Pub Date : 2024-11-05DOI: 10.1007/s11302-024-10061-8
Yong Tang, Peter Illes, Charles Kennedy
{"title":"Honouring Geoff Burnstock.","authors":"Yong Tang, Peter Illes, Charles Kennedy","doi":"10.1007/s11302-024-10061-8","DOIUrl":"https://doi.org/10.1007/s11302-024-10061-8","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1007/s11302-024-10056-5
Jun Meng, Zhenglang Zhang, Yujie Wang, Lina Long, Anqi Luo, Zhenhui Luo, Kexin Cai, Xi Chen, Hong Nie
An increasing number of traditional Chinese medicine(TCM) have been confirmed to possess analgesic bioactivity. 701 Dieda Zhentong patch(701-DZP) which includes 14 kinds of TCMs exhibited excellent efficacy in alleviating back or leg pain after a soft-tissue injury. In this study, UPLC/MS was used to construct the fingerprint of 701-DZP and excavate the potential bioactive ingredients of it. 21 compounds were detected and identified in the fingerprint including 12 compounds that pass through the skin and 6 compounds observed in the plasma. Then, the role of 701-DZP in neuropathic pain(NPP) was assessed by network pharmacology and CCI rats. 701-DZP inhibited pain sensitization(MWT and TWL) and the release of inflammation mediators(IL-1β and IL-6) in CCI rats which were in keeping with the core targets of the PPI network. The results of IHC and Western blot showed that the expression of the P2X3 receptor in the DRG and SC of CCI rats was significantly reduced after the treatment with 701-DZP. Moreover, the 701-DZP down-regulated the level of phosphorylation of ERK1/2 MAPK instead of P38 MAPK in the DRG of CCI rats. In conclusion, this study has clarified 6 potential analgesic active compounds of 701-DZP and explored the analgesic properties, which may inhibit the expression of the P2X3 receptor to reduce the release of inflammatory mediators based on the ERK1/2 MAPK pathway to alleviate the NPP.
{"title":"The exploration of active components of 701 Dieda Zhentong patch and analgesic properties on chronic constriction injury rats.","authors":"Jun Meng, Zhenglang Zhang, Yujie Wang, Lina Long, Anqi Luo, Zhenhui Luo, Kexin Cai, Xi Chen, Hong Nie","doi":"10.1007/s11302-024-10056-5","DOIUrl":"https://doi.org/10.1007/s11302-024-10056-5","url":null,"abstract":"<p><p>An increasing number of traditional Chinese medicine(TCM) have been confirmed to possess analgesic bioactivity. 701 Dieda Zhentong patch(701-DZP) which includes 14 kinds of TCMs exhibited excellent efficacy in alleviating back or leg pain after a soft-tissue injury. In this study, UPLC/MS was used to construct the fingerprint of 701-DZP and excavate the potential bioactive ingredients of it. 21 compounds were detected and identified in the fingerprint including 12 compounds that pass through the skin and 6 compounds observed in the plasma. Then, the role of 701-DZP in neuropathic pain(NPP) was assessed by network pharmacology and CCI rats. 701-DZP inhibited pain sensitization(MWT and TWL) and the release of inflammation mediators(IL-1β and IL-6) in CCI rats which were in keeping with the core targets of the PPI network. The results of IHC and Western blot showed that the expression of the P2X3 receptor in the DRG and SC of CCI rats was significantly reduced after the treatment with 701-DZP. Moreover, the 701-DZP down-regulated the level of phosphorylation of ERK1/2 MAPK instead of P38 MAPK in the DRG of CCI rats. In conclusion, this study has clarified 6 potential analgesic active compounds of 701-DZP and explored the analgesic properties, which may inhibit the expression of the P2X3 receptor to reduce the release of inflammatory mediators based on the ERK1/2 MAPK pathway to alleviate the NPP.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental condition characterized by persistent inattention, hyperactivity, and impulsivity. Although its precise etiology remains unclear, current evidence suggests that dysregulation within the neurotransmitter system plays a key role in the pathogenesis of ADHD. Adenosine, an endogenous nucleoside widely distributed throughout the body, modulates various physiological processes, including neurotransmitter release, sleep regulation, and cognitive functions through its receptors. This review critically examines the role of the adenosine system in ADHD, focusing on the links between adenosine receptor function and ADHD-related symptoms. Additionally, it explores how adenosine interacts with dopamine and other neurotransmitter pathways, shedding light on its involvement in ADHD pathophysiology. This review aims to provide insights into the potential therapeutic implications of targeting the adenosine system for ADHD management.
{"title":"Role of adenosine in the pathophysiology and treatment of attention deficit hyperactivity disorder.","authors":"Qingxia Jia, Hongwan Tan, Tingsong Li, Xiaoling Duan","doi":"10.1007/s11302-024-10059-2","DOIUrl":"10.1007/s11302-024-10059-2","url":null,"abstract":"<p><p>Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental condition characterized by persistent inattention, hyperactivity, and impulsivity. Although its precise etiology remains unclear, current evidence suggests that dysregulation within the neurotransmitter system plays a key role in the pathogenesis of ADHD. Adenosine, an endogenous nucleoside widely distributed throughout the body, modulates various physiological processes, including neurotransmitter release, sleep regulation, and cognitive functions through its receptors. This review critically examines the role of the adenosine system in ADHD, focusing on the links between adenosine receptor function and ADHD-related symptoms. Additionally, it explores how adenosine interacts with dopamine and other neurotransmitter pathways, shedding light on its involvement in ADHD pathophysiology. This review aims to provide insights into the potential therapeutic implications of targeting the adenosine system for ADHD management.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The pro-inflammatory enzyme cyclooxygenase 2 (COX-2) has been known to impart metastatic property to cancer cells. However, blocking of COX-2 with nonsteroidal anti-inflammatory drugs or COX-2-specific inhibitors has failed in clinical trials due to adverse effects associated with their prolonged use. We have previously shown that extracellular ATP (eATP), a major component of the tumor microenvironment, enhances COX-2 expression several-fold, both in macrophages and in various cancer cells, by acting on purinergic (P2) receptors. In this study, we show that blocking of P2 receptors significantly reduced tumor growth in a mouse model of lymphoma. Tumors were induced in mice through subcutaneous injection of syngeneic EL4 lymphoma cells. Various P2 receptor antagonists were injected within the tumors after they were palpable. The broad-spectrum P2 receptor antagonist, suramin, P2X7 receptor-specific antagonist, oATP, P2Y6 receptor-specific antagonist, MRS 2578, and P2Y12 receptor-specific antagonist, AR-C 69931, all showed significant arrest in tumor growth. Both suramin and AR-C 69931-treated tumors showed strong reduction in COX-2 expression and modulation of various metastatic markers. Disaggregated cells from AR-C 69931-treated tumors, when injected intravenously in naïve mice, did not exhibit metastasis in various tissues which was observed in mice injected with cells from saline-treated tumors. Our results show that blocking of P2 receptors is a therapeutic alternative to inhibit COX-2 expression, and thereby, arrest tumor progression and metastasis.
{"title":"P2Y12 receptor-mediated cyclooxygenase 2 (COX-2) expression enhances tumor cell progression in a mouse model of lymphoma.","authors":"Shilpa Sharma, Khagendra Ghimeray, Md Mostafizur Rahman, Aparna Upadrasta, Ravi Shankar Akundi","doi":"10.1007/s11302-024-10057-4","DOIUrl":"https://doi.org/10.1007/s11302-024-10057-4","url":null,"abstract":"<p><p>The pro-inflammatory enzyme cyclooxygenase 2 (COX-2) has been known to impart metastatic property to cancer cells. However, blocking of COX-2 with nonsteroidal anti-inflammatory drugs or COX-2-specific inhibitors has failed in clinical trials due to adverse effects associated with their prolonged use. We have previously shown that extracellular ATP (eATP), a major component of the tumor microenvironment, enhances COX-2 expression several-fold, both in macrophages and in various cancer cells, by acting on purinergic (P2) receptors. In this study, we show that blocking of P2 receptors significantly reduced tumor growth in a mouse model of lymphoma. Tumors were induced in mice through subcutaneous injection of syngeneic EL4 lymphoma cells. Various P2 receptor antagonists were injected within the tumors after they were palpable. The broad-spectrum P2 receptor antagonist, suramin, P2X7 receptor-specific antagonist, oATP, P2Y6 receptor-specific antagonist, MRS 2578, and P2Y12 receptor-specific antagonist, AR-C 69931, all showed significant arrest in tumor growth. Both suramin and AR-C 69931-treated tumors showed strong reduction in COX-2 expression and modulation of various metastatic markers. Disaggregated cells from AR-C 69931-treated tumors, when injected intravenously in naïve mice, did not exhibit metastasis in various tissues which was observed in mice injected with cells from saline-treated tumors. Our results show that blocking of P2 receptors is a therapeutic alternative to inhibit COX-2 expression, and thereby, arrest tumor progression and metastasis.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1007/s11302-024-10055-6
Stefan Bidula, Waraporn Piyasirananda, Hanna Bielecka, Lučka Bibič, Andrew Beekman, Leanne Stokes
P2X7 is an emerging therapeutic target for several disorders and diseases due to its role in inflammatory signalling. This study aimed to exploit the unique chemical libraries of plants used in traditional medicinal practices to discover novel allosteric modulators from natural sources. We identified several compounds from the NCI Natural Product library as P2X7 antagonists including confertifolin and digallic acid (IC50 values 3.86 µM and 4.05 µM). We also identified scopafungin as a novel positive allosteric modulator of hP2X7. Screening a traditional medicinal plant extract library revealed 39 plant species with inhibitory action at hP2X7 and 17 plant species with positive allosteric modulator activity. Using computational docking to filter identified components from these plant species and determine potential antagonists, we investigated nine purified chemicals including flavonoids quercetin, kaempferol, ECG, and EGCG. These were shown to inhibit ATP-induced YO-PRO-1 uptake into HEK-hP2X7 cells; however, we also showed that all four flavonoids demonstrated significant assay interference using a cell-free DNA YO-PRO-1 fluorescence test. One plant extract, Dioscorea nipponica, demonstrating positive modulator activity was investigated, and dioscin was identified as a glycoside with PAM activity in ATP-induced YO-PRO-1 uptake assay and whole-cell patch-clamp recordings. However, membrane permeabilisation was observed following application > 10 min limiting the use of dioscin as a pharmacological tool. This work describes a useful workflow with multiple assays for the identification of novel allosteric modulators for human P2X7.
{"title":"Screening herbal and natural product libraries to aid discovery of novel allosteric modulators of human P2X7.","authors":"Stefan Bidula, Waraporn Piyasirananda, Hanna Bielecka, Lučka Bibič, Andrew Beekman, Leanne Stokes","doi":"10.1007/s11302-024-10055-6","DOIUrl":"https://doi.org/10.1007/s11302-024-10055-6","url":null,"abstract":"<p><p> P2X7 is an emerging therapeutic target for several disorders and diseases due to its role in inflammatory signalling. This study aimed to exploit the unique chemical libraries of plants used in traditional medicinal practices to discover novel allosteric modulators from natural sources. We identified several compounds from the NCI Natural Product library as P2X7 antagonists including confertifolin and digallic acid (IC<sub>50</sub> values 3.86 µM and 4.05 µM). We also identified scopafungin as a novel positive allosteric modulator of hP2X7. Screening a traditional medicinal plant extract library revealed 39 plant species with inhibitory action at hP2X7 and 17 plant species with positive allosteric modulator activity. Using computational docking to filter identified components from these plant species and determine potential antagonists, we investigated nine purified chemicals including flavonoids quercetin, kaempferol, ECG, and EGCG. These were shown to inhibit ATP-induced YO-PRO-1 uptake into HEK-hP2X7 cells; however, we also showed that all four flavonoids demonstrated significant assay interference using a cell-free DNA YO-PRO-1 fluorescence test. One plant extract, Dioscorea nipponica, demonstrating positive modulator activity was investigated, and dioscin was identified as a glycoside with PAM activity in ATP-induced YO-PRO-1 uptake assay and whole-cell patch-clamp recordings. However, membrane permeabilisation was observed following application > 10 min limiting the use of dioscin as a pharmacological tool. This work describes a useful workflow with multiple assays for the identification of novel allosteric modulators for human P2X7.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor-associated macrophages (TAMs) exhibit antitumor or protumor responses related to inflammatory (or M1) and alternative (or M2) phenotypes, respectively. The P2X7 receptor plays a key role in macrophage polarization, influencing inflammation and immunosuppression. In this study, we investigated the role of the P2X7 receptor in TAMs. Using P2X7 receptor-deficient macrophages, we analyzed gene expression profiles and their implications for neuroblastoma invasion and chemoresistance. Our results showed that P2X7 receptor deficiency altered the expression of classical polarization markers, such as nitric oxide synthase 2 (Nos2) and tumor necrosis factor-α (Tnf), as well as alternative phenotype markers, including mannose receptor C-type 1 (Mrc1) and arginase 1 (Arg1). P2X7 deficiency also influenced the expression of the ectonucleotidases Entpd1 and Nt5e and other purinergic receptors, especially P2ry2, suggesting compensatory mechanisms involved in macrophage polarization. In particular, TAMs deficient in P2X7 showed a phenotype with characteristics intermideiate between resting macrophages (M0) and M1 polarization rather than the M2-type phenotype like and wild-type TAM macrophages. In addition, P2rx7-/- TAMs regulated the expression of P2X7 receptor isoforms in neuroblastoma cells, with downregulation of the P2X7 A and B isoforms leading to a decrease in chemotherapy-induced cell death. However, TAMs expressing P2X7 downregulated only the B isoform, suggesting that TAMs play a role in modulating tumor behavior through P2X7 receptor isoform regulation. Taken together, our data underscore the regulatory function of the P2X7 receptor in orchestrating alternative macrophage polarization and in the interplay between tumor cells and TAMs. These findings help to clarify the complex interplay of purinergic signaling in cancer progression and open up avenues for future research and therapeutic interventions.
肿瘤相关巨噬细胞(TAMs)表现出的抗肿瘤或原肿瘤反应分别与炎症(或 M1)和替代(或 M2)表型有关。P2X7 受体在巨噬细胞极化、影响炎症和免疫抑制中起着关键作用。在这项研究中,我们研究了 P2X7 受体在 TAMs 中的作用。利用 P2X7 受体缺陷的巨噬细胞,我们分析了基因表达谱及其对神经母细胞瘤侵袭和化疗抗性的影响。我们的研究结果表明,P2X7受体缺乏会改变一氧化氮合酶2(Nos2)和肿瘤坏死因子-α(Tnf)等经典极化标记物以及甘露糖受体C型1(Mrc1)和精氨酸酶1(Arg1)等替代表型标记物的表达。P2X7 缺乏也会影响外切核苷酸酶 Entpd1 和 Nt5e 以及其他嘌呤能受体(尤其是 P2ry2)的表达,这表明巨噬细胞极化过程中存在补偿机制。特别是,缺乏 P2X7 的 TAM 表现出介于静息巨噬细胞(M0)和 M1 极化之间的表型,而不是像野生型 TAM 巨噬细胞那样的 M2 型表型。此外,P2rx7-/-TAMs 还能调节神经母细胞瘤细胞中 P2X7 受体同工酶的表达,P2X7 A 和 B 同工酶的下调会导致化疗诱导的细胞死亡减少。然而,表达 P2X7 的 TAMs 只下调 B 异构体,这表明 TAMs 在通过 P2X7 受体异构体调节肿瘤行为方面发挥作用。综上所述,我们的数据强调了 P2X7 受体在协调巨噬细胞替代性极化以及肿瘤细胞与 TAMs 相互作用中的调控功能。这些发现有助于阐明嘌呤能信号在癌症进展中的复杂相互作用,并为未来的研究和治疗干预开辟了道路。
{"title":"P2X7 receptor in macrophage polarization and its implications in neuroblastoma tumor behavior.","authors":"Carolina Adriane Bento, Vanessa Fernandes Arnaud-Sampaio, Talita Glaser, Elena Adinolfi, Robson Coutinho-Silva, Henning Ulrich, Claudiana Lameu","doi":"10.1007/s11302-024-10051-w","DOIUrl":"https://doi.org/10.1007/s11302-024-10051-w","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) exhibit antitumor or protumor responses related to inflammatory (or M1) and alternative (or M2) phenotypes, respectively. The P2X7 receptor plays a key role in macrophage polarization, influencing inflammation and immunosuppression. In this study, we investigated the role of the P2X7 receptor in TAMs. Using P2X7 receptor-deficient macrophages, we analyzed gene expression profiles and their implications for neuroblastoma invasion and chemoresistance. Our results showed that P2X7 receptor deficiency altered the expression of classical polarization markers, such as nitric oxide synthase 2 (Nos2) and tumor necrosis factor-α (Tnf), as well as alternative phenotype markers, including mannose receptor C-type 1 (Mrc1) and arginase 1 (Arg1). P2X7 deficiency also influenced the expression of the ectonucleotidases Entpd1 and Nt5e and other purinergic receptors, especially P2ry2, suggesting compensatory mechanisms involved in macrophage polarization. In particular, TAMs deficient in P2X7 showed a phenotype with characteristics intermideiate between resting macrophages (M0) and M1 polarization rather than the M2-type phenotype like and wild-type TAM macrophages. In addition, P2rx7<sup>-/-</sup> TAMs regulated the expression of P2X7 receptor isoforms in neuroblastoma cells, with downregulation of the P2X7 A and B isoforms leading to a decrease in chemotherapy-induced cell death. However, TAMs expressing P2X7 downregulated only the B isoform, suggesting that TAMs play a role in modulating tumor behavior through P2X7 receptor isoform regulation. Taken together, our data underscore the regulatory function of the P2X7 receptor in orchestrating alternative macrophage polarization and in the interplay between tumor cells and TAMs. These findings help to clarify the complex interplay of purinergic signaling in cancer progression and open up avenues for future research and therapeutic interventions.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1007/s11302-024-10054-7
Vahinipriya Manoharan, Oluwafemi O Adegbayi, Janielle P Maynard
P2 purinergic receptor expression is dysregulated in multiple cancer subtypes and is associated with worse outcomes. Studies identify roles for P2 purinergic receptors in tumor cells that drive disease aggressiveness. There is also sufficient evidence that P2 purinergic receptor expression within the tumor microenvironment (TME) is critical for disease initiation and progression. Immune cells constitute a significant component of the TME and display both tumorigenic and anti-tumorigenic potential. Studies pre-dating the investigation of P2 purinergic receptors in cancer identify P2 receptor expression on multiple immune cells including macrophages, neutrophils, T-cells, and dendritic cells; all of which are implicated in tumor initiation, tumor promotion, or response to treatment. Herein, we discuss P2 purinergic receptor expression and function in tumor-related immune cells. We provide a rationale for further investigations of P2 purinergic receptors within the TME to better define the mechanistic pathways of inflammation-mediate tumorigenesis and explore P2 purinergic receptors as potential targets for novel immunotherapeutic approaches.
{"title":"P2 purinergic receptor expression and function in tumor-related immune cells.","authors":"Vahinipriya Manoharan, Oluwafemi O Adegbayi, Janielle P Maynard","doi":"10.1007/s11302-024-10054-7","DOIUrl":"https://doi.org/10.1007/s11302-024-10054-7","url":null,"abstract":"<p><p>P2 purinergic receptor expression is dysregulated in multiple cancer subtypes and is associated with worse outcomes. Studies identify roles for P2 purinergic receptors in tumor cells that drive disease aggressiveness. There is also sufficient evidence that P2 purinergic receptor expression within the tumor microenvironment (TME) is critical for disease initiation and progression. Immune cells constitute a significant component of the TME and display both tumorigenic and anti-tumorigenic potential. Studies pre-dating the investigation of P2 purinergic receptors in cancer identify P2 receptor expression on multiple immune cells including macrophages, neutrophils, T-cells, and dendritic cells; all of which are implicated in tumor initiation, tumor promotion, or response to treatment. Herein, we discuss P2 purinergic receptor expression and function in tumor-related immune cells. We provide a rationale for further investigations of P2 purinergic receptors within the TME to better define the mechanistic pathways of inflammation-mediate tumorigenesis and explore P2 purinergic receptors as potential targets for novel immunotherapeutic approaches.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-11-24DOI: 10.1007/s11302-023-09980-9
Nancy da Rocha Torres Pavione, João Victor Badaró de Moraes, Isadora Cunha Ribeiro, Raissa Barbosa de Castro, Walmir da Silva, Anna Cláudia Alves de Souza, Victor Hugo Ferraz da Silva, Raphael de Souza Vasconcellos, Gustavo da Costa Bressan, Juliana Lopes Rangel Fietto
Leishmania braziliensis is a pathogenic protozoan parasite that causes American Tegumentary Leishmaniasis (ATL), an important tropical neglected disease. ENTPDases are nucleotidases that hydrolyze intracellular and/or extracellular nucleotides. ENTPDases are known as regulators of purinergic signalling induced by extracellular nucleotides. Leishmania species have two isoforms of ENTPDase, and, particularly, ENTPDase2 seems to be involved in infectivity and virulence. In this study, we conducted the heterologous expression and biochemical characterization of the recombinant ENTPDase2 of L. braziliensis (rLbNTPDase2). Our results show that this enzyme is a canonical ENTPDase with apyrase activity, capable of hydrolysing triphosphate and diphosphate nucleotides, and it is dependent on divalent cations (calcium or magnesium). Substrate specificity was characterized as UDP>GDP>ADP>GTP>ATP=UTP. The enzyme showed optimal activity at a neutral to basic pH and was partially inhibited by suramin and DIDS. Furthermore, the low apparent Km for ADP suggests that the enzyme may play a role in adenosine-mediated signalling. The biochemical characterization of this enzyme can open new avenues for using LbNTPDase2 as a drug target.
{"title":"Heterologous expression and biochemical characterization of the recombinant nucleoside triphosphate diphosphohydrolase 2 (LbNTPDase2) from Leishmania (Viannia) braziliensis.","authors":"Nancy da Rocha Torres Pavione, João Victor Badaró de Moraes, Isadora Cunha Ribeiro, Raissa Barbosa de Castro, Walmir da Silva, Anna Cláudia Alves de Souza, Victor Hugo Ferraz da Silva, Raphael de Souza Vasconcellos, Gustavo da Costa Bressan, Juliana Lopes Rangel Fietto","doi":"10.1007/s11302-023-09980-9","DOIUrl":"10.1007/s11302-023-09980-9","url":null,"abstract":"<p><p>Leishmania braziliensis is a pathogenic protozoan parasite that causes American Tegumentary Leishmaniasis (ATL), an important tropical neglected disease. ENTPDases are nucleotidases that hydrolyze intracellular and/or extracellular nucleotides. ENTPDases are known as regulators of purinergic signalling induced by extracellular nucleotides. Leishmania species have two isoforms of ENTPDase, and, particularly, ENTPDase2 seems to be involved in infectivity and virulence. In this study, we conducted the heterologous expression and biochemical characterization of the recombinant ENTPDase2 of L. braziliensis (rLbNTPDase2). Our results show that this enzyme is a canonical ENTPDase with apyrase activity, capable of hydrolysing triphosphate and diphosphate nucleotides, and it is dependent on divalent cations (calcium or magnesium). Substrate specificity was characterized as UDP>GDP>ADP>GTP>ATP=UTP. The enzyme showed optimal activity at a neutral to basic pH and was partially inhibited by suramin and DIDS. Furthermore, the low apparent Km for ADP suggests that the enzyme may play a role in adenosine-mediated signalling. The biochemical characterization of this enzyme can open new avenues for using LbNTPDase2 as a drug target.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138299840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-05-03DOI: 10.1007/s11302-024-10013-2
Amelia Fascì, Silvia Deaglio
{"title":"Role of CD73 and the purinergic signaling pathway in the pathogenesis of fusion-negative rhabdomyosarcoma.","authors":"Amelia Fascì, Silvia Deaglio","doi":"10.1007/s11302-024-10013-2","DOIUrl":"10.1007/s11302-024-10013-2","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1007/s11302-024-10052-9
Jianchen Fan, Zhihua Gao
The glymphatic system is critical for brain homeostasis by eliminating metabolic waste, whose disturbance contributes to the accumulation of pathogenic proteins in neurodegenerative diseases. Promoting glymphatic clearance is a potential and attractive strategy for several brain disorders, including neurodegenerative diseases. Previous studies have uncovered that 40 Hz flickering augmented glymphatic flow and facilitated sleep (Zhou et al. in Cell Res 34:214-231, 2024) since sleep drives waste clearance via glymphatic flow (Xie et al. in Science 342:373-377, 2013). However, it remains unclear whether 40 Hz light flickering directly increased glymphatic flow or indirectly by promoting sleep. A recent article published in Cell Discovery by Chen et al. (Sun et al. in Cell Discov 10:81, 2024) revealed that 40 Hz light flickering facilitated glymphatic flow, by promoting the polarization of astrocytic aquaporin-4 (AQP4) and vasomotion through upregulated adenosine-A2A receptor (A2AR) signaling, independent of sleep. These findings suggest that 40 Hz light flickering may be used as a non-invasive approach to control the function of the glymphatic-lymphatic system, to help remove metabolic waste in the brain, thereby presenting a potential strategy for neurodegenerative disease treatment.
{"title":"Promoting glymphatic flow: A non-invasive strategy using 40 Hz light flickering.","authors":"Jianchen Fan, Zhihua Gao","doi":"10.1007/s11302-024-10052-9","DOIUrl":"https://doi.org/10.1007/s11302-024-10052-9","url":null,"abstract":"<p><p>The glymphatic system is critical for brain homeostasis by eliminating metabolic waste, whose disturbance contributes to the accumulation of pathogenic proteins in neurodegenerative diseases. Promoting glymphatic clearance is a potential and attractive strategy for several brain disorders, including neurodegenerative diseases. Previous studies have uncovered that 40 Hz flickering augmented glymphatic flow and facilitated sleep (Zhou et al. in Cell Res 34:214-231, 2024) since sleep drives waste clearance via glymphatic flow (Xie et al. in Science 342:373-377, 2013). However, it remains unclear whether 40 Hz light flickering directly increased glymphatic flow or indirectly by promoting sleep. A recent article published in Cell Discovery by Chen et al. (Sun et al. in Cell Discov 10:81, 2024) revealed that 40 Hz light flickering facilitated glymphatic flow, by promoting the polarization of astrocytic aquaporin-4 (AQP4) and vasomotion through upregulated adenosine-A<sub>2A</sub> receptor (A<sub>2A</sub>R) signaling, independent of sleep. These findings suggest that 40 Hz light flickering may be used as a non-invasive approach to control the function of the glymphatic-lymphatic system, to help remove metabolic waste in the brain, thereby presenting a potential strategy for neurodegenerative disease treatment.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}