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Environment International Oct 2023Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic...
Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes.
Topics: Mice; Animals; Pregnancy; Humans; Female; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Ferroptosis; Abortion, Spontaneous; Benzo(a)pyrene; Endothelial Cells; Placenta; Proteins
PubMed: 37802009
DOI: 10.1016/j.envint.2023.108237 -
Pharmaceutics Jul 2023Lung cancer is a major public health problem and a leading cause of cancer-related deaths worldwide. Despite advances in treatment options, the five-year survival rate... (Review)
Review
Lung cancer is a major public health problem and a leading cause of cancer-related deaths worldwide. Despite advances in treatment options, the five-year survival rate for lung cancer patients remains low, emphasizing the urgent need for innovative diagnostic and therapeutic strategies. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets for lung cancer due to their crucial roles in regulating cell proliferation, differentiation, and apoptosis. For example, miR-34a and miR-150, once delivered to lung cancer via liposomes or nanoparticles, can inhibit tumor growth by downregulating critical cancer promoting genes. Conversely, miR-21 and miR-155, frequently overexpressed in lung cancer, are associated with increased cell proliferation, invasion, and chemotherapy resistance. In this review, we summarize the current knowledge of the roles of miRNAs in lung carcinogenesis, especially those induced by exposure to environmental pollutants, namely, arsenic and benzopyrene, which account for up to 1/10 of lung cancer cases. We then discuss the recent advances in miRNA-based cancer therapeutics and diagnostics. Such information will provide new insights into lung cancer pathogenesis and innovative diagnostic and therapeutic modalities based on miRNAs.
PubMed: 37631277
DOI: 10.3390/pharmaceutics15082061 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self-antigen, autoantibody production, and abnormal immune response....
BACKGROUND
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self-antigen, autoantibody production, and abnormal immune response. Cuproptosis is a recently reported cell death form correlated with the initiation and development of multiple diseases. This study intended to probe cuproptosis-related molecular clusters in SLE and constructed a predictive model.
METHODS
We analyzed the expression profile and immune features of cuproptosis-related genes (CRGs) in SLE based on GSE61635 and GSE50772 datasets and identified core module genes associated with SLE occurrence using the weighted correlation network analysis (WGCNA). We selected the optimal machine-learning model by comparing the random forest (RF) model, support vector machine (SVM) model, generalized linear model (GLM), and the extreme gradient boosting (XGB) model. The predictive performance of the model was validated by nomogram, calibration curve, decision curve analysis (DCA), and external dataset GSE72326. Subsequently, a CeRNA network based on 5 core diagnostic markers was established. Drugs targeting core diagnostic markers were acquired using the CTD database, and Autodock vina software was employed to perform molecular docking.
RESULTS
Blue module genes identified using WGCNA were highly related to SLE initiation. Among the four machine-learning models, the SVM model presented the best discriminative performance with relatively low residual and root-mean-square error (RMSE) and high area under the curve (AUC = 0.998). An SVM model was constructed based on 5 genes and performed favorably in the GSE72326 dataset for validation (AUC = 0.943). The nomogram, calibration curve, and DCA validated the predictive accuracy of the model for SLE as well. The CeRNA regulatory network includes 166 nodes (5 core diagnostic markers, 61 miRNAs, and 100 lncRNAs) and 175 lines. Drug detection showed that D00156 (Benzo (a) pyrene), D016604 (Aflatoxin B1), D014212 (Tretinoin), and D009532 (Nickel) could simultaneously act on the 5 core diagnostic markers.
CONCLUSION
We revealed the correlation between CRGs and immune cell infiltration in SLE patients. The SVM model using 5 genes was selected as the optimal machine learning model to accurately evaluate SLE patients. A CeRNA network based on 5 core diagnostic markers was constructed. Drugs targeting core diagnostic markers were retrieved with molecular docking performed.
Topics: Humans; Aflatoxin B1; Autoimmune Diseases; Benzo(a)pyrene; Lupus Erythematosus, Systemic; MicroRNAs; Molecular Docking Simulation; Copper; Apoptosis
PubMed: 37313407
DOI: 10.3389/fimmu.2023.1157196 -
Journal of Translational Medicine Oct 2023Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the...
BACKGROUND
Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated.
METHODS
Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking.
RESULTS
F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC.
CONCLUSIONS
Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.
Topics: Humans; Fusobacterium nucleatum; Matrix Metalloproteinase 7; Colorectal Neoplasms; Molecular Docking Simulation; Fusobacterium Infections
PubMed: 37814323
DOI: 10.1186/s12967-023-04527-3 -
Advanced Science (Weinheim,... Sep 2023Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show...
Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon-λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.
Topics: Aged; Male; Humans; Animals; Mice; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Benzo(a)pyrene; Lung; Nuclear Receptor Subfamily 4, Group A, Member 2; Serine Endopeptidases
PubMed: 37428471
DOI: 10.1002/advs.202300834 -
Redox Biology Nov 2023Benzo[α]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the...
Benzo[α]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the hepatotoxicity of Bap is mainly caused by its metabolites, although it remains unclear whether Bap itself induces such damage. This study integrated metabolomics and chemical proteomics approaches to comprehensively identify the potential target proteins affected by Bap in liver cells. The results from the metabolomics showed that the significant changed metabolites were related with cellular redox homeostasis. CEllular Thermal Shift Assay (CETSA) showed that Bap induced protein thermal displacement of superoxide dismutase 3 (SOD3) and glutathione peroxidase 4 (GPX4), which are closely related to oxidative homeostasis. Further validation through in vitro CETSA and drug affinity response target stability (DARTS) revealed that Bap directly affected the stability of SOD3 and GPX4 proteins. The binding affinities of Bap to the potential target proteins were further evaluated using molecular docking, while the isothermal titration calorimetry (ITC) interaction measurements indicated nanomolar-level Kd values. Importantly, we found that Bap weakened the antioxidant capacity by destroying the activities of SOD3 and GPX4, which provided a new understanding of the mechanism of hepatotoxicity induced by Bap. Moreover, our provided workflow integrating metabolomics and label-free chemical proteomics, can be regarded as a practical way to identify the targets and inter-mechanisms for the various environmental compounds.
Topics: Humans; Benzo(a)pyrene; Proteomics; Molecular Docking Simulation; Superoxide Dismutase; Proteins; Chemical and Drug Induced Liver Injury
PubMed: 37847980
DOI: 10.1016/j.redox.2023.102930 -
Environment International Feb 2024Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been... (Meta-Analysis)
Meta-Analysis
Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERβ) regulated by PAHs in CRC as well as the underlying mechanisms of ERβ-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERβ expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E had the opposite effects. Additionally, this study mapped ERβ genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERβ binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERβ by PAHs and endogenous E may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERβ and its downstream targets for CRC prevention and treatment.
Topics: Humans; Estrogen Receptor beta; Benzo(a)pyrene; Genome-Wide Association Study; Tandem Mass Spectrometry; Polycyclic Aromatic Hydrocarbons; Estrogens; Colorectal Neoplasms
PubMed: 38277997
DOI: 10.1016/j.envint.2024.108443 -
Environmental Health Perspectives Jan 2024The association between alcohol and certain cancers is well established, yet beyond ethanol and its metabolite acetaldehyde, little is known about the presence of other... (Review)
Review
BACKGROUND
The association between alcohol and certain cancers is well established, yet beyond ethanol and its metabolite acetaldehyde, little is known about the presence of other carcinogenic compounds in alcoholic beverages, including polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (a Group I carcinogen).
OBJECTIVES
We summarized the published literature on PAH levels in alcoholic beverages to identify potential gaps in knowledge to inform future research.
METHODS
Medline and Scopus were searched for primary research published from January 1966 to November 2023 that quantified PAH levels among various types of alcoholic beverages, including whisky, rum, brandy, gin, vodka, wine, and beer. Studies that were not primary literature were excluded; only studies that quantified PAH content in the specified alcoholic beverages were included.
RESULTS
Ten studies published from 1966 to 2019 met the criteria for review. Other than beverage type, no publication reported selection criteria for their samples of tested alcohol products. Studies used a variety of analytical methods to detect PAHs. Of the 10 studies, 7 were published after 2000, and 6 assessed products. Of the studies, 7 examined spirits; 3, beer; and 4, wines. Benzo[a]pyrene was most prevalent among spirit products, particularly whisky, with values generally exceeding acceptable levels for drinking water. Some beer and wine products also contained PAHs, albeit at lower levels and less frequently than spirit products.
DISCUSSION
PAHs are found in some alcohol products and appear to vary by beverage type. However, there is an incomplete understanding of their presence and levels among large, representative samples from the range of currently available alcohol products. Addressing this gap could improve understanding of alcohol-cancer relationships and may have important implications for public health and the regulation of alcohol products. In addition, novel methods, such as direct mass spectroscopy, may facilitate more thorough testing of samples to further investigate this relationship. https://doi.org/10.1289/EHP13506.
Topics: Polycyclic Aromatic Hydrocarbons; Benzo(a)pyrene; Alcoholic Beverages; Beer; Wine; Ethanol; Carcinogens
PubMed: 38241192
DOI: 10.1289/EHP13506 -
Food Science & Nutrition Jun 2023Mongolian butter and Tude are traditional high-fat dairy products produced in Xilin Gol, China, which have unique chemical and microbiological characteristics. Mongolian...
Mongolian butter and Tude are traditional high-fat dairy products produced in Xilin Gol, China, which have unique chemical and microbiological characteristics. Mongolian Tude is made from Mongolian butter, dreg, and flour. In this study, the traditional manufacturing process of Mongolian butter and Tude was investigated for the first time. Mongolian butter was characterized by high-fat content (99.38 ± 0.63%) and high acidity (77.09 ± 52.91°T), whereas Mongolian Tude was considered a high-fat (21.45 ± 1.23%) and high-protein (8.28 ± 0.65%) dairy product obtained by butter, dreg, and flour. Mongolian butter and Tude were proven to be safe for human consumption in terms of benzopyrene content. In addition, , , , coliforms, and aflatoxin M1 were not detected in the samples. Bacteria and molds were not isolated from Mongolian butter; in contrast, the total count of bacteria and molds in Mongolian Tude was within the range of 4.5 × 10 to 9.5 × 10 and 0 to 2.2 × 10, respectively. Moreover, (41.55%), (11.05%), (40.20%), and (12.90%) were the predominant bacterial and fungal genera, and (15.6%), (9.6%), (8.5%), (6.1%), (4.2%), (3.5%), (3.5%), (46.2%), (14.7%), and (11.7%) were the predominant species in the microbiota of Mongolian Tude. Thus, it can be stated that the microbiota of food products produced by different small families varied significantly. Collectively, the findings presented herein are the first report of chemical and microbiological characterization of products of geographical origin and highlight the need for standardization of manufacturing procedures of Mongolian butter and Tude in the future.
PubMed: 37324868
DOI: 10.1002/fsn3.3283 -
Scientific Reports Nov 2023Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection...
Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection still need to be better understood. Thus, this study aims to detect common differential genes and potential hub genes (HubGs), emphasizing their actions, signaling pathways, regulatory biomarkers for diagnosing RD and candidate drugs for treating RD. In this paper we used integrated bioinformatics approaches (such as, gene ontology (GO) and KEGG pathway enrichment analysis, molecular docking, molecular dynamic simulation and network-based molecular interaction analysis). We discovered 73 common DEGs (CDEGs) and ten HubGs (ATAD2B, PPP1CB, FOXO1, AKT3, BCR, PDE4D, ITGB1, PCBP2, CD44 and SMARCA2). Several significant functions and signaling pathways were strongly related to RD. We recognized six transcription factor (TF) proteins (FOXC1, GATA2, FOXL1, YY1, POU2F2 and HINFP) and five microRNAs (hsa-mir-218-5p, hsa-mir-335-5p, hsa-mir-16-5p, hsa-mir-106b-5p and hsa-mir-15b-5p) as the important transcription and post-transcription regulators of RD. Ten HubGs and six major TF proteins were considered drug-specific receptors. Their binding energy analysis study was carried out with the 63 drug agents detected from network analysis. Finally, the five complexes (the PDE4D-benzo[a]pyrene, SMARCA2-benzo[a]pyrene, HINFP-benzo[a]pyrene, CD44-ketotifen and ATAD2B-ponatinib) were selected for RD based on their strong binding affinity scores and stable performance as the most probable repurposable protein-drug complexes. We believe our findings will give readers, wet-lab scientists, and pharmaceuticals a thorough grasp of the biology behind RD.
Topics: Humans; Molecular Docking Simulation; Benzo(a)pyrene; MicroRNAs; Genetic Markers; Respiration Disorders; Respiratory Tract Diseases; Computational Biology; Gene Regulatory Networks; RNA-Binding Proteins
PubMed: 37925496
DOI: 10.1038/s41598-023-46455-8