RESUMO
This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Receptor com Domínio Discoidina 1 , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Animais , Estrutura Molecular , Camundongos , Descoberta de Drogas , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVE: Most cases of hepatocellular carcinoma (HCC) arise as a consequence of cirrhosis. In this study, our objective is to construct a comprehensive diagnostic model that investigates the diagnostic markers distinguishing between cirrhosis and HCC. METHODS: Based on multiple GEO datasets containing cirrhosis and HCC samples, we used lasso regression, random forest (RF)-recursive feature elimination (RFE) and receiver operator characteristic analysis to screen for characteristic genes. Subsequently, we integrated these genes into a multivariable logistic regression model and validated the linear prediction scores in both training and validation cohorts. The ssGSEA algorithm was used to estimate the fraction of infiltrating immune cells in the samples. Finally, molecular typing for patients with cirrhosis was performed using the CCP algorithm. RESULTS: The study identified 137 differentially expressed genes (DEGs) and selected five significant genes (CXCL14, CAP2, FCN2, CCBE1 and UBE2C) to construct a diagnostic model. In both the training and validation cohorts, the model exhibited an area under the curve (AUC) greater than 0.9 and a kappa value of approximately 0.9. Additionally, the calibration curve demonstrated excellent concordance between observed and predicted incidence rates. Comparatively, HCC displayed overall downregulation of infiltrating immune cells compared to cirrhosis. Notably, CCBE1 showed strong correlations with the tumour immune microenvironment as well as genes associated with cell death and cellular ageing processes. Furthermore, cirrhosis subtypes with high linear predictive scores were enriched in multiple cancer-related pathways. CONCLUSION: In conclusion, we successfully identified diagnostic markers distinguishing between cirrhosis and hepatocellular carcinoma and developed a novel diagnostic model for discriminating the two conditions. CCBE1 might exert a pivotal role in regulating the tumour microenvironment, cell death and senescence.
Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Cirrose Hepática , Neoplasias Hepáticas , Aprendizado de Máquina , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Radiation-induced lung injury (RILI), divided into early radiation pneumonia (RP) and late radiation-induced pulmonary fibrosis (RIPF), is a common serious disease after clinical chest radiotherapy or nuclear accident, which seriously threatens the life safety of patients. There has been no effective prevention or treatment strategy till now. Epithelial-mesenchymal transition (EMT) is a key step in the occurrence and development of RILI. In this study, we demonstrated that emetine dihydrochloride (EDD) alleviated RILI through inhibiting EMT. We found that EDD significantly attenuated EMT-related markers, reduced Smad3 phosphorylation expression after radiation. Then, for the first time, we observed EDD alleviated lung hyperaemia and reduced collagen deposit induced by irradiation, providing protection against RILI. Finally, it was found that EDD inhibited radiation-induced EMT in lung tissues. Our study suggested that EDD alleviated RILI through inhibiting EMT by blocking Smad3 signalling pathways. In summary, our results indicated that EDD is a novel potential radioprotector for RILI.
Assuntos
Lesão Pulmonar , Fibrose Pulmonar , Lesões por Radiação , Humanos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Emetina/farmacologia , Pulmão/patologia , Lesões por Radiação/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Transição Epitelial-MesenquimalRESUMO
Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 µg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-ß-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.
Assuntos
Asma , Animais , Camundongos , Ovalbumina , Simulação de Acoplamento Molecular , Pulmão , Líquido da Lavagem Broncoalveolar , Cloreto de Metacolina/farmacologia , Inflamação/tratamento farmacológico , Imunoglobulina E , Purinas/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Citocinas/metabolismoRESUMO
Despite the wide application of radiotherapy in HCC, radiotherapy efficacy is sometimes limited due to radioresistance. Although radioresistance is reported with high glycolysis, the underlying mechanism between radioresistance and cancer metabolism, as well as the role of cathepsin H (CTSH) within it, remain unclear. In this study, tumor-bearing models and HCC cell lines were used to observe the effect of CTSH on radioresistance. Proteome mass spectrometry, followed by enrichment analysis, were used to investigate the cascades and targets regulated by CTSH. Technologies such as immunofluorescence co-localization flow cytometry and Western blot were used for further detection and verification. Through these methods, we originally found CTSH knockdown (KD) perturbed aerobic glycolysis and enhanced aerobic respiration, and thus promoted apoptosis through up-regulation and the release of proapoptotic factors such as AIFM1, HTRA2, and DIABLO, consequently reducing radioresistance. We also found that CTSH, together with its regulatory targets (such as PFKL, HK2, LDH, and AIFM1), was correlated with tumorigenesis and poor prognosis. In summary, our study found that the cancer metabolic switch and apoptosis were regulated by CTSH signaling, leading to the occurrence of radioresistance in HCC cells and suggesting the potential value of HCC diagnosis and therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/metabolismo , Catepsina H/metabolismo , Transdução de Sinais , Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Glicólise , Proliferação de Células , Linhagem Celular TumoralRESUMO
In this study, we aimed to elucidate the roles of Adipor1 in radiation-induced cell death of Hepatocellular carcinoma (HCC). The human HCC cell line MHCC97-H and HepG2 were used to investigate the underlying mechanisms. Western blotting was used to detect protein expression, and flow cytometry was used to detect cell cycle and cell death. Orthotopic allograft HCC models were established in Rats. LV-Adipor1-RNAi virus were injected into the tumor before radiation. Such parameters as tumor diameter, blood indicators, and liver function index were detected.In vitro results indicated that Adipor1 knockdown enhanced radiation-induced cell death and DNA damage, and inhibited cell cycle arrest at the G2/M and autophagy, leading to increased apoptosis. In vivo experiments showed that Adipor1 knockdown increased radiosensitivity and significantly inhibited liver tumor growth, upregulated the number of red blood cell, platelet count and Hemoglobin content, decreased the content of ALT, AST and ALP. To sum up, Adipor1 blockade enhance therapeutic effects of radiation by inhibiting cell cycle arrest and autophagy, and promoting DNA damage and apoptosis in Hepatoma Carcinoma Cells.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Tolerância a Radiação , RatosRESUMO
Ferroptosis is the name given to the type of non-apoptotic cell death that is caused by iron accumulation and subsequent lipid peroxidation. However, how ionizing radiation (IR)-induced ferroptosis is regulated in estrogen receptor-positive (ER+) breast cancer cells remains unclear. To attempt to resolve this issue, bioinformatics analysis was performed to evaluate the prognostic value of estrogen receptor 1 (ESR1) in breast cancer tissues. A total of four breast cancer cell lines and an MCF10A non-malignant counterpart were used. Western blotting was used to analyze the levels of protein expression, whereas immunoprecipitation (IP) and ubiquitination experiments were used to test protein binding and ubiquitination levels, respectively. Flow cytometry was subsequently used to analyze cell death and lipid peroxidation levels. The results showed that a high expression level of ESR1 was significantly correlated with poor overall survival in breast cancer. ESR1 knockdown significantly enhanced IR-induced ferroptosis and increased the CD71 protein level. The IP results showed that ESR1 enhanced the binding of the E3 ubiquitin ligase NEDD4L to CD71, promoting the ubiquitination and degradation of CD71, suggesting that CD71 expression was regulated by both ESR1 and NEDD4L. Taken together, the findings in the present study have demonstrated a regulatory relationship between ESR1 and NEDD4L/CD71 in IR-induced ferroptosis. In addition, the ESR1/NEDD4L/CD71 axis may be a potential target for the radiotherapy of breast cancer.
Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio/metabolismo , Ferroptose , Antígenos CD/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Radiação Ionizante , Receptores da Transferrina/metabolismoRESUMO
Overexpressed tubulin and continuously activated STAT3 play important roles in the development of many cancers and are potential therapeutic targets. A series of 4-methoxy-N -(1-naphthalene) benzenesulfonamide derivatives were designed and optimized based on ß-tubulin inhibitor ABT-751 to verify whether STAT3 and tubulin dual target inhibitors have better antitumor effects. Compound DL14 showed strong inhibitory activity against A549, MDA-MB-231 and HCT-116 cells in vitro with IC50 values of 1.35 µM, 2.85 µM and 3.04 µM, respectively. Further experiments showed that DL14 not only competitively bound to colchicine binding site to inhibit tubulin polymerization with IC50 values 0.83 µM, but also directly bound to STAT3 protein to inhibit STAT3 phosphorylation with IC50 value of 6.84 µM. Three other compounds (TG03, DL15, and DL16) also inhibit this phosphorylation. In terms of single target inhibition, DL14 is slightly inferior to positive drugs, but it shows a good anti-tumor effect in vivo, and can inhibit >80% of xenograft tumor growth. This study describes a novel 4-methoxy-N-(1-naphthyl) benzenesulfonamide skeleton as an effective double-targeted anticancer agent targeting STAT3 and tubulin.
Assuntos
Antineoplásicos , Tubulina (Proteína) , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , BenzenossulfonamidasRESUMO
Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator which has been proven to be a potential target for cancer therapy. We observed that PRMT5 underwent alternative splicing (AS) and generated a spliced isoform PRMT5-ISO5 in hepatocellular carcinoma (HCC) patients after radiotherapy. However, the regulatory mechanism and the clinical implications of IR-induced PRMT5 AS are unclear. This work revealed that serine and arginine rich splicing factor 3 (SRSF3) silencing increased PRMT5-ISO5 level, whereas heterogeneous nuclear ribonucleoprotein H 1 (HNRNPH1) silencing reduced it. Then, we found that SRSF3 and HNRNPH1 competitively combined with PRMT5 pre-mRNA located at the region around the 3'- splicing site on intron 2 and the alternative 3'- splicing site on exon 4. IR-induced SRSF3 downregulation led to an elevated level of PRMT5-ISO5, and exogenous expression of PRMT5-ISO5 enhanced cell radiosensitivity. Finally, we confirmed in vivo that IR induced the increased level of PRMT5-ISO5 which in turn enhanced tumor killing and regression, and liver-specific Prmt5 depletion reduced hepatic steatosis and delayed tumor progression of spontaneous HCC. In conclusion, our data uncover the competitive antagonistic interaction of SRSF3 and HNRNPH1 in regulating PRMT5 splicing induced by IR, providing potentially effective radiotherapy by modulating PRMT5 splicing against HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Processamento Alternativo/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/radioterapia , Linhagem Celular Tumoral , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Precursores de RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismoRESUMO
PURPOSE: Since protein arginine methyltransferase 5 (PRMT5) is abnormally expressed in various tumors, in this study we aim to assess the association between PRMT5 and clinicopathological and prognostic features. METHODS: Electronic databases including PubMed, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were searched until July 25, 2021. The critical appraisal of the eligible studies was performed using the Newcastle-Ottawa Quality Assessment Scale. Pooled hazard ratios (HR) and pooled odds ratios (OR) were calculated to assess the effect. Engauge Digitizer version 12.1, STATA version 15.1, and R version 4.0.5 were used to obtain and analysis the data. RESULTS: A total of 32 original studies covering 15,583 patients were included. In our data, it indicated that high level of PRMT5 was significantly correlated with advanced tumor stage (OR = 2.12, 95% CI: 1.22-3.70, P =.008; I2 = 80.7%) and positively correlated with poor overall survival (HR = 1.59, 95% CI: 1.46-1.73, P < .001; I2 = 50%) and progression-free survival (HR = 1.53, 95% CI: 1.24-1.88, P < .001; I2 = 0%). In addition, sub-group analysis showed that high level of PRMT5 was associated with poor overall survival for such 5 kinds of cancers as hepatocellular carcinoma, pancreatic cancer, breast cancer, gastric cancer, and lung cancer. CONCLUSION: For the first time we found PRMT5 was pan-cancerous as a prognostic biomarker and high level of PRMT5 was associated with poor prognosis for certain cancers.
Assuntos
Neoplasias/patologia , Proteína-Arginina N-Metiltransferases/biossíntese , Humanos , Estadiamento de Neoplasias , Neoplasias/mortalidade , Análise de SobrevidaRESUMO
Pancreatic ductal adenocarcinoma (PDA) is an aggressive type of malignant tumor with a poor prognosis and high mortality. Aberrant activation of hedgehog signaling plays a crucial role in the maintenance and progression of PDA. Here, we report that the dietary bioflavonoid quercetin has therapeutic potential for PDA by targeting sonic hedgehog (SHH) signaling. The effects of quercetin on the proliferation, apoptosis, migration, and invasion of pancreatic cancer cells (PCCs) and tumor growth and metastasis in PDA xenograft mouse models were evaluated. Additionally, SHH signaling activity was determined. Quercetin significantly inhibited PCC proliferation by downregulating c-Myc expression. In addition, quercetin suppressed epithelial-mesenchymal transition (EMT) by reducing TGF-ß1 level, which resulted in inhibition of PCC migration and invasion. Moreover, quercetin induced PCC apoptosis through mitochondrial and death receptor pathways. In nude mouse models, PDA growth and metastasis were reduced by quercetin treatment. Mechanically, quercetin exerts its therapeutic effects on PDA by decreasing SHH activity. Interestingly, quercetin-induced SHH inactivation is mainly dependent on Gli2, but not Gli1. Enhance SHH activity by recombinant Shh protein abolished the quercetin-mediated inhibition of PCC proliferation, migration, and invasion. Furthermore, Shh activated TGF-ß1/Smad2/3 signaling and promoted EMT by inducing the expression of Zeb2 and Snail1 that eventually resulted in a partial reversal of quercetin-mediated inhibition of PCC migration and invasion. We conclude that quercetin inhibited the growth, migration, and invasion and induced apoptosis of PCCs by antagonizing SHH and TGF-ß/Smad signaling pathways. Thus, quercetin may be a potential candidate for PDA treatment.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteínas Hedgehog/genética , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Proteínas Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad3/genética , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
Cystine/glutamic acid reverse transporter (System Xc - ), a member of the amino acid transporter family, consists of two subunits, light chain xCT and heavy chain 4F2hc. xCT is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11), which promotes cystine uptake and glutathione biosynthetic, thus protecting against oxidative stress and ferroptosis. Studies have confirmed that xCT is highly expressed in a variety of tumour and is associated with tumour proliferation, invasion, metastasis, drug resistance and ferroptosis, and can be used as a potential target for tumour treatment. This review provides insights into the biological effects of xCT and contribute to the development of new xCT-based strategies.
Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Neoplasias/patologia , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/genética , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sulfassalazina/metabolismo , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêuticoRESUMO
BACKGROUND: The no-reflow phenomenon (NRP) is a serious complication of primary percutaneous coronary intervention (PPCI) and is an independent predictor of poor prognosis. We aimed to find a simple but effective risk stratification method for the prediction of NRP. METHODS: This retrospective single-center study included 454 consecutive patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI) and treated by PPCI, who were admitted to our emergency department between January 2017 and March 2019. The patients were divided according to the post-PPCI thrombolysis in the myocardial infarction flow rate: the NRP group and the control group. The CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HSF scores were calculated for all the patients in this study, and multivariable regression and receiver operating characteristic curve analyses were conducted to determine the independent predictors of NRP and the predictive value of the three scores. RESULTS: A total of 454 patients were analyzed in this study: 80 in the no-reflow group and 374 in the control group. The incidence of NRP was 17.6%. Creatine kinase-myocardial band, Killip class, stent length, and multivessel disease also independently predicted NRP. The CHA2DS2-VASc-HSF score had a higher predictive value than the other two scores, and a CHA2DS2-VASc-HSF score of ≥4 predicted NRP with a sensitivity of 72.5% and specificity of 66.5% (area under the curve: 0.755, 95% confidence interval [0.702-0.808]). CONCLUSION: Although the CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HSF scores can all be used as simple tools to predict NRP, our findings show that the CHA2DS2-VASc-HSF score had the highest predictive value. Thus, the CHA2DS2-VASc-HSF score may be an optimal tool for predicting high-risk patients.
Assuntos
Regras de Decisão Clínica , Fenômeno de não Refluxo/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Tomada de Decisão Clínica , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Fenômeno de não Refluxo/diagnóstico , Fenômeno de não Refluxo/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Resultado do TratamentoRESUMO
Based on central dogma of genetics, protein is the embodiment and executor of genetic function, post-translational modifications (PTMs) of protein are particularly important and involved in almost all aspects of cell biology and pathogenesis. Studies have shown that ionizing radiation (IR) alters gene expression much more profoundly and a broad variety of cell-process pathways, lots of proteins are modified and activated. Our understanding of the protein in response to ionizing radiation is steadily increasing. Among the various biological processes known to induce radioresistance, PTMs have attracted marked attention in recent years. The present review summarizes the latest knowledge about how PTMs response to ionizing radiation and pathway analysis were conducted. The data provided insights into biological effects of IR and contributing to the development of novel IR-based strategies.
Assuntos
Processamento de Proteína Pós-Traducional/efeitos da radiação , Proteínas/efeitos da radiação , Radiação Ionizante , Motivos de Aminoácidos , Dano ao DNA/efeitos da radiação , Genoma Humano/efeitos da radiação , Glicosilação/efeitos da radiação , Humanos , Metilação/efeitos da radiação , Neoplasias/radioterapia , Fosforilação/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Ubiquitinação/efeitos da radiaçãoRESUMO
OBJECTIVE: To evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), and platelet distribution width (PDW) for the no-reflow phenomenon in patients with ST-segment elevation myocardial infarction. Methods: Patients who underwent primary percutaneous coronary intervention from January 2017 to April 2019 were consecutively enrolled in this study and were split into the control and no-reflow groups. Logistic regression analysis was used to determine the independent predictors. Receiver operating characteristic curves were carried out to evaluate the predictive value. Results: A total of 455 patients were included and the incidence of the no-reflow was 19.6%. After the adjustment of confounding factors, logistic regression analyses showed that the NLR (odds ratio [OR] per unit increase: 1.107, 95% confidence interval [CI]: 1.044-1.172, p = .001), MPV (OR: 1.398, 95% CI: 1.010-1.937, p = .044), and PDW (OR: 1.392, 95% CI: 1.012-1.914, p = .042) were all independent predictors. In the prediction of the no-reflow, the NLR had the largest area under the curve of 0.650 (95% CI: 0.593-0.708) with 90% sensitivity and 36% specificity. The area under the curve of the combination of NLR + MPV was 0.676 and that of NLR + PDW was 0.654. Conclusions: The NLR, MPV and PDW are all associated with the no-reflow. However, there is no significant difference in the predictive value of these indicators. The combinations of NLR and platelet-associated parameters also do not show a better predictive value than NLR alone.
Assuntos
Plaquetas , Linfócitos , Neutrófilos , Fenômeno de não Refluxo/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenômeno de não Refluxo/diagnóstico , Contagem de Plaquetas , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Resultado do TratamentoRESUMO
Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti-tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic.
Assuntos
Benzamidas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Sorafenibe/farmacologia , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Quimioterapia Combinada , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Fosforilação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mitochondria as the critical powerhouse of eukaryotic cells play important roles in regulating cell survival or cell death. Under numerous stimuli, impaired mitochondria will generate massive reactive oxygen species (ROS) which participate in the regulation of vital signals and could even determine the fate of cancer cells. While the roles of mitochondria in radiation-induced autophagic cell death still need to be elucidated. Human cervical cancer cell line, Hela, was used, and the SOD2 silencing model (SOD2-Ri) was established by gene engineering. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assays, MitoTracker Green staining was used to detect mitochondrial mass, Western blot was used to detect protein expression, and the level of ROS, autophagy, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Ionizing radiation (IR) could induce the increase of MAPLC3-II/MAPLC3-I ratio, Beclin1 expression, and ROS generation but decrease the MMP in a time-dependent manner. After SOD2 silencing, the IR-induced changes of ROS and the MMP were significantly enhanced. Moreover, both the radio sensitivity and autophagy increased in SOD2-Ri cells. Whereas, compared with SOD2-Ri, the opposite results were obtained by NAC, an antioxidant. After the treatment with the inhibitor of mitochondrial electron-transport chain complex II, thenoyltrifluoroacetone (TTFA), the rate of autophagy, ROS, and the total cell death induced by IR increased. In addition, the decrease of MMP was more obvious. However, these results were reversed by cyclosporine A (CsA). IR could induce ROS generation and mitochondrial damage which lead to autophagic cell death in Hela cells.
Assuntos
Autofagia/efeitos da radiação , Mitocôndrias/fisiologia , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Feminino , Células HeLa , Humanos , Mitocôndrias/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/radioterapiaRESUMO
Lysosome is a highly membrane-bound organelle which possesses a sequence of biological functions including protein degradation, cell signal transduction, plasma membrane repairment, homoeostasis, and autophagy. The lysosome contains more than 50 soluble acid hydrolases, and the acidification of lysosome is the most important biological characteristic. The integrity of lysosome is of vital importance. During the past few years, it was reported that the destabilization of lysosomal membrane can result in the release of lysosomal contents into cytosol and trigger cell death in a caspase-dependent or caspase-independent pathway. Lysosome functions at the late stage of autophagy and degrades cellular components delivered by autophagosome, which is a complicated process. The present article will summarize the current knowledge on the role of lysosome in cell death regulation and the underlying mechanisms.
Assuntos
Morte Celular/fisiologia , Lisossomos/fisiologia , Animais , Humanos , Neoplasias/fisiopatologiaRESUMO
Nowadays, heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, has become the target of antitumor drugs as a result of its close relationship with the occurrence and development, biological behavior, and prognosis of a tumor. Autophagy has attracted big attention recently for its paradoxical roles in cell survival and cell death, especially in the pathogenesis and treatment of cancer. Moreover, it has been verified that Hsp90 plays a role in autophagy via regulating the stability and activity of signaling proteins, and some Hsp90 inhibitors can induce autophagy. However, the underlying mechanisms for these important processes have not been clarified so far. In this study, we focus on the roles of Hsp90 in the regulation of autophagy, such as toll-like receptor (TLR)-mediated autophagy, Ulk1-mediated mitophagy, and chaperone-mediated autophagy (CMA). The roles of Hsp90 inhibitors in cancer therapy will also be elucidated.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Animais , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Proteínas de Ciclo Celular/metabolismo , Morte Celular , Sobrevivência Celular , Chaperoninas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Camundongos , Chaperonas Moleculares/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismoRESUMO
Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway.