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1.
Food Funct ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32232236

RESUMO

In this study, we aimed to examine the effects of fucoxanthin on inflammation triggered by palmitate in macrophages. Raw 264.7 cells were treated with palmitate with or without fucoxanthin co-treatment. Fucoxanthin greatly alleviated palmitate-induced decrease in cell viability and loss of mitochondrial membrane potential. Fucoxanthin also significantly attenuated the palmitate-induced transcriptional expression of Il-6, Il-1ß, Tnfα and Nlrp3 inflammasomes and increased the expression of Tgfb. In addition, fucoxanthin decreased triglyceride accumulation induced by palmitate through enhancing the expression of Cpt1a, Pparg and other lipid metabolism genes. Inhibition of CPT1a by etomoxir attenuated the anti-inflammatory effect of fucoxanthin. Furthermore, fucoxanthin increased AMPK phosphorylation and AMPKa1 knockdown by its specific siRNA diminished protective function. In addition, fucoxanthin restored palmitate-mediated mitochondrial dysfunction and improved mitophagy-related gene expression. These findings suggest that fucoxanthin could attenuate free fatty acid-induced inflammation in macrophages through modulating lipid metabolism and mitigating mitochondrial dysfunction.

2.
Microb Pathog ; 142: 104062, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32058024

RESUMO

Pneumonia is the leading cause of morbidity and mortality in children under five years of age worldwide. Over the past decades, studies have shown that the upper respiratory pathogens are closely related to the occurrence of pneumonia. However, the co-occurrence of gut microbiome dysbiosis may have clinical manifestation in the prognosis of childhood pneumonia. The aim of the present study is to investigate the differences in gut microbial communities between children's diagnosed community-acquired pneumonia (CAP) under five compared to healthy controls in Inner Mongolia. Fecal samples were collected from children with CAP and healthy controls (<5 years old) and the genomic microbiome 16S rRNA was amplified using the hypervariable V4 region and subjected to MiSeq Illumina sequencing, and then analyzed for microbiota composition and phenotype. Finally functional profiling was performed by KEGG pathways analyses. Our results revealed a gut microbiota dysbiosis in children with CAP. Distinct gut microbiome composition and structure were associated with childhood CAP between two age categories compared to healthy controls. In addition, the phylogenic phenotype's prediction was found to be significantly different between the groups. The prominent genera in age group of 0-3 were Bifidobacterium and Enterococcus. On the contrary, Escherichia-Shigella, Prevotella, Faecalibacterium and Enterobacter were remarkably decreased in most of the fecal samples from CAP patients in age group of 0-3 compared to the control. At the genus level, the CAP children in the age group of 4-5 showed an increase in the abundance of Escherichia/Shigella, Bifidobacterium, Streptococcus and Psychrobacter and, a decrease in the abundance of Faecalibacterium, Bacteroides, Lachnospiraceae and Ruminococcus compared with the matched healthy controls. Moreover, CAP children in both age groups exhibited distinct profiles in the KEGG functional analysis. Our data revealed that the gut microbiota differ between CAP patients and health children and certain gut microbial species are associated with CAP. Further research to identify specific microbial species which may contribute to the development CAP are merited. In addition, rectification of microbiota dysbiosis may provide supplemental benefits for treatment of the childhood CAP.

3.
Life Sci ; 248: 117449, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088212

RESUMO

AIMS: Prostate cancer (PCa) is the most common type of cancer and a major cause of death in men worldwide. Aberrant Androgen receptor (AR) and PI3K-AKT signaling are very frequent in PCa patients and, therefore, considered as therapeutic targets in the clinic. Sin1 is an essential component of mTORC2 complex, which determines full AKT activation and PCa development in PTEN-/- mice. Here we examined the role of Sin1 in human PCa cell lines and respective tumor samples. MAIN METHODS: Western blotting and immunohistochemistry (IHC) were performed to analyze the expression of Sin1-mTORC2-AKT related proteins in human PCa cells, as well as prostate tumors and normal tissue counterparts. Cell viability and invasion assays were also pursued in the presence or not of Sin1 in PCa cells. Immunoprecipitation assays were additionally carried out to examine the interaction of Sin1 with AR. KEY FINDINGS: We have presently demonstrated that high levels of Sin1 expression in human PCa tissues correlate with cancer progression. Sin1-mediated cell proliferation and invasion of PCa cells occurs by regulating mTORC2-AKT signaling, epithelial-mesenchymal transition and matrix metalloproteinases. Moreover, androgens are able to induce Sin1 expression, which is further translocated to the nucleus of PCa cells. Finally, Sin1 interacts with AR to suppress its transcriptional activity. SIGNIFICANCE: Taken together, these data indicate that both Sin1-mediated mTORC2-AKT signaling and Sin1-AR interaction regulate PCa development. Hence, Sin1 may be considered a novel biomarker of PCa progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Regulação Neoplásica da Expressão Gênica , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Androgênicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Humanos , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise Serial de Tecidos
4.
Medicine (Baltimore) ; 99(7): e19190, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049855

RESUMO

To analyze the degree and pattern of influence of contrast-enhanced ultrasonography (CEUS) on the Bosniak classification system for complex renal cystic mass as compared with conventional ultrasonography (US). One hundred two consecutive patients with complex renal cystic masses were retrospectively analyzed. The diagnostic performance of the Conventional US and CEUS were evaluated separately for malignant and benign lesions. The diagnostic concordance rates were calculated according to pathologic diagnoses. ROC curve analysis determined the confidence in the diagnostic accuracy by calculating the area under each ROC curve. Compared to the Conventional US, septae number, wall and/or septae thickness, solid component and the Bosniak classification changed in 17 (16.7%), 39 (38.2%), 31 (30.4%), and 67 (65.7%) patients as compared with 0 (0.0%), 21 (20.6%), 31 (30.4%), and 37 (36.3%) of the treatment strategy that changed after CEUS respectively. The diagnostic performance of CEUS showed overall higher in terms of sensitivity (100.0 vs 97.2%); specificity (90.9 vs 62.1%); positive predictive value (PPV) (85.7 vs 58.3%); negative predictive value (NPV) (100.0 vs 97.6%); and the concordance with pathology (kappa = 0.876 vs 0.515). CEUS had a higher diagnostic confidence (P < .05) according to the area under the ROC curve (AUC = 0.968 vs 0.799).CEUS performed better than the Conventional US in the diagnosis of complex renal cystic mass, and it might be considered as the first tool to evaluate a complex cystic renal mass, especially for these Bosniak III masses displaying the presence of hemorrhage or infection.


Assuntos
Doenças Renais Císticas/diagnóstico por imagem , Fosfolipídeos , Hexafluoreto de Enxofre , Ultrassonografia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doenças Renais Císticas/classificação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
5.
Cell Death Differ ; 27(2): 662-675, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31273299

RESUMO

The amino acid antiporter system Xc- is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ferroptosis). While the activity of system Xc- often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc- activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc- is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc-, depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc- and promote ferroptosis repressed by this antiporter.

6.
Cell Death Differ ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31796886

RESUMO

Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin "trap" and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

7.
J Agric Food Chem ; 67(37): 10534-10542, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31464434

RESUMO

Fucosylated chondroitin sulfate from sea cucumber Stichopus japonicus (FCSSJ) has been demonstrated with various biological activities; however, its precise structure is still controversial, and digestive behavior remains poorly understood. FCSSJ was purified, and its detailed structure was elucidated mainly based on the NMR spectroscopic methods. Its main chain was characterized as →4)-ß-d-GlcA-(1 → 3)-ß-d-GalNAc-(1→ with GalNAc4S6S:GalNAc4S in a ratio of 1.5:1, and three types of sulfated fucosyl branches attaching C-3 of GlcA, namely, Fucp2S4S, Fucp3S4S, and Fucp4S, were found in a ratio of 2:1.5:1. The digestibility of FCSSJ was investigated in vitro, and the unchanged molecular weight and reducing sugar content indicated that FCSSJ was not broken down under salivary and gastrointestinal digestion. Furthermore, FCSSJ showed a significant inhibitory impact on pancreatic lipase dose-dependently but not on α-amylase, indicating that the inhibition of pancreatic lipase by FCSSJ might be a pathway for its hypolipidemic effect. These findings propose a fucosylated chondroitin sulfate and provide insight into the mechanism of its physiological effects in the digestion system.


Assuntos
Sulfatos de Condroitina/química , Sulfatos de Condroitina/metabolismo , Stichopus/química , Animais , Digestão , Trato Gastrointestinal/metabolismo , Humanos , Espectroscopia de Ressonância Magnética
8.
Int J Biol Macromol ; 136: 579-585, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220498

RESUMO

In the present study, two polysaccharides, SVP2-1 and SVP2-2, were isolated from Patinopecten yessoensis viscera and purified by using DEAE-52 cellulose and Sepharose CL-6B. Both SVP2-1 and SVP2-2 could extend activated partial thromboplastin time (APTT) and thrombin time (TT) and inhibit the transformation of fibrinogen into fibrin (FIB) concentration-dependently, indicating they inhibited clotting and thrombin through intrinsic and common pathways. Of note, SVP2-2 had stronger anticoagulant activity than SVP2-1, and its backbone was determined as →6)-α-Manp (1 → 2)-α-Galp(1 → with Xyl or Glc substituted at C4 of Gal. Based on monosaccharide composition analysis, methylation analysis, and NMR analysis. Further comparison of their monosaccharide analysis and NMR spectra indicates SVP2-1 and SVP2-2 possess the same core structure features, so the higher sulfate content and lower molecular weight may be the possible reasons for the stronger anticoagulant capability of SVP2-2. The present study suggests acidic polysaccharides from scallop viscera as promising anticoagulant candidates.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Pectinidae , Polissacarídeos/química , Polissacarídeos/farmacologia , Vísceras/química , Animais , Fibrina/metabolismo , Fibrinogênio/metabolismo , Metilação , Peso Molecular , Monossacarídeos/análise , Tempo de Tromboplastina Parcial , Coelhos , Tempo de Trombina
9.
Cancer Res ; 79(15): 3837-3850, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088832

RESUMO

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.


Assuntos
Neuroblastoma , Serina , Vias Biossintéticas , Carbono , Linhagem Celular Tumoral , Criança , Glicina , Humanos , Proteína Proto-Oncogênica N-Myc
10.
Foodborne Pathog Dis ; 16(5): 317-324, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30964334

RESUMO

Coenzyme Q0 (CoQ0), one of benzoquinone compounds, has been demonstrated to possess antineoplastic, anti-inflammatory and antioxidant activities. However, its antimicrobial effect has not been extensively reported. In this study, antimicrobial activity of CoQ0 against Staphylococcus aureus was evaluated by measurement of inhibition zone, minimum inhibitory concentration (MIC), and growth curves. Time-kill assay was performed to assess the bactericidal activity of CoQ0 against S. aureus in tryptone soya broth and pasteurized milk. The possible mechanism of action was explored through measuring changes in intracellular ATP concentrations, membrane potential, and cell morphology. Furthermore, propidium iodide (PI) staining assay was performed to evaluate the effect of CoQ0 on cell membrane integrity. The MIC of CoQ0 against tested strains ranged from 7.8 to 62.5 µg/mL. CoQ0 at 2 × MIC showed bactericidal effect on S. aureus in tryptic soy broth (TSB) and pasteurized milk. Decrease in intracellular ATP concentration and membrane potential were detected when cells were treated with CoQ0. PI staining demonstrated destruction of bacterial cell membrane. CoQ0 also induced abnormal cell morphological changes, as confirmed by field emission scanning electron microscopy. These findings suggested that CoQ0 exhibited antimicrobial effect on S. aureus, which was partly because of its ability to damage cell membrane.

11.
Cell Mol Life Sci ; 76(17): 3433-3447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30980109

RESUMO

Enhancement of insulin-like growth factor 1 receptor (IGF-IR) degradation by heat shock protein 90 (HSP90) inhibitor is a potential antitumor therapeutic strategy. However, very little is known about how IGF-IR protein levels are degraded by HSP90 inhibitors in pancreatic cancer (PC). We found that the HSP90α inhibitor NVP-AUY922 (922) effectively downregulated and destabilized the IGF-1Rß protein, substantially reduced the levels of downstream signaling molecules (p-AKT, AKT and p-ERK1/2), and resulted in growth inhibition and apoptosis in IGF-1Rß-overexpressing PC cells. Preincubation with a proteasome or lysosome inhibitor (MG132, 3 MA or CQ) mainly led to IGF-1Rß degradation via the lysosome degradation pathway, rather than the proteasome-dependent pathway, after PC cells were treated with 922 for 24 h. These results might be associated with the inhibition of pancreatic cellular chymotrypsin-peptidase activity by 922 for 24 h. Interestingly, 922 induced autophagic flux by increasing LC3II expression and puncta formation. However, knockdown of the crucial autophagy component AGT5 and the chemical inhibitor 3 MA-blocked 922-induced autophagy did not abrogate 922-triggered IGF-1Rß degradation. Furthermore, 922 could enhance chaperone-mediated autophagy (CMA) activity and promote the association between HSP/HSC70 and IGF-1Rß or LAMP2A in coimmunoprecipitation and immunofluorescence analyses. Silencing of LAMP2A to inhibit CMA activity reversed 922-induced IGF-1Rß degradation, suggesting that IGF-1Rß degradation by 922 was partially dependent on the CMA pathway rather than macroautophagy. This finding is mirrored by the identification of the KFERQ-like motif in IGF-1Rß. These observations support the potential application of 922 for IGF-1Rß-overexpressing PC therapy and first identify the role of the CMA pathway in IGF-1Rß degradation by an HSP90 inhibitor.


Assuntos
Autofagia/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Isoxazóis/farmacologia , Receptor IGF Tipo 1/metabolismo , Resorcinóis/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Sequência de Aminoácidos , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/antagonistas & inibidores , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Lisossomos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/parasitologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/genética , Alinhamento de Sequência , Transdução de Sinais/efeitos dos fármacos
12.
Onco Targets Ther ; 12: 883-896, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774375

RESUMO

Purpose: Esophageal squamous-cell carcinoma (ESCC) is the most common subtype of esophageal cancer, with a poor clinical outcome. Cryptotanshinone (CTS) is the main bioactive compound from the root of Salvia miltiorrhiza Bunge. Our study aimed to investigate the anti-cancer effects and molecular mechanisms of CTS on ESCC. Materials and methods: We investigated the anti-tumor activity of CTS on ESCC in vitro and in vivo. Activation of the STAT3 signaling pathway was evaluated in ESCC and HEK-Blue™ IL-6 cells. Cell viability was assessed by the MTT assay. Apoptosis and cell cycle arrest were assessed using flow cytometry. Cell migration was detected by a scratch wound assay. Results: CTS inhibited STAT3 expression and IL-6-mediated STAT3 activation in esophageal cancer cells. Subsequently, CTS dose-dependently inhibited the proliferation of esophageal cancer cells via induction of cell apoptosis. Furthermore, CTS suppressed the migration of esophageal cancer cells. In vivo, CTS inhibited tumor growth of EC109 cell in xenograft mice without any obvious effect on body weight. Conclusion: Our results indicated that STAT3 inhibition may be a therapeutic target for esophageal cancer. CTS could provide a potential approach for esophageal cancer therapy by influencing the janus kinase-2/STAT3 signaling pathway.

13.
Oncogenesis ; 8(1): 3, 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30631055

RESUMO

Induction of differentiation is a therapeutic strategy in high-risk neuroblastoma, a childhood cancer of the sympathetic nervous system. Neuroblastoma differentiation requires transcriptional upregulation of neuronal genes. How this process is regulated at epigenetic levels is not well understood. Here we report that the histone H3 lysine 27 demethylase KDM6B is an epigenetic activator of neuroblastoma cell differentiation. KDM6B mRNA expression is downregulated in poorly differentiated high-risk neuroblastomas and upregulated in differentiated tumors, and high KDM6B expression is prognostic for better survival in neuroblastoma patients. In neuroblastoma cell lines, KDM6B depletion promotes cell proliferation, whereas KDM6B overexpression induces neuronal differentiation and inhibits cell proliferation and tumorgenicity. Mechanistically, KDM6B epigenetically activates the transcription of neuronal genes by removing the repressive chromatin marker histone H3 lysine 27 trimethylation. In addition, we show that KDM6B functions downstream of the retinoic acid-HOXC9 axis in inducing neuroblastoma cell differentiation: KDM6B expression is upregulated by retinoic acid via HOXC9, and KDM6B is required for HOXC9-induced neuroblastoma cell differentiation. Finally, we present evidence that KDM6B interacts with HOXC9 to target neuronal genes for epigenetic activation. These findings identify a KDM6B-dependent epigenetic mechanism in the control of neuroblastoma cell differentiation, providing a rationale for reducing histone H3 lysine 27 trimethylation as a strategy for enhancing differentiation-based therapy in high-risk neuroblastoma.

14.
Eur J Med Chem ; 162: 122-131, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445262

RESUMO

A series of novel fusidic acid (FA) derivatives were synthesized and screened for their in vitro cytotoxicity against the Hela, U87, KBV and MKN45 cancer cell lines. Selected FA derivatives with anti-tumor activity were firstly identified including compound 4, which exhibited good anti-proliferative activity with IC50 values in the range of 1.26-3.57 µM. Further research revealed that compound 4 induced Hela cells to undergo apoptosis by increasing the ratio of the cells in the Sub-G0/G1 phase via decreasing the neo-synthesized proteins in a dose-dependent manner from 1 to 10 µM. Compound 4 also showed good in vivo anti-tumor activity against the xenograft tumor of Hela cells and had no apparent toxicity. This study highlights the advantage of introducing the medium-length amino-terminal groups at the 3-OH position of FA to enhance its anti-tumor activity and suggests that compound 4 provides a starting point for designing more potent derivatives in the future.


Assuntos
Antineoplásicos/síntese química , Ácido Fusídico/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Fusídico/síntese química , Ácido Fusídico/uso terapêutico , Xenoenxertos , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
15.
Nat Commun ; 9(1): 4777, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429468

RESUMO

Cell-based drug delivery systems have shown promising capability for tumor-targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio-effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug-loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils' viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Glioma/tratamento farmacológico , Nanopartículas , Neutrófilos , Animais , Neoplasias Encefálicas/cirurgia , Movimento Celular , Rastreamento de Células , Quimioterapia Adjuvante , Sistemas de Liberação de Medicamentos , Armadilhas Extracelulares , Óxido Ferroso-Férrico , Glioma/cirurgia , Imagem por Ressonância Magnética , Imãs , Camundongos , Microscopia Eletrônica de Transmissão , Dióxido de Silício
16.
Cancer Lett ; 432: 47-55, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-29859875

RESUMO

Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 µM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ±â€¯0.3 and 18.5 ±â€¯1.0 µM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Canal de Cátion TRPC6/antagonistas & inibidores , Animais , Apoptose , Cálcio/metabolismo , Movimento Celular , Proliferação de Células , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Canal de Cátion TRPC6/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Proc Natl Acad Sci U S A ; 115(13): 3249-3254, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29531094

RESUMO

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/química , Apoproteínas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Heme/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Concentração Inibidora 50 , Mioglobina/química
18.
World J Gastroenterol ; 24(9): 957-970, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29531460

RESUMO

Two-dimensional shear wave elastography (2D-SWE) is a rapid, simple and novel noninvasive method that has been proposed for assessing hepatic fibrosis in patients with chronic liver diseases (CLDs) based on measurements of liver stiffness. 2D-SWE can be performed easily at the bedside or in an outpatient clinic and yields immediate results with good reproducibility. Furthermore, 2D-SWE was an efficient method for evaluating liver fibrosis in small to moderately sized clinical trials. However, the quality criteria for the staging of liver fibrosis are not yet well defined. Liver fibrosis is the main pathological basis of liver stiffness and a key step in the progression from CLD to cirrhosis; thus, the management of CLD largely depends on the extent and progression of liver fibrosis. 2D-SWE appears to be an excellent tool for the early detection of cirrhosis and may have prognostic value in this context. Because 2D-SWE has high patient acceptance, it could be useful for monitoring fibrosis progression and regression in individual cases. However, multicenter data are needed to support its use. This study reviews the current status and future perspectives of 2D-SWE for assessments of liver fibrosis and discusses the technical advantages and limitations that impact its effective and rational clinical use.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Fígado/diagnóstico por imagem , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Cirrose Hepática/etiologia , Cirrose Hepática/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
20.
Toxicol Appl Pharmacol ; 341: 98-105, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29408042

RESUMO

Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel α-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Animais , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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