Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization’. There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations (microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.
{"title":"Cell polarization in ischemic stroke: molecular mechanisms and advances","authors":"Yuanwei Li, Xiaoxiao Xu, Xuan Wu, Jiarui Li, Shiling Chen, Danyang Chen, Gaigai Li, Zhouping Tang","doi":"10.4103/nrr.nrr-d-23-01336","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01336","url":null,"abstract":"\u0000 Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization’. There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations (microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"159 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140473985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-23-01588
Bridget Martinez, P. Peplow
Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of bipolar disorder. We performed a PubMed search for microRNA biomarkers in bipolar disorder and found 18 original research articles on studies performed with human patients and published from January 2011 to June 2023. These studies included microRNA profiling in blood-and brain-based materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for bipolar disorder in adults could be miR-140-3p, -30d- 5p, -330-5p, -378a-5p, -21-3p, -330-3p, -345-5p in whole blood, miR-19b-3p, -1180-3p, -125a-5p, let-7e-5p in blood plasma, and miR-7-5p, -23b-5p, -142-3p, -221-5p, -370-3p in the blood serum. Two of the studies had investigated the changes in microRNA expression of patients with bipolar disorder receiving treatment. One showed a significant increase in plasma miR-134 compared to baseline after 4 weeks of treatment which included typical antipsychotics, atypical antipsychotics, and benzodiazepines. The other study had assessed the effects of prescribed medications which included neurotransmitter receptor-site binders (drug class B) and sedatives, hypnotics, anticonvulsants, and analgesics (drug class C) on microRNA results. The combined effects of the two drug classes increased the significance of the results for miR-219 and -29c with miR-30e-3p and -526b* acquiring significance. MicroRNAs were tested to see if they could serve as biomarkers of bipolar disorder at different clinical states of mania, depression, and euthymia. One study showed that upregulation in whole blood of miR-9-5p, -29a-3p, -106a-5p, -106b-5p, -107, -125a-3p, -125b-5p and of miR-107, -125a-3p occurred in manic and euthymic patients compared to controls, respectively, and that upregulation of miR-106a-5p, -107 was found for manic compared to euthymic patients. In two other studies using blood plasma, downregulation of miR-134 was observed in manic patients compared to controls, and dysregulation of miR-134, -152, -607, -633, -652. -155 occurred in euthymic patients compared to controls. Finally, microRNAs such as miR-34a, -34b, -34c, -137 and -140- 3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p were shown to have diagnostic potential in distinguishing bipolar disorder patients from schizophrenia or major depressive disorder patients, respectively. Further studies are warranted with adolescents and young adults having bipolar disorder and consideration should be given to using animal models of the disorder to investigate the effects of suppressing or overexpressing specific microRNAs.
{"title":"MicroRNAs as potential diagnostic biomarkers for bipolar disorder","authors":"Bridget Martinez, P. Peplow","doi":"10.4103/nrr.nrr-d-23-01588","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01588","url":null,"abstract":"\u0000 Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of bipolar disorder. We performed a PubMed search for microRNA biomarkers in bipolar disorder and found 18 original research articles on studies performed with human patients and published from January 2011 to June 2023. These studies included microRNA profiling in blood-and brain-based materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for bipolar disorder in adults could be miR-140-3p, -30d- 5p, -330-5p, -378a-5p, -21-3p, -330-3p, -345-5p in whole blood, miR-19b-3p, -1180-3p, -125a-5p, let-7e-5p in blood plasma, and miR-7-5p, -23b-5p, -142-3p, -221-5p, -370-3p in the blood serum. Two of the studies had investigated the changes in microRNA expression of patients with bipolar disorder receiving treatment. One showed a significant increase in plasma miR-134 compared to baseline after 4 weeks of treatment which included typical antipsychotics, atypical antipsychotics, and benzodiazepines. The other study had assessed the effects of prescribed medications which included neurotransmitter receptor-site binders (drug class B) and sedatives, hypnotics, anticonvulsants, and analgesics (drug class C) on microRNA results. The combined effects of the two drug classes increased the significance of the results for miR-219 and -29c with miR-30e-3p and -526b* acquiring significance. MicroRNAs were tested to see if they could serve as biomarkers of bipolar disorder at different clinical states of mania, depression, and euthymia. One study showed that upregulation in whole blood of miR-9-5p, -29a-3p, -106a-5p, -106b-5p, -107, -125a-3p, -125b-5p and of miR-107, -125a-3p occurred in manic and euthymic patients compared to controls, respectively, and that upregulation of miR-106a-5p, -107 was found for manic compared to euthymic patients. In two other studies using blood plasma, downregulation of miR-134 was observed in manic patients compared to controls, and dysregulation of miR-134, -152, -607, -633, -652. -155 occurred in euthymic patients compared to controls. Finally, microRNAs such as miR-34a, -34b, -34c, -137 and -140- 3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p were shown to have diagnostic potential in distinguishing bipolar disorder patients from schizophrenia or major depressive disorder patients, respectively. Further studies are warranted with adolescents and young adults having bipolar disorder and consideration should be given to using animal models of the disorder to investigate the effects of suppressing or overexpressing specific microRNAs.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"11 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140477286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-23-01353
Xiaorong Zhang, Zhiying Chen, Yinyi Xiong, Qin Zhou, Ling-Qiang Zhu, Dan Liu
With an increase in global aging, the number of people affected by cerebrovascular diseases is also increasing, and the incidence of vascular dementia—closely related to cerebrovascular risk—is increasing at an epidemic rate. However, few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients. Similarly in Alzheimer’s disease and other neurological disorders, synaptic dysfunction is recognized as the main reason for cognitive decline. Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system. Recently, nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia. This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction, neuroinflammation, oxidative stress, and blood-brain barrier dysfunction that underlie the progress of vascular dementia. Additionally, we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.
{"title":"The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia","authors":"Xiaorong Zhang, Zhiying Chen, Yinyi Xiong, Qin Zhou, Ling-Qiang Zhu, Dan Liu","doi":"10.4103/nrr.nrr-d-23-01353","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01353","url":null,"abstract":"\u0000 With an increase in global aging, the number of people affected by cerebrovascular diseases is also increasing, and the incidence of vascular dementia—closely related to cerebrovascular risk—is increasing at an epidemic rate. However, few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients. Similarly in Alzheimer’s disease and other neurological disorders, synaptic dysfunction is recognized as the main reason for cognitive decline. Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system. Recently, nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia. This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction, neuroinflammation, oxidative stress, and blood-brain barrier dysfunction that underlie the progress of vascular dementia. Additionally, we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"322 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140470874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-23-01051
Zige Jiang, Dexiang Liu, Ting-ting Li, C. Gai, Dan-qing Xin, Yijing Zhao, Yan Song, Yahong Cheng, Tong Li, Zhen Wang
The pathophysiology of Huntington’s disease involves high levels of the neurotoxin quinolinic acid (Quin). Quin accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which Quin contributes to Huntington’s disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington’s disease by administering Quin to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide (H2S) in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for H2S production. However, treatment with NaHS (a H2S donor) increased H2S levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Finally, treatment with the Nrf2 inhibitor ML385 reversed the beneficial impact of exogenous H2S on Quin-induced oxidative stress. Taken together, our findings show that H2S reduces oxidative stress in Huntington’s disease by activating Nrf2, suggesting that H2S is a novel neuroprotective drug candidate for treating patients with Huntington’s disease.
{"title":"Hydrogen sulfide reduces oxidative stress in Huntington’s disease via Nrf2","authors":"Zige Jiang, Dexiang Liu, Ting-ting Li, C. Gai, Dan-qing Xin, Yijing Zhao, Yan Song, Yahong Cheng, Tong Li, Zhen Wang","doi":"10.4103/nrr.nrr-d-23-01051","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01051","url":null,"abstract":"\u0000 The pathophysiology of Huntington’s disease involves high levels of the neurotoxin quinolinic acid (Quin). Quin accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which Quin contributes to Huntington’s disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington’s disease by administering Quin to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide (H2S) in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for H2S production. However, treatment with NaHS (a H2S donor) increased H2S levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Finally, treatment with the Nrf2 inhibitor ML385 reversed the beneficial impact of exogenous H2S on Quin-induced oxidative stress. Taken together, our findings show that H2S reduces oxidative stress in Huntington’s disease by activating Nrf2, suggesting that H2S is a novel neuroprotective drug candidate for treating patients with Huntington’s disease.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"537 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140479419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of ER-phagy in neurodegenerative disorders.
{"title":"Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases","authors":"Xiu-Yun Zhao, De-En Xu, Ming-Lei Wu, Ji-Chuan Liu, Zi-Ling Shi, Quan-Hong Ma","doi":"10.4103/nrr.nrr-d-23-00995","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-00995","url":null,"abstract":"\u0000 The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of ER-phagy in neurodegenerative disorders.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140478096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human brain development is a complex process, and animal models often have significant limitations. To address this, researchers have developed pluripotent stem cell-derived three-dimensional structures, known as brain-like organoids, to more accurately model early human brain development and disease. To enable more consistent and intuitive reproduction of early brain development, in this study, we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture. This involved embedding organoids in matrix glue for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrix glue for further cultivation, resulting in a new type of human brain organoid system. This cerebral organoid system replicated the temporospatial characteristics of early human brain development, including neuroepithelium derivation, neural progenitor cell production and maintenance, neuron differentiation and migration, and cortical layer patterning and formation, providing more consistent and reproducible organoids for developmental modeling and toxicology testing. As a proof of concept, we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins. Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns, including bursts of cortical cell death and premature differentiation. Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity, accompanied by compensatory cell proliferation at ectopic locations. The convenience, flexibility, and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental, neurological, and neurotoxicological studies.
{"title":"Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins","authors":"Daiyu Hu, Yuanqing Cao, Chenglin Cai, Guangming Wang, Min Zhou, Luying Peng, Yantao Fan, Qiong Lai, Zhengliang Gao","doi":"10.4103/nrr.nrr-d-23-00928","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-00928","url":null,"abstract":"\u0000 Human brain development is a complex process, and animal models often have significant limitations. To address this, researchers have developed pluripotent stem cell-derived three-dimensional structures, known as brain-like organoids, to more accurately model early human brain development and disease. To enable more consistent and intuitive reproduction of early brain development, in this study, we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture. This involved embedding organoids in matrix glue for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrix glue for further cultivation, resulting in a new type of human brain organoid system. This cerebral organoid system replicated the temporospatial characteristics of early human brain development, including neuroepithelium derivation, neural progenitor cell production and maintenance, neuron differentiation and migration, and cortical layer patterning and formation, providing more consistent and reproducible organoids for developmental modeling and toxicology testing. As a proof of concept, we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins. Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns, including bursts of cortical cell death and premature differentiation. Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity, accompanied by compensatory cell proliferation at ectopic locations. The convenience, flexibility, and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental, neurological, and neurotoxicological studies.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"556 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140470987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-22-01198
Simeon C. Daeschler, Katelyn J.W. So, Konstantin Feinberg, M. Manoraj, Jenny Cheung, Jennifer J. Zhang, Kaveh Mirmoeini, J. P. Santerre, Tessa Gordon, G. Borschel
Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
{"title":"A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair","authors":"Simeon C. Daeschler, Katelyn J.W. So, Konstantin Feinberg, M. Manoraj, Jenny Cheung, Jennifer J. Zhang, Kaveh Mirmoeini, J. P. Santerre, Tessa Gordon, G. Borschel","doi":"10.4103/nrr.nrr-d-22-01198","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-22-01198","url":null,"abstract":"\u0000 Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"486 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140474564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transforming growth factor-beta 1 (TGF-β1) has been extensively studied for its pleiotropic effects on central nervous system diseases. The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved. Voltage-gated sodium channels (VGSCs) are essential ion channels for the generation of action potentials in neurons, and are involved in various neuroexcitation-related diseases. However, the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear. In this study, we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice. We found that TGF-β1 increased VGSC current density in a dose- and time-dependent manner, which was attributable to the upregulation of Nav1.3 expression. Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase (PD98059), p38 mitogen-activated protein kinase (SB203580), and Jun NH2-terminal kinase 1/2 inhibitor (SP600125). Interestingly, TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons. These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2–JNK– MAPK pathway, which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions. Thus, this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.
{"title":"Transforming growth factor-beta 1 enhances discharge activity of cortical neurons","authors":"Zhihui Ren, Tianfei Li, Xueer Liu, Zelin Zhang, Xiaoxuan Chen, Weiqiang Chen, Kangsheng Li, Jiangtao Sheng","doi":"10.4103/nrr.nrr-d-23-00756","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-00756","url":null,"abstract":"\u0000 Transforming growth factor-beta 1 (TGF-β1) has been extensively studied for its pleiotropic effects on central nervous system diseases. The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved. Voltage-gated sodium channels (VGSCs) are essential ion channels for the generation of action potentials in neurons, and are involved in various neuroexcitation-related diseases. However, the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear. In this study, we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice. We found that TGF-β1 increased VGSC current density in a dose- and time-dependent manner, which was attributable to the upregulation of Nav1.3 expression. Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase (PD98059), p38 mitogen-activated protein kinase (SB203580), and Jun NH2-terminal kinase 1/2 inhibitor (SP600125). Interestingly, TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons. These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2–JNK– MAPK pathway, which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions. Thus, this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"297 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140475348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-23-01198
Huiqing Zhu, J. D. Guest, Sarah Dunlop, Jia-Xin Xie, Sujuan Gao, Zhuojing Luo, Joe E. Springer, Wutian Wu, Wise Young, Wai Sang Poon, Song Liu, Hongkun Gao, Tao Yu, Dianchun Wang, Shengping Wu, Lei Zhong, Fang Niu, Xiaomei Wang, Yan-sheng Liu, Kwok-Fai So, Xiao-Ming Xu
For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered on ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.
对于慢性脊髓损伤患者，传统的治疗方法是康复和治疗脊髓损伤并发症，如尿路感染、压疮、骨质疏松症和深静脉血栓。对慢性期脊髓损伤患者很少进行手术治疗，而且很少有治疗方法被证明对慢性脊髓损伤患者有效。我们需要开发针对慢性脊髓损伤患者的有效疗法。我们在慢性完全性胸椎脊髓损伤患者中开展了一项随机对照临床试验，比较单纯强化康复（负重行走训练）与手术干预加强化康复。该临床试验已在ClinicalTrials.gov（NCT02663310）上注册。手术干预的目标是脊髓脱系、恢复脑脊液流动和消除残余脊髓压迫。我们发现，与单独进行负重行走训练相比，手术干预加负重行走训练与美国脊柱损伤协会损伤量表改善率、痉挛减少率以及肠道和膀胱功能恢复更快相关。总体而言，手术治疗和强化康复是安全的。与T2-T6损伤相比，美国脊柱损伤协会损伤量表（American Spinal Injury Association Impairment Scale）的改善在T7-T11损伤中更为常见。手术结合康复治疗似乎在慢性脊髓损伤患者的治疗中发挥了作用。
{"title":"Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury: a randomized controlled study","authors":"Huiqing Zhu, J. D. Guest, Sarah Dunlop, Jia-Xin Xie, Sujuan Gao, Zhuojing Luo, Joe E. Springer, Wutian Wu, Wise Young, Wai Sang Poon, Song Liu, Hongkun Gao, Tao Yu, Dianchun Wang, Shengping Wu, Lei Zhong, Fang Niu, Xiaomei Wang, Yan-sheng Liu, Kwok-Fai So, Xiao-Ming Xu","doi":"10.4103/nrr.nrr-d-23-01198","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01198","url":null,"abstract":"\u0000 For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered on ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"12 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140478932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.4103/nrr.nrr-d-23-01069
Zhen-zhong Zheng, Jialin Chen, Jinghong Xu, Bing Jiang, Lei Li, Yawei Li, Yuliang Dai, Bing Wang
Degenerative cervical myelopathy is a common cause of spinal cord injury, with longer symptom duration and higher myelopathy severity indicating a worse prognosis. While numerous studies have investigated serological biomarkers for acute spinal cord injury, few studies have explored such biomarkers for diagnosing degenerative cervical myelopathy. This study involved 30 patients with degenerative cervical myelopathy (51.3 ± 7.3 years old, 12 women and 18 men), seven healthy controls (25.7 ± 1.7 years old, one woman and six men), and nine patients with cervical spondylotic radiculopathy (51.9 ± 8.6 years old, three women and six men). Analysis of blood samples from the three groups showed clear differences in transcriptomic characteristics. Enrichment analysis identified 128 differentially expressed genes that were enriched in patients with neurological disabilities. Using least absolute shrinkage and selection operator analysis, we constructed a five-gene model (TBCD, TPM2, PNKD, EIF4G2, and AP5Z1) to diagnose degenerative cervical myelopathy with an accuracy of 93.5%. One-gene models (TCAP and SDHA) identified mild and severe degenerative cervical myelopathy with accuracies of 83.3% and 76.7%, respectively. Signatures of two immune cell types (memory B cells and memory-activated CD4+ T cells) predicted lesion severity in degenerative cervical myelopathy with 80% accuracy. Our results suggest that peripheral blood RNA biomarkers could be used to predict levels of lesions in degenerative cervical myelopathy.
{"title":"Peripheral blood RNA biomarkers can predict lesion severity in degenerative cervical myelopathy","authors":"Zhen-zhong Zheng, Jialin Chen, Jinghong Xu, Bing Jiang, Lei Li, Yawei Li, Yuliang Dai, Bing Wang","doi":"10.4103/nrr.nrr-d-23-01069","DOIUrl":"https://doi.org/10.4103/nrr.nrr-d-23-01069","url":null,"abstract":"\u0000 Degenerative cervical myelopathy is a common cause of spinal cord injury, with longer symptom duration and higher myelopathy severity indicating a worse prognosis. While numerous studies have investigated serological biomarkers for acute spinal cord injury, few studies have explored such biomarkers for diagnosing degenerative cervical myelopathy. This study involved 30 patients with degenerative cervical myelopathy (51.3 ± 7.3 years old, 12 women and 18 men), seven healthy controls (25.7 ± 1.7 years old, one woman and six men), and nine patients with cervical spondylotic radiculopathy (51.9 ± 8.6 years old, three women and six men). Analysis of blood samples from the three groups showed clear differences in transcriptomic characteristics. Enrichment analysis identified 128 differentially expressed genes that were enriched in patients with neurological disabilities. Using least absolute shrinkage and selection operator analysis, we constructed a five-gene model (TBCD, TPM2, PNKD, EIF4G2, and AP5Z1) to diagnose degenerative cervical myelopathy with an accuracy of 93.5%. One-gene models (TCAP and SDHA) identified mild and severe degenerative cervical myelopathy with accuracies of 83.3% and 76.7%, respectively. Signatures of two immune cell types (memory B cells and memory-activated CD4+ T cells) predicted lesion severity in degenerative cervical myelopathy with 80% accuracy. Our results suggest that peripheral blood RNA biomarkers could be used to predict levels of lesions in degenerative cervical myelopathy.","PeriodicalId":506566,"journal":{"name":"Neural Regeneration Research","volume":"163 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140475149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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