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Molecules (Basel, Switzerland) May 2024A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A, A, A, and A adenosine receptor...
A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A, A, A, and A adenosine receptor subtypes. Eleven purines showed potent antagonism at A, A, dual A/A, A/A, or A/A adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.
Topics: Humans; Structure-Activity Relationship; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Molecular Structure; Adenine; Morpholines; Purines; CHO Cells
PubMed: 38893418
DOI: 10.3390/molecules29112543 -
Nutrients Jun 2024Xanthohumol (Xn) is an antioxidant flavonoid mainly extracted from hops (), one of the main ingredients of beer. As with other bioactive compounds, their therapeutic...
Xanthohumol (Xn) is an antioxidant flavonoid mainly extracted from hops (), one of the main ingredients of beer. As with other bioactive compounds, their therapeutic potential against different diseases has been tested, one of which is Alzheimer's disease (AD). Adenosine is a neuromodulatory nucleoside that acts through four different G protein-coupled receptors: A and A, which inhibit the adenylyl cyclases (AC) pathway, and A and A which stimulate this activity, causing either a decrease or an increase, respectively, in the release of excitatory neurotransmitters such as glutamate. This adenosinergic pathway, which is altered in AD, could be involved in the excitotoxicity process. Therefore, the aim of this work is to describe the effect of Xn on the adenosinergic pathway using cell lines. For this purpose, two different cellular models, rat glioma C6 and human neuroblastoma SH-SY5Y, were exposed to a non-cytotoxic 10 µM Xn concentration. Adenosine A and A, receptor levels, and activities related to the adenosine pathway, such as adenylate cyclase, protein kinase A, and 5'-nucleotidase, were analyzed. The adenosine A receptor was significantly increased after Xn exposure, while no changes in A receptor membrane levels or AC activity were reported. Regarding 5'-nucleotidases, modulation of their activity by Xn was noted since CD73, the extracellular membrane attached to 5'-nucleotidase, was significantly decreased in the C6 cell line. In conclusion, here we describe a novel pathway in which the bioactive flavonoid Xn could have potentially beneficial effects on AD as it increases membrane A1 receptors while modulating enzymes related to the adenosine pathway in cell cultures.
Topics: Humans; Flavonoids; Rats; Propiophenones; Animals; Adenosine; Cell Line, Tumor; Humulus; Neuroblastoma; Glioma; Receptor, Adenosine A1; Signal Transduction; Adenylyl Cyclases; Receptor, Adenosine A2A
PubMed: 38892725
DOI: 10.3390/nu16111792 -
International Journal of Molecular... Jun 2024SARS-CoV-2 infection ranges from mild to severe presentations, according to the intensity of the aberrant inflammatory response. Purinergic receptors dually control the...
SARS-CoV-2 infection ranges from mild to severe presentations, according to the intensity of the aberrant inflammatory response. Purinergic receptors dually control the inflammatory response: while adenosine A2A receptors (A2ARs) are anti-inflammatory, ATP P2X7 receptors (P2X7Rs) exert pro-inflammatory effects. The aim of this study was to assess if there were differences in allelic and genotypic frequencies of a loss-of-function SNP of ADORA2A (rs2298383) and a gain-of-function single nucleotide polymorphism (SNP) of P2RX7 (rs208294) in the severity of SARS-CoV-2-associated infection. Fifty-five individuals were enrolled and categorized according to the severity of the infection. Endpoint genotyping was performed in blood cells to screen for both SNPs. The TT genotype (vs. CT + CC) and the T allele (vs. C allele) of P2RX7 SNP were found to be associated with more severe forms of COVID-19, whereas the association between ADORA2A SNP and the severity of infection was not significantly different. The T allele of P2RX7 SNP was more frequent in people with more than one comorbidity and with cardiovascular conditions and was associated with colorectal cancer. Our findings suggest a more prominent role of P2X7R rather than of A2AR polymorphisms in SARS-CoV-2 infection, although larger population-based studies should be performed to validate our conclusions.
Topics: Humans; Male; Middle Aged; Aged; Aged, 80 and over; Polymorphism, Single Nucleotide; Receptors, Purinergic P2X7; Receptor, Adenosine A2A; Patient Acuity; COVID-19; Genotype; Gene Frequency; Cardiovascular Diseases; Colonic Neoplasms
PubMed: 38892324
DOI: 10.3390/ijms25116135 -
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 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 -
Stem Cell Research & Therapy Jun 2024Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing...
Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women.
BACKGROUND
Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing osteogenic differentiation. Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors. This prompted us to investigate whether in vitro MS of BM-MSCs from Pm women could rehabilitate their osteogenic commitment and whether xenotransplantation of MS purinome-primed Pm cells promote repair of critical bone defects in an in vivo animal model.
METHODS
BM-MSCs were harvested from the neck of femora of Pm women (70 ± 3 years old) undergoing total hip replacement. The cells grew, for 35 days, in an osteogenic-inducing medium either submitted (SS) or not (CTR) to MS (90 r.p.m. for 30 min) twice a week. Increases in alkaline phosphatase activity and in the amount of osteogenic transcription factors, osterix and osteopontin, denoted osteogenic cells differentiation, while bone nodules formation was ascertain by the alizarin red-staining assay. The luciferin-luciferase bioluminescence assay was used to quantify extracellular ATP. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC. The density of P2Y and P2X7 purinoceptors in the cells was assessed by immunofluorescence confocal microscopy. MS-stimulated BM-MSCs from Pm women were xenotransplanted into critical bone defects drilled in the great trochanter of femora of one-year female Wistar rats; bone repair was assessed by histological analysis 10 days after xenotransplantation.
RESULTS
MS-stimulated Pm BM-MSCs in culture (i) release 1.6-fold higher ATP amounts, (ii) overexpress P2X7 and P2Y purinoceptors, (iii) exhibit higher alkaline phosphatase activity and overexpress the osteogenic transcription factors, osterix and osteopontin, and (iv) form larger bone nodules, than CTR cells. Selective blockage of P2X7 and P2Y purinoceptors with A438079 (3 µM) and MRS 2578 (0.1 µM), respectively, prevented the osteogenic commitment of cultured Pm BM-MSCs. Xenotransplanted MS purinome-primed Pm BM-MSCs accelerated the repair of critical bone defects in the in vivo rat model.
CONCLUSIONS
Data suggest that in vitro MS restores the purinergic cell-to-cell communication fostering the osteogenic differentiation and osteointegration of BM-MSCs from Pm women, a strategy that may be used in bone regeneration and repair tactics.
Topics: Female; Mesenchymal Stem Cells; Humans; Osteogenesis; Animals; Cell Differentiation; Aged; Postmenopause; Rats; Bone Marrow Cells; Mesenchymal Stem Cell Transplantation; Sp7 Transcription Factor; Cells, Cultured; Transcription Factors; Rats, Wistar
PubMed: 38886849
DOI: 10.1186/s13287-024-03775-4 -
International Journal of Oral Science Jun 2024Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on...
Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A receptor (AR) on trigeminal ganglia. Antagonism of trigeminal AR with a selective AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal AR. Therefore, we established trigeminal AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.
Topics: Animals; Mice; Mouth Neoplasms; Receptor, Adenosine A2A; Carcinoma, Squamous Cell; Humans; Calcitonin Gene-Related Peptide; Disease Progression; Trigeminal Nerve; Cell Line, Tumor; Adenosine A2 Receptor Antagonists; Pyrimidines; Triazoles
PubMed: 38886342
DOI: 10.1038/s41368-024-00308-w -
Biological & Pharmaceutical Bulletin 2024The increasing number of patients with depressive disorder is a serious socioeconomic problem worldwide. Although several therapeutic agents have been developed and used...
The increasing number of patients with depressive disorder is a serious socioeconomic problem worldwide. Although several therapeutic agents have been developed and used clinically, their effectiveness is insufficient and thus discovery of novel therapeutic targets is desired. Here, focusing on dysregulation of neuronal purinergic signaling in depressive-like behavior, we examined the expression profiles of ATP channels and ectonucleotidases in astrocytes of cerebral cortex and hippocampus of chronic social defeat stress (CSDS)-susceptible BALB/c mice. Mice were exposed to 10-d CSDS, and their astrocytes were obtained using a commercially available kit based on magnetic activated cell sorting technology. In astrocytes derived from cerebral cortex of CSDS-susceptible mice, the expression levels of mRNAs for connexin 43, P2X7 receptors and maxi anion channels were increased, those for connexin 43 and P2X7 receptors being inversely correlated with mouse sociability, and the expression of mRNAs for ecto-nucleoside triphosphate diphosphohydrase 2 and ecto-5'nucleotidase was decreased and increased, respectively. On the other hand, the alteration profiles of ATP channels and ectonucleotidases in hippocampal astrocytes of CSDS-susceptible mice were different from in the case of cortical astrocytes, and there was no significant correlation between expression levels of their mRNAs and mouse sociability. These findings imply that increased expression of ATP channels in cerebral cortex might be involved in the development of reduced sociability in CSDS-subjected BALB/c mice. Together with recent findings, it is suggested that ATP channels expressed by cortical astrocytes might be potential therapeutic targets for depressive disorder.
Topics: Animals; Astrocytes; Cerebral Cortex; Hippocampus; Mice, Inbred BALB C; Stress, Psychological; Male; Social Defeat; Mice; Receptors, Purinergic P2X7; Connexin 43; 5'-Nucleotidase; Adenosine Triphosphatases; RNA, Messenger
PubMed: 38880625
DOI: 10.1248/bpb.b24-00236 -
Nature Communications Jun 2024Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the...
Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell G signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α-cell G-coupled A adenosine receptors. Studies with α-cell-specific Gα knockout mice showed that α-cell G also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched G-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.
Topics: Glucagon; Animals; Glucagon-Secreting Cells; Signal Transduction; Mice, Knockout; Mice; GTP-Binding Protein alpha Subunits, Gs; Adenosine; Receptor, Adenosine A2A; Male; Mice, Inbred C57BL; Islets of Langerhans
PubMed: 38879678
DOI: 10.1038/s41467-024-49537-x