Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

Nucleus-localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription.

Accumulating evidence indicates that circular RNAs (circRNAs) are inextricably linked to cancer development. However, the function and mechanism of nucleus-localized circRNAs in hepatocellular carcinoma (HCC) still require investigation. Here, qRT-PCR and receiver-operating characteristic curve were used to detect the expression and diagnostic potential of circSLC39A5 for HCC. The biological function of circSLC39A5 in HCC was investigated in vitro and in vivo. Nucleoplasmic separation assay, fluorescence in situ hybridization, RNA pulldown, RNA immunoprecipitation, the HDOCK Server, the NucleicNet Webserver, crosslinking-immunoprecipitation, MG132 treatment, and chromatin immunoprecipitation were utilized to explore the potential molecular mechanism of circSLC39A5 in HCC. The results showed that circSLC39A5 was downregulated in both HCC tissues and plasma and was associated with satellite nodules and lymph node metastasis/vascular invasion. CircSLC39A5 was stably expressed in plasma samples under different storage conditions, showing good diagnostic potential for HCC (AUC = 0.915). CircSLC39A5 inhibited proliferation, migration, and invasion, facilitated the apoptosis of HCC cells, and was associated with low expression of Ki67 and CD34. Remarkably, circSLC39A5 is mainly localized in the nucleus and binds to the transcription factor signal transducer and activator of transcription 1 (STAT1), affecting its stabilization and expression. STAT1 binds to the promoter of thymine DNA glycosylase (TDG). Overexpression of circSLC39A5 elevates TDG expression and reverses the increase of proliferating cell nuclear antigen (PCNA) expression and the overactive cell proliferation caused by TDG silencing. Our findings uncovered a novel plasma circRNA, circSLC39A5, which may be a potential circulating diagnostic marker for HCC, and the mechanism by which nucleus-localized circSLC39A5 exerts a transcriptional regulatory role in HCC by affecting STAT1/TDG/PCNA provides new insights into the mechanism of circRNAs.

Synergistic Antibacterial Surface with Liquid Repellency and Enhanced Photothermal Bactericidal Activity.

The presence of microorganisms on biomedical devices and food packaging surfaces poses an important threat to human health. Superhydrophobic surfaces, a powerful tool to combat pathogenic bacterial adhesion, are threatened by their poor robustness. As a supplement, photothermal bactericidal surfaces may be expected to kill adhered bacteria. Using copper mesh as a mask, we prepared a superhydrophobic surface with a homogeneous conical array. The surface shows synergistic antibacterial properties, including a superhydrophobic character against bacterial adhesion and photothermal bactericidal activity. As a result of the excellent liquid repellency, the surface could highly repel the adherence of bacteria after immersing in a bacterial suspension for 10 s (95%) and 1 h (57%). Photothermal graphene can easily eliminate most adhered bacteria during the subsequent treatment of near-infrared (NIR) radiation. After a self-cleaning wash, the deactivated bacteria were easily rinsed off the surface. Furthermore, this antibacterial surface exhibited an approximately 99.9% resisted bacterial adhesion rate regardless of planar and various uneven surfaces. The results offer promising advancement of an antibacterial surface combining both adhesion resistance and photothermal bactericidal activity in fighting microbial infections.

Co-Exposure to Bisphenols, Parabens, and Antimicrobials and Association with Coronary Heart Disease: Oxidative Stress as a Potential Mediating Factor?

Coronary heart disease (CHD) is the leading cause of global morbidity, but the effect of plasticizers and antimicrobial additives on CHD is unknown. Here, we conducted a case-control study to investigate the mediating role of oxidative stress in the association between co-exposure to seven bisphenols, four parabens, triclosan (TCS), triclocarban, and CHD risk in Guangzhou, China. Quantile-based g-computation and weighted quantile sum regression were used to analyze mixture-outcome associations. Quantile-based g-computation showed a positive joint effect of a decile increase in exposure to all examined pollutants on CHD risk (OR: 1.52, 95% CI: 1.25-1.84), with bisphenol A (BPA), bisphenol F (BPF), n-butyl paraben (BuP), and TCS representing major contributors. The results also showed a decile nonmonotonic increase in the exposure mixtures, positively correlated with a 2.22 ng/mL (95% CI: 1.21-3.23 ng/mL) elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), with BuP, TCS, bisphenol AP (BPAP), and BPF contributing dominantly. Mediation analysis showed that 8-OHdG mediated the relationship between BPA, BPF, BPAP, and TCS, and CHD risk. Moreover, the mediating role of high-density lipoprotein (HDL) between several bisphenols and CHD was also identified. It is yet to be verified, but bisphenols may elevate CHD risk by reducing HDL status and increasing oxidative stress.

Perchlorate in fine particulate matter in Shenzhen, China, and implications for human inhalation exposure.

The wide application of perchlorate in military and aerospace industries raises potential exposure risks for humans. Previous studies have mainly focused on perchlorate in drinking water, foodstuffs and dust, while its exposure in fine particulate matter (PM2.5) has received less attention. Thus, we investigated its concentrations and temporal variability in PM2.5 from October 2020 to September 2021 in Shenzhen, southern China. We also assessed the native population's intake and uptake of perchlorate in PM2.5 via inhalation. Measured PM2.5 concentrations in samples from Shenzhen ranged from 2.0 to 91.9 µg m-3. According to air quality guidelines proposed by the World Health Organization, 12.7% of all the samples exceeded interim target 1 (> 35 µg m-3), and only 37.3% met interim target 3 (< 15 µg m-3). Logistic regression analysis showed that perchlorate concentrations positively correlated with the PM2.5 concentrations and negatively correlated with precipitation. The median estimated daily intake (EDI) was highest for infants (0.029 ng kg-1 day-1), and both EDIs and estimated daily uptakes (EDUs) gradually decreased with age. All the EDIs and EDUs were below the reference dose provided by the US National Academy of Sciences (NAS), indicating that exposure to perchlorate in PM2.5 posed negligible health risks for Shenzhen residents. However, the exposure of infants and specific groups who tend to be more highly exposed than average still warrants attention.

CircUSP36 attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signal axis.

Circular RNAs (circRNAs) play important roles in a variety of physiological and pathological processes. Researches demonstrated that circRNAs provided novel strategies for the prevention and treatment of IS. However, the biological function of hsa_circ_0045932 (circUSP36) has not been revealed yet. Here, we explored the effect of circUSP36 on IS and its mechanism. In the present study, we found that circUSP36 expression was significantly decreased in the peripheral blood of IS patients and was negatively correlated with the severity, infarct volume and poor prognosis of IS. Functionally, circUSP36 silencing inhibited cellular activity and proliferation and promoted apoptosis after oxygen-glucose deprivation/reperfusion (OGD/R) treatment, while circUSP36 overexpression reversed these cellular phenotypes in vitro. Adeno-associated virus (AAV)-mediated overexpression of circUSP36 attenuates brain injury and neurological deficit and promotes motor function recovery of transient middle cerebral artery occlusion (tMCAO) mice. Subsequently, the RNA antisense purification (RAP) and luciferase reporter assay confirmed that circUSP36 acts as a sponge to adsorb miR-139-3p, and miR-139-3p could bind and inhibit SMAD3 expression. Further rescue experiments showed that both miR-139-3p overexpression and SMAD3 silencing could abolish the antiapoptotic effect of circUSP36. In summary, we reveal for the first time that circUSP36 attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signal axis, which make circUSP36 a potential therapeutic target for IS.

Circular RNA circGLIS3 promotes bladder cancer proliferation via the miR-1273f/SKP1/Cyclin D1 axis.

Extensive research confirmed that circRNA can play a regulatory role in various stages of tumors by interacting with various molecules. Identifying the differentially expressed circRNA in bladder cancer and exploring its regulatory mechanism on bladder cancer progression are urgent. In this study, we screened out a circRNA-circGLIS3 with a significant upregulation trend in both bladder cancer tissues and cells. Bioinformatics prediction results showed that circGLIS3 may be involved in multiple tumor-related pathways. Function gain and loss experiments verified circGLIS3 can affect the proliferation, migration, and invasion of bladder cancer cells in vitro. Moreover, silencing circGLIS3 inhibited bladder cancer cell growth in vivo. Subsequent research results indicated circGLIS3 regulated the expression of cyclin D1, a cell cycle-related protein, and cell cycle progression. Mechanically, circGLIS3 upregulates the expression of SKP1 by adsorbing miR-1273f and then promotes cyclin D1 expression, ultimately promoting the proliferation of bladder cancer cells. In summary, our study indicates that circGLIS3 plays an oncogene role in the development of bladder cancer and has potential to be a candidate for bladder cancer.

LncRNA SERPINB9P1 expression and polymorphisms are associated with ischemic stroke in a Chinese Han population.

Long noncoding RNAs (lncRNAs) were reported to play important roles in the pathogenesis of ischemic stroke (IS). Our study aimed to investigate the role of lncRNA SERPINB9P1 expression in ischemic stroke and the association between SERPINB9P1 polymorphisms and IS risk, as well as examine the correlation of SERPINB9P1 expression and variants with clinical parameters of IS. The SERPINB9P1 levels in human participants and oxygen-glucose deprivation (OGD)-treated human A172 cells were measured by qRT-PCR. The SERPINB9P1 polymorphisms (rs375556 and rs318429) were genotyped by the MassARRAY platform. We found that the SERPINB9P1 expression was significantly downregulated in patients with IS compared with that in healthy controls. On the 14th day in the hospital, the SERPINB9P1 level in patients with moderate and severe stroke was significantly downregulated compared with the normal group. After stratification by gender, the rs375556 polymorphism was significantly associated with susceptibility to female IS in the recessive model, and the significant association remained after adjusting for age. After adjusting for gender and age, rs318429 was significantly associated with FPG and D-D levels, and rs375556 was significantly associated with INR and PTA levels in IS cases. Besides, the lncRNA SERPINB9P1 expressed downregulated in OGD/reoxygenation-treated human A172 cells. In conclusion, the lncRNA SERPINB9P1 may protect against cerebral ischemia-reperfusion injury and neurological impairment after IS. The SERPINB9P1 rs375556 polymorphism was associated with susceptibility to female IS, and SERPINB9P1 polymorphisms may influence the metabolism of blood glucose and regulation of coagulation function in patients with IS.

Analysis of expression profiles and bioinformatics suggests that plasma exosomal circular RNAs may be involved in ischemic stroke in the Chinese Han population.

Circular RNAs (circRNAs) have been confirmed to be associated with ischemic stroke(IS), but the involvement of exosomal circRNAs in plasma still needs to be extensively discussed. Therefore, we aimed to investigate the expression profile of exosomal circRNAs in plasma and the potential roles and mechanisms of exosomal circRNAs in the pathogenesis of ischemic stroke in the Chinese Han population. In this study, the plasma exosomal circRNA expression profiles of three IS patients and three healthy controls were analyzed using circRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and circRNA-miRNA-mRNA regulatory network analysis were performed for the aberrantly expressed genes. Protein-protein interaction (PPI) networks and molecular complex detection algorithms (MCODEs) were analyzed by STRING and Cystoscope for functional annotation and construction, respectively. RNA-Seq analysis revealed that a total of 3540 circRNAs were aberrantly expressed in exosomes, 1177 circRNAs were significantly upregulated, and 2363 circRNAs were downregulated in IS patients compared to healthy controls. Bioinformatics analysis revealed that the parental genes of differentially expressed circRNAs as well as the mRNAs predicted in the circRNA-miRNA-mRNA regulatory network are enriched for signaling pathways associated with IS pathology, such as the MAPK signaling pathway, lipid and atherosclerosis, neurotrophic factor signaling pathways, mTOR signaling pathway, the p53 signaling pathway etc. Then, 10 hub genes were identified from the PPI and module networks, including FBXW11, FBXW7, UBE2V2, ANAPC7, CDC27, UBC, CDC5L, POLR2H, POLR2F and RBX1. Overall, the present study provides evidence of an altered plasma exosomal circRNA expression profile and its potential function in IS. Our findings may contribute to the study of the pathogenesis of circRNAs in IS and provide ideas for studying potential diagnostic biomarkers and therapeutic targets for IS.

Application of machine learning in diagnostic value of mRNAs for bipolar disorder.

PURPOSE: Bipolar disorder (BD) is a type of severe mental illness with symptoms of mania or depression, it is necessary to find out effective diagnostic biomarkers for BD due to diagnosing BD is based on clinical interviews without objective indicators. MATERIALS AND METHODS: The mRNA expression levels of genes included PIK3R1, FYN, TP53, PRKCZ, PRKCB, and YWHAB in the peripheral blood of 43 patients with bipolar disorder and 47 healthy controls were detected. Machine learning methods included Artificial Neural Networks, Extreme Gradient Boosting, Random Forest, and Support Vector Machine were adopted to fit different gene combinations to evaluate diagnostic value for bipolar disorder. RESULTS: The combination 'PIK3R1 + FYN' in the SVM model showed the best diagnostic value, with AUC, sensitivity, and specificity values of 0.951, 0.928, and 0.937, respectively. CONCLUSIONS: The diagnostic efficiency for bipolar disorder was significantly improved by fitting PIK3R1 and FYN through the Support Vector Machine model.

A 3' Untranslated Region Polymorphism of CTNNB1 (Rs2953) Alters MiR-3161 Binding and Affects the Risk of Ischemic Stroke and Coronary Artery Disease in Chinese Han Population.

BACKGROUND: CTNNB1 is reported to be related to the pathological process of ischemic stroke (IS) and coronary artery disease (CAD). Polymorphism located in the 3' untranslated region (3'UTR) of a gene might affect gene expression by modifying binding sites for microRNAs (miRNAs). This study aimed to analyze the association between polymorphism rs2953, which locates in the 3'UTR of CTNNB1, and the risk of IS and CAD. METHODS: The CTNNB1 messenger RNA (mRNA) expression level in peripheral venous blood was measured. In total, 533 patients with IS, 500 patients with CAD, and 531 healthy individuals were genotyped by Sequenom Mass-Array technology. The binding of miR-3161 to CTNNB1 was determined by dual-luciferase reporter assay. RESULTS: The CTNNB1 mRNA expression level for the IS group was significantly lower than that for the control group. Rs2953 was significantly associated with both IS risk and CAD risk. Significant association was also found between polymorphism rs2953 and many conventional factors, such as serum lipid level, blood coagulation markers, blood glucose level, and homocysteine level in patients. Rs2953 T allele introduced a binding site to miRNA-3161 and thus decreased luciferase activity. CONCLUSION: Polymorphism rs2953 is associated with the risk of both IS and CAD. Moreover, polymorphism rs2953 (T) introduces a binding site to miRNA-3161 and thus decreases luciferase activity in cell lines.

LncRNA H19 rs4929984 Variant is Associated with Coronary Artery Disease Susceptibility in Han Chinese Female Population.

Long non-coding RNAs (lncRNAs) have been reported to play an important role in cardiovascular diseases. The present study aimed to investigate the levels of lncRNA H19 in patients with coronary artery disease (CAD) and the genetic association of lncRNA H19 rs217727 and rs4929984 polymorphisms with CAD susceptibility. We detected an upregulated expression of lncRNA H19 in the peripheral blood of CAD patients compared with healthy controls, and the area under the receiver operating characteristic curve of lncRNA H19 for CAD diagnosis was 0.918. In addition, rs4929984 was associated with the susceptibility of Han Chinese females to CAD, as shown in the additive and dominant models, and the significant association remained after adjusting for age and Bonferroni correction. The A allele carriers of rs4929984 were correlated with females' susceptibility to CAD compared with the C allele, and the A-G haplotype of rs4929984-rs217727 was associated with females' susceptibility to CAD. Furthermore, rs217727 and rs4929984 were associated with the levels of clinicopathological parameters of CAD cases. We suggest that lncRNA H19 has a potential to be a diagnostic biomarker for CAD; rs4929984 polymorphism is associated with females' susceptibility to CAD in the Han Chinese population, and lncRNA H19 variants may influence lipid metabolism, inflammation, and coagulation function of CAD patients.

Phosphoinositide-3-kinase regulatory subunit 1 gene polymorphisms are associated with schizophrenia and bipolar disorder in the Han Chinese population.

Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric disorders that share many genetic risk factors. This study aimed to investigate the association of phosphoinositide-3-kinase regulatory subunit1 (PIK3R1) gene rs3756668 and rs3730089 polymorphisms with SCZ and BD risks and determine the expression levels of PIK3R1. A total of 548 SCZ cases, 512 BD cases, and 598 healthy controls were included in this study. Single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom MassARRAY platform, and quantitative reverse transcription polymerase chain reaction was conducted to examine the mRNA expression of PIK3R1. The genotypic distribution of rs3756668 in the BD group was significantly different from that in the healthy controls (P = 0.038). After adjustment for gender and age was made, rs3730089 was significantly associated with the risk of SCZ [AA/(AG + GG): OR = 2.25, Padj = 0.040; AA/GG: OR = 2.27, Padj = 0.038]. The SNP rs3756668 was associated with the susceptibility of BD (AA+GG/AG: OR = 0.73, P = 0.011) and the association remained after adjusting for gender and age. The mRNA level of PIK3R1 was significantly upregulated in patients with BD compared with that in the control group (P < 0.001). In terms of the diagnostic value of PIK3R1 for BD, the receiver operating characteristic curve analysis showed an area under the curve of 0.809 with 74.0% sensitivity and 73.9% specificity. PIK3R1 may be the shared susceptibility gene of SCZ and BD and may be a potential diagnostic biomarker for BD.

Rs7219 Regulates the Expression of GRB2 by Affecting miR-1288-Mediated Inhibition and Contributes to the Risk of Schizophrenia in the Chinese Han Population.

In the present study, we examined a potential genetic association between the variant rs7219 within the 3'-UTR of GRB2 and the susceptibility to schizophrenia (SCZ) and bipolar disorder (BD) in the Chinese Han population. A genetic association study, including 548 SCZ patients, 512 BD patients, and 598 normal controls, was conducted in the Chinese Han population. Genotyping was performed through the Sequenom MassARRAY technology platform. The expression of GRB2 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A dual-luciferase reporter assay was performed to determine whether miR-1288 could bind to the 3'-UTR region of GRB2 containing rs7219. We found that rs7219 was significantly associated with the susceptibility to SCZ under different genetic models, including additive [OR (95% CI) = 1.24 (1.02-1.49), P = 0.027], dominant [OR (95% CI) = 1.31 (1.04-1.66), P = 0.025], and allelic models[OR (95% CI) = 1.24 (1.03-1.49), P = 0.027]. However, no significant associations were found between rs7219 and the risk for BD (all P > 0.05). Moreover, we observed that the expression of GRB2 significantly decreased in SCZ patients compared with the controls (P = 0.004). The dual-luciferase reporter assay showed that the minor allele C of rs7219 significantly decreased the luciferase activity by binding miR-1288 (P < 0.001). In summary, we are the first to reveal that rs7219 is significantly associated with the susceptibility to SCZ in the Chinese Han population. Moreover, the minor allele C of rs7219 is identified as a risk allele for SCZ because it generates a binding site for miR-1288, thereby resulting in decreased expression of GRB2 and ultimately increasing the risk of SCZ.

Association of long noncoding RNA H19 polymorphisms with the susceptibility and clinical features of ischemic stroke in southern Chinese Han population.

Stroke is the leading cause of death in China. Previous studies have demonstrated that long noncoding RNAs play important roles in ischemic stroke (IS). This study aimed to investigate long noncoding RNA H19 (lncRNA H19) expression in IS cases and the association between lncRNA H19 variants and IS risk and IS-related risk factors. A total of 550 IS cases and 550 controls were recruited for this study. LncRNA H19 expression was detected using quantitative real-time polymerase chain reaction. Genotyping was conducted by the Sequenom MassARRAY technology. LncRNA H19 level in peripheral blood of IS cases was significantly upregulated compared with healthy controls (P = 0.046). No significant association was observed between lncRNA H19 rs217727 and rs4929984 polymorphisms with IS risk in all genetic models, and rs217727-rs4929984 haplotypes are not associated with IS susceptibility. Further meta-analysis also implied that the rs217727 and rs4929984 polymorphisms were not associated with IS in Chinese population. However, rs4929984 is significantly associated with the diastolic blood pressure level of IS patients (additive model: Padj = 0.007; dominant model: Padj = 0.013), whereas rs217727 is associated with international normalized ratio (additive model: Padj = 0.019; recessive model: Padj = 0.004), prothrombin time activity level (additive model: Padj = 0.026; recessive model: Padj = 0.004), and homocysteine level (recessive model: Padj = 0.048) in patients with IS. Our findings suggest that lncRNA H19 level may affect the occurrence of IS, and lncRNA H19 variants may influence blood pressure, coagulation function, and homocysteine metabolism of patients with IS in the southern Chinese Han population.

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke.

BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) are potential biomarkers of tumors, cardiac disease, and cerebral disease because of their interaction with coding RNAs. This work focused on ischemic stroke (IS) and aimed to identify novel lncRNA biomarkers and construct lncRNA-related networks in IS. METHODS: Differentially expressed lncRNAs were identified using Arraystar Human LncRNA Microarray v4.0, and validated with qRT-PCR. A lncRNA-mRNA co-expression network and a lncRNA-miRNA-mRNA regulatory network were constructed. Functional and pathway analyses were then performed. RESULTS: In total, 560 up-regulated and 690 down-regulated differentially expressed lncRNAs were found (P < 0.05, false discovery rate < 0.05, absolute fold change ≥ 2). qRT-PCR results confirmed that lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084 exhibited significant differential expression between IS and controls (all P < 0.05). Areas under the curves (AUCs) for these lncRNAs were 0.733, 0.743, and 0.690, respectively, and the combined AUC was 0.843. A coding-noncoding co-expression (CNC) network was constructed based on Pearson's correlation coefficient. A specific lncRNA-miRNA-mRNA regulatory network of ENST00000568297, ENST00000568243, and NR_046084 was also constructed. Functional annotation of the up- and down-regulated mRNAs was performed. Pathway analysis enriched IS-related pathways with mRNAs in the lncRNA-miRNA-mRNA regulatory network. CONCLUSION: LncRNA and mRNA expression profiles in human peripheral blood were altered after IS. ENST00000568297, ENST00000568243, and NR_046084 were identified as novel potential diagnostic biomarkers of IS. Analysis of the CNC network and lncRNA-miRNA-mRNA regulatory network suggested that lncRNAs may participate in IS pathophysiology by regulating pivotal miRNAs, mRNAs, or IS-related pathways.

LncRNA ANRIL Expression and ANRIL Gene Polymorphisms Contribute to the Risk of Ischemic Stroke in the Chinese Han Population.

The aim of the present study was to explore the role of lncRNA ANRIL in the pathogenesis of ischemic stroke (IS) and coronary artery disease (CAD) and to determine the association between ANRIL variants and the genetic susceptibility of IS and CAD in the Chinese Han population. A genetic association study including 550 IS patients, 550 CAD patients, and 550 healthy controls was conducted. The expression levels of lncRNA ANRIL, CDKN2A, and CDKN2B were detected using qRT-PCR. Genotyping was performed by Sequenom MassARRAY on an Agena platform. Our study showed that IS patients had an increased lncRNA ANRIL expression (P = 0.002) and a decreased CDKN2A expression (P < 0.001) compared with normal controls. A significant difference with regard to the genotype distribution of rs2383207 was found between male IS patients and controls (P = 0.011). The minor allele of rs2383207 significantly increased the IS risk under a recessive model (OR = 1.52, 95% CI = 1.05-2.21, P = 0.027). The minor allele of rs1333049 was significantly associated with the risk of IS among the male patients under a recessive model (OR = 1.56, 95% CI = 1.04-2.35, P = 0.031). However, no significant association was found between the ANRIL variants and the risk of CAD (all P > 0.050). In addition, we found a decreased lncRNA ANRIL expression in IS patients who carried the GG genotype of rs1333049 compared with IS patients who carried the CC or CG genotype (P = 0.041). In summary, we found that IS patients had an increased lncRNA ANRIL expression and a decreased CDKN2A expression compared with the controls, which might play an impellent role in pathological processes of IS. The ANRIL variants rs2383207 and rs1333049 were significantly associated with the risk of IS among males but not females in the Chinese Han population.

Wnt/ß-catenin signaling mediates the seizure-facilitating effect of postischemic reactive astrocytes after pentylenetetrazole-kindling.

Ischemia not only leads to tissue damage, but also induces seizures, which in turn worsens the outcome of ischemia. Recent studies have revealed the impaired homeostatic functions of reactive astrocytes, which were thought to facilitate the development of seizures. However, how this phenotype of reactive astrocytes is regulated remains unclear. Here, using pentylenetetrazole (PTZ)-kindling model, we investigated the roles of reactive astrocytes and their intracellular Wnt/ß-catenin signaling in the ischemia-increased seizure susceptibility. Our data showed that somatosensory cortical ischemia significantly increased the susceptibility to PTZ-induced seizure. Genetic ablation of Nestin-positive reactive astrocytes significantly decreased the incidence and severity of seizures. By using a Wnt signaling reporter mice line Topgal mice, we found that Wnt/ß-catenin signaling was upregulated in reactive astrocytes after ischemia. Depletion of ß-catenin in reactive astrocytes significantly decreased the susceptibility of seizures and the expression of c-Fos induced by PTZ in the ischemic cortex. Overexpression of ß-catenin in reactive astrocytes, in contrast, significantly increased seizure susceptibility and the expression of c-Fos. Furthermore, the expression of aquaporin-4 (AQP-4) and inwardly rectifying K(+) channel 4.1 (Kir4.1), two molecules reportedly associated with seizure development, was oppositely affected in reactive astrocytes with ß-catenin depletion or overexpression. Taken together, these data indicated that astrocytic Wnt/ß-catenin signaling accounts, at least partially, for the ischemia-increased seizure susceptibility. Inhibiting Wnt/ß-catenin signaling may be utilized in the future for preventing postischemic seizures.

Sca-1(+) mesenchymal stromal cells inhibit splenic marginal zone B lymphocytes commitment through Caspase-3.

Mesenchymal stromal cells (MSCs) have been characterized as an important component of hematopoietic niche, which are capable of modulating the immune system through interaction with a wide range of immune cells. Marginal zone B cells, one main type of mature B lymphocytes, play a central role in eliciting antibody response against pathogens. However, how MSCs and its subpopulations regulate marginal zone B cells commitment is unknown yet. In this study, we assessed the contribution of Sca-1(+) MSCs on marginal zone B cells commitment. Our results showed that Sca-1(+) MSCs inhibit the commitment of marginal zone B lymphocytes. The inhibition was exerted through lowered Caspase-3 expression. Furthermore, we found marginal zone B lymphocytes in spleen of Caspase-3 knockout mice decreased and Caspase-3 knockout Sca-1(+) MSCs accounted for the MZB lymphocytes decrease. In conclusion, our investigation provided clues about Sca-1(+) MSCs regulation on the commitment of marginal zone B cells through Caspase-3 gene.

Construction of an immune-related gene prognostic model with experimental validation and analysis of immune cell infiltration in lung adenocarcinoma.

There is a correlation between tumors and immunity with the degree of immune cell infiltration in tumors being closely related to tumor growth and progression. Therefore, the present study identified immune-related prognostic genes and evaluated the immune infiltration level in lung adenocarcinoma (LUAD). This study performed Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis (GSEA) enrichment analyses on differential immune-associated genes. A risk model was created and validated using six immune-related prognostic genes. Reverse transcription-quantitative PCR was used to assess the prognostic gene expression in non-small cell lung cancer cells. Immune cell infiltration in LUAD was analyzed using the CIBERSORT method. Single sample GSEA was used to compare Tumor Immune Dysfunction and Exclusion (TIDE) scores between high and low-risk groups and to assess the activation of thirteen immune-related pathways. Multifactor Cox proportional hazards model analysis identified six prognostic risk genes (S100A16, FURIN, FGF2, LGR4, TNFRSF11A and VIPR1) to construct a risk model. The survival and receiver operating characteristic curves indicated that patients with higher risk scores had lower overall survival rates. The expression levels of prognostic genes S100A16, FURIN, LGR4, TNFRSF11A and VIPR1 were significantly increased in LUAD. B cells naive, plasma cells, T cells CD4 memory activated, T cells follicular helper, T cells regulatory, NK cells activated, macrophages M1, macrophages M2, and Dendritic cells resting cells showed elevated expression in LUAD. The prognostic genes were differentially associated with individual immune cells. Immune-related function scores, such as those for antigen presenting cell (APC) co-stimulation, APC co-inhibition, check-point, Cytolytic-activity, chemokine receptor, parainflammation, major histocompatibility complex-class-I, type-I-IFN-reponse and T-cell-co-inhibition, were higher in the high-risk group compared with the low-risk group. Furthermore, the TIDE score of the high-risk group was significantly lower than the low-risk group. This immune-related gene prognostic model has the potential to predict the prognosis of LUAD patients, supporting the development of a personalized clinical diagnosis and treatment plan.