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ACS Omega Oct 2023Stimuli-responsive ruthenium complexes - and -[Ru(Ctpy)(Cpyqu) OH] (- and -; Ctpy = 4'-decyloxy-2,2':6',2″-terpyridine and Cpyqu =...
Stimuli-responsive ruthenium complexes - and -[Ru(Ctpy)(Cpyqu) OH] (- and -; Ctpy = 4'-decyloxy-2,2':6',2″-terpyridine and Cpyqu = 2-[2'-(6'-decyloxy)-pyridyl]quinoline) were experimentally studied for adduct formation with a model DNA base. At 303 K, - exhibited 1:1 adduct formation with 9-ethylguanine (9-EtG) to yield -[Ru(Ctpy)(Cpyqu)(9-EtG)] (-). Rotation of the guanine ligand on the ruthenium center was sterically hindered by the presence of an adjacent quinoline moiety at 303 K. Results from H NMR measurements indicated that photoirradiation of a - solution caused photoisomerization to -, whereas heating of - caused ligand substitution to -. The distal isomer of the aqua complex, -, was observed to slowly revert to - at 303 K. In the presence of 9-EtG, - underwent thermal back-isomerization to - and adduct formation to -. Kinetic analysis of H NMR measurements showed that adduct formation between - and 9-EtG was 8-fold faster than that between - and 9-EtG. This difference may be attributed to intramolecular hydrogen bonding and steric repulsion between the aqua ligand and the pendant moiety of the bidentate ligand..
PubMed: 37841177
DOI: 10.1021/acsomega.3c05343 -
Scientific Reports Oct 2023To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by...
To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: r = 0.912, P < 0.01; GR: r = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (r = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: r = - 0.855, P < 0.01; 8-OHDG:r = - 0.412, P < 0.05, DNA adduct: γ = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship.
Topics: Mice; Animals; Male; DNA Adducts; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Oxidative Stress; Formaldehyde; Proteins; Superoxide Dismutase; Deoxyguanosine
PubMed: 37838763
DOI: 10.1038/s41598-023-44788-y -
BioRxiv : the Preprint Server For... Sep 2023Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the two primary risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA...
Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the two primary risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. We have adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts. We have found that transcription-coupled repair plays a major role in the damage removal process and the released excision products have a distinctive length distribution pattern. We further analyzed the impact of 3D genome organization on the repair of AFB1-induced DNA adducts. We have revealed that chromosomes close to the nuclear center and A compartments undergo expedited repair processes. Notably, we observed an accelerated repair around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced liver cancer.
PubMed: 37808841
DOI: 10.1101/2023.09.27.559858 -
Archives of Toxicology Dec 2023Aflatoxin B (AFB) is a highly hepatotoxic and carcinogenic mycotoxin produced by Aspergillus species. The compound is mainly metabolized in the liver and its metabolism...
Aflatoxin B (AFB) is a highly hepatotoxic and carcinogenic mycotoxin produced by Aspergillus species. The compound is mainly metabolized in the liver and its metabolism varies between species. The present study quantified relevant AFB- metabolites formed by mouse, rat, and human primary hepatocytes after treatment with 1 µM and 10 µM AFB. The use of liquid chromatographic separation coupled with tandem mass spectrometric detection enabled the selective and sensitive determination of phase I and phase II metabolites of AFB over incubation times of up to 24 h. The binding of AFB to macromolecules was also considered. The fastest metabolism of AFB was observed in mouse hepatocytes which formed aflatoxin P as a major metabolite and also its glucuronidated form, while AFP occurred only in traces in the other species. Aflatoxin M was formed in all species and was, together with aflatoxin Q and aflatoxicol, the main metabolite in human cells. Effective epoxidation led to high amounts of DNA adducts already 30 min post-treatment, especially in rat hepatocytes. Lower levels of DNA adducts and fast DNA repair were found in mouse hepatocytes. Also, protein adducts arising from reactive intermediates were formed rapidly in all three species. Detoxification via glutathione conjugation and subsequent formation of the N-acetylcysteine derivative appeared to be similar in mice and in rats and strongly differed from human hepatocytes which did not form these metabolites at all. The use of qualitative reference material of a multitude of metabolites and the comparison of hepatocyte metabolism in three species using advanced methods enabled considerations on toxification and detoxification mechanisms of AFB. In addition to glutathione conjugation, phase I metabolism is strongly involved in the detoxification of AFB.
Topics: Humans; Rats; Mice; Animals; Aflatoxin B1; Chromatography, High Pressure Liquid; DNA Adducts; Tandem Mass Spectrometry; DNA; Aflatoxins; Liver; Hepatocytes; Glutathione
PubMed: 37794256
DOI: 10.1007/s00204-023-03607-z -
Biomolecules Aug 2023High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of...
High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of post-translational modification, particularly acetylation and oxidation, mediate HMGB1 release and confer distinct extracellular HMGB1 signaling activity. Here we report that cisplatin but not carboplatin induces secretion of HMGB1 from human A549 non-small cell lung cancer (NSCLC) cells. Cisplatin-mediated HMGB1 secretion was dose-dependent and was regulated by nuclear exportin 1 (XPO1) also known as chromosomal maintenance 1 (CRM1) rather than adenosine diphosphate (ADP)-ribosylation, acetylation, or oxidation. HMGB1, as well as lysine acetylation and cysteine disulfide oxidation of secreted HMGB1, were monitored by sensitive and specific assays using immunoprecipitation, stable isotope dilution, differential alkylation, and nano liquid chromatography parallel reaction monitoring/high-resolution mass spectrometry (nano-LC-PRM/HRMS). A major fraction of the HMGB1 secreted by low-dose cisplatin treatment of A549 NSCLC cells was found to be in the fully reduced form. In contrast, mainly oxidized forms of HMGB1 were secreted by dimethyl sulfoxide (DMSO)-mediated apoptosis. These findings suggest that inhibition of XPO1 could potentiate the anti-tumor activity of cisplatin by increasing the nuclear accumulation of HMGB1 protein, an inhibitor of cisplatin DNA-adduct repair. Furthermore, low-dose cisplatin therapy could modulate the immune response in NSCLC through the established chemokine activity of extracellular reduced HMGB1. This could potentially enhance the efficacy of subsequent immunotherapy treatment.
Topics: Humans; Cisplatin; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; HMGB1 Protein; Immunity
PubMed: 37759736
DOI: 10.3390/biom13091335 -
PeerJ 2023We were curious if the urinary proteome could reflect the effects of e-cigarettes on the organism.
BACKGROUND
We were curious if the urinary proteome could reflect the effects of e-cigarettes on the organism.
METHODS
Urine samples were collected from a rat e-cigarette model before, during, and after two weeks of e-cigarette smoking. Urine proteomes before and after smoking of each rat were compared individually, while the control group was set up to rule out differences caused by rat growth and development.
RESULTS
Fetuin-B, a biomarker of chronic obstructive pulmonary disease (COPD), and annexin A2, which is recognized as a multiple tumour marker, were identified as differential proteins in five out of six smoking rats on day 3. To our surprise, odourant-binding proteins expressed in the olfactory epithelium were also found and were significantly upregulated. Pathways enriched by the differential proteins include the apelin signalling pathway, folate biosynthesis pathway, arachidonic acid metabolism, chemical carcinogenesis-DNA adducts and chemical carcinogenesis-reactive oxygen species. They have been reported to be associated with immune system, cardiovascular system, respiratory system,
CONCLUSIONS
Urinary proteome could reflect the effects of e-cigarettes in rats.
Topics: Animals; Rats; Electronic Nicotine Delivery Systems; Proteome; Proteomics; Urinalysis; Carcinogenesis
PubMed: 37753171
DOI: 10.7717/peerj.16041 -
Nucleic Acids Research Oct 2023Homologous recombination (HR) requires bidirectional end resection initiated by a nick formed close to a DNA double-strand break (DSB), dysregulation favoring...
Homologous recombination (HR) requires bidirectional end resection initiated by a nick formed close to a DNA double-strand break (DSB), dysregulation favoring error-prone DNA end-joining pathways. Here we investigate the role of the ATAD5, a PCNA unloading protein, in short-range end resection, long-range resection not being affected by ATAD5 deficiency. Rapid PCNA loading onto DNA at DSB sites depends on the RFC PCNA loader complex and MRE11-RAD50-NBS1 nuclease complexes bound to CtIP. Based on our cytological analyses and on an in vitro system for short-range end resection, we propose that PCNA unloading by ATAD5 is required for the completion of short-range resection. Hampering PCNA unloading also leads to failure to remove the KU70/80 complex from the termini of DSBs hindering DNA repair synthesis and the completion of HR. In line with this model, ATAD5-depleted cells are defective for HR, show increased sensitivity to camptothecin, a drug forming protein-DNA adducts, and an augmented dependency on end-joining pathways. Our study highlights the importance of PCNA regulation at DSB for proper end resection and HR.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Endodeoxyribonucleases; Homologous Recombination; Proliferating Cell Nuclear Antigen; Humans
PubMed: 37739427
DOI: 10.1093/nar/gkad776 -
ACS Omega Sep 2023HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the...
HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the DNA minor groove of AT-rich stretches. HMGA are functionally involved in regulating transcription, RNA processing, DNA repair, and chromatin remodeling and dynamics. These proteins are highly expressed and play essential functions during embryonic development. They are almost undetectable in adult tissues but are re-expressed at high levels in all cancers where they are involved in neoplastic transformation and cancer progression. We focused on identifying new small molecules capable of binding into the minor groove of AT-rich DNA sequences that could compete with HMGA for DNA binding and, thus, potentially interfere with their activities. Here, a docking-based virtual screening of a unique high diversity in-house library composed of around 1000 individual natural products identified 16 natural compounds as potential minor groove binders that could inhibit the interaction between HMGA and DNA. To verify the ability of these selected compounds to compete with HMGA proteins, we screened them using electrophoretic mobility shift assays. We identified Sorocein C, a Diels-Alder (D-A)-type adducts, isolated from and with an HMGA/DNA-displacing activity and compared its activity with that of two structurally related compounds, Sorocein A and Sorocein B. All these compounds showed a cytotoxicity effect on cancer cells, suggesting that the Sorocein-structural family may provide new and yet unexplored chemotypes for the development of minor groove binders to be evaluated as anticancer agents.
PubMed: 37720761
DOI: 10.1021/acsomega.3c02043 -
Ecotoxicology and Environmental Safety Oct 2023Aflatoxin B1 (AFB1) is considered the most toxic carcinogenic compound, and exposure to AFB1 is highly associated with hepatocellular carcinoma. The aim of this study...
Aflatoxin B1 (AFB1) is considered the most toxic carcinogenic compound, and exposure to AFB1 is highly associated with hepatocellular carcinoma. The aim of this study was to investigate the effects of different doses of AFB1 on growth performance and the liver of rabbits, as well as explore its underlying mechanisms. A total of eighty 30-day-old meat rabbits were randomly divided into four treatments. The control group was fed a pollution-free diet, while the AFL, AFM, and AFH groups were fed contaminated diets containing 13 μg/kg, 19 μg/kg, and 25 μg/kg of AFB1, respectively. The results showed that AFB1 had detrimental effects on the production performance of rabbits, resulting in decreased weight gain. Additionally, AFB1 exposure was associated with increased activity of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), as well as decreased levels of total protein (TP) and albumin (ALB) in the serum. AFB1 induced the production of reactive oxygen species (ROS) and malondialdehyde (MDA) while inhibiting the activity of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activity in liver tissues. AFB1 decreased the mRNA transcription and protein expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone-1 (NQO-1). AFB1 not only decreased the contents of cytochrome P4501A2 (CYP1A2), cytochrome P4502A6 (CYP2A6) and cytochrome P4503A4 (CYP3A4) but also increased the content of AFB1-DNA adducts in the liver. Furthermore, AFB1 enhanced the expression of cytochrome c (cyt-c), caspase-9, caspase-3, and Bcl-2-associated X protein (Bax), while inhibiting the expression of B-cell lymphoma 2 (Bcl-2). Therefore, we demonstrated that AFB1 triggered apoptosis in rabbit hepatocytes via mediating oxidative stress and switching on the mitochondrial apoptosis pathway, and decreased rabbit performance.
Topics: Animals; Rabbits; Aflatoxin B1; Oxidative Stress; Hepatocytes; Apoptosis; Antioxidants; Liver; Glutathione; Cytochromes
PubMed: 37716070
DOI: 10.1016/j.ecoenv.2023.115478 -
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