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At high levels, extracellular ATP operates as a "danger" molecule under pathologic conditions through purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Its endogenous activation is associated with neurodevelopmental disorders; however, its function during early embryonic stages remains largely unclear. Our objective was to determine the role of P2X7R in the regulation of neuronal outgrowth. For this purpose, we performed Sholl analysis of dendritic branches on primary hippocampal neurons and in acute hippocampal slices from WT mice and mice with genetic deficiency or pharmacological blockade of P2X7R. Because abnormal dendritic branching is a hallmark of certain neurodevelopmental disorders, such as schizophrenia, a model of maternal immune activation (MIA)-induced schizophrenia, was used for further morphologic investigations. Subsequently, we studied MIA-induced behavioral deficits in young adult mice females and males. Genetic deficiency or pharmacological blockade of P2X7R led to branching deficits under physiological conditions. Moreover, pathologic activation of the receptor led to deficits in dendritic outgrowth on primary neurons from WT mice but not those from P2X7R KO mice exposed to MIA. Likewise, only MIA-exposed WT mice displayed schizophrenia-like behavioral and cognitive deficits. Therefore, we conclude that P2X7R has different roles in the development of hippocampal dendritic arborization under physiological and pathologic conditions.SIGNIFICANCE STATEMENT Our main finding is a novel role for P2X7R in neuronal branching in the early stages of development under physiological conditions. We show how a decrease in the expression of P2X7R during brain development causes the receptor to play pathologic roles in adulthood. Moreover, we studied a neurodevelopmental model of schizophrenia and found that, at higher ATP concentrations, endogenous activation of P2X7R is necessary and sufficient for the development of positive and cognitive symptoms.
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Neuronas , Receptores Purinérgicos P2X7 , Animales , Femenino , Masculino , Ratones , Adenosina Trifosfato/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Receptores Purinérgicos P2X7/genética , DendritasRESUMEN
BACKGROUND: Radiotheranostics differs from the vast majority of other cancer therapies in its capacity for simultaneous imaging and therapy, and it is becoming more widely implemented. A balance between diagnostic and treatment requirements is essential for achieving effective radiotheranostics. Herein, we propose a proof-of-concept strategy aiming to address the profound differences in the specific requirements of the diagnosis and treatment of radiotheranostics. RESULTS: To validate the concept, we designed an s-tetrazine (Tz) conjugated prostate-specific membrane antigen (PSMA) ligand (DOTA-PSMA-Tz) for 68Ga or 177Lu radiolabeling and tumor radiotheranostics, a trans-cyclooctene (TCO) modified Pd@Au nanoplates (Pd@Au-PEG-TCO) for signal amplification, respectively. We then demonstrated this radiotheranostic strategy in the tumor-bearing mice with the following three-step procedures: (1) i.v. injection of the [68Ga]Ga-PSMA-Tz for diagnosis; (2) i.v. injection of the signal amplification module Pd@Au-PEG-TCO; (3) i.v. injection of the [177Lu]Lu-PSMA-Tz for therapy. Firstly, this strategy was demonstrated in 22Rv1 tumor-bearing mice via positron emission tomography (PET) imaging with [68Ga]Ga-PSMA-Tz. We observed significantly higher tumor uptake (11.5 ± 0.8%ID/g) with the injection of Pd@Au-PEG-TCO than with the injection [68Ga]Ga-PSMA-Tz alone (5.5 ± 0.9%ID/g). Furthermore, we validated this strategy through biodistribution studies of [177Lu]Lu-PSMA-Tz, with the injection of the signal amplification module, approximately five-fold higher tumor uptake of [177Lu]Lu-PSMA-Tz (24.33 ± 2.53% ID/g) was obtained when compared to [177Lu]Lu-PSMA-Tz alone (5.19 ± 0.26%ID/g) at 48 h post-injection. CONCLUSION: In summary, the proposed strategy has the potential to expand the toolbox of pretargeted radiotherapy in the field of theranostics.
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Neoplasias Colorrectales , Radiofármacos , Masculino , Animales , Ratones , Radioisótopos de Galio , Distribución Tisular , Línea Celular Tumoral , Neoplasias Colorrectales/patologíaRESUMEN
Reactive oxygen species (ROS) are a cluster of highly reactive and short-lived oxygen-containing molecules that lead to metabolic disorders where production exceeds catabolism in an organism. Many specific radiotracers for positron/single-photon emission tomography have been developed to reveal the discrepancy of ROS levels in normal and damaged tissues and further clarify the relationship between ROS and diseases. This review summarizes the advances achieved for the development of ROS radiotracers to date. The structure design, radiosynthesis, and imaging performance of existing radiotracers are discussed with the individual ROS-response mechanisms highlighted.
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Diagnóstico por Imagen , Especies Reactivas de Oxígeno/metabolismoRESUMEN
PURPOSE: Bacterial infection and antibiotic resistance are serious threats to human health. This study aimed to develop two novel radiotracers, 18F-NTRP and 18F-NCRP, that possess a specific nitroreductase (NTR) response to image deep-seated bacterial infections using positron emission tomography (PET). This method can distinguish infection from sterile inflammation. METHODS: 18F-NTRP and 18F-NCRP were synthesized via a one-step method; all the steps usually involved in tracer radiosynthesis were successfully adapted in the All-In-One automated module. After the physiochemical properties of 18F-NTRP and 18F-NCRP were characterized, their specificity and selectivity for NTR were verified in E. coli and S. aureus. The ex vivo biodistribution of the tracers was evaluated in normal mice. MicroPET-CT imaging was performed in mouse models of bacterial infection and inflammation after the administration of 18F-NTRP or 18F-NCRP. RESULTS: Fully automated radiosynthesis of 18F-NTRP and 18F-NCRP was achieved within 90-110 min with overall decay-uncorrected, isolated radiochemical yields of 21.24 ± 4.25% and 11.3 ± 3.78%, respectively. The molar activities of 18F-NTRP and 18F-NCRP were 320 ± 40 GBq/µmol and 275 ± 33 GBq/µmol, respectively. In addition, 18F-NTRP and 18F-NCRP exhibited high selectivity and specificity for NTR response. PET-CT imaging in bacteria-infected mouse models with 18F-NTRP or 18F-NCRP showed significant radioactivity uptake in either E. coli- or S. aureus-infected muscles. The uptake for E. coli-infected muscles, 2.4 ± 0.2%ID/g with 18F-NTRP and 4.05 ± 0.49%ID/g with 18F-NCRP, was up to three times greater than that for uninfected control muscles. Furthermore, for both 18F-NTRP and 18F-NCRP, the uptake in bacterial infection was 2.6 times higher than that in sterile inflammation, allowing an effective distinction of infection from inflammation. CONCLUSION: 18F-NTRP and 18F-NCRP are worth further investigation to verify their potential clinical application for distinguishing bacterial infection from sterile inflammation via their specific NTR responsiveness.
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Infecciones Bacterianas , Mecloretamina , Animales , Escherichia coli , Radioisótopos de Flúor/química , Humanos , Inflamación/diagnóstico por imagen , Ratones , Nitrorreductasas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones/métodos , Staphylococcus aureus , Distribución Tisular , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Stimulator of interferon genes (STING) protein plays a vital role in the immune surveillance of tumor microenvironment. Monitoring STING expression in tumors benefits the relevant STING therapy. This study aimed to develop a novel 18F-labeled agonist, dimeric amidobenzimidazole (diABZI), and firstly evaluate the feasibility of noninvasive positron emission tomography (PET) imaging of STING expression in the tumor microenvironment. METHODS: An analog of the STING agonist NOTA-DABI was synthesized and labeled with 18F via Al18F-NOTA complexation (denoted as [18F]F-DABI). Physicochemical properties, STING protein-binding affinity, and specificity of [18F]F-DABI were evaluated using cell uptake and docking assays. In vivo small-animal PET imaging and biodistribution studies of [18F]F-DABI in tumor-bearing mice were performed to verify the pharmacokinetics and tumor targeting ability. The correlation between tumor uptake and STING expression was also analyzed. RESULTS: [18F]F-DABI was produced conveniently with high radiochemical yield (44 ± 15%), radiochemical purity (> 97%) and molar activity (15-30 GBq/µmol). In vitro binding assays demonstrated that [18F]F-DABI has a favorable affinity and specificity for STING with a KD of 12.98 ± 2.07 nM. In vivo studies demonstrated the specificity of [18F]F-DABI for PET imaging of STING expression with B16F10 tumor uptake of 10.93 ± 0.93%ID/g, which was significantly different from that of blocking groups (3.13 ± 0.88%ID/g, ***p < 0.0001). Furthermore, tumor uptake of [18F]F-DABI was well positively correlated with STING expression in different tumor types. Biodistribution results demonstrated that [18F]F-DABI was predominately uptaken in the liver and intestines, indicating its hepatobiliary elimination. CONCLUSION: This proof-of-concept study demonstrated a STING-binding radioligand for PET imaging, which could be used as a potential companion diagnostic tool for related STING-agonist therapies.
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Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Animales , Ratones , Radioisótopos de Flúor/farmacocinética , Distribución Tisular , Línea Celular Tumoral , Tomografía de Emisión de Positrones/métodos , Expresión Génica , InterferonesRESUMEN
PURPOSE: Postoperative urinary retention (POUR) is a common complication following colorectal surgery. The incidence of POUR among colorectal surgery patients varies widely, and the risk factors and outcomes of POUR are also debatable. This meta-analysis aims to systematically evaluate the risk factors for POUR in patients after colorectal surgery. METHODS: PubMed, Web of Science, the Cochrane Library, Embase, Medline, and Chinese databases (CBM, CNKI, and WanFang Databases) were searched to identify relevant cohort studies (from inception to August 2022). Two researchers independently conducted literature quality evaluation and data extraction. All data were analyzed by using the Review Manager 5.4 software. RESULTS: Nineteen studies with 101,025 patients were included in this meta-analysis. The risk factors for POUR in colorectal surgery patients were male sex, older age, diabetes mellitus, urological diseases, tumor location in the lower rectum, APR, laparoscopic surgery, operation time ≥ 4 h, postoperative date of urinary catheter removal, excessive intraoperative intravenous fluid volume, and postoperative ileus. The postoperative anastomotic leak, on the other hand, was not a risk factor for POUR. CONCLUSIONS: Multiple risk factors influence the incidence of POUR in patients undergoing colorectal surgery. To reduce the incidence of POUR in colorectal surgery patients, medical staff should identify risk factors early and enforce interventions to prevent them.
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Cirugía Colorrectal , Procedimientos Quirúrgicos del Sistema Digestivo , Retención Urinaria , Humanos , Masculino , Femenino , Retención Urinaria/epidemiología , Retención Urinaria/etiología , Cirugía Colorrectal/efectos adversos , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Estudios RetrospectivosRESUMEN
Superoxide (O2â¢-) is a specific molecular target for xenobiotics, cytokines, and bacteria during inflammatory diseases. The aim of this study is to develop a single-photon emission computed tomography (SPECT) imaging agent and to quantify the distribution of O2â¢- in vivo. 125/131I-PISO was obtained in good radiochemical yield (65.4 ± 9.2%) and high radiochemical purity (>98%) after HPLC purification. 125/131I-PISO (log P = 2.46) could be oxidized by O2â¢- selectively and sensitively, converted to a hydrophilic compound 125/131I-PISA (log P = -1.62) with negative charge simultaneously and conglutinated with biomolecules by electrostatic interactions. The specific accumulation of 131I-PISA in the O2â¢- rich region were verified in cell efflux assay and SPECT/CT imaging in situ O2â¢- enrichment model mice. SPECT/CT imaging showed higher accumulation of 125I-PISO in the inflamed ankles compared to the control. Radioiodinated PISO is a potential SPECT agent to image O2â¢- distribution in vivo through specific and sensitive O2â¢- triggered retention.
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Benzofuranos/química , Colorantes Fluorescentes/química , Radiofármacos/química , Superóxidos/análisis , Animales , Benzofuranos/síntesis química , Colorantes Fluorescentes/síntesis química , Inflamación/inducido químicamente , Inflamación/metabolismo , Radioisótopos de Yodo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos ICR , Células RAW 264.7 , Radiofármacos/síntesis química , Superóxidos/metabolismo , Distribución Tisular/fisiología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
OBJECTIVE: To analyze the mediating effects of caregiver illness uncertainty and psychological resilience in caregiver burden and readiness in patients with moderate-to-severe traumatic brain injuries (TBIs). This can help improve caregiver readiness in patients with moderate-to-severe TBIs. METHODS: A purposive sampling method was used to recruit patients with moderate-to-severe TBIs, and their caregivers, who were hospitalized in the Department of Neurosurgery of the Affiliated Hospital of Yangzhou University between October 2022 and August 2023. The Zarit Caregiver Burden Interview, Mishel Uncertainty In Scale for Family Member, Connor-Davidson Resilience Scale, and Caregivers Preparedness Scale, as well as general information questionnaire, were used to conduct the survey. RESULTS: Caregiver readiness correlated with caregiver burden, illness uncertainty, and psychological resilience in patients with moderate-to-severe TBI (P < 0.01). Caregiver readiness was not only directly affected by caregiver burden (95% confidence interval: -0.510, -0.196) but was also affected through the chain mediation of illness uncertainty and psychological resilience (95% confidence interval: -0.146, -0.011). CONCLUSIONS: Caregiver burden in patients with moderate-to-severe TBI influences caregiver readiness levels and is mediated by illness uncertainty and psychological resilience. By improving caregivers' illness uncertainty and increasing their psychological resilience, the impact of low caregiver readiness caused by high caregiver burden could be reduced.
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Lesiones Traumáticas del Encéfalo , Carga del Cuidador , Cuidadores , Resiliencia Psicológica , Humanos , Lesiones Traumáticas del Encéfalo/psicología , Masculino , Femenino , Incertidumbre , Adulto , Persona de Mediana Edad , Cuidadores/psicología , Carga del Cuidador/psicología , Adulto Joven , Anciano , Encuestas y CuestionariosRESUMEN
Objectives: The aim of this meta-analysis is to evaluate the effect of astragalus injection (AI) on left ventricular remodeling (LVR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: The randomized controlled trials (RCTs) of AI in treating HFmrEF were retrieved from 8 major English and Chinese electronic databases, up until November 30, 2023. To evaluate the methodological quality of the included studies, the Cochrane bias risk tool and the Modified Jadad Scale were employed. Stata 17.0 software was utilized for statistical analysis, sensitivity analysis, and assessment of publication bias. Results: Ten RCTs with 995 patients (562 males and 433 females) were identified. Meta-analysis indicated that compared to conventional treatment (CT), AI significantly improved LVR, specifically increasing left ventricular ejection fraction (LVEF, MD = 4.56, 95% CI: 3.68-5.44, p < 0.00001), decreasing left ventricular end-diastolic volume (LVEDV, MD = -7.89, 95% CI: -11.13 to -4.64, p < 0.00001), left ventricular end-diastolic diameter (LVEDD, MD = -4.18, 95% CI: -5.79 to -2.56, p < 0.00001), left ventricular end-systolic volume (LVESV, MD = -8.11, 95% CI: -11.79 to -4.43, p < 0.00001), and left ventricular end-systolic diameter (LVESD, MD = -3.42, 95% CI: -4.90 to -1.93, p < 0.00001). AI also improved clinical efficacy (RR = 4.62, 95% CI: 3.11-6.88, p < 0.00001), reduced N-terminal pro-brain natriuretic peptide (NT-pro BNP, MD = -27.94, 95% CI: -43.3 to -12.36) level, without increasing the incidence of adverse reactions (RR = 1.60, 95% CI: 0.59-4.29, p = 0.35). Sensitivity analysis confirmed the reliability of the merged results, and Begg's and Egger's tests showed no significant publication bias. Conclusion: The systematic review and meta-analysis revealed that combining AI with CT improves LVR without increasing adverse events in HFmrEF patients. However, caution is needed in interpreting the results due to limited evidence. Future high-quality RCTs are needed to support these conclusions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO [CRD42022347248].
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Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease. However, the definitive diagnosis of IPF is impeded by the limited capabilities of current diagnostic methods, which may fail to capture the optimal timing for treatment. The main goal of this study is to determine the feasibility of a nitroreductase (NTR) responsive probe, 18F-NCRP, for early detection and deterioration monitoring of IPF. 18F-NCRP was obtained with high radiochemical purity (>95 %). BLM-injured mice were established by intratracheal instillation with bleomycin (BLM) and characterized through histological analysis. Longitudinal PET/CT imaging, biodistribution study and in vitro autoradiography were performed. The correlations between the uptake of 18F-NCRP and mean lung density (tested by CT), as well as histopathological characteristics were analyzed. In PET imaging study, 18F-NCRP exhibited promising efficacy in monitoring the progression of IPF, which was earlier than CT. The ratio of uptake in BLM-injured lung to control lung increased from 1.4-fold on D15 to 2.2-fold on D22. Biodistribution data showed a significant lung uptake of 18F-NCRP in BLM-injured mice. There was a strong positive correlation between the 18F-NCRP uptake in the BLM-injured lungs and the histopathological characteristics. Given that, 18F-NCRP PET imaging of NTR, a promising biomarker for investigating the underlying pathogenic mechanism of IPF, is attainable as well as desirable, which might lay the foundation for establishing an NTR-targeted imaging evaluation system of IPF.
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Diagnóstico Precoz , Fibrosis Pulmonar Idiopática , Nitrorreductasas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Ratones , Nitrorreductasas/metabolismo , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/inducido químicamente , Bleomicina , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/metabolismo , Humanos , Modelos Animales de Enfermedad , Distribución Tisular , Masculino , Radioisótopos de Flúor , RadiofármacosRESUMEN
Activation of the adenosine 2A receptor (A2AR) can lead to tumor immunosuppression, which results in poor prognosis of immunotherapy. The aim of this study was to design novel 18F-labeled probes ([18F]F-PFP2 and [18F]F-PFP4) to visualize A2AR in the tumor. The uptake of radioprobes in A2AR-negative 4T1 breast tumor was lower than that of A2AR-positive B16F10 melanoma at 1 h p.i. (1.22 ± 0.36% ID/g vs 2.80 ± 0.72% ID/g), 2 h p.i. (1.09 ± 0.20% ID/g vs 2.93 ± 0.76% ID/g) and 3 h p.i. (0.89 ± 0.27% ID/g vs 2.73 ± 0.58% ID/g), respectively. B16F10 lung metastasis models were employed to expand the application scenarios, observing significantly higher uptake of [18F]F-PFP2 in metastatic lesions compared to normal lung tissue (5.55 ± 2.18% ID/g vs 1.89 ± 0.65% ID/g, tumor/lung ratio â¼3). It is given that [18F]F-PFP2 might lay the foundation for establishing an A2AR-targeted imaging evaluation system for tumors, which will provide more precise guidance for personalized treatment.
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Radiofármacos , Receptor de Adenosina A2A , Animales , Ratones , Receptor de Adenosina A2A/metabolismo , Radiofármacos/química , Radiofármacos/farmacocinética , Femenino , Línea Celular Tumoral , Radioisótopos de Flúor/química , Humanos , Tomografía de Emisión de Positrones/métodos , Ratones Endogámicos BALB C , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Distribución Tisular , Ratones Endogámicos C57BL , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Melanoma Experimental/patologíaRESUMEN
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is a prevalent cardiovascular disease globally, posing a significant burden on healthcare and society. Left ventricular remodelling is the primary pathology responsible for HFrEF development and progression, leading to increased morbidity and mortality. Pueraria, a traditional Chinese herbal medicine and food, is commonly used in China to treat HFrEF. Accumulating evidence suggests that pueraria can effectively reverse left ventricular remodelling in HFrEF patients. This meta-analysis aims to assess the impact of pueraria on left ventricular remodelling in HFrEF patients. METHODS: Eight electronic databases, including PubMed, EMBASE, Clinicaltrials.gov, Cochrane Library, Wanfang, CNKI, CQVIP, and CBM were searched for literature from inception to June 2023. All randomized controlled trials (RCTs) using pueraria in the treatment of HFrEF were included. The Cochrane Risk of Bias tool was utilized for RCTs' methodological evaluation, while Review Manager 5.4.1 was used to analyze the data. RESULTS: Nineteen RCTs with a total of 1,911 patients (1,077 males and 834 females) were identified. Meta-analysis indicated that combination medication of pueraria and conventional medicine (CM) was superior to the CM alone in raising left ventricular ejection fraction (LVEF; MD = 6.46, 95% CI, 4.88 to 8.04, P < 0.00001), and decreasing left ventricular end-diastolic diameter (LVEDD; MD = -4.78, 95% CI, -6.55 to -3.01, P < 0.00001), left ventricular end-Systolic diameter (LVESD; MD = -3.98, 95% CI, -5.98 to -1.99, P < 0.00001) and N-terminal pro-brain natriuretic peptide (NT-proBNP; MD = -126.16, 95% CI, -185.30 to -67.03, P < 0.0001). Besides, combination medication improved clinical efficacy rate (RR = 3.42, 95% CI, 2.54 to 4.59, P < 0.00001), 6-min walk test (6-MWT; MD = 65.54, 95% CI, 41.77 to 89.31, P < 0.00001), and TCM syndrome score efficacy (RR = 3.03, 95% CI, 1.57 to 5.83, P = 0.0009). Regarding safety, no difference was observed for adverse events (RR = 0.59, 95% CI, 0.22 to 1.54, P = 0.28). CONCLUSION: The use of pueraria combined with conventional medicine in HFrEF patients has superiority over conventional medicine alone in ameliorating cardiac function and reversing left ventricular remodeling. Moreover, combination medication has no increase in adverse drug events. Given some limitations, more prudence and high-quality clinical trials are needed in the future to verify the conclusions.
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Insuficiencia Cardíaca , Pueraria , Masculino , Femenino , Humanos , Remodelación Ventricular , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely unclear. Here, by using whole-cell patch-clamp technique to record AMPA- and NMDA receptor-mediated excitatory postsynaptic currents (s/mEPSCs) in dentate gyrus granule cells (DG GCs), we revealed a modulation by P2X7Rs of presynaptic sites, especially originated from entorhinal cortex (EC)-GC path but not the mossy cell (MC)-GC path. The involvement of P2X7Rs was confirmed using a pharmacological approach. Additionally, the acute activation of P2X7Rs directly elevated calcium influx from EC-GC terminals. In postnatal phencyclidine (PCP)-induced mouse model of schizophrenia, we observed that P2X7R deficiency restored the EC-GC synapse alteration and alleviated PCP-induced symptoms. To summarize, P2X7Rs participate in the modulation of GC excitatory neurotransmission in the DG via EC-GC pathway, contributing to pathological alterations of neuronal functions leading to neurodevelopmental disorders.
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Oxidative stress (OS) has been implicated in the progression of multiple neuropsychiatric disorders, including schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism. However, whether glial purinergic signaling interaction with oxidative/antioxidative system displays an important role in neuropsychiatric disorders is still unclear. In this review, we firstly summarize the oxidative/antioxidative pathways shared in different glial cells and highlight the cell type-specific difference in response to OS. Then, we collect the evidence showing the regulation of purinergic signaling in OS with an emphasis on adenosine and its receptors, P2Y1 receptor in the P2Y family and P2X7receptor in the P2X family. Available data shows that the activation of P1 receptors and P2X accelerates the OS; reversely, the activation of the P2Y family (P2Y1) causes protective effect against OS. Finally, we discuss current findings demonstrating the contribution of the purinergic signaling system to neuropsychiatric disorders and point out the potential role of OS in this process to propose a "glial purinergic-oxidative stress" ("GPOS") hypothesis for future development of therapeutic strategies against a variety of neuropsychiatric disorders.
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Trastornos Mentales/fisiopatología , Neuroglía/fisiología , Estrés Oxidativo/fisiología , Humanos , Transducción de SeñalRESUMEN
Non-noble materials with high efficiency and stability are essential for renewable energy applications. Herein, cobalt phosphide nanoparticles-decorated covalent organic frameworks (CTF-CoP) are synthesized via an in situ self-assembly method combined with the calcination process. In such a configuration, an intimate interaction between CoP and CTF matrix is gained through the Co-N chemical bonds, which not only significantly enhance the recyclability of CoP nanoparticles but also significantly improve the charge separation efficiency. Besides, the synergistically interactive Pδ--Coδ+-Nδ- states induced by the polarization effect of N-anchoring sites benefit for the adsorption and dissociation of water molecules in CTF-CoP. Consequently, CTF-CoP exhibits a higher photocatalytic hydrogen evolution rate (261.7 µmol g-1 h-1) and better durability as compared with the physically fixed CTF/CoP composite (64.8 µmol g-1 h-1) and even the noble metal-based CTF-Pt (191.3 µmol g-1 h-1). This work provides an avenue to construct highly stable non-noble photocatalyst for energy conversion and also emphasizes the potential of CTFs in constructing efficient heterojunctions.
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This study aims to develop a novel 68Ga-labeled tracer, which can covalently bind to albumin in vivo based on the maleimide-thiol strategy, and to evaluate its potential applications using positron emission tomography (PET). 68Ga-labeled maleimide-monoamide-DOTA (denoted as [68Ga]Ga-DM) was prepared conveniently with a high radiochemical yield (>90%) and radiochemical purity (>99%). Its molar activity was calculated as 249.60 ± 68.50 GBq/µmol, and the octanol-water partition coefficient (LogP) was -3.15 ± 0.08 with good stabilities. In vitro experiments showed that [68Ga]Ga-DM can bind to albumin efficiently and rapidly, with a binding fraction of over 70%. High uptake and excellent retention in blood were observed with a long half-life (t 1/2Z) of 190.15 ± 24.14 min, which makes it possible for blood pool PET imaging with high contrast. The transient micro-bleeding in the rat model was detected successfully with PET imaging. In addition, the uptakes of [68Ga]Ga-DM in the inflammatory popliteal lymph nodes depend on the severity (5.90% ID/g and 2.32% ID/g vs 1.01% ID/g for healthy lymph nodes at 0.5 h post-injection) indicating its feasibility for lymphatic imaging. In conclusion, a novel 68Ga-labeled tracer was prepared with high efficiency and yield in mild conditions. Based on the promising properties of bonding covalently to albumin, great stability, high blood contrast with a long half-life, and well environmental tolerance, [68Ga]Ga-DM could be developed as a potential tracer for PET imaging of blood pool, bleeding, and vascular permeability alteration diseases in the clinic.
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Schizophrenia is a common psychiatric disorder which affects approximately 1% of the population worldwide. However, the complexity of etiology, treatment resistance and side effects induced by current antipsychotics, relapse prevention, and psychosocial rehabilitation are still to be uncovered. Caffeine, as the world's most widely consumed psychoactive drug, plays a crucial role in daily life. Plenty of preclinical and clinical evidence has illustrated that caffeine consumption could have a beneficial effect on schizophrenia. In this review, we firstly summarize the factors associated with the caffeine-induced beneficial effect. Then, a variety of mechanism of actions independent of adenosine receptor signaling will be discussed with an emphasis on the potential contribution of the microbiome-gut-brain axis to provide more possibilities for future therapeutic, prognosis, and social rehabilitation strategy.
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Antipsicóticos , Esquizofrenia , Antipsicóticos/efectos adversos , Eje Cerebro-Intestino , Cafeína/uso terapéutico , Humanos , Receptores Purinérgicos P1/uso terapéutico , Esquizofrenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Diabetes is one of the most common chronic diseases in the world. In recent years, with the continuous improvement of people's living standards and changes in dietary structure, the incidence of diabetes is gradually increasing. Studies have shown that ascorbic acid supplementation can reduce blood glucose, increase insulin synthesis and secretion, improve insulin resistance, and reduce the occurrence and development of complications of type 2 diabetes mellitus (T2DM). However, relevant studies have common problems such as the lack of large sample studies and low quality of included studies. Therefore, it is needed that we meta-analyze the clinical trials with high quality to elucidate the efficacy and safety of ascorbic acid supplementation in patients with T2DM. METHODS: We will search randomized controlled trials published by PubMed, Embase, the Cochrane Library, Web of Science, and the Clinical Trials.gov website from inception to August 2020 on the effects of ascorbic acid supplementation on blood glucose, glycosylated hemoglobin, serum insulin, insulin resistance and other variables in T2DM patients with no language restrictions. The retrieval adopts the combination of medical subject headings and random words, and traces the references of the included literature to supplement the acquisition of relevant literature. Two researchers will independently screen the retrieved literature, extract the data and cross-check, and the Review Manage software V5.3.0 will be utilized for meta-analysis. RESULTS: Our study will provide a high-quality and in-depth comprehensive analysis of the effects of ascorbic acid supplementation on blood glucose control, glycosylated hemoglobin and insulin resistance in type 2 diabetic patients. CONCLUSION: This systematic review and meta-analysis concerning randomized controlled trials of ascorbic acid supplementation for type 2 diabetic patients will provide a new direction and strong evidence to evaluate whether ascorbic acid supplementation is of benefit to glucose control and insulin resistance in T2DM. PROSPERO REGISTRATION NUMBER: CRD 42019146826.
Asunto(s)
Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metaanálisis como Asunto , Proyectos de Investigación , Revisiones Sistemáticas como Asunto , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
A novel "turn-off" strategy for controllable radionuclide clearance is established. 1,4-dihydropyridine (DHP) is used as a conditional linker to connect a radioisotope labeled moiety and nano-agent. A highly specific, sensitive and effective C-C bond cleavage of DHP happens in vivo when treated with nitric oxide which is provided by glyceryl trinitrate (GTN). The radioactive cut-off part from the nanoparticle is observed to be cleared quickly by microSPECT-CT. 3-5 times decreases of radioactivity in the blood, kidneys, intestine, heart and lungs are observed after GTN treatment in a biodistribution assay. The radioactivity redistribution indicates that the radioactive leaving part is indeed cut off and the radionuclide metabolism accelerated. Organ level internal dose assessment reveals the GTN treated groups carry only ½ the radiation dose of the control group. Collectively, a feasible pathway for controllable radionuclide clearance is for the first time provided for high contrast and low radiation nuclear imaging.
RESUMEN
The purinergic signaling system, including P2 receptors, plays an important role in various central nervous system (CNS) disorders. Over the last few decades, a substantial amount of accumulated data suggest that most P2 receptor subtypes (P2X1, 2, 3, 4, 6, and 7, and P2Y1, 2, 6, 12, and 13) regulate neuronal/neuroglial developmental processes, such as proliferation, differentiation, migration of neuronal precursors, and neurite outgrowth. However, only a few of these subtypes (P2X2, P2X3, P2X4, P2X7, P2Y1, and P2Y2) have been investigated in the context of neurodevelopmental psychiatric disorders. The activation of these potential target receptors and their underlying mechanisms mainly influence the process of neuroinflammation. In particular, P2 receptor-mediated inflammatory cytokine release has been indicated to contribute to the complex mechanisms of a variety of CNS disorders. The released inflammatory cytokines could be utilized as biomarkers for neurodevelopmental and psychiatric disorders to improve the early diagnosis intervention, and prognosis. The population changes in gut microbiota after birth are closely linked to neurodevelopmental/neuropsychiatric disorders in later life; thus, the dynamic expression and function of P2 receptors on gut epithelial cells during disease processes indicate a novel avenue for the evaluation of disease progression and for the discovery of related therapeutic compounds.