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International Journal of Molecular... Jun 2024Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this... (Review)
Review
Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A, A, A, and A) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo.
Topics: Bone Regeneration; Humans; Animals; Receptors, Purinergic P1; Purinergic P1 Receptor Agonists; Adenosine; Signal Transduction; Translational Research, Biomedical
PubMed: 38892291
DOI: 10.3390/ijms25116104 -
International Journal of Molecular... May 2024A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with...
A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of and its editing, however, are still largely undefined. In this study, we first demonstrated that editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant () exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" () counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both deficient () and mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of 's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.
Topics: Animals; RNA Editing; Mice; Olfactory Perception; Adenosine Deaminase; Olfactory Bulb; RNA-Binding Proteins; Neurons; CRISPR-Cas Systems; Male; Mice, Inbred C57BL; Nerve Tissue Proteins
PubMed: 38892173
DOI: 10.3390/ijms25115985 -
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 2024Regulatory cystathionine β-synthase (CBS) domains are widespread in proteins; however, difficulty in structure determination prevents a comprehensive understanding of...
Regulatory cystathionine β-synthase (CBS) domains are widespread in proteins; however, difficulty in structure determination prevents a comprehensive understanding of the underlying regulation mechanism. Tetrameric microbial inorganic pyrophosphatase containing such domains (CBS-PPase) is allosterically inhibited by AMP and ADP and activated by ATP and cell alarmones diadenosine polyphosphates. Each CBS-PPase subunit contains a pair of CBS domains but binds cooperatively to only one molecule of the mono-adenosine derivatives. We used site-directed mutagenesis of CBS-PPase to identify the key elements determining the direction of the effect (activation or inhibition) and the "half-of-the-sites" ligand binding stoichiometry. Seven amino acid residues were selected in the CBS1 domain, based on the available X-ray structure of the regulatory domains, and substituted by alanine and other residues. The interaction of 11 CBS-PPase variants with the regulating ligands was characterized by activity measurements and isothermal titration calorimetry. Lys100 replacement reversed the effect of ADP from inhibition to activation, whereas Lys95 and Gly118 replacements made ADP an activator at low concentrations but an inhibitor at high concentrations. Replacement of these residues for alanine increased the stoichiometry of mono-adenosine phosphate binding by twofold. These findings identified several key protein residues and suggested a "two non-interacting pairs of interacting regulatory sites" concept in CBS-PPase regulation.
Topics: Cystathionine beta-Synthase; Mutation; Protein Binding; Mutagenesis, Site-Directed; Adenine Nucleotides; Protein Domains; Pyrophosphatases; Adenosine Diphosphate; Adenosine Triphosphate; Bacterial Proteins; Inorganic Pyrophosphatase; Models, Molecular; Binding Sites
PubMed: 38891956
DOI: 10.3390/ijms25115768 -
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 -
International Journal of Molecular... May 2024The dynamic process of spermatogenesis involves asymmetric division, mitosis, and meiosis, which ultimately results in the production of mature spermatozoa. Disorders...
The dynamic process of spermatogenesis involves asymmetric division, mitosis, and meiosis, which ultimately results in the production of mature spermatozoa. Disorders of spermatogenesis can lead to infertility in males. ADAR (adenosine deaminase acting on RNA) mutations in cause male infertility, yet the causative factors remain unclear. In this study, immunofluorescence staining was employed to visualize endogenous ADAR proteins and assess protein levels via fluorescence-intensity analysis. In addition, the early differentiation disorders and homeostatic alterations during early spermatogenesis in the testes were examined through quantification of transit-amplifying region length, counting the number of GSCs (germline stem cells), and fertility experiments. Our findings suggest that deletion of ADAR causes testicular tip transit-amplifying cells to accumulate and become infertile in older male . By overexpressing ADAR in early germline cells, male infertility can be partially rescued. Transcriptome analysis showed that ADAR maintained early spermatogenesis homeostasis through the bone-morphogenetic-protein (BMP) signaling pathway. Taken together, these findings have the potential to help explore the role of ADAR in early spermatogenesis.
Topics: Animals; Male; Spermatogenesis; Drosophila melanogaster; Signal Transduction; Drosophila Proteins; Adenosine Deaminase; Bone Morphogenetic Proteins; Infertility, Male; RNA-Binding Proteins; Testis
PubMed: 38891830
DOI: 10.3390/ijms25115643 -
Polymers May 2024Sample pretreatment is a key step for qualitative and quantitative analysis of trace substances in complex samples. Cis-dihydroxyl (cis-diol) group-containing substances...
Sample pretreatment is a key step for qualitative and quantitative analysis of trace substances in complex samples. Cis-dihydroxyl (cis-diol) group-containing substances exist widely in biological samples and can be selectively bound by boronate affinity adsorbents. Based on this, in this article, we proposed a simple method for the preparation of novel spherical three-dimensionally ordered macropore (3DOM) materials based on a combination of the boronate affinity technique and colloidal crystal template method. The prepared 3DOM materials were characterized using Fourier transform-infrared spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, and thermo-gravimetric analysis, and results showed that they possessed the characteristics of a high specific surface area, high porosity, and more boronic acid recognition sites. The adsorption performance evaluation results showed that the maximum adsorption capacity of the boron affinity 3DOMs on ovalbumin (OVA) could reach to 438.79 mg/g. Kinetic and isothermal adsorption experiments indicated that the boronate affinity 3DOM material exhibited a high affinity and selectivity towards OVA and adenosine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the proteins in egg whites was conducted and proved that the glycoprotein in the egg whites could be separated and enriched with a good performance. Therefore, a novel boronate affinity 3DOM material a with highly ordered and interconnected pore structure was prepared and could be applied in the separation and enrichment of molecules with cis-diol groups from complex samples with a good selectivity, efficiency, and high throughput.
PubMed: 38891485
DOI: 10.3390/polym16111539 -
Plants (Basel, Switzerland) May 2024This study aimed to reveal the impact of MeJA and ZnSO treatments on the physiological metabolism of barley seedlings and the content of phenolic acid. The results...
This study aimed to reveal the impact of MeJA and ZnSO treatments on the physiological metabolism of barley seedlings and the content of phenolic acid. The results showed that MeJA (100 μM) and ZnSO (4 mM) treatments effectively increased the phenolic acid content by increasing the activities of phenylalanine ammonia-lyase and cinnamate-4-hydroxylase (PAL) and cinnamic acid 4-hydroxylase (C4H) and by up-regulating the expression of genes involved in phenolic acid synthesis. As a result of the MeJA or ZnSO treatment, the phenolic acid content increased by 35.3% and 30.9% at four days and by 33.8% and 34.5% at six days, respectively, compared to the control. Furthermore, MeJA and ZnSO treatments significantly increased the malondialdehyde content, causing cell membrane damage and decreasing the fresh weight and seedling length. Barley seedlings responded to MeJA- and ZnSO-induced stress by increasing the activities of antioxidant enzymes and controlling their gene expression levels. Meanwhile, MeJA and ZnSO treatments significantly upregulated , , and genes in barley seedlings. This suggested that Ca may be the signaling molecule that promotes phenolic acid synthesis under MeJA and ZnSO treatment. This study deepens the understanding of the phenolic acid enrichment process in barley seedlings under MeJA and ZnSO treatments.
PubMed: 38891320
DOI: 10.3390/plants13111512