RESUMEN
OBJECTIVE: The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes. DATA SOURCES: We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021. STUDY ELIGIBILITY CRITERIA: Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone. METHODS: A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder. RESULTS: A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes. CONCLUSION: Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings.
Asunto(s)
Vejiga Urinaria Hiperactiva , Humanos , Vejiga Urinaria Hiperactiva/terapia , Canales Catiónicos TRPV/uso terapéutico , Marcadores Genéticos , Antagonistas Colinérgicos/uso terapéutico , Receptores Colinérgicos/uso terapéutico , Receptores Purinérgicos/uso terapéutico , Receptor Muscarínico M3/uso terapéuticoRESUMEN
Intraerythrocytic stages of Plasmodium falciparum responsible for all clinical manifestations of malaria are regulated by array of signalling cascades that represent attractive targets for antimalarial therapy. G-protein coupled receptors (GPCRs) are druggable targets in the treatment of various pathological conditions, however, there is limited understanding about the role of GPCRs in malaria pathogenesis. In Plasmodium, serpentine receptors (PfSR1, PfSR10, PfSR12 and PfSR25) with GPCR-like membrane topology have been reported with the finite knowledge about their potential as antimalarial targets. We analyzed the localization of these receptors in malaria parasite by immunofluorescence assays. All four receptors were expressed in blood stages with PfSR12 expressing more in late intraerythrocytic stages. Further, we evaluated the druggability of PfSR12 using FDA-approved P2Y purinergic receptor antagonist, Prasugrel and its active metabolite R138727, which is proposed to be specific towards PfSR12. Interestingly, biophysical analysis indicated strong binding between PfSR12 and R138727 as compared to the prodrug Prasugrel. This binding interaction was further confirmed by thermal shift assay. Treatment of parasite with Prasugrel and R138727 resulted in growth inhibition of P. falciparum indicating an important role of purinergic signalling and PfSR12 in parasite survival. Next, progression studies indicated the inhibitory effect of Prasugrel begins in late erythrocyte stages corroborating with PfSR12 expression at these stages. Furthermore, Prasugrel also blocked in vivo growth of malaria parasite in a mouse experimental model. This study indicates the presence of P2Y type of purinergic signalling in growth and development of malaria parasite and suggests PfSR12, putative purinergic receptor druggability through Prasugrel.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria , Animales , Ratones , Plasmodium falciparum , Antimaláricos/metabolismo , Clorhidrato de Prasugrel/metabolismo , Clorhidrato de Prasugrel/farmacología , Clorhidrato de Prasugrel/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria/tratamiento farmacológico , Receptores Purinérgicos/metabolismo , Receptores Purinérgicos/uso terapéutico , Receptores Acoplados a Proteínas G/metabolismo , Eritrocitos/metabolismo , Antagonistas Purinérgicos/metabolismo , Antagonistas Purinérgicos/farmacología , Antagonistas Purinérgicos/uso terapéutico , Proteínas Protozoarias/metabolismoRESUMEN
In the last decade evidence accumulated that nucleosides and nucleotides of both uridine and adenine can act as extracellular signaling factors. Their action is mediated by two main types of surface receptors commonly known as purinergic. P1 receptors are metabotropic and activated by adenosine, whereas receptors for nucleotides (ATP, ADP, UTP and UDP) and nucleotide-sugars (UDP-glucose and UDP-galactose) can be either metabotropic (P2Y) or ionotropic (P2X). The importance and complexity of this signaling system is evidenced by various mechanisms of nucleotide release, as well as by the ibiquitous distribution of various types of ectonucleotidases which catalyze and convert extracellular nucleotides. Up to now about twenty receptors have been cloned and found to modulate the nerve impulse, inflammatory response, insuline secretion, the regulation of the vascular tone and nociception, among other processes. In the present review we describe the main structural and pharmacological features of purinergic receptors, and analyze how the dynamic interaction between these receptors, nucleotides and nucleosides, and ectonucleotidases modulate several biological responses. Particular focus is given to platelet aggregation and thrombus formation, the immune response and the hydration of the mucosal linings of the respiratory tract.
Asunto(s)
Antígenos CD/fisiología , Apirasa/fisiología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Nucleótidos/fisiología , Agregación Plaquetaria/fisiología , Receptores Purinérgicos/fisiología , Animales , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Nucleotidasas/fisiología , Nucleótidos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Receptores Purinérgicos/uso terapéutico , Transducción de Señal/fisiologíaRESUMEN
En la última década se ha aportado clara evidencia de que tanto nucleósidos como nucleótidos de adenina y uridina pueden funcionar como factores de señalización extracelular. Su acción es mediada por dos tipos principales de receptores de superficie denominados purinérgicos. Los receptores P1 se activan por adenosina, y son todos metabotrópicos, mientras que los receptores de nucleótidos (ATP, ADP, UTP y UDP) y nucleótidos-azúcares (UDP-glucosa y UDP-galactosa) pueden ser metabotrópicos (P2Y) o ionotrópicos (P2X). La importancia y complejidad de este sistema de señalización se evidencia por la diversidad de mecanismos de liberación de nucleótidos al medio extracelular y por la distribución ubicua de varios grupos de ectonucleotidasas capaces de catalizar la degradación y conversión de nucleótidos. Hasta el momento se han descrito y clonado una veintena de estos receptores que modulan una variedad de respuestas, como el impulso nervioso, la respuesta inflamatoria, la secreción de insulina, la regulación del tono vascular y la percepción del dolor. En la presente revisión se describen las características estructurales y farmacológicas de los receptores purinérgicos y se analiza la interacción dinámica entre estos receptores, los nucleósidos y nucleótidos, y las ectonucleotidasas, con especial atención a la dinámica de la agregación plaquetaria, la respuesta inmune y la hidratación de las mucosas respiratorias.
In the last decade evidence accumulated that nucleosides and nucleotides of both uridine and adenine can act as extracellular signaling factors. Their action is mediated by two main types of surface receptors commonly known as purinergic. P1 receptors are metabotropic and activated by adenosine, whereas receptors for nucleotides (ATP, ADP, UTP and UDP) and nucleotide-sugars (UDP-glucose and UDP-galactose) can be either metabotropic (P2Y) or ionotropic (P2X). The importance and complexity of this signaling system is evidenced by various mechanisms of nucleotide release, as well as by the ibiquitous distribution of various types of ectonucleotidases which catalyze and convert extracellular nucleotides. Up to now about twenty receptors have been cloned and found to modulate the nerve impulse, inflammatory response, insuline secretion, the regulation of the vascular tone and nociception, among other processes. In the present review we describe the main structural and pharmacological features of purinergic receptors, and analyze how the dynamic interaction between these receptors, nucleotides and nucleosides, and ectonucleotidases modulate several biological responses. Particular focus is given to platelet aggregation and thrombus formation, the immune response and the hydration of the mucosal linings of the respiratory tract.
Asunto(s)
Animales , Humanos , Antígenos CD/fisiología , Apirasa/fisiología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Nucleótidos/fisiología , Agregación Plaquetaria/fisiología , Receptores Purinérgicos/fisiología , Enfermedades Pulmonares/tratamiento farmacológico , Nucleotidasas/fisiología , Nucleótidos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Receptores Purinérgicos/uso terapéutico , Transducción de Señal/fisiologíaRESUMEN
Platelets play a major role in thromboembolic diseases, and so antiplatelet therapy remains crucial in treatment and prophylaxis. Upon vascular injury, platelets rapidly adhere to the exposed subendothelial matrix, after which they become activated, resulting in the recruitment of additional platelets from the circulation to eventually form a stable arterial platelet plug. Although controlled plug formation is desired for the prevention of excessive blood loss and for promoting wound healing, several pathological conditions may result in the formation of occlusive thrombi leading to severe clinical complications, including myocardial infarction and ischaemic stroke. Many antiplatelet approaches have been investigated, interfering with one or more of the different stages in thrombus formation. This review discusses antiplatelet agents that interfere with the three principal phases in thrombus formation: platelet adhesion, amplification of platelet activation and platelet aggregation. For each stage, novel experimental targets and clinically established antiplatelet strategies will be reviewed. Limitations and possible benefits will be discussed for each target.
Asunto(s)
Plaquetas/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Trombosis/prevención & control , Humanos , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptores Purinérgicos/uso terapéutico , Serotonina/uso terapéutico , Trombina/uso terapéutico , Tromboxano A2/uso terapéuticoRESUMEN
The studies on the purinergic system in the kidney clearly showed its role on the renal hemodynamics, glomerular filtration and tubular function. The effectsof purinergic agonists on the mechanisms of tubuloglomerular feedback, and tubular transport of water and solutes, are well defined. In addition, severalstudies have documented the role of adenosine and specific ATP receptors on the processes of renal diseases, with special interest on the ischemiareperfusioninjury, renal cystic disease, glomerular and tubulointerstitial diseases. Therefore, the purinergic system has become a growing field for researchin renal physiology and pathophysiology, leading to therapeutic possibilities of using specific agonists and antagonists.
Os estudos sobre o sistema purinérgico no rim evidenciaram ao longo dos anos a sua participação na hemodinâmica renal, filtração glomerular e funçãotubular. É bem conhecida a participação de efetores purinérgicos no mecanismo de feedback túbulo-glomerular e transporte tubular de água e solutos.Além disso, vários trabalhos têm mostrado a participação da adenosina e de receptores específicos de ATP em processos de doença renal, com umespecial interesse na lesão da isquemia-reperfusão, doença cística renal, doenças glomerulares e túbulo-intersticiais. Portanto, o sistema purinérgico temse tornado alvo crescente de pesquisa em fisiologia e fisiopatologia renal, voltando-se para as possibilidades terapêuticas no uso de agentes agonistas eantagonistas específicos.
Asunto(s)
Humanos , Adenosina/análisis , Enfermedades Renales/terapia , Receptores Purinérgicos , Receptores Purinérgicos/uso terapéutico , Adenosina Trifosfato/análisisRESUMEN
El concepto de un sistema de señalización purinérgica, empleando los nucleótidos y nucleósidos de purina como mensajeros extracelulares, fue propuesto hace unos 30 años. Después de una breve introducción y puesta al día de los subtipos de receptores purinérgicos, este artículo se centra en los aspectos fisiopatológicos desempeñados por el ATP, ADP, UTP y adenosina. Estas moléculas median respuestas a corto plazo (agudas), como en la neurotransmisión, secreción y vasodilatación, y también respuestas a largo plazo (crónicas), como la señalización en el desarrollo, regeneración, proliferación y muerte celular. En condiciones patológicas, se observa que la expresión de los purinoceptores es muy versátil, incluyendo un incremento en el componente purinérgico del control nervioso parasimpático de la vejiga humana en el caso de sufrir cistitis intersticial y obstrucción del flujo, y también como cotransmisor en el control simpático de los vasos sanguíneos en ratas hipertensas. La acción antitrombótica del clopidogrel, un antagonista del receptor P2Y12, ha demostrado ser particularmente útil en la prevención de los infartos cerebrales recurrentes e infartos cardíacos en recientes ensayos clínicos. El papel del receptor P2X3 en la nocicepción y una nueva hipótesis sobre la transducción mecano-sensible en el dolor visceral, serán consideradas, así como el potencial terapéutico de los agonistas y antagonistas purinérgicos para el tratamiento de la taquicardia supraventricular, cáncer, ojo seco, hiperactividad de vejiga, disfunción eréctil, osteoporosis, diabetes, motilidad intestinal y anomalías respiratorias y vasculares
The concept of a purinergic signalling system, using purine nucleotides and nucleosides as extracellular messengers, was first proposed over 30 years ago. After a brief introduction and update of purinoceptor subtypes, this article focuses on the diverse pathophysiological roles of ATP, ADP, UTP and adenosine. These molecules mediate short-term (acute) signalling functions in neurotransmission, secretion and vasodilatation and long-term (chronic) signalling functions in development, regeneration, proliferation and cell death. Plasticity of purinoceptor expression in pathological conditions is frequently observed, including an increase in the purinergic component of parasympathetic nervous control of the human bladder in interstitial cystitis and outflow obstruction, and in sympathetic cotransmitter control of blood vessels in hypertensive rats. The antithrombotic action of clopidogrel, a P2Y12 receptor antagonist, has been shown to be particularly useful in the prevention of recurrent strokes and heart attacks in recent clinical trials. The role of P2X3 receptors in nociception and a novel hypothesis about purinergic mechano-sensory transduction in visceral pain will be considered, as well as the therapeutic potential of purinergic agonists or antagonists for the treatment of supraventricular tachycardia, cancer, dry eye, bladder hyperactivity, erectile dysfunction, osteoporosis, diabetes, gut motility, respiratory and vascular disorders
Asunto(s)
Nucleótidos de Purina/farmacología , Nucleósidos de Purina/farmacología , Receptores Purinérgicos/uso terapéutico , Adenosina Trifosfato/fisiología , Cistitis Intersticial , Trombosis/inducido químicamente , Osteoporosis/fisiopatología , Infarto Cerebral/prevención & control , Receptores Purinérgicos P2/uso terapéutico , Receptores Purinérgicos P1/uso terapéutico , Muerte Celular , Adenosina/fisiología , Adenosina Trifosfato/farmacología , Cistitis Intersticial/diagnóstico , Uridina Trifosfato/fisiología , Receptores Purinérgicos/administración & dosificación , Antígenos de Neoplasias/farmacología , Antígenos de Neoplasias/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & controlRESUMEN
Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na(+) absorption, mediated by epithelial Na(+) channels (ENaC), and deficient Cl(-) transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO(3)(-) secretion. In other epithelial tissues, epithelial Na(+) conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl(-) channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl(-) channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways. In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y(2) receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na(+) absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca(2+)-dependent Cl(-) channel is activated that may compensate for the CFTR Cl(-) channel defect. Thus activation of P2Y(2) receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y(2) receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na(+) transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Fibrosis Quística/tratamiento farmacológico , Transporte Iónico/efectos de los fármacos , Nucleótidos/uso terapéutico , Antagonistas Purinérgicos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/fisiología , Animales , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/fisiología , Femenino , Humanos , Masculino , Depuración Mucociliar/efectos de los fármacos , Depuración Mucociliar/fisiología , Preparaciones Farmacéuticas/administración & dosificación , Pronóstico , Receptores Purinérgicos/uso terapéutico , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , OvinosRESUMEN
Os modelos fisiopatologicos da esquizofrenia classicamente tem abordado diversos neurotransmissores, como a dopamina, a serotonina e o glutamato. Neste trabalho, propomos que alteracoes envolvendo o sistema purinergico...