaf from 35,400,000 years ago, and abundant tea-related literatures and art works. Moreover, tea may be the first Chinese herbal medicine (CHM) used by Chinese people in ancient times. Tea drinking has many benefits to our physical health via its antioxidant, anti-inflammatory, immuno-regulatory, anticancer, cardiovascular-protective, anti-diabetic, and anti-obesity activities. At the moment, COVID-19 is wreaking havoc across the globe and causing severe damages to people's health and lives. Tea has anti-COVID-19 functions via the enhancement of the innate immune response and inhibition of viral growth. Besides, drinking tea can allow people to acquire a peaceful, relaxed, refreshed and cheerful enjoyment, and even longevity. According to the meridian theory of traditional Chinese medicine, different kinds of tea can activate different meridian systems in the human body. At present, black tea (fermented tea) and green tea (non-fermented tea) are the most popular in the world. Black tea accounts for over 90% of all teas sold in western countries. The world's top-grade black teas include Qi Men black in China, Darjeeling and Assam black tea in India, and Uva black tea in Sri Lanka. However, all top ten famous green teas in the world are produced in China, and Xi Hu Long Jing tea is the most famous among all green teas. More than 700 different kinds of components and 27 mineral elements can be found in tea. Tea polyphenols and theaflavin/thearubigins are considered to be the major bioactive components of black tea and green tea, respectively. Overly strong or overheated tea liquid should be avoided when drinking tea. CONCLUSIONS: Today, CAM provides an array of treatment modalities for the health promotion in both developed and developing countries all over the world. Tea drinking, a simple herb-based CAM therapy, has become a popular man-made non-alcoholic beverage widely consumed worldwide, and it can improve the growth of economy as well. Tea can improve our physical and mental health and promote the harmonious development of society through its chemical and cultural elements.

14.
Artículo en Inglés | MEDLINE | ID: mdl-33688367

RESUMEN

Schisandrae Fructus (SF), the fruit of Schisandra chinensis (Turcz.) Baillon, has been used for the treatment of liver injury and metabolism-related disorders in China. The objective of this study was to investigate the effects of supplementation with ethanol extract of SF seed (EtSF-S) on serum/hepatic lipid and glucose levels as well as fecal total cholesterol (TC) contents in mice fed a normal diet (ND) or high-fat/fructose diet (HFFD) containing 15% lard oil and 15% fructose. Female ICR mice (18-20 g in body weight) were fed with ND or HFFD for 3 months, and then EtSF-S was added to both chow diets at increasing concentrations of 1, 5, and 10% (w/w). Thirty days later, serum and hepatic lipids, including TC, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucose, were measured. Dietary supplementation with EtSF-S reduced hepatic TC (36 and 18%) and TG levels (38 and 28%) and increased serum HDL/LDL ratio (16 and 26%) in both ND- and HFFD-fed mice, respectively. Moreover, supplementation with EtSF-S elevated serum HDL (31%) in HFFD-fed mice and reduced serum LDL (27%) in ND-fed mice. EtSF-S treatment reduced fat mass (40%) in ND-fed mice and increased fecal TC contents (33%) in HFFD-fed mice. EtSF-S supplementation decreased hepatic glucose contents (29%) in both ND- and HFFD-fed mice. However, diet supplemented with EtSF-S elevated serum TG levels (up to 123%) and hepatic size (28%), but more importantly, suppressed the body weight gain (approximately 130%) in mice fed with HFFD. These findings suggested that dietary supplementation with EtSF-S as natural herbal function food may be a useful strategy for the treatment of patients with fatty liver disease or overweight without a high intake of sugar and fat.

15.
Life Sci ; 241: 117169, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31843524

RESUMEN

AIMS: Melanoma is lethal. Constitutively active signal transducer and activator of transcription 3 (STAT3) has been proposed as a pathogenic factor and a therapeutic target of melanoma. Brevilin A, a sesquiterpene lactone isolated from Centipeda minima (L.) A. Br. et Aschers., has been shown to exert antineoplastic effects and inhibit the STAT3 pathway in nasopharyngeal, lung, prostate and breast cancer cells. This study aimed to determine whether brevilin A has anti-melanoma effects, and whether STAT3 signaling is involved in the effects. MAIN METHODS: A mouse A375 xenograft model, as well as A375 and A2058 cell models were employed to assess the in vivo and in vitro anti-melanoma effects of brevilin A. A375 cells stably expressing STAT3C, a constitutively active STAT3 mutant, were used to determine the role of STAT3 signaling in brevilin A's anti-melanoma effects. KEY FINDINGS: Intraperitoneal injection of brevilin A dose-dependently inhibited melanoma growth in mice and suppressed STAT3 phosphorylation in the tumors. In cultured cells, brevilin A reduced cell viability, induced apoptosis, suppressed migration and invasion, decreased protein levels of phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and restrained STAT3 nuclear localization. STAT3 over-activation diminished brevilin A's effects on cell viability and migration. Collectively, brevilin A exerts anti-melanoma effects and these effects are at least in part attributed to the inhibition of the JAK2/STAT3 pathway. SIGNIFICANCE: Our findings provide a pharmacological basis for developing brevilin A as a new phytotherapeutic agent against melanoma.


Asunto(s)
Crotonatos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Janus Quinasa 2/metabolismo , Melanoma/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Sesquiterpenos/farmacología , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Humanos , Janus Quinasa 2/genética , Masculino , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , Factor de Transcripción STAT3/genética , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Cell Death Dis ; 11(4): 246, 2020 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-32312954

RESUMEN

Malignant melanoma is aggressive and has a high mortality rate. Toll-like receptor 4 (TLR4) has been linked to melanoma growth, angiogenesis and metastasis. However, signal transduction mediated by TLR4 for driving melanoma progression is not fully understood. Signal transducer and activator of transcription 3 (STAT3) has been identified as a major oncogene in melanoma progression. We found: that TLR4 expression positively correlates with activation/phosphorylation of STAT3 in human melanoma samples; that TLR4 ligands activate STAT3 through MYD88 and TRIF in melanoma cells; and that intratumoral activation of TLR4 increases STAT3 activation in the tumor and promotes tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT) and the formation of an immunosuppressive tumor microenvironment in mice. Further, we found that the effects mediated by activating TLR4 are weakened by suppressing STAT3 function with a dominant negative STAT3 variant in melanoma. Collectively, our work identifies STAT3 activation as a key event in TLR4 signaling-mediated melanoma progression, shedding new light on the pathophysiology of melanoma.


Asunto(s)
Melanoma/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Humanos , Lipopolisacáridos/farmacología , Melanoma/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
17.
Oncol Lett ; 19(3): 2508-2514, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32194752

RESUMEN

Late stage melanoma is associated with a high mortality rate. Signal transducer and activator of transcription 3 (STAT3) is currently a target for melanoma treatment as it is constitutively activated with high frequency in melanoma. Dioscin is a natural steroid saponin that is present in several medical herbs. A previous study demonstrated that dioscin inhibits STAT3 signaling in a cerebral ischemia-reperfusion injury rat model. Furthermore, dioscin has been reported to exert anti-melanoma effects in B16 melanoma cells and a B16 allograft mouse model. The present study investigated whether inhibition of STAT3 signaling is involved in the anti-melanoma effects of dioscin. The results of the present study demonstrated that dioscin significantly decreased viability, induced apoptosis and suppressed migration of human A375 melanoma cells and murine B16F10 melanoma cells. Furthermore, dioscin inhibited the phosphorylation of STAT3 and Src (an upstream kinase of STAT3), and downregulated mRNA levels of STAT3-targeted genes, including B-cell lymphoma-2, cyclin D1 and matrix metalloproteinase-2. In addition, overexpression of STAT3 decreased the anti-proliferative effects of dioscin. Overall, the results of the present study indicate that inhibiting the Src/STAT3 signaling pathway contributes to the anti-melanoma molecular mechanisms of dioscin. These results provide further pharmacological groundwork for developing dioscin as a novel anti-melanoma agent.

18.
Phytomedicine ; 68: 153173, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31999977

RESUMEN

BACKGROUND: Chrysoeriol is a flavone found in diverse dietary and medicinal herbs such as Lonicerae Japonicae Flos (the dried flower bud or newly bloomed flower of Lonicera japonica Thunb.). These herbs are commonly used for treating inflammatory diseases. Herbal extracts containing chrysoeriol have been shown to have anti-inflammatory effects and inhibit nuclear factor-kappa B (NF-κB) signaling. Some of these extracts can inhibit signal transducers and activators of transcription 3 (STAT3) signaling in cancer cells. PURPOSE: This study aimed to determine whether chrysoeriol has anti-inflammatory effects and whether NF-κB and STAT3 pathways are involved in the effects. STUDY DESIGN AND METHODS: A TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ear edema mouse model and LPS-stimulated RAW264.7 cells were used to evaluate the effects of chrysoeriol. Griess reagent was used to measure the production of nitric oxide (NO). Western blot and enzyme-linked immunosorbent assays were employed to detect protein levels. RT-qPCR analyses were used to detect mRNA levels. Haematoxylin and eosin (H&E) staining was employed to examine the pathological conditions in animal tissues. RESULTS: In the mouse model, chrysoeriol ameliorated acute skin inflammation, evidenced by reduced ear thickness, ear weight and number of inflammatory cells in inflamed ear tissues. The compound lowered protein levels of phospho-p65 (Ser536), phospho-STAT3 (Tyr705), inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), IL-1ß and tumor necrosis factor α (TNF-α) in mouse swollen ears. In LPS-stimulated RAW264.7 cells, chrysoeriol also lowered levels of these proteins. In addition, chrysoeriol decreased the production of NO and prostaglandin E2; inhibited the phosphorylation of inhibitor of κB (Ser32), p65 (Ser536) and Janus kinase 2 (Tyr1007/1008); decreased nuclear localization of p50, p65 and STAT3; and down-regulated mRNA levels of pro-inflammatory cytokines IL-6, IL-1ß and TNF-α that are transcriptionally regulated by NF-κB and STAT3 in the cell model. CONCLUSION: We for the first time demonstrated that chrysoeriol ameliorates TPA-induced ear edema in mice, and that inhibition of JAK2/STAT3 and IκB/p65 NF-κB pathways are involved in the anti-inflammatory effects of chrysoeriol. This study provides chemical and pharmacological justifications for the use of chrysoeriol-containing herbs in treating inflammatory diseases, and provides pharmacological groundwork for developing chrysoeriol as a novel anti-inflammatory agent.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Erupciones por Medicamentos/tratamiento farmacológico , Flavonas/farmacología , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Erupciones por Medicamentos/metabolismo , Erupciones por Medicamentos/patología , Regulación de la Expresión Génica , Proteínas I-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidad
19.
Toxins (Basel) ; 11(12)2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31779275

RESUMEN

Alpha-momorcharin (α-MMC), a member of the ribosome-inactivating protein (RIP) family, has been found in the seeds of Momordica charantia (bitter melon). α-MMC contributes a number of pharmacological activities; however, its inflammatory properties have not been well studied. Here, we aim to determine the inflammatory responses induced by recombinant α-MMC and identify the underlying mechanisms using cell culture and animal models. Recombinant α-MMC was generated in Rosetta™(DE3)pLysS and purified by the way of nitrilotriacetic acid (NTA) chromatography. Treatment of recombinant α-MMC at 40 µg/mL exerted sub-lethal cytotoxic effect on THP-1 monocytic cells. Transcriptional profiling revealed that various genes coding for cytokines and other proinflammatory proteins were upregulated upon recombinant α-MMC treatment in THP-1 cells, including MCP-1, IL-8, IL-1ß, and TNF-α. Recombinant α-MMC was shown to activate IKK/NF-κB and JNK pathways and the α-MMC-induced inflammatory gene expression could be blocked by IKKß and JNK inhibitors. Furthermore, murine inflammatory models further demonstrated that α-MMC induced inflammatory responses in vivo. We conclude that α-MMC stimulates inflammatory responses in human monocytes by activating of IKK/NF-κB and JNK pathways, raising the possibility that consumption of α-MMC-containing food may lead to inflammatory-related diseases.


Asunto(s)
Inflamación/inducido químicamente , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Momordica charantia/química , FN-kappa B/efectos de los fármacos , Proteínas Inactivadoras de Ribosomas/química , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocinas/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Análisis por Micromatrices , Plantas Comestibles , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , Proteínas Inactivadoras de Ribosomas/farmacología
20.
Phytomedicine ; 64: 153084, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31514083

RESUMEN

BACKGROUND: Metastasized melanoma is extremely difficult to treat. Activation of C-C chemokine receptor type 7 (CCR7) has been linked to melanoma metastasis. CCR7 can be directly regulated by miR-let-7. We have previously shown that an ethanolic extract of an herbal formula comprising Sophorae Flos and Lonicerae Japonicae Flos (SLE) inhibits melanoma cell migration and invasion. PURPOSE: In this study, we determined whether SLE suppresses melanoma metastasis, and whether regulation of miR-let-7a/f-CCR7 signaling is involved in the effect. STUDY DESIGN AND METHODS: Small RNA sequencing was conducted to compare miRNA expression profiles of B16F10 tumors dissected from SLE-treated or untreated mice. Western blot and RT-qPCR analyses were employed to examine protein and miRNA levels, respectively. A B16F10 melanoma lung metastasis mouse model was used to evaluate the effects of SLE on melanoma metastasis. MiR-let-7a/f-knockdown and CCR7-overexpression cell models were used to investigate the involvement of miR-let-7a/f-CCR7 signaling in the anti-metastatic effects of SLE. RESULTS: It was found that SLE upregulated levels of miR-let-7a/f in B16F10 melanoma tissues. SLE significantly elevated levels of miR-let-7a/f, lowered the protein level of CCR7, inhibited the phosphorylation of CCR7 downstream molecules p38 and JNK in B16F10 and A375 melanoma cells. SLE inhibited B16F10 melanoma lung metastasis in mice. SLE upregulated levels of miR-let-7a/f, and lowered protein levels of CCR7, MMP-2, MMP-9, phospho-p38 (Thr180/Tyr182) and phospho-JNK (Thr183/Tyr185) in melanoma-invaded lung tissues. Knockdown of miR-let-7a/f diminished the effects of SLE on CCR7 signaling in, and invasion of, melanoma cells. Overexpression of CCR7 lessened the effects of SLE in inhibiting the phosphorylation of p38 and JNK in, and the invasive capability of, melanoma cells. CONCLUSION: We for the first time demonstrated that SLE inhibits melanoma metastasis in mice, and that regulation of the miR-let-7a/f-CCR7 pathway contributes to the anti-metastatic mechanisms of SLE. These findings provide a pharmacological basis for developing SLE as a modern agent for treating metastatic melanoma. Additionally and importantly, this study suggests that regulating the miR-let-7a/f-CCR7 pathway is a novel strategy for controlling melanoma metastasis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Melanoma Experimental/tratamiento farmacológico , MicroARNs/metabolismo , Extractos Vegetales/farmacología , Receptores CCR7/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lonicera , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Extractos Vegetales/química , Receptores CCR7/genética , Sophora/química
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