Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Med ; 27(1): 142, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732131

RESUMO

BACKGROUND: Cardiotoxicity is a common complication following anthracycline chemotherapy and represents one of the serious adverse reactions affecting life, which severely limits the effective use of anthracyclines in cancer therapy. Although some genes have been investigated by individual studies, the comprehensive analysis of key genes and molecular regulatory network in anthracyclines-induced cardiotoxicity (AIC) is lacking but urgently needed. METHODS: The present study integrating several transcription profiling datasets aimed to identify key genes associated with AIC by weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) and also constructed miRNA-transcription factor-gene regulatory network. A total of three transcription profiling datasets involving 47 samples comprising 41 rat heart tissues and 6 human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) samples were enrolled. RESULTS: The WGCNA and DEA with E-MTAB-1168 identified 14 common genes affected by doxorubicin administrated by 4 weeks or 6 weeks. Functional and signal enrichment analyses revealed that these genes were mainly enriched in the regulation of heart contraction, muscle contraction, heart process, and oxytocin signaling pathway. Ten (Ryr2, Casq1, Fcgr2b, Postn, Tceal5, Ccn2, Tnfrsf12a, Mybpc2, Ankrd23, Scn3b) of the 14 genes were verified by another gene expression profile GSE154603. Importantly, three key genes (Ryr2, Tnfrsf12a, Scn3b) were further validated in a hiPSCMs-based in-vitro model. Additionally, the miRNA-transcription factor-gene regulatory revealed several top-ranked transcription factors including Tcf12, Ctcf, Spdef, Ebf1, Sp1, Rcor1 and miRNAs including miR-124-3p, miR-195-5p, miR-146a-5p, miR-17-5p, miR-15b-5p, miR-424-5p which may be involved in the regulation of genes associated with AIC. CONCLUSIONS: Collectively, the current study suggested the important role of the key genes, oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network in elucidating the molecular mechanism of AIC.

2.
DNA Cell Biol ; 40(10): 1251-1260, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34491823

RESUMO

Microsatellite instability (MSI) is emerging as a promising subtype related to immunotherapy in gastric cancer (GC). However, the underlying mechanism between MSI and microsatellite stability (MSS) remains unclear. In this study, we conducted a weighted gene co-expression network analysis and found that the expression of heterogeneous nuclear ribonucleoprotein L (HNRNPL) was significantly increased in MSI GC compared with MSS GC. This finding was further validated in public GC cohorts and commercialized human GC tissue microarray. The significant negative correlation with the expression of mismatch repair protein mutL homolog 1 (MLH1) may be one of the potential mechanisms for the upregulation of HNRNPL expression in MSI GC (R = -0.689, p = 8.59e-11). In addition, HNRNPL expression was markedly upregulated in GC tissues compared with adjacent normal tissues. High HNRNPL expression also predicted a poor prognosis in GC patients. Finally, gene set enrichment analysis revealed that high HNRNPL MSI GC samples were highly positive associated with the biological functions of inflammation and cell proliferation, such as interferon gamma response, MYC targets, E2F targets, and G2/M checkpoints. In conclusion, HNRNPL could be a new MSI-associated prognostic biomarker in GC and could be a new target for the MSI GC treatment.


Assuntos
Biomarcadores Tumorais/genética , Instabilidade Genômica , Repetições de Microssatélites , Ribonucleoproteínas/genética , Neoplasias Gástricas/genética , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Ribonucleoproteínas/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima
3.
Arch Gynecol Obstet ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34324029

RESUMO

BACKGROUND: Breast cancer is an aggressive tumor, which poses a heavy burden to human health. Circular RNAs have been involved in the pathogenesis of breast cancer. This study aims to investigate whether circ_0008673 mediates breast cancer malignant progression by microRNA-153-3p (miR-153-3p)/cofilin 2 (CFL2) pathway. METHODS: The RNA levels of circ_0008673, miR-153-3p and CFL2 were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of CFL2, E-cadherin and N-cadherin was determined by western blot analysis. Cell proliferation was demonstrated through cell counting kit-8 and cell colony-formation assays. Cell apoptosis was detected by flow cytometry analysis. Cell migratory and invasive capacities were determined by transwell assay. The associated relationship between miR-153-3p and circ_0008673 or CFL2 was predicted by online databases, and testified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo assay was employed to demonstrate the effects of circ_0008673 silencing on tumor formation in vivo. RESULTS: Circ_0008673 and CFL2 expressions were upregulated, while miR-153-3p expression was downregulated in breast cancer tissues and cells compared with adjacent normal breast tissues and cells, respectively. Circ_0008673 overexpression promoted cell proliferation, migration and invasion, and repressed cell apoptosis, while circ_0008673 silencing had opposite effects. Additionally, circ_0008673 served as a sponge of miR-153-3p. And circ_0008673 was proved to regulate breast cancer cell malignancy by sponging miR-153-3p. MiR-153-3p was found to modulate breast cancer cell carcinogenesis via targeting CFL2. Furthermore, circ_0008673 silencing repressed tumor growth in vivo. CONCLUSION: Circ_0008673 promoted breast cancer progression by upregulating CFL2 expression through sponging miR-153-3p. This study provides a theoretical basis for researching circRNA-directed treatment of breast cancer.

4.
Front Pharmacol ; 12: 638993, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935728

RESUMO

Anthraquinones are bioactive natural products, some of which are active components in medicinal medicines, especially Chinese medicines. These compounds exert actions including purgation, anti-inflammation, immunoregulation, antihyperlipidemia, and anticancer effects. This study aimed to review the pharmacokinetics (PKs) of anthraquinones, which are importantly associated with their pharmacological and toxicological effects. Anthraquinones are absorbed mainly in intestines. The absorption rates of free anthraquinones are faster than those of their conjugated glycosides because of the higher liposolubility. A fluctuation in blood concentration and two absorption peaks of anthraquinones may result from the hepato-intestinal circulation, reabsorption, and transformation. Anthraquinones are widely distributed throughout the body, mainly in blood-flow rich organs and tissues, such as blood, intestines, stomach, liver, lung, kidney, and fat. The metabolic pathways of anthraquinones are hydrolysis, glycuronidation, sulfation, methylation/demethylation, hydroxylation/dehydroxylation, oxidation/reduction (hydrogenation), acetylation and esterification by intestinal flora and liver metabolic enzymes, among which hydrolysis, glycuronidation and sulfation are dominant. Of note, anthraquinones can be transformed into each other. The main excretion routes for anthraquinones are the kidney, recta, and gallbladder. Conclusion: Some anthraquinones and their glycosides, such as aloe-emodin, chrysophanol, emodin, physcion, rhein and sennosides, have attracted the most PK research interest due to their more biological activities and/or detectability. Anthraquinones are mainly absorbed in the intestines and are mostly distributed in blood flow-rich tissues and organs. Transformation into another anthraquinone may increase the blood concentration of the latter, leading to an increased pharmacological and/or toxicological effect. Drug-drug interactions influencing PK may provide insights into drug compatibility theory to enhance or reduce pharmacological/toxicological effects in Chinese medicine formulae and deserve deep investigation.

5.
J Mater Sci Mater Med ; 32(1): 9, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471206

RESUMO

Electrospun fibrous scaffolds capable of providing dual growth factor delivery in a controlled manner have distinctive advantages for tissue engineering. In this study, we have investigated the formation, structure, and characteristics/properties of fibrous bicomponent scaffolds for the dual delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) for peripheral nerve tissue regeneration. GDNF and NGF were incorporated into core-shell structured poly(lactic-co-glycolic acid) (PLGA) and poly (D,L-lactic acid) (PDLLA) nanofibers, respectively, through emulsion electrospinning. Using dual-source dual-power electrospinning, bicomponent scaffolds composed of GDNF/PLGA fibers and NGF/PDLLA fibers with different fiber component ratios were produced. The structure, properties, and in vitro release behavior of mono- and bicomponent scaffolds were systematically investigated. Concurrent and sustained release of GDNF and NGF from bicomponent scaffolds was achieved and their release profiles could be tuned. In vitro biological investigations were conducted. Rat pheochromocytoma cells were found to attach, spread, and proliferate on all scaffolds. The release of growth factors from scaffolds could induce much improved neurite outgrowth and neural differentiation. GDNF and NGF released from GDNF/PLGA scaffolds and NGF/PDLLA scaffolds, respectively, could induce dose-dependent neural differentiation separately. GDNF and NGF released from bicomponent scaffolds exerted a synergistic effect on promoting neural differentiation.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Nanopartículas/química , Fator de Crescimento Neural/metabolismo , Tecidos Suporte/química , Animais , Diferenciação Celular , Proliferação de Células , Sistemas de Liberação de Medicamentos , Técnicas In Vitro , Microscopia de Fluorescência , Regeneração Nervosa , Células PC12 , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos , Engenharia Tecidual/métodos
6.
Mol Biotechnol ; 63(1): 63-79, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33141343

RESUMO

Polymeric vectors are safer alternatives for gene delivery owing to their advantages as compared to viral vectors. To improve the stability and transfection efficiency of poly(lactic-co-glycolic acid) (PLGA)- and poly(ethylenimine) (PEI)-based vectors, poly(ethylene glycol) (PEG), folic acid (FA), arginylglycylaspartic acid (RGD) peptides and isoleucine-lysine-valine-alanine-valine (IKVAV) peptides were employed and PLGA-PEI-PEG-FA and PLGA-PEI-PEG-RGD copolymers were synthesized. PLGA-PEI-PEG-FA/DNA, PLGA-PEI-PEG-RGD/DNA and PLGA-PEI-PEG-RGD/IKVAV/DNA nanocomplexes (NCs) were formed through bulk mixing. The structure and properties, including morphology, particle size, surface charge and DNA encapsulation, of NCs were studied. Robust NCs with spherical shape, uniform size distribution and slightly positive charge were able to completely bind DNA above their respective N/P ratios. The critical N/P ratio for PLGA-PEI-PEG-FA/DNA, PLGA-PEI-PEG-RGD/DNA and PLGA-PEI-PEG-RGD/IKVAV/DNA NCs was identified to be 12:1, 8:1 and 10:1, respectively. The covalent modification of PEI through a combination of biodegradable PLGA, hydrophilic PEG and targeting motifs significantly decreased the cytotoxicity of PEI. The developed NCs showed both N/P ratio and cell type-dependent transfection efficiency. An increase in N/P ratio resulted in increased transfection efficiency, and much improved transfection efficiency of NCs was observed above their respective critical N/P ratios. This study provides a promising means to produce polymeric vectors for gene delivery.


Assuntos
DNA/química , Ácido Fólico/química , Técnicas de Transferência de Genes , Nanocompostos/química , Peptídeos/química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Transfecção/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Materiais Biocompatíveis/química , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Laminina/química , Microscopia Eletrônica de Varredura , Nanocompostos/toxicidade , Nanocompostos/ultraestrutura , Tamanho da Partícula , Fragmentos de Peptídeos/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Polietilenoimina/síntese química , Polietilenoimina/química , Polietilenoimina/toxicidade , Polímeros/síntese química , Polímeros/química , Polímeros/toxicidade , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Dose Response ; 18(2): 1559325820917824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32284703

RESUMO

Objective: The prognostic value of C-reactive protein to albumin ratio (CAR) has been identified in several cancers but not in extranodal natural killer T-cell lymphoma (ENKTL) as yet. We aimed to evaluate the prognostic value of CAR in ENKTL. Methods: A retrospective study with 246 patients with ENKTL was performed to determine the prognostic value of pretreatment CAR and examine the prognostic performance of CAR incorporating with International Prognostic Index (IPI) or natural killer/T-cell lymphoma prognostic index (NKPI) by nomogram. Results: The Cox regression analyses showed that high CAR (>0.3) independently predicted unfavorable progression-free survival (PFS, P = .011) and overall survival (OS, P = .012). In the stratification analysis, the CAR was able to separate patients into different prognoses regarding both OS and PFS in Ann Arbor stage I+II as well as III+IV, IPI score 0 to 1, and NKPI score 1 to 2 subgroups (all P < .05). Additionally, the predictive accuracy of the IPI-based nomogram incorporating CAR, albumin to globulin ratio (AGR), and IPI for OS and PFS appeared to be lower than the NKPI-based nomogram incorporating CAR, age, AGR, extranodal site, and NKPI. Conclusion: Pretreatment CAR is a simple and easily accessible parameter for independently predicting OS and PFS in patients with ENKTL.

8.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32152220

RESUMO

BACKGROUND: Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs). METHODS: Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin ß3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles. RESULTS: IFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs. CONCLUSIONS: In melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.


Assuntos
Proteína DEAD-box 58/metabolismo , Integrina beta3/metabolismo , Interferon-alfa/farmacologia , Melanoma Experimental/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína DEAD-box 58/antagonistas & inibidores , Proteína DEAD-box 58/genética , Regulação para Baixo , Feminino , Células Hep G2 , Humanos , Fatores Imunológicos/farmacologia , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Taxa de Sobrevida
9.
Exp Gerontol ; 130: 110814, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31857133

RESUMO

OBJECTIVE: Many microRNAs (miRNAs) have been reported to be aberrantly expressed in Alzheimer's disease (AD) patients. The present study aimed to explore the diagnostic value and neuroprotective role of miR-193a-3p in AD. METHODS: 108 sporadic AD patients and 93 healthy controls were included. An Aß25-35 insult cellular AD model of PC12 and SH-SY5Y was established. The relative expression levels of miR-193a-3p were calculated using qRT-PCR. Receiver operating characteristic (ROC) curve was applied to evaluate the usefulness of miR-193a-3p for detecting AD. Cell viability and apoptotic rates were calculated. Luciferase reporter assay was performed to confirm the interaction between miR-193a-3p and PTEN. RESULTS: miR-193a-3p expression was downregulated in both AD patients and the cellular AD model (all P < 0.001). Remarkable positive association was detected between serum miR-193a-3p level and MMSE score in AD patients (r = 0.5889, P < 0.0001). The diagnostic sensitivity and specificity were 89.8% and 77.4%, respectively, and the area under the curve (AUC) was 0.914. Overexpression of miR-193a-3p weakened Aß25-35 induced cell viability inhibition, and reduced Aß25-35 induced cell apoptosis in PC12 cells (all P < 0.01). Downregulation of miR-193a-3p intensified the effect of Aß25-35 PTEN was proved to be the target gene of miR-193a-3p. CONCLUSION: MiR-193a-3p could be a novel biomarker for AD diagnosis, and may protect against neurotoxicity in AD by targeting PTEN.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , MicroRNAs/sangue , PTEN Fosfo-Hidrolase/metabolismo , Fragmentos de Peptídeos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Animais , Apoptose , Biomarcadores/sangue , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Células PC12 , Ratos
10.
Front Pharmacol ; 10: 927, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616288

RESUMO

Thoracic radiotherapy is a mainstay of the treatment for lung, esophageal, and breast cancers. Radiation-induced pulmonary injury (RIPI) is a common side effect of thoracic radiotherapy, which may limit the radiotherapy dose and compromise the treatment results. However, the current strategies for RIPI are not satisfactory and may induce other side effects. Chinese medicines (CMs) have been used for more than a thousand years to treat a wide range of diseases, including lung disorders. In this review, we screened the literature from 2007 to 2017 in different online databases, including China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wanfang, and PubMed; summarized the effectiveness of CMs in preventing and treating RIPI; explored the most frequently used drugs; and aimed to provide insights into potential CMs for RIPI. Altogether, CMs attenuated the risk of RIPI with an occurrence rate of 11.37% vs. 27.78% (P < 0.001) compared with the control groups. We also found that CMs (alone and combined with Western medical treatment) for treating RIPI exerted a higher efficacy rate than that of the control groups (78.33% vs. 28.09%, P < 0.001). In the screened literature, 38 CMs were used for the prevention and treatment of RIPI. The top five most frequently used CMs were Astragali Radix (with a frequency of 8.47%), Ophiopogonis Radix (with a frequency of 6.78%), Glycyrrhizae Radix et Rhizome (with a frequency of 5.08%), Paeoniae Radix Rubra (with a frequency of 5.08%), and Prunellae Spica (with a frequency of 5.08%). However, further high-quality investigations in CM source, pharmacological effects and underlying mechanisms, toxicological aspects, and ethical issues are warranted. Taken together, CMs might have a potential role in RIPI prevention and treatment and still have a long way to investigate.

11.
Front Pharmacol ; 10: 709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297058

RESUMO

Reynoutria multiflora (Thunb.) Moldenke (He Shou Wu) has been used for about 20 centuries as a Chinese medicinal herb for its activities of anticancer, anti-hyperlipidemia, and anti-aging. Previously, we found that He Shou Wu ethanol extract could induce apoptosis in hepatocellular carcinoma cells, and we also screened its active components. In this study, we investigated whether lowering lipid metabolism of emodin, a main active component in He Shou Wu, was associated with inhibitory effects in hepatocellular carcinoma cells. The correlation of apoptosis induction and lipid metabolism was investigated. The intrinsic apoptotic cell death, lipid production, and their signaling pathways were investigated in emodin-treated human hepatocellular carcinoma cells Bel-7402. The data showed that emodin triggered apoptosis in Bel-7402 cells. The mitochondrial membrane potential (ΔΨm) was reduced in emodin-treated Bel-7402 cells. We also found that emodin activated the expression of intrinsic apoptosis signaling pathway-related proteins, cleaved-caspase 9 and 3, Apaf 1, cytochrome c (CYTC), apoptosis-inducing factor, endonuclease G, Bax, and Bcl-2. Furthermore, the level of triglycerides and desaturation of fatty acids was reduced in Bel-7402 cells when exposed to emodin. Furthermore, the expression level of messenger RNA (mRNA) and protein of sterol regulatory element binding protein 1 (SREBP1) as well as its downstream signaling pathway and the synthesis and the desaturation of fatty acid metabolism-associated proteins (adenosine triphosphate citrate lyase, acetyl-CoA carboxylase alpha, fatty acid synthase (FASN), and stearoyl-CoA desaturase D) were also decreased. Notably, knock-out of SREBP1 in Bel-7402 cells was also found to induce less intrinsic apoptosis than did emodin. In conclusion, these results indicated that emodin could induce apoptosis in an SREBP1-dependent and SREBP1-independent manner in hepatocellular carcinoma cells.

12.
J Med Genet ; 56(10): 647-653, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30981987

RESUMO

BACKGROUND: Early detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumour (ct) DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery. METHODS: The multicentre clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white cell count genomic DNA (gDNA) and tumour tissue gDNA of each patient were analysed by ultra-deep sequencing to an average of 35 000× of the coding regions of 65 lung cancer-related genes. RESULTS: The cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients are at stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for stages I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harboured mutations in the patients with lung cancer with the largest number found in TP53 (30% plasma and 62% tumour tissue samples) and EGFR (20% and 40%, respectively). CONCLUSION: Plasma ctDNA was analysed in lung nodule assessment and early cancer detection, while an algorithm combining clinical information enhanced the test performance. TRIAL REGISTRATION NUMBER: NCT03081741.


Assuntos
DNA Tumoral Circulante/análise , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Adulto , Idoso , Ácidos Nucleicos Livres , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Estudos Prospectivos , Sensibilidade e Especificidade , Análise de Sequência de DNA
14.
Redox Biol ; 20: 451-457, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30439686

RESUMO

Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease.


Assuntos
Neoplasias do Colo/metabolismo , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piruvatos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Transporte Biológico , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Mitocôndrias/genética , Modelos Biológicos , Oxirredução , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo
15.
J Exp Clin Cancer Res ; 37(1): 259, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373678

RESUMO

BACKGROUND: Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS: The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS: HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS: HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Hidroxicloroquina/farmacologia , Neoplasias Pulmonares/patologia , Lisossomos/química , Lisossomos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cell Physiol Biochem ; 49(3): 837-847, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30184547

RESUMO

BACKGROUND/AIMS: Previous studies on the effect of metformin therapy on survival of pancreatic cancer patients obtained inconsistent findings. To reevaluate the prognostic value of metformin adjuvant treatment, a meta-analysis was carried out. METHODS: Relevant articles addressing the association between metformin use and pancreatic cancer survival were electronically searched to identify eligible studies. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. RESULTS: Totally, seventeen studies involving 36791 participants were included. Overall, metformin use was found to be significantly associated with a favorable OS (HR=0.88, 95% CI=0.80-0.97). Subgroup analyses by ethnicity showed a significantly reduced risk of death for metformin users compared with non-users in Asians (HR=0.74, 95% CI=0.58-0.94) but nonsignificant in Caucasians. When stratified by clinical stage, a remarkable reduction of mortality risk in patients at stage I-II treated with metformin (HR=0.76, 95% CI=0.68-0.86) was found as well as the group at stage I-IV (HR=0.88, 95% CI=0.79-0.99), but not in patients at stage III-IV. In the stratification analyses based on treatment strategy, metformin therapy was found to be associated with a better clinical outcome in patients receiving surgery or comprehensive therapy (HR=0.73, 95% CI=0.62-0.87; HR=0.88, 95% CI=0.79-0.97) but not chemotherapy. However, the overall analysis failed to show a significant association between metformin use and DFS (HR=1.54, 95% CI=0.94 -2.50) with only 2 studies enrolled. CONCLUSION: The current study has evidenced a significant association of metformin adjuvant treatment with the survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment. Further investigation is needed.


Assuntos
Metformina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Quimioterapia Adjuvante , Bases de Dados Factuais , Intervalo Livre de Doença , Humanos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida
17.
Food Chem Toxicol ; 119: 169-175, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29702135

RESUMO

Hepatocellular carcinoma (HCC) is the major incidence and one of the most life-threatening cancer. How to conquer HCC is a worldwide issue for patients. Zhiheshouwu (Polygoni multiflori Radix Praeparata) is a Chinese medicinal herb exhibiting both lowering lipid and inhibiting cancer cells. However, it remains a matter if its inhibiting cancer cells is related to its lowering lipid. In this study, we investigate the effects of Zhiheshouwu ethanolic extract (HSWE) on apoptosis and the underlying mechanisms in Bel-7402 cells. The results showed that HSWE inhibited the proliferation with an increased level of ALT and AST in Bel-7402 cells. The decreased mitochondrial membrane potential (ΔΨm) was observed in HSWE-treated Bel-7402 cells. The flow cytometry results showed that HSWE triggered apoptosis. Since mitochondrial injury is characterized as intrinsic apoptotic cell death, these data indicated that HSWE may induce intrinsic apoptosis in Bel-7402 cells. In addition, HSWE decreased the production of unsaturated fatty acids, and inhibited the mRNA and protein of SCD1 and its up-stream factor, sterol-regulatory element binding proteins 1 (SREBP1), a master transcriptional regulator of lipogenic gene. Taken together, these data suggest that HSWE induces an intrinsic apoptosis, and reduced unsaturated fatty acids by blocking SREBP1 in hepatocellular carcinoma cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/química , Ácidos Graxos Insaturados/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Linhagem Celular Tumoral , Etanol , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas , Extratos Vegetais , Transdução de Sinais
18.
Oncotarget ; 8(43): 74527-74538, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-29088805

RESUMO

Maslinic acid (2α, 3ß-dihydroxyolean-12-en-28-oic acid, MA) was isolated from natural plants and showed anti-cancer activity in rat Pheochromocytoma PC12 cells in our previous studies. We now discover that MA disrupts the interaction between Bcl2 and autophagy scaffold protein Beclin1 in the above cell line, leading to the up-regulation of autophagy. We investigated the effect of MA on the interaction between Bcl2 and Beclin1 by biochemical and biophysical methods in combination with autophagy characterization in the above cell line. Our results suggest that MA may serve as an autophagy activator by directly blocking the Bcl2-Beclin1 interaction to release free Beclin1 required for the recruitment of autophagy positive regulators, implying MA may exert its anti-cancer activity by regulating autophagy.

19.
Biochem Biophys Res Commun ; 491(1): 104-111, 2017 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709865

RESUMO

PURPOSE: The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. RESULTS: Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage(p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade(p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. CONCLUSION: Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Fucosiltransferases/metabolismo , Receptor Notch1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Regulação para Cima
20.
Tumour Biol ; 39(6): 1010428317700410, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28635398

RESUMO

Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha-fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan-Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor-node-metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor-node-metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Glutationa Peroxidase/genética , Neoplasias Hepáticas/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/biossíntese , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , alfa-Fetoproteínas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...