ABSTRACT
BACKGROUND: Currently, many emerging polycyclic aromatic hydrocarbons (PAHs) have been found to be widely present in the environment. However, little has been reported about their toxicity, particularly in relation to CYP1A1. OBJECTIVES: This study aimed to explore the toxicity of naphtho[2,1-a]pyrene (N21aP) and elucidate the mechanism underlying N21aP-induced expression of CYP1A1. METHODS: The concentration and sources of N21aP were detected and analyzed by gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) and diagnostic ratio analysis. Then the effects of CYP1A1 on the toxicity of N21aP were conducted in male wild-type (WT) and Cyp1a1 knockout mice exposed to N21aP (0.02, 0.2, and 2mg/kg) through intratracheal instillation. Further, the aryl hydrocarbon receptor (AhR) pathway was examined through luciferase and chromatin immunoprecipitation (ChIP) assays. N6-methyladenosine (m6A) modification levels were measured on global RNA and specifically on CYP1A1 mRNA using dot blotting and methylated RNA immunoprecipitation-quantitative real-time polymerase chain reaction (MeRIP qRT-PCR), with validation by m6A inhibitors, DAA and SAH. m6A sites on CYP1A1 were identified by bioinformatics and luciferase assays, and CYP1A1 mRNA's interaction with IGF2BP3 was confirmed by RNA pull-down, luciferase, and RNA binding protein immunoprecipitation (RIP) assays. RESULTS: N21aP was of the same environmental origin as benzo[a]pyrene (BaP) but was more stably present in the environment. N21aP could be metabolically activated by CYP1A1 to produce epoxides, causing DNA damage and further leading to lung inflammation. Importantly, in addition to the classical AhR pathway (i.e., BaP), N21aP also induced CYP1A1 expression with a posttranscriptional modification of m6A in CYP1A1 mRNA via the METTL14-IGF2BP3-CYP1A1 axis. Specifically, in the two recognition sites of METTL14 on the CYP1A1 mRNA transcript (position at 2700 and 5218), a methylation site (position at 5218) in the 3'-untranslated region (UTR) was recognized by IGF2BP3, enhanced the stability of CYP1A1 mRNA, and finally resulted in an increase in CYP1A1 expression. DISCUSSION: This study systematically demonstrated that in addition to AhR-mediated transcriptional regulation, N21aP, had a new additional mechanism of m6A-mediated posttranscriptional modification, jointly contributing to CYP1A1 expression. Given that PAHs are the metabolic substrates of CYP1A1, this study not only helps to understand the significance of environment-genetic interactions for the toxicity of PAHs but also helps to better understand the health risks of the emerging PAHs at environmental exposure levels. https://doi.org/10.1289/EHP14055.
Subject(s)
Cytochrome P-450 CYP1A1 , Receptors, Aryl Hydrocarbon , Animals , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1A1/genetics , Mice , Male , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/genetics , Mice, Knockout , Adenosine/analogs & derivatives , Adenosine/metabolism , Environmental Pollutants/toxicity , RNA Processing, Post-Transcriptional/drug effectsABSTRACT
Recently, research on the circadian rhythm of hypertension has gained popularity. However, few bibliometric analyses have been conducted in this field. In this study, CiteSpace 6.1. R6, VOSviewer 1.6.18, R language (version 4.2.3), R package Bibliometrix (4.1.2), and Microsoft Excel 365 were used to conduct the data mining and knowledge visualization analysis. A total of 1,560 papers from 1,825 institutions in 77 countries were included. Research on the role of circadian rhythms in hypertension is increasing annually. Overall, Chronobiology International published the most literature and Hypertension received the most citations. Ramon Hermida from the Universidade de Vigo in Spain published the most papers and had the most citations. The United States of America and Japan have been the most productive countries. The University of Ferrara, Universidade de Vigo, and the University of California system produced the most publications. Amongst authors, Hermida had the most and longest literature bursts. Keywords such as "chronic kidney disease," "oxidative stress," and "gene expression" have been breakout keywords since 2014. This study revealed the dynamic evolution of research on circadian rhythms in hypertension and provides a knowledge base for researchers.
Subject(s)
Bibliometrics , Circadian Rhythm , Hypertension , Circadian Rhythm/physiology , Humans , Hypertension/physiopathologyABSTRACT
Previous research has linked serum metabolite levels to iridocyclitis, yet their causal relationship remains unexplored. This study investigated this potential causality by analyzing pooled data from 7824 iridocyclitis patients in a Genome-Wide Association Study (GWAS) using Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC). Employing rigorous quality control and comprehensive statistical methods, including sensitivity analyses, we examined the influence of 486 serum metabolites on iridocyclitis. Our MR analysis identified 23 metabolites with significant causal effects on iridocyclitis, comprising 17 known and 6 unidentified metabolites. Further refinement using Cochran's Q test and MR-PRESSO indicated 16 metabolites significantly associated with iridocyclitis risk. LDSC highlighted the heritability of certain metabolites, underscoring genetic influences on their levels. Notably, tryptophan, proline, theobromine, and 7-methylxanthine emerged as risk factors, while 3,4-dihydroxybutyrate appeared protective. These findings enhance our understanding of the metabolic interactions in iridocyclitis, offering insights for diagnosis, unraveling pathophysiological mechanisms, and informing potential avenues for prevention and personalized treatment.
Subject(s)
Genome-Wide Association Study , Iridocyclitis , Mendelian Randomization Analysis , Humans , Iridocyclitis/genetics , Iridocyclitis/blood , Risk Factors , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Male , Female , Genetic Predisposition to DiseaseABSTRACT
Background: Allergic conjunctivitis (AC) afflicts a significant portion of the global populace. Yet, its metabolic foundations remain largely unexplored. Methods: We applied Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) to scrutinize a cohort comprising 20 958 AC cases and 356 319 controls. Data were amalgamated from the metabolomics GWAS server and the FinnGen project, under strict quality control protocols. Results: Using two-sample MR analysis, 486 blood metabolites were investigated in relation to AC. The IVW approach highlighted 18 metabolites as closely tied to AC risk; of these, 16 retained significance post sensitivity assessments for heterogeneity and horizontal pleiotropy. LDSC analysis, adopted to bolster our findings and negate confounders from shared genetic markers, revealed 8 metabolites with marked heritability, including: palmitate (OR = 0.614), 3-methoxytyrosine (OR = 0.657), carnitine (OR = 1.368), threonate (OR = 0.828), N-[3-(2-Oxopyrrolidin-1-yl)propyl]acetamide (OR = 1.257), metoprolol acid metabolite (OR = 0.982), oleoylcarnitine (OR = 0.635), and 2-palmitoylglycerophosphocholine (OR = 1.351). Conclusion: AC is precipitated by ocular responses to environmental allergens. Our study unveils a causal link between 8 blood metabolites and AC. This insight accentuates the role of metabolites in AC onset, suggesting novel avenues for its early prediction, targeted prevention, and tailored therapeutic interventions.
ABSTRACT
Structural alerts (SAs) are essential to identify chemicals for toxicity evaluation and health risk assessment. We constructed a novel SMILES split-based deep learning model (SSDL) that was trained and verified with 5850 chemicals from the ISSSTY database and 384 external test chemicals from published papers. The training accuracy was above 0.90 and the evaluation metrics (precision, recall and F1-score) all reached 0.78 or above on both internal and external test chemicals. In this model, the molecular-specific fragment importance of chemicals was first quantified independently. Then, the SA identification method based on the importance of these fragments was statistically analyzed and verified with the ISSSTY test and external test chemicals containing one of 28 typical SAs, and most of the performances were better than that of expert rules. Furthermore, a mutagenicity mechanism prediction method was developed using 237 chemicals with four known mutagenic mechanisms based on molecular similarity calibrated by the SSDL method and fragment importance, which significantly improved accuracy in three mechanisms and had comparable accuracy in the other one compared to traditional methods. Overall, the SSDL model quantifying fragment toxicity within molecules would be a novel potentially powerful tool in the determination and visualization of molecular-specific SAs and the prediction of mutagenicity mechanisms for environmental or industrial compounds and drugs.
Subject(s)
Mutagens , Neural Networks, Computer , Mutagens/toxicity , Mutagens/chemistry , Databases, Factual , Biometry , Risk AssessmentABSTRACT
Lipid metabolism plays a key role in erectile dysfunction. Our purpose was to evaluate the influence of lipid-lowering drugs on erectile dysfunction employing a two-sample Mendelian randomization (MR) study. Genetic instruments were employed to represent the exposure of lipid-lowering drugs. Inverse variance-weighted MR (IVWMR) was employed to calculate the estimation of effects. IVW-MR analysis showed that the positive relationship between the expression of HMGCR and the risk of erectile dysfunction (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.03-1.57; p = 0.028). No significant relationship was detected between NPC1L1, PSK9 expression and erectile dysfunction. This MR study suggested that HMGCR inhibitors are a more desirable treatment modality for patients with ED.
Subject(s)
Erectile Dysfunction , Male , Humans , Erectile Dysfunction/genetics , Mendelian Randomization Analysis , Hypolipidemic Agents , Lipid Metabolism , Lipids , Genome-Wide Association Study , Polymorphism, Single NucleotideABSTRACT
To investigate the mechanical properties of high-strength stainless steel wire mesh (HSSSWM) in Engineering Cementitious Composites (ECCs) and determine a reasonable lap length, a total of 39 specimens in 13 sets were designed and fabricated by considering the diameter of the steel strand, spacing of the transverse steel strand, and lap length. The lap-spliced performance of the specimens was tested through a pull-out test. The results revealed two failure modes in the lap connection of steel wire mesh in ECCs: pull-out failure and rupture failure. The spacing of the transverse steel strand had little effect on the ultimate pull-out force, but it restricted the slip of the longitudinal steel strand. A positive correlation was found between the spacing of the transverse steel strand and the slip amount of the longitudinal steel strand. With an increase in lap length, the slip amount and 'lap stiffness' to peak load increased, while the ultimate bond strength decreased. Based on the experimental analysis, a calculation formula for lap strength considering the correction coefficient ß was established.
ABSTRACT
Gastrointestinal cancers are the most common type of cancer affecting humans. High expression of HOX transcript antisense intergenic RNA (HOTAIR), a long noncoding RNA (lncRNA), in various types of different tumors may be associated with poor prognosis. In the present study, we performed a meta-analysis of the relationship between HOTAIR expression and gastrointestinal cancers. Five databases were comprehensively searched for all literature until January 2023. Moreover, the target genes of HOTAIR were predicted by coexpression analysis based on The Cancer Genome Atlas (TCGA) gene expression matrix for six gastrointestinal cancer types. Finally, the mechanism through which HOTAIR affects tumors of the digestive system was systematically reviewed. Our results showed that the high HOTAIR expression group had worse outcomes with a pooled hazard ratio (HR) of 1.56 (95% confidence interval [CI] = 1.38-1.75, P<0.001). Furthermore, HOTAIR was identified as an unfavorable prognostic factor for overall survival (OS) in the esophageal carcinoma (ESCA) and gastric cancer (GC), as the HR were 1.94 and 1.58, respectively. The high correlation between the expression of homeobox C (HOXC) family genes and HOTAIR, with correlation coefficients of 0.863 (HOXC11), 0.664 (HOXC10), 0.645 (HOXC8), and 0.581 (HOXC12). The 'cell cycle' pathway and pathways relating to infections, namely 'herpes simplex virus 1 infection' and 'complement and coagulation cascades' were significantly enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Also, we perform a systematic review to summarize the related oncogenic mechanism of HOTAIR. In conclusion, the HOTAIR has been identified as a potential prognostic factor in patients with gastrointestinal cancers.
Subject(s)
Esophageal Neoplasms , RNA, Long Noncoding , Stomach Neoplasms , Humans , Biomarkers , Esophageal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Prognosis , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Stomach Neoplasms/diagnosis , Stomach Neoplasms/geneticsABSTRACT
BACKGROUND: Immunosenescence, the aging of the immune system, leads to a decline in the body's adaptability to the environment and plays an important role in various diseases. Immunosenescence has been widely studied in recent years. However, to date, no relevant bibliometric analyses have been conducted. This study aimed to analyze the foundation and frontiers of immunosenescence research through bibliometric analysis. METHODS: Articles and reviews on immunosenescence from 1970 to 2021 were obtained from the Web of Science Core Collection. Countries, institutions, authors, journals, references, and keywords were analyzed and visualized using VOSviewer and CiteSpace. The R language and Microsoft Excel 365 were used for statistical analyses. RESULTS: In total, 3763 publications were included in the study. The global literature on immunosenescence research has increased from 1970 to 2021. The United States was the most productive country with 1409 papers and the highest H-index. Italy had the highest average number of citations per article (58.50). Among the top 10 institutions, 50 % were in the United States. The University of California was the most productive institution, with 159 articles. Kroemer G, Franceschi C, Goronzy JJ, Solana R, and Fulop T were among the top 10 most productive and co-cited authors. Experimental Gerontology (n = 170) published the most papers on immunosenescence. The analysis of keywords found that current research focuses on "inflammaging", "gut microbiota", "cellular senescence", and "COVID-19". CONCLUSIONS: Immunosenescence research has increased over the years, and future cooperation and interaction between countries and institutions must be expanded. The connection between inflammaging, gut microbiota, age-related diseases, and immunosenescence is a current research priority. Individualized treatment of immunosenescence, reducing its negative effects, and promoting healthy longevity will become an emerging research direction.
Subject(s)
COVID-19 , Immunosenescence , Humans , Cellular Senescence , BibliometricsABSTRACT
Background: Diabetic retinopathy (DR), a leading cause of vision loss, has limited options for effective prevention and treatment. This study aims to utilize genomics and proteomics data to identify potential drug targets for DR. Methods: We utilized plasma protein quantitative trait loci data from the Atherosclerosis Risk in Communities Study and the Icelandic Decoding Genetics Study for discovery and replication, respectively. Genetic associations with DR, including its subtypes, were derived from the FinnGen study. Mendelian Randomization (MR) analysis estimated associations between protein levels and DR risk, complemented by colocalization analysis to examine shared causal variants. Results: Our MR analysis identified significant associations of specific plasma proteins with DR and proliferative DR (PDR). Elevated genetically predicted levels of WARS (OR = 1.16; 95% CI = 0.095-0.208, FDR = 1.31×10-4) and SIRPG (OR = 1.15; 95% CI = 0.071-0.201, FDR = 1.46×10-2) were associated with higher DR risk, while increased levels of ALDOC (OR = 1.56; 95% CI = 0.246-0.637, FDR = 5.48×10-3) and SIRPG (OR = 1.15; 95% CI = 0.068-0.208, FDR = 4.73×10-2) were associated with higher PDR risk. These findings were corroborated by strong colocalization evidence. Conclusions: Our study highlights WARS, SIRPG, and ALDOC as significant proteins associated with DR and PDR, providing a basis for further exploration in drug development. Additional studies are needed to validate these proteins as disease biomarkers across diverse populations.
Subject(s)
Diabetes Mellitus , Diabetic Retinopathy , Humans , Mendelian Randomization Analysis , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/genetics , Blood Proteins , BiomarkersABSTRACT
Bond behavior is a key factor in the engineering application of composite material. This study focuses on the constitutive model of the bond behavior between high-strength stainless steel strand mesh and Engineered Cementitious Composites (ECC). In this paper, the effects of strand diameter, bond length and transverse steel strand spacing on bond behavior were studied based on 51 direct pullout tests. Experimental results showed that the high-strength stainless steel strand mesh provided specimens an excellent ductility. Based on the experimental data, the existing bond-slip model was revised using the theory of damage mechanics, which fully considered the influence of the steel strand diameter on the initial tangent stiffness of the bond-slip curve. The results of the model verification analysis show that errors are within 10% for most parameters of the bond-slip model proposed, especially in the ascending section, the errors are within 5%, indicating that the calculated results using the revised model are in good agreement with the test results. In addition, the revised model was applied to the finite element analysis by using the software ABAQUS to simulate the pullout test, in which the spring-2 nonlinear spring element was used to stimulate the bond behavior between steel strand meshes and ECC. The simulation results show that the numerical analysis fits the experimental result well, which further verifies the accuracy of the model and the feasibility and applicability of the numerical analysis method.