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1.
ACS Appl Mater Interfaces ; 12(1): 451-460, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31805228

RESUMO

Inorganic lead halide perovskite quantum dots (iLHP-QDs) have recently been used in the photocatalytic reaction. However, the factors that influence the photocatalytic performance of the iLHP-QDs have not been fully investigated. Herein, we synthesized a series of iLHP-QDs with varied halide ratios (CsPbX3, X = I, I0.67Br0.33, I0.5Br0.5, I0.33Br0.67, Br) and studied their influence on the photocatalytic performance by monitoring the polymerization of 2,2',5',2″-ter-3,4-ethylenedioxythiophene (TerEDOT). The CsPbI3 QDs showed the best performance owing to their narrow band gap and low exciton binding energy. Moreover, the photocatalytic performance of the iLHP-QDs could be simply improved by being treated with methyl acetate, which can be attributed to the replacement of the oleic acid by the short acetate acid and the introduction of the traps on the surface of QDs in the post-treatment. These results could help design a more efficient photocatalytic system and further promote the application of iLHP-QDs.

2.
Medicine (Baltimore) ; 98(46): e17403, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725603

RESUMO

Studies investigating the association between gene variants and depression susceptibility found inconsistent data. The present study aimed to clarify whether CNR1rs1049353, CNR1 AAT triplet repeat, and CNR2rs2501432 polymorphisms confer higher risk for depressive disorder.Literature from PubMed, Medline, Embase, Scopus, Cochrance Library, and Wanfang databases was searched (up to August 20, 2018). Seven case-control studies with various comorbidities were eligible. We targeted CNR single-nucleotide polymorphisms (SNPs) that have been reported by 2 or more studies to be involved in the current meta-analysis, resulting in a final list of 3 SNPs: CNR1rs1049353, CNR1 AAT triplet repeat polymorphism, and CNR2rs2501432. Odds ratios (ORs) and 95% confidence intervals (CIs) for allele and homozygote comparisons, dominant and recessive models, and triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5) were assessed using a random effect model as measures of association. Heterogeneity among included studies was analyzed using sensitivity test. Publication bias was also explored by Egger and rank correlation test.overall, no significant association was found between depression and CNR1rs1049353 (G vs A: OR [95% CI] = 1.09 [0.61-1.95]; GG vs AA: 1.29 [0.73-2.26]; GG vs GA+AA: 1.10 [0.57-2.10]; GG+GA vs AA: 1.25 [0.72-2.18]; and AAT triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5): 1.92 [0.59-6.27]. In contrast, a significant association between CNR2rs2501432 and depression was detected, and the ORs and 95% CIs are as follows: allele contrast (OR = 1.39, 95% CI = [1.12-1.72], P = .003); homozygous (OR = 2.19, 95% CI = [1.34-3.59], P = .002); dominant (OR = 1.93,95% CI = [1.23-3.04], P = .005); and recessive (OR = 1.41, 95% CI = [1.04-1.92], P = .03).This meta-analysis revealed that CNR1rs1049353 or AAT triplet repeat polymorphism had no association with susceptibility to depression, while CNR2rs2501432 polymorphism was a remarkable mark for depression patients.


Assuntos
Depressão/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Alelos , Estudos de Casos e Controles , Humanos , Razão de Chances , Fatores de Risco
4.
Med Sci Monit ; 25: 5350-5355, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31322139

RESUMO

BACKGROUND Emergency endoscopic intestinal stenting has been applied with increasing frequency in colorectal cancer patients with acute intestinal obstruction. However, its clinical effectiveness as compared to emergency surgery remains controversial. MATERIAL AND METHODS The clinical data of 96 patients with acute intestinal obstruction caused by colorectal cancer from April 2012 to April 2018 were retrospectively collected. Statistical technique success rate, clinical success rate, operative time, average indwelling time of stent, complications, transition time to second-stage surgery, postoperative hospital stay, sputum rate, and postoperative infection rate were studied. RESULTS Endoscopic colonoscopy was successfully performed in 94 patients. The success rate of stent placement was 97.9%, and the average operative time was 35 minutes (range, 25-85 minutes). Forty-two patients underwent stage I colectomy after relief of the obstruction. The average stent retention time was 7 days (range, 5-15 days). Two patients suffered from anastomotic infection. Their intestinal preparation time, hospital stay, fistula rate, and infection rate were lower than those of patients undergoing emergency operation for colon cancer intestinal obstruction. A total of 52 patients with colon cancer underwent palliative stent placement. Three patients had complications, including 1 case of stent displacement in the palliative care group and 2 cases with perforation in the bridge surgery group. CONCLUSIONS Emergency endoscopic placement of an intestinal stent is safe and effective in the treatment of patients with acute intestinal obstruction caused by colorectal cancer. It is also a safe and simple procedure for patients receiving advanced palliative treatment, which greatly improves their quality of life and is easy for patients' families to accept.

5.
Theranostics ; 9(8): 2346-2360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31149048

RESUMO

Myocardial infarction (MI), a main cause of heart failure, leads to irreversible cardiomyocytes loss and cardiac function impairment. Current clinical treatments for MI are largely ineffective as they mostly aim to alleviate symptoms rather than repairing the injured myocardium. Thus, development of more effective therapies is compelling. This study aims to investigate whether the extracellular vesicles (EVs) carrying specific anti-apoptotic miRNA can be efficiently internalized into myocardium to achieve desired therapeutic outcomes. Methods: EVs were isolated from HEK293T cells overexpressing miRNA-21 (miR21-EVs) and identified. The RNase resistant rate of miR21-EVs was calculated by real-time PCR and compared with liposomes and polyethylenimine (PEI). Confocal laser scanning microscopy was used for visualizing the cellular internalization of miR21-EVs in primary cultured mouse neonatal cardiomyocytes (CMs), H9c2 rat cardiomyoblasts, and human umbilical vein endothelial cells (HUVECs). The effect of miR21-EVs on the expression of PDCD4, a pro-apoptotic protein that plays an important role in regulating myocardial apoptosis, was also evaluated in these three cell types by real-time PCR and Western blot analysis. In vivo, miR21-EVs was directly injected into the infarct zone following ligation of the left anterior descending of coronary artery in mice. The miR21-EVs distribution and blood vessel (capillary and arteriole) density were evaluated by immunofluorescence staining. Fluorescence in situ hybridization of miRNA-21 was also carried out to confirm the miR21-EVs distribution in vitro and in vivo. The protein level of PDCD4 in myocardium was assessed by immunohistochemical staining. The anti-apoptotic effect of miR21-EVs in cardiomyocytes and endothelial cells were measured using TUNEL staining. Four weeks after injection, the cardiac histological and functional recovery was evaluated by histochemistry staining and echocardiography, respectively. Results: In contrast to liposomes and PEI, EVs significantly inhibited miRNA-21 degradation. MiR21-EVs efficiently delivered miRNA-21 into cardiomyocytes and endothelial cells within 4 hours. Exogenous miRNA-21 in turn significantly reduced PDCD4 expression and attenuated cell apoptosis in vitro. Consistently and importantly, in a preclinical MI animal model, miRNA-21-loaded EVs effectively sent miRNA-21 into cardiomyocytes and endothelial cells, drastically inhibited cell apoptosis and led to significant cardiac function improvement. Conclusion: Our results suggest the cell-derived, genetically engineered EVs may be used therapeutically for the delivery of miRNAs for the rescue of MI and may benefit patients in the future.

6.
Andrologia ; 51(5): e13251, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30821033

RESUMO

The aim of this study was to elucidate the reproductive toxicity of the coadministration of diltiazem and cyclosporine A or tacrolimus. Testicular development, semen quality, sex hormones and testicular tissues were assessed in unilateral nephrectomised (UN) rats, including the control group, UN group, UN+CsA group, UN+FK506 group, UN+Rapa group, UN+CsA+Dil group and UN+FK506+Dil group. The testicular coefficient, the sperm number and the sperm motility were lower in the treatment groups (except UN+FK506) than in the control and UN groups (all p < 0.05). The lowest sperm number and motility were identified in the UN+CsA+Dil group, followed by the UN+CsA group. The proportion of abnormal sperm was higher in the UN+CsA and UN+CsA+Dil groups than in the control and UN groups, respectively (p < 0.05). The plasma concentrations of sex hormones were changed in the treatment groups. Dil can increase the blood concentrations of CsA and FK506 (◇p < 0.05, ◆p < 0.05). Therapeutic doses of these agents induced morphological changes in the testicular tissue and ultrastructural changes in the testosterone, mesenchymal cells and supporting cells. Our present study suggests that Dil can increase the testicular toxicity of CNIs (calcineurin inhibitors, including CsA and FK506) by enhancing the plasma concentrations of CNIs.


Assuntos
Inibidores de Calcineurina/toxicidade , Bloqueadores dos Canais de Cálcio/toxicidade , Ciclosporina/toxicidade , Diltiazem/toxicidade , Imunossupressores/toxicidade , Tacrolimo/toxicidade , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada/efeitos adversos , Hormônios Esteroides Gonadais/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Rim/cirurgia , Transplante de Rim/efeitos adversos , Masculino , Microscopia Eletrônica de Transmissão , Nefrectomia , Ratos , Ratos Sprague-Dawley , Análise do Sêmen , Motilidade Espermática/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Testículo/ultraestrutura
7.
Cell Death Differ ; 26(2): 291-305, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29769640

RESUMO

Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice. The activation of miR-191 under hypoxic conditions is mediated by hypoxia-inducible factor-1α (HIF1α) binding to its promoter region. Global miR-191 KO mice were constructed by CRISPR/Cas9 system, and we found that miR-191 deficiency markedly reduces liver tissue damage, cell inflammatory responses and cell death in a mouse hepatic IRI model. Under the H/R condition, miR-191 overexpression promotes G0/G1 cell cycle arrest and cell apoptosis, but inhibition of miR-191 facilitates cell cycle progression and decreases cell death. Mechanistically, upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. Moreover, the effects of miR-191 on cell cycle arrest and cell apoptosis are abrogated by ZONAB overexpression, and vice versa. Taken together, our results indicate an important role of the HIF1α/miR-191/ZONAB signaling pathway in hepatic IRI and suggest miR-191 as a novel therapeutic target for the treatment of liver IRI.

8.
Cell Death Dis ; 9(5): 553, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29748582

RESUMO

The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination. Furthermore, USP49 rendered HCT116 cells more sensitive to etoposide (Eto)-induced DNA damage and was upregulated in response to several types of cell stress, including DNA damage. Remarkably, USP49 expression was regulated by p53 and USP49 in knockout mice, which are more susceptible to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.


Assuntos
Dano ao DNA , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação , Animais , Células HCT116 , Humanos , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/genética , Ubiquitina Tiolesterase/genética
9.
Int J Mol Med ; 41(2): 935-945, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29251315

RESUMO

Monocytes infiltrate damaged liver tissue during noninfectious liver injury and often have dual roles, perpetuating inflammation and promoting resolution of inflammation and fibrosis. However, how monocyte subsets distribute and are differentially recruited in the liver remain unclear. In the current study, the subpopulations of infiltrating monocytes were examined following liver ischemia/reperfusion (I/R) injury in mice using flow cytometry. CD11b+Ly6C high (Ly6Chi) cells (inflammatory monocytes) and CD11b+Ly6C low cells (reparative monocytes) were recruited into the liver following I/R injury. Treatment with clodronate­loaded liposomes, which transiently deplete systemic macrophages, alleviated hepatic damage. Mice genetically deficient in C­C motif chemokine ligand 2 (CCL2), or its receptor C­C chemokine receptor 2 (CCR2), exhibited diminished hepatic damage compared with wild­type mice following I/R, by controlling intrahepatic inflammatory Ly6Chi monocyte accumulation. In addition, the CCR2 specific inhibitor RS504393 alleviated hepatic I/R injury. The results suggest that the CCR2/CCL2 axis has an important role in monocyte infiltration and may represent a novel target for the treatment of liver I/R injury.


Assuntos
Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Monócitos/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Quimiocina CCL2/metabolismo , Ácido Clodrônico/farmacologia , Citometria de Fluxo , Inflamação/imunologia , Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Receptores CCR2/metabolismo , Traumatismo por Reperfusão/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Cell Death Differ ; 24(12): 2199-2209, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28960206

RESUMO

miR-148a has been shown to regulate inflammation, immunity and the growth of certain tumors, but its roles in colitis and colorectal tumorigenesis remain largely undetermined. Here we found miR-148a-deficient mice to be more susceptible to colitis and colitis-associated tumorigenesis. Both were associated with increased nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling. Bone marrow- and non-bone marrow-derived miR-148a contributed to colitis and colitis-associated tumorigenesis. miR-148a loss of heterozygosity exacerbated Apcmin/+ colon and small intestinal spontaneous tumor development. Restoring miR-148a expression prevented both spontaneous and carcinogen-induced colon tumor development. miR-148a was downregulated in human inflammatory bowel disease (IBD) and colorectal cancer patient tissues. This correlated with a high degree of miR-148a promoter methylation mediated by a complex comprised of P65 and DNA methyltransferase 3 alpha (DNMT3A). miR-148a directly targets several well-accepted upstream regulators of NF-κB and STAT3 signaling, including GP130, IKKα, IKKß, IL1R1 and TNFR2, which leads to decreased NF-κB and STAT3 activation in macrophages and colon tissues. Our findings reveal that miR-148a is an indirect tumor suppressor that modulates colitis and colitis-associated tumorigenesis by suppressing the expression of signaling by NF-κB and STAT3 and their pro-inflammatory consequences.


Assuntos
Carcinogênese/genética , Colite/terapia , Neoplasias Colorretais/terapia , MicroRNAs/administração & dosagem , Animais , Carcinogênese/metabolismo , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Terapia Genética , Humanos , Lentivirus/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/biossíntese , MicroRNAs/genética , Transdução de Sinais
11.
Am J Transl Res ; 9(6): 2878-2890, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28670376

RESUMO

Liver ischemia-reperfusion injury (IRI) is a common clinical problem in which neutrophil recruitment is an essential event. Our previous study revealed the important role of C-C motif chemokine receptor 2 (CCR2) in neutrophils during liver IRI. The aim of the present study was to further investigate the underlying mechanisms mediating the changes in CCR2 expression in neutrophils during this pathophysiological process. Herein, we found that TLR4 ablation reduced neutrophil mobilization from the bone marrow and the subsequent infiltration into the liver during liver IRI; neutrophil-derived CCR2 expression was also repressed. In addition, neutrophil mobilization was dependent on CCR2 expression in neutrophils, which in turn relied on activation of the TLR4-p38 axis during liver IRI. In conclusion, neutrophil-derived CCR2 expression regulates neutrophil mobilization from the bone marrow and infiltration into the liver, which requires activation of the TLR4-p38 axis during liver IRI.

12.
Cell Death Dis ; 8(7): e2916, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28703810

RESUMO

miRNAs are involved in many physiologic and disease processes by virtue of degrading specific mRNAs or inhibiting their translation. miR-148a has been implicated in the control of tumor growth and cholesterol and triglyceride homeostasis using in vitro or in vivo gene expression- and silencing-based approaches. Here miR-148a knockout (KO) mice were used to investigate the intrinsic role of miR-148a in liver physiology and hepatocarcinogenesis in mice. miR-148a downregulation was found to be correlated with poor clinical outcomes in hepatocellular carcinoma (HCC) patients. Under regular chow diet (RCD) or high fat diet (HFD), miR-148a deletion significantly accelerated DEN-induced hepatocarcinogenesis in mice. Mechanistically, miR-148a deletion promotes lipid metabolic disorders in mice. Moreover, restoration of miR-148a reversed these defects. Finally, miR-148a was found to directly inhibit several key regulators of hepatocarcinogenesis and lipid metabolism. These findings reveal crucial roles for miR-148a in the hepatic lipid metabolism and hepatocarcinogenesis. They further identify miR-148a as a potential therapeutic target for certain liver diseases, including cancer.


Assuntos
Carcinoma Hepatocelular/patologia , Metabolismo dos Lipídeos/fisiologia , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Colesterol/sangue , Dietilnitrosamina/toxicidade , Regulação para Baixo , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo , Taxa de Sobrevida , Triglicerídeos/sangue , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo
13.
Cell Death Differ ; 24(7): 1253-1262, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28475173

RESUMO

Frequent KRAS mutations contribute to multiple cancers including ~40% of human colorectal cancers (CRCs). Systematic screening of 1255 microRNAs (miRNAs) identified miR-30a as a synthetic lethal in KRAS-mutant CRC cells. miR-30a was downregulated in CRCs and repressed by P65. miR-30a directly targeted malic enzyme 1 (ME1) and KRAS, and inhibited anchorage-independent growth and in vivo tumorigenesis by KRAS-mutant CRC cells. ME1 was significantly upregulated in KRAS-mutant CRCs. Eliminating ME1 by short hairpin RNA (shRNA) resulted in obviously decreased NADPH production, levels of triglyceride and fatty acid, and an inhibition of tumorigenicity of KRAS-mutant CRCs. miR-30a overexpression and ME1 suppression attenuated AOM/DSS-induced colorectal tumorigenesis. The critical roles of miR-30a and ME1 in the development of KRAS-mutant CRCs indicate therapy potentials for this subtype of cancer.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Malato Desidrogenase/metabolismo , MicroRNAs/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Sulfato de Dextrana , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Regulação para Cima/genética
14.
Med Sci Monit ; 23: 1768-1774, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28400549

RESUMO

BACKGROUND Prostate carcinoma (PCa) is often not diagnosed until advanced disease with bone metastasis. Predictive factors for bone metastasis are required to improve patient outcomes. The study aimed to analyze the factors associated with bone metastases in newly diagnosed patients with PCa. MATERIAL AND METHODS This was a retrospective study of 80 patients newly diagnosed with PCa by pathological examination between January 2012 and December 2014. Bone metastases were diagnosed by positron emission computed tomography. Clinical data, serological laboratory results, and pathological examination results were collected. RESULTS Among the 80 patients, 45 (56%) had bone metastases. Age, serum alkaline phosphatase, prostate-specific antigen (PSA), erythrocyte sedimentation rate, PCa tissue Gleason score, androgen receptor (AR) expression, and Ki-67 expression were higher in patients with bone metastasis compared with those without (all P<0.05). Multivariate logistic regression showed that PSA (OR: 1.005; 95%CI: 1.001-1.010; P=0.016), Gleason score (OR: 4.095; 95%CI: 1.592-10.529; P=0.003), and AR expression (OR: 14.023; 95%CI: 3.531-55.6981; P=0.005) were independently associated with bone metastases. Cut-off values for PSA, Gleason score, and AR expression were 67.1 ng/ml (sensitivity: 55.6%; specificity: 97.1%), 7.5 (sensitivity: 75.6%; specificity: 82.9%), and 2.5 (sensitivity: 84.0%; specificity: 91.4%), respectively. CONCLUSIONS PSA, Gleason score, and AR expression in PCa tissues were independently associated with PCa bone metastases. These results could help identifying patients with PCa at high risk of bone metastases.


Assuntos
Neoplasias Ósseas/secundário , Calicreínas/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Receptores Androgênicos/biossíntese , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/sangue , Estudos Retrospectivos
15.
Crit Rev Oncog ; 22(5-6): 371-388, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29604918

RESUMO

Cancer biomarker discovery is a critical part of cancer prevention and treatment. Despite the decades of effort, only a small number of cancer biomarkers have been identified for and validated in clinical settings. Conceptual and methodological breakthroughs may help accelerate the discovery of additional cancer biomarkers, particularly their use for diagnostics. In this review, we have attempted to review the emerging concepts in cancer biomarker discovery, including real-world evidence, open access data, and data paucity in rare or uncommon cancers. We have also summarized the recent methodological progress in cancer biomarker discovery, such as high-throughput sequencing, liquid biopsy, big data, artificial intelligence (AI), and deep learning and neural networks. Much attention has been given to the methodological details and comparison of the methodologies. Notably, these concepts and methodologies interact with each other and will likely lead to synergistic effects when carefully combined. Newer, more innovative concepts and methodologies are emerging as the current emerging ones became mainstream and widely applied to the field. Some future challenges are also discussed. This review contributes to the development of future theoretical frameworks and technologies in cancer biomarker discovery and will contribute to the discovery of more useful cancer biomarkers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias/genética , Biomarcadores Tumorais/isolamento & purificação , Humanos
16.
Acta Biomater ; 41: 210-23, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27262742

RESUMO

UNLABELLED: Acute myocardial infarction (MI) leads to morbidity and mortality due to cardiac dysfunction. Here we identify sericin, a silk-derived protein, as an injectable therapeutic biomaterial for the minimally invasive MI repair. For the first time, sericin prepared in the form of an injectable hydrogel has been utilized for cardiac tissue engineering and its therapeutical outcomes evaluated in a mouse MI model. The injection of this sericin hydrogel into MI area reduces scar formation and infarct size, increases wall thickness and neovascularization, and inhibits the MI-induced inflammatory responses and apoptosis, thereby leading to a significant functional improvement. The potential therapeutical mechanisms have been further analyzed in vitro. Our results indicate that sericin downregulates pro-inflammatory cytokines (TNF-α and IL-18) and chemokine (CCL2) and reduces TNF-α expression by suppressing the TLR4-MAPK/NF-κB pathways. Moreover, sericin exhibits angiogenic activity by promoting migration and tubular formation of human umbilical vessel endothelial cells (HUVECs). Also, sericin stimulates VEGFa expression via activating ERK phosphorylation. Further, sericin protects endothelial cells and cardiomyocytes from apoptosis by inhibiting the activation of caspase 3. Together, these diverse biochemical activities of sericin protein lead to a significant recovery of cardiac function. This work represents the first study reporting sericin as an effective therapeutic biomaterial for ischemic myocardial repair in vivo. STATEMENT OF SIGNIFICANCE: Intramyocardial biomaterial injection is thought to be a potential therapeutic approach to improve cardiac performance after ischemic myocardial infarction. In this study, we report the successful fabrication and in vivo application of an injectable sericin hydrogel for ischemic heart disease. We for the first time show that the injection of in situ forming crosslinked sericin hydrogel promotes heart functional recovery accompanied with reduced inflammatory responses, attenuated apoptosis and increased microvessel density in the infarcted hearts. Further, we reveal that the improvement in those aspects is ascribed to sericin protein's functional bioactivities that are comprehensively uncovered in this study. Thus, we identify sericin, a natural protein, as a biomaterial suitable for myocardial repair and demonstrate that the in vivo application of this injectable sericin hydrogel can be an effective strategy for treating MI.


Assuntos
Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Injeções , Infarto do Miocárdio/fisiopatologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Sericinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/farmacologia , Citocinas/metabolismo , Citoproteção/efeitos dos fármacos , Fibrose , Células Endoteliais da Veia Umbilical Humana/citologia , Inflamação/patologia , Iridoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Células NIH 3T3 , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Sericinas/isolamento & purificação , Transcrição Genética/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
J Surg Res ; 202(2): 352-62, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27229110

RESUMO

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is a type of uncontrolled inflammatory cascade in which neutrophils, an early infiltrating immune cell population, elicit significant tissue damage. However, the precise mechanism for neutrophil recruitment and infiltration remains to be fully characterized. METHODS: A hepatic partial I/R model was reproduced in wild-type, CCL2(-/-) and CCR2(-/-) mice. Tissue damage was evaluated by serum enzyme analysis, hematoxylin-eosin staining, and cytokine production measurement. Mobilization of neutrophils from the bone marrow and subsequent infiltration into the liver were measured by flow cytometry. C-C motif chemokine receptor 2 (CCR2) expression on neutrophils and C-C motif chemokine ligand 2 (CCL2) chemotaxis were measured using flow cytometry. The cellular source of CCL2 in the liver was determined by deleting specific cell groups and performing intracellular staining. RESULTS: Liver damage was ameliorated, and neutrophil recruitment and accumulation were decreased in both CCL2(-/-) and CCR2(-/-) mice compared with wild-type mice. Neutrophils displayed upregulated expression of CCR2 during I/R, and these cells were required for CCL2-induced chemotaxis. Depletion of Kupffer cells protected the liver from I/R injury. Furthermore, genetic ablation of CCL2 reduced liver injury, as demonstrated by decreases in the levels of alanine aminotransferase and aspartate aminotransferase and subsequent reductions in neutrophil recruitment and accumulation. CONCLUSIONS: Kupffer cells secrete CCL2 to promote CCR2-expressing neutrophil recruitment from the bone marrow and subsequent infiltration into the liver during I/R. These findings reveal a novel pro-inflammatory role of cell-mediated CCL2-CCR2 interactions during this sterile insult.


Assuntos
Quimiocina CCL2/metabolismo , Insuficiência Hepática/etiologia , Fígado/metabolismo , Receptores CCR2/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Insuficiência Hepática/metabolismo , Insuficiência Hepática/patologia , Macrófagos do Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Regulação para Cima
18.
J Mol Cell Biol ; 8(5): 400-410, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27001970

RESUMO

Deregulation of microRNAs (miRNAs) and c-Myc (Myc) contributes to hepatocellular carcinoma (HCC) progression, but how miRNAs and Myc regulate each other in hepatocarcinogenesis is still poorly understood. Using a functional screen, we identified miR-129-5p as a miRNA that inhibits HCC cell growth. miR-129-5p targets the mitochondrial matrix protein pyruvate dehydrogenase kinase 4 (PDK4), which leads to decreased phosphorylation of the E1α subunit of pyruvate dehyrogenase (PDH) complex, inhibition of glycolysis, retarded tumor growth, and impaired lung colonization. Enforced expression of PDK4 refractory to inhibition by miR-129-5p rescued all of these phenotypes. Targeting PDK4 by shRNA recapitulated the effects caused by miR-129-5p. miR-129-5p is transcriptionally repressed by a complex comprised of Myc, histone deacetylase 3 (HDAC3), and enhancer of zeste 2 polycomb repressive complex 2 (EZH2). Levels of miR-129-5p negatively correlated with clinical stages in human HCC. Restoring miR-129-5p expression suppressed the diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Thus, we concluded that miR-129-5p, which is a negative target of Myc, blocks glycolysis to retard hepatocarcinogenesis via targeting PDK4. The critical link between miR-129-5p and PDK4 in the progression of HCC suggests potential points of therapeutic intervention for this disease.

19.
Sci Rep ; 6: 20248, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26832817

RESUMO

Excessive inflammation resulting from activation of the innate immune system significantly contributes to ischemia/reperfusion injury (IRI). Inflammatory reactions in both IRI and infections share the same signaling pathways evoked by danger/pathogen associated molecular pattern molecules. The cytosolic retinoid-inducible gene I(RIG-I)-like RNA receptor (RLR) RNA sensing pathway mediates type I IFN production during viral infection and the sensing of viral RNA is regulated by adenosine deaminase acting on RNA 1 (ADAR1). Using a model of liver IRI, we provide evidence that ADAR1 also regulates cytosolic RNA-sensing pathways in the setting of ischemic stress. Suppression of ADAR1 significantly enhanced inflammation and liver damage following IRI, which was accompanied by significant increases in type I IFN through cytosolic RNA-sensing pathways. In addition, knocking ADAR1 down in hepatocytes exaggerates inflammatory signaling to dsRNA or endotoxin and results in over production of type I IFN, which could be abolished by the interruption of RIG-I. Therefore, we identified a novel ADAR1-dependent protective contribution through which hepatocytes guard against aberrant cytosolic RLR-RNA-sensing pathway mediated inflammatory reaction in response to acute liver IR. ADAR1 protects against over activation of viral RNA-sensing pathways in non-infectious tissue stress.


Assuntos
Adenosina Desaminase/genética , Fígado/metabolismo , RNA/genética , RNA/imunologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Adenosina Desaminase/metabolismo , Animais , Apoptose/genética , Citocinas/biossíntese , Citosol/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Hipóxia/genética , Hipóxia/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Necrose/genética , Necrose/metabolismo , Necrose/patologia , Proteínas de Ligação a RNA/metabolismo , Traumatismo por Reperfusão/patologia
20.
ACS Appl Mater Interfaces ; 8(10): 6411-22, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26900631

RESUMO

Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericin's photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems.


Assuntos
Dextranos , Doxorrubicina , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis , Melanoma/tratamento farmacológico , Sericinas , Animais , Linhagem Celular Tumoral , Dextranos/química , Dextranos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Sericinas/química , Sericinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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