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International Journal of Molecular... Dec 2021Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes,... (Review)
Review
Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka (), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP-BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.
Topics: 5-Methylcytosine; Animals; Benzo(a)pyrene; Biotin; Carcinogenesis; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Histone Deacetylases; Humans; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34948252
DOI: 10.3390/ijms222413453 -
International Journal of Molecular... Jun 2022Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments.... (Review)
Review
Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments. It is present in cigarette smoke as well as in food products, especially when smoked and grilled. Human exposure to B[]P is therefore common. Research shows growing evidence concerning toxic effects induced by this substance. This xenobiotic is metabolized by cytochrome P450 (CYP P450) to carcinogenic metabolite: 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[]pyrene (BPDE), which creates DNA adducts, causing mutations and malignant transformations. Moreover, B[]P is epigenotoxic, neurotoxic, and teratogenic, and exhibits pro-oxidative potential and causes impairment of animals' fertility. CYP P450 is strongly involved in B[]P metabolism, and it is simultaneously expressed as a result of the association of B[]P with aromatic hydrocarbon receptor (AhR), playing an essential role in the cancerogenic potential of various xenobiotics. In turn, polymorphism of genes determines the sensitivity of the organism to B[]P. It was also observed that B[]P facilitates the multiplication of viruses, which may be an additional problem with the widespread COVID-19 pandemic. Based on publications mainly from 2017 to 2022, this paper presents the occurrence of B[]P in various environmental compartments and human surroundings, shows the exposure of humans to this substance, and describes the mechanisms of its toxicity.
Topics: Animals; Benzo(a)pyrene; COVID-19; Carcinogens; Cytochrome P-450 Enzyme System; DNA Adducts; Humans; Pandemics; Polycyclic Aromatic Hydrocarbons
PubMed: 35683027
DOI: 10.3390/ijms23116348 -
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 -
Microorganisms Jun 2022Probiotic consumption is recognized as being generally safe and correlates with multiple and valuable health benefits. However, the mechanism by which it helps detoxify... (Review)
Review
Probiotic consumption is recognized as being generally safe and correlates with multiple and valuable health benefits. However, the mechanism by which it helps detoxify the body and its anti-carcinogenic and antimutagenic potential is less discussed. A widely known fact is that globalization and mass food production/cultivation make it impossible to keep all possible risks under control. Scientists associate the multitude of diseases in the days when we live with these risks that threaten the population's safety in terms of food. This review aims to explore whether the use of probiotics may be a safe, economically viable, and versatile tool in biodetoxification despite the numerous risks associated with food and the limited possibility to evaluate the contaminants. Based on scientific data, this paper focuses on the aspects mentioned above and demonstrates the probiotics' possible risks, as well as their anti-carcinogenic and antimutagenic potential. After reviewing the probiotic capacity to react with pathogens, fungi infection, mycotoxins, acrylamide toxicity, benzopyrene, and heavy metals, we can conclude that the specific probiotic strain and probiotic combinations bring significant health outcomes. Furthermore, the biodetoxification maximization process can be performed using probiotic-bioactive compound association.
PubMed: 35888997
DOI: 10.3390/microorganisms10071278 -
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 -
Acta Pharmaceutica Sinica. B Feb 2022Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize....
Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-2 expressions were examined in clinical tissues ( = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis inhibition of miR-7-5p. TGF-2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-2; the expressions of both miR-7-5p and TGF-2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.
PubMed: 35251919
DOI: 10.1016/j.apsb.2021.06.009 -
Biomedicines Jan 2023Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization... (Review)
Review
Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization in various life processes in beehives. Since ancient times, propolis has been a unique traditional remedy globally utilized for several purposes, and it has secured value in pharmaceutical and nutraceutical areas in recent years. The chemical composition of propolis comprises diverse constituents and deviations in the precise composition of the honeybee species, plant source used for propolis production by bees, climate conditions and harvesting season. Over 300 molecular structures have been discovered from propolis, and important classes include phenolic acids, flavonoids, terpenoids, benzofurans, benzopyrene and chalcones. Propolis has also been reported to have diverse pharmacological activities, such as antidiabetic, anti-inflammatory, antioxidant, anticancer, immunomodulatory, antibacterial, antiviral, antifungal, and anticaries. As chronic diseases have risen as a global health threat, abundant research has been conducted to track propolis and its constituents as alternative therapies for chronic diseases. Several clinical trials have also revealed the potency of propolis and its constituents for preventing and curing some chronic diseases. This review explores the beneficial effect of propolis and its active constituents with credible mechanisms and computational studies on chronic diseases.
PubMed: 36830794
DOI: 10.3390/biomedicines11020259 -
Biochimie Aug 2019Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers.... (Review)
Review
Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants, notably chemicals like polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread pollutants in our environment resulting from incomplete combustion or pyrolysis of organic material, and thus produced by both natural and anthropic sources; notably benzo[a]pyrene (B[a]P), i.e. the prototypical molecule of this family, that can be detected in cigarette smoke, diesel exhaust particles, occupational-related fumes, and grilled food. This molecule is a well-recognized carcinogen belonging to group 1 carcinogens. Indeed, it can target the different steps of the carcinogenic process and all cancer hallmarks. Interestingly, H dynamics have been described as key parameters for the occurrence of several, if not all, of these hallmarks. However, information regarding the role of such parameters during environmental carcinogenesis is still very scarce. The present review will thus mainly give an overview of the impact of B[a]P on H dynamics in liver cells, and will show how such alterations might impact different aspects related to the finely-tuned balance between cell death and survival processes, thereby likely favoring environmental carcinogenesis. In total, the main objective of this review is to encourage further research in this poorly explored field of environmental molecular toxicology.
Topics: Animals; Benzo(a)pyrene; Carcinogenesis; Carcinogens; Environmental Exposure; Humans; Liver; Neoplasms; Protons
PubMed: 31228544
DOI: 10.1016/j.biochi.2019.06.013 -
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