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1.
J Transl Med ; 22(1): 166, 2024 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365767

RESUMO

BACKGROUND: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. METHODS: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. RESULTS: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. CONCLUSIONS: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.


Assuntos
Medicamentos de Ervas Chinesas , Sirolimo , Animais , Coelhos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/uso terapêutico , Hiperplasia/tratamento farmacológico , Metaloproteinase 9 da Matriz , Farmacologia em Rede , Proteínas Proto-Oncogênicas c-akt , Neointima , Ponte de Artéria Coronária/efeitos adversos
2.
Bioorg Med Chem Lett ; 26(19): 4753-4756, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27597252

RESUMO

Some cancer cells are resistant to apoptosis, rendering them irresponsive towards apoptosis-inducing chemotherapy drugs. Another mode of action to kill these apoptosis-defective cells is essential and autophagy, a dynamic process that degrades cytoplasmic contents for cellular maintenance, has been considered as one of the alternate routes. A small molecule inducer of autophagy, autophagonizer was reported to induce cell death through a novel process that is independent of extrinsic apoptosis and the normal signaling pathways of autophagy. Here, we describe an efficient synthetic procedure for the autophagonizer. The newly synthesized autophagonizer (DK-1-49) resulted in an accumulation of autophagy-associated LC3-II and enhanced levels of autophagosomes and acidic vacuoles. Furthermore, cell viability was inhibited by autophagic cell death in not only human cancer cells but also Bax/Bak double-knockout cells. These findings highlight that intrinsic apoptosis is not also involved in the induction of cellular death by the autophagonizer suggesting the autophagonizer is a promising candidate for anticancer therapeutics for cancer cells that are resistant to apoptosis-inducing chemotherapy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Relação Estrutura-Atividade , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
3.
J Am Chem Soc ; 135(20): 7503-10, 2013 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-23611538

RESUMO

Protein misfolding and/or aggregation has been implicated as the cause of several human diseases, such as Alzheimer's and Parkinson's diseases and familial amyloid polyneuropathy. These maladies are referred to as amyloid diseases, named after the cross-ß-sheet amyloid fibril aggregates or deposits common to these disorders. Epigallocatechin-3-gallate (EGCG), the principal polyphenol present in green tea, has been shown to be effective at preventing aggregation and is able to remodel amyloid fibrils comprising different amyloidogenic proteins, although the mechanistic underpinnings are unclear. Herein, we work toward an understanding of the molecular mechanism(s) by which EGCG remodels mature amyloid fibrils made up of Aß(1-40), IAPP(8-24), or Sup35NM(7-16). We show that EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG. Oxidized and unoxidized EGCG binds to amyloid fibrils, preventing the binding of thioflavin T. This engagement of the hydrophobic binding sites in Aß(1-40), IAPP(8-24), or Sup35NM(Ac7-16) Y→F amyloid fibrils seems to be sufficient to explain the majority of the amyloid remodeling observed by EGCG treatment, although how EGCG oxidation drives remodeling remains unclear. Oxidized EGCG molecules react with free amines within the amyloid fibril through the formation of Schiff bases, cross-linking the fibrils, which may prevent dissociation and toxicity, but these aberrant post-translational modifications do not appear to be the major driving force for amyloid remodeling by EGCG treatment. These insights into the molecular mechanism of action of EGCG provide boundary conditions for exploring amyloid remodeling in more detail.


Assuntos
Amiloide/química , Catequina/análogos & derivados , Amiloide/metabolismo , Catequina/síntese química , Catequina/química , Catequina/farmacologia , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular
4.
Mol Biosyst ; 4(1): 59-65, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18075676

RESUMO

Chromophore-assisted light inactivation (CALI) of proteins is a potentially powerful tool in biological research for the triggered disruption of protein function. It involves the creation of chimeric molecules that can bind specifically to the protein target and can also sensitize the photo-generation of singlet oxygen, which inactivates the target protein. There remains a need for more efficient chromophores for singlet oxygen generation. Here we report a general and convenient system with which to evaluate the efficiency of chromophores in CALI both in crude extracts and in living cells. We employ this system to show that a readily available derivative of ruthenium(II) tris-bipyridyl dication is an unusually efficient "warhead" for CALI, exhibiting a performance markedly superior to the commonly used organic fluorophore, fluorescein.


Assuntos
Corantes Fluorescentes/química , Compostos Organometálicos/farmacologia , Fototerapia/métodos , Proteínas/metabolismo , Rutênio/farmacologia , Catálise , Sistemas de Liberação de Medicamentos , Fluoresceína/química , Fluoresceína/farmacologia , Células HeLa , Humanos , Luz , Modelos Biológicos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Rutênio/química , Oxigênio Singlete/farmacologia
5.
Planta Med ; 70(2): 171-3, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14994197

RESUMO

A homoisoflavanone, 5,7-dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-6-methoxychroman-4-one ( 1), was isolated from the bulb of Cremastra appendiculata (D. Don) Makino (Orchidaceae) as a potent inhibitor of angiogenesis. It inhibited basic fibroblast growth factor (bFGF)-induced in vitro angiogenesis and in vivo angiogenesis of the chorioallantoic membrane (CAM) of chick embryo without showing any toxicity.


Assuntos
Inibidores da Angiogênese/farmacologia , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Orchidaceae , Fitoterapia , Extratos Vegetais/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Animais , Embrião de Galinha , Córion/irrigação sanguínea , Córion/efeitos dos fármacos , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico
6.
Brain Res ; 965(1-2): 130-6, 2003 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-12591129

RESUMO

The flavonoids quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether were isolated from the ethyl acetate fractions of the fruits and stems of Opuntia ficus-indica var. saboten. In the present study, we evaluated their protective effects against oxidative neuronal injuries induced in primary cultured rat cortical cells and their antioxidant activities by using three different cell-free bioassays. Quercetin was found to inhibit H(2)O(2)- or xanthine (X)/xanthine oxidase (XO)-induced oxidative neuronal cell injury, with an estimated IC(50) of 4-5 micro g/ml. However, it was no more protective at concentrations of 30 micro g/ml and above. (+)-Dihydroquercetin concentration-dependently inhibited oxidative neuronal injuries, but it was less potent than quercetin. On the other hand, quercetin 3-methyl ether potently and dramatically inhibited H(2)O(2)- and X/XO-induced neuronal injuries, with IC(50) values of 0.6 and 0.7 micro g/ml, respectively. All three principles markedly inhibited lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl free radicals. In addition, quercetin and quercetin 3-methyl ether were shown to inhibit XO activity in vitro, with respective IC(50) values of 10.67 and 42.01 micro g/ml. These results indicate that quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether are the active antioxidant principles in the fruits and stems of Opuntia ficus-indica var. saboten exhibiting neuroprotective actions against the oxidative injuries induced in cortical cell cultures. Furthermore, quercetin 3-methyl ether appears to be the most potent neuroprotectant of the three flavonoids isolated from this plant.


Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Opuntia , Quercetina/análogos & derivados , Quercetina/farmacologia , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonóis , Frutas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Opuntia/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Caules de Planta/química , Quercetina/química , Quercetina/isolamento & purificação , Ratos , Ratos Sprague-Dawley
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