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1.
Am J Chin Med ; 52(2): 471-492, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38480499

RESUMEN

The stimulator of interferon genes (STING) signaling pathway is crucial for the pathogenesis of autoimmune and inflammatory disorders, including acute lung injury (ALI). Apigenin (4[Formula: see text],5,7-trihydroxyflavone) is a natural flavonoid widely found in fruits, vegetables, and Chinese medicinal herbs that exhibits a range of pharmacological effects, such as antibacterial and anti-inflammatory activities. However, the efficacy of apigenin in STING pathway-mediated diseases remains unclear. Accordingly, this study screened Chinese medicines to identify potent agents that reduced the synthesis of type I interferons (IFNs). The results revealed apigenin as a potent compound with low cytotoxicity that markedly reduced the synthesis of type I IFNs in response to STING pathway agonists. Besides, apigenin markedly suppressed innate immune responses triggered by the STING agonist SR-717. Mechanistically, apigenin downregulated IFN beta 1 (IFNB1) expression mediated by the STING pathway via dose-dependent inhibition of STING expression, reduction of dimerization, nuclear translocation of phosphorylated IRF3, and disruption of the association between STING and IRF3. Moreover, apigenin effectively mitigated pathological pulmonary inflammation and lung edema in lipopolysaccharide (LPS)-induced ALI in mice. Apigenin further strongly attenuated the hallmarks of immoderate inflammation (interleukin (IL)-6, IL-1[Formula: see text], and tumor necrosis factor [Formula: see text]) and innate immune responses (IFNB1, C-X-C motif chemokine ligand 10, and IFN-stimulated gene 15) by preventing the activation of the STING/IRF3 pathway both in vitro and in vivo. Importantly, SR-717 significantly reversed the inhibitory effects of apigenin in LPS-induced THP1-BlueTM ISG macrophages. Collectively, apigenin effectively alleviated innate immune responses and mitigated inflammation in LPS-induced ALI via inhibition of the STING/IRF3 pathway. These findings suggest the potential of apigenin as a prophylactic and therapeutic candidate for managing STING-mediated diseases.


Asunto(s)
Apigenina , Lipopolisacáridos , Animales , Ratones , Lipopolisacáridos/toxicidad , Apigenina/farmacología , Apigenina/uso terapéutico , Proteínas de la Membrana/metabolismo , Inmunidad Innata , Inflamación/tratamiento farmacológico , Interleucina-6
2.
J Nat Med ; 76(3): 584-593, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35171398

RESUMEN

Medulloblastoma (MB), accounting for nearly 10% of all childhood brain tumors, are implicated with aberrant activation of the Hedgehog (Hh) signaling pathway. Saikosaponin B1 (SSB1) and Saikosaponin D (SSD), two bioactive constituents of Radix Bupleuri, are reported to have many biological activities including anticancer activities. In our work, we evaluated the inhibition of SSB1 and SSD on MB tumor growth in allograft mice and explored the underlying mechanisms. The associated biological activity was investigated in Shh Light II cells, an Hh-responsive fibroblast cell line, using the Dual-Glo® Luciferase Assay System. First, SSB1 (IC50, 241.8 nM) and SSD (IC50, 168.7 nM) inhibited GLI-luciferase activity in Shh Light II cells stimulated with ShhN CM, as well as Gli1 and Ptch1 mRNA expression. In addition, both compounds suppressed the Hh signaling activity provoked by smoothened agonist (SAG) or excessive Smoothened (SMO) expression. Meanwhile, SSB1 and SSD did not inhibit glioma-associated oncogene homolog (GLI) luciferase activity activated by abnormal expression of downstream molecules, suppressor of fuse (SUFU) knockdown or GLI2 overexpression. Consequently, SSB1 (30 mg/kg, ip) and SSD (10 mg/kg, ip) displayed excellent in vivo inhibitory activity in MB allografts, and the tumor growth inhibition ratios were approximately 50% and 70%, respectively. Our findings, thus, identify SSB1 and SSD significantly inhibit tumor growth in MB models by inhibiting the Hedgehog pathway through targeting SMO.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Aloinjertos/metabolismo , Aloinjertos/patología , Animales , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Ácido Oleanólico/análogos & derivados , Saponinas , Transducción de Señal , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo
3.
Cell Death Dis ; 12(7): 707, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34267186

RESUMEN

Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.


Asunto(s)
Neoplasias Colorrectales/enzimología , Dinoprostona/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas Nucleares/metabolismo , Proteína Gli2 con Dedos de Zinc/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Activación Enzimática , Genes APC , Humanos , Masculino , Ratones Transgénicos , Proteínas Nucleares/genética , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Estabilidad Proteica , Proteolisis , Transducción de Señal , Ubiquitinación , Proteína Gli2 con Dedos de Zinc/genética
4.
Acta Pharmacol Sin ; 42(7): 1190-1194, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32958873

RESUMEN

Hedgehog plays an important role in a wide range of physiological and pathological conditions. Paracrine activation of Hedgehog pathway in stromal cells increases the expression of VEGF, which promotes neovascularization in colorectal cancer and ultimately the growth of colorectal cancer. Berberine (BBR) has anticancer activity. In this study we investigated whether BBR inhibited the growth of colon cancer through suppressing the paracrine sonic hedgehog (SHH) signaling in vitro and in vivo. We showed that BBR (1-10 µM) dose-dependently inhibited the secretion and expression of SHH protein in HT-29 and SW480 cells. BBR did not influence the transcription of SHH, but promoted the degradation of SHH mRNA, thus decreased the SHH mRNA expression in the colorectal cancer cells. In nude mice bearing HT-29 xenograft, oral administration of BBR (100 mg · kg-1 · d-1) or a positive control drug GDC-0449 (100 mg · kg-1 · d-1) for 4 weeks markedly suppressed the growth of HT-29 tumor with BBR exhibiting a better antitumor efficacy. The tumor growth inhibition caused by BBR or GDC-0449 was comparable to their respective inhibitory effect on the mouse-specific Gli mRNA expression in the tumor. However, BBR (20 µM) did not affect the expression of human transcription factor Gli1 mRNA in HT-29 and SW480 cells. In conclusion, BBR promotes the degradation of SHH mRNA in colorectal cancer cells, interrupting the paracrine Hedgehog signaling pathway activity thus suppresses the colorectal cancer growth. This study reveals a novel molecular mechanism underlying the anticancer action of BBR.


Asunto(s)
Antineoplásicos/uso terapéutico , Berberina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Hedgehog/metabolismo , Animales , Línea Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , ARN/metabolismo , Estabilidad del ARN/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Cancer Lett ; 420: 195-207, 2018 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-29425683

RESUMEN

Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli. In addition, both eipmers significantly suppress Hh pathway-dependent Ptch+/-; p53-/- medulloblastoma in vitro and in vivo. Furthermore, both CBC and CBD inhibited two Smo mutants induced Hh pathway activation, which suggested that they are potential compounds for the treatment of medulloblastoma with primary or acquired resistance to current Smo inhibitors. These results highlight the potential of CBC and CBD as effective lead compounds in the treatment of medulloblastoma and other Hh-dependent malignancy.


Asunto(s)
Neoplasias Cerebelosas/tratamiento farmacológico , Cynanchum/química , Meduloblastoma/tratamiento farmacológico , Fitosteroles/administración & dosificación , Fitosteroles/aislamiento & purificación , Transducción de Señal/efectos de los fármacos , Animales , Neoplasias Cerebelosas/metabolismo , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Ratones , Células 3T3 NIH , Fitosteroles/química , Fitosteroles/farmacología , Extractos Vegetales/análisis , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína con Dedos de Zinc GLI1/metabolismo
6.
Molecules ; 21(10)2016 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-27754442

RESUMEN

The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1. However, we found that solasonine exhibited no effect on the transcriptional factors activities provoked by TNF-α and PGE2, thus suggesting its selectivity against Hh pathway activity. Furthermore, we identified that solasonine inhibited the Hh pathway activity by acting on its transcriptional factor Gli using a series of complementary data. We also observed that solasonine obviously inhibited the Gli-luciferase activity provoked by ectopic expression of Smo mutants which may cause the resistance to the current Smo inhibitors. Our study suggests that solasonine may significantly inhibit the Hh pathway activity by acting on Gli, therefore indicating the possibility to use solasonine as a lead compound to develop anticancer drugs for combating the resistance of current Smo inhibitors.


Asunto(s)
Alcaloides Solanáceos/farmacología , Transcripción Genética/efectos de los fármacos , Proteína con Dedos de Zinc GLI1/genética , Fosfatasa Alcalina/metabolismo , Animales , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Células 3T3 NIH , Receptor Patched-1/genética , Transducción de Señal/efectos de los fármacos , Proteína con Dedos de Zinc GLI1/metabolismo
7.
Phytomedicine ; 20(7): 640-7, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23562365

RESUMEN

Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound VB1 purified from EVn-50. The cytotoxic effect of EVn-50 and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10 µg/ml. Treatment with EVn-50 or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Lignanos/farmacología , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Vitex/química , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Ciclina B1/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración 50 Inhibidora , Fosforilación/efectos de los fármacos , Plantas Medicinales/química , Tirosina/metabolismo , Fosfatasas cdc25/metabolismo
8.
Clin Cancer Res ; 10(24): 8266-74, 2004 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-15623602

RESUMEN

PURPOSE: Pseudolaric acid B (PAB), the naturally occurring diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), possesses potent antifungal and pregnancy-terminating effects that may be tightly associated with angiogenesis. This study was to examine its angiogenic inhibition, impact on vascular endothelial growth factor (VEGF) secretion from tumor cells and the possible mechanism of action. EXPERIMENTAL DESIGN: Angiogenesis inhibition was assessed by the human umbilical vascular endothelial cell proliferation, migration, and tube-formation assays, as well as the chorioallantoic membrane assay. ELISA, reverse transcription-PCR, and Western blotting analyses were performed to examine VEGF protein secretion, mRNA expression, and the possible mechanism in hypoxic MDA-MB-468 cells. RESULTS: PAB displayed potent in vitro antiangiogenic activity shown by inhibiting VEGF-stimulated proliferation and migration and fetal bovine serum-stimulated tube formation of human umbilical vascular endothelial cells in a concentration-dependent manner. Moreover, PAB (10 nmol per egg) significantly suppressed in vivo angiogenesis in the chorioallantoic membrane assay. On the other hand, PAB abrogated hypoxia-induced VEGF secretion from MDA-MB-468 cells via reducing HIF-1alpha protein. Additional analyses using LY294002 and U0126 indicated that the increase in hypoxia-inducible factor 1 (HIF-1)alpha protein level was highly dependent on phosphatidylinositol 3'-kinase and p42/p44 mitogen-activated protein kinase activities in hypoxic MDA-MB-468 cells. However, PAB treatment did not affect the active (phosphorylated) forms of Akt and Erk. Interestingly, the selective proteasome inhibitor MG-132 completely reversed the reduction of HIF-1alpha protein in the PAB-treated MDA-MB-468 cells. CONCLUSIONS: PAB displays the dual antiangiogenic activities of directly inhibiting endothelial cells and abrogating paracrine stimulation of VEGF from tumor cells due to reducing HIF-1alpha protein by promoting its proteasome-mediated degradation in MDA-MB-468 cells, which has potential clinical relevance.


Asunto(s)
Diterpenos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Neovascularización Patológica/prevención & control , Complejo de la Endopetidasa Proteasomal/metabolismo , Factores de Transcripción/metabolismo , Animales , Western Blotting , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Pollos , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/metabolismo , Huevos/análisis , Endotelio Vascular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neovascularización Patológica/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Pinaceae/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Venas Umbilicales/efectos de los fármacos , Venas Umbilicales/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
9.
Eur J Pharmacol ; 499(3): 219-28, 2004 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-15381043

RESUMEN

Angiogenesis is controlled by a number of growth factors, including vascular endothelial growth factor (VEGF). In this study, pseudolarix acid B, isolated from the traditional Chinese medicinal plant Pseudolarix kaempferi and originally identified as an early pregnancy-terminating agent, was evaluated for its potential as an angiogenesis inhibitor, using in vitro and in vivo models. After exposure to pseudolarix acid B 0.625-5 microM for 72 h, the proliferation of human umbilical vein endothelial cells was significantly inhibited. Pseudolarix acid B 0.313-2.5 microM for 24 h potently blocked the VEGF-induced tube formation of human umbilical vein endothelial cells in a dose-dependent manner. Matrigel plug assays disclosed that pseudolarix acid B reduced angiogenesis induced by VEGF in vivo. In addition, pseudolarix acid B antagonized VEGF-mediated anti-apoptotic effects on serum-deprived human umbilical vein endothelial cells and increased apoptosis of endothelial cells induced by VEGF in Matrigel plug assays. Moreover, pseudolarix acid B significantly inhibited VEGF-induced tyrosine phosphorylation of kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/flk-1), in correlation with a marked decrease in the phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings collectively suggest that pseudolarix acid B possesses anti-angiogenic activity. One of the main anti-angiogenesis mechanisms of pseudolarix acid B may involve antagonism of the VEGF-mediated anti-apoptosis effect via inhibition of KDR/flk-1, ERK1/2, and Akt phosphorylation in endothelial cells.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Apoptosis/efectos de los fármacos , Diterpenos/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/crecimiento & desarrollo , División Celular/efectos de los fármacos , Células Cultivadas , Colágeno/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Etiquetado Corte-Fin in Situ , Laminina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteoglicanos/administración & dosificación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Venas Umbilicales/citología , Venas Umbilicales/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
10.
Eur J Pharmacol ; 494(2-3): 101-9, 2004 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-15212963

RESUMEN

The Chinese folk medicine Shiraia bambusicola has long been utilized in the treatment of rheumatoid arthritis, a disease in which angiogenesis plays an important role. We report here the isolation of the compound Shiraiachrome A from S. bambusicola and the demonstration of its anti-angiogenic properties. We found that Shiraiachrome A significantly inhibited the proliferation, migration, and tube formation of human microvascular endothelial cells (HMEC) in a dose-dependent manner, with average IC(50) values of 2.1+/-0.36, 1.97+/-0.44, and 1.65+/-0.59 microM, respectively. In addition, Shiraiachrome A inhibited the formation of new microvessels in a rat aorta culture model as well as in the chick embryo chorioallantoic membrane (CAM) assay. Investigation of the mechanism of action of Shiraiachrome A demonstrated that this compound suppressed the autophosphorylation of four receptor tyrosine kinases (RTKs), with IC(50) values ranging from 2.2 to 4.3 microM. These results suggest that Shiraiachrome A inhibits angiogenesis by blocking growth factor-stimulated autophosphorylation of RTKs. These findings also indicate that Shiraiachrome A may be a potent therapeutic agent for angiogenesis-related diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Artritis Reumatoide/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Perileno/análogos & derivados , Perileno/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/aislamiento & purificación , Animales , Aorta Torácica/citología , Aorta Torácica/efectos de los fármacos , Capilares/efectos de los fármacos , Capilares/ultraestructura , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Corion/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Células Endoteliales/efectos de los fármacos , Immunoblotting , Indicadores y Reactivos , Ratones , Microtúbulos/efectos de los fármacos , Microtúbulos/ultraestructura , Células 3T3 NIH , Perileno/química , Perileno/aislamiento & purificación , Fosforilación , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo
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