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1.
Eur Radiol ; 31(8): 6312-6322, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33533988

RESUMO

OBJECTIVE: To investigate the gray matter (GM) alterations in patients with insomnia disorder (ID) at different severity stages and the relationship between GM alterations and sleep, mood, and cognitive measures. METHODS: One hundred one ID patients and 63 healthy controls (HC) were included. Each patient underwent structural MRI and completed sleep-, mood-, and cognitive-related questionnaires. The ID patients were further grouped into subthreshold insomnia (SI) group and clinical insomnia (CI) group. We investigated changes in GM volumes in ID patients via diffeomorphic anatomical registration through exponentiated lie algebra voxel-based morphometry (DARTEL-VBM). We first compared voxel-wise differences in GM volumes between the HC group and the ID group. Analysis of variance was performed on individual GM maps in the SI, CI, and HC groups to further investigate the effects of different stages of ID severity on GM volumes. Multiple regression was used to model the relationship between altered GM volumes in SI and CI groups and clinical measures. RESULTS: GM hypertrophies in the left anterior and middle cingulate gyrus, right middle and inferior temporal gyrus, and right cerebellum Crus II were detected in ID. Increased GM volume in the right middle temporal gyrus was detected in the SI group, whereas all three regions in the CI group. Regression analysis showed that mood- and cognitive-related measures had a positive correlation with GM volumes, while sleep-related measures had a negative correlation with GM volumes in the CI group. CONCLUSIONS: Our findings of the progressively increased GM volumes in ID suggest that a hypertrophic cortical morphological mechanism may underlie the altered neuroanatomy induced by insomnia. KEY POINTS: • Insomnia-induced GM hypertrophies in the cingulate gyrus, temporal gyrus, and cerebellum Crus II. • The middle temporal gyrus was early detectable in the SI group. • The increased GM volumes in the CI group were correlated with clinical measures.


Assuntos
Substância Cinzenta , Distúrbios do Início e da Manutenção do Sono , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Humanos , Hipertrofia , Imageamento por Ressonância Magnética , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Lobo Temporal
2.
Chem Pharm Bull (Tokyo) ; 67(11): 1255-1258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685754

RESUMO

One new 3,24-dinor-2,4-seco-ursane triterpene, rosanortriterpene C (1), together with four known compounds including 24-norursane-type nortriterpenes (2-3), 24-noroleanane-type nortriterpene (4), ursane-type triterpene (5), was isolated from the fruits of Rosa laevigata var. leiocapus. The new structure was elucidated through comprehensive spectroscopic analysis, including one dimensional (1D) and 2D NMR data, as well as electrospray ionization high resolution (HR-ESI) MS and IR spectrometry. Compounds 1-5 showed moderate anti-inflammatory activities against the production of nitric oxide (NO) in RAW264.7 cells stimulated by lipopolysaccharide (LPS) with IC50 values of 10.35 ± 0.92, 14.28 ± 1.20, 5.04 ± 1.43, 29.29 ± 3.64, and 14.37 ± 0.59 µM, respectively.


Assuntos
Anti-Inflamatórios/farmacologia , Frutas/química , Rosa/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação
3.
J Asian Nat Prod Res ; 20(9): 837-843, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28868919

RESUMO

Three new dimeric kavalactones, designated as diyangonins A-C (1-3), along with two known analogs were isolated from the roots of Piper methysticum. Their structures were elucidated by means of extensive analysis of their 1D, 2D NMR, and mass spectroscopic data. All these dimers possess a skeleton featuring a cyclobutane ring connecting two kavalactone units in head-to-tail or head-to-head mode. Compounds 1-5 were evaluated for their cytotoxic activities against human tumor cell lines.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Kava/química , Lactonas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lactonas/química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Raízes de Plantas/química
4.
J Asian Nat Prod Res ; 20(10): 962-968, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28891321

RESUMO

Two new ent-kaurane diterpenes (1-2), together with five known analogs, were isolated from the stems of Eurya chinensis. The structures of new compounds were established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. Compound 3 exhibited noticeable anti-inflammatory activity as denoted by inhibiting LPS-induced nitric oxide (NO) production in RAW264.7 cells with an IC50 value of 7.82 µM. Compound 4 showed potent cytotoxic activity against human cancer cell lines NCI-H46, HepG2 and SW480 with IC50 values ranging from 7.45 to 8.54 µM.


Assuntos
Diterpenos do Tipo Caurano/isolamento & purificação , Theaceae/química , Animais , Linhagem Celular Tumoral , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Caules de Planta/química , Células RAW 264.7
5.
Microvasc Res ; 97: 167-80, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25446010

RESUMO

Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1ß with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1ß-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1ß activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Esôfago/irrigação sanguínea , Intestinos/irrigação sanguínea , Microvasos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rubus , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Frutas , Humanos , Mediadores da Inflamação/metabolismo , Microvasos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Fitoterapia , Plantas Medicinais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
6.
Am J Physiol Cell Physiol ; 307(9): C859-77, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25163519

RESUMO

Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1ß and transforming growth factor-ß2 (TGF-ß2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1ß and TGF-ß2 gene silencing in OE33 cells. Recombinant IL-1ß and TGF-ß2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression.


Assuntos
Adenocarcinoma/patologia , Células Endoteliais/citologia , Neoplasias Esofágicas/patologia , Esôfago/citologia , Interleucina-1beta/fisiologia , Mesoderma/citologia , Fator de Crescimento Transformador beta2/fisiologia , Microambiente Tumoral , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/antagonistas & inibidores , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Am J Physiol Gastrointest Liver Physiol ; 306(7): G557-74, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24481601

RESUMO

Squamous esophageal epithelium adapts to acid reflux-mediated injury by proliferation and differentiation via signal transduction pathways. Induction of the Wnt antagonist Dickkopf-1 (Dkk1) is involved in tissue repair during inflammation and cellular injury. In this study, we aimed to identify the biological role of Dkk1 in human reflux esophagitis with respect to cell growth and regulation of Wnt signaling. Esophageal biopsies from reflux-esophagitis patients (n = 15) and healthy individuals (n = 10) were characterized in terms of Dkk1 expression. The role of Dkk1 in response to acid-mediated epithelial injury was analyzed by cellular assays in vitro utilizing squamous esophageal epithelial cell lines (EPC1-hTERT, EPC2-hTERT, and HEEC). Dkk1 was significantly overexpressed in human reflux-esophagitis tissue compared with healthy esophageal mucosa at transcriptional and translational levels. After acute and chronic acid (pH 4) exposure, esophageal squamous epithelial cell lines expressed and secreted high levels of Dkk1 in response to stress-associated DNA injury. High extracellular levels of human recombinant Dkk1 inhibited epithelial cell growth and induced cellular senescence in vitro, as demonstrated by reduced cell proliferation, G0/G1 cell cycle arrest, elevated senescence-associated ß-galactosidase activity, and upregulation of p16. Acid pulsing induced Dkk1-mediated senescence, which was directly linked to the ability of Dkk1 to antagonize the canonical Wnt/ß-catenin signaling. In healthy esophageal mucosa, Dkk1 expression was associated with low expression of transcriptionally active ß-catenin, while in reflux-esophagitis tissue, Dkk1 overexpression correlated with increased senescence-associated ß-galactosidase activity and p16 upregulation. The data indicate that, in human reflux esophagitis, Dkk1 functions as a secreted growth inhibitor by suppressing Wnt/ß-catenin signaling and promoting cellular senescence. These findings suggest a significant role for Dkk1 and cellular senescence in esophageal tissue homeostasis during reflux esophagitis.


Assuntos
Senescência Celular , Células Epiteliais/metabolismo , Esofagite Péptica/metabolismo , Esôfago/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Via de Sinalização Wnt , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais/patologia , Esofagite Péptica/genética , Esofagite Péptica/patologia , Esôfago/patologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Mucosa/metabolismo , Mucosa/patologia , Interferência de RNA , Fatores de Tempo , Transfecção , Regulação para Cima , Adulto Jovem , beta Catenina/metabolismo , beta-Galactosidase/metabolismo
8.
Biochem Biophys Rep ; 37: 101629, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38298210

RESUMO

Background: Primary insomnia (PI) refers to syndromes of difficulty falling asleep, poor sleep quality, early awakening, and difficulty falling asleep after waking up. Although there have been numerous studies, the specific etiology and pathogenesis of PI are still misunderstanding. In recent years, the gut microbiota has been proved to be involved in the metabolism of many mental disorders. But the specific mechanisms of its involvement in PI have not been fully elucidated. This study aims to explore the relationship between the gut microbiota and the symptoms, cognitive function changes in PI. Methods: In this study, the gut microbiota of PI patients and healthy controls was profiled by performing stool 16s rRNA gene sequencing. The co-occurrence network was constructed by using Weight Gene Co-expression Network Analysis (WGCNA) algorithm. The correlation between gut microbiota associated pathways and traits in PI were predicted. Results: WGCNA results demonstrated several Operational Taxonomic Units (OTU) modules are correlated to symptoms. By using PICRUSt2 software, we predicted the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of microbiota in modules. For instance, sleep efficiency may be correlated with the presence of Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane and chlorobenzene degradation. Total sleep time may be correlated with the presence of Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation and Biosynthesis of unsaturated fatty acids. The severity of insomnia may be correlated with Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism and RNA polymerase. Change of name score in Montreal Cognitive Assessment (MoCA) may be correlated with Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation in Gut Microbiota (GM). Conclusion: This study revealed the potential relationships between gut microbiota and PI. By using pathway prediction and enrichment analysis, we concluded many metabolic pathways may associated with some important traits of insomnia patients, including sleep efficiency, severe insomnia, total sleep time and change of name score in MoCA. The metabolic pathways include Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane, chlorobenzene degradation, Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation.Our study demonstrated that PI patients demonstrate significant changes in gut microbiota, which will help delineate the relationship between gut microbiota and syndromes of PI.

9.
Artigo em Inglês | MEDLINE | ID: mdl-38662912

RESUMO

The conventional von Neumann architecture has proven to be inadequate in keeping up with the rapid progress in artificial intelligence. Memristors have become the favored devices for simulating synaptic behavior and enabling neuromorphic computations to address challenges. An artificial synapse utilizing the perovskite structure PbHfO3 (PHO) has been created to tackle these concerns. By employing the sol-gel technique, a ferroelectric film composed of Au/PHO/FTO was created on FTO/glass for the purpose of this endeavor. The artificial synapse is composed of Au/PHO/FTO and exhibits learning and memory characteristics that are similar to those observed in biological neurons. The recognition accuracy for both MNIST and Fashion-MNIST data sets saw an increase, reaching 92.93% and 76.75%, respectively. This enhancement resulted from employing a convolutional neural network architecture and implementing an improved stochastic adaptive algorithm. The presented findings showcase a viable approach to achieve neuromorphic computation by employing artificial synapses fabricated with PHO.

10.
bioRxiv ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39345557

RESUMO

Persistent DNA double-strand breaks (DSBs) are enigmatically implicated in neurodegenerative diseases including Huntington's disease (HD), the inherited late-onset disorder caused by CAG repeat elongations in Huntingtin (HTT). Here we combine biochemistry, computation and molecular cell biology to unveil a mechanism whereby HTT coordinates a Transcription-Coupled Non-Homologous End-Joining (TC-NHEJ) complex. HTT joins TC-NHEJ proteins PNKP, Ku70/80, and XRCC4 with chromatin remodeler Brahma-related Gene 1 (BRG1) to resolve transcription-associated DSBs in brain. HTT recruitment to DSBs in transcriptionally active gene- rich regions is BRG1-dependent while efficient TC-NHEJ protein recruitment is HTT-dependent. Notably, mHTT compromises TC-NHEJ interactions and repair activity, promoting DSB accumulation in HD tissues. Importantly, HTT or PNKP overexpression restores TC-NHEJ in a Drosophila HD model dramatically improving genome integrity, motor defects, and lifespan. Collective results uncover HTT stimulation of DSB repair by organizing a TC-NHEJ complex that is impaired by mHTT thereby implicating dysregulation of transcription-coupled DSB repair in mHTT pathophysiology. Highlights: BRG1 recruits HTT and NHEJ components to transcriptionally active DSBs.HTT joins BRG1 and PNKP to efficiently repair transcription related DSBs in brain.Mutant HTT impairs the functional integrity of TC-NHEJ complex for DSB repair.HTT expression improves DSB repair, genome integrity and phenotypes in HD flies.

11.
Int J Nanomedicine ; 17: 4861-4877, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36262189

RESUMO

Bioavailability is an eternal topic that cannot be circumvented by peroral drug delivery. Adequate blood drug exposure after oral administration is a prerequisite for effective treatment. Nanovesicles as pleiotropic oral vehicles can solubilize, encapsulate, stabilize an active ingredient and promote the payload absorption via various mechanisms. Vesicular systems with nanoscale size, such as liposomes, niosomes and polymersomes, provide a versatile platform for oral delivery of drugs with distinct nature. The amphiphilicity of vesicles in structure allows hydrophilic and lipophilic molecule(s) either or both to be loaded, being encapsulated in the aqueous cavity or the inner core, respectively. Depending on high oral transport efficiency based on their structural flexibility, gastrointestinal stability, biocompatibility, and/or intestinal epithelial affinity, nanovesicles can markedly augment the oral bioavailability of various poorly absorbed drugs. Vesicular drug delivery systems (VDDSs) demonstrate a lot of preferences and are becoming more prominent of late years in biomedical applications. Equally, these systems can potentiate a drug's therapeutic index by ameliorating the oral absorption. This review devotes to comment on various VDDSs with special emphasis on the peroral drug delivery. The classification of nanovesicles, preparative processes, intestinal transport mechanisms, in vivo fate, and design rationale were expounded. Knowledge on vesicles-mediated oral drug delivery for bioavailability enhancement has been properly provided. It can be concluded that VDDSs with many merits will step into an energetic arena in oral drug delivery.


Assuntos
Excipientes , Lipossomos , Disponibilidade Biológica , Lipossomos/química , Administração Oral , Interações Hidrofóbicas e Hidrofílicas
12.
Int J Nanomedicine ; 17: 6639-6654, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36582460

RESUMO

Intestinal flora has become a therapeutic target for the intervention of colonic diseases (CDs) with better understanding of the interplay between microbiota and CDs. Depending on unique properties and prominent ability of regulating the intestinal flora, prebiotics can not only achieve a colon-specific drug delivery but also maintain the intestinal homeostasis, thus playing a positive role in the intervention of CDs. Currently, different studies on prebiotic-based nanoparticles have been contrived for colonic drug delivery and have shown great potential in curing various CDs, such as colitis and colorectal cancer. Nevertheless, there is a lack of systematic survey on the use of prebiotic nanoparticles for the treatment of CDs. This review aims to generalize the state-of-the-art of prebiotic nanomedicines specific for CDs. The species and function of intestinal flora and various kinds of prebiotics available as well as their regulating effects on intestinal flora were expounded. A variety of prebiotic nanoparticles pertinent to colon-targeted drug delivery systems were illustrated with particular emphasis on their curative activities on CDs. The efficacy and safety of prebiotic-based colonic drug delivery systems (p-CDDs) were also analyzed. In conclusion, the synergy between prebiotic nanoparticles and their cargos may hold promise for the treatment and intervention of CDs.


Assuntos
Colite , Nanopartículas , Humanos , Prebióticos
13.
Nat Prod Res ; 35(7): 1172-1179, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31328555

RESUMO

One new oleanane-type nortriterpene, rosanortriterpene A (1), and one new ursane-type nortriterpene, rosanortriterpene B (2), were isolated from the fruits of Rosa laevigata var. leiocapus. The structures of 1-2 were fully characterised on the basis of extensive spectroscopic analysis, including IR, HRESIMS, as well as 1D and 2D NMR spectral data (HSQC, 1H-1H COSY, and HMBC). To the best of our knowledge, this represents the first study on the chemical constituents of R. laevigata var. leiocapus. Compounds 1-2 exhibited moderate inhibitory effects on NO production in LPS stimulated RAW264.7 cells with IC50 values of 29.29 ± 3.64 and 14.28 ± 1.20 µM, respectively.


Assuntos
Frutas/química , Rosa/química , Triterpenos/isolamento & purificação , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Triterpenos/química , Triterpenos/farmacologia
14.
Am J Physiol Gastrointest Liver Physiol ; 298(6): G865-77, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20299603

RESUMO

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.


Assuntos
Curcumina/farmacologia , Células Endoteliais/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiossensibilizantes/farmacologia , Anormalidades Induzidas por Radiação/tratamento farmacológico , Animais , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos da radiação , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Intestinos/irrigação sanguínea , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Microvasos/citologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR
15.
Artigo em Inglês | MEDLINE | ID: mdl-32595744

RESUMO

Radiation enteritis is a common side effect of radiotherapy for abdominal and pelvic malignancies, which can lead to a decrease in patients' tolerance to radiotherapy and the quality of life. It has been demonstrated that glycyrrhizin (GL) possesses significant anti-inflammatory activity. However, little is known about its anti-inflammatory effect in radiation enteritis. In the present study, we aimed to investigate the potential anti-inflammatory effects of GL on radiation enteritis and elucidate the possible underlying molecular mechanisms involved. The C57BL/6 mice were subjected to 6.5 Gy abdominal X-ray irradiation to establish a model of radiation enteritis. Hematoxylin and eosin staining was performed to analyze the pathological changes in the jejunum. The expression of TNF-α in the jejunum was analyzed by immunochemistry. The levels of inflammatory cytokines, such as TNF-α, IL-6, IL-1ß, and HMGB1 in the serum were determined by enzyme-linked immunosorbent assay. The intestinal absorption capacity was tested using the D-xylose absorption assay. The levels of HMGB1 and TLR4 were analyzed by western blotting and immunofluorescence staining. We found that GL significantly alleviated the intestinal damage and reduced the levels of inflammatory cytokines, such as TNF-α, IL-6, IL-1ß, and HMGB1 levels. Furthermore, the HMGB1/TLR4 signaling pathway was significantly downregulated by GL treatment. In conclusion, these findings indicate that GL has a protective effect against radiation enteritis through the inhibition of the intestinal damage and the inflammatory responses, as well as the HMGB1/TLR4 signaling pathway. Thereby, GL might be a potential therapeutic agent for the treatment of radiation enteritis.

16.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(8): 957-963, 2019 Aug 30.
Artigo em Zh | MEDLINE | ID: mdl-31511217

RESUMO

OBJECTIVE: To observe the therapeutic effect of tetramethylpyrazine on immune-mediated bone marrow failure (BMF) induced by different doses of X-ray exposure in C57 mice. METHODS: C57BL6 mice were randomized into 4 groups, including a blank control group and 3 X-ray exposure groups with X-ray exposure at low (5.0 Gy), moderate (5.75 Gy), and high (6.5 Gy) doses. After total body irradiation with 0.98 Gy/min X-ray. The mice as recipient received injections of 4×106 lymphocytes from DBA/2 mice via the tail vein within 4 h. The survival rate of the recipient mice, peripheral blood cell counts, bone marrow nucleated cell count, and bone marrow pathology were examined at 14 days after the exposure. In the subsequent experiment, C57 mice were exposed to 5.0 Gy X-ray and treated with intraperitoneal injection of tetramethylpyrazine at the low (5 mg/mL), moderate (10 mg/mL), or high (20 mg/mL) doses (12 mice in each group) for 14 consecutive days, and the changes in BMF were observed. RESULTS: X-ray exposure, especially at the high dose, resulted in significantly lowered survival rate in the mouse models of BMF at 14 days. As the X-ray dose increased, the mice showed significantly reduced peripheral blood counts of red blood cells, white blood cells, platelets and lowered bone marrow nucleated cell counts with obvious bone marrow congestion and reduction of nucleated cells (P < 0.05 or 0.001). In the mice exposed to 5.0 Gy X-ray, tetramethylpyrazine at the high dose most obviously increased bone marrow nucleated cells (P < 0.01) and red blood cells (P < 0.001), and even at the low dose, tetramethylpyrazine significantly increased the counts of white blood cells (P < 0.05) and platelets (P < 0.01) following the exposure. Tetramethylpyrazine dose-dependently alleviated bone marrow hyperemia, increased bone marrow nucleated cell counts, and lowered Fas protein expression in the bone marrow. CONCLUSIONS: X-ray irradiation at 5.0 Gy is suitable for establish mouse models of immune-mediated BMF. Tetramethylpyrazine promotes bone marrow repair by regulating Fas cell apoptosis signals, which further expands the traditional Chinese medicine theory of "removing blood stasis to create new."


Assuntos
Medula Óssea , Irradiação Corporal Total , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pirazinas
17.
Am J Cancer Res ; 9(2): 330-346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906632

RESUMO

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/ß-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active ß-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of ß-catenin signaling in EAC in comparison with Barrett's and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline ß-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate ß-catenin transcription. These findings suggest that the ß-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC.

18.
Nat Prod Res ; 32(2): 182-188, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28641459

RESUMO

One new ent-kaurane diterpene derivative (1), along with four known diterpenes, was isolated from the stems of Eurya chinensis R.Br. The structure of the new compound was established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. Compound 1 showed moderate anti-inflammatory activities with IC50 value of 8.12 µM. This is the first example of diterpenoids with 4-hydroxy-4-(2-hydroxyethyl)-1-hydroxyl-cyclohexanoyl substituent.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Diterpenos do Tipo Caurano/isolamento & purificação , Caules de Planta/química , Plantas Medicinais/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Estrutura Molecular , Análise Espectral
19.
Artigo em Inglês | MEDLINE | ID: mdl-30631303

RESUMO

Background: Pre-operative non-invasive differentiation of benign and malignant thyroid nodules is difficult for doctors. This study aims to determine whether amide proton transfer (APT) imaging and zonally oblique multi-slice (ZOOM) diffusion-weighted imaging (DWI) can provide increased accuracy in differentiating benign and malignant thyroid nodules. Methods: This retrospective study was approved by the institutional review board and included 60 thyroid nodules in 50 patients. All of the nodules were classified as malignant (n = 21) or benign (n = 39) based on pathology. It was meaningful to analyze the APT and apparent diffusion coefficient (ADC) values of the two groups by independent t-test to identify the benign and malignant thyroid nodules. The relationship between APT and ZOOM DWI was explored through Pearson correlation analysis. The diagnostic efficacy of APT and ZOOM DWI in determining if thyroid nodules were benign or malignant was compared using receiver operating characteristic (ROC) curve analysis. Results: The mean APTw value of the benign nodules was 2.99 ± 0.79, while that of the malignant nodules was 2.14 ± 0.73. Additionally, there was a significant difference in the APTw values of the two groups (P < 0.05). The mean ADC value of the benign nodules was 1.84 ± 0.41, and was significantly different from that of the malignant nodules, which was 1.21 ± 0.19 (P < 0.05). Scatter point and Pearson test showed a moderate positive correlation between the APT and ADC values (P < 0.05). The ROC curve showed that the area under the curve (AUC) value of ZOOM DWI (AUC = 0.937) was greater than that of APT (AUC = 0.783) (P = 0.028). Conclusion: APT and ZOOM DWI imaging improved the accuracy of distinguishing between benign and malignant thyroid nodules. ZOOM DWI is superior to APTw imaging (Z = 2.198, P < 0.05).

20.
Nat Prod Res ; 31(21): 2459-2466, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28391729

RESUMO

Three new kavalactone dimers, designated as yangonindimers A-C (1-3), along with one known analogue were isolated from the roots of Piper methysticum. Their structures were elucidated via extensive analysis of their 1D, 2D NMR and mass spectroscopic data. All these dimers possess a skeleton featuring a cyclobutane ring connecting two kavalactone units. Compounds 1-4 were evaluated for their cytotoxic activities against human tumour cell lines NCI-H46, SW480 and HepG2, but none showed significant activity.


Assuntos
Ciclobutanos/isolamento & purificação , Kava/química , Lactonas/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclobutanos/química , Ciclobutanos/farmacologia , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Lactonas/química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Raízes de Plantas/química
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