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1.
Stem Cell Res Ther ; 15(1): 118, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38659053

RESUMEN

BACKGROUND: Cerebral organoids (COs) are the most advanced in vitro models that resemble the human brain. The use of COs as a model for Alzheimer's disease (AD), as well as other brain diseases, has recently gained attention. This study aimed to develop a human AD CO model using normal human pluripotent stem cells (hPSCs) that recapitulates the pathological phenotypes of AD and to determine the usefulness of this model for drug screening. METHODS: We established AD hPSC lines from normal hPSCs by introducing genes that harbor familial AD mutations, and the COs were generated using these hPSC lines. The pathological features of AD, including extensive amyloid-ß (Aß) accumulation, tauopathy, and neurodegeneration, were analyzed using enzyme-linked immunosorbent assay, Amylo-Glo staining, thioflavin-S staining, immunohistochemistry, Bielschowsky's staining, and western blot analysis. RESULTS: The AD COs exhibited extensive Aß accumulation. The levels of paired helical filament tau and neurofibrillary tangle-like silver deposits were highly increased in the AD COs. The number of cells immunoreactive for cleaved caspase-3 was significantly increased in the AD COs. In addition, treatment of AD COs with BACE1 inhibitor IV, a ß-secretase inhibitor, and compound E, a γ-secretase inhibitor, significantly attenuated the AD pathological features. CONCLUSION: Our model effectively recapitulates AD pathology. Hence, it is a valuable platform for understanding the mechanisms underlying AD pathogenesis and can be used to test the efficacy of anti-AD drugs.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Organoides , Células Madre Pluripotentes , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Organoides/metabolismo , Organoides/patología , Células Madre Pluripotentes/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Proteínas tau/metabolismo , Proteínas tau/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Encéfalo/metabolismo , Encéfalo/patología , Modelos Biológicos
2.
Molecules ; 24(20)2019 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-31635244

RESUMEN

Chrysanthemum boreale is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from C. boreale (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, ß-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. ß- Caryophyllene induced G1 cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21CIP1/WAF1 and p27KIP1. These results indicate that ß-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Chrysanthemum/química , Neoplasias Pulmonares/metabolismo , Sesquiterpenos Policíclicos/farmacología , Células A549 , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Aceites Volátiles/farmacología
3.
Molecules ; 23(9)2018 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-30177658

RESUMEN

Silicon dioxide nanoparticles (SiONPs), which are metal oxide nanoparticles, have been used in a wide variety of applications. In this study, acute pulmonary responses were examined after the intranasal instillation of SiONPs in mice primed with or without lipopolysaccharide (LPS, intranasal, 5 µg/mouse). The exposure to SiONPs increased the inflammatory cell counts and proinflammatory cytokines in the bronchoalveolar lavage fluid. SiONPs induced airway inflammation with increases in the phosphorylation of mitogen-activated protein kinases (MAPKs). The ratios of the inflammatory responses induced by the SiONPs were increased in the acute pulmonary disease model primed by LPS. Taken together, SiONPs exhibited toxicity to the respiratory system, which was associated with MAPK phosphorylation. In addition, the exposure to SiONPs exacerbated any existing inflammatory pulmonary diseases. These data showed the additive, as well as synergistic, interaction effects of SiONPs and LPS. We conclude that the exposure to SiONPs causes potential toxicity in humans, especially those with respiratory diseases.


Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Citocinas/metabolismo , Endotoxinas/efectos adversos , Dióxido de Silicio/efectos adversos , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/metabolismo , Administración Intranasal , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Endotoxinas/administración & dosificación , Humanos , Instilación de Medicamentos , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Nanopartículas , Fosforilación/efectos de los fármacos , Dióxido de Silicio/administración & dosificación
4.
Phytother Res ; 31(3): 475-487, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28127806

RESUMEN

In this study, we investigated the antiinflammatory effects of ethanol extracts of Potentilla. supina Linne (EPS) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and septic mice. EPS suppressed LPS-induced nitric oxide, prostaglandin E2 , TNF-α, interleukin-6 and interleukin-1ß at production and mRNA levels in LPS-induced RAW 264.7 macrophages. Consistent with these observations, EPS attenuated the expressions of inducible nitric oxide synthase and cyclooxygenase-2 by downregulation of their promoter activities. Molecularly, EPS reduced the LPS-induced transcriptional activity and DNA-binding activity of nuclear factor-κB (NF-κB), and this was associated with a decrease of translocation and phosphorylation of p65 NF-κB by inhibiting the inhibitory κB-α degradation and IKK-α/ß phosphorylation. Furthermore, EPS inhibited the LPS-induced activation of activator protein-1 by reducing the expression of c-Fos and c-Jun in nuclear. EPS also suppressed the phosphorylation of mitogen-activated protein kinase, such as p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In an LPS-induced endotoxemia mouse model, pretreatment with EPS reduced the mRNA levels of inducible nitric oxide synthase, cyclooxygenase-2 and proinflammatory cytokines and increased the survival rate of mice. Collectively, these results suggest that the antiinflammatory effects of EPS were associated with the suppression of NF-κB and activator protein-1 activation and support its possible therapeutic role for the treatment of endotoxemia. Copyright © 2017 John Wiley & Sons, Ltd.


Asunto(s)
Antiinflamatorios/farmacología , Etanol/química , Inflamación/prevención & control , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Potentilla/química , Choque Séptico/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Línea Celular , Citocinas/metabolismo , Endotoxinas , Etanol/farmacología , Inflamación/inducido químicamente , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Choque Séptico/metabolismo , Factor de Transcripción AP-1/antagonistas & inhibidores , Factor de Transcripción AP-1/metabolismo
5.
Oncotarget ; 7(33): 53178-53190, 2016 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-27449291

RESUMEN

Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27. However, unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, we found that a small molecule, zerumbone (ZER), induced altered dimerization of HSP27 by cross linking the cysteine residues required to build a large oligomer, led to sensitization in combination with radiation. In this study, we identified another small molecule, a xanthone compound, more capable of altering dimeric HSP27 than ZER and yielding sensitization in human lung cancer cells when combined with HSP90 inhibitors or standard anticancer modalities such as irradiation and cytotoxic anticancer drugs. Therefore, altered dimerization of HSP27 represents a good strategy for anticancer therapy in HSP27-overexpressing cancer cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Neoplasias Pulmonares/terapia , Multimerización de Proteína/efectos de los fármacos , Xantonas/farmacología , Animales , Antineoplásicos/administración & dosificación , Benzoquinonas/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Quimioradioterapia , Proteínas de Choque Térmico HSP27/química , Proteínas de Choque Térmico HSP27/genética , Humanos , Estimación de Kaplan-Meier , Lactamas Macrocíclicas/administración & dosificación , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Interferencia de ARN , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Xantonas/administración & dosificación , Xantonas/química , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Biol Pharm Bull ; 39(5): 657-64, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27150139

RESUMEN

We investigated the effect of chikusetsusaponin IVa (CS) and chikusetsusaponin IVa methyl ester (CS-ME) from the roots of Achyranthes japonica NAKAI on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 macrophages. CS-ME more potently inhibited LPS-induced NO and PGE2 production than CS. CS-ME concentration-dependently inhibited LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 and IL-1ß production in RAW264.7 macrophages and mouse peritoneal macrophages. Consistent with these findings, CS-ME suppressed LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at protein level as well as iNOS, COX-2, TNF-α, IL-6, and IL-1ß at mRNA level. In addition, CS-ME suppressed LPS-induced transcriptional activity of nuclear factor (NF)-κB and activator protein (AP)-1. The anti-inflammatory properties of CS-ME might result from suppression of iNOS, COX-2, TNF-α, IL-6, and IL-1ß expression through downregulation of NF-κB and AP-1 in macrophages.


Asunto(s)
Achyranthes , Antiinflamatorios/farmacología , Ésteres/farmacología , Ácido Oleanólico/análogos & derivados , Saponinas/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Ésteres/aislamiento & purificación , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos , Ratones , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Raíces de Plantas/química , Células RAW 264.7 , Saponinas/aislamiento & purificación , Factor de Transcripción AP-1/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
7.
J Cell Biochem ; 117(10): 2327-39, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26931732

RESUMEN

α-Solanine, a trisaccharide glycoalkaloid, has been reported to possess anti-cancer effects. In this study, we investigated the anti-inflammatory effects of α-solanine isolated from "Jayoung" a dark purple-fleshed potato by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines in LPS-induced RAW 264.7 macrophages and its in vivo effects on LPS-induced septic shock in a mouse model. α-Solanine suppressed the expression of iNOS and COX-2 both at protein and mRNA levels and consequently inhibited nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in LPS-induced RAW 264.7 macrophages. α-Solanine also reduced the production and mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) induced by LPS. Furthermore, molecular mechanism studies indicated that α-solanine inhibited LPS-induced activation of nuclear factor-κB (NF-κB) by reducing nuclear translocation of p65, degradation of inhibitory κBα (IκBα), and phosphorylation of IκB kinaseα/ß (IKKα/ß). In an in vivo experiment of LPS-induced endotoxemia, treatment with α-solanine suppressed mRNA expressions of iNOS, COX-2, IL-6, TNF-α, and IL-1ß, and the activation of NF-κB in liver. Importantly, α-solanine increased the survival rate of mice in LPS-induced endotoxemia and polymicrobial sepsis models. Taken together, our data suggest that the α-solanine may be a promising therapeutic against inflammatory diseases by inhibiting the NF-κB signaling pathway. J. Cell. Biochem. 117: 2327-2339, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Colitis/prevención & control , Inflamación/prevención & control , Macrófagos/efectos de los fármacos , FN-kappa B/metabolismo , Choque Séptico/prevención & control , Solanina/farmacología , Solanum tuberosum/química , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colitis/inducido químicamente , Colitis/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/citología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Óxido Nítrico/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Choque Séptico/inducido químicamente , Choque Séptico/metabolismo , Transducción de Señal/efectos de los fármacos
8.
Chem Biol Interact ; 235: 85-94, 2015 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-25913072

RESUMEN

In this study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of α-chaconine in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and in LPS-induced septic mice. α-Chaconine inhibited the expressions of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) at the transcriptional level, and attenuated the transcriptional activity of activator protein-1 (AP-1) by reducing the translocation and phosphorylation of c-Jun. α-Chaconine also suppressed the phosphorylation of TGF-ß-activated kinase-1 (TAK1), which lies upstream of mitogen-activated protein kinase kinase 7 (MKK7)/Jun N-terminal kinase (JNK) signaling. JNK knockdown using siRNA prevented the α-chaconine-mediated inhibition of pro-inflammatory mediators. In a sepsis model, pretreatment with α-chaconine reduced the LPS-induced lethality and the mRNA and production levels of pro-inflammatory mediators by inhibiting c-Jun activation. These results suggest that the anti-inflammatory effects of α-chaconine are associated with the suppression of AP-1, and support its possible therapeutic role for the treatment of sepsis.


Asunto(s)
Endotoxinas/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Solanina/análogos & derivados , Solanum tuberosum/química , Factor de Transcripción AP-1/metabolismo , Animales , Línea Celular , Ciclooxigenasa 2/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , MAP Quinasa Quinasa 4/metabolismo , MAP Quinasa Quinasa 7 , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Solanina/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
9.
Angiogenesis ; 15(2): 229-42, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22350794

RESUMEN

Endothelial cell function is critical for angiogenic balance in both physiological and pathological conditions, such as wound healing and cancer, respectively. We report here that soluble heat shock protein beta-1 (HSPB1) is released primarily from endothelial cells (ECs), and plays a key role in regulating angiogenic balance via direct interaction with vascular endothelial growth factor (VEGF). VEGF-mediated phosphorylation of intracellular HSPB1 inhibited the secretion of HSPB1 and their binding activity in ECs. Interestingly, co-culture of tumor ECs with tumor cells decreased HSPB1 secretion from tumor ECs, suggesting that inhibition of HSPB1 secretion allows VEGF to promote angiogenesis. Additionally, neutralization of HSPB1 in a primary mouse sarcoma model promoted tumor growth, indicating the anti-angiogenic role of soluble HSPB1. Overexpression of HSPB1 by HSPB1 adenovirus was sufficient to suppress lung metastases of CT26 colon carcinoma in vivo, while neutralization of HSPB1 promoted in vivo wound healing. While VEGF-induced regulation of angiogenesis has been studied extensively, these findings illustrate the key contribution of HSPB1-VEGF interactions in the balance between physiological and pathological angiogenesis.


Asunto(s)
Neoplasias del Colon/metabolismo , Células Endoteliales/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Células Endoteliales/patología , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico/genética , Humanos , Ratones , Ratones Transgénicos , Chaperonas Moleculares , Proteínas de Neoplasias/genética , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Factor A de Crecimiento Endotelial Vascular/genética , Cicatrización de Heridas/genética
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