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1.
Chem Commun (Camb) ; 59(90): 13514-13517, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37885376

RESUMEN

Aberrant PCK2 overexpression has been linked to an unfavorable prognosis and shorter survival, particularly in hepatocellular carcinoma (HCC). Thus, the inactivation of PCK2 provides a promising strategy for HCC treatment. In this study, we used a chemical genetic strategy to identify a natural-derived small-molecule cucurbitacin B (CuB) as a selective PCK2 inhibitor. CuB covalently bound to PCK2 at a unique Cys63 site, blocking the Ω-loop lid domain formation via a previously undisclosed allosteric mechanism. Additionally, targeted lipidomics analysis also revealed that CuB destroyed mitochondrial membrane integrity, leading to the disruption of mitochondrial fusion-fission dynamics. Taken together, this study highlights the discovery of a small-molecule CuB, which reprograms lipid metabolism for controlling mitochondrial dynamics via targeting PCK2 in cancer cells.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Dinámicas Mitocondriales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Regulación Alostérica , Fosfoenolpiruvato Carboxiquinasa (ATP)
3.
Signal Transduct Target Ther ; 6(1): 71, 2021 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-33602894

RESUMEN

Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α' subunit (CK2α') as a direct cellular target, and genetic knockdown of CK2α' abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α' conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α'/BTF3 complex facilitates ß-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α'+/- mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/ß-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.


Asunto(s)
Quinasa de la Caseína II/genética , GTP Fosfohidrolasas/genética , Glicósidos/farmacología , Accidente Cerebrovascular Isquémico/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Animales , Quinasa de la Caseína II/antagonistas & inhibidores , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Infarto de la Arteria Cerebral Media , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/patología , Factor de Unión 1 al Potenciador Linfoide/genética , Ratones , Dinámicas Mitocondriales/genética , Complejos Multiproteicos/genética , Neuroprotección/genética , Factor 1 de Transcripción de Linfocitos T/genética , Transcripción Genética/efectos de los fármacos , beta Catenina/genética
4.
ACS Chem Neurosci ; 11(24): 4223-4230, 2020 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-33225685

RESUMEN

Cerebral ischemia is accompanied by mitochondrial integrity destruction. Thus, reversion of mitochondrial damage holds great potential for cerebral ischemia therapy. As a crucial Bcl-2 family member, pro-apoptotic Bax protein is a main effector of mitochondrial permeabilization and plays an important role in mitochondrial homeostasis. However, there is still a lack of an effective cerebral protective strategy through selectively targeting Bax. In this study, we reported that natural small-molecule protosappanin A (PTA) showed a significant mitochondrial protective effect on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cells injury through increasing ATP production and maintaining mitochondrial DNA (mtDNA) content. The mechanism study revealed that PTA selectively induced pro-apoptotic protein Bax degradation, without affecting other Bcl-2 family members such as Bcl-2, Bcl-xl, Bad, Puma, Bid, Bim, and Bik. In addition, we found that PTA promoted the association of autophagosomal marker LC3B to Bax for its degradation via an autophagy-dependent manner but not the ubiquitin-proteasome pathway. Collectively, our findings offered a new pharmacological strategy for maintaining mitochondrial function by inducing autophagic degradation of Bax and also provided a novel drug candidate against ischemic neuronal injury.


Asunto(s)
Apoptosis , Mitocondrias , Animales , Autofagia , Homeostasis , Fenoles , Ratas , Proteína X Asociada a bcl-2
5.
Theranostics ; 10(2): 797-815, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31903151

RESUMEN

Background: Histone post-translational modifications (PTMs) are involved in various biological processes such as transcriptional activation, chromosome packaging, and DNA repair. Previous studies mainly focused on PTMs by directly targeting histone-modifying enzymes such as HDACs and HATs. Methods and Results: In this study, we discovered a previously unexplored regulation mechanism for histone PTMs by targeting transcription regulation factor 14-3-3ζ. Mechanistic studies revealed 14-3-3ζ dimerization as a key prerequisite, which could be dynamically induced via an allosteric effect. The selective inhibition of 14-3-3ζ dimer interaction with histone H3 modulated histone H3 PTMs by exposing specific modification sites including acetylation, trimethylation, and phosphorylation, and reprogrammed gene transcription profiles for autophagy-lysosome function and endoplasmic reticulum stress. Conclusion: Our findings demonstrate the feasibility of editing histone PTM patterns by targeting transcription regulation factor 14-3-3ζ, and provide a distinctive PTM editing strategy which differs from current histone modification approaches.


Asunto(s)
Proteínas 14-3-3/antagonistas & inhibidores , Autofagia , Regulación de la Expresión Génica , Histonas/metabolismo , Fenoles/farmacología , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , Acetilación , Regulación Alostérica , Animales , Línea Celular , Histonas/química , Humanos , Masculino , Metilación , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Modelos Animales , Fosforilación , Ratas , Ratas Sprague-Dawley
6.
Oxid Med Cell Longev ; 2019: 7940808, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31178973

RESUMEN

Diabetic encephalopathy (DE) is a serious complication caused by long-term cognitive impairment in diabetic patients. At present, there is no effective treatment for DE. Icariin (ICA) is a bioactive ingredient isolated from Epimedium. Previous research indicated that ICA was neuroprotective against Aß-induced PC12 cell insult; however, the effect of ICA on an advanced glycosylation end product- (AGE-) induced neural injury model has not been studied. In this study, we investigated the neuroprotective effects of ICA on AGE-induced injury in PC12 cells. Our findings revealed that ICA could effectively protect PC12 cells from AGE-induced cell apoptosis by suppressing oxidative stress. Moreover, we observed that ICA could significantly protect against mitochondrial depolarization following AGE stimulation and inactivate the mitochondria-dependent caspase-9/3 apoptosis pathway. Most notably, we identified the direct target protein of ICA as apoptosis regulator Bax by a pulldown assay. We found that ICA could specifically target Bax protein and inhibit Bax dimer formation and migration to mitochondria. Furthermore, a siRNA knockdown experiment revealed that ICA could inhibit PC12 cell apoptosis and oxidative stress through targeting Bax. Taken together, our findings demonstrated that ICA could attenuate AGE-induced oxidative stress and mitochondrial apoptosis by specifically targeting Bax and further regulating the biological function of Bax on mitochondria.


Asunto(s)
Flavonoides/uso terapéutico , Productos Finales de Glicación Avanzada/efectos de los fármacos , Animales , Apoptosis , Complicaciones de la Diabetes , Flavonoides/farmacología , Células PC12 , Ratas , Transfección , Proteína X Asociada a bcl-2/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 42(19): 3650-3655, 2017 Oct.
Artículo en Chino | MEDLINE | ID: mdl-29235274

RESUMEN

Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula for coronary heart disease with Qi deficiency. However, the detailed pharmacological mechanism of BYD is still unknown because of its complicated chemical compositions. In this study, we synthesized a kind of solid beads with benzophenone groups on its surface. Benzophenone can be activated and chemically cross-linked with the C-H bonds of the chemical compositions in BYD (BYD beads) under UV activation. We thus captured all the target proteins from mouse heart tissue lysates by using BYD beads. Based on proteomics analysis, we discovered totally 46 potential binding target proteins, most of which were located in mitochondria. KEGG analysis revealed that these target proteins were mainly associated with TCA cycle and amino acid metabolism signaling pathways, suggesting that the cardioprotection of BYD might be associated with regulating mitochondrial function and energy production. Moreover, JC-1 staining analysis also confirmed the protective effect of BYD on mitochondrial damage. In summary, our findings elucidated the potential mechanism of BYD on cardioprotection through "target fishing" strategy, and further explained its traditional efficacy in the molecular level. In addition, we also provide an approach for investigating the target group of complicated compositions in Chinese herbal formula. This novel method may provide a methodological reference for exploring the pharmacological mechanism of traditional Chinese formula in the future.


Asunto(s)
Benzofenonas/química , Cardiotónicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Animales , Ratones , Proteínas Mitocondriales/química , Transducción de Señal
8.
Zhongguo Zhong Yao Za Zhi ; 42(19): 3656-3660, 2017 Oct.
Artículo en Chino | MEDLINE | ID: mdl-29235275

RESUMEN

Targets group identification in complex Chinese medicine system is a key step for revealing the potential mechanism of Chinese medicine. The solid beads with magnetic core and benzophenone-modified surface were made in our study, and then benzophenone was activated and cross-linked with the C-H bonds of chemical compositions in Chinese medicines under UV excitation. Thus the chemical compositions of modified Wuzi Yanzong pill(MWP) were linked to the solid bead surface, and enriched the neuroprotective targets group of MWP after being co-incubated with nerve cell lysate. We performed proteomics analysis on these targets and discovereda total of 32 potential binding targets. KEGG analysis revealed that these targets were mainly associated with Hippo and Cell cycle signaling pathways, suggesting that MWP might be involved in regulating the proliferation and differentiation of neural stem cells. Our findings elucidate the potential targets and mechanism of MWP on anti-dementia and neuroprotection, and further providean approach for investigating the targets group in complex Chinese medicine system. This novel method may provide methodological references for exploring the pharmacological mechanism of Chinese medicinal formulae in the future.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Neuronas/efectos de los fármacos , Neuroprotección , Ciclo Celular , Células Cultivadas , Vía de Señalización Hippo , Humanos , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal
9.
Chin J Nat Med ; 15(9): 674-679, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28991528

RESUMEN

Microglial activation and resultant neuroinflammatory response are implicated in various brain diseases including Alzheimer's disease and Parkinson's disease. Treatment with anti-neuroinflammatory agents could provide therapeutic benefits for such disorders. Protosappanin A (PTA) is a major bioactive ingredient isolated from Caesalpinia sappan L.. In this work, the anti-neuroinflammatory effects of PTA on LPS-stimulated BV2 cells were investigated and the underlying mechanisms were explored. Results showed that PTA significantly inhibited the production of TNF-α and IL-1ß in LPS-activated BV2 microglia. Moreover, the mRNA expressions of IL-6, IL-1ß, and MCP-1 were reduced by PTA in a dose-dependent manner. Furthermore, PTA suppressed JAK2/STAT3-dependent inflammation pathway through down-regulating the phosphorylation of JAK2 and STAT3, as well as STAT3 nuclear translocation against LPS treatment. These observations suggested a novel role for PTA in regulating LPS-induced neuroinflammatory injuries.


Asunto(s)
Antiinflamatorios/farmacología , Inflamación/inmunología , Lipopolisacáridos/farmacología , Microglía/efectos de los fármacos , Fenoles/farmacología , Factor de Transcripción STAT3/inmunología , Animales , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Ratones , Microglía/inmunología , Óxido Nítrico/genética , Óxido Nítrico/inmunología , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
10.
EBioMedicine ; 23: 160-172, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28807514

RESUMEN

Heat shock protein 70 (Hsp70) is widely involved in immune disorders, making it as an attractive drug target for inflammation diseases. Nonselective induction of Hsp70 upregulation for inflammation therapy could cause extensive interference in inflammation-unrelated protein functions, potentially resulting in side effects. Nevertheless, direct pharmacological activation of Hsp70 via targeting specific functional amino acid residue may provide an insight into precise Hsp70 function regulation and a more satisfactory treatment effect for inflammation, which has not been extensively focused. Here we show a cysteine residue (Cys306) for selective Hsp70 activation using natural small-molecule handelin. Covalent modification of Cys306 significantly elevates Hsp70 activity and shows more satisfactory anti-neuroinflammation effects. Mechanism study reveals Cys306 modification by handelin induces an allosteric regulation to facilitate adenosine triphosphate hydrolysis capacity of Hsp70, which leads to the effective blockage of subsequent inflammation signaling pathway. Collectively, our study offers some insights into direct pharmacological activation of Hsp70 by specially targeting functional cysteine residue, thus providing a powerful tool for accurately modulating neuroinflammation pathogenesis in human with fewer undesirable adverse effects.


Asunto(s)
Sitio Alostérico , Proteínas HSP70 de Choque Térmico/agonistas , Proteínas HSP70 de Choque Térmico/química , Relación Estructura-Actividad Cuantitativa , Terpenos/química , Terpenos/farmacología , Regulación Alostérica , Animales , Sitios de Unión , Caenorhabditis elegans , Línea Celular , Cisteína/química , Citocinas/metabolismo , Activación Enzimática , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Ligandos , Masculino , Ratones , Modelos Biológicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Mutación , FN-kappa B/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Unión Proteica , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitinación/efectos de los fármacos , Pez Cebra
11.
Proc Natl Acad Sci U S A ; 114(29): E5986-E5994, 2017 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-28674004

RESUMEN

Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.


Asunto(s)
Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , IMP Deshidrogenasa/metabolismo , Inflamación/tratamiento farmacológico , Isoflavonas/farmacología , Regulación Alostérica , Sustitución de Aminoácidos , Animales , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Cisteína/metabolismo , Humanos , IMP Deshidrogenasa/química , IMP Deshidrogenasa/genética , Inflamación/metabolismo , Isoflavonas/química , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/patología , Terapia Molecular Dirigida/métodos , Relación Estructura-Actividad
12.
Sci Rep ; 6: 37959, 2016 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-27885275

RESUMEN

Prolonged ischemia can result in apoptotic death of vascular endothelial cells and lead to ischemic vascular diseases including vascular dementia, arteriosclerosis and brain oedema. Finding protective strategies to prevent this is therefore an urgent mission. Recent studies have shown that dysregulation of microRNAs (miRNAs) can lead to imbalance of Bcl-2 family proteins and mitochondrial dysfunction, leading to further damage of vascular cells under ischemic conditions. However, whether miRNAs can be used as a drug target for treating vascular diseases is not fully understood. In this study, we observed that the natural product 2,4,5-trihydroxybenzaldehyde (TDB) could effectively inhibit vascular cell apoptosis following oxygen-glucose deprivation/reperfusion (OGD/R) by maintaining mitochondrial membrane potential (MMP) and suppressing activation of the mitochondria-dependent caspase-9/3 apoptosis pathway. Furthermore, we identified miR-34a, a crucial negative regulator of Bcl-2, as a target for the protective effect of TDB on vascular cells. TDB-induced suppression of miR-34a resulted in a significant upregulation of Bcl-2 protein, MMP maintenance, and the survival of vascular cells following OGD/R. Our findings suggest that targeting miR-34a with the natural product TDB may provide a novel strategy for the treatment of ischemic vascular injuries, and demonstrate the therapeutic potential in targeting miRNAs using appropriate small molecules.


Asunto(s)
Benzaldehídos/administración & dosificación , Isquemia Encefálica/prevención & control , Células Endoteliales/efectos de los fármacos , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Animales , Apoptosis/efectos de los fármacos , Benzaldehídos/farmacología , Isquemia Encefálica/genética , Línea Celular , Modelos Animales de Enfermedad , Células Endoteliales/citología , Glucosa/deficiencia , Células Endoteliales de la Vena Umbilical Humana , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba
13.
Zhongguo Zhong Yao Za Zhi ; 41(10): 1792-1796, 2016 May.
Artículo en Chino | MEDLINE | ID: mdl-28895322

RESUMEN

Hydrophidae, one of the precious traditional Chinese medicines, is generally drily preserved to prevent corruption, but it is hard to identify the species of Hydrophidae through the appearance because of the change due to the drying process. The identification through analysis on gene barcode, a new technique in species identification, can avoid this problem. The gene barcodes of the 5 species of Hydrophidae, Lapemis hardwickii, Hydrophis fasciatus, Aipysurus eydouxii, Hydrophis belcher and Hydrophis lamberti, were acquired through DNA extraction and gene sequencing. These barcodes were then in sequence alignment and test the identification efficiency by BLAST. Our results showed that the 16S rDNA sequences identified Hydrophidae briefly and the COI sequenceshad obvious difference between intra-and inter-species, indicating that DNA bar-coding was an efficiency method of Hydrophidae identification.


Asunto(s)
Código de Barras del ADN Taxonómico , Complejo IV de Transporte de Electrones/genética , Hydrophiidae/clasificación , Animales , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Especificidad de la Especie
14.
Zhongguo Zhong Yao Za Zhi ; 41(13): 2506-2510, 2016 Jul.
Artículo en Chino | MEDLINE | ID: mdl-28905576

RESUMEN

To investigate the inhibitory effects of acteoside (ACT) on BV-2 microglial cells and the potential mechanism,LPS was used to treat BV-2 cells with or without ACT (12.5,25,50 µmol•L ⁻¹). Then, the expressions of inflammatory factors (NO,TNF-α,IL-6) and inflammation related proteins (iNOS,COX-2,p-IKKß,IKKß,p-ⅠκB,ⅠκB) were detected. In addition,the nuclear translocation of NF-κB was explored. The results showed that ACT could significantly suppress the inflammatory response against LPS stimulation by decreasing the expressions of NO,IL-6,TNF-α,iNOS,COX-2 and the phosphorylations of IKKß and IκB. Moreover,the nuclear translocation of NF-κB p65 was inhibited by ACT. Taken together, ACT could significantly inhibit the inflammatory response of BV-2 microglial cells which were induced by LPS via inhibition of NF-κB signaling pathway.


Asunto(s)
Antiinflamatorios/farmacología , Microglía/efectos de los fármacos , Animales , Línea Celular , Ciclooxigenasa 2/metabolismo , Glucósidos , Inflamación/inducido químicamente , Lipopolisacáridos , Ratones , Óxido Nítrico , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fenoles , Factor de Transcripción ReIA/metabolismo
15.
Zhongguo Zhong Yao Za Zhi ; 41(1): 6-13, 2016 Jan.
Artículo en Chino | MEDLINE | ID: mdl-28845631

RESUMEN

Drug targets are special molecules that can interact with drugs and exert pharmacological functions in human body. The natural active small molecules are the bioactive basis of traditional Chinese medicine, and the mechanism study is a hot topic now, especially for the identification of their target proteins. However, little progress has been made in this field until now. Here, we summarized the recent technologies and methods for the identification of target proteins of natural bioactive small molecules, and introduced the main research methods, principles and successful cases in this field. We also explored the applicability and discussed the advantages and disadvantages among different methods. We hope this review can be used as a reference for the researchers who engaged in natural pharmaceutical chemistry, pharmacology and chemical biology.


Asunto(s)
Proteínas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas , Humanos , Proteínas/genética , Proteínas/metabolismo , Proteómica , Bibliotecas de Moléculas Pequeñas/farmacología
16.
Eur J Pharmacol ; 767: 82-93, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26455476

RESUMEN

This work aims to evaluate the anti-neuroinflammatory effects of natural sesquiterpene dimer caruifolin D from Artemisia absinthium L., which is an edible vegetable or traditional medicinal food in East Asia due to its sedation, anti-asthma and antipruritic effects. In this study, we reported that caruifolin D significantly inhibited the productions of various neuroinflammatory mediators from microglia in response to bacterial lipopolysaccharide stimulation. Moreover, anti-inflammatory mechanism study showed that caruifolin D markedly suppressed the production of intracellular reactive oxygen species, which was an important player involved in neuroinflammation, leading to inhibitory effects on the activations of protein kinase C (PKC) and c-Jun N-terminal kinase (JNK), which were two major neuroinflammatory signaling pathways in the brains. Furthermore, caruifolin D protected neurons against microglia-mediated neuronal inflammatory damages by up-regulating neuronal viability and maintaining healthy neuronal morphology. Taken together, these results expanded our knowledge about the anti-neuroinflammatory and neuroprotective mechanism of Artemisia absinthium L., and also suggested that caruifolin D was a major anti-inflammatory component from Artemisia absinthium L., which might be developed as a drug candidate for neuroinflammation-related diseases.


Asunto(s)
Antiinflamatorios/farmacología , Artemisia absinthium/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Proteína Quinasa C/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Triterpenos/farmacología , Animales , Técnicas de Cocultivo , Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Ratones , Microglía/metabolismo , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos
17.
Sci Rep ; 5: 14715, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26423026

RESUMEN

TNF receptor-associated factor 6 (TRAF6) is a key hub protein involved in Toll-like receptor-dependent inflammatory signaling pathway, and it recruits additional proteins to form multiprotein complexes capable of activating downstream NF-κB inflammatory signaling pathway. Ubiquitin-proteasome system (UPS) plays a crucial role in various protein degradations, such as TRAF6, leading to inhibitory effects on inflammatory response and immunologic function. However, whether ubiquitination-dependent TRAF6 degradation can be used as a novel anti-inflammatory drug target still remains to be explored. FMHM, a bioactive natural small molecule compound extracted from Chinese herbal medicine Radix Polygalae, suppressed acute inflammatory response by targeting ubiquitin protein and inducing UPS-dependent TRAF6 degradation mechanism. It was found that FMHM targeted ubiquitin protein via Lys48 site directly induced Lys48 residue-linked polyubiquitination. This promoted Lys48 residue-linked polyubiquitin chain formation on TRAF6, resulting in increased TRAF6 degradation via UPS and inactivation of downstream NF-κB inflammatory pathway. Consequently, FMHM down-regulated inflammatory mediator levels in circulation, protected multiple organs against inflammatory injury in vivo, and prolong the survival of endotoxemia mouse models. Therefore, FMHM can serve as a novel lead compound for the development of TRAF6 scavenging agent via ubiquitination-dependent mode, which represents a promising strategy for treating inflammatory diseases.


Asunto(s)
Antiinflamatorios/farmacología , Productos Biológicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Inflamación/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitinación/efectos de los fármacos , Animales , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Endotoxemia/tratamiento farmacológico , Endotoxemia/etiología , Endotoxemia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/etiología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/inmunología , Ratones , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B , Óxido Nítrico/metabolismo , Unión Proteica , Proteolisis , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Ubiquitina/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo
18.
J Cell Biochem ; 116(7): 1286-99, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25676331

RESUMEN

MC13 is a novel coumarin compound found in Murraya, an economic crop whose leaves are widely used as condiment (curry) in cuisine. The aims of the present study were to investigate the neuroprotective effects of MC13 on microglia-mediated inflammatory injury model as well as potential molecular mechanism. Cell viability and apoptosis assay demonstrated that MC13 was not toxic to neurons and significantly protected neurons from microglia-mediated inflammatory injury upon lipopolysaccharide (LPS) stimulation. Results showed that MC13 markedly inhibited LPS-induced production of various inflammatory mediators, including nitrite oxide (Griess method), TNF-α and IL-6 (ELISA assay) in a concentration-dependent manner. Mechanism study showed that MC13 could suppress the activation of NF-κB, which was the central regulator for inflammatory response, and also decreased the interaction of TGF-ß-activated kinase 1 (TAK1)-binding protein (TAB2) with TAK1 and TNF receptor associated factor (TRAF6), leading to the decreased phosphorylation levels of NF-κB upstream regulators such as IκB and IκB kinase (IKK). MC13 also significantly down-regulated the phosphorylation levels of ERK and p38 MAPKs, which played key roles in microglia-mediated inflammatory response. Furthermore, MC13 inhibited Jak2-dependent Stat1/3 signaling pathway activation by blocking Jak2 phosphorylation, Stat1/3 phosphorylation, and nuclear translocation. Taken together, our results demonstrated that MC13 protected neurons from microglia-mediated neuroinflammatory injury by inhibiting TRAF6-TAK1-NF-κB, p38/ERK MAPKs, and Jak2-Stat1/3 pathways. Finally, MC13 might interact with LPS and interfere LPS-binding to cell membrane surface. These findings suggested that coumarin might act as a potential medicinal agent for treating neuroinflammation as well as inflammation-related neurodegenerative diseases.


Asunto(s)
Antiinflamatorios/farmacología , Cumarinas/farmacología , Inflamación/metabolismo , Microglía/efectos de los fármacos , Murraya/química , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lipopolisacáridos , Ratones , Microglía/citología , Microglía/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
19.
Eur J Pharmacol ; 751: 13-23, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25657114

RESUMEN

Protosappanin B (PTB) is a bioactive dibenzoxocin derivative isolated from Caesalpinia sappan L. Here, we investigated the neuroprotective effects and the potential mechanisms of PTB on oxygen-glucose deprivation (OGD)-injured PC12 cells. Results showed that PTB significantly increased cell viability, inhibited cell apoptosis and up-regulated the expression of growth-associated protein 43 (a marker of neural outgrowth). Moreover, our study revealed that PTB effectively maintained mitochondrial homeostasis by up-regulation of mitochondrial membrane potential (MMP), inhibition of cytochrome c release from mitochondria and inactivation of mitochondrial caspase-9/3 apoptosis pathway. Further study showed that PTB significantly promoted cytoplasmic component degradation of p53 protein, a key negative regulator for mitochondrial function, resulting in a release of Bcl-2 from p53-Bcl-2 complex and an enhancing translocation of Bcl-2 to mitochondrial outer membrane. Finally, we found the degradation of p53 protein was induced by PTB via activation of a MDM2-dependent ubiquitination process. Taken together, our findings provided a new viewpoint of neuronal protection strategy for anoxia and ischemic injury with natural small molecular dibenzoxocin derivative by activating ubiquitin-dependent p53 protein degradation as well as increasing mitochondrial function.


Asunto(s)
Glucosa/deficiencia , Homeostasis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxocinas/farmacología , Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitinas/metabolismo , Animales , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Muerte Celular/efectos de los fármacos , Citocromos c/metabolismo , Mitocondrias/metabolismo , Neuronas/citología , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Células PC12 , Transporte de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ratas , Ubiquitinación/efectos de los fármacos
20.
Eur J Pharmacol ; 748: 18-29, 2015 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-25530267

RESUMEN

Caesalpinia sappan L. (Lignum Sappan) is a Chinese medicinal plant for treating ischemic cerebral apoplexy. Deoxysappanone B (DSB), a homoisoflavone compound isolated from C. sappan L. (Lignum Sappan), was studied for anti-neuroinflammatory and neuroprotective properties using lipopolysaccharide (LPS)-induced BV-2 microglia neuroinflammation model and LPS-induced microglia-neuron co-culture system. Our findings showed that DSB effectively inhibited BV-2 microglia-mediated neuroinflammatory mediators׳ release including NO, PGE2, TNF-α, IL-6 and reactive oxygen species. Moreover, DSB markedly protected neurons against inflammatory microglia-mediated neurotoxicity in a microglia-neuron co-culture system. Mechanism study revealed that DSB blocked two major neuroinflammation-related signaling pathways including IKK-IκB-nuclear factor kappaB (NF-κB) and p38/ERK mitogen-activated protein kinase (MAPK) cascades, further leading to the inhibition of neuroinflammatory mediators׳ production. The present study provides evidence that the anti-neuroinflammatory and neuroprotective effect of DSB are due to the suppression of neuroinflammatory mediators׳ production as well as inflammation-induced neurotoxicity through regulation of multi-targets. Therefore, DSB may serve as a neuroprotective agent for the treatment of neuroinflammatory disorders and inflammation-related neuronal injury.


Asunto(s)
Caesalpinia/química , Flavonoides/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Isoflavonas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Línea Celular , Dinoprostona/biosíntesis , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Flavonoides/uso terapéutico , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/biosíntesis , Isoflavonas/uso terapéutico , Lipopolisacáridos/farmacología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Microglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico/biosíntesis , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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