ABSTRACT
AIM: To analyze the effects of pterostilbene on myocardial function, myocardial fibrosis and inflammatory response in rats with acute myocardial infarction and on Notch1/eIF3a signaling pathway. METHODS: Seventy-five Wistar male rats of SPF grade were selected and divided into 5 groups. The low-, medium-, high-dose groups of pterostilbene were pretreated with pterostilbene solution before modeling. The dosage was 10, 20 and 40 mg/kg of the pterostilbene sputum solution, rats of the model group and the normal group were intragastrically administered with the same dose of normal saline; except for the normal group, other rats were prepared with AMI model. The left ventricular function, cardiac blood flow index, myocardial histopathology and fibrosis, myocardial inflammatory factor content, eIF3a and Notch1 protein and mRNA expression were observed. RESULTS: LVFS and LVEF were lower in the model group than in the normal group. LVEDd, LVESd, LVESV and LVEDV were higher than those in the normal group. The LVFS and LVEF in the low, medium and high dose groups of the pterostilbene were higher than those in the model group, LVEDd, LVESd, LVESV, and LVEDV were lower than the model group, and the difference was statistically significant (P<0.05).In the model group, the -dp/dtmax, +dp/dtmax, and LVSP were lower than the normal group, and the LVEDP was higher than the normal group. The -dp/dtmax, +dp/dtmax, and LVSP in the low, medium, and high dose groups of the pterostilbene were increased as compared with model group; while LVEDP was lower than the model group, and the difference was statistically significant (P<0.05).The contents of IL-6, IL-1β and TNF-α in the myocardial tissue of the model group were higher than those in the normal group. The contents of IL-6, IL-1β and TNF-α in the myocardial tissue of rats with low, medium and dose groups of the pterostilbene were decreased as compared with the model group, the difference was statistically significant (P<0.05). The expression of eIF3a and Notch1 protein and mRNA in the myocardial tissue of the model group was higher than that in the normal group. eIF3a, Notch1 protein and mRNA expression in the low-, medium-, and high-dose rat myocardial tissue were lower than the model group, and the difference was statistically significant (P<0.05).CONCLUSION: The development of myocardial inflammation and fibrosis in AMI rats may be associated with the increase of eIF3a expression in the downstream of Notch signaling pathway. Pretreatment of pterostilbene can significantly improve ventricular remodeling in AMI rats, and its mechanism may be related to the inhibition of eIF3a and Notch1 expression.
ABSTRACT
To investigate whether the protection of rutaecarpine against bleomycin-induced pulmonary fibrosis is mediated by inhibiting Notch1/eukaryotic initiation factor 3a (eIF3a) signaling pathway, and whether these effects are related to the synthesis and release of calcitonin gene-related peptide (CGRP) and inhibition of epithelial-mesenchymal transition (EMT) of alveolar epithelial cells, male Sprague-Dawley rats were randomly divided into five groups (=12), respectively, Control group, bleomycin group, rutaecarpine (100, 300 mg·kg⁻¹) group and capsaicin plus rutaecarpine (300 mg·kg⁻¹) group. Bleomycin (5 mg·kg⁻¹) was used to induce pulmonary fibrosis rat model. Rats were given capsaicin (50 mg·kg⁻¹) by subcutaneous injections 1 days before and 7, 14, 21 days after induce pulmonary fibrosis rat model to deplete endogenous CGRP. At the end of experiments, blood was collected from carotid artery to determinate the plasma levels of CGRP by ELISA. Pulmonary tissue change was observed by HE staining. Masson's trichrome stain was used to demonstration collagen deposition. The collagen I expression in pulmonary tissue was measured by immunohistochemisty. The expression of CGRP, Notch1, eIF3a, collagen I, vimentin, alpha-smooth muscle actin (α-SMA), E-cadherin and zonula occludens-1 (ZO-1) was detected by qPCR or Western blot. Compared with the control group, the pulmonary tissue of the bleomycin group showed significant fibrosis, including significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, and concomitantly with the decrease in plasma CGRP and expression of CGRP. Importantly the expression of E-cadherin and ZO-1 was decreased and expression of Notch1, eIF3a, collagen I, vimentin and α-SMA was increased in bleomycin group (<0.05 or <0.01). Compared with the bleomycin group, rutaecarpine (100, 300 mg·kg⁻¹) group significantly reduced bleomycin-induced pulmonary injury concomitantly with the increase in plasma CGRP and expression of CGRP. Importantly the expression of E-cadherin and ZO-1 was increased and expression of Notch1, eIF3a, collagen I, vimentin and α-SMA was decreased by rutaecarpine treatment (<0.05 or <0.01). All these effects of rutaecarpine were abolished by capsaicin.These results suggest that rutaecarpine protects against bleomycin-induced pulmonary fibrosis by inhibiting Notch1/eIF3a signaling pathway, alleviating EMT process, which is related to the increased synthesis and release of CGRP.
ABSTRACT
Identifying a target molecule that is crucially involved in pancreatic tumor growth and metastasis is necessary in developing an effective treatment. The study aimed to investigate the role of the eukaryotic translation initiation factor 3a (eIF3a) in the cell proliferation and motility in pancreatic cancer. Our data showed that the expression of eIF3a was upregulated in pancreatic ductal adenocarcinoma as compared with its expression in normal pancreatic tissues. Knockdown of eIF3a by a specific shRNA caused significant decreases in cell proliferation and clonogenic abilities in pancreatic cancer SW1990 and Capan-1 cells. Consistently, the pancreatic cancer cell growth rates were also impaired in xenotransplanted mice. Moreover, wound-healing assay showed that depletion of eIF3a significantly slowed down the wound recovery processes in SW1990 and Capan-1 cells. Transwell migration and invasion assays further showed that cell migration and invasion abilities were significantly inhibited by knockdown of eIF3a in SW1990 and Capan-1 cells. Statistical analysis of eIF3a expression in 140 cases of pancreatic ductal adenocarcinoma samples revealed that eIF3a expression was significantly associated with tumor metastasis and TNM staging. These analyses suggest that eIF3a contributes to cell proliferation and motility in pancreatic ductal adenocarcinoma.
Subject(s)
Animals , Mice , Adenocarcinoma , Cell Movement , Cell Proliferation , Neoplasm Metastasis , Neoplasm Staging , Pancreatic Ducts , Pancreatic Neoplasms , Peptide Initiation Factors , RNA, Small Interfering , Wounds and InjuriesABSTRACT
Translation is a fundamental step in regulation of gene expression and abnormalities in this process may lead to cancer. In eukaryotic cells, translation of mRNA is mainly regulated by many eukaryotic initiation factors ( eIFs) . EIF3 plays an impor-tant role in translational regulation, cell growth and oncogenesis. The largest subunit of eIF3, eIF3a may play a role as a regulator of mRNAs. The relationship between eIF3a and oncogenesis has been found. Moreover, the eIF3a mRNA is ubiquitously ex-pressed in different cancer cells and can modulate the cell cycle. However, some studies indicate that eIF3a could provide protec-tion against evolution into higher malignancy and reduce the re-sistance to chemotherapy . The patients of high eIF3a expression could get a better prognosis . In fact, the role of eIF3a is still un-clear in cancer cells. EIF3a may be involved in the process of tumor pathophysiology, but its regulatory role is undulatory.
ABSTRACT
Objective: To investigate the correlation between eukaryotic translation initiation factor 3, subunit A (eIF3a) and human epididymis protein 4 (HE4) expression and ovarian cancer. Methods: RT-PCR or immunohistochemistry was used to examine eIF3a and HE4 mRNA or protein expression in ovarian tissues from patients with ovarian cancer (n=181) or benign ovariantumors, or from the healthy women. Results: hTere were signiifcant differences in mRNA and protein expression of eIF3a and HE4 among normal ovarian tissues, benign ovarian tumor tissues, and ovarian cancer tissues (P<0.05). hTere were signiifcant differences in mRNA expression of eIF3a and HE4 between the normal tissues and the ovarian cancer tissues, or between the benign ovarian tumor tissues and the normal tissues (P<0.001). hTe mRNA expression of eIF3a in the normal ovarian tissues was signiifcantly higher than that in the benign ovarian tumor tissues or that in the ovarian cancer tissues. hTe mRNA expression of HE4 was gradually increased from the normal ovarian tissues, the benign ovarian tumor tissues to the ovarian cancer tissues. hTe mRNA expression of HE4 in the ovarian cancer tissues was signiifcantly higher than that in the benign ovarian tumor tissues (P<0.001). Positive expression rates for eIF3a or HE4 protein in normal, benign tumor, and cancer tissues were 0, 66.7%, and 81.0% or 0, 27.8%, and 56.2%, respectively. hTere were signiifcant differences in positive expression rates of eIF3a protein and HE4 protein between the ovarian tumor tissues and benign ovarian tumor tissues, between the ovarian cancer tissues and the normal ovarian tissues, or between the benign ovarian tumor tissues and the normal ovarian tissues (P<0.001). hTe eIF3a protein expression was positively correlated with HE4 protein expression (r=0.575,P<0.05). Conclusion: The expressions of eIF3a and HE4 are associated with ovarian cancer, and extracellular regulated protein kinases may play a role in the interaction between eIF3a and HE4.
ABSTRACT
Objective To explore the dose-dependent and time-dependent effect of docetaxel on the expression of mammalian eukaryotic initiation factor 3 subunit A (eIF3a) in lung cancer cell line. Methods The human lung cancer cell line A549 was treated with gradient concentrations of docetaxel for different time. Real-time PCR and Western blot were used to detect mRNA and protein expression levels of eIF3a and α-tubulin, respectively. Results Docetaxel did not affect α-tubulin expression at either mRNA level or protein level. When A549 cells were treated with high concentration of docetaxel (30 μg/L), the expression level of eIF3a mRNA tended to increase in a time-dependent manner. Protein expression level of α-tubulin was not associated with eIF3a expression significantly in cells treated by docetaxel.Conclusion Docetaxel could slightly increase the expression of eIF3a mRNA, and eIF3a does not regulate the expression of α-tubulin in A549 cells treated by docetaxel.