-
International Journal of Molecular... May 2024The genome is continuously exposed to a variety of harmful factors that result in a significant amount of DNA damage. This article examines the influence of a...
The genome is continuously exposed to a variety of harmful factors that result in a significant amount of DNA damage. This article examines the influence of a multi-damage site containing oxidized imino-allantoin (Ia) and 7,8-dihydro-8-oxo-2'-deoxyguanosine (dG) on the spatial geometry, electronic properties, and ds-DNA charge transfer. The ground stage of a d[AIaAGA]*d[TCTCT] structure was obtained at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the condensed phase, with the energies obtained at the M06-2X/6-31++G** level. The non-equilibrated and equilibrated solvent-solute interactions were also considered. Theoretical studies reveal that the radical cation prefers to settle on the G moiety, irrespective of the presence of Ia in a ds-oligo. The lowest vertical and adiabatic ionization potential values were found for the G:::C base pair (5.94 and 5.52 [eV], respectively). Conversely, the highest vertical and adiabatic electron affinity was assigned for IaC as follows: 3.15 and 3.49 [eV]. The charge transfers were analyzed according to Marcus' theory. The highest value of charge transfer rate constant for hole and excess electron migration was found for the process towards the GC moiety. Surprisingly, the values obtained for the driving force and activation energy of electro-transfer towards IaC located this process in the Marcus inverted region, which is thermodynamically unfavorable. Therefore, the presence of Ia can slow down the recognition and removal processes of other DNA lesions. However, with regard to anticancer therapy (radio/chemo), the presence of Ia in the structure of clustered DNA damage can result in improved cancer treatment outcomes.
Topics: Oxidation-Reduction; Allantoin; DNA; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Thermodynamics; Models, Molecular
PubMed: 38892152
DOI: 10.3390/ijms25115962 -
International Journal of Molecular... May 2024This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial... (Review)
Review
This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial roles in cardiovascular physiology and pathology. Its release and effects, mediated by specific receptors, influence vasomotor function, blood pressure regulation, heart rate, and platelet activity. Adenosine therapeutic effects include treatment of the no-reflow phenomenon and paroxysmal supraventricular tachycardia. The production of adenosine involves complex cellular pathways, with extracellular and intracellular synthesis mechanisms. Adenosine's rapid metabolism underscores its short half-life and physiological turnover. Furthermore, adenosine's involvement in side effects of antiplatelet therapy, particularly ticagrelor and cangrelor, highlights its clinical significance. Moreover, adenosine serves as a valuable tool in CAD diagnosis, aiding stress testing modalities and guiding intracoronary physiological assessments. Its use in assessing epicardial stenosis and microvascular dysfunction is pivotal for treatment decisions. Overall, understanding adenosine's mechanisms and clinical implications is essential for optimizing CAD management strategies, encompassing both therapeutic interventions and diagnostic approaches.
Topics: Humans; Adenosine; Coronary Artery Disease; Animals; Adenosine Monophosphate; Platelet Aggregation Inhibitors
PubMed: 38892037
DOI: 10.3390/ijms25115852 -
International Journal of Molecular... May 2024Inflammatory skin diseases highlight inflammation as a central driver of skin pathologies, involving a multiplicity of mediators and cell types, including immune and... (Review)
Review
Inflammatory skin diseases highlight inflammation as a central driver of skin pathologies, involving a multiplicity of mediators and cell types, including immune and non-immune cells. Adenosine, a ubiquitous endogenous immune modulator, generated from adenosine triphosphate (ATP), acts via four G protein-coupled receptors (A, A, A, and A). Given the widespread expression of those receptors and their regulatory effects on multiple immune signaling pathways, targeting adenosine receptors emerges as a compelling strategy for anti-inflammatory intervention. Animal models of psoriasis, contact hypersensitivity (CHS), and other dermatitis have elucidated the involvement of adenosine receptors in the pathogenesis of these conditions. Targeting adenosine receptors is effective in attenuating inflammation and remodeling the epidermal structure, potentially showing synergistic effects with fewer adverse effects when combined with conventional therapies. What is noteworthy are the promising outcomes observed with A agonists in animal models and ongoing clinical trials investigating A agonists, underscoring a potential therapeutic approach for the management of inflammatory skin disorders.
Topics: Humans; Animals; Adenosine; Receptors, Purinergic P1; Skin Diseases; Dermatitis; Inflammation; Psoriasis; Signal Transduction; Anti-Inflammatory Agents
PubMed: 38891997
DOI: 10.3390/ijms25115810 -
International Journal of Molecular... May 2024Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem,... (Review)
Review
Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including AAR, AAR, AAR, and AAR. In addition to AAR, AAR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on AAR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including G or G protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several AAR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating AARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target AARs as potential treatments for heart diseases.
Topics: Humans; Animals; Signal Transduction; Receptor, Adenosine A3; Heart Diseases; Adenosine A3 Receptor Agonists; Adenosine
PubMed: 38891948
DOI: 10.3390/ijms25115763 -
International Journal of Molecular... May 2024Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine...
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
Topics: Deoxyadenosines; Humans; Neoplasms; Cyclic AMP; Molecular Dynamics Simulation; Adenosine Triphosphate; Signal Transduction; Computer Simulation; Adenylyl Cyclases
PubMed: 38891880
DOI: 10.3390/ijms25115692 -
Fly Dec 2024Adenosine-to-inosine (A-to-I) RNA editing recodes the genome and confers flexibility for the organisms to adapt to the environment. It is believed that RNA recoding...
Adenosine-to-inosine (A-to-I) RNA editing recodes the genome and confers flexibility for the organisms to adapt to the environment. It is believed that RNA recoding sites are well suited for facilitating adaptive evolution by increasing the proteomic diversity in a temporal-spatial manner. The function and essentiality of a few conserved recoding sites are recognized. However, the experimentally discovered functional sites only make up a small corner of the total sites, and there is still the need to expand the repertoire of such functional sites with bioinformatic approaches. In this study, we define a new category of RNA editing sites termed 'conserved editing with non-conserved recoding' and systematically identify such sites in editomes, figuring out their selection pressure and signals of adaptation at inter-species and intra-species levels. Surprisingly, conserved editing sites with non-conserved recoding are not suppressed and are even slightly overrepresented in . DNA mutations leading to such cases are also favoured during evolution, suggesting that the function of those recoding events in different species might be diverged, specialized, and maintained. Finally, structural prediction suggests that such recoding in potassium channel Shab might increase ion permeability and compensate the effect of low temperature. In conclusion, conserved editing with non-conserved recoding might be functional as well. Our study provides novel aspects in considering the adaptive evolution of RNA editing sites and meanwhile expands the candidates of functional recoding sites for future validation.
Topics: Animals; RNA Editing; Inosine; Drosophila; Adenosine; Drosophila melanogaster; Evolution, Molecular; Drosophila Proteins
PubMed: 38889318
DOI: 10.1080/19336934.2024.2367359 -
Bioinformatics (Oxford, England) Jun 2024Nanopore direct RNA sequencing (DRS) enables the detection of RNA N6-methyladenosine (m6A) without extra laboratory techniques. A number of supervised or comparative...
MOTIVATION
Nanopore direct RNA sequencing (DRS) enables the detection of RNA N6-methyladenosine (m6A) without extra laboratory techniques. A number of supervised or comparative approaches have been developed to identify m6A from Nanopore DRS reads. However, existing methods typically utilize either statistical features of the current signals or basecalling-error features, ignoring the richer information of the raw signals of DRS reads.
RESULTS
Here, we propose RedNano, a deep-learning method designed to detect m6A from Nanopore DRS reads by utilizing both raw signals and basecalling errors. RedNano processes the raw-signal feature and basecalling-error feature through residual networks. We validated the effectiveness of RedNano using synthesized, Arabidopsis, and human DRS data. The results demonstrate that RedNano surpasses existing methods by achieving higher area under the ROC curve (AUC) and area under the precision-recall curve (AUPRs) in all three datasets. Furthermore, RedNano performs better in cross-species validation, demonstrating its robustness. Additionally, when detecting m6A from an independent dataset of Populus trichocarpa, RedNano achieves the highest AUC and AUPR, which are 3.8%-9.9% and 5.5%-13.8% higher than other methods, respectively.
AVAILABILITY AND IMPLEMENTATION
The source code of RedNano is freely available at https://github.com/Derryxu/RedNano.
Topics: Arabidopsis; Humans; Sequence Analysis, RNA; Adenosine; Nanopore Sequencing; Deep Learning; RNA; Nanopores
PubMed: 38889266
DOI: 10.1093/bioinformatics/btae375 -
Cell Death & Disease Jun 2024TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (mA) stands as one of the most abundant modifications on the mRNA...
TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (mA) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-β1 with mRNA mA modification, especially the effect of mRNA translation efficiency associated with mA modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-β1 expression in GBC. Overexpression of FOXA1 inhibited TGF-β1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-β1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-β1 promoted mA modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-β1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting mA modification on the CDS region of FOXA1 mRNA. Moreover, TGF-β1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-β1 in regulating TGF-β1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through mA modification.
Topics: Hepatocyte Nuclear Factor 3-alpha; Humans; Transforming Growth Factor beta1; Gallbladder Neoplasms; Animals; Epithelial-Mesenchymal Transition; Cell Line, Tumor; Adenosine; Mice, Nude; Mice; Protein Biosynthesis; Neoplasm Metastasis; Gene Expression Regulation, Neoplastic; Cell Movement; RNA, Messenger; Mice, Inbred BALB C; Male
PubMed: 38886389
DOI: 10.1038/s41419-024-06800-9 -
Nature Communications Jun 2024Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of...
Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and S-adenosylmethionine (AdoMet)-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures of Chaetomium thermophilum MTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form of cMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites in hMTHFR, three of which were previously unidentified. Based on the structural framework provided by our cMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.
Topics: Methylenetetrahydrofolate Reductase (NADPH2); S-Adenosylmethionine; Allosteric Regulation; Chaetomium; Phosphorylation; Humans; Crystallography, X-Ray; Models, Molecular; Flavin-Adenine Dinucleotide
PubMed: 38886362
DOI: 10.1038/s41467-024-49327-5 -
Clinical and Translational Medicine Jun 2024Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal... (Review)
Review
Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N-methyladenosine (mA) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-mA RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the mA modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-mA RNA modifications. In this review, we mainly focus on the roles and implications of non-mA RNA modifications, including N-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N-methyladenosine and N-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-mA RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-mA RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-mA modifiers in blood cancer.
Topics: Humans; Hematologic Neoplasms; RNA Processing, Post-Transcriptional; RNA; Adenosine
PubMed: 38880983
DOI: 10.1002/ctm2.1666