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Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Linhagem Celular Tumoral , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/farmacologia , Desacetilase 6 de Histona/uso terapêutico , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by the infection-related host response disorder. Adequate mean arterial pressure is an important prerequisite of tissue and organ perfusion, which runs through the treatment of sepsis patients, and an appropriate mean arterial pressure titration in the early-stage correlates to the positive outcome of the treatment. Therefore, in the present study, we aimed to elucidate the relationship between early mean arterial pressure levels and short-term mortality in sepsis patients. METHODS: We included all suspected sepsis patients from MIMIC-III database with average mean arterial pressure ≥ 60 mmHg on the first day of intensive care unit stay. Those patients were then divided into a permissive low-mean arterial pressure group (60-65 mmHg) and a high-mean arterial pressure group (> 65 mmHg). Multivariate Cox regression analysis was conducted to analyze the relationship between MAP level and 30-day, 60-day, and 100-day mortality of suspected sepsis patients in the two groups. Propensity score matching, inverse probability of treatment weighing, standardized mortality ratio weighting, PA weighting, overlap weighting, and doubly robust analysis were used to verify our results. RESULTS: A total of 14,031 suspected sepsis patients were eligible for inclusion in our study, among which 1305 (9.3%) had an average first-day mean arterial pressure of 60-65 mmHg, and the remaining 12,726 patients had an average first-day mean arterial pressure of more than 65 mmHg. The risk of 30-day mortality was reduced in the high mean arterial pressure group compared with the permissive low-mean arterial pressure group (HR 0.67 (95% CI 0.60-0.75; p < 0.001)). The higher mean arterial pressure was also associated with lower 60-day and 100-day in-hospital mortality as well as with shorter duration of intensive care unit stay. Patients in the high-mean arterial pressure group also had more urine output on the first and second days of intensive care unit admission. CONCLUSIONS: After risk adjustment, the initial mean arterial pressure of above 65 mmHg was associated with reduced short-term mortality, shorter intensive care unit stay, and higher urine volume in the first two days among patients with sepsis.
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Hipotensão , Sepse , Humanos , Estudos Retrospectivos , Pontuação de Propensão , Sepse/terapia , Pressão Arterial , Unidades de Terapia IntensivaRESUMO
Doxorubicin (Dox) is the standard treatment approach for osteosarcoma (OS), while acquired drug resistance seriously attenuates its treatment efficiency. The present study aimed to investigate the potential roles of metabolic reprogramming and the related regulatory mechanism in Dox-resistant OS cells. The results showed that the ATP levels, lactate generation, glucose consumption and oxygen consumption rate were significantly increased in Dox-resistant OS cells compared with parental cells. Furthermore, the results revealed that the increased expression of estrogen-related receptor alpha (ERRα) was involved in metabolic reprogramming in chemotherapy resistant OS cells, since targeted inhibition of ERRα restored the shifting of metabolic profiles. Mechanistic analysis indicated that the mRNA stability, rather than ERRα transcription was markedly increased in chemoresistant OS cells. Therefore, it was hypothesized that the 3'-untranslated region of ERRα mRNA was methylated by N6-methyladenine, which could further recruit insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress mRNA decay and increase mRNA stability. IGF2BP1 knockdown downregulated ERRα and reversed the metabolic alteration of resistant OS cells. Additionally, the oncogenic effect of the IGF2BP1/ERRα axis on Dox-resistant OS cells was verified by in vitro and in vivo experiments. Clinical analysis also revealed that the expression levels of IGF2BP1 and ERRα were associated with the clinical progression of OS. Collectively, the current study suggested that the IGF2BP1/ERRα axis could regulate metabolic reprogramming to contribute to the chemoresistance of OS cells.
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Neoplasias Ósseas , Osteossarcoma , Regiões 3' não Traduzidas/genética , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Receptores de Estrogênio , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Long non-coding RNAs (lncRNAs) have been indicated for the regulatory roles in cardiovascular diseases. This study determined the expression of lncRNA TNK2 antisense RNA 1 (TNK2-AS1) in oxidized low-density lipoprotein (ox-LDL)-stimulated human aortic smooth muscle cells (HASMCs) and examined the mechanistic role of TNK2-AS1 in the proliferation and migration of HASMCs. Our results demonstrated that ox-LDL promoted HASMC proliferation and migration, and the enhanced proliferation and migration in ox-LDL-treated HASMCs were accompanied by the up-regulation of TNK2-AS1. In vitro functional studies showed that TNK2-AS1 knockdown suppressed cell proliferation and migration of ox-LDL-stimulated HASMCs, while TNK2-AS1 overexpression enhanced HASMC proliferation and migration. Additionally, TNK2-AS1 inversely regulated miR-150-5p expression via acting as a competing endogenous RNA (ceRNA), and the enhanced effects of TNK2-AS1 overexpression on HASMC proliferation and migration were attenuated by miR-150-5p overexpression. Moreover, miR-150-5p could target the 3' untranslated regions of vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) to regulate FGF1 and VEGFA expression in HASMCs, and the inhibitory effects of miR-150-5p overexpression in ox-LDL-stimulated HASMCs were attenuated by enforced expression of VEGFA and FGF1. Enforced expression of VEGFA and FGF1 also partially restored the suppressed cell proliferation and migration induced by TNK2-AS1 knockdown in ox-LDL-stimulated HASMCs, while the enhanced effects of TNK2-AS1 overexpression on HASMC proliferation and migration were attenuated by the knockdown of VEGFA and FGF1. Collectively, our findings showed that TNK2-AS1 exerted its action in ox-LDL-stimulated HASMCs via regulating VEGFA and FGF1 expression by acting as a ceRNA for miR-150-5p.
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Fator 1 de Crescimento de Fibroblastos/metabolismo , Lipoproteínas LDL/farmacologia , MicroRNAs/genética , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , RNA Longo não Codificante/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Fator 1 de Crescimento de Fibroblastos/genética , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oligonucleotídeos Antissenso/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Chemotherapy resistance is one of the major challenges for the treatment of osteosarcoma (OS). The potential roles of oestrogenic signals in the chemoresistance of OS cells were investigated. As compare to the parental cells, the doxorubicin and cisplatin (CDDP) resistant OS cells had greater levels of oestrogen-related receptors alpha (ERRα). Targeted inhibition of ERRα by its specific siRNAs or inverse agonist XCT-790 can restore the sensitivity of OS resistant cells to chemotherapy. This might be due to that si-ERRα can decrease the expression of P-glycoprotein (P-gp, encoded by ABCB1), one important ABC membrane transporter for drug efflux. XCT-790 can decrease the transcription and mRNA stability of ABCB1, while had no effect on protein stability of P-gp. ERRα can bind to the transcription factor of SP3 to increase the transcription of ABCB1. Furthermore, XCT-790 treatment decreased the expression of miR-9, which can bind to the 3'UTR of ABCB1 and trigger its decay. Collectively, we found that ERRα can regulate the chemoresistance of OS cells via regulating the transcription and mRNA stability of ABCB1. Targeted inhibition of ERRα might be a potential approach for OS therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Receptores de Estrogênio/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/genética , Nitrilas/farmacologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Ligação Proteica , Interferência de RNA , Receptores de Estrogênio/metabolismo , Fator de Transcrição Sp3/genética , Fator de Transcrição Sp3/metabolismo , Tiazóis/farmacologia , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
AIM: Laparoscopic hepatectomy (LH), microwave ablation (MWA), and open hepatectomy (OH) are three widely used methods to treat small hepatocellular carcinoma (HCC). However, few studies have compared the short- and long-term outcomes of these three treatments. The aim of this study was to investigate their effectiveness. METHODS: The data were reviewed from 280 patients with HCCs measuring ≤3 cm (Barcelona Clinic Liver Cancer stage 0 or A) who received LH (n = 133), OH (n = 87), or MWA (n = 60) in our research center from 2005 to 2010. Short-term outcomes included intraoperative blood loss, operation time, and length of hospital stay. The disease-free survival and overall survival rates were analyzed as long-term outcomes. RESULTS: The patients in the MWA and LH groups showed better short-term outcomes compared with those in the OH group. There were no significant differences in overall survival rates among the three treatments. The LH group showed significantly lower recurrence rates than the MWA group (P = 0.0146). CONCLUSIONS: Laparoscopic hepatectomy may be a better option for patients with small HCC located on the liver surface and left lateral lobe. The short-term outcome of MWA is promising, although the high risk of local recurrence after the operation should be considered when planning treatment.
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INTRODUCTION: Lenvatinib has recently become available as the first-line therapy for advanced hepatocellular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown. OBJECTIVES: The current study aims to identify the molecular mechanisms of lenvatinib in HCC. METHODS: Gene expression microarrays, flow cytometry, western blot, qRT-PCR, immunohistochemistry and immunofluorescence were used to study the response of HCC cells to lenvatinib. Xenograft tumor of Huh7 cells was also established to detect the effect of lenvatinib in vivo. RESULTS: Herein, we found that lenvatinib could induce apoptosis via increasing reactive oxygen species (ROS) levels in HCC cells. Then, microarray analysis and qRT-PCR results confirmed that GPX2 was a vital target for lenvatinib against HCC. Loss and gain function of experiment showed that regulating GPX2 levels markedly affected the lenvatinib-induced ROS levels and apoptosis in HCC cells. In addition, analyses of The Cancer Genome Atlas database and the qRT-PCR results in our cohort both showed that GPX2 markedly overexpressed in tumor tissues and correlated with poor overall survival in HCC. Mechanistically, our findings further demonstrated that GPX2 was a downstream gene regulated by ß-catenin, while lenvatinib could prevent nuclear translocation of ß-catenin and further inhibit GPX2 expression in HCC cells. More importantly, the correlation of GPX2 expression with lenvatinib response was further analyzed in 22 HCC patients who received lenvatinib therapy, and the results showed that the objective response rate (ORR) in patients with low GPX2 expression was 44.4% (4/9), while the ORR in patients with high GPX2 levels was only 7.7% (1/13). CONCLUSION: Our findings indicated that GPX2 plays an important role in lenvatinib-induced HCC cell apoptosis, which might serve as a biomarker for instruction of lenvatinib therapy in HCC patients.
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Carcinoma Hepatocelular , Glutationa Peroxidase , Neoplasias Hepáticas , Humanos , Apoptose , beta Catenina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Glutationa Peroxidase/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , AnimaisRESUMO
Circulating tumor cells (CTCs) in cancer patients' peripheral blood have been demonstrated to be a significant biomarker for metastasis detection, disease prognosis, and therapy response. Due to their extremely low concentrations, efficient enrichment and non-destructive release are needed. Herein, an FTO chip modified with multifunctional gelatin nanoparticles (GNPs) was designed for the specific capture and non-destructive release of CTCs. These nanoparticles share a similar dimension with the microvilli and pseudopodium of the cellular surface; thus, they can enhance adhesion to CTCs, and then GNPs can be degraded by the enzyme matrix metalloproteinase (MMP-9), gently releasing the captured cells. In addition, the transparency of the chip makes it possible for fluorescence immunoassay identification in situ under a microscope. Our chip attained a high capture efficiency of 89.27%, a release efficiency of 91.98%, and an excellent cellular viability of 96.91% when the concentration of MMP-9 was 0.2 mg/mL. Moreover, we successfully identified CTCs from cancer patients' blood samples. This simple-to-operate, low-cost chip exhibits great potential for clinical application.
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Background: The molecular pathways along with the clinical significance of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) remain uncertain. Our study sought to identify and characterize lncRNAs associated with HCC. Methods: LncRNA TMCO1-AS1 was identified by differential expression analysis, receiver operating characteristic (ROC) analysis, and univariate analysis using RNA sequencing and clinical information of HCC from the public database. Then clinical correlations and survival analysis were conducted to further appraise the prognostic significance of lncRNA TMCO1-AS1 in HCC. Hepatoma and adjoining normal tissues from 66 patients who received surgical operation at our center were used to verify the results of the bioinformatics analysis. A survival prognostic model was established combining TMCO1-AS1 expression and other clinical characteristics. Results: Bioinformatics analysis showed the aberrant high expression of TMCO1-AS1 in HCC tissue. TMCO1-AS1 expression was positively correlated with alpha-fetoprotein (AFP) level, vascular invasion, tumor stage, as well as tumor differentiation. Moreover, survival analysis found a significant inverse association between the expression of TMCO1-AS1 and the survival of patients with HCC. Cox analysis indicated that TMCO1-AS1 was an independent factor for HCC prognosis. Analysis of the HCC tissues from patients at our center provided results similar to those of the bioinformatics analysis. Risk models for overall survival (OS) and recurrence-free survival (RFS) incorporating TMCO1-AS1 exhibited better sensitivity and specificity than using clinical characteristics alone. Conclusion: High TMCO1-AS1 expression is significantly correlated with the unfavorable poor prognosis of HCC, indicating its potential of being a novel prognostic marker for HCC.
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The isolation and analysis of scarce circulating tumor cells (CTCs) with immunomagnetic nanoparticles (IMNs) have shown promising outcomes in noninvasive cancer diagnosis. However, the IMNs adsorb nonspecific proteins after entering into biofluids and the formed protein coronas cover surface targeting ligands, limiting the detection efficiency of IMNs. In addition, the interaction between surface targeting ligands and white blood cells (WBCs) significantly limits the purity of CTCs isolated by IMNs. Furthermore, the interfacial collision of nanoparticles and cells has negative effects on the viability of isolated CTCs. All of these limitations synthetically restrict the isolation and analysis of rare CTCs for early diagnosis and precision medicine. Here, we proposed that surface functionalization of IMNs with neutrophil membranes can simultaneously reduce nonspecific protein adsorption, enhance the interaction with CTCs, reduce the distraction from WBCs, and improve the viability of isolated CTCs. In spiked blood samples, our neutrophil membrane-coated IMNs (Neu-IMNs) exhibited a superior separation efficiency from 41.36% to 96.82% and an improved purity from 40.25% to 90.68% when compared to bare IMNs. Additionally, we successfully isolated CTCs in 19 out of total 20 blood samples from breast cancer patients using Neu-IMNs and further confirmed the feasibility of the isolated CTCs for downstream cell sequencing. Our work provides a new perspective on engineered IMNs for efficient isolation and analysis of CTCs, paving the way for early noninvasive diagnosis of cancer.
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Técnicas Biossensoriais , Nanopartículas , Células Neoplásicas Circulantes , Linhagem Celular Tumoral , Separação Celular , Humanos , Separação Imunomagnética , Ligantes , Células Neoplásicas Circulantes/patologia , Neutrófilos/patologiaRESUMO
Prenatal diagnostics holds great significance for pregnant women desiring healthy babies. Fetal nucleated red blood cells (fNRBCs), bearing the complete genome of the fetus, have been regarded as an important biomarker for noninvasive prenatal diagnostics (NIPD). The high-performance detection and enrichment of fNRBCs from maternal blood, especially during early pregnancy, is urgently needed for NIPD, which, unfortunately, remains a big challenge for early-pregnancy fNRBC isolation. In this study, we developed an innovative platform based on silica microbeads for fNRBC isolation and release in early pregnancy. Microbeads were coated with self-assembled MnO2 nanoparticles (SiO2@MnO2) and then modified with a specific antibody. Benefiting from the three-dimensional nanostructure of the MnO2 nanoparticles, the isolation efficiency of the fNRBCs was enhanced. Subsequently, fNRBCs were released via dissolving the MnO2-nanoparticle coating using oxalic acid. We successfully isolated fNRBCs from the maternal peripheral blood samples of 20 pregnant women in the early pregnancy period, ranging from 41 to 62 gestational days. More importantly, the fetal origin of isolated cells was confirmed via fluorescent in situ hybridization and short tandem repeat analysis. This platform based on SiO2@MnO2 microbeads has verified the existence of fNRBCs in early-pregnancy maternal blood and is a promising approach for NIPD in early pregnancy.
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Eritrócitos/citologia , Sangue Fetal/citologia , Microesferas , Nanoestruturas/química , Diagnóstico Pré-Natal , Feminino , Humanos , Compostos de Manganês/química , Óxidos/química , Gravidez , Dióxido de Silício/químicaRESUMO
In recent years, the deoxycytidine analogue gemcitabine (2',2',-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment.
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Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Intervalo Livre de Doença , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , GencitabinaRESUMO
The underlying mechanism of the myocardial protective effect of fisetin was studied in a rat ischemia/reperfusion injury model. Sprague-Dawley rats were randomly assigned to seven groups and pretreated with different solutions by gavage administration. A rat model of cardiac ischemia/reperfusion injury was established. Plasma levels of Von Willebrand factor (vWF) were determined by ELISA, flow cytometry was used to determine the level of cardiomyocyte apoptosis and 2,3,5-triphenyltetrazolium staining was used to determine the size of myocardial infarcts. Hematoxylin and eosin-stained sections of myocardial tissues were examined for pathological changes. Expressions of nuclear factor (NF)-κB and matrix metallopeptidase 9 (MMP-9) were measured by immunohistochemistry. Compared with the model group, rats pretreated with fisetin, quercetin and aspirin showed significant prolongation of clotting time, prothrombin time, thrombin time and activated partial thromboplastin time. Fisetin treatment better maintained the integrity of myocardial fibers and nuclear integrity, reduced the percentage of apoptotic myocardial cells, inhibited expression of NF-κB, decreased the loss of MMP-9 and reduced nuclear translocation of NF-kB. Rats pretreated with fisetin also demonstrated a significant decrease in plasma levels of vWF. In addition, the protective effect of fisetin on myocardial cells was found to be dose dependent.
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Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease and associated with a wide spectrum of hepatic disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). NASH is projected to become the most common indication for liver transplantation, and the annual incidence rate of NASH-related HCC is 5.29 cases per 1000 person-years. Owing to the epidemics of NAFLD and the unclear mechanism of NAFLD progression, it is important to elucidate the underlying NAFLD mechanisms in detail. NASH is mainly caused by the development of NAFL Therefore, it is also of great significance to understand the mechanism of progression from NAFL to NASH. Gene expression chip data for NAFLD and NASH were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between NAFLD and normal controls (called DEGs for NAFLD), as well as between NASH and normal tissue (called DEGs for NASH-Normal), and between NASH and NAFL tissue (called DEGs for NASH-NAFL). For DEGs for the NAFLD group, key genes were identified by studying the form of intersection. Potential functions of DEGs for NASH were then analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein-protein interaction network (PPI) was constructed using the STRING database. A total of 249 DEGs and one key gene for NAFLD were identified. For NASH-Normal, 514 DEGs and 11 hub genes were identified, three of which were closely related to the survival analysis of HCC, and potentially closely related to progression from NASH to HCC. One key gene for NASH-NAFL (AKR1B10) was identified. These genes appear to mediate the molecular mechanism underlying NAFLD and may be promising biomarkers for the presence of NASH.
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Aldo-Ceto Redutases/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Aldo-Ceto Redutases/metabolismo , Biomarcadores/metabolismo , Carcinoma Hepatocelular/genética , Biologia Computacional , Conjuntos de Dados como Assunto , Diagnóstico Diferencial , Progressão da Doença , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas/genéticaRESUMO
Nϵ-carboxymethyl-lysine (CML), an advanced glycation end product, is involved in vascular calcification (VC) in diabetic atherosclerosis. This study aimed to investigate the effects of CML on VC in diabetic atherosclerosis induced by vascular smooth muscle cell (VSMC)-derived foam cells. Human studies, animal studies and cell studies were performed. The human study results from 100 patients revealed a poor blood glucose and lipid status and more severe coronary lesions and stenosis in patients with coronary artery disease and diabetes mellitus. Intraperitoneal injection of streptozotocin combined with a high-fat diet was used to build a diabetic atherosclerosis model in ApoE-/- mice. The animal study results indicated that CML accelerated VC progression in diabetic atherosclerosis by accelerating the accumulation of VSMC-derived foam cells in ApoE-/- mice. The cell study results illustrated that CML induced VSMC-derived foam cells apoptosis and aggravated foam cells calcification. Consistent with this finding, calcium content and the expression levels of alkaline phosphatase, bone morphogenetic protein 2 and runt-related transcription factor 2 were significantly elevated in A7r5 cells treated with oxidation-low-density lipoprotein and CML. Thus, we concluded that CML promoted VSMC-derived foam cells calcification to aggravate VC in diabetic atherosclerosis, providing evidence for the contribution of foam cells to diabetic VC.
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BACKGROUND: Long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis of various malignant tumors. However, the clinical significance of aberrant lncRNA expression in hepatocellular carcinoma (HCC) is still elusive. METHODS: Firstly, a differentially expressed lncRNA CTC-297N7.9 in HCC was detected by analyzing the data from The Cancer Genome Atlas (TCGA). Secondly, the expression level of CTC-297N7.9 was examined in four HCC cell lines and 60 pairs of HCC tissues by polymerase chain reaction (PCR) assay at our center. Thirdly, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of CTC-297N7.9 for HCC. Correlation and survival analysis of HCC patients from the TCGA and our center were also carried out to assess the predictive value of CTC-297N7.9. Finally, survival prognostic models were established combining lncRNA expression and other clinical parameters. RESULTS: The expression of CTC-297N7.9 was downregulated in HCC cell lines and HCC tissues. ROC curve revealed its significant diagnostic value in HCC. CTC-297N7.9 expression correlated with serum alpha-fetal protein (AFP), tumor stage, and tumor differentiation. Survival analysis indicated that overall survival (OS) and disease-free survival (DFS) are all positively associated with CTC-297N7.9 expression, especially in patients without viral hepatitis or cirrhosis. Cox regression analysis showed that CTC-297N7.9 expression level is an independent prognostic factor for both OS and DFS in HCC patients. Based on the model, CTC-297N7.9 was observed to be negatively correlated to risk score, indicating its role as a protective factor for HCC. CONCLUSION: Our study demonstrated that the low expression of CTC-297N7.9 is associated with poor prognosis in HCC patients, suggesting its possible role as a potential prognostic marker for HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , RNA Longo não Codificante , Adulto , Idoso , Carcinoma Hepatocelular/diagnóstico , Linhagem Celular , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Curva ROCRESUMO
OBJECTIVE: To increase the accuracy of non-invasive diagnosis of nonalcoholic fatty liver disease (NAFLD), clinical and laboratory NAFLD indicators were integrated into a diagnostic formula. METHODS: A total of 141 patients with clinically diagnosed NAFLD and 30 healthy controls were enrolled. We collected case history, body weight, height and mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase, blood urea nitrogen and blood uric acid (UA), serum creatinine, plasma total cholesterol, triglyceride, low density lipoprotein, glycosylated hemoglobin, fasting plasma glucose, fasting insulin, ultrasonic tests, Fibroscans, and other data. Linear correlation, multiple linear regressions, and receiver operating characteristic (ROC) curve methods were used to process and analyze the collected data. The performance of Fibroscan and our diagnostic formula was compared in reference to the findings of liver biopsy. RESULTS: The identified NAFLD diagnostic indices consisted of BMI, ALT, AST and UA. A regression formula was proposed as: CAPâ¯=â¯113.163â¯+â¯0.252â¯*â¯ALTâ¯+â¯6.316â¯*â¯BMI. Diagnosis of the area under the ROC curve was 0.927, the sensitivity was 87.68%, and specificity was 90%. The cutoff was 277.67 (pâ¯<â¯0.01). The accuracy of the NAFLD diagnosis with the proposed formula was significantly higher than FibroScan (82.6% vs 69.6%; pâ¯=â¯0.005). CONCLUSIONS: NAFLD diagnosis with the proposed formula demonstrated both high sensitivity and specificity, and its accuracy was significantly higher than FibroScan. This formula only utilized non-invasive clinical and laboratory findings and the calculation was simple. It can be conveniently used for clinical diagnosis of NAFLD.
Assuntos
Testes de Química Clínica , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Tecido Adiposo/patologia , Adulto , Alanina Transaminase/sangue , Algoritmos , Biópsia , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Valor Preditivo dos Testes , Curva ROC , Análise de Regressão , Fatores de Risco , Ultrassonografia/métodosRESUMO
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. In the present study, we aimed to profile the possible changes in plasma phospholipid fatty acid composition of HCC patients, and to identify the fatty acid biomarkers that could distinguish HCC patients from healthy controls. A total of 37 plasma samples from healthy controls and HCC patients were collected and their phospholipid fatty acid profiles were characterized by gas chromatography-mass spectrometry followed by multivariate statistical analysis. Twenty-five fatty acids were identified and quantified, their proportions varied greatly between two groups, suggesting each group has its own fatty acid pattern. Orthogonal partial least squares discriminant analysis in terms of fatty acid profiles showed that HCC patients could be clearly distinguished from healthy controls. More importantly, linoleic acid (18:2n-6), oleic acid (18:1n-9), arachidonic acid (20:4n-6) and palmitic acid (16:0) were identified as the potential fatty acid biomarkers of HCC patients. Additionally, to further identify the major cause of the abnormality of plasma fatty acid profile, fatty acid distributions of cancerous tissue and its surrounding tissue from 42 HCC patients were also examined. Due to have similar variation trend of major fatty acid biomarkers, linoleic acid (18:2n-6), oleic acid (18:1n-9), abnormalities in plasma phospholipid fatty acid profiles of HCC patients may be mainly attributed to the alternation of intrinsic fatty acid metabolism caused by cancer per se, but not to the differences in dietary factors.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Ácidos Graxos/sangue , Neoplasias Hepáticas/sangue , Fosfolipídeos/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
We report here a novel doxorubicin (DOX) prodrug that reduces the proportion of inactive materials and minimizes drug leak. In aqueous solutions, the resulting DOX prodrug could spontaneously form stable micelles with diameters of â¼80 nm with a DOX loading content as high as â¼40 wt%. The subsequent cytotoxicity and cell internalization behavior indicated that the resulting prodrug could show a high in vitro anticancer efficacy. We believe that this strategy could be developed to design prodrugs of various anticancer drugs and thus offer new prodrugs for cancer therapy.