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European Journal of Medicinal Chemistry Dec 2023A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η-CH)(N,N)(PPh(CHCOOR)][CFSO] (1-10) in which...
A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η-CH)(N,N)(PPh(CHCOOR)][CFSO] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CHCHOH; R' = -H, -CH, -OCH, -CHOH, and -CH-biotin) was prepared from [Ru(η-CH)(PPh(CHCOOH))Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η-CH)(PPh(CHCOOH))Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well. Notably, compounds 6 and 7 (R CHCHOH and (N,N) = bipy or Mebipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains. Solution speciation studies revealed that the complexes bearing the PPh(CHCOO) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones. In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2'-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.
Topics: Humans; 2,2'-Dipyridyl; Carcinoma, Non-Small-Cell Lung; Ligands; Lung Neoplasms; Serum Albumin, Human; DNA; Anti-Bacterial Agents; Ethylene Glycols; Antineoplastic Agents; Ruthenium; Coordination Complexes; Cell Line, Tumor
PubMed: 37944388
DOI: 10.1016/j.ejmech.2023.115922 -
BioRxiv : the Preprint Server For... Mar 2024Bulky DNA adducts such as those induced by ultraviolet light are removed from the genomes of multicellular organisms by nucleotide excision repair, which occurs through...
Bulky DNA adducts such as those induced by ultraviolet light are removed from the genomes of multicellular organisms by nucleotide excision repair, which occurs through two distinct mechanisms, global repair, requiring the DNA damage recognition-factor XPC (xeroderma pigmentosum complementation group C), and transcription-coupled repair (TCR), which does not. TCR is initiated when elongating RNA polymerase II encounters DNA damage, and thus analysis of genome-wide excision repair in XPC-mutants only repairing by TCR provides a unique opportunity to map transcription events missed by methods dependent on capturing RNA transcription products and thus limited by their stability and/or modifications (5'-capping or 3'-polyadenylation). Here, we have performed the eXcision Repair-sequencing (XR-seq) in the model organism to generate genome-wide repair maps from a wild-type strain with normal excision repair, a strain lacking TCR (), or one that only repairs by TCR (-). Analysis of the intersections between the XR-seq repair maps with RNA-mapping datasets (RNA-seq, long- and short-capped RNA-seq) reveal previously unrecognized sites of transcription and further enhance our understanding of the genome of this important model organism.
PubMed: 37904932
DOI: 10.1101/2023.10.12.562083 -
World Journal of Gastroenterology Oct 2023Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F synthase (PGF)...
BACKGROUND
Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F synthase (PGF) (PGFS), an enzyme that catalyzes the production of PGF, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear.
AIM
To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.
METHODS
The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products.
RESULTS
Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment and . The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF-independent manner. PGF exerts its protective effect against DNA damage by reducing ROS levels.
CONCLUSION
PGFS promotes resistance to Oxa in CRC both PGF-dependent and PGF-independent mechanisms.
Topics: Humans; Oxaliplatin; Platinum; DNA Adducts; Reactive Oxygen Species; Colorectal Neoplasms; RNA, Messenger; Prostaglandins; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 37900995
DOI: 10.3748/wjg.v29.i39.5452 -
Biomolecules Oct 2023We examined the reaction of hydroxyl radicals (HO) and sulfate radical anions (SO), which is generated by ionizing radiation in aqueous solutions under anoxic...
We examined the reaction of hydroxyl radicals (HO) and sulfate radical anions (SO), which is generated by ionizing radiation in aqueous solutions under anoxic conditions, with an alternating GC doubled-stranded oligodeoxynucleotide (ds-ODN), i.e., the palindromic 5'-d(GCGCGC)-3'. In particular, the optical spectra of the intermediate species and associated kinetic data in the range of ns to ms were obtained via pulse radiolysis. Computational studies by means of density functional theory (DFT) for structural and time-dependent DFT for spectroscopic features were performed on 5'-d(GCGC)-3'. Comprehensively, our results suggest the addition of HO to the G:C pair moiety, affording the [8-HO-G:C] detectable adduct. The previous reported spectra of one-electron oxidation of a variety of ds-ODN were assigned to [G(-H):C] after deprotonation. Regarding 5'-d(GCGCGC)-3' ds-ODN, the spectrum at 800 ns has a completely different spectral shape and kinetic behavior. By means of calculations, we assigned the species to [G:C/C:G], in which the electron hole is predicted to be delocalized on the two stacked base pairs. This transient species was further hydrated to afford the [8-HO-G:C] detectable adduct. These remarkable findings suggest that the double-stranded alternating GC sequences allow for a new type of electron hole stabilization via delocalization over the whole sequence or part of it.
Topics: Oligonucleotides; Hydroxyl Radical; Electrons; Free Radicals; Oxidation-Reduction; Oligodeoxyribonucleotides
PubMed: 37892175
DOI: 10.3390/biom13101493 -
Genes and Environment : the Official... Oct 2023The DNA-damaging compounds in heated cooking oil were identified as guanosine adducts. Heated vegetable oil was subjected to deep-frying conditions at 170 °C for...
BACKGROUND
The DNA-damaging compounds in heated cooking oil were identified as guanosine adducts. Heated vegetable oil was subjected to deep-frying conditions at 170 °C for 45 min, reacted with isopropylidene guanosine (ipG) at pH 7.4, and the resulting compounds were separated by high-performance liquid chromatography (HPLC).
RESULTS
Two adducts, 8-hydroxy-ipG and 1,N-etheno-ipG, were identified in the reaction mixture. One of the major components in heated cooking oil, 2,4-heptadienal (HDE), efficiently produced etheno-ipG from ipG in the presence of tBuOOH. An oxidized HDE solution was fractionated using HPLC to identify causative agents, and each fraction was tested for etheno-ipG formation. In addition to the known lipid peroxidation product, 4,5-epoxy-2-heptenal, two unknown polar components with potent etheno-ipG formation activity were discovered. Based on Mass and UV spectra, their structures were identified as 6-oxo- and 6-hydroxy-2,4-HDE. Similarly, 6-oxo- and 6-hydroxy-2,4- decadienal (DDE) were formed from 2,4-DDE. Significant amounts of 6-oxo- and 6-hydroxy-2,4-alkadienal were detected in the heated cooking oil. These compounds induced the formation of 1,N-ethenoguanine in nucleosides and DNA, especially in the presence of tBuOOH. Moreover, the formation of 6-oxo- and 6-OH-HDE from 2,4-HDE was accelerated in the presence of hemin and tBuOOH.
CONCLUSION
The results suggest that these compounds are not only generated during the oil heating process but also produced from 2,4-alkadienal through digestion under normal physiological conditions, especially after ingesting heme- and alkyl-OOH-containing diets. Moreover, these compounds can be formed within cells under oxidative stress, potentially linking them to gastrointestinal carcinogenesis.
PubMed: 37880746
DOI: 10.1186/s41021-023-00284-3 -
Chemical Research in Toxicology Nov 2023Methyleugenol (ME), found in numerous plants and spices, is a rodent carcinogen and is classified as "possibly carcinogenic to humans". The hypothesis of a carcinogenic...
Methyleugenol (ME), found in numerous plants and spices, is a rodent carcinogen and is classified as "possibly carcinogenic to humans". The hypothesis of a carcinogenic risk for humans is supported by the observation of ME-derived DNA adducts in almost all human liver and lung samples examined. Therefore, a risk assessment of ME is needed. Unfortunately, biomarkers of exposure for epidemiological studies are not yet available. We hereby present the first detection of -acetyl-l-cysteine conjugates (mercapturic acids) of ME in human urine samples after consumption of a popular ME-containing meal, pasta with basil pesto. We synthesized mercapturic acid conjugates of ME, identified the major product as -acetyl--[3'-(3,4-dimethoxyphenyl)allyl]-l-cysteine (-3'-MEMA), and developed methods for its extraction and LC-MS/MS quantification in human urine. For conducting an exposure study in humans, a basil cultivar with a suitable ME content was grown for the preparation of basil pesto. A defined meal containing 100 g of basil pesto, corresponding to 1.7 mg ME, was served to 12 participants, who collected the complete urine at defined time intervals for 48 h. Using --3'-MEMA as an internal standard for LC-MS/MS quantification, we were able to detect -3'-MEMA in urine samples of all participants collected after the ME-containing meal. Excretion was maximal between 2 and 6 h after the meal and was completed within about 12 h (concentrations below the limit of detection). Excreted amounts were only between 1 and 85 ppm of the ME intake, indicating that the ultimate genotoxicant, 1'-sulfooxy-ME, is formed to a subordinate extent or is not efficiently detoxified by glutathione conjugation and subsequent conversion to mercapturic acids. Both explanations may apply cumulatively, with the ubiquitous detection of ME DNA adducts in human lung and liver specimens arguing against an extremely low formation of 1'-sulfooxy-ME. Taken together, we hereby present the first noninvasive human biomarker reflecting an internal exposure toward reactive ME species.
Topics: Animals; Humans; Acetylcysteine; Carcinogens; Ocimum basilicum; Rodentia; Chromatography, Liquid; DNA Adducts; Tandem Mass Spectrometry
PubMed: 37875262
DOI: 10.1021/acs.chemrestox.3c00212 -
The Journal of International Medical... Oct 2023Acetaldehyde can accumulate in cells and form acetaldehyde-DNA adducts that result in digestive tract cancer development. Acetaldehyde dehydrogenase 2 (ALDH2) enzymatic...
OBJECTIVE
Acetaldehyde can accumulate in cells and form acetaldehyde-DNA adducts that result in digestive tract cancer development. Acetaldehyde dehydrogenase 2 (ALDH2) enzymatic activity is involved in this process. Here, we aimed to analyze the relationship between an gene polymorphism and the digestive tract cancer risk in the Hakka population in China.
METHODS
This was a retrospective study, with the rs671 genotype and medical record information collected from all subjects. The relationships between these factors, including various blood cell parameters, and digestive tract cancer susceptibility were analyzed.
RESULTS
Overall, 307 cancer patients and 317 controls were included. The cancer patients had significantly higher percentages with a history of smoking and drinking alcohol, as well as an increased platelet to lymphocyte ratio and lower lymphocyte to monocyte ratio, compared with the controls. The rs671 genotype and allele distributions were significantly different between the cancer patients and controls. Logistic regression analysis showed that the G/A genotype (G/A vs. G/G) and A/A genotype (A/A vs. G/G) in the co-dominant mode were risk factors for digestive tract cancer susceptibility.
CONCLUSIONS
rs671 G/A or A/A genotype carriers may have an increased risk of developing digestive tract cancers among the Hakka people.
Topics: Humans; Aldehyde Dehydrogenase, Mitochondrial; Retrospective Studies; Polymorphism, Genetic; Gastrointestinal Neoplasms; Genotype; Risk Factors; Alcohol Drinking; Acetaldehyde; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37871625
DOI: 10.1177/03000605231206257 -
Nucleic Acids Research Nov 2023Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate...
Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate that polyamines featuring at least one secondary 1,2-diamine fragment in combination with aromatic units form covalent DNA adducts upon reaction with AP sites (with concomitant cleavage of the AP strand), fU and, to a lesser extent, fC residues. Using small-molecule mimics of AP site and fU, we show that reaction of secondary 1,2-diamines with AP sites leads to the formation of unprecedented 3'-tetrahydrofuro[2,3,4-ef]-1,4-diazepane ('ribodiazepane') scaffold, whereas the reaction with fU produces cationic 2,3-dihydro-1,4-diazepinium adducts via uracil ring opening. The reactivity of polyamines towards AP sites versus fU and fC can be tuned by modulating their chemical structure and pH of the reaction medium, enabling up to 20-fold chemoselectivity for AP sites with respect to fU and fC. This reaction is efficient in near-physiological conditions at low-micromolar concentration of polyamines and tolerant to the presence of a large excess of unmodified DNA. Remarkably, 3'-ribodiazepane adducts are chemically stable and resistant to the action of apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphoesterase 1 (TDP1), two DNA repair enzymes known to cleanse a variety of 3' end-blocking DNA lesions.
Topics: DNA; DNA Adducts; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Nucleic Acid Conformation; Polyamines
PubMed: 37850658
DOI: 10.1093/nar/gkad837 -
Cureus Sep 2023Red and processed meat consumption rates are increasing in the United States. In this review, we present the current evidence that links red meat consumption and cancer... (Review)
Review
Red and processed meat consumption rates are increasing in the United States. In this review, we present the current evidence that links red meat consumption and cancer development. A literature search was conducted in the PubMed and Google Scholar databases to review red meat consumption and its association with breast cancer and gastrointestinal cancer. Due to the presence of heme iron, which triggers oxidative reactions that eventually result in tumor formation, red meat consumption is strongly associated with the development of breast cancer. Ingestion of red meat increases Helicobacter pylori infections, resulting in enhanced expression of the CagA gene and the secretion of pro-inflammatory cytokines. This is the leading cause of gastric cancer. There is a strong correlation between heterocyclic amines and polycyclic aromatic hydrocarbons in red meat and the development of pancreatic cancer. However, additional research is necessary to confirm this finding. Adult colorectal cancer is caused by the formation of heterocyclic amines and DNA adducts due to the intake of red and processed meats cooked at higher temperatures. The consumption of poultry is associated with a reduced risk of breast and gastrointestinal cancers, but the results are inconsistent. The evidence is strong for the association between red meat and breast cancer and most gastric cancers. The presence of aromatic hydrocarbons, heterocyclic amines, and heme iron in red meat has been found to be behind tumorigenesis. Poultry has been shown to have a low association with cancer, but additional research is needed.
PubMed: 37849565
DOI: 10.7759/cureus.45324 -
Nucleic Acids Research Nov 2023DNA damage causes genomic instability underlying many diseases, with traditional analytical approaches providing minimal insight into the spectrum of DNA lesions in...
DNA damage causes genomic instability underlying many diseases, with traditional analytical approaches providing minimal insight into the spectrum of DNA lesions in vivo. Here we used untargeted chromatography-coupled tandem mass spectrometry-based adductomics (LC-MS/MS) to begin to define the landscape of DNA modifications in rat and human tissues. A basis set of 114 putative DNA adducts was identified in heart, liver, brain, and kidney in 1-26-month-old rats and 111 in human heart and brain by 'stepped MRM' LC-MS/MS. Subsequent targeted analysis of these species revealed species-, tissue-, age- and sex-biases. Structural characterization of 10 selected adductomic signals as known DNA modifications validated the method and established confidence in the DNA origins of the signals. Along with strong tissue biases, we observed significant age-dependence for 36 adducts, including N2-CMdG, 5-HMdC and 8-Oxo-dG in rats and 1,N6-ϵdA in human heart, as well as sex biases for 67 adducts in rat tissues. These results demonstrate the potential of adductomics for discovering the true spectrum of disease-driving DNA adducts. Our dataset of 114 putative adducts serves as a resource for characterizing dozens of new forms of DNA damage, defining mechanisms of their formation and repair, and developing them as biomarkers of aging and disease.
Topics: Animals; Female; Humans; Male; Rats; Chromatography, Liquid; DNA; DNA Adducts; Rodentia; Tandem Mass Spectrometry
PubMed: 37843128
DOI: 10.1093/nar/gkad822