Estrogen-related receptor alpha (ESRRA) was reported to play an important role in multiple biological processes of neoplastic diseases. The roles of ESRRA in endometrial cancer have not been fully investigated yet.Expression data and clinicopathological data of patients with uteri corpus endometrial carcinoma (UCEC) were obtained from The Cancer Genome Atlas (TCGA). Comprehensive bioinformatics analysis was performed, including receiver operating characteristics (ROC) curve analysis, Kaplan-Meier survival analysis, gene ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Immunohistochemistry was used to detect the protein expression level of ESRRA and CCK-8 assay was performed to evaluate the effect of ESRRA on the proliferation ability.A total of 552 UCEC tissues and 35 normal tissues were obtained from the TCGA database. The mRNA and protein expression level of ESRRA was highly elevated in UCEC compared with normal tissues, and was closely associated with poor prognosis. ROC analysis indicated a very high diagnostic value of ESRRA for patients with UCEC. GO and GSEA functional analysis showed that ESRRA might be mainly involved in cellular metabolism processes, in turn, tumorigenesis and progression of UCEC. Knockdown of ESRRA inhibited the proliferation of UCEC cells in vitro. Further immune cell infiltration demonstrated that ESRRA enhanced the infiltration level of neutrophil cell and reduced that of T cell (CD4+ naïve), NK cell, and cancer associated fibroblast (CAF). The alteration of immune microenvironment will greatly help in developing immune checkpoint therapy for UCEC.Our study comprehensively analyzed the expression level, clinical value, and possible mechanisms of action of ESRRA in UCEC. These findings showed that ESRRA might be a potential diagnostic and therapeutic target.
Parkinson's disease (PD), also known as paralysis tremor, is a chronic disease of the central nervous system. It has been reported that hepatocyte nuclear factor 4 alpha (HNF4A) is upregulated in PD, but its specific function has not been well explored.We established an in vitro PD model in SH-SY5Y cells stimulated with 1-methyl-4-phenylpyridinium (MPP+ ). Meanwhile, the effect of HNF4A on MPP+ -treated SH-SY5Y cell behavior was monitored by functional assays. Mechanism assays were conducted to verify the relationship among LINC00667/miR-34c-5p/HNF4A. Rescue experiments validated the regulatory mechanism in PD model.The results revealed that depletion of HNF4A suppressed cell cytotoxicity and apoptosis caused by MPP+ . Knockdown of HNF4A recovered MPP+ -stimulated oxidative stress and neuroinflammation. Mechanically, HNF4A was targeted and inhibited by miR-34c-5p. Furthermore, we found that LINC00667 positively modulated HNF4A expression via sequestering miR-34c-5p in MPP+ -stimulated SH-SY5Y cells. Interestingly, the data indicated that HNF4A could transcriptionally activate LINC00667 expression. Rescue experiments presented that miR-34c-5p interference or HNF4A overexpression could mitigate the effects of LINC00667 knockdown on cell viability, cytotoxicity, cell apoptosis, oxidative stress, and neuroinflammation in MPP+ -treated SH-SY5Y cells.Our study first proved LINC00667, miR-34c-5p, and HNF4A constructed a positive feedback loop in MPP+ -treated SH-SY5Y cells, enriching our understanding of PD.
To investigate whether genomic instability (GI)-derived long non-coding RNAs (lncRNAs) have a prognostic impact on the patients with endometrial cancer. Patients with Uterine Corpus Endometrial Carcinoma (UCEC) were selected from The Cancer Genome Atlas (TCGA) database. Systematic bioinformatics analyses were performed, including Pearson correlations, GO and KEGG enrichment analysis, bivariate and multiple logistic regression analysis, and Kaplan–Meier (KM) method. A total of 552 UCEC samples were included in the study. The differentially expressed lncRNAs (DELs) were identified, including 79 down-regulated lncRNAs and 31 up-regulated lncRNAs. Bivariate logistic regression analysis showed that 19 GI-derived lncRNAs were prognostic factors. By further multivariate logistic regression analysis, AC005256.1 (estimated coefficient = −0.474), AC026336.3 (estimated coefficient = −0.030), AL161618.1 (estimated coefficient = −1.661), and BX322234.1 (estimated coefficient = 1.511) were used to construct a prognostic risk model. In the train set and test set, the risk model was shown to have both a high prognostic and a diagnostic value. We developed a novel GI-derived 4-lncRNA signature for the diagnosis and prognosis of patients with endometrial cancer. These findings offered a novel perspective in the clinical management of endometrial cancer.
Objective
To investigate the relationship between changes of cholinergic system and memory ability impairment in rats long-term exposed to hypoxia-hypercapnia.
Methods
Forty-eight SD rats were randomly divided into control group，2 weeks hypoxia-hypercapnia group and 4 weeks hypoxia-hypercapnia group.The chronic hypoxia-hypercapnia rat model was set up.The memory ability was assessed by eight-arm radial maze.Morphological changes were observed by the HE staining and Nissl staining.Acetylcholine (ACh) content，choline acetyl-transferase (ChAT) activity and acetyl-cholinesterase (AChE) activity in the hippocampus were detected by spectrophotometry，while expression of α7 neuronal nicotinic acetylcholine receptor (α7 nAChR) protein by Western blot.
Results
Memory ability，especially the working memory was impaired in rats exposed to chronic hypoxia-hypercapnia.And the memory ability decreased more markedly in four weeks group.Compared with those of normoxic rats，the levels of ACh and the activities of AChE and ChAT in the hippocampus of the two weeks group were significantly decreased (ACh: (58.9±2.7) vs (47.4±3.2) μg/mg (protein); AChE: (0.326±0.019) vs (0.247±0.020) U/mg (protein); ChAT: (127.1±8.6) vs (90.4±6.9) U/g (tissue wet weight)，t=7.674，8.139，9.408，all P<0.05).Compared with the two weeks group，those changes were more obvious in the four weeks group rats (ACh: (47.4±3.2) vs (32.5±3.2) μg/mg (protein) ; AChE: (0.247±0.020)，(0.170±0.019) U/mg (protein) ; ChAT: (90.4±6.9)，(55.6±6.0) U/g (tissue wet weight)，t=9.279，8.036，10.781，all P<0.05).Compared with the normoxic rats，the expressions ofα7 nAChR protein were significantly decreased in two weeks group rats (t=4.481，P<0.05).Moreover，the expressions ofα7 nAChR protein were significantly decreased in four weeks group rats comparing with the two weeks group (t=4.965，P<0.05).
Conclusions
An impairment of rat’s memory ability may be induced by hypoxia-hypercapnia，and the injury degree is correlated with the exposure time.Cholinergic system dysfunctions may contribute to the memory function defects in chronic hypoxia-hypercapnia rats.
Key words:
Anoxia; Hypercapnia; Memory disorders; Acetylcholine; Receptors，cholinergic; Rats
Background Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway. Methods and Findings Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9∼11%O2, 5.5∼6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection. Conclusions These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.
Scutellaria baicalensis which is a traditional plant amedica in China possesses a wide anti-cancer effect. However, the inhibition effect and mechanism of S. baicalensis on cervical cancer is not clear up to now. In our study, two kinds of ethanol extract of S. baicalensis were used in U14 cervical cancer mice. The rate of tumor inhibition was detected, and the tumor cell morphology was observed by hematoxylin and eosin (H.E.) staining method. The cell cycle and apoptosis rate were examined by flow cytometry and the content of tumor necrosis factor-alpha (TNF-α) in serum was determined by enzymelinked immunosorbent assay (ELISA) kit. Furthermore, the expression of B-cell lymphoma 2 (Bcl-2) and Bax gene was detected by immunohistochemistry method. The results showed that the tumor growth could be inhibited with the highest inhibition rate of 59.86% and the apoptosis of tumor cells could be induced and cell cycles were arrested at S phase in the ethanol extract of S. baicalensis groups. Besides, the content of TNF-α in serum was significantly increased (P<0.05). The Bcl-2 positive cells got significance reduction and Bax positive cells were increased. So we conclude that the ethanol extract of S. baicalensis can inhibit the growth of tumor cells, arrest the cell cycle and induce the cells apoptosis and increase the content of tumor necrosis factor-alpha TNF-α in serum. The mechanism of anti-tumor activity might be associated with down regulating the level of Bcl-2 gene and up regulating the level of Bax gene.
Cognitive impairment is a common finding in patients with chronic obstructive pulmonary disease (COPD), but little attention has been focused on therapeutic intervention for this complication. Chronic intermittent hypoxia hypercapnia (CIHH) exposure is considered to be responsible for the pathogenesis of COPD. Dl-3n-Butylphthalide (NBP), extracted from Apium graveolens Linn, has displayed a broad spectrum of neuroprotective properties. Our study aimed to investigate the potential of NBP on CIHH-induced cognitive deficits. The cognitive function of rats after CIHH exposure was evaluated by the Morris water maze, which showed that the NBP treated group performed better in the navigation test. NBP activated BDNF and phosphorylated CREB, the both are responsible for neuroprotection. Additionally, NBP decreased CIHH induced apoptosis. Moreover, NBP further induced the expression of HIF-1α, accompanied by the up-regulation of the autophagy proteins Bnip3, Beclin-1 and LC3-II. Finally, NBP also reversed the decreased expression of SIRT1 and PGC-1α, but the expression of Tfam, Cox II and mtDNA remained unchanged. These results suggested that the neuroprotective effects of NBP under CIHH condition possibly occurred through the inhibition of apoptosis, promotion of hypoxia-induced autophagy and activation of the SIRT1/PGC-1α signalling pathway, while stimulation of mitochondrial biogenesis may not be a characteristic response.
Purpose Both the International Federation of Gynecology and Obstetrics (FIGO) and the American Joint Committee on Cancer (AJCC) staging system for endometrial cancer (EC) defined the N category by the location of metastatic lymph nodes (LNs) rather than the metastatic LN count. We aimed to compare the accuracy of the AJCC staging system and the LN count-based staging system. Patients and Methods EC patients were selected from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2016. Patients’ characteristics were collected, including age, race, marital status, histological type, grade, therapeutic measures, the number of metastatic LNs, the number of dissected LNs, vital status, and survival in months. Overall survival (OS) was analyzed by the Kaplan–Meier (KM) method and the concordance index (C-index) was used to compare the prognostic value of the AJCC staging system and the LN count-based staging system. Results We identified 4,276 EC cases from the SEER database, including 2,693 patients with stage IIIC1 and 1,583 patients with stage IIIC2. Multivariate analyses showed that independent prognostic factors for patients with stage IIIC1 included age, race, marital status, grade, histology, chemotherapy, and radiotherapy. Independent prognostic factors for patients with stage IIIC2 included age, marital status, grade, histology, chemotherapy, and radiotherapy. The C-index of the AJCC staging system and the LN count-based staging system were 0.483 and 0.617, respectively. At least six LNs should be dissected to ensure the accuracy of the LN count-based staging system. Conclusion A modified AJCC staging system based on the count of metastatic LNs might be superior to the current AJCC staging system, which still had room for improvement and further refinements were required. For accurate staging, we recommended that at least six LNs should be examined in the modified AJCC staging system.
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