Potential Adverse Outcome Pathways of Chlorinated Organophosphate Flame Retardants.

What is already known about this topic?: Chlorinated organophosphate flame retardants (Cl-OPFRs) are frequently detected chemicals in the environment and biological samples, yet there is a lack of systematic evaluation regarding the adverse effects and toxicological mechanisms of Cl-OPFRs. What is added by this report?: This study utilizes the adverse outcome pathway (AOP) framework to assess the health implications and mechanisms of Cl-OPFRs, identifying multi-system toxicity, with a particular emphasis on reproductive issues and the possible toxic mechanisms. What are the implications for public health practice?: These results enhance knowledge of the health hazards linked to Cl-OPFRs, supporting the creation of focused risk evaluations and suitable regulatory actions.

Genetic variants in C1GALT1 are associated with gastric cancer risk and immune infiltrations.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-ß-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer susceptibility. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated these associations with a logistic regression model and identified that the rs35999583 in C1GALT1 was associated with gastric cancer risk (odd ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; P = 3.95 × 10 -4]. C1GALT1 mRNA expression was significantly higher in gastric tumor tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had the worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; P log-rank = 1.90 × 10 -2). Furthermore, we found that C1GALT1 copy number variations differed in various immune cells and C1GALT1 mRNA expression was positively correlated with the infiltrating levels of CD4 + T cells and macrophages. These results highlight that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 to be a promising predictor of gastric cancer susceptibility and immune status.

Non-selective microbiota reduction after the elicitation of a seaweed's immune response.

Pattern-triggered immunity (PTI) is an integral part of the innate immune system of many eukaryotic hosts, assisting in the defence against pathogen invasions. In plants and animals, PTI exerts a selective pressure on the microbiota that can alter community composition. However, the effect of PTI on the microbiota for non-model hosts, including seaweeds, remains unknown. Using quantitative polymerase chain reaction complemented with 16S rRNA gene and transcript amplicon sequencing, this study profiled the impact that PTI of the red seaweed Gracilaria gracilis has on its microbiota. PTI elicitation with agar oligosaccharides resulted in a significant reduction in the number of bacteria (by >75% within 72 h after treatment). However, the PTI elicitation did not cause any significant difference in the community diversity or structure. These findings demonstrated that PTI can be non-selective, and this might help to maintain a stable microbiota by uniformly reducing bacterial loads.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Ecological relevance of flagellar motility in soil bacterial communities.

Flagellar motility is a key bacterial trait as it allows bacteria to navigate their immediate surroundings. Not all bacteria are capable of flagellar motility, and the distribution of this trait, its ecological associations, and the life history strategies of flagellated taxa remain poorly characterized. We developed and validated a genome-based approach to infer the potential for flagellar motility across 12 bacterial phyla (26 192 unique genomes). The capacity for flagellar motility was associated with a higher prevalence of genes for carbohydrate metabolism and higher maximum potential growth rates, suggesting that flagellar motility is more prevalent in environments with higher carbon availability. To test this hypothesis, we applied a method to infer the prevalence of flagellar motility in whole bacterial communities from metagenomic data and quantified the prevalence of flagellar motility across four independent field studies that each captured putative gradients in soil carbon availability (148 metagenomes). We observed a positive relationship between the prevalence of bacterial flagellar motility and soil carbon availability in all datasets. Since soil carbon availability is often correlated with other factors that could influence the prevalence of flagellar motility, we validated these observations using metagenomic data from a soil incubation experiment where carbon availability was directly manipulated with glucose amendments. This confirmed that the prevalence of bacterial flagellar motility is consistently associated with soil carbon availability over other potential confounding factors. This work highlights the value of combining predictive genomic and metagenomic approaches to expand our understanding of microbial phenotypic traits and reveal their general environmental associations.

Regional microbial biogeography linked to soil respiration.

The relationships between α-diversity and ecosystem functioning (BEF) have been extensively examined. However, it remains unknown how spatial heterogeneity of microbial community, i.e., microbial ß-diversity within a region, shapes ecosystem functioning. Here, we examined microbial community compositions and soil respiration (Rs) along an elevation gradient of 853-4420 m a.s.l. in the southeastern Tibetan Plateau, which is renowned as one of the world's biodiversity hotspots. There were significant distance-decay relationships for both bacterial and fungal communities. Stochastic processes played a dominant role in shaping bacterial and fungal community compositions, while soil temperature was the most important environmental factor that affected microbial communities. We evaluated BEF relationships based on α-diversity measured by species richness and ß-diversity measured by community dispersions, revealing significantly positive correlations between microbial ß-diversities and Rs. These correlations became stronger with increasing sample size, differing from those between microbial α-diversities and Rs. Using Structural Equation Modeling (SEM), we found that soil temperature, soil moisture, and total nitrogen were the most important edaphic properties in explaining Rs. Meanwhile, stochastic processes (e.g., homogenous dispersal and dispersal limitation) significantly mediated effects between microbial ß-diversities and Rs. Microbial α-diversity poorly explained Rs, directly or indirectly. In a nutshell, we identified a previously unknown BEF relationship between microbial ß-diversity and Rs. By complementing common practices to examine BEF with α-diversity, we demonstrate that a focus on ß-diversity could be leveraged to explain Rs.

Diversity and distribution of biosynthetic gene clusters in agricultural soil microbiomes.

Bacterial secondary metabolites serve as an important source of molecules for drug discovery. They also play an important function in mediating the interactions of microbial producers with their living environment and surrounding organisms. However, little is known about the genetic novelty, distribution, and community-level impacts of soil bacterial biosynthetic potential on a large geographic scale. Here, we constructed the first catalog of 11,149 biosynthetic gene clusters (BGCs) from agricultural soils across China and unearthed hidden biosynthetic potential for new natural product discovery from the not-yet-cultivated soil bacteria. Notably, we revealed soil pH as the strongest environmental driver of BGC biogeography and predicted that soil acidification and global climate change could damage the biosynthetic potential of the soil microbiome. The co-occurrence network of bacterial genomes revealed two BGC-rich species, i.e., Nocardia niigatensis from Actinobacteriota and PSRF01 from Acidobacteriota, as the module hub and connector, respectively, indicating their keystone positions in the soil microbial communities. We also uncovered a dominant role of BGC-inferred biotic interactions over environmental drivers in structuring the soil microbiome. Overall, this study achieved novel insights into the BGC landscape in agricultural soils of China, substantially expanding our understanding of the diversity and novelty of bacterial secondary metabolism and the potential role of secondary metabolites in microbiota assembly.IMPORTANCEBacterial secondary metabolites not only serve as the foundation for numerous therapeutics (e.g., antibiotics and anticancer drugs), but they also play critical ecological roles in mediating microbial interactions (e.g., competition and communication). However, our knowledge of bacterial secondary metabolism is limited to only a small fraction of cultured strains, thus restricting our comprehensive understanding of their diversity, novelty, and potential ecological roles in soil ecosystems. Here, we used culture-independent metagenomics to explore biosynthetic potentials in agricultural soils of China. Our analyses revealed a high degree of genetic diversity and novelty within biosynthetic gene clusters in agricultural soil environments, offering valuable insights for biochemists seeking to synthesize novel bioactive products. Furthermore, we uncovered the pivotal role of BGC-rich species in microbial communities and the significant relationship between BGC richness and microbial phylogenetic turnover. This information emphasizes the importance of biosynthetic potential in the assembly of microbial communities.

Biogeographic patterns and drivers of soil viromes.

Viruses are crucial in shaping soil microbial functions and ecosystems. However, studies on soil viromes have been limited in both spatial scale and biome coverage. Here we present a comprehensive synthesis of soil virome biogeographic patterns using the Global Soil Virome dataset (GSV) wherein we analysed 1,824 soil metagenomes worldwide, uncovering 80,750 partial genomes of DNA viruses, 96.7% of which are taxonomically unassigned. The biogeography of soil viral diversity and community structure varies across different biomes. Interestingly, the diversity of viruses does not align with microbial diversity and contrasts with it by showing low diversity in forest and shrubland soils. Soil texture and moisture conditions are further corroborated as key factors affecting diversity by our predicted soil viral diversity atlas, revealing higher diversity in humid and subhumid regions. In addition, the binomial degree distribution pattern suggests a random co-occurrence pattern of soil viruses. These findings are essential for elucidating soil viral ecology and for the comprehensive incorporation of viruses into soil ecosystem models.

Nitrogen fertilization reduces plant diversity by changing the diversity and stability of arbuscular mycorrhizal fungal community in a temperate steppe.

Nitrogen (N) deposition resulting from anthropogenic activities poses threats to ecosystem stability by reducing plant and microbial diversity. However, the role of soil microbes, particularly arbuscular mycorrhizal fungi (AMF), as mediators of N-induced shifts in plant diversity remains unclear. In this study, we conducted 6 and 11 years of N addition field experiments in a temperate steppe to investigate AMF richness and network stability and their associations with plant species richness in response to N deposition. The N fertilization, especially in the 11 years of N addition, profoundly decreased the AMF richness and plant species richness. Furthermore, N fertilization significantly decreased the AMF network complexity and stability, with these effects becoming more enhanced with the increase in N addition duration. AMF richness and network stability showed positive associations with plant diversity, and these associations were stronger after 11 than 6 years of N addition. Our findings suggest that N deposition may lead to plant diversity loss via a reduction of AMF richness and network stability, with these effects strengthened over time. This study provides a better understanding of plant-AMF interactions and their response to the prevailing global N deposition.

Assessment of human exposure to cadmium and its nephrotoxicity in the Chinese population.

BACKGROUND: Cadmium (Cd) is a toxic heavy metal that widely detected in environment and accumulated in kidney, posing a great threat to human health. However, there is a lack of systematic investigation of exposure profile and association of Cd exposure with renal function in the Chinese population. METHODS: Related articles were searched from PubMed, Web of Science, China National Knowledge Internet, and Wanfang to construct an aggregate exposure pathway (AEP) framework for Cd and to explore the correlation between Cd and renal function using random effects models. RESULTS: A total of 220 articles were included in this study, among which 215 investigated human exposure and 12 investigated the association of Cd with renal outcomes. The AEP framework showed that 96.5 % and 62.5 % of total Cd intake were attributed to dietary intake in nonsmokers and smokers, respectively. And 35.2 % originated from cigarette smoke inhalation in smokers. In human body, Cd was detected in blood, urine, placenta, etc. Although the concentrations of Cd in blood and urine from subjects living in polluted areas showed a sharp downward trend since the early 21st century, higher concentration of Cd in the environment and human body in polluted areas was found. Kidney was the target organ. The level of blood Cd was positively associated with urinary ß2-microglobulin [ß2-MG, r (95 % CI) = 0.12 (0.05, 0.19)], albumin [0.13 (0.06, 0.20)], and retinol-binding protein [RBP, 0.14 (0.03, 0.24)]. Elevated urinary Cd was correlated with increases in ß2-MG [0.22 (0.15, 0.29)], albumin [0.23 (0.16, 0.29)], N-acetyl-ß-d-glucosaminidase [NAG, 0.33 (0.22, 0.44)], and RBP [0.22 (0.14, 0.30)]. CONCLUSIONS: Foods and cigarette smoke were two major ways for Cd intake, and Cd induced renal injury in the Chinese population. This study enhanced the understanding of human exposure and nephrotoxicity of Cd, and emphasized the need for controlling Cd level in polluted areas.

Positive associations fuel soil biodiversity and ecological networks worldwide.

Microbial interactions are key to maintaining soil biodiversity. However, whether negative or positive associations govern the soil microbial system at a global scale remains virtually unknown, limiting our understanding of how microbes interact to support soil biodiversity and functions. Here, we explored ecological networks among multitrophic soil organisms involving bacteria, protists, fungi, and invertebrates in a global soil survey across 20 regions of the planet and found that positive associations among both pairs and triads of soil taxa governed global soil microbial networks. We further revealed that soil networks with greater levels of positive associations supported larger soil biodiversity and resulted in lower network fragility to withstand potential perturbations of species losses. Our study provides unique evidence of the widespread positive associations between soil organisms and their crucial role in maintaining the multitrophic structure of soil biodiversity worldwide.

Genetic variants in hypoxia-inducible factor pathway are associated with colorectal cancer risk and immune infiltration.

Hypoxia-inducible factor (HIF) pathway genes influence tumorigenesis and immune status. However, the associations between genetic variants in hypoxia-related genes and colorectal cancer risk and the immune status of hypoxia-associated genes in colorectal cancer have not been systematically characterized. The associations between genetic variants and colorectal cancer risk were evaluated in Chinese, Japanese and European populations using logistic regression analysis. The relationships between target genes and tumour immune infiltration were predicted by Tumour Immune Estimation Resource (TIMER). We found that rs34533650 in EPAS1 was associated with colorectal cancer risk (OR = 1.43, 95% CI = 1.20-1.70, P(FDR) = 8.35 × 10-4 ), and this finding was validated in two independent populations (Japanese: OR = 1.07, 95% CI = 1.01-1.15, p = 3.38 × 10-2 ; European: OR = 1.11, 95% CI = 1.03-1.19, p = 6.04 × 10-3 ). EPAS1-associated genes were enriched in immune-related pathways. In addition, we found that EPAS1 copy number variation (CNV) was associated with the degree of infiltration of immune cells and observed correlations between EPAS1 expression and immune cell infiltration levels in colorectal cancer. These results highlight that genetic variants of hypoxia-related genes play roles in colorectal cancer risk and provide new insight that EPAS1 might be a promising predictor of colorectal cancer susceptibility and immune status.

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk.

Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159-1.583, P = 1.33 × 10 -4; rs2683524: OR = 1.378, 95% CI: 1.164-1.632, P = 2.03 × 10 -4; rs11540872: OR = 1.472, 95% CI: 1.193-1.815, P = 3.06 × 10 -4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer ( P trend = 2.87 × 10 -12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3' untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

Hepatic sialic acid synthesis modulates glucose homeostasis in both liver and skeletal muscle.

OBJECTIVE: Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. METHODS: To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. RESULTS: Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. CONCLUSION: These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor.

Reactive Oxygen Species-Triggered Curcumin Release from Hollow Mesoporous Silica Nanoparticles for PM2.5-Induced Acute Lung Injury Treatment.

Exposure to fine particulate matter with a diameter ≤2.5 µm (PM2.5) can result in serious inflammation and oxidative stress in lung tissue. However, there is presently very few effective treatments for PM2.5-induced many pulmonary diseases, such as acute lung injury (ALI). Herein, curcumin-loaded reactive oxygen species (ROS)-responsive hollow mesoporous silica nanoparticles (Cur@HMSN-BSA) are proposed for scavenging the intracellular ROS and suppressing inflammatory responses against PM2.5-induced ALI. The prepared nanoparticles were coated with bovine serum albumin (BSA) via an ROS-sensitive thioketal (TK)-containing linker, in which the TK-containing linker would be cleaved by the excessive amounts of ROS in inflammatory sites to induce the detachment of BSA from the nanoparticles surface and thus triggering release of loaded curcumin. The Cur@HMSN-BSA nanoparticles could be used as ROS scavengers because of their excellent ROS-responsiveness, which were able to efficiently consume high concentrations of intracellular ROS. Furthermore, it was also found that Cur@HMSN-BSA downregulated the secretion of several important pro-inflammatory cytokines and promoted the polarization from M1 phenotypic macrophages to M2 phenotypic macrophages for eliminating PM2.5-induced inflammatory activation. Therefore, this work provided a promising strategy to synergistically scavenge intracellular ROS and suppress the inflammation responses, which may serve as an ideal therapeutic platform for pneumonia treatment.

Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.

Soil edaphic factors and climate seasonality explain the turnover of methanotrophic communities in riparian wetlands.

Aerobic CH4-oxidizing bacteria (methanotrophs) represent a biological model system for the removal of atmospheric CH4, which is sensitive to the dynamics of water tables. However, little attention has been given to the turnover of methanotrophic communities across wet and dry periods in riparian wetlands. Here, by sequencing the pmoA gene, we investigated the turnover of soil methanotrophic communities across wet and dry periods in typical riparian wetlands that experience intensive agricultural practices. The results demonstrated that the methanotrophic abundance and diversity were significantly higher in the wet period than in the dry period, probably owing to the climatic seasonal succession and associated variation in soil edaphic factors. The co-occurrence patterns of the interspecies association analysis demonstrated that the key ecological clusters (i.e., Mod#1, Mod#2, Mod#4, Mod#5) showed contrasting correlations with soil edaphic properties between wet and dry periods. The linear regression slope of the relationships between the relative abundance of Mod#1 and the carbon to nitrogen ratio was higher in the wet period than in the dry period, whereas the linear regression slope of the relationships between the relative abundance of Mod#2 and soil nitrogen content (i.e., dissolved organic nitrogen, nitrate, and total nitrogen) was higher in the dry period than in the wet period. Moreover, Stegen's null model combined with phylogenetic group-based assembly analysis demonstrated that the methanotrophic community exhibited a higher proportion of drift (55.0%) and a lower contribution of dispersal limitation (24.5%) in the wet period than in the dry period (43.8% and 35.7%, respectively). Overall, these findings demonstrate that the turnover of methanotrophic communities across wet and dry periods were soil edaphic factors and climate dependent.

linc01515 regulates PM2.5-induced oxidative stress via targeting NRF2 in airway epithelial cells.

Dysregulation of long non-coding RNAs (lncRNAs) is involved in the adverse effects caused by fine particulate matter (PM2.5). However, the molecular mechanism is not fully clarified. In this study, we performed lncRNA sequencing on PM2.5-treated human bronchial epithelial (HBE) cells to identify vital lncRNAs, and verified the differential expression of the lncRNAs by RT-qPCR in HBE and human normal lung epithelial (BEAS-2B) cells. A total of 657 and 652 lncRNAs were dysregulated after exposure to 125 and 250 µg/mL of PM2.5, respectively. Of these, lncRNA linc01515 was upregulated in HBE and BEAS-2B cells with PM2.5 treatment. Subcellular localization experiments showed that linc01515 was mostly localized in the nucleus. Functionally, we downregulated the expression of linc01515 in HBE and BEAS-2B cells before PM2.5 treatment, which can decrease malonydialdehyde (MDA) and reactive oxygen species (ROS) levels, and improve superoxide dismutase (SOD) activity. Correspondingly, linc01515 overexpression enhanced PM2.5-induced oxidative injury in airway epithelial cells. Mechanistically, N6-methyladenosine RNA binding protein immunoprecipitation (MeRIP) assay showed that the enrichment level of m6A on linc01515 was increased after PM2.5 treatment, and the m6A modification level and expression of linc01515 was decreased in the HBE cells with 3-deazaadenosine (DAA) treatment or knockdown of METTL3 to inhibit the RNA methylation level. Western blot found that NRF2, a vital transcription factor, was enhanced remarkably in linc01515-silenced cells and decreased in linc01515-overexpressed cells. Furthermore, inhibition of NRF2 activity significantly rescued effect of downregulated linc01515 expression on PM2.5-induced cytotoxicity. In addition, we observed the similar effect when downregulating linc01515 and NRF2 expression in HBE and BEAS-2B cells before PM2.5 treatment. Taken together, our findings demonstrated that PM2.5 treatment may upregulate the expression of linc01515 by enhancing its m6A modification, and then regulate NRF2 to induce oxidative damage of airway epithelial cells.

LncRNA BCLET variant confers bladder cancer susceptibility through alternative splicing of MSANTD2 exon 1.

BACKGROUND: Alternative splicing (AS)-related single nucleotide polymorphisms (SNPs) are associated with risk of cancers, but the potential mechanism has not been fully elucidated. METHODS: Two-stage case-control studies comprising 1630 cases and 2504 controls were conducted to investigate the association between the AS-SNPs and bladder cancer susceptibility. A series of assays were used to evaluate the functional effect of AS-SNPs on bladder cancer risk. RESULTS: We observed that SNP rs558814 A>G located in lncRNA BCLET (Bladder Cancer Low-Expressed Transcript, ENSG00000245498) can decrease the risk of bladder cancer (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.76-0.92, p = 3.26 × 10-4 ). Additionally, the G allele of rs558814 had transcriptional regulatory effects and facilitated the expression of BCLET transcripts, including BCLET-long and BCLET-short. We also found decreased BCLET expression in bladder cancer tissues and cells, and BCLET transcript upregulation substantially inhibited tumor growth of both bladder cancer cells and xenograft models. Mechanistically, BCLET recognized and regulated AS of MSANTD2 to participate in bladder carcinogenesis, preferentially promoting the production of MSANTD2-004. CONCLUSIONS: SNP rs558814 was associated with the expression of BCLET, which mainly increased the expression of MSANTD2-004 through AS of MSANTD2.