Search Results (115)

1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mutagenic monoadducts and DNA–DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in mutagenicity is a well-established mode of action for 1,3-butadiene, characterization of the extent of inter-individual variability in response to BD exposure is a gap in our knowledge. Previous studies showed that population-wide mouse models can be used to evaluate variability in 1,3-butadiene DNA adducts; therefore, we hypothesized that this approach can be used to also study variability in the formation and loss of BD DNA adducts across tissues and between sexes. To test this hypothesis, female and male mice from five genetically diverse Collaborative Cross (CC) strains were exposed to filtered air or 1,3-butadiene (600 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Some animals were kept for two additional weeks after exposure to study DNA adduct persistence. EB-GII and bis-N7G-BD adducts were quantified in liver, lungs and kidney using established isotope dilution ESI-MS/MS methods. We observed strain- and sex-specific effects on both the accumulation and loss of both DNA adducts, indicating that both factors play important roles in the mutagenicity of 1,3-butadiene. In addition, we quantified the intra-species variability for each adduct and found that for most tissues/adducts, variability values across strains were modest compared to default uncertainty factors. Full article

The mudflat crab (H. tientsinensis) is a dominant species in coastal tidal flat areas, primarily inhabiting the high tide region of the intertidal zone, and possesses significant ecological and economic value. Vibrio species are one of the main bacterial pathogens responsible for diseases in marine organisms, and they are widely distributed in seawater and estuarine environments. However, the immune mechanisms employed by H. tientsinensis in response to Vibrio infections remain unclear. This study aims to investigate the physiological and immune mechanisms by analyzing the structural changes and differential gene expression in the gill and hepatopancreas following Vibrio parahaemolyticus infection. The results indicate that V. parahaemolyticus infection causes cellular damage, with structural alterations observed in the gills (epithelial cell edema in the gill filaments, and aneurysm formation) and the hepatopancreas (changes in lumen size, nuclear condensation, and modifications in connective tissue morphology). Transcriptome analysis revealed 9766 differentially expressed genes (DEGs) in the gills of the experimental group, with 4687 upregulated and 5079 downregulated genes. These DEGs are primarily involved in different ribosomal subunits. In the hepatopancreas, 1594 DEGs were identified, with 834 upregulated and 760 downregulated. These DEGs are predominantly associated with energy-coupled proton transmembrane transport, electron transport-coupled proton transport, and lipid transporter activity. H. tientsinensis gene annotation and KEGG enrichment analysis revealed that chemical carcinogens DNA adducts, amino acid metabolism, and some immune pathways play key roles in the ability of H. tientsinensis to defend against V. parahaemolyticus infection. The findings of this study contribute to a deeper understanding of the immune mechanisms of H. tientsinensis against V. parahaemolyticus infection and provide new insights for aquaculture management. Full article

Aflatoxins (AFs), harmful secondary metabolites produced by the genus Aspergillus, particularly Aspergillus flavus and Aspergillus parasiticus, are one of the best-known potent mycotoxins, posing a significant risk to public health. The primary type, especially aflatoxin B₁ (AFB₁), is a potent carcinogen associated with liver cancer, immunosuppression, and other health problems. Environmental factors such as high temperatures, humidity, and inadequate storage conditions promote the formation of aflatoxin in staple foods such as maize, peanuts, and rice. Immunocompromised individuals, including those with HIV/AIDS, hepatitis, cancer, or diabetes, are at increased risk due to their reduced detoxification capacity and weakened immune defenses. Chronic exposure to AF in these populations exacerbates liver damage, infection rates, and disease progression, particularly in developing countries and moderate-income populations where food safety regulations are inadequate and reliance on contaminated staple foods is widespread. Biomarkers such as aflatoxin-albumin complexes, urinary aflatoxin M₁, and aflatoxin (AF) DNA adducts provide valuable insights but remain underutilized in resource-limited settings. Despite the globally recognized health risk posed by AF, research focused on monitoring human exposure remains limited, particularly among immunocompromised individuals. This dynamic emphasizes the need for targeted studies and interventions to address the particular risks faced by immunocompromised individuals. This review provides an up-to-date overview of AF exposure in immunocompromised populations, including individuals with cancer, hepatitis, diabetes, malnutrition, pregnant women, and the elderly. It also highlights exposure pathways, biomarkers, and biomonitoring strategies, while emphasizing the need for targeted interventions, advanced diagnostics, and policy frameworks to mitigate health risks in these vulnerable groups. Addressing these gaps is crucial to reducing the health burden and developing public health strategies in high-risk regions. Full article

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive intake has been shown to lead to chronic inflammation, which is related to increased production of reactive oxygen species (ROS). This conditioncan initiate lipid peroxidation in cell membranes, leading to the degradation of their fatty acids. One of the main products of omega-6 peroxidation is the α,β-unsaturated aldehyde, i.e., 4-hydroxynonenal (4-HNE), which is able to form four diastereoisomeric adducts with guanine. These 4-HNE adducts have been identified in the DNA of humans and rodents. Depending on their stereochemistry, they are able to influence double helix stability and cause DNA–DNA or DNA–Protein cross-links. Moreover, studies have shown that 4-HNE adducts formed in the human genome are considered mutation hotspots in hepatocellular carcinoma. Although the cell possesses defence mechanisms, without a well-balanced diet allowing correct cell function, they may not be sufficient to protect the genetic code. This review provides an overview of the molecular mechanisms underlying oxidative stress, lipid peroxidation, and the formation of DNA adducts. Particular emphasis is placed on the role of an omega-6-rich diet in inflammatory diseases, and on the formation of 4-HNE, which is a major product of lipid peroxidation, and its broader implications for genome stability, ageing, and disease progression. Full article

Estrogens are considered the most important risk factor for the development of breast cancer. Therefore, attempts are being made to reduce their level through diminished synthesis on one hand and to protect against the formation of DNA-damaging estrogen metabolites on the other. Cytochromes P450 (CYPs) play key roles in estrogen synthesis and catabolism, leading to potentially carcinogenic metabolites. CYP19 (aromatase) catalyzes the conversion of androgens to estrogens. The estrogen receptor-dependent pathway induces cell growth. CYP1 family enzymes, particularly CYP1B1, are involved in the redox cycling of estrogen metabolites and the subsequent estrogen–DNA adducts formation. Naturally occurring phytochemicals of different classes were shown to modulate the CYP expression and activity in cell-free systems or breast cancer cells. One of the most promising CYP19 inhibitors is chrysin (flavone), while stilbenes seem to be the most effective CYP1B1 inhibitors. In most cases, their effect is not specific. Therefore, different approaches are made to find the best candidate for the drug prototype of a new therapeutic or chemopreventive agent and to improve its pharmacokinetic parameters. This review presents and discusses the possible effects on major CYPs involved in estrogen metabolism by phytochemicals from the most investigated classes, namely flavonoids, stilbenes, and glucosinolates breakdown products. Full article

Background: Nedaplatin is a platinum-based anticancer drug that combines the benefits of Cisplatin and Carboplatin, retaining Cisplatin’s anticancer activity while reducing toxicity similar to Carboplatin. After hydrolysis, Nedaplatin targets purines in DNA and forms cross-links that induce cell death via apoptosis. However, it is important to consider how the presence of other chemical compounds with structural similarities to Adenine or Guanine, such as aromatic, purine, or pyrimidine compounds containing a nitrogen atom with a free electron pair, might influence its activity at the cellular level. Alkaloids with structures similar to DNA nucleobases are common, and their influence on Nedaplatin’s activity requires investigation. Methods: In this study, the interactions between Nedaplatin (including its hydrolyzed forms, such as [Pt(NH₃)₂(H₂O)₂]²⁺ and [Pt(NH₃)₂(H₂O)(OH)]⁺) and nucleobases (Adenine and Guanine) and purine alkaloids (Caffeine, Theobromine and Theophylline) were thoroughly investigated using theoretical (density functional theory, DFT) and experimental (UV-Vis spectroscopy) methods. DFT calculations were performed at the B3LYP/6-31G(d,p)/LANL2DZ and MN15/def2-TZVP levels, with structure optimization and harmonic analysis in the gas phase and aqueous solution (modeled using IEF-PCM). UV-Vis spectroscopy was used to verify theoretical findings by examining changes in absorption spectra. Results: Both theoretical and experimental studies confirmed that Nedaplatin forms complexes with both nucleobases and purine alkaloids. Nedaplatin was found to exhibit a higher affinity for nucleobases than for purine alkaloids. Furthermore, this affinity was dependent on the computational method used and on the hydrolyzed form of Nedaplatin. Theoretical calculations showed the formation of stable complexes through bonding with nitrogen atoms in the ligand molecules, which was confirmed by changes in UV-Vis spectra, indicating adduct formation. Conclusions: The results indicate that Nedaplatin readily forms complexes with both nucleobases and purine alkaloids, showing a stronger affinity for nucleobases. This finding highlights the potential importance of Nedaplatin’s interactions with other compounds present in the body, which may influence its effectiveness and mechanism of action in cancer therapy. These studies provide new insights into the molecular mechanisms of Nedaplatin’s action and may contribute to a better understanding of its pharmacological interactions. However, research requires confirmation not only in in vivo studies but also in clinical trials. Full article

Hepatocellular carcinoma (HCC) imposes a significant burden on global public health. Exposure to aflatoxins, potent mycotoxins produced by Aspergillus fungi contaminating staple foods, and chronic hepatitis B virus (HBV) infection are major etiological factors, especially where they co-exist. This review examines the critical role of the p53 tumor suppressor pathway as a primary target and convergence point for the carcinogenic actions of aflatoxins and HBV. Aflatoxin B₁ (AFB₁), a Group 1 carcinogen, exerts significant genotoxicity, characteristically inducing a specific hotspot mutation (R249S) in the TP53 gene via DNA adduct formation, thereby compromising p53’s critical tumor suppressor functions. This R249S mutation is considered a molecular fingerprint of aflatoxin exposure. Concurrently, the HBV X protein (HBx) functionally inactivates wild-type p53 through direct binding and by promoting its degradation. The synergistic disruption of the p53 pathway, driven by AFB₁-induced mutation and amplified by HBV-mediated functional inhibition, significantly enhances the risk of HCC development. This review addresses how aflatoxin exposure alters key aspects of p53 and how this damage interacts with HBV-mediated p53 suppression, providing crucial insights into hepatocarcinogenesis. The knowledge synthesized here underscores the importance of mitigating aflatoxin exposure alongside HBV control for effective HCC prevention and treatment strategies. Full article

Alcohol consumption is a known risk factor for esophageal and liver cancers. Recently, it was reported that mutation signatures characterized by T:A to C:G mutations (SBS16), which are suggested to be associated with alcohol intake, are frequently detected in esophageal, liver, and stomach cancers among the Japanese population. However, the scientific evidence linking alcohol consumption to SBS16 remains lacking. Acetaldehyde (AA), a carcinogenic metabolite of alcohol, is considered a key contributor to alcohol-related cancer development. Although the guanine adducts associated with alcohol exposure have been reported as part of its carcinogenic mechanism, an adenine adduct, N⁶-ethyl-deoxyadenosine (N⁶-ethyl-dA), a potential contributor to the SBS16 mutation pattern, was recently identified using a mass spectrometry-based DNA adductome approach. However, the mutagenicity assessment of N⁶-ethyl-dA using primer extension assays and the supF gene mutation test showed that this adenine adduct is not mutagenic. To identify another candidate as a driver adduct for SBS16, a DNA adductome approach was conducted, leading to the identification of a novel adenine adduct, 3-(2′-deoxyribos-1′-yl)-7,9-dimethyl-3,9-dihydro-7H-[1,3,5]oxadiazino[4,3-i]purine (N¹-oxydiethylidene-dA), in which two AA molecules are bound to an adenine base. Moreover, N¹-oxydiethylidene-dA was detected in mouse livers, and its levels increased following ethanol administration, suggesting that alcohol may contribute to SBS16 induction via the formation of N¹-oxydiethylidene-dA. Full article

In this study, the chemopreventive effects of rosmarinic acid (RA), a major phenolic acid of the plant Rosmarinus officinalis L., against the carcinogenic naturally occurring mycotoxin aflatoxin B1 (AFB1) were investigated using both in silico and in vitro approaches. The in silico investigation of the chemical reactions between rosmarinic acid and the carcinogenic metabolite of AFB1, aflatoxin B1 exo-8,9-epoxide (AFBO), was conducted by activation free energies calculations with DFT functionals M11-L and MN12-L, in conjunction with the 6-311++G(d,p) flexible basis set and implicit solvation model density (SMD), according to a newly developed quantum mechanics-based protocol for the evaluation of carcinogen scavenging activity (QM-CSA). Following the computational analyses, the chemoprotective effects of RA were further studied in vitro in human hepatocellular carcinoma HepG2 cells by analyzing its influence on AFB1-induced genotoxicity using a comet assay, γH2AX, and p-H3, while its impact on cell proliferation and cell cycle modulation was assessed using flow cytometry. Our computational results revealed that the activation free energy required for the reaction of RA with AFBO (14.86 kcal/mol) is significantly lower than the activation free energy for the competing reaction of AFBO with guanine (16.88 kcal/mol), which indicates that RA acts as an efficient natural scavenger of AFBO, potentially preventing AFB1-specific DNA adduct formation. The chemoprotective activity of RA was confirmed through in vitro experiments, which demonstrated a statistically significant (p < 0.05) reduction in AFB1-induced single- and double-strand breaks in HepG2 cells exposed to a mixture of AFB1 and RA at non-cytotoxic concentrations. In addition, RA reversed the AFB1-induced reduction in cell proliferation. Full article

Background: The pyrrolobenzodiazepine (PBD) dimer SJG-136 reached Phase II clinical trials in ovarian cancer and leukaemia in the UK and USA in the 2000s. Several structural analogues of SJG-136 are currently in clinical development as payloads for Antibody-Drug Conjugates (ADCs). There is growing evidence that PBDs exert their pharmacological effects through inhibition of transcription factors (TFs) in addition to arrest at the replication fork, DNA strand breakage, and inhibition of enzymes including endonucleases and RNA polymerases. Hence, PBDs can be used to target specific DNA sequences to inhibit TFs as a novel anticancer therapy. Objective: To explore the ability of SJG-136 to bind to the cognate sequences of transcription factors using a previously described HPLC/MS method, to obtain preliminary mechanistic evidence of its ability to inhibit transcription factors (TF), and to determine its effect on TF-dependent gene expression. Methods: An HPLC/MS method was used to assess the kinetics and thermodynamics of adduct formation between the PBD dimer SJG-136 and the cognate recognition sequence of the TFs NF-κB, EGR-1, AP-1, and STAT3. CD spectroscopy, molecular dynamics simulations, and gene expression analyses were used to rationalize the findings of the HPLC/MS study. Results: Notable differences in the rate and extent of adduct formation were observed with different DNA sequences, which might explain the variations in cytotoxicity of SJG-136 observed across different tumour cell lines. The differences in adduct formation result in variable downregulation of several STAT3-dependent genes in the human colon carcinoma cell line HT-29 and the human breast cancer cell line MDA-MB-231. Conclusions: SJG-136 can disrupt transcription factor-mediated gene expression, which contributes to its exceptional cytotoxicity in addition to the DNA-strand cleavage initiated by its ability to crosslink DNA. Full article

The control of waterborne diseases through water disinfection is a significant advancement in public health. However, the disinfection process generates disinfection by-products (DBPs), including trihalomethanes (THMs), which are considered to influence the occurrence of cancer. This analysis aims to quantitatively evaluate the relationship between blood concentrations of THMs and cancer. Additionally, the relationship between blood chloroform concentration and cancer is analyzed separately. Following PRISMA guidelines, we conducted a thorough search in the PubMed, Web of Science, and CNKI databases. Statistical analysis was performed using Review Manager 5.4 software. After screening, seven studies meeting the evaluation criteria were included. A total of 1027 blood samples from patients with cancer and 7351 blood samples from the control group were collected. The average concentration of THMs in the blood of the experimental group was 46.71 pg/mL, while it was 36.406 pg/mL in the control group. The difference between the two groups was statistically significant (SMD = −0.36, 95% CI: −0.45 to −0.27, p < 0.00001). However, due to the limited research data on the relationship between blood THMs and cancer, the conclusions drawn exhibit high heterogeneity. Additionally, we discussed the carcinogenic mechanisms of THMs, which involve multiple biological pathways such as oxidative stress, DNA adduct formation, and endocrine disruption, with variations in accumulation and target sites potentially leading to different cancer types, for which evidence is currently lacking. In the future, further epidemiological and animal model studies on THMs should be conducted to obtain more accurate conclusions. Full article

Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal of PA-derived DNA adducts remains largely unexplored. In the present study, Sprague Dawley (SD) rats were exposed to retrorsine (RTS), a representative PA, at a human-relevant dose of 3.3 mg/kg/day for 28 days. The rats were divided into three groups: control, RTS-28 (sacrificed after continuous RTS exposure), and RTS-161 (sacrificed at 133 days post-RTS-exposure). The multi-omics analyses demonstrated the involvement of homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways as a response to PA-induced DNA damage. Additionally, the characteristic guanine adducts induced by RTS exposure were in accordance with the higher expression of XPA and XPC, indicating that nucleotide excision repair (NER) and base excision repair (BER) also contributed to repairing RTS-induced DNA damage. Furthermore, we also showed that DNA damage persisted after PA exposure, and mutagenically related repair errors might occur due to the prolonged genotoxic effects. The present study lays the foundation for bridging PA-derived DNA adducts, DNA damage, DNA repair, and the follow-up mutagenesis and carcinogenesis associated with PA exposure. Full article

Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug–drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. Conclusions: The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy. Full article

The literature analysis conducted in this review discusses the latest achievements in the identification of cardiovascular damage induced by oxidative stress with secondary platelet mitochondrial dysfunction. Damage to the platelets of mitochondria as a result of their interactions with reactive oxygen species (ROS) and reactive nitrogen species (RNS) can lead to their numerous ischemic events associated with hypoxia or hyperoxia processes in the cell. Disturbances in redox reactions in the platelet mitochondrial membrane lead to the direct oxidation of cellular macromolecules, including nucleic acids (DNA base oxidation), membrane lipids (lipid peroxidation process) and cellular proteins (formation of reducing groups in repair proteins and amino acid peroxides). Oxidative changes in biomolecules inducing tissue damage leads to inflammation, initiating pathogenic processes associated with faster cell aging or their apoptosis. The consequence of damage to platelet mitochondria and their excessive activation is the induction of cardiovascular and neurodegenerative diseases (Parkinson’s and Alzheimer’s), as well as carbohydrate metabolism disorders (diabetes). The oxidation of mitochondrial DNA can lead to modifications in its bases, inducing the formation of exocyclic adducts of the ethano and propano type. As a consequence, it disrupts DNA repair processes and conduces to premature neoplastic transformation in critical genes such as the p53 suppressor gene, which leads to the development of various types of tumors. The topic of new innovative methods and techniques for the analysis of oxidative stress in platelet mitochondria based on methods such as a nicking assay, oxygen consumption assay, Total Thrombus formation Analysis System (T-Tas), and continuous-flow left ventricular assist devices (CF-LVADs) was also discussed. They were put together into one scientific and research platform. This will enable the facilitation of faster diagnostics and the identification of platelet mitochondrial damage by clinicians and scientists in order to implement adequate therapeutic procedures and minimize the risk of the induction of cardiovascular diseases, including ischemic events correlated with them. A quantitative analysis of the processes of thrombus formation in cardiovascular diseases will provide an opportunity to select specific anticoagulant and thrombolytic drugs under conditions of preserved hemostasis. Full article

Determining a novel etiology and mechanism of human cancer requires extraction of characteristic mutational signatures derived from chemical substances. This study explored the mutational signatures of N-nitroso bile acid conjugates using Salmonella strains. Exposing S. typhimurium TA1535 to N-nitroso-glycine/taurine bile acid conjugates induced a predominance of C:G to T:A transitions. Two mutational signatures, B1 and B2, were extracted. Signature B1 is associated with N-nitroso-glycine bile acid conjugates, while Signature B2 is linked to N-nitroso-taurine bile acid conjugates. Signature B1 revealed a strong transcribed strand bias with GCC and GCT contexts, and the mutation pattern of N-nitroso-glycine bile acid conjugates in YG7108, which lacks O⁶-methylguanine DNA methyltransferases, matched that of the wild-type strain TA1535, suggesting that O⁶-methyl-deoxyguanosine contributes to mutations in the relevant regions. COSMIC database-based similarity analysis revealed that Signature B1 closely resembled SBS42, which is associated with occupational cholangiocarcinoma caused by overexposure to 1,2-dichlolopropane (1,2-DCP) and/or dichloromethane (DCM). Moreover, the inflammatory response pathway was induced by 1,2-DCP exposure in a human cholangiocyte cell line, and iNOS expression was positive in occupational cholangiocarcinomas. These results suggest that 1,2-DCP triggers an inflammatory response in biliary epithelial cells by upregulating iNOS and N-nitroso-glycine bile acid conjugate production, resulting in cholangiocarcinoma via DNA adduct formation. Full article