RESUMO
Cancer, a complex array of diseases, involves the unbridled proliferation and dissemination of aberrant cells in the body, forming tumors that can infiltrate neighboring tissues and metastasize to distant sites. With over 200 types, each cancer has unique attributes, risks, and treatment avenues. Therapeutic options encompass surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, targeted therapy, or a blend of these methods. Yet, these treatments face challenges like late-stage diagnoses, tumor diversity, severe side effects, drug resistance, targeted drug delivery hurdles, and cost barriers. Despite these hurdles, advancements in cancer research, encompassing biology, genetics, and treatment, have enhanced early detection methods, treatment options, and survival rates. Adenosine receptors (ARs), including A1, A2A, A2B, and A3 subtypes, exhibit diverse roles in cancer progression, sometimes promoting or inhibiting tumor growth depending on the receptor subtype, cancer type, and tumor microenvironment. Research on AR ligands has revealed promising anticancer effects in lab studies and animal models, hinting at their potential as cancer therapeutics. Understanding the intricate signaling pathways and interactions of adenosine receptors in cancer is pivotal for crafting targeted therapies that optimize benefits while mitigating drawbacks. This review delves into each adenosine receptor subtype's distinct roles and signaling pathways in cancer, shedding light on their potential as targets for improving cancer treatment outcomes.
Assuntos
Neoplasias , Receptores Purinérgicos P1 , Transdução de Sinais , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptores Purinérgicos P1/metabolismo , Animais , Microambiente Tumoral , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Alvo MolecularRESUMO
The suppressive tumour microenvironment significantly hinders the efficacy of immunotherapy in treating solid tumors. In this context, stromal cells, such as tumour-associated fibroblasts, undergo changes that include an increase in the number and function of immunosuppressive cells. Adenosine, a factor that promotes tumour growth, is produced from ATP breakdown and is markedly elevated in the tumour microenvironment. It acts through specific binding to adenosine receptors, with A2A and A2B adenosine receptor being primary drivers of immunosuppression. This paper presents the roles of various adenosine receptors in different tumour microenvironments. This review focus on the function of adenosine receptors in the stromal cells and non-cellular components of the tumour microenvironment. Additionally, we summarize and discuss recent advances and potential trends in using adenosine receptor antagonists combined with immunotherapy.
Assuntos
Neoplasias , Receptores Purinérgicos P1 , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P1/imunologia , Animais , Imunoterapia/métodos , Adenosina/metabolismo , Adenosina/imunologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/uso terapêuticoRESUMO
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 (A1, A2A, A2B, and A3). 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 A2A agonists in animal models and ongoing clinical trials investigating A3 agonists, underscoring a potential therapeutic approach for the management of inflammatory skin disorders.
Assuntos
Adenosina , Receptores Purinérgicos P1 , Humanos , Animais , Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo , Dermatite/metabolismo , Dermatite/tratamento farmacológico , Dermatite/patologia , Dermatite/etiologia , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Transdução de Sinais , Anti-Inflamatórios/uso terapêuticoRESUMO
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 (A1, A2A, A2B, and A3) 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.
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Regeneração Óssea , Agonistas do Receptor Purinérgico P1 , Receptores Purinérgicos P1 , Regeneração Óssea/efeitos dos fármacos , Humanos , Animais , Receptores Purinérgicos P1/metabolismo , Agonistas do Receptor Purinérgico P1/farmacologia , Agonistas do Receptor Purinérgico P1/uso terapêutico , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pesquisa Translacional BiomédicaRESUMO
Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes.
Assuntos
Adenosina , Síndrome Metabólica , Receptores Purinérgicos P1 , Humanos , Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Síndrome Metabólica/metabolismo , Transdução de Sinais , Doenças do Sistema Nervoso/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Barreira Hematoencefálica/metabolismo , Resistência à Insulina/fisiologiaRESUMO
A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 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.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Humanos , Relação Estrutura-Atividade , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/metabolismo , Estrutura Molecular , Adenina/análogos & derivados , Adenina/química , Adenina/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Purinas/química , Purinas/farmacologia , Purinas/síntese química , Células CHORESUMO
AIMS: The preoptic area (POA) of the hypothalamus, crucial in thermoregulation, has long been implicated in the pain process. However, whether nociceptive stimulation affects body temperature and its mechanism remains poorly studied. METHODS: We used capsaicin, formalin, and surgery to induce acute nociceptive stimulation and monitored rectal temperature. Optical fiber recording, chemical genetics, confocal imaging, and pharmacology assays were employed to confirm the role and interaction of POA astrocytes and extracellular adenosine. Immunofluorescence was utilized for further validation. RESULTS: Acute nociception could activate POA astrocytes and induce a decrease in body temperature. Manipulation of astrocytes allowed bidirectional control of body temperature. Furthermore, acute nociception and astrocyte activation led to increased extracellular adenosine concentration within the POA. Activation of adenosine A1 or A2A receptors contributed to decreased body temperature, while inhibition of these receptors mitigated the thermo-lowering effect of astrocytes. CONCLUSION: Our results elucidate the interplay between acute nociception and thermoregulation, specifically highlighting POA astrocyte activation. This enriches our understanding of physiological responses to painful stimuli and contributes to the analysis of the anatomical basis involved in the process.
Assuntos
Astrócitos , Hipotermia , Nociceptividade , Área Pré-Óptica , Animais , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Nociceptividade/fisiologia , Hipotermia/induzido quimicamente , Masculino , Camundongos , Receptores Purinérgicos P1/metabolismo , Camundongos Endogâmicos C57BL , Adenosina/metabolismo , Capsaicina/farmacologia , Formaldeído/toxicidade , Formaldeído/farmacologiaRESUMO
One of the ways in which macrophages support tumorigenic growth is by producing adenosine, which acts to dampen antitumor immune responses and is generated by both tumor and immune cells in the tumor microenvironment (TME). Two cell surface expressed molecules, CD73 and CD39, boost catalytic adenosine triphosphate, leading to further increased adenosine synthesis, under hypoxic circumstances in the TME. There are four receptors (A1, A2A, A2B, and A3) expressed on macrophages that allow adenosine to perform its immunomodulatory effect. Researchers have shown that adenosine signaling is a key factor in tumor progression and an attractive therapeutic target for treating cancer. Several antagonistic adenosine-targeting biological therapies that decrease the suppressive action of tumor-associated macrophages have been produced and explored to transform this result from basic research into a therapeutic advantage. Here, we'll review the newest findings from studies of pharmacological compounds that target adenosine receptors, and their potential therapeutic value based on blocking the suppressive action of macrophages in tumors.
Assuntos
Adenosina , Imunoterapia , Neoplasias , Receptores Purinérgicos P1 , Transdução de Sinais , Microambiente Tumoral , Humanos , Adenosina/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Receptores Purinérgicos P1/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Terapia de Alvo Molecular , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/uso terapêuticoRESUMO
BACKGROUND: Cardiomyocytes form, transport, and metabolize the omnipresent metabolite adenosine. Depending upon the adenosine concentrations and the pharmacological properties of receptor subtypes, adenosine exerts (patho)physiological responses in the cardiovascular system. The objective of this review is to present different protective mechanisms of A1-adenosine receptor inhibitors in cardiovascular diseases. METHODS AND RESULTS: Literature references were collected and sorted using relevant keywords and key phrases as search terms in scientific databases such as Web of Science, PubMed and Google Scholar. A1 adenosine receptor regulates free fatty acid metabolism, lipolysis, heart rate, blood pressure, and cardiovascular toxicity. The evidence clearly supporting the therapeutic potency of pharmacological A1 adenosine receptors agonists and antagonists in modulating cardiovascular risk factor parameters and treatment of cardiovascular diseases. CONCLUSION: This review summarizes the protective role of pharmacological A1-adenosine receptor regulators in the pathogenesis of cardiovascular diseases for a better management of cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Antagonistas de Receptores Purinérgicos P1 , Humanos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Pressão Sanguínea , Adenosina , Receptores Purinérgicos P1RESUMO
Adenosine metabolism through adenosine receptors plays a critical role in lung cancer biology. Although recent studies showed the potential of targeting adenosine receptors as drug targets for lung cancer treatment, conventional methods for investigating receptor activities often suffer from various drawbacks, including low sensitivity and slow analysis speed. In this study, adenosine receptor activities in nonsmall cell lung cancer (NSCLC) cells were monitored in real time with high sensitivity through a carbon nanotube field-effect transistor (CNT-FET). In this method, we hybridized a CNT-FET with NSCLC cells expressing A2A and A2B adenosine receptors to construct a hybrid platform. This platform could detect adenosine, an endogenous ligand of adenosine receptors, down to 1 fM in real time and sensitively discriminate adenosine among other nucleosides. Furthermore, we could also utilize the platform to detect adenosine in complicated environments, such as human serum. Notably, our hybrid platform allowed us to monitor pharmacological effects between adenosine and other drugs, including dipyridamole and theophylline, even in human serum samples. These results indicate that the NSCLC cell-hybridized CNT-FET can be a practical tool for biomedical applications, such as the evaluation and screening of drug-candidate substances.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanotubos de Carbono , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptores Purinérgicos P1 , Adenosina/farmacologiaRESUMO
This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1H-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y2847.55 in TMD7 and Y2938.54 in H8 and by π-NH bonding between Y2847.55 and the exocyclic amine. The 2-cyclohexyl group is positioned "upward" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N-1 amine of the heterocycle and the carbonyl of G291.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y2938.54; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1H-imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A3AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A3AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1H-imidazo[4,5-c]quinolin-4-amine class of A3AR positive allosteric modulators.
Assuntos
Aminas , Receptores Purinérgicos P1 , Simulação de Acoplamento Molecular , Regulação Alostérica , Receptores Purinérgicos P1/metabolismo , Sítios de Ligação , Sítio Alostérico , Simulação de Dinâmica Molecular , LipídeosRESUMO
A structure-based drug design pipeline that considers both thermodynamic and kinetic binding data of ligands against a receptor will enable the computational design of improved drug molecules. For unresolved GPCR-ligand complexes, a workflow that can apply both thermodynamic and kinetic binding data in combination with alpha-fold (AF)-derived or other homology models and experimentally resolved binding modes of relevant ligands in GPCR-homologs needs to be tested. Here, as test case, we studied a congeneric set of ligands that bind to a structurally unresolved G protein-coupled receptor (GPCR), the inactive human adenosine A3 receptor (hA3R). We tested three available homology models from which two have been generated from experimental structures of hA1R or hA2AR and one model was a multistate alphafold 2 (AF2)-derived model. We applied alchemical calculations with thermodynamic integration coupled with molecular dynamics (TI/MD) simulations to calculate the experimental relative binding free energies and residence time (τ)-random accelerated MD (τ-RAMD) simulations to calculate the relative residence times (RTs) for antagonists. While the TI/MD calculations produced, for the three homology models, good Pearson correlation coefficients, correspondingly, r = 0.74, 0.62, and 0.67 and mean unsigned error (mue) values of 0.94, 1.31, and 0.81 kcal mol-1, the τ-RAMD method showed r = 0.92 and 0.52 for the first two models but failed to produce accurate results for the multistate AF2-derived model. With subsequent optimization of the AF2-derived model by reorientation of the side chain of R1735.34 located in the extracellular loop 2 (EL2) that blocked ligand's unbinding, the computational model showed r = 0.84 for kinetic data and improved performance for thermodynamic data (r = 0.81, mue = 0.56 kcal mol-1). Overall, after refining the multistate AF2 model with physics-based tools, we were able to show a strong correlation between predicted and experimental ligand relative residence times and affinities, achieving a level of accuracy comparable to an experimental structure. The computational workflow used can be applied to other receptors, helping to rank candidate drugs in a congeneric series and enabling the prioritization of leads with stronger binding affinities and longer residence times.
Assuntos
Furilfuramida , Simulação de Dinâmica Molecular , Humanos , Ligantes , Fluxo de Trabalho , Termodinâmica , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores Purinérgicos P1/metabolismo , Desenho de Fármacos , AdenosinaRESUMO
Ethanol is one of the most commonly used and abused substances in the world. While the behavioral effects of ethanol are well characterized, mechanisms of its action on neurons and synapses remain elusive. Prior research suggested that ethanol could affect neurons by interfering with metabolism of biologically active molecules, such as adenosine. Here, we explored the involvement of adenosine A1 receptors (A1R) in mediating ethanol's effects on synaptic transmission to layer 2/3 pyramidal neurons of visual cortex using wild type (WT) and A1R knock-out (KO) mice. Ethanol differentially affected excitatory and inhibitory transmission in WT and KO mice. In slices from WT mice ethanol had heterogeneous effects on excitatory transmission (facilitation, suppression or no change), with no net change. Ethanol's effects remained heterogeneous during acute blockade of A1Rs with a selective antagonist DPCPX. However, in A1RKO mice ethanol consistently suppressed excitatory transmission, with no cases of enhancement observed. Inhibitory transmission was suppressed by ethanol in both WT and A1RKO mice. At both excitatory and inhibitory synapses, changes of response amplitude correlated with changes of paired-pulse ratio, suggesting involvement of presynaptic mechanisms. We conclude that A1Rs are not involved in mediating effects of ethanol on synaptic transmission in mouse visual cortex. However, A1Rs are necessary for development of mechanisms mediating facilitation at some excitatory synapses. Our results add evidence for the diversity of ethanol's effects and mechanisms of action on synaptic transmission in different brain structures, and even in the same brain area (visual cortex) in different species, rats vs mice.
Assuntos
Etanol , Córtex Visual , Ratos , Camundongos , Animais , Etanol/farmacologia , Adenosina/metabolismo , Camundongos Knockout , Transmissão Sináptica/fisiologia , Sinapses/metabolismo , Receptores Purinérgicos P1/metabolismo , Córtex Visual/fisiologiaRESUMO
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and adolescents. Fusion-negative RMS (FN-RMS) accounts for more than 80% of all RMS cases. The long-term event-free survival rate for patients with high-grade FN-RMS is below 30%, highlighting the need for improved therapeutic strategies. CD73 is a 5' ectonucleotidase that hydrolyzes AMP to adenosine and regulates the purinergic signaling pathway. We found that CD73 is elevated in FN-RMS tumors that express high levels of TWIST2. While high expression of CD73 contributes to the pathogenesis of multiple cancers, its role in FN-RMS has not been investigated. We found that CD73 knockdown decreased FN-RMS cell growth while up-regulating the myogenic differentiation program. Moreover, mutation of the catalytic residues of CD73 rendered the protein enzymatically inactive and abolished its ability to stimulate FN-RMS growth. Overexpression of wildtype CD73, but not the catalytically inactive mutant, in CD73 knockdown FN-RMS cells restored their growth capacity. Likewise, treatment with an adenosine receptor A2A-B agonist partially rescued FN-RMS cell proliferation and bypassed the CD73 knockdown defective growth phenotype. These results demonstrate that the catalytic activity of CD73 contributes to the pathogenic growth of FN-RMS through the activation of the purinergic signaling pathway. Therefore, targeting CD73 and the purinergic signaling pathway represents a potential therapeutic approach for FN-RMS patients.
Assuntos
Rabdomiossarcoma , Adolescente , Criança , Humanos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Receptores Purinérgicos P1 , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Transdução de SinaisRESUMO
Interest has been focused in recent years on the analgesic effects exerted by adenosine and its receptors, A1, A2A, A2B, and A3 adenosine receptor (AR) subtypes, in different in vivo models of chronic pain. In particular, it was demonstrated that selective A3AR agonists reduced pro-nociceptive N-type Ca2+ channels in dorsal root ganglion (DRG) neurons isolated from rats and, by this mechanism, inhibit post inflammatory visceral hypersensitivity. In the present study, we investigate the effect of a previously reported irreversibly binding A3AR agonist, ICBM, on Ca2+ currents (ICa) in rat DRG neurons. Present data demonstrate that ICBM, an isothiocyanate derivative designed for covalent binding to the receptor, concentration-dependently inhibits ICa. This effect is irreversible, since it persists after drug removal, differently from the prototypical A3AR agonist, Cl-IB-MECA. ICBM pre-exposure inhibits the effect of a subsequent Cl-IB-MECA application. Thus, covalent A3AR agonists such as ICBM may represent an innovative, beneficial, and longer-lasting strategy to achieve efficacious chronic pain control versus commonly used, reversible, A3AR agonists. However, the possible limitations of this drug and other covalent drugs may be, for example, a characteristic adverse effect profile, suggesting that more pre-clinical studies are needed.
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Dor Crônica , Gânglios Espinais , Ratos , Animais , Gânglios Espinais/metabolismo , Dor Crônica/metabolismo , Neurônios/metabolismo , Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptor A3 de Adenosina/metabolismo , Agonistas do Receptor A3 de Adenosina/farmacologiaRESUMO
A variety of observational studies have demonstrated that coffee, likely acting through caffeine, improves health outcomes in patients with chronic liver disease. The primary pharmacologic role of caffeine is to act as an inhibitor of adenosine receptors. Because key liver cells express adenosine receptors linked to liver injury, regeneration, and fibrosis, it is plausible that the biological effects of coffee are explained by effects of caffeine on adenosinergic signaling in the liver. This review is designed to help the reader make sense of that hypothesis, highlighting key observations in the literature that support or dispute it.
Assuntos
Cafeína , Café , Humanos , Cafeína/farmacologia , Cirrose Hepática , Adenosina/farmacologia , Fígado , Receptores Purinérgicos P1RESUMO
Caffeine, a widely consumed stimulant, is known for its effects on alertness and fatigue reduction by blockade of adenosine receptors. While it holds therapeutic potential, its diverse impacts pose risks, particularly in early development. This study explores the developmental effects of caffeine exposure using Caenorhabditis elegans (C. elegans) as a model organism. We investigated morphological and behavioral changes induced by caffeine exposure at the L1 stage and assessed their impact at the L4 stage, which roughly corresponds to human infancy and adolescence, respectively. Caffeine-exposed worms displayed increased body length, body bends, and pharyngeal pumping rates compared to control worms. These findings indicate heightened food-seeking behavior and greater food intake, leading to the observed morphological changes. While caffeine did not affect other locomotor behaviors, its stimulatory effect on growth and development highlights its significance. This study provides insights into the potential impact of early-life caffeine exposure on long-term health and development, offering a foundation for future research in vertebrates to uncover its implications on metabolism and other metrics of health.
Assuntos
Proteínas de Caenorhabditis elegans , Cafeína , Animais , Humanos , Cafeína/farmacologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Receptores Purinérgicos P1RESUMO
The occurrence and development of the tumor are very complex biological processes. In recent years, a large number of research data shows that CD73 is closely related to tumor growth and metastasis. It has been confirmed that the cascade hydrolysis of extracellular ATP to adenosine is one of the most important immunosuppressive regulatory pathways in the tumor microenvironment. The metabolite adenosine can mediate immunosuppression by activating adenosine receptor (such as A2A) on effector Immune cells and enable tumor cells to achieve immune escape. Therefore, attenuating or completely removing adenosine-mediated immunosuppression in the tumor microenvironment by inhibiting CD73 is a promising approach in the treatment of solid tumors. This paper focuses on the research progress of CD73 enzyme and CD73 small molecule inhibitors, and is expected to provide some insights into the development of small-molecule antitumor drugs targeting CD73.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/metabolismo , Adenosina/farmacologia , Adenosina/metabolismo , Antineoplásicos/farmacologia , Imunossupressores , Receptores Purinérgicos P1 , 5'-Nucleotidase , Microambiente TumoralRESUMO
RATIONALE: Using routine synthetic drugs in the treatment of psychiatric disorders may have some restrictions due to serious side effects and pharmacoresistance. Some natural agents may be promising alternatives in this case. The neuroprotective activity of the neuromodulator adenosine and its receptor, A1 receptor (A1R) in the central nervous system has been mentioned in different studies. OBJECTIVE: We aimed to determine the anxiolytic, antidepressant and sedative effects of Japanese sake yeast as the first report. METHOD: Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose levels of 100, 200 and 300 mg kg-1 once daily for a week. The anxiolytic, antidepressant, and sedative actions of sake yeast were evaluated with the related tests. RESULTS: In all dose regiments, sake yeast significantly improved functions in the EPM and FST. 200 and 300 mg/kg of sake yeast significantly increased sleep duration and reduced sleep latency. Anxiolytic and antidepressant-like activities of sake yeast were maintained by the injection of ZM241385 (15 mg kg-1), a selective adenosine A2AR antagonist but completely counteracted by the injection of 8-cyclopentyltheophylline (10 mg kg-1), a selective adenosine A1R antagonist. 300 mg/kg of the yeast significantly increased the BDNF levels. Amygdala corticosterone levels did not show any significant changes at any dosage. Amygdala TNF-α, IL-6 and IL-1ß levels also decreased significantly with all the sake regiments compared to the control group. CONCLUSIONS: We conclude that oral sake yeast supplement exerts a neurobehavioral protective effect predominantly by activating central A1Rs.
Assuntos
Ansiolíticos , Saccharomyces cerevisiae , Humanos , Camundongos , Animais , Ansiolíticos/farmacologia , Bebidas Alcoólicas , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Fermentação , Ansiedade/tratamento farmacológico , Ansiedade/prevenção & controle , Adenosina/farmacologia , Antidepressivos/farmacologia , Receptores Purinérgicos P1RESUMO
Traditionally, platelets are known to play an important role in haemostasis and thrombosis; however, they serve also as important modulators of inflammation and immunity. Platelets secrete adhesion molecules and cytokines, interact with leukocytes and endothelium, and express toll-like receptors involved in a direct interaction with pathogens. Platelets express A2A and A2B subtypes of receptors for adenosine. The activation of these receptors leads to an increase in cAMP concentration in the cytoplasm, thereby resulting in inhibited secretion of pro-inflammatory mediators and reduced cell activation. Therefore, platelet adenosine receptors could be a potential target for inhibiting platelet activation and thus down-regulating inflammation or immunity. The biological effects of adenosine are short-lasting, because the compound is rapidly metabolized; hence, its lability has triggered efforts to synthesize new, longer-lasting adenosine analogues. In this article, we have reviewed the literature regarding the pharmacological potential of adenosine and other agonists of A2A and A2B receptors to affect platelet function during inflammation. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.