Pub Date : 2023-12-31eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0332
Sylwia Wasiak, Li Fu, Emily Daze, Dean Gilham, Brooke D Rakai, Stephanie C Stotz, Laura M Tsujikawa, Chris D Sarsons, Deborah Studer, Kristina D Rinker, Ravi Jahagirdar, Norman C W Wong, Michael Sweeney, Jan O Johansson, Ewelina Kulikowski
Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of in vitro endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation.
{"title":"The BET inhibitor apabetalone decreases neuroendothelial proinflammatory activation <i>in vitro</i> and in a mouse model of systemic inflammation.","authors":"Sylwia Wasiak, Li Fu, Emily Daze, Dean Gilham, Brooke D Rakai, Stephanie C Stotz, Laura M Tsujikawa, Chris D Sarsons, Deborah Studer, Kristina D Rinker, Ravi Jahagirdar, Norman C W Wong, Michael Sweeney, Jan O Johansson, Ewelina Kulikowski","doi":"10.1515/tnsci-2022-0332","DOIUrl":"10.1515/tnsci-2022-0332","url":null,"abstract":"<p><p>Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of <i>in vitro</i> endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes <i>in vitro</i> and in the mouse brain during systemic inflammation.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10787226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466864","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 : 2023-12-31eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0329
Haofuzi Zhang, Xiaofan Jiang
David M. Holtzman and his team at the University of Washington School of Medicine have made breakthroughs in their research on neurodegenerative diseases. They discovered that the infiltration of T cells into the brain, instigated by activated microglia, is a critical factor in the progression of tauopathy. The groundbreaking findings were published in Nature on March 8, 2023. This research delineates a pivotal immune hub linked to tauopathy and neurodegeneration; a complex interplay involving activated microglia and T cell responses. This discovery could potentially become a target for developing therapeutic interventions for Alzheimer's disease and primary neurodegeneration.
华盛顿大学医学院的戴维-霍尔茨曼(David M. Holtzman)及其团队在神经退行性疾病的研究中取得了突破性进展。他们发现,在活化的小胶质细胞的煽动下,T 细胞渗入大脑是导致牛磺酸病进展的关键因素。这一突破性研究成果于2023年3月8日发表在《自然》杂志上。这项研究勾勒出了一个与tauopathy和神经退行性病变有关的关键免疫枢纽;一个涉及活化小胶质细胞和T细胞反应的复杂相互作用。这一发现有可能成为开发阿尔茨海默病和原发性神经变性治疗干预措施的目标。
{"title":"Revealing key role of T cells in neurodegenerative diseases, with potential to develop new targeted therapies.","authors":"Haofuzi Zhang, Xiaofan Jiang","doi":"10.1515/tnsci-2022-0329","DOIUrl":"10.1515/tnsci-2022-0329","url":null,"abstract":"<p><p>David M. Holtzman and his team at the University of Washington School of Medicine have made breakthroughs in their research on neurodegenerative diseases. They discovered that the infiltration of T cells into the brain, instigated by activated microglia, is a critical factor in the progression of tauopathy. The groundbreaking findings were published in Nature on March 8, 2023. This research delineates a pivotal immune hub linked to tauopathy and neurodegeneration; a complex interplay involving activated microglia and T cell responses. This discovery could potentially become a target for developing therapeutic interventions for Alzheimer's disease and primary neurodegeneration.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404519","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}
Hypoxic-ischemic encephalopathy (HIE) is a common neurological disorder characterized by ischemia and hypoxia in the perinatal period, which seriously affects the growth and development of newborns. To date, there is no specific drug for the treatment of HIE. Previous studies have shown that ferroptosis plays an important role in the pathogenesis of HIE. Carthamin yellow (CY) is believed to have antioxidant and anti-inflammatory effects. However, no studies have reported the role of CY in ferroptosis in HIE in vivo until now. The aim of this study was to investigate the effect and mechanism of CY on HIE in vivo and to provide an experimental basis for the clinical treatment of HIE. The results demonstrated that CY increased the expression of NeuN in the neonatal rat hypoxic-ischemic brain damage (HIBD) model. Further exploration revealed that CY increased the expression of glutathione peroxidase 4 and ferritin heavy chain 1 while it decreased the expression of PTGS2 and ACSL2. Moreover, CY decreased malondialdehyde expression and increased superoxide dismutase and glutathione expression in vivo. The findings also indicated that CY downregulated the expression of Nrf2 and Keap-1. In conclusion, this study demonstrated that CY attenuated brain injury in an experimental HIBD model, potentially by alleviating hippocampal neuronal ferroptosis through inhibition of the Nrf2/Keap-1 signaling pathway. These findings provide a novel therapeutic strategy for the clinical treatment of HIE.
缺氧缺血性脑病(HIE)是一种常见的神经系统疾病,其特点是围产期缺血缺氧,严重影响新生儿的生长发育。迄今为止,还没有治疗 HIE 的特效药物。以往的研究表明,高铁血症在 HIE 的发病机制中起着重要作用。卡他明黄(CY)被认为具有抗氧化和抗炎作用。然而,迄今为止还没有研究报道 CY 在 HIE 体内铁蛋白沉积中的作用。本研究旨在探讨 CY 对体内 HIE 的影响和机制,为临床治疗 HIE 提供实验依据。结果表明,在新生大鼠缺氧缺血性脑损伤(HIBD)模型中,CY能增加NeuN的表达。进一步研究发现,CY能增加谷胱甘肽过氧化物酶4和铁蛋白重链1的表达,同时降低PTGS2和ACSL2的表达。此外,CY 还能降低丙二醛的表达,增加超氧化物歧化酶和谷胱甘肽的表达。研究结果还表明,CY 下调了 Nrf2 和 Keap-1 的表达。总之,本研究表明,CY 可通过抑制 Nrf2/Keap-1 信号通路减轻海马神经元铁突变,从而减轻实验性 HIBD 模型的脑损伤。这些发现为临床治疗 HIE 提供了一种新的治疗策略。
{"title":"Carthamin yellow attenuates brain injury in a neonatal rat model of ischemic-hypoxic encephalopathy by inhibiting neuronal ferroptosis in the hippocampus.","authors":"Yuanyu Zhou, Yuebin Wang, Xiaoqing Wu, Junjie Wu, Jianhui Yan, Wei Su","doi":"10.1515/tnsci-2022-0331","DOIUrl":"10.1515/tnsci-2022-0331","url":null,"abstract":"<p><p>Hypoxic-ischemic encephalopathy (HIE) is a common neurological disorder characterized by ischemia and hypoxia in the perinatal period, which seriously affects the growth and development of newborns. To date, there is no specific drug for the treatment of HIE. Previous studies have shown that ferroptosis plays an important role in the pathogenesis of HIE. Carthamin yellow (CY) is believed to have antioxidant and anti-inflammatory effects. However, no studies have reported the role of CY in ferroptosis in HIE <i>in vivo</i> until now. The aim of this study was to investigate the effect and mechanism of CY on HIE <i>in vivo</i> and to provide an experimental basis for the clinical treatment of HIE. The results demonstrated that CY increased the expression of NeuN in the neonatal rat hypoxic-ischemic brain damage (HIBD) model. Further exploration revealed that CY increased the expression of glutathione peroxidase 4 and ferritin heavy chain 1 while it decreased the expression of PTGS2 and ACSL2. Moreover, CY decreased malondialdehyde expression and increased superoxide dismutase and glutathione expression <i>in vivo</i>. The findings also indicated that CY downregulated the expression of Nrf2 and Keap-1. In conclusion, this study demonstrated that CY attenuated brain injury in an experimental HIBD model, potentially by alleviating hippocampal neuronal ferroptosis through inhibition of the Nrf2/Keap-1 signaling pathway. These findings provide a novel therapeutic strategy for the clinical treatment of HIE.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10795005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139492235","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 : 2023-12-26eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0325
Juergen K Mai, Milan Majtanik
C. and O. Vogt had set up a research program with the aim of establishing a detailed cartography of the medullary fiber distribution of the human brain. As part of this program, around 200 cortical fields were differentiated based on their myeloarchitectural characteristics and mapped with regard to their exact location in the isocortex. The typical features were graphically documented and classified by a sophisticated linguistic coding. Their results have only recently received adequate attention and applications. The reasons for the revival of this spectrum of their research include interest in the myeloarchitecture of the cortex as a differentiating feature of the cortex architecture and function, as well as the importance for advanced imaging methodologies, particularly tractography and molecular imaging. Here, we describe our approach to exploit the original work of the Vogts and their co-workers to construct a myeloarchitectonic map that is referenced to the Atlas of the Human Brain (AHB) in standard space. We developed a semi-automatic pipeline for processing and integrating the various original maps into a single coherent map. To optimize the precision of the registration between the published maps and the AHB, we augmented the maps with topographic landmarks of the brains that were originally analyzed. Registration of all maps into the AHB opened several possibilities. First, for the majority of the fields, multiple maps from different authors are available, which allows for sophisticated statistical integration, for example, unification with a label-fusion technique. Second, each field in the myeloarchitectonic surface map can be visualized on the myelin-stained cross-section of the AHB at the best possible correspondence. The features of each field can be correlated with the fiber-stained cross-sections in the AHB and with the extensive published materials from the Vogt school and, if necessary, corrected. Third, mapping to the AHB allows the relationship between fiber characteristics of the cortex and the subcortex to be examined. Fourth, the cytoarchitectonic maps from Brodmann and von Economo and Koskinas, which are also registered to the AHB, can be compared. This option allows the study of the correspondence between cyto- and myeloarchitecture in each field. Finally, by using our "stripe" technology - where any other feature registered to the same space can be directly compared owing to the linear and parallel representation of the correlated cortex segments - this map becomes part of a multidimensional co-registration platform.
{"title":"Myeloarchitectonic maps of the human cerebral cortex registered to surface and sections of a standard atlas brain.","authors":"Juergen K Mai, Milan Majtanik","doi":"10.1515/tnsci-2022-0325","DOIUrl":"10.1515/tnsci-2022-0325","url":null,"abstract":"<p><p>C. and O. Vogt had set up a research program with the aim of establishing a detailed cartography of the medullary fiber distribution of the human brain. As part of this program, around 200 cortical fields were differentiated based on their myeloarchitectural characteristics and mapped with regard to their exact location in the isocortex. The typical features were graphically documented and classified by a sophisticated linguistic coding. Their results have only recently received adequate attention and applications. The reasons for the revival of this spectrum of their research include interest in the myeloarchitecture of the cortex as a differentiating feature of the cortex architecture and function, as well as the importance for advanced imaging methodologies, particularly tractography and molecular imaging. Here, we describe our approach to exploit the original work of the Vogts and their co-workers to construct a myeloarchitectonic map that is referenced to the Atlas of the Human Brain (AHB) in standard space. We developed a semi-automatic pipeline for processing and integrating the various original maps into a single coherent map. To optimize the precision of the registration between the published maps and the AHB, we augmented the maps with topographic landmarks of the brains that were originally analyzed. Registration of all maps into the AHB opened several possibilities. First, for the majority of the fields, multiple maps from different authors are available, which allows for sophisticated statistical integration, for example, unification with a label-fusion technique. Second, each field in the myeloarchitectonic surface map can be visualized on the myelin-stained cross-section of the AHB at the best possible correspondence. The features of each field can be correlated with the fiber-stained cross-sections in the AHB and with the extensive published materials from the Vogt school and, if necessary, corrected. Third, mapping to the AHB allows the relationship between fiber characteristics of the cortex and the subcortex to be examined. Fourth, the cytoarchitectonic maps from Brodmann and von Economo and Koskinas, which are also registered to the AHB, can be compared. This option allows the study of the correspondence between cyto- and myeloarchitecture in each field. Finally, by using our \"stripe\" technology - where any other feature registered to the same space can be directly compared owing to the linear and parallel representation of the correlated cortex segments - this map becomes part of a multidimensional co-registration platform.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049365","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 : 2023-12-16eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0323
Éva Simon, Csaba Csipkés, Dániel Andráskó, Veronika Kovács, Zoltán Szabó-Maák, Béla Tankó, Gyula Buchholcz, Béla Fülesdi, Csilla Molnár
Background and purpose: Headache attributed to craniotomy is an underestimated and under-treated condition. Previous studies confirmed the efficacy of preemptive analgesia with non-steroidal anti-inflammatory agents. The aim of the present work was to test the hypothesis of whether a single preoperatively administered dose of dexketoprofen (DEX) has the potency to decrease postcraniotomy headache (PCH) as compared to placebo (PL).
Patients and methods: This is a single-centre, randomized, PL-controlled trial comparing the effect of a single oral dose of 25 mg DEX to PL on the intensity of PCH. Patients undergoing craniotomy were randomly allocated to DEX and PL groups. Patients rated their actual and worst daily pain using visual analogue scale (VAS) scores during intrahospital treatment (0-5 days) and 30 and 90 days postoperatively.
Results: Two hundred patients were included. DEX decreased the worst daily pain intensity in the first 24 h only; the 5-days cumulative score of actual pain was 9.7 ± 7.9 cm for the DEX group and 12.6 ± 10.5 cm for the PL group, respectively (p = 0.03). This difference disappeared in the late, 30-, and 90-day follow-up period. No differences in VAS scores could be detected in supra- and infratentorial cases among the DEX and PL groups.
Conclusions: A single preoperative dose of 25 mg of DEX slightly decreases the intensity of PCH in the first 5 days after craniotomy but it does not have an effect on chronic headaches and postoperative analgesic requirements.
{"title":"Preoperatively administered single dose of dexketoprofen decreases pain intensity on the first 5 days after craniotomy: A single-centre placebo-controlled, randomized trial.","authors":"Éva Simon, Csaba Csipkés, Dániel Andráskó, Veronika Kovács, Zoltán Szabó-Maák, Béla Tankó, Gyula Buchholcz, Béla Fülesdi, Csilla Molnár","doi":"10.1515/tnsci-2022-0323","DOIUrl":"10.1515/tnsci-2022-0323","url":null,"abstract":"<p><strong>Background and purpose: </strong>Headache attributed to craniotomy is an underestimated and under-treated condition. Previous studies confirmed the efficacy of preemptive analgesia with non-steroidal anti-inflammatory agents. The aim of the present work was to test the hypothesis of whether a single preoperatively administered dose of dexketoprofen (DEX) has the potency to decrease postcraniotomy headache (PCH) as compared to placebo (PL).</p><p><strong>Patients and methods: </strong>This is a single-centre, randomized, PL-controlled trial comparing the effect of a single oral dose of 25 mg DEX to PL on the intensity of PCH. Patients undergoing craniotomy were randomly allocated to DEX and PL groups. Patients rated their actual and worst daily pain using visual analogue scale (VAS) scores during intrahospital treatment (0-5 days) and 30 and 90 days postoperatively.</p><p><strong>Results: </strong>Two hundred patients were included. DEX decreased the worst daily pain intensity in the first 24 h only; the 5-days cumulative score of actual pain was 9.7 ± 7.9 cm for the DEX group and 12.6 ± 10.5 cm for the PL group, respectively (<i>p</i> = 0.03). This difference disappeared in the late, 30-, and 90-day follow-up period. No differences in VAS scores could be detected in supra- and infratentorial cases among the DEX and PL groups.</p><p><strong>Conclusions: </strong>A single preoperative dose of 25 mg of DEX slightly decreases the intensity of PCH in the first 5 days after craniotomy but it does not have an effect on chronic headaches and postoperative analgesic requirements.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049377","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 : 2023-12-16eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0328
Sebastián García Menéndez, Walter Manucha
Neuroinflammation, a complex process involving the activation of microglia, astrocytes, and other immune cells in the brain, plays a role in neurodegeneration and psychiatric disorders. Current therapeutic strategies for neuroinflammation are limited, necessitating the development of improved approaches. Nanopharmacology offers unprecedented opportunities to access and treat neuroinflammatory disorders at the brain level. Nanoscaffolds can target specific cells or tissues and protect drugs from degradation or elimination, making them ideal candidates for treating neurodegenerative and psychiatric diseases. Recent advancements in nanoparticle development have enabled the targeting of microglia, astrocytes, and other immune cells in the brain, reducing neuroinflammation and protecting neurons from injury. Nanoparticles targeting specific neurons have also been developed. Clinical trials are in progress to evaluate the safety and efficacy of nano drugs for treating neuroinflammatory, neurodegenerative, and psychiatric diseases. The successful development of these nanodrugs holds immense promise for treating these devastating and increasingly prevalent conditions. On the other hand, several limitations and unanswered questions remain. First, the long-term effects of nanoparticles on the brain need to be thoroughly investigated to ensure their safety. Second, optimizing the targeting and delivery of nanoparticles to specific brain regions remains a challenge. Understanding the complex interplay between nanoparticles and the brain's immune system is crucial for developing effective nanotherapies. Despite these limitations, nanopharmacology presents a transformative approach to treating neuroinflammatory disorders. Future research should address the aforementioned limitations and further elucidate the mechanisms of nanoparticle-mediated therapy. The successful development of safe and effective nanodrugs can revolutionize the treatment of neuroinflammatory disorders, alleviating the suffering of millions.
{"title":"Nanopharmacology as a new approach to treat neuroinflammatory disorders.","authors":"Sebastián García Menéndez, Walter Manucha","doi":"10.1515/tnsci-2022-0328","DOIUrl":"10.1515/tnsci-2022-0328","url":null,"abstract":"<p><p>Neuroinflammation, a complex process involving the activation of microglia, astrocytes, and other immune cells in the brain, plays a role in neurodegeneration and psychiatric disorders. Current therapeutic strategies for neuroinflammation are limited, necessitating the development of improved approaches. Nanopharmacology offers unprecedented opportunities to access and treat neuroinflammatory disorders at the brain level. Nanoscaffolds can target specific cells or tissues and protect drugs from degradation or elimination, making them ideal candidates for treating neurodegenerative and psychiatric diseases. Recent advancements in nanoparticle development have enabled the targeting of microglia, astrocytes, and other immune cells in the brain, reducing neuroinflammation and protecting neurons from injury. Nanoparticles targeting specific neurons have also been developed. Clinical trials are in progress to evaluate the safety and efficacy of nano drugs for treating neuroinflammatory, neurodegenerative, and psychiatric diseases. The successful development of these nanodrugs holds immense promise for treating these devastating and increasingly prevalent conditions. On the other hand, several limitations and unanswered questions remain. First, the long-term effects of nanoparticles on the brain need to be thoroughly investigated to ensure their safety. Second, optimizing the targeting and delivery of nanoparticles to specific brain regions remains a challenge. Understanding the complex interplay between nanoparticles and the brain's immune system is crucial for developing effective nanotherapies. Despite these limitations, nanopharmacology presents a transformative approach to treating neuroinflammatory disorders. Future research should address the aforementioned limitations and further elucidate the mechanisms of nanoparticle-mediated therapy. The successful development of safe and effective nanodrugs can revolutionize the treatment of neuroinflammatory disorders, alleviating the suffering of millions.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049366","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}
Dorsal root injury usually leads to irreversible sensory function loss and lacks effective treatments. (-)-epigallocatechin-3-gallate (EGCG) is reported to exert neuroprotective roles in the nervous systems. However, the function of EGCG in treating dorsal root injury remains unclear. Hence, we built the dorsal root crush injury (DRCI) rat model to be treated with EGCG, followed by the western blot, Enzyme-linked immunosorbent assay, and sensory behavior tests. We observed that EGCG can upregulate the Lysine acetyltransferase 6A (KAT6A) level and inhibit the pyroptosis, indicated by downregulated gasdermin-D, caspase-1, and interleukin 18 protein levels, and alleviate the neuropathic pain, indicated by the decreased paw withdraw threshold in Plantar test and decreased paw withdraw latency in von Frey test, and downregulated calcitonin gene-related peptide, nerve growth factor, and c-Fos protein levels. But EGCG cannot alleviate the neuropathic pain when the KAT6A was inhibited by CTX-0124143 and pyroptosis was activated by Miltirone. These combined results indicated that EGCG can promote the sensory function recovery in rats after DRCI via upregulating KAT6A and inhibiting pyroptosis, laying the foundation for EGCG to be a novel candidate for the treatment of dorsal root injury.
{"title":"EGCG promotes the sensory function recovery in rats after dorsal root crush injury by upregulating KAT6A and inhibiting pyroptosis.","authors":"Jianjun Wang, Zuer Yu, Yichun Hu, Fuyu Li, Xiaoyu Huang, Xiangyue Zhao, Yaqi Tang, Shujuan Fang, Yinjuan Tang","doi":"10.1515/tnsci-2022-0326","DOIUrl":"10.1515/tnsci-2022-0326","url":null,"abstract":"<p><p>Dorsal root injury usually leads to irreversible sensory function loss and lacks effective treatments. (-)-epigallocatechin-3-gallate (EGCG) is reported to exert neuroprotective roles in the nervous systems. However, the function of EGCG in treating dorsal root injury remains unclear. Hence, we built the dorsal root crush injury (DRCI) rat model to be treated with EGCG, followed by the western blot, Enzyme-linked immunosorbent assay, and sensory behavior tests. We observed that EGCG can upregulate the Lysine acetyltransferase 6A (KAT6A) level and inhibit the pyroptosis, indicated by downregulated gasdermin-D, caspase-1, and interleukin 18 protein levels, and alleviate the neuropathic pain, indicated by the decreased paw withdraw threshold in Plantar test and decreased paw withdraw latency in von Frey test, and downregulated calcitonin gene-related peptide, nerve growth factor, and c-Fos protein levels. But EGCG cannot alleviate the neuropathic pain when the KAT6A was inhibited by CTX-0124143 and pyroptosis was activated by Miltirone. These combined results indicated that EGCG can promote the sensory function recovery in rats after DRCI via upregulating KAT6A and inhibiting pyroptosis, laying the foundation for EGCG to be a novel candidate for the treatment of dorsal root injury.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049364","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}
Background: Endovascular therapy (EVT) was the standard treatment for acute ischemic stroke with large vessel occlusion. Prognosis after EVT is always a major concern. Here, we aimed to explore a predictive model for patients after EVT.
Method: A total of 156 patients were retrospectively enrolled. The primary outcome was functional dependence (defined as a 90-day modified Rankin Scale score ≤ 2). Least absolute shrinkage and selection operator and univariate logistic regression were used to select predictive factors. Various machine learning algorithms, including multivariate logistic regression, linear discriminant analysis, support vector machine, k-nearest neighbors, and decision tree algorithms, were applied to construct prognostic models.
Result: Six predictive factors were selected, namely, age, baseline National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early CT (ASPECT) score, modified thrombolysis in cerebral infarction score, symptomatic intracerebral hemorrhage (sICH), and complications (pulmonary infection, gastrointestinal bleeding, and cardiovascular events). Based on these variables, various models were constructed and showed good discrimination. Finally, a nomogram was constructed by multivariate logistic regression and showed a good performance.
Conclusion: Our nomogram, which was composed of age, baseline NIHSS score, ASPECT score, recanalization status, sICH, and complications, showed a very good performance in predicting outcome after EVT.
{"title":"Predicting functional outcome in acute ischemic stroke patients after endovascular treatment by machine learning.","authors":"Zhenxing Liu, Renwei Zhang, Keni Ouyang, Botong Hou, Qi Cai, Yu Xie, Yumin Liu","doi":"10.1515/tnsci-2022-0324","DOIUrl":"10.1515/tnsci-2022-0324","url":null,"abstract":"<p><strong>Background: </strong>Endovascular therapy (EVT) was the standard treatment for acute ischemic stroke with large vessel occlusion. Prognosis after EVT is always a major concern. Here, we aimed to explore a predictive model for patients after EVT.</p><p><strong>Method: </strong>A total of 156 patients were retrospectively enrolled. The primary outcome was functional dependence (defined as a 90-day modified Rankin Scale score ≤ 2). Least absolute shrinkage and selection operator and univariate logistic regression were used to select predictive factors. Various machine learning algorithms, including multivariate logistic regression, linear discriminant analysis, support vector machine, <i>k</i>-nearest neighbors, and decision tree algorithms, were applied to construct prognostic models.</p><p><strong>Result: </strong>Six predictive factors were selected, namely, age, baseline National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early CT (ASPECT) score, modified thrombolysis in cerebral infarction score, symptomatic intracerebral hemorrhage (sICH), and complications (pulmonary infection, gastrointestinal bleeding, and cardiovascular events). Based on these variables, various models were constructed and showed good discrimination. Finally, a nomogram was constructed by multivariate logistic regression and showed a good performance.</p><p><strong>Conclusion: </strong>Our nomogram, which was composed of age, baseline NIHSS score, ASPECT score, recanalization status, sICH, and complications, showed a very good performance in predicting outcome after EVT.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10685342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462851","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}
Background: Due to high rates of incidence and disability, postoperative cognitive dysfunction (POCD) currently receives a lot of clinical attention. Disturbance of fatty acid oxidation is a potential pathophysiological manifestation underlying POCD. Peroxisome proliferator-activated receptor α (PPARα) is a significant transcription factor of fatty acid oxidation that facilitates the transfer of fatty acids into the mitochondria for oxidation. The potential role of PPARα intervention in POCD warrants consideration.
Objective: The present study is aimed to investigate whether PPARα agonist fenofibrate (FF) could protect long-term isoflurane anesthesia-induced POCD model and to explore the potential underlying function of fatty acid oxidation in the process.
Methods: We established the POCD model via 6 h long-term isoflurane anesthesia in vivo with C57BL/6J mice and in vitro with N2a cells. Cells and mice were pretreated with PPARα agonist FF before anesthesia, after which fatty acid oxidation and cognitive function were assessed. The level of fatty acid oxidation-related proteins was determined using western blotting. The contextual fear conditioning test was utilized to evaluate mice's learning and memory.
Results: Our results showed that 6 h long-term isoflurane anesthesia induced contextual memory damage in mice, accompanied by decreases of fatty acid oxidation-related proteins (peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1A, and PPARα) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPARα agonist FF led to the upregulation of fatty acid oxidation-related proteins. In vivo results showed that preconditioned FF reached similar effects. More crucially, FF has been shown to reduce cognitive damage in mice after long-term isoflurane anesthesia. Additionally, our data showed that after blocking fatty acid oxidation by Etomoxir, FF failed to protect cognitive function from long-term isoflurane anesthesia.
Conclusions: Pretreatment of PPARα agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation.
{"title":"PPARα agonist fenofibrate prevents postoperative cognitive dysfunction by enhancing fatty acid oxidation in mice.","authors":"Tiantian Liu, Xinlu Chen, Ziqi Wei, Xue Han, Yujia Liu, Zhengliang Ma, Tianjiao Xia, Xiaoping Gu","doi":"10.1515/tnsci-2022-0317","DOIUrl":"https://doi.org/10.1515/tnsci-2022-0317","url":null,"abstract":"<p><strong>Background: </strong>Due to high rates of incidence and disability, postoperative cognitive dysfunction (POCD) currently receives a lot of clinical attention. Disturbance of fatty acid oxidation is a potential pathophysiological manifestation underlying POCD. Peroxisome proliferator-activated receptor α (PPARα) is a significant transcription factor of fatty acid oxidation that facilitates the transfer of fatty acids into the mitochondria for oxidation. The potential role of PPARα intervention in POCD warrants consideration.</p><p><strong>Objective: </strong>The present study is aimed to investigate whether PPARα agonist fenofibrate (FF) could protect long-term isoflurane anesthesia-induced POCD model and to explore the potential underlying function of fatty acid oxidation in the process.</p><p><strong>Methods: </strong>We established the POCD model via 6 h long-term isoflurane anesthesia <i>in vivo</i> with C57BL/6J mice and <i>in vitro</i> with N2a cells. Cells and mice were pretreated with PPARα agonist FF before anesthesia, after which fatty acid oxidation and cognitive function were assessed. The level of fatty acid oxidation-related proteins was determined using western blotting. The contextual fear conditioning test was utilized to evaluate mice's learning and memory.</p><p><strong>Results: </strong>Our results showed that 6 h long-term isoflurane anesthesia induced contextual memory damage in mice, accompanied by decreases of fatty acid oxidation-related proteins (peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1A, and PPARα) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPARα agonist FF led to the upregulation of fatty acid oxidation-related proteins. <i>In vivo</i> results showed that preconditioned FF reached similar effects. More crucially, FF has been shown to reduce cognitive damage in mice after long-term isoflurane anesthesia. Additionally, our data showed that after blocking fatty acid oxidation by Etomoxir, FF failed to protect cognitive function from long-term isoflurane anesthesia.</p><p><strong>Conclusions: </strong>Pretreatment of PPARα agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462850","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 : 2023-11-11eCollection Date: 2023-01-01DOI: 10.1515/tnsci-2022-0320
Hui Zhao, Jingyi Yang, Jie Yang, Hongying Jiang, Yecai Qin, Qian Lei
Spinal cord injury (SCI) is a serious disabling injury, and the main factors causing SCI in patients include car accidents, falls from heights, as well as heavy blows and falls. These factors can all cause spinal cord compression or even complete rupture. After SCI, problems with the movement, balance, and walking ability of the lower limbs are most common, and SCI can cause abnormalities in patient's movement, sensation, and other aspects. Therefore, in the treatment of SCI, it is necessary to strengthen the rehabilitation training (RT) of patients based on data science to improve their motor ability and play a positive role in the recovery of their walking ability. This article used lower limb rehabilitation robot (LLRR) to improve the walking ability of SCI patients and applied them to SCI rehabilitation. The purpose is to improve the limb movement function of patients by imitating and assisting their limb movements, thereby achieving pain relief and muscle strength enhancement and promoting rehabilitation. The experimental results showed that the functional ambulation category (FAC) scale scores of Group A and Group B were 0.79 and 0.81, respectively, in the first 10 weeks of the experiment. After 10 weeks of the experiment, the FAC scores of Group A and Group B were 2.42 and 4.36, respectively. After the experiment, the FAC score of Group B was much higher than that of Group A, indicating that Group B was more effective in improving patients' walking ability compared to Group A. This also indicated that LLRR rehabilitation training can enhance the walking ability of SCI patients.
{"title":"Evaluation of the improvement of walking ability in patients with spinal cord injury using lower limb rehabilitation robots based on data science.","authors":"Hui Zhao, Jingyi Yang, Jie Yang, Hongying Jiang, Yecai Qin, Qian Lei","doi":"10.1515/tnsci-2022-0320","DOIUrl":"10.1515/tnsci-2022-0320","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a serious disabling injury, and the main factors causing SCI in patients include car accidents, falls from heights, as well as heavy blows and falls. These factors can all cause spinal cord compression or even complete rupture. After SCI, problems with the movement, balance, and walking ability of the lower limbs are most common, and SCI can cause abnormalities in patient's movement, sensation, and other aspects. Therefore, in the treatment of SCI, it is necessary to strengthen the rehabilitation training (RT) of patients based on data science to improve their motor ability and play a positive role in the recovery of their walking ability. This article used lower limb rehabilitation robot (LLRR) to improve the walking ability of SCI patients and applied them to SCI rehabilitation. The purpose is to improve the limb movement function of patients by imitating and assisting their limb movements, thereby achieving pain relief and muscle strength enhancement and promoting rehabilitation. The experimental results showed that the functional ambulation category (FAC) scale scores of Group A and Group B were 0.79 and 0.81, respectively, in the first 10 weeks of the experiment. After 10 weeks of the experiment, the FAC scores of Group A and Group B were 2.42 and 4.36, respectively. After the experiment, the FAC score of Group B was much higher than that of Group A, indicating that Group B was more effective in improving patients' walking ability compared to Group A. This also indicated that LLRR rehabilitation training can enhance the walking ability of SCI patients.</p>","PeriodicalId":23227,"journal":{"name":"Translational Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10638838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89719639","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}