The Effect of Asymmetric Intersexual Selection Power Perception on the Choice Deferral Behavior of Men and Women.

Consumers always delay their choices, which can cause companies to suffer tremendous losses. One reason for such delay is a lack of confidence. Confidence in consumer decision-making can stem from many sources, including social power. In this research, we find that selection power with regard to choosing a romantic mate increases consumers' decision confidence and, in turn, decreases choice deferral. We define the concept of intersexual selection power (ISP), and propose certain factors that can induce individuals' asymmetric ISP. We conducted four studies to explore four factors that could influence consumers' ISP perceptions (sex, mating cues, sex ratio, and mate value) and the effects of such power perception on choice deferral. The results showed that individuals with high ISP perception have more decision confidence and a lower choice deferral rate than individuals with low ISP perception regardless of the way in which choice deferral is measured.

Development and Validation of an Immune-Related Prognostic Signature in Cervical Cancer.

Background: Cervical cancer is the fourth most frequent gynecological malignancy across the world. Immunotherapies have proved to improve prognosis of cervical cancer. However, few studies on immune-related prognostic signature had been reported in cervical cancer. Methods: Raw data and clinical information of cervical cancer samples were downloaded from TCGA and UCSC Xena website. Immunophenoscore of immune infiltration cells in cervical cancer samples was calculated through the ssGSEA method using GSVA package. WGCNA, Cox regression analysis, LASSO analysis, and GSEA analysis were performed to classify cervical cancer prognosis and explore the biological signaling pathway. Results: There were eight immune infiltration cells associated with prognosis of cervical cancer. Through WGCNA, 153 genes from 402 immune-related genes were significantly correlated with prognosis of cervical cancer. A 15-gene signature demonstrated powerful predictive ability in prognosis of cervical cancer. GSEA analysis showed multiple signaling pathways containing Programmed cell death ligand-1 (PD-L1) expression and PD-1 checkpoint pathway differences between high-risk and low-risk groups. Furthermore, the 15-gene signature was associated with multiple immune cells and immune infiltration in tumor microenvironment. Conclusion: The 15-gene signature is an effective potential prognostic classifier in the immunotherapies and surveillance of cervical cancer.

Antiangiogenic Strategies in Epithelial Ovarian Cancer: Mechanism, Resistance, and Combination Therapy.

Angiogenesis is one of the hallmarks of cancer and plays a crucial role in carcinogenesis and progression of epithelial ovarian cancer. Antiangiogenic agent is the first approved targeted agent in ovarian cancer. Anti-angiogenic agents mainly include agents target VEGF/VEGFR pathway, such as bevacizumab and agents target receptor tyrosine kinase, and non-VEGF/VEGFR targets of angiogenesis. Antiangiogenic agents demonstrate certain effects in ovarian cancer treatment either as monotherapy or combined with chemotherapy. Unfortunately, antiangiogenic agents, such as bevacizumab, integrated into the ovarian cancer treatment paradigm do not increase cures. Thus, the benefits of anti-angiogenic agents must be carefully weighed against the cost and associated toxicities. Antiangiogenic agents drug resistance and short of predictive biomarkers are main obstacles in ovarian cancer treatment. A combination of poly (ADP-ribose) polymerase inhibitors or immune checkpoint inhibitors might be great strategies to overcome resistance as well as enhance anti-tumor activity of anti-angiogenic drugs. Predictive biomarkers of antiangiogenic agents are in urgent need.

Apelin receptor homodimer inhibits apoptosis in vascular dementia.

Apelin receptor (APJ), a member of family A of the G protein-coupled receptors (GPCRs), is a potential pharmaceutical target for diseases of the nervous system. Our previous work revealed that human APJ can form a homodimer that has different functional characteristics than the monomer. To investigate the effects of APJ homodimers on neuroprotection in vascular dementia (VD), we established VD model in rats and treated the animals by injecting apelin-13 into the lateral ventricle. In addition, we established an oxygen-glucose deprivation/reoxygenation (OGD/R) model in SH-SY5Y cells treated with apelin-13. After apelin-13 stimulation in the VD rat, the level of APJ and APJ homodimer were elevated. Furthermore, APJ homodimer decreased the level of cleaved caspase-3 and cleaved caspase-9 via the Gαi3 and Gαq signaling pathway, thereby increasing the number of neurons and inhibiting apoptosis. Consequently, APJ homodimers may serve as a unique mechanism for neuroprotection against VD and provide new pharmaceutical targets for VD.

NR4A1 enhances MKP7 expression to diminish JNK activation induced by ROS or ER-stress in pancreatic ß cells for surviving.

Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic ß cells. ROS or ER-stress damages ß-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in ß cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic ß cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic ß cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic ß cells upon treatment with TG or H2O2. After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic ß cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.

Identification of hub genes in key hallmarks of ovarian cancer via bioinformatics analysis.

BACKGROUND: Ovarian cancer is one of the most lethal malignant gynecologic tumors worldwide. We aimed to identify critical hallmarks of the surface epithelium between normal ovaries and serous ovarian carcinomas and then obtain the hub genes associated with these critical hallmarks. METHODS: We chose GSE36668, GSE54388 and GSE69428 as data sources and then determined the common gene sets through gene set enrichment analysis (GSEA) to explore essential hallmarks and hub genes driving normal ovarian cells to evolve progressively into a neoplastic state. The differentially expressed genes (DEGs) extracted separately in each gene set were analyzed again through the Metascape website. Kaplan-Meier plotter was used to obtain significant prognostic information. The hub genes were obtained through protein-protein interaction (PPI) network by Cytoscape. Hub genes were confirmed to have higher mRNA and protein expression levels in ovarian cancer tissues than in normal tissues through public databases [Gene Expression Profiling Interactive Analysis (GEPIA) and The Human Protein Atlas]. Correlation analysis of six hub genes showed a strong correlation via R. RESULTS: We obtained 11 common hallmarks from GSEA of the three mentioned datasets and 22 hub genes that showed a significant association with poor survival. CONCLUSIONS: Not only the gene sets enriched by GSEA but also the hub genes extracted by the PPI network indicate that the most fundamental trait of ovarian cancer cells involves their ability to sustain chronic proliferation.

NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic ß-cells for protection.

Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic ß-cells. ER stress or ROS causes c-Jun N-terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi-stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual-luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in ß-cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p-JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome-dependent manner. We found that NR4A1 increased the expression of cbl-b (an E3 ligase); knocking down cbl-b expression increased MKK4 and p-JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl-b promoter by physical association. We further confirmed that cbl-b expression in ß-cells was reduced in NR4A1-knockout mice compared with WT mice. NR4A1 down-regulates JNK activation by ER stress or ROS in ß-cells via enhancing cbl-b expression.

Long Non-coding RNA HIX003209 Promotes Inflammation by Sponging miR-6089 via TLR4/NF-κB Signaling Pathway in Rheumatoid Arthritis.

Accumulating studies have suggested that long non-coding RNAs (lncRNAs) have drawn more and more attention in rheumatoid arthritis (RA), which can function as competitive endogenous RNAs (ceRNAs) in inflammation and immune disorders. Previously, we have found that lncRNA HIX003209 is differentially expressed in RA. However, the precise mechanism of lncRNA HIX003209 in RA is still vague. We aim to elucidate the role and its targeted microRNA of lncRNA HIX003209 in RA as ceRNA. Significantly increased expression of lncRNA HIX003209 was observed in the peripheral blood mononuclear cells (PBMCs) from RA cases. It was positively associated with TLR2 and TLR4 in RA. Besides, peptidoglycan (PGN) and lipopolysaccharide (LPS) could enhance the expression of lncRNA HIX003209, which reversely promoted the proliferation and activation of macrophages through IκBα/NF-κB signaling pathway. Moreover, HIX003209 was involved in TLR4-mediated inflammation via targeting miR-6089 in macrophages. LncRNA HIX003209 functions as a ceRNA and exaggerates inflammation by sponging miR-6089 through TLR4/NF-κB pathway in macrophages, which offers promising therapeutic strategies for RA.

Exosome-encapsulated miR-6089 regulates inflammatory response via targeting TLR4.

Exosome-encapsulated microRNAs (miRNAs) have been identified as potential biomarkers in autoimmune diseases. However, little is known about the role of exosome-delivered miRNAs in rheumatoid arthritis (RA). In this study, we investigated the profile of specific exosomal miRNAs by microarray analysis of serum exosomes from three patients with RA and three healthy controls. Quantitative real-time PCR (qRT-PCR) was performed to validate the aberrantly expressed exosomal miRNAs. A total of 20 exosome-encapsulated miRNAs were identified to be differently expressed in the serum of patients with RA compared with controls. Interestingly, we found that exosome-encapsulated miR-6089 was significantly decreased after validation by qRT-PCR in serum exosomes from 76 patients with RA and 20 controls. Besides, miR-6089 could inhibit lipopolysaccharide (LPS)-induced cell proliferation and activation of macrophage-like THP-1 cells. TLR4 was a direct target for miR-6089. MiR-6089 regulated the generation of IL-6, IL-29, and TNF-α by targetedly controlling TLR4 signaling. In conclusion, exosome-encapsulated miR-6089 regulates LPS/TLR4-mediated inflammatory response, which may serve as a novel, promising biomarker in RA.

miR-657 Promotes Macrophage Polarization toward M1 by Targeting FAM46C in Gestational Diabetes Mellitus.

MicroRNA (miRNA) has been widely suggested to play a vital role of in the pathogenesis of gestational diabetes mellitus (GDM). We have previously demonstrated that miR-657 can regulate macrophage inflammatory response in GDM. However, the role of miR-657 on M1/M2 macrophage polarization in GDM pathogenesis is not clear yet. This study is aimed at elucidating this issue and identifying novel potential GDM therapeutic targets based on miRNA network. miR-657 is found to be upregulated in placental macrophages demonstrated by real-time PCR, which can enhance macrophage proliferation and migration in vitro. Luciferase reporter assay shows the evidence that FAM46C is a target of miR-657. In addition, miR-657 can promote macrophage polarization toward the M1 phenotype by downregulating FAM46C in macrophages. The present study strongly suggests miR-657 is involved in GDM pathogenesis by regulating macrophage proliferation, migration, and polarization via targeting FAM46C. miR-657/FAM46C may serve as promising targets for GDM diagnosis and treatment.

Exosomal miR-6803-5p as potential diagnostic and prognostic marker in colorectal cancer.

Accumulating data have suggested exosome-delivered microRNAs (miRNAs) play critical role in carcinogenesis and cancer progression. However, little is known about the influence of exosomal miR-6803-5p on the development and prognosis of colorectal cancer (CRC). Levels of serum exosomal miR-6803-5p were determined by microarray analysis and verified by quantitative real-time PCR (qRT-PCR). Outcomes of overall survival (OS) and disease-free survival (DFS) of CRC patients were estimated by Kaplan-Meier analysis. We used cox regression analysis to investigate the association between exosomes-encapsulated miR-6803-5p and the clinicopathological factors of CRC patients. The exosomal miR-6803-5p was significantly increased in serum samples from patients with CRC in contrast to healthy controls. Significantly higher levels of serum exosomal miR-6803-5p were observed in CRC patients at later TNM stage or with lymph node metastasis as well as liver metastasis. Patients with elevated levels of serum exosomal miR-6803-5p had much poorer OS and DFS. Cox regression analysis revealed high levels of exosomal miR-6803-5p was associated with poor prognosis in CRC independent of other confounding factors. Thus, exosomal miR-6803-5p is a potential diagnostic and prognostic biomarker for patients with CRC.

MicroRNA-6869-5p acts as a tumor suppressor via targeting TLR4/NF-κB signaling pathway in colorectal cancer.

Many studies have implicated that microRNAs (miRNAs), as non-coding RNAs, play important roles in the development and progression of colorectal cancer (CRC). However, little is known about the role of a newly identified miRNA, miR-6869-5p, in CRC. We aim to investigate the modifying effects and underlying mechanisms of miR-6869-5 in colorectal carcinogenesis and progression. Significantly reduced levels of miR-6869-5p were observed in both serum exosomes tumor tissue samples from patients with CRC. The prediction of targets of miR-6869-5p in databases of targetscan, microRNA. ORG and miRDBA revealed that toll-like receptor 4 (TLR4) is a potential target for this miRNA. MiR-6869-5p could inhibit cell proliferation and the production of inflammatory cytokines (TNF-α and IL-6) in CRC cells via directly targeting TLR4. The protective effect of miR-6869-5p from colorectal carcinogenesis was dependent on TLR4/NF-κB signaling pathway. In addition, the 3-year survival was poor among CRC patients with decreased levels of miR-6869-5p in serum exosomes. Thus, miR-6869-5p may serve as a tumor suppressor in CRC, and serum exosomal miR-6869-5p is a promising circulating biomarker for the prediction of CRC prognosis.

Downregulation of circulating exosomal miR-638 predicts poor prognosis in colon cancer patients.

Exosome-encapsulated microRNAs have been recognized as novel and stable biomarkers for cancer. However, little is known about the role of exosomal microRNAs in colon cancer. In the present study, we investigated the expression of serous exosomal microRNA-638 (miR-638) and its prognostic effect in patients with colon cancer. Serous exosomal samples were assayed by quantitative real-time PCR. Kaplan-Meier analysis was adopted to determine the overall survival (OS) and disease-free survival (DFS) of colon cancer patients. Cox regression analysis was applied to assess the potential association between serous exosomal miR-638 and clinicopathological factors of colon cancer patients. MiR-638 was significantly reduced in serum exosomes of colon cancer patients compared with healthy controls. Decreased level of serous exosomal miR-638 was more significant in colon cancer patients at later TNM stage or with liver metastasis. Kaplan-Meier analysis showed that colon cancer patients with reduced level of serous exosomal miR-638 had poor OS and DFS. In addition, the Cox regression analysis suggested serous exosomal miR-638 was a prognostic factor for colon cancer independent of TNM stage and liver metastasis. In conclusion, serous exosomal miR-638 is a useful biomarker for the prediction of colon cancer prognosis.

Puerarin accelerates re-endothelialization in a carotid arterial injury model: impact on vasodilator concentration and vascular cell functions.

Puerarin, a main isoflavone glucoside derived from the Chinese medicine Radix puerariae, has been employed clinically to prevent and treat various cardiovascular disorders. However, little research has been performed to identify the in vivo effects of puerarin on the re-endothelialization and neointimal hyperplasia of injured vessels, and its detailed mechanisms of action remain to be elucidated. In this study, Sprague-Dawley rats were treated with puerarin at the dosages of 0, 50, and 100 mg·kg(-1)·day(-1) i.p. after balloon carotid denudation for 2 weeks. The results showed that puerarin accelerated re-endothelialization after surgery, resulting in a significant reduction of neointima formation. Moreover, puerarin increased the serum levels of vasodilators, such as nitric oxide and prostaglandin I(2), in a dose-dependent manner. In vitro, puerarin exhibited protective effects on late endothelial progenitor cells and mature endothelial cells, and inhibitory effects on the migration of vascular smooth muscle cells. Taken together, these data indicate that puerarin accelerates re-endothelialization, inhibits neointima formation, and attenuates vascular remodeling at sites of arterial injury, possibly due to the cytoprotective effects on endothelial lineage and the suppression of vascular smooth muscle cell migration.

Hyperglycaemia exerts deleterious effects on late endothelial progenitor cell secretion actions.

Endothelial progenitor cells (EPCs) play a fundamental role in tissue regeneration and vascular repair both by differentiating into endothelial cells and by secretion of vasoactive substances that promote angiogenesis and maintain vascular homeostasis. It has previously been shown that hyperglycaemia impairs early and late EPC functions, such as differentiation, proliferation and adhesion. However, its role in the regulation of the production of vasoactive substances in EPCs, especially in late EPCs, is less well defined. We investigated the effects of hyperglycaemia on the production of vasodilator, fibrinolytic and angiogenic growth factors, and also on the activity of superoxide dismutase (SOD) in late EPCs. For this purpose, late EPCs were incubated with different concentrations of D-glucose (5-40 mmol/L) for 24 hr. Levels of nitric oxide (NO), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), prostaglandin I(2) (PGI(2)), vascular endothelial growth factor (VEGF) and the activity of SOD were measured by enzyme-linked immunosorbent assay (ELISA). Under high glucose stress conditions, late EPCs exhibited lower levels of NO, t-PA, PAI-1, PGI(2) and VEGF compared to control medium (5 mmol/L glucose). Moreover, high glucose was also observed to decrease the activity of SOD in late EPCs. These results suggest that hyperglycaemia-induced impairment of late EPC secretion functions could contribute to the development of vascular disease in diabetes.