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Molecules (Basel, Switzerland) Jun 2024Rare tautomeric forms of nucleobases can lead to Watson-Crick-like (WC-like) mispairs in DNA, but the process of proton transfer is fast and difficult to detect...
Electronic and Nuclear Quantum Effects on Proton Transfer Reactions of Guanine-Thymine (G-T) Mispairs Using Combined Quantum Mechanical/Molecular Mechanical and Machine Learning Potentials.
Rare tautomeric forms of nucleobases can lead to Watson-Crick-like (WC-like) mispairs in DNA, but the process of proton transfer is fast and difficult to detect experimentally. NMR studies show evidence for the existence of short-time WC-like guanine-thymine (G-T) mispairs; however, the mechanism of proton transfer and the degree to which nuclear quantum effects play a role are unclear. We use a B-DNA helix exhibiting a wGT mispair as a model system to study tautomerization reactions. We perform (PBE0/6-31G*) quantum mechanical/molecular mechanical (QM/MM) simulations to examine the free energy surface for tautomerization. We demonstrate that while the QM/MM simulations are accurate, considerable sampling is required to achieve high precision in the free energy barriers. To address this problem, we develop a QM/MM machine learning potential correction (QM/MM-ΔMLP) that is able to improve the computational efficiency, greatly extend the accessible time scales of the simulations, and enable practical application of path integral molecular dynamics to examine nuclear quantum effects. We find that the inclusion of nuclear quantum effects has only a modest effect on the mechanistic pathway but leads to a considerable lowering of the free energy barrier for the GT*⇌G*T equilibrium. Our results enable a rationalization of observed experimental data and the prediction of populations of rare tautomeric forms of nucleobases and rates of their interconversion in B-DNA.
Topics: Guanine; Quantum Theory; Protons; Machine Learning; Thymine; Base Pairing; Molecular Dynamics Simulation; DNA; Thermodynamics
PubMed: 38893576
DOI: 10.3390/molecules29112703 -
Molecules (Basel, Switzerland) May 2024Herbicides are useful tools for managing weeds and promoting food production and sustainable agriculture. In this study, we report on the development of a novel class of...
Herbicides are useful tools for managing weeds and promoting food production and sustainable agriculture. In this study, we report on the development of a novel class of lipophilic pyrimidine-biphenyl (PMB) herbicides. Firstly, three PMBs, , , and , were rationally designed via a scaffold hopping strategy and were determined to inhibit acetohydroxyacid synthase (AHAS). Computational simulation was carried out to investigate the molecular basis for the efficiency of PMBs against AHAS. With a rational binding mode, and the highest in vitro as well as in vivo potency, was identified as a preferable hit. Furthermore, these integrated analyses guided the design of eighteen new PMBs, which were synthesized via a one-step Suzuki-Miyaura cross-coupling reaction. These new PMBs, , were more effective in post-emergence control of grass weeds compared with . Interestingly, six of the PMBs displayed 98-100% inhibition in the control of grass weeds at 750 g ai/ha. Remarkably, exhibited ≥ 80% control against grass weeds at 187.5 g ai/ha. Overall, our comprehensive and systematic investigation revealed that a structurally distinct class of lipophilic PMB herbicides, which pair excellent herbicidal activities with new interactions with AHAS, represent a noteworthy development in the pursuit of sustainable weed control solutions.
Topics: Herbicides; Pyrimidines; Acetolactate Synthase; Biphenyl Compounds; Molecular Docking Simulation; Plant Weeds; Structure-Activity Relationship; Molecular Structure
PubMed: 38893290
DOI: 10.3390/molecules29112409 -
Nutrients May 2024This study investigated the effect of astragalus polysaccharide (APS, an ingredient with hypoglycemic function in a traditional Chinese herbal medicine) on gut...
This study investigated the effect of astragalus polysaccharide (APS, an ingredient with hypoglycemic function in a traditional Chinese herbal medicine) on gut microbiota and metabolites of type 2 diabetes mellitus (T2DM) patients using a simulated fermentation model in vitro. The main components of APS were isolated, purified, and structure characterized. APS fermentation was found to increase the abundance of and and decrease the level in the fecal microbiota of T2DM patients. Apart from increasing propionic acid, APS also caused an increase in all-trans-retinoic acid and thiamine (both have antioxidant properties), with their enrichment in the KEGG pathway associated with thiamine metabolism, etc. Notably, APS could also enhance fecal antioxidant properties. Correlation analysis confirmed a significant positive correlation of Lactobacillus with thiamine and DPPH-clearance rate, suggesting the antioxidant activity of APS was related to its ability to enrich some specific bacteria and upregulate their metabolites.
Topics: Gastrointestinal Microbiome; Humans; Diabetes Mellitus, Type 2; Fermentation; Polysaccharides; Astragalus Plant; Feces; Antioxidants; Male; Female; Middle Aged; Thiamine; Bifidobacterium; Lactobacillus; Hypoglycemic Agents
PubMed: 38892631
DOI: 10.3390/nu16111698 -
International Journal of Molecular... Jun 2024Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a...
Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca leak and Ca alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.
Topics: Animals; Benzamides; Male; Rats; Rats, Sprague-Dawley; Agammaglobulinaemia Tyrosine Kinase; Arrhythmias, Cardiac; Piperidines; Action Potentials; Ventricular Remodeling; Protein Kinase Inhibitors; Pyrazines; Calcium; Adenine; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Heart Ventricles; Pyrimidines; Calcium Signaling; Pyrazoles; Tyrosine Kinase Inhibitors
PubMed: 38892396
DOI: 10.3390/ijms25116207 -
International Journal of Molecular... May 2024The DNA building blocks 2'-deoxynucleotides are enantiomeric, with their natural β-D-configuration dictated by the sugar moiety. Their synthetic β-L-enantiomers...
The DNA building blocks 2'-deoxynucleotides are enantiomeric, with their natural β-D-configuration dictated by the sugar moiety. Their synthetic β-L-enantiomers (βLdNs) can be used to obtain L-DNA, which, when fully substituted, is resistant to nucleases and is finding use in many biosensing and nanotechnology applications. However, much less is known about the enzymatic recognition and processing of individual βLdNs embedded in D-DNA. Here, we address the template properties of βLdNs for several DNA polymerases and the ability of base excision repair enzymes to remove these modifications from DNA. The Klenow fragment was fully blocked by βLdNs, whereas DNA polymerase κ bypassed them in an error-free manner. Phage RB69 DNA polymerase and DNA polymerase β treated βLdNs as non-instructive but the latter enzyme shifted towards error-free incorporation on a gapped DNA substrate. DNA glycosylases and AP endonucleases did not process βLdNs. DNA glycosylases sensitive to the base opposite their cognate lesions also did not recognize βLdNs as a correct pairing partner. Nevertheless, when placed in a reporter plasmid, pyrimidine βLdNs were resistant to repair in human cells, whereas purine βLdNs appear to be partly repaired. Overall, βLdNs are unique modifications that are mostly non-instructive but have dual non-instructive/instructive properties in special cases.
Topics: DNA Damage; Humans; DNA Repair; DNA; Nucleotides; Nucleic Acid Conformation; DNA Polymerase beta; DNA-Directed DNA Polymerase; Stereoisomerism
PubMed: 38892193
DOI: 10.3390/ijms25116006 -
International Journal of Molecular... May 2024Currently, an important group of biomaterials used in the research in the field of tissue engineering is thermosensitive chitosan hydrogels. Their main advantage is the...
Currently, an important group of biomaterials used in the research in the field of tissue engineering is thermosensitive chitosan hydrogels. Their main advantage is the possibility of introducing their precursors (sols) into the implantation site using a minimally invasive method-by injection. In this publication, the results of studies on the new chitosan structures in the form of thermosensitive hydrogels containing graphene oxide as a nanofiller are presented. These systems were prepared from chitosan lactate and chitosan chloride solutions with the use of a salt of pyrimidine nucleotide-uridine 5'-monophosphate disodium salt-as the cross-linking agent. In order to perform the characterization of the developed hydrogels, the sol-gel transition temperature of the colloidal systems was first determined based on rheological measurements. The hydrogels were also analyzed using FTIR spectroscopy and SEM. Biological studies assessed the cytotoxicity (resazurin assay) and genotoxicity (alkaline version of the comet assay) of the nanocomposite chitosan hydrogels against normal human BJ fibroblasts. The conducted research allowed us to conclude that the developed hydrogels containing graphene oxide are an attractive material for potential use as scaffolds for the regeneration of damaged tissues.
Topics: Chitosan; Hydrogels; Nanocomposites; Humans; Graphite; Fibroblasts; Biocompatible Materials; Temperature; Cell Line; Cell Survival; Tissue Engineering; Rheology
PubMed: 38892176
DOI: 10.3390/ijms25115989 -
International Journal of Molecular... May 2024Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery,...
Different Drug Mobilities in Hydrophobic Cavities of Host-Guest Complexes between β-Cyclodextrin and 5-Fluorouracil at Different Stoichiometries: A Molecular Dynamics Study in Water.
Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between β-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between β-CD and 5-FU. Both 1:1 and 1:2 β-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 β-CD/5-FU complexes, the intermolecular interactions affect the drug's mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the β-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights.
Topics: Fluorouracil; Molecular Dynamics Simulation; beta-Cyclodextrins; Hydrophobic and Hydrophilic Interactions; Water; Solubility
PubMed: 38892075
DOI: 10.3390/ijms25115888 -
International Journal of Molecular... May 20244-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus , shows anticarcinogenic effects on various cancer...
4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus , shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.
Topics: Humans; Fluorouracil; Colorectal Neoplasms; Wnt Signaling Pathway; Apoptosis; Drug Synergism; beta Catenin; Cell Proliferation; Cell Line, Tumor; Drug Resistance, Neoplasm; TOR Serine-Threonine Kinases
PubMed: 38891932
DOI: 10.3390/ijms25115746 -
International Journal of Molecular... May 2024Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8)...
Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RASmediated RAFMEKERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.
Topics: Humans; Colorectal Neoplasms; Interleukin-8; Fluorouracil; Butadienes; Nitriles; Cell Line, Tumor; Organoplatinum Compounds; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Female; Male; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; MAP Kinase Signaling System; MutL Protein Homolog 1; Middle Aged; Aged; Gene Expression Regulation, Neoplastic; Phosphorylation
PubMed: 38891846
DOI: 10.3390/ijms25115658 -
International Journal of Molecular... May 2024FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory...
FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.
Topics: Humans; Colorectal Neoplasms; Cell Line, Tumor; Fluorouracil; Oncolytic Virotherapy; MicroRNAs; Oncolytic Viruses; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Enterovirus B, Human; Combined Modality Therapy; Irinotecan
PubMed: 38891807
DOI: 10.3390/ijms25115618