ABSTRACT
Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research.
Subject(s)
Erythropoietin , Neuroprotective Agents , Peripheral Nerve Injuries , Erythropoietin/therapeutic use , Humans , Peripheral Nerve Injuries/drug therapy , Animals , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/pharmacology , Peptides/therapeutic use , Peptides/pharmacology , OligopeptidesABSTRACT
Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.
Subject(s)
Chemokine CXCL1 , Peripheral Nerve Injuries , Receptors, Interleukin-8B , Animals , Mice , Chemokine CXCL1/metabolism , Macrophages/metabolism , Phenylurea Compounds/pharmacology , Sciatic NerveABSTRACT
Understanding the mechanisms of resistance of hepatocellular carcinoma (HCC) to targeted therapies and immune checkpoint blockade is critical for the development of new combination therapies and improving patient survival. Here, we found that in HCC, anti-programmed cell death 1 ligand 1 (PD-L1) therapy reduces liver cancer growth, but the tumors eventually become resistant to continued therapy. Experimental analyses shows that the infiltration of pathogenic T helper 17 (pTh17) cells increases in drug-resistant HCC, and pTh17 cells secrete interleukin-17A (IL-17A), which promotes the expression of PD-L1 on the surface of HCC cells and produces resistance to anti-PD-L1 therapy. Anti-IL-17A combined with PD-L1 blockade significantly increased the infiltration of cytotoxic CD8+ T cells expressing high levels of interferon-γ and reduced treatment resistance in HCC. These results support the combination of anti-PD-L1 and anti-IL-17A as a novel strategy to induce effective T cell-mediated anti-tumor immune responses.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , CD8-Positive T-Lymphocytes , B7-H1 Antigen/metabolism , Th17 Cells/metabolism , Immunotherapy/methods , Antibodies, Monoclonal/metabolism , Tumor MicroenvironmentABSTRACT
BACKGROUND: To construct and validate a risk assessment model for acute kidney injury (AKI) in patients with acute pancreatitis (AP) in the intensive care unit (ICU). METHODS: A total of 963 patients diagnosed with acute pancreatitis (AP) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database was included. These patients were randomly divided into training set (N = 674) and validation set (N = 289) at a ratio of 7:3. Clinical characteristics were utilized to establish a nomogram for the prediction of AKI during ICU stay. These variables were selected by the least absolute shrinkage and selection operation (LASSO) regression and included in multivariate logistic regression analysis. Variables with P-values less than 0.05 were included in the final model. A nomogram was constructed based on the final model. The predicted accuracy of the nomogram was assessed by calculating the receiver operating characteristic curve (ROC) and the area under the curve (AUC). Moreover, calibration curves and Hosmer-Lemeshow goodness-of-fit test (HL test) were performed to evaluate model performance. Decision curve analysis (DCA) evaluated the clinical net benefit of the model. RESULTS: A multivariable model that included 6 variables: weight, SOFA score, white blood cell count, albumin, chronic heart failure, and sepsis. The C-index of the nomogram was 0.82, and the area under the receiver operating characteristic curve (AUC) of the training set and validation set were 0.82 (95% confidence interval:0.79-0.86) and 0.76 (95% confidence interval: 0.70-0.82), respectively. Calibration plots showed good consistency between predicted and observed outcomes in both the training and validation sets. DCA confirmed the clinical value of the model and its good impact on actual decision-making. CONCLUSION: We identified risk factors associated with the development of AKI in patients with AP. A risk prediction model for AKI in ICU patients with AP was constructed, and improving the treatment strategy of relevant factors in the model can reduce the risk of AKI in AP patients.
Subject(s)
Acute Kidney Injury , Pancreatitis , Humans , Acute Disease , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Intensive Care Units , Pancreatitis/diagnosis , Retrospective Studies , Risk AssessmentABSTRACT
Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.
Subject(s)
Autoimmune Diseases , Neoplasms , Humans , CD8-Positive T-Lymphocytes , Immunity, Innate , Interleukin-17 , Neoplasms/drug therapy , Th17 CellsABSTRACT
Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, but the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. Based on these, we explore whether CXCL12-CXCR4 axis regulates the NLRP3 inflammasome in the peripheral nerve. We found that CXCR4/CXCL12, NLRP3 inflammasome-related components, pyroptosis-related proteins and inflammatory factors in the sciatic nerve injured rats were markedly increased compared with the sham-operated group. AMD3100, a CXCR4 antagonist, reverses the activation of NLRP3 inflammasome, Schwann cell pyroptosis and sciatic nerve demyelination. We further treated rat Schwann cells with LPS (lipopolysaccharide) and adenosine triphosphate (ATP) to mimic the cellular inflammation model of sciatic nerve injury, and the results were consistent with those in vivo. In addition, both in vivo and in vitro experiments demonstrated that AMD3100 treatment reduced the phosphorylation of nuclear factor κB (NF-κB) and the expression of thioredoxin interacting protein (TXNIP), which contributes to activating NLRP3 inflammasome. Therefore, our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome and slow the recovery process of the sciatic nerve.
Subject(s)
Demyelinating Diseases , Inflammasomes , Rats , Animals , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , NLR Proteins/metabolism , Sciatic Nerve , Schwann Cells/metabolism , Inflammation/metabolism , Demyelinating Diseases/metabolism , Cell Cycle Proteins/metabolism , Chemokine CXCL12/metabolismABSTRACT
OBJECTIVE: To explore the effect of interleukin-17A (IL-17A) on liver and kidney injury and prognosis in septic mice. METHODS: A total of 84 SPF male C57BL/6 mice were randomly divided into sham operation group (Sham group), cecal ligation and puncture (CLP) induced sepsis model group (CLP group), and IL-17A intervention group. IL-17A intervention group were then divided into five subgroups according to the dose of IL-17A (0.25, 0.5, 1, 2, 4 µg). Mice in the IL-17A intervention group were intraperitoneally injected with the corresponding dose of IL-17A 100 µL immediately after surgery. The other groups were intraperitoneally injected with 100 µL phosphate buffer solution (PBS). The survival rate of mice was observed at 7 days, and peripheral blood and liver, kidney and spleen tissues were collected. According to the 7-day survival, another 18 mice were randomly divided into Sham group, CLP group, and 1 µg IL-17A intervention group. Peripheral blood samples were collected at 12 hours and 24 hours after CLP, and the mice were sacrificed to obtain liver, kidney, and spleen tissues. The behavior and abdominal cavity of each group were observed. The levels of peripheral blood liver and kidney function indexes and inflammatory factors were detected. The histopathological changes of liver and kidney were observed under light microscope. The peripheral blood and spleen tissues were inoculated in the medium, the number of bacterial colonies was calculated, and the bacterial migration of each group was evaluated in vitro. RESULTS: Except for the Sham group, the 7-day survival rate of mice in the 1 µg IL-17A intervention group was the highest (75.0%), so this condition was selected as the intervention condition for the subsequent study. Compared with Sham group, the liver and kidney functions of CLP group were significantly damaged at each time point after operation. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and serum creatinine (SCr) reached the peak at 24 hours after operation, and the liver and kidney pathological scores reached the peak at 7 days after operation, the levels of inflammatory cytokines interleukin (IL-17A, IL-6, IL-10) reached the peak at 12 hours after operation, and tumor necrosis factor-α (TNF-α) reached the peak at 24 hours after operation. In addition, a large number of bacteria proliferated in the peripheral blood and spleen, which reached the peak on day 7. Compared with the CLP group, exogenous administration of 1 µg IL-17A significantly delayed the rising trend of each index in the early stage of sepsis [24-hour ALT (U/L): 166.95±5.20 vs. 271.30±6.11, 24-hour AST (U/L): 599.42±7.25 vs. 1 013.27±3.37, 24-hour BUN (mg/L): 815.4±26.3 vs. 1 191.2±39.4, 24-hour SCr (µmol/L): 29.34±0.87 vs. 60.75±3.83, 7-day liver pathological score: 2.50 (2.00, 3.00) vs. 9.00 (8.50, 9.00), 7-day kidney pathological score: 1.00 (1.00, 2.00) vs. 5.00 (4.50, 5.00), 12-hour IL-17A (ng/L): 105.21±0.31 vs. 111.28±1.37, 12-hour IL-6 (ng/L): 83.22±1.01 vs. 108.88±0.99, 12-hour IL-10 (ng/L): 731.54±3.04 vs. 790.25±2.54, 24-hour TNF-α (µg/L): 454.67±0.66 vs. 576.18±0.76, 7-day peripheral blood colony count (CFU/mL): 600 (400, 600) vs. 4 200 (4 200, 4 300), 7-day spleen tissue colony count (CFU/g): 4 600 (4 400, 4 600) vs. 23 400 (23 200, 23 500), all P < 0.05]. CONCLUSIONS: Appropriate dose (1 µg) of exogenous IL-17A can reduce the lethal inflammatory response induced by CLP and improve the ability of bacterial clearance, thereby alleviating liver and kidney injury and improving the 7-day survival rate of septic mice.
Subject(s)
Interleukin-17 , Sepsis , Animals , Male , Mice , Interleukin-10 , Interleukin-17/pharmacology , Interleukin-6 , Kidney/physiopathology , Liver/physiopathology , Mice, Inbred C57BL , Prognosis , Tumor Necrosis Factor-alphaABSTRACT
Accumulating evidence suggested that both gut microbiome and sex play a critical role in the efficacy of immune checkpoint blockade therapy. Considering the reciprocal relationship between sex hormones and gut microbiome, the sex hormone-gut microbiome axis may participate in the regulation of the response to immune checkpoint inhibitors (ICIs). In this review, it was attempted to summarize the current knowledge about the influences of both sex and gut microbiome on the antitumor efficacy of ICIs and describe the interaction between sex hormones and gut microbiome. Accordingly, this review discussed the potential of enhancing the antitumor efficacy of ICIs through regulating the levels of sex hormones through manipulation of gut microbiome. Collectively, this review provided reliable evidence concerning the role of the sex hormone-gut microbiome axis in tumor immunotherapy.
Subject(s)
Gastrointestinal Microbiome , Neoplasms , Humans , Immunotherapy , Gonadal Steroid Hormones , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/therapyABSTRACT
Railway accident prediction is of great significance for establishing an early warning mechanism and preventing the occurrences of accidents. Safety agencies rely on prediction models to design railroad risk management strategies. Based on historical railway accident data, an ensemble learning strategy for accident prediction is proposed. Firstly, an improved K-nearest neighbors (KNN) data imputation algorithm is proposed to solve the problem of missing data in the dataset. Then, to reduce the impact of imbalanced data on prediction performance, an AdaBoost-Bagging method is presented. Finally, according to the feature importance in the prediction model, accident features are ranked to identify new insights into the cause of the accident. The AdaBoost-Bagging prediction method is applied to the Federal Railroad Administration (FRA) dataset. The application results show that, compared with Artificial Neural Network (ANN), XGBoost, GBDT, Stacking and AdaBoost methods, AdaBoost-Bagging method has a smaller prediction error and faster inference time in predicting railway accidents. Accuracy, Precision, Recall and F1-score are 0.879, 0.879, 0.883 and 0.881 respectively, and the inference time is reduced by 23.38%, 12.15%, 6.66%, 3.17% and 11.41% respectively. The prediction method can well mine important features of railway accidents without knowing the accident mechanism or the relationship between various railway accidents and factors, e.g., the critic risk factors related to derailment and collision accidents are investigated in the prediction. The findings will be helpful to the prevention and management of railway accidents.
Subject(s)
Accidents, Traffic , Railroads , Accidents, Traffic/prevention & control , Algorithms , Humans , Machine Learning , Neural Networks, ComputerABSTRACT
Nerve injury and nerve pain are common diseases caused by neuroinflammation. Numerous studies have shown that the activation of NLRP3 (nod-like receptor family, pyrin domain-containing 3) inflammasome is involved in a various inflammatory response, such as Alzheimer's disease, diabetes, nerve damage and other diseases. The NLRP3 inflammasome is a complex containing NLRP3 protein, ASC (apoptosis-associated speckle-like protein), and pro-caspase-1, which is highly expressed and activated to promote the secretion of IL-1ß and IL-18 in response to the stimulation of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in immune cells such as macrophages and dendritic cells. The activation of NLRP3 inflammasome can cause cell death through caspase-1-mediated cell pyroptosis and plays an important role in the development of nervous system injury and inflammation-related diseases. This discussion aims to summarize the mechanisms of nerve damage and pain caused by excessive activation of the NLRP3 inflammasome.
Subject(s)
Neuralgia , Peripheral Nerve Injuries , Caspase 1/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolismABSTRACT
OBJECTIVE: To investigate the function and mechanism of CXC chemokine receptor 7 (CXCR7) in neuronal cells of ischemic stroke. METHODS: The expression of CXCR7 in human neuroblastoma SH-SY5Y cells was interfered by small interfering RNA (si-RNA) technique. Oxygen-glucose deprivation/reoxygenation (OGD/R) injury model was constructed in SH-SY5Y cells. CXCR7 protein expression and cell cycle were detected by flow cytometry (FCM). The protein expression of CXCR7 and Akt signaling pathway was detected by Western blotting. RESULTS: After 6 hours of OGD/R, the expression of CXCR7 was significantly decreased compared with OGD/R 0 hour (CXCR7/GAPDH: 0.483±0.098 vs. 1.000±0.000 by Western blotting and 0.686±0.0524 vs. 1.000±0.000 by FCM, both P < 0.01), cell cycle arrest in G0/G1 phase (1.190±0.040 vs. 1.000±0.000, P < 0.01). After CXCR7 si-RNA interference with SH-SY5Y cells, OGD/R was constructed again for 6 hours. Compared with negative control group (si-NC group) under the same environment, the expression of CXCR7 and phosphorylated Akt (p-Akt) was significantly decreased (CXCR7/GAPDH: 0.471±0.051 vs. 1.000±0.000, p-Akt/GAPDH: 0.616±0.027 vs. 1.000±0.000, both P < 0.001) and cell cycle arrest in G0/G1 phase (1.105±0.033 vs. 1.000±0.000, P < 0.05). CONCLUSIONS: The CXCR7 could regulate the cycle of neuronal cells in ischemic stroke through Akt signaling pathway, which has a protective effect on neuronal cells.
Subject(s)
Ischemic Stroke , Receptors, CXCR , Cell Cycle , Glucose/metabolism , Humans , Oxygen/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/geneticsABSTRACT
Introduction: Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) is a protein localized to the cell membrane and is known for its ability to co-localize with PD-L1 on the plasma membrane, prevent PD-L1 degradation, and maintain PD-L1 expression on the cell membrane. CMTM6 is highly expressed and plays an important role in various tumors such as oral squamous cell carcinoma (OSCC) and colorectal cancer (CRC), however, its role in Glioblastoma multiforme (GBM) is unclear. Methods: In this paper, to investigate the role of CMTM6 in GBM, we analyzed the expression of CMTM6 in GBM, the interaction with CMTM6 and the associated genes by bioinformatics. Importantly, we analyzed the expression of CMTM6 in GBM in relation to tumor-infiltrating lymphocytes (TILs), immunoinhibitors, immunostimulators, chemokines and chemokine receptors. We further analyzed the function of CMTM6 and performed in vitro experiments to verify it. Finally, the sensitivity of CMTM6 to drugs was also analyzed and the relationship between CMTM6 and the anticancer drug Piperlonguminine (PL) was verified in vitro. Results: The results showed that CMTM6 was highly expressed in GBM and correlated with multiple genes. Furthermore, CMTM6 is closely related to the immune microenvironment and inflammatory response in GBM. Bioinformatic analysis of CMTM6 correlated with the function of GBM, and our experiments demonstrated that CMTM6 significantly promoted the migration of GBM cells and epithelial-mesenchymal transition (EMT), but had no significant effect on other functions. Interestingly, we found that in GBM, PL promotes the expression of CMTM6. Discussion: In this paper, we have performed a detailed analysis and validation of the role of CMTM6 in GBM using bioinformatics analysis and in vitro experiments to demonstrate that CMTM6 may be a potential target for glioma therapy.
ABSTRACT
The CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6), which binds to the programmed death ligand 1 (PD-L1) and stabilizes the expression of PD-L1 on the cell surface, has been recently discovered as a novel regulator of PD-L1 expression in cancer. PD-L1 is an immune checkpoint inhibitory molecule that can mediate the immune escape of tumor cells in various tumors and has been studied intensively in recent years. In 2017, two articles simultaneously reported that CMTM6 can stabilize the expression of PD-L1 on the plasma membrane and prevent PD-L1 from being degraded by lysosomes; therefore, CMTM6 may play an important role in tumor cell immune escape and immunosuppression. At present, there are few studies on the relationship between the expression of CMTM6 and PD-L1 in different tumors and diseases. These studies together suggested that CMTM6 may be a potential novel immunotherapy target. In this review, we briefly describe the latest research progresses of CMTM6 in various cancers and other diseases.
Subject(s)
B7-H1 Antigen/metabolism , Cell Membrane/metabolism , MARVEL Domain-Containing Proteins/metabolism , Myelin Proteins/metabolism , Neoplasms/immunology , Neoplasms/pathology , Tumor Escape/immunology , Humans , Immunotherapy , Lysosomes/metabolism , Tumor Microenvironment/immunologyABSTRACT
BACKGROUND: Knowledge of the optimal protocol and safety of particularly high-intensity exercise applied to individuals with stroke is lacking. OBJECTIVE: This systematic review and meta-analysis aimed to investigate the effect of high-intensity exercise on cardiorespiratory fitness in stroke survivors. METHODS: We performed a systematic electronic search for articles in MedLine via PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, CINAHL, and SPORTSDiscus up to April 1, 2019. Peak oxygen consumption (VO2peak), 6-min walk test (6MWT), fastest 10-m walk test (10MWT), and adverse events were assessed. The standardized mean difference (SMD), weighted mean difference (WMD), and odds ratios (ORs) were used to compute the effect size, and subgroup analysis was conducted to test the consistency of results as well as sensitivity analysis to assess the robustness of the results. The quality of evidence was assessed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: We included 17 studies (PEDro score≥4) in the meta-analysis. Post-intervention, high-intensity exercise had a significant effect on peak oxygen uptake (VO2peak; SMD=0.56, P<0.01, I2=8%; WMD=2.53mL/kg/min; high quality of evidence) and 6MWT (SMD=0.26, P<0.01, I2=40%; WMD=17.08m; moderate quality of evidence) but not fastest 10MWT (SMD=0.33, P=0.27, I2=77%; WMD=0.05m/s; low quality of evidence). Subgroup analysis showed better effects of higher-intensity treadmill training (≥70% heart rate reserve/VO2peak) for a longer duration (≥12 weeks) on VO2peak and 6MWT in sub-acute or chronic stroke survivors. The high-intensity exercise and control groups did not differ in adverse events including falls [odds ratio (OR) 1.40, P=0.35, I2=11%; low quality of evidence], pain (OR 3.34, P=0.09, I2=0%; moderate quality of evidence), or skin injuries (OR 1.08, P=0.90, I2=0%; low quality of evidence). CONCLUSIONS: Our meta-analysis suggests that high-intensity exercise is beneficial for cardiorespiratory fitness in stroke survivors and might be safe as a novel intervention in cardiopulmonary rehabilitation after stroke.
Subject(s)
Cardiorespiratory Fitness , Exercise Therapy/methods , Exercise/physiology , Stroke Rehabilitation/methods , Exercise Therapy/adverse effects , Humans , Oxygen Consumption , Stroke/physiopathology , Stroke Rehabilitation/adverse effects , Walk TestABSTRACT
PURPOSE: To explore the effect of miR-449a inhibits migration and invasion by targeting Notch1 and regulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and further study on the molecular mechanism. PATIENTS AND METHODS: The expression of miR-449a and Notch1 in HCC cells and tissues was detected by qRT-PCR. The HCC cell line HCCLM3 and SMMC-7721 were transfected with miR-449a. The invasion and migration of HCC cell lines were detected by transwell assay and wound healing assay. The Notch pathway and EMT related protein were detected with Western Blotting. The specific binding site of mir-449a on notch1 gene was detected by luciferase assay. RESULTS: We found the expression of miR-449a was related to short-term recurrence of hepatocellular carcinoma after hepatectomy and acted as independent risk factors of DFS and OS. The expression of miR-449a decreased in tumor tissues and HCC cell lines, but the expression of Notch1 increased. The overexpressed miR-449a promoted the invasiveness in vitro by regulating EMT via Notch pathway. Mechanically, miR-449a inhibited the translation of Notch1 protein by binding to 3' UTR of its mRNA directly. CONCLUSION: miR-449a is short-term recurrence-related miRNA and inhibits the invasion and metastasis ability of HCC cells by regulating EMT via Notch pathway. miR-449a may be a new effective therapeutic target for HCC.
ABSTRACT
Neural precursor cell-expressed, developmentally-downregulated 9 (NEDD9) is a multi-domain skeleton protein that serves an important role in the cell signaling process via modulating invasion, metastasis, proliferation and apoptosis of tumor cells. The present study identified that the expression levels of NEDD9 in colorectal cancer were elevated. Therefore, the effect of downregulating the expression of NEDD9 in terms of invasion and migration of colorectal cancer cells was investigated and the role of the JNK pathway in these processes was also investigated. The data revealed that downregulation of NEDD9 and JNK inhibitors suppressed invasion and migration, decreased expression levels of phosphorylated JNK, increased the expression levels of E-cadherin and decreased the expression levels of vimentin. In summary, NEDD9 promotes invasion and migration of colorectal cancer cells via the JNK pathway.
ABSTRACT
Background: MicroRNAs (miRNAs) are non-coding small RNAs that have been shown to play a key role in the development of many tumors. However, its specific mechanism of action in non-small cell lung cancer (NSCLC) is not very clear. Purpose: This study was to identify the effect of miRNA-449a on NSCLC invasion and migration. Methods: We used quantitative real-time PCR experiments to demonstrate that miRNA-449a is down-regulated in NSCLC tissues and cell lines. We also used the Transwell assay to detect cell invasion and migration, and the Western Blot assay was used to detect protein expression. The dual luciferase assay was used to detect the targeting relationship between miR-449a and A Disintegrin And Metalloproteinases 10 (ADAM10). Results: Our experiments demonstrated that miRNA-449a was down-regulated in NSCLC tissues and cell lines. When miRNA-449a was up-regulated in NSCLC cells, the invasion and migration ability of the cells was weakened, and the expression of ADAM10 was decreased. After down-regulation of miRNA-449a, the cell's invasion and migration ability was enhanced, and the expression of ADAM10 was increased. Through dual luciferase assays, we also found that miRNA-449a can target ADAM10 to delay the progression of epithelial-mesenchymal transition (EMT) and inhibit invasion and migration. Conclusion: Our experiments demonstrated that miRNA-449a acted as a tumor suppressor gene through inhibiting the expression of ADAM10 in NSCLC.