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Exploration of Targeted Anti-tumor... 2023DNA damage involves in the carcinogenesis of some cancer and may act as a target for therapeutic intervention of cancers. However, it is unclear whether aflatoxin B1...
AIM
DNA damage involves in the carcinogenesis of some cancer and may act as a target for therapeutic intervention of cancers. However, it is unclear whether aflatoxin B1 (AFB1)-DNA adducts (ADAs), an important kind of DNA damage caused by AFB1, affect the efficiency of post-operative adjuvant transarterial chemoembolization (po-TACE) treatment improving hepatocellular carcinoma (HCC) survival.
METHODS
A hospital-based retrospective study, including 318 patients with Barcelona Clinic Liver Cancer (BCLC)-C stage HCC from high AFB1 exposure areas, to investigate the potential effects of ADAs in the tissues with HCC on po-TACE treatment. The amount of ADAs in the cancerous tissues was tested by competitive enzyme-linked immunosorbent assay (c-ELISA).
RESULTS
Among these patients with HCC, the average amount of ADAs was 3.00 µmol/mol ± 1.51 µmol/mol DNA in their tissues with cancer. For these patients, increasing amount of ADAs was significantly associated with poorer overall survival (OS) and tumor reoccurrence-free survival (RFS), with corresponding death risk (DR) of 3.69 (2.78-4.91) and tumor recurrence risk (TRR) of 2.95 (2.24-3.88). The po-TACE therapy can efficiently improve their prognosis [DR = 0.59 (0.46-0.76), TRR = 0.63 (0.49-0.82)]. Interestingly, this improving role was more noticeable among these patients with high ADAs [DR = 0.36 (0.24-0.53), TRR = 0.40 (0.28-0.59)], but not among those with low ADAs ( > 0.05).
CONCLUSIONS
These results suggest that increasing ADAs in the cancerous tissues may be beneficial for po-TACE in ameliorating the survival of patients with HCC.
PubMed: 37711588
DOI: 10.37349/etat.2023.00167 -
The Science of the Total Environment Dec 2023Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that contributes to the global rise in liver-related morbidity and mortality. Wood tar (WT)...
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that contributes to the global rise in liver-related morbidity and mortality. Wood tar (WT) aerosols are a significant fraction of carbonaceous aerosol originating from biomass smoldering, contributing to air pollution particles smaller than 2.5 mm (PM). Mechanistic biological associations exist between exposure to PM and increased NAFLD phenotypes in both cell and animal models. Therefore, this study examines whether an existing NAFLD-like condition can enhance the biological susceptibility of liver cells exposed to air pollution in the form of WT material. Liver cells were incubated with lauric or oleic acid (LA, OA, respectively) for 24 h to accumulate lipids and served as an in vitro hepatic steatosis model. When exposed to 0.02 or 0.2 g/L water-soluble WT aerosols, both steatosis model cells showed increased cell death compared to the control cells (blank-treated cells with or without pre-incubation with LA or OA) or compared to WT-treated cells without pre-incubation with LA or OA. Furthermore, alterations in oxidative status included variations in reactive oxygen species (ROS) levels, elevated levels of lipid peroxidation adducts, and decreased expression of antioxidant genes associated with the NRF2 transcription factor. In addition, steatosis model cells exposed to WT had a higher degree of DNA damage than the control cells (blank-treated cells with or without pre-incubation with LA or OA). These results support a possible systemic effect through the direct inflammatory and oxidative stress response following exposure to water-soluble WT on liver cells, especially those predisposed to fatty liver. Furthermore, the liver steatosis model can be influenced by the type of fatty acid used; increased adverse effects of WT on metabolic dysregulation were observed in the LA model to a higher extent compared to the OA model.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Biomass; Liver; Oxidative Stress; Particulate Matter; Aerosols; Water
PubMed: 37704129
DOI: 10.1016/j.scitotenv.2023.166988 -
IScience Sep 2023High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for...
High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability.
PubMed: 37664608
DOI: 10.1016/j.isci.2023.107573 -
Cancers Aug 2023Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and... (Review)
Review
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated () loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.
PubMed: 37627183
DOI: 10.3390/cancers15164155 -
Turkish Journal of Chemistry 2022Polycyclic aromatic hydrocarbons (PAHs) are common and persistent environmental pollutants produced during the incomplete combustion of fuels. They are known for their...
Polycyclic aromatic hydrocarbons (PAHs) are common and persistent environmental pollutants produced during the incomplete combustion of fuels. They are known for their carcinogenic and mutagenic properties. Thus, their removal from water bodies is highly crucial and has become a critical issue globally. As a solution, here an electrospun polycaprolactone (PCL) membrane with a mean fiber diameter of 2.74 ± 1.3 μm was produced by electrospinning. Water contact angle (WCA) analysis confirmed the hydrophobic nature of the PCL membrane with a WCA of 124°, which remained stable over time. Differential scanning calorimetry analysis (DSC) revealed the semicrystalline nature of the membrane with the respective melting temperature () of 61.5 °C and crystallization temperature () of 29.6 °C. X-ray diffraction (XRD) analysis demonstrated that the crystalline structure of the PCL membrane could be preserved after electrospinning. Scanning electron microscopy analysis revealed that the membrane could be stretched without any rupture. The PCL membrane was used to scavenge PAHs (i.e. phenanthrene and anthracene) from water; the membrane could reach equilibrium capacity in a few hours, demonstrating the rapid removal of PAHs from water. The adsorption capacities for anthracene and phenanthrene were found to be 173 ± 17 and 560 ± 51 μg/g, respectively. The adsorption data fitted well with the pseudo-first-order kinetics model for both PAH molecules. The sorption could be attributed to hydrophobic adsorption, which allowed using the PCL membrane repeatedly with ethanol exposure to get rid of the adsorbed PAHs from the membrane's surface. The partial degradation of the fibrous membrane in water was observed due to their hydrolysis-induced bulk erosion. However, the degradation was slow for the membrane kept in the air for 3 months. Overall, the PCL membrane with inherent biocompatibility, biodegradability, and good PAH sorption performance is a promising material for water depollution from toxic PAH compounds.
PubMed: 37621343
DOI: 10.55730/1300-0527.3504 -
DNA Dec 2022DNA-Protein cross-links (DPCs) are cytotoxic DNA lesions with a protein covalently bound to the DNA. Although much has been learned about the formation, repair, and...
DNA-Protein cross-links (DPCs) are cytotoxic DNA lesions with a protein covalently bound to the DNA. Although much has been learned about the formation, repair, and biological consequences of DPCs in the nucleus, little is known regarding mitochondrial DPCs. This is due in part to the lack of robust and specific methods to measure mitochondrial DPCs. Herein, we reported an enzyme-linked immunosorbent assay (ELISA)-based method for detecting mitochondrial DPCs formed between DNA and mitochondrial transcription factor A (TFAM) in cultured human cells. To optimize the purification and detection workflow, we prepared model TFAM-DPCs via Schiff base chemistry using recombinant human TFAM and a DNA substrate containing an abasic (AP) lesion. We optimized the isolation of TFAM-DPCs using commercial silica gel-based columns to achieve a high recovery yield for DPCs. We evaluated the microplate, DNA-coating solution, and HRP substrate for specific and sensitive detection of TFAM-DPCs. Additionally, we optimized the mtDNA isolation procedure to eliminate almost all nuclear DNA contaminants. For proof of concept, we detected the different levels of TFAM-DPCs in mtDNA from HEK293 cells under different biological conditions. The method is based on commercially available materials and can be amended to detect other types of DPCs in mitochondria.
PubMed: 37601565
DOI: 10.3390/dna2040019 -
Cancers Jul 2023Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a...
Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a -proficient or -deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the -proficient vs. deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers.
PubMed: 37568590
DOI: 10.3390/cancers15153774 -
Drug Metabolism and Disposition: the... Aug 2023Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver...
Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by B.B. Brodie's group in the 1970s have resulted in important insight into the pathophysiology. Although the metabolic activation of APAP with generation of a reactive metabolite, glutathione depletion and protein adduct formation are critical initiating events, more recently the mitochondria came into focus as important target and decision point of cell death. This review provides a comprehensive overview of the induction of mitochondrial superoxide and peroxynitrite formation and its propagation through a mitogen activated protein kinase cascade, the mitochondrial permeability transition pore opening caused by iron-catalyzed protein nitration and the mitochondria-dependent nuclear DNA fragmentation. In addition, the role of adaptive mechanisms that can modulate the pathophysiology including autophagy, mitophagy, Nrf2 activation and mitochondrial biogenesis, are discussed. Importantly, it is outlined how the mechanisms elucidated in mice translate to human hepatocytes and APAP overdose patients, and how this mechanistic insight explains the mechanism of action of the clinically approved antidote -acetylcysteine and led to the recent discovery of a novel compound, fomepizole, which is currently under clinical development. Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in western countries. Extensive mechanistic research over the last several decades revealed a central role of mitochondria in the pathophysiology of APAP hepatotoxicity. This review article provides a comprehensive discussion of a) mitochondrial protein adducts and oxidative/nitrosative stress, b) mitochondria-regulated nuclear DNA fragmentation, c) adaptive mechanisms to APAP-induced cellular stress, d) translation of cell death mechanisms to overdose patients, and e) mechanism-based antidotes against APAP-induced liver injury.
PubMed: 37567742
DOI: 10.1124/dmd.123.001279 -
Chemical Research in Toxicology Sep 2023Adductomics studies are used for the detection and characterization of various chemical modifications (adducts) of nucleic acids and proteins. The advancements in liquid...
Adductomics studies are used for the detection and characterization of various chemical modifications (adducts) of nucleic acids and proteins. The advancements in liquid chromatography coupled with high-resolution tandem mass spectrometry (HRMS/MS) have resulted in efficient methods for qualitative and quantitative adductomics. We developed an HRMS-based method for the simultaneous analysis of RNA and DNA adducts in a single run and demonstrated its application using Baltic amphipods, useful sentinels of environmental disturbances, as test organisms. The novelty of this method is screening for RNA and DNA adducts by a single injection on an Orbitrap HRMS instrument using full scan and data-independent acquisition. The MS raw files were processed with an open-source program, , to identify and distinguish RNA and DNA adducts based on the characteristic neutral loss of ribonucleosides and 2'-deoxyribonucleosides, respectively. In the amphipods, in addition to the nearly 150 putative DNA adducts characterized earlier, we detected 60 putative RNA adducts. For the structural identification of the detected RNA adducts, the MODOMICS database was used. The identified RNA adducts included simple mono- and dimethylation and other larger functional groups on different ribonucleosides and deaminated product inosine. However, 54 of these RNA adducts are not yet structurally identified, and further work on their characterization may uncover new layers of information related to the transcriptome and help understand their biological significance. Considering the susceptibility of nucleic acids to environmental factors, including pollutants, the developed multi-adductomics methodology with further advancement has the potential to provide biomarkers for diagnostics of pollution effects in biota.
Topics: DNA Adducts; RNA; DNA; Tandem Mass Spectrometry; Chromatography, Liquid
PubMed: 37566384
DOI: 10.1021/acs.chemrestox.3c00041 -
NAR Cancer Sep 2023Targeting - and -deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer...
Targeting - and -deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro--diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills - and xeroderma pigmentosum A-deficient cells. CDEAH is a monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of -deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits -deficient xenograft tumor growth compared to isogenic -proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.
PubMed: 37554969
DOI: 10.1093/narcan/zcad042