A2aR

A2aR
  • 文章类型: Journal Article
    腺苷是通过G蛋白偶联细胞表面受体起作用的神经和免疫调节剂。几种微生物,包括病毒,利用腺苷信号通路逃避宿主防御系统。由于其在健康和疾病中的作用最近的研究进展,腺苷及其信号通路因靶向治疗多种疾病而备受关注。腺苷的治疗作用已经被广泛的研究神经学,心血管,炎症性疾病和细菌病理生理学,但是缺乏有关腺苷在病毒感染中作用的公开数据。因此,这篇综述文章的目的是详细解释腺苷信号对病毒感染的治疗作用,特别是COVID-19和HIV。针对A2AR介导的途径的几种治疗方法正在开发中,并在降低炎症反应的强度方面显示出令人鼓舞的结果。在COVID-19期间,缺氧-腺苷化能机制提供了对炎症介导的组织损伤的保护。与健康受试者相比,从HIV患者收获的CD39和CD8T细胞中的A2AR表达显着增加。通过阻断PD-1和CD39/腺苷信号传导进行的联合体外治疗在恢复HIV患者的CD8+T细胞功能方面产生了协同结果。我们建议A2AR是针对病毒感染的药物干预的理想目标,因为它可以减少炎症。防止疾病进展,并最终提高患者的生存率。
    Adenosine is a neuro- and immunomodulator that functions via G protein-coupled cell surface receptors. Several microbes, including viruses, use the adenosine signaling pathway to escape from host defense systems. Since the recent research developments in its role in health and disease, adenosine and its signaling pathway have attracted attention for targeting to treat many diseases. The therapeutic role of adenosine has been extensively studied for neurological, cardiovascular, and inflammatory disorders and bacterial pathophysiology, but published data on the role of adenosine in viral infections are lacking. Therefore, the purpose of this review article was to explain in detail the therapeutic role of adenosine signaling against viral infections, particularly COVID-19 and HIV. Several therapeutic approaches targeting A2AR-mediated pathways are in development and have shown encouraging results in decreasing the intensity of inflammatory reaction. The hypoxia-adenosinergic mechanism provides protection from inflammation-mediated tissue injury during COVID-19. A2AR expression increased remarkably in CD39 + and CD8 + T cells harvested from HIV patients in comparison to healthy subjects. A combined in vitro treatment performed by blocking PD-1 and CD39/adenosine signaling produced a synergistic outcome in restoring the CD8 + T cells funstion in HIV patients. We suggest that A2AR is an ideal target for pharmacological interventions against viral infections because it reduces inflammation, prevents disease progression, and ultimately improves patient survival.
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  • 文章类型: Journal Article
    炎症在纤维化的进展中起着至关重要的作用。环氧二十碳三烯酸(EET)在不同疾病中具有多重保护作用,但是它们抑制LPS诱导的纤维化发展的能力仍然未知。在LPS诱导的纤维化的体外模型中研究了11,12-EET的潜在治疗作用。将小鼠胚胎成纤维细胞NIH/3T3与1μM11,12-EET和/或结构类似物和选择性EET拮抗剂14,15-环氧-5(Z)-烯酸预孵育,然后暴露于LPS。通过NF-κB的蛋白和mRNA表达来评价EET的作用。胶原蛋白I和III,和α-平滑肌肌动蛋白通过蛋白质印迹和定量逆转录PCR,分别。LPS在NIH/3T3细胞中引起炎症和纤维化样变化,并伴有NF-κB和胶原蛋白的表达升高。我们还研究了11,12-EET对完整和LPS处理的NIH/3T3细胞中A2AR和PI3K/Akt信号通路的影响。11,12-EET通过上调A2AR和PI3K/Akt信号通路预防炎症和纤维化样变化。我们的发现证明了11,12-EET的潜在抗纤维化作用,它可以是组织纤维化的天然拮抗剂。
    Inflammation plays a crucial role in progression of fibrosis. Epoxyeicosatrienoic acids (EET) have multiple protective effects in different diseases, but their ability to inhibit the development of LPS-induced fibrosis remains unknown. The potential therapeutic effects of 11,12-EET were studied in in vitro model of LPS-induced fibrosis. Mouse embryonic fibroblast cells NIH/3T3 were pre-incubated with 1 μM 11,12-EET and/or a structural analogue and selective EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid before exposing to LPS. The effect of EET was evaluated by the protein and mRNA expression of NF-κB, collagens I and III, and α-smooth muscle actin by Western blotting and quantitative reverse transcription PCR, respectively. LPS provoked inflammation and fibrosis-like changes accompanied by elevated expression of NF-κB and collagens in NIH/3T3 cells. We also studied the effects of 11,12-EET on the A2AR and PI3K/Akt signaling pathways in intact and LPS-treated NIH/3T3 cells. 11,12-EET prevented inflammation and fibrosis-like changes through up-regulation of A2AR and PI3K/Akt signaling pathways. Our findings demonstrate the potential antifibrotic effects of 11,12-EET, which can be natural antagonists of tissue fibrosis.
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  • 文章类型: Journal Article
    肝硬化引起的心肌炎症和细胞凋亡是肝硬化心肌病的主要机制之一。CD73,一种常见的细胞外核苷酸酶,也称为5'-核苷酸酶,与多个器官的炎症和免疫进展有关。然而,CD73参与肝硬化心肌炎症和细胞凋亡的机制尚不清楚.
    在这项研究中,通过胆管结扎建立肝硬化心肌病小鼠模型。通过尾静脉注射AAV9(腺相关病毒)-cTNT-NT5E-mCherry,使用超声心动图评估小鼠的心脏功能。通过病理观察和ELISA测定评估心肌炎症浸润和凋亡。CD73、A2AR的表达,凋亡标志物,并测定心肌组织中与NF-κB通路相关的蛋白。
    在肝硬化心肌病小鼠模型的心肌组织中,CD73和A2AR的表达增加。通过AAV9注射和CGS21680刺激A2AR在心肌中的过表达CD73抑制了肝硬化引起的心肌炎症和心肌细胞凋亡。此外,CD73的过表达通过上调腺苷受体A2A的表达来抑制NF-κB途径的激活。
    我们的研究表明,CD73/A2AR信号轴通过NF-κB通路的负反馈调节减轻肝硬化诱导的心肌炎症和凋亡。
    UNASSIGNED: Myocardial inflammation and apoptosis induced by cirrhosis are among the primary mechanisms of cirrhotic cardiomyopathy. CD73, a common extracellular nucleotidase also known as 5\'-nucleotidase, is associated with the progression of inflammation and immunity in multiple organs. However, the mechanism by which CD73 contributes to myocardial inflammation and apoptosis in cirrhosis remains unclear.
    UNASSIGNED: In this study, a cirrhotic cardiomyopathy model in mice was established by bile duct ligation. Myocardial-specific overexpression of CD73 was achieved by tail vein injection of AAV9 (adeno-associated virus)-cTNT-NT5E-mCherry, and cardiac function in mice was assessed using echocardiography. Myocardial inflammation infiltration and apoptosis were evaluated through pathological observation and ELISA assays. The expression of CD73, A2AR, apoptotic markers, and proteins related to the NF-κB pathway in myocardial tissue were measured.
    UNASSIGNED: In the myocardial tissue of the cirrhotic cardiomyopathy mouse model, the expression of CD73 and A2AR increased. Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A.
    UNASSIGNED: Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway.
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  • 文章类型: Journal Article
    银屑病是一种常见的炎症性全身性疾病,其特征是在真皮层中浸润的促炎巨噬细胞活化(M1巨噬细胞)。M1巨噬细胞如何导致牛皮癣仍然未知。在这项研究中,我们发现腺苷A2A受体(A2AR)激动剂CGS21680HCl通过减少M1浸润减轻咪喹莫特(IMQ)和小鼠IL-23蛋白(rmIL-23)诱导的银屑病炎症。相反,小鼠中的Adora2a缺失加剧了牛皮癣样表型。机械上,A2AR激活通过NF-κB-KRT16途径抑制M1巨噬细胞活化,减少CXCL10/11的分泌,抑制Th1/17分化。值得注意的是,在我们的研究中,首先在M1巨噬细胞中发现了KRT16的表达,不仅在角质形成细胞(KCs)中。使用单细胞RNA测序(scRNA-Seq),首次将CXCL10/11鉴定为主要源自巨噬细胞和树突状细胞(DC),而不是牛皮癣中的KC。总的来说,该研究强调M1作为先天免疫细胞在银屑病发病机制中的重要性。
    Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.
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  • 文章类型: Journal Article
    CD8+肿瘤浸润淋巴细胞(TIL)耗尽是弥漫性大B细胞淋巴瘤(DLBCL)中有效控制肿瘤的主要障碍,并且可能由具有不同功能状态的异质群体组成。我们分析了CD8+TIL耗竭异质性,并通过单细胞RNA测序探索其临床意义以及潜在机制(n=7),批量RNA测序(n=3300),免疫组织化学(n=116),逆转录-定量聚合酶链反应(n=95),和体细胞突变数据(n=48)。我们的结果表明,DLBCL中耗尽的CD8TIL由CCL5和TUBA1B表征的祖细胞和终末状态组成,分别。高终末耗尽CD8+TIL表示免疫抑制肿瘤微环境,激活的B细胞样亚型,预后较差,DLBCL对免疫检查点阻断治疗的反应较差。我们的研究进一步证明,CD39/A2AR相关的信号传导可能是促进DLBCL中祖细胞向终末耗尽的CD8TIL过渡的潜在途径。此外,DLBCL中的CD39/A2AR相关通路可能受耗尽的CD8+TIL中的BATF和STAT3调节,和肿瘤细胞中的MYD88突变。我们的研究强调了CD8+TIL耗竭异质性及其可能的调节机制提供了一个新的预后指标,可以促进个体化免疫治疗的优化。
    CD8+ tumor-infiltrating lymphocytes (TILs) exhaustion is a major barrier to effective tumor control in diffuse large B-cell lymphoma (DLBCL) and may consist of heterogeneous populations with different functional states. We profiled the CD8+TILs exhaustion heterogeneity and explored its clinical significance as well as the underlying mechanism through single-cell RNA sequencing (n = 7), bulk RNA sequencing (n = 3300), immunohistochemistry (n = 116), and reverse transcription-quantitative polymerase chain reaction (n = 95), and somatic mutation data (n = 48). Our results demonstrated that exhausted CD8+TILs in DLBCL were composed of progenitor and terminal states characterized by CCL5 and TUBA1B, respectively. High terminally exhausted CD8+TILs indicated an immunosuppressive tumor microenvironment, activated B-cell-like subtype, inferior prognosis, and poor response to immune checkpoint blockade therapy in DLBCL. Our study further demonstrated that the CD39/A2AR-related signaling may be the potential pathway that promoted the transition of progenitor toward terminally exhausted CD8+TILs in DLBCL. Furthermore, the CD39/A2AR-related pathway in DLBCL may be regulated by BATF and STAT3 in exhausted CD8+TILs, and MYD88 mutation in tumor cells. Our study highlights CD8+TILs exhaustion heterogeneity and its possible regulatory mechanism provides a novel prognostic indicator and can facilitate the optimization of individualized immunotherapy.
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  • 文章类型: Journal Article
    嵌合抗原受体(CAR)T细胞疗法已改变了血液恶性肿瘤的治疗方法。然而,其在实体瘤中的疗效受到免疫抑制性肿瘤微环境的限制,该环境损害了临床环境中的CART细胞抗肿瘤功能.为了克服这一挑战,研究人员研究了抑制特定免疫检查点受体的潜力,包括A2aR(腺苷A2受体)和Tim3(T细胞免疫球蛋白和含粘蛋白结构域的蛋白3),以增强CAR-T细胞功能。在这项研究中,我们在体外和体内评估了基因靶向Tim3和A2a受体对人间皮素特异性CAR-T细胞(MSLN-CAR)抗肿瘤功能的影响.
    使用标准细胞和分子技术产生第二代抗间皮素CART细胞。使用shRNA介导的基因沉默产生A2aR-敲低和/或Tim3-敲低抗间皮素-CART细胞。通过测量细胞因子的产生来评估CART细胞的抗肿瘤功能。扩散,通过与宫颈癌细胞(HeLa细胞系)共培养在体外具有细胞毒性。为了评估制造的CART细胞的体内抗肿瘤功效,在人宫颈癌异种移植模型中监测肿瘤生长和小鼠存活。
    体外实验表明,单独敲除A2aR或与Tim3联合使用可显著提高CAR-T细胞增殖,细胞因子产生,和以抗原特异性方式存在肿瘤细胞的细胞毒性。此外,在人性化的异种移植模型中,双敲低CART细胞和对照CART细胞均能有效控制肿瘤生长。然而,单个敲低CART细胞与小鼠存活率降低有关。
    这些发现强调了伴随基因靶向Tim3和A2a受体以增强CAR-T细胞疗法在实体瘤中的功效的潜力。然而,根据我们观察到的单敲除MSLN-CAR-T细胞治疗的小鼠存活率降低,应谨慎行事。强调需要仔细考虑功效。
    UNASSIGNED: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo.
    UNASSIGNED: Second-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model.
    UNASSIGNED: In vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in mice.
    UNASSIGNED: These findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.
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  • 文章类型: Journal Article
    背景:慢性含咖啡因(CAFF)饮料的影响的证据,单独或与阿戈美拉汀(AGO)或喹硫平(QUET)合用,脑电图(EEG),这与认知有关,癫痫发生,和卵巢功能,仍然缺乏。雌激素,腺苷碱能,褪黑激素信号可能与这些物质的动力学有关。
    目的:比较CAFF与AGO+CAFF和QUET+CAFF对脑和卵巢的影响。雌激素的影响,腺苷碱能,并研究了褪黑激素信号和脑-卵巢串扰。
    方法:给成年雌性大鼠服用AGO(10mg/kg),QUET(10mg/kg),CAFF,老+CAFF,或QUET+CAFF,每天一次,共8周。脑电图,发情周期进展,并检查了大脑和卵巢的微观结构。脑和卵巢17β-雌二醇(E2),抗苗勒管激素(AMH),雌激素受体α(E2Rα),腺苷受体2A(A2AR),和褪黑素受体2(MT2R)进行评估。
    结果:CAFF,单独或与AGO或QUET结合使用,降低了最大脑电图峰值,与卵巢E2Rα呈正相关,与皮质神经变性和卵巢MT2R呈负相关,与囊性卵巢有关.AGO+CAFF和QUET+CAFF出现大量黄体,拮抗CAFF介导的卵巢A2AR增加和皮质E2Rα减少。AGO+CAFF引起TTP延迟和卵巢AMH增加,而QUETCAFF将源脑电图频率减慢至δ范围,并增加了大脑E2。
    结论:CAFF治疗引发的脑和卵巢紊乱与AGO或QUET同时给药部分拮抗,但对发情周期进展没有明显影响。雌激素,腺苷碱能,褪黑激素信号和脑-卵巢串扰可以解释这些影响。
    BACKGROUND: Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances.
    OBJECTIVE: The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated.
    METHODS: Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17β-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed.
    RESULTS: CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2.
    CONCLUSIONS: CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects.
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  • 文章类型: Journal Article
    肿瘤相关巨噬细胞(TAMs)在肿瘤中含量丰富,并与肿瘤细胞相互作用,导致免疫抑制微环境的形成和肿瘤进展。尽管许多研究已经探索了TAM极化及其免疫抑制功能的潜在机制,对其进展的理解仍然有限。TAMs通过分泌细胞因子促进肿瘤进展,随后招募免疫抑制细胞来抑制抗肿瘤免疫。在这项研究中,我们建立了巨噬细胞和非小细胞肺癌(NSCLC)细胞共培养的体外模型,以探索细胞间串扰的机制。我们观察到在NSCLC中,由于腺苷对A2AR的刺激,C-X-C基序趋化因子配体5(CXCL5)在巨噬细胞中上调。腺苷在巨噬细胞和肿瘤细胞中被CD39和CD73催化,分别。核因子κB(NFκB)介导巨噬细胞中CXCL5上调的A2AR刺激。此外,CXCL5刺激中性粒细胞中的NETosis。中性粒细胞胞外诱捕网(NETs)处理的CD8+T细胞表现出耗竭相关和胞质DNA传感途径的上调和效应子相关基因的下调。然而,A2AR抑制显著下调CXCL5表达,减少中性粒细胞浸润,从而减轻CD8+T细胞功能障碍。我们的发现表明肿瘤和免疫细胞之间的复杂相互作用及其作为治疗靶点的潜力。
    Tumor-associated macrophages (TAMs) are abundant in tumors and interact with tumor cells, leading to the formation of an immunosuppressive microenvironment and tumor progression. Although many studies have explored the mechanisms underlying TAM polarization and its immunosuppressive functions, understanding of its progression remains limited. TAMs promote tumor progression by secreting cytokines, which subsequently recruit immunosuppressive cells to suppress the antitumor immunity. In this study, we established an in vitro model of macrophage and non-small cell lung cancer (NSCLC) cell co-culture to explore the mechanisms of cell-cell crosstalk. We observed that in NSCLC, the C-X-C motif chemokine ligand 5 (CXCL5) was upregulated in macrophages because of the stimulation of A2AR by adenosine. Adenosine was catalyzed by CD39 and CD73 in macrophages and tumor cells, respectively. Nuclear factor kappa B (NFκB) mediated the A2AR stimulation of CXCL5 upregulation in macrophages. Additionally, CXCL5 stimulated NETosis in neutrophils. Neutrophil extracellular traps (NETs)-treated CD8+ T cells exhibited upregulation of exhaustion-related and cytosolic DNA sensing pathways and downregulation of effector-related genes. However, A2AR inhibition significantly downregulated CXCL5 expression and reduced neutrophil infiltration, consequently alleviating CD8+ T cell dysfunction. Our findings suggest a complex interaction between tumor and immune cells and its potential as therapeutic target.
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  • 文章类型: Journal Article
    实验性自身免疫性脑脊髓炎(EAE)是广泛使用的多发性硬化(MS)动物模型。该疾病的特征是由浸润的自身免疫细胞及其与星形胶质细胞和小胶质细胞的相互作用引发的脱髓鞘和神经变性。虽然神经炎症最常见于脊髓和脑干,它在小脑中不那么普遍,它容易导致疾病快速进展。由于EAE的诱导和进展受到腺苷能信号的严格调节,在本研究中,我们比较了腺苷产生和降解酶,ecto-5'-核苷酸酶(eN/CD73)和腺苷脱氨酶(ADA),以及腺苷受体A1R和A2AR亚型在第四脑室周围区域的表达水平,脉络丛(CP),还有小脑.在相同的水平切片水平上,桥脑被盖和小脑之间的组织病理学发现存在显着差异。CP和脑桥被膜中的反应性星形胶质细胞增生和CD4细胞和巨噬细胞的大量浸润导致局部脱髓鞘。在小脑,没有渗透的证据,小胶质细胞增生和神经炎症在相同的截面水平。此外,伯格曼胶质细胞没有反应性胶质增生的迹象。至于腺苷能信号,在所有研究领域都观察到了eN/CD73的显着上调,但与不同的腺苷受体亚型有关。在CP和脑桥中,eN/CD73的过表达与A2AR的诱导相关,而在小脑,居民Bergman胶质细胞中eN/CD73的适度增加伴随着相同类型星形胶质细胞中A1R的强烈诱导。因此,特化星形胶质细胞的存在和腺苷能信号的内在差异可能在EAE炎症的不同区域易感性中起关键作用.
    Experimental autoimmune encephalomyelitis (EAE) is widely used animal model of multiple sclerosis (MS). The disease is characterized by demyelination and neurodegeneration triggered by infiltrated autoimmune cells and their interaction with astrocytes and microglia. While neuroinflammation is most common in the spinal cord and brainstem, it is less prevalent in the cerebellum, where it predisposes to rapid disease progression. Because the induction and progression of EAE are tightly regulated by adenosinergic signaling, in the present study we compared the adenosine-producing and -degrading enzymes, ecto-5\'-nucleotidase (eN/CD73) and adenosine deaminase (ADA), as well as the expression levels of adenosine receptors A1R and A2AR subtypes in nearby areas around the fourth cerebral ventricle-the pontine tegmentum, the choroid plexus (CP), and the cerebellum. Significant differences in histopathological findings were observed between pontine tegmentum and cerebellum on the same horizontal section level. Reactive astrogliosis and massive infiltration of CD4 + cells and macrophages in CP and pontine tegmentum resulted in local demyelination. In cerebellum, there was no evidence of infiltrates, microgliosis and neuroinflammation at the same sectional level. In addition, Bergman glia showed no signs of reactive gliosis. As for adenosinergic signaling, significant upregulation of eN/CD73 was observed in all areas studied, but in association with different adenosine receptor subtypes. In CP and pons, overexpression of eN/CD73 was coupled with induction of A2AR, whereas in cerebellum, a modest increase in eN/CD73 in resident Bergman glia was accompanied by a strong induction of A1R in the same type of astrocytes. Thus, the presence of specialized astroglia and intrinsic differences in adenosinergic signaling may play a critical role in the differential regional susceptibility to EAE inflammation.
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  • 文章类型: Journal Article
    腺苷亚家族G蛋白偶联受体A2AR和A2BR已被鉴定为有希望的癌症免疫治疗候选物。A2AR/A2BR双拮抗剂之一,AB928已进入治疗直肠癌的II期临床试验。然而,其双重拮抗特性的确切机制仍然难以捉摸。在这里,我们报道了与AB928和选择性A2AR拮抗剂2-118复合的A2AR的晶体结构。这些结构揭示了A2AR上常见的结合模式,其中配体与来自正构和次级口袋的残基建立了广泛的相互作用。相比之下,cAMP测定以及A2AR和A2BR分子动力学模拟表明,配体在A2BR上采用了不同的结合模式。对它们化学结构的详细分析表明,AB928很容易适应A2BR口袋,而2-118并不是由于内在的差异。这种差异潜在地解释了A2BR和A2AR之间抑制功效的差异。这项研究为将来开发靶向A2AR/A2BR的选择性或双重抑制剂用于癌症治疗提供了有价值的结构模板。
    The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates. One of the A2AR/A2BR dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2-118. The structures revealed a common binding mode on A2AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.
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