Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated...Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.展开更多
Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the curr...Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.展开更多
The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functio...Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.展开更多
Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairmen...Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairments in cognition,emotion,and physical activity.Recently,near-infrared(NIR)photobiomodulation(PBM)has emerged as a promising physical intervention method for ABI,demonstrating that low-level light therapy can modulate cellular metabolic processes,reduce the in flammation and reactive oxygen species of ABI microenvironments,and promote neural repair and regeneration.Preclinical studies using ABI models have been carried out,revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages.In this review,we first inspected the possible physical and biological mechanisms of NIR-PBM,and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention.Therefore,the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications.展开更多
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela ...Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.展开更多
Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for pati...Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In ...Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.展开更多
BACKGROUND:Post-cardiac arrest brain injury remains the leading cause of mortality and longterm disability in patients following cardiac arrest(CA).However,optimizing clinical management strategies for bundled therapy...BACKGROUND:Post-cardiac arrest brain injury remains the leading cause of mortality and longterm disability in patients following cardiac arrest(CA).However,optimizing clinical management strategies for bundled therapy after CA still faces challenges.METHODS:For this literature review,we searched PubMed,Web of Science,and SpringerLink databases for high-quality studies published between December 1982 and July 1,2024.The search included randomized clinical trials,meta-analyses,systematic reviews,and observational studies.References in included studies were also checked to identify additional sources.RESULTS:Many studies have identified potential targets for interventions to mitigate brain injury and improve outcomes for post-resuscitated patients.To optimize clinical management strategies to minimize brain injury after CA,we developed the acronym “SOOTEST-ICU” bundle,which includes “SOOTEST” therapy to optimize peripheral oxygen delivery and “ICU” intervention to optimize the cerebral oxygen cascade.The order of the “SOOTEST” treatment was organized based on the severity and importance of brain oxygen aff ecting brain injury.It includes systolic blood pressure and mean arterial pressure management,oxygenation and ventilation management,original etiological treatment,temperature control,electrolytes and acid basic status,seizure control,and targeted substrate delivery.The acronym “ICU” intervention includes intracerebral oxygen delivery,cerebral oxygen diff usion,and oxygen utilization.CONCLUSION:The “SOOTEST-ICU” therapy is developed to optimize oxygen and substrate cascades to minimize brain injury after CA.展开更多
BACKGROUND:Electrolyte imbalance is common following traumatic brain injury(TBI)and can significantly impact patient outcomes.We aimed to explore the occurrence,patterns,and consequences of electrolyte imbalance in ad...BACKGROUND:Electrolyte imbalance is common following traumatic brain injury(TBI)and can significantly impact patient outcomes.We aimed to explore the occurrence,patterns,and consequences of electrolyte imbalance in adult patients with TBI.METHODS:A retrospective study was conducted from 2016 to 2021 at a level 1 trauma center among hospitalized TBI patients.On admission,the levels of serum electrolytes,including sodium,potassium,calcium,magnesium,and phosphate,were analyzed.Demographics,injury characteristics,and interventions were assessed.The primary outcome was the in-hospital mortality.Multivariate logistic regression analysis was performed to identify independent predictors of mortality in TBI patients.RESULTS:A total of 922 TBI patients were included in the analysis,of whom 902(98%)had electrolyte imbalance.The mean age of patients with electrolyte imbalance was 32.0±15.0 years.Most patients were males(94%).The most common electrolyte abnormalities were hypocalcemia,hypophosphatemia,and hypokalemia.The overall in-hospital mortality rate was 22%in the entire cohort.In multivariate logistic analysis,the predictors of mortality included age(odds ratio[OR]=1.029,95%confidence intervals[CI]:1.013-1.046,P<0.001),low GCS(OR=0.883,95%CI:0.816-0.956,P=0.002),high Injury Severity Score(ISS)scale(OR=1.051,95%CI:1.026-1.078,P<0.001),hypernatremia(OR=2.175,95%CI:1.196-3.955,P=0.011),hyperkalemia(OR=4.862,95%CI:1.222-19.347;P=0.025),low serum bicarbonate levels(OR=0.926,95%CI:0.868-0.988,P=0.020),high serum lactate levels(OR=1.128,95%CI:1.022-1.244,P=0.017),high glucose levels(OR=1.072,95%CI:1.014-1.133,P=0.015),a longer activated partial thromboplastin time(OR=1.054,95%CI:1.024-1.084,P<0.001)and higer international normalized ratio(INR)(OR=3.825,95%CI:1.592-9.188,P=0.003).CONCLUSION:Electrolyte imbalance is common in TBI patients,with the significant prevalence of hypocalcemia,hypophosphatemia,and hypokalemia.However,hypernatremia and hyperkalemia were associated with the risk of mortality,emphasizing the need for further research to comprehend electrolyte dynamics in TBI patients.展开更多
Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-i...Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-inflammato ry agents,the use of glucoco rticoids in traumatic brain injury is still controversial,and their regulatory effects on microglial polarization are not yet known.In the present study,we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action.In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization.Lipopolysaccharide,dexamethasone,RU486(a glucocorticoid receptor antagonist),and ruxolitinib(a Janus kinase 1 antagonist)were administered.RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone.The Morris water maze,quantitative reverse transcription-polymerase chain reaction,western blotting,immunofluorescence and confocal microscopy analysis,and TUNEL,Nissl,and Golgi staining were performed to investigate our hypothesis.High-throughput sequencing results showed that arginase 1,a marker of M2 microglia,was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at3 days post-traumatic brain injury.Thus dexamethasone inhibited M1 and M2 microglia,with a more pronounced inhibitory effect on M2microglia in vitro and in vivo.Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury.Additionally,glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death,and also decreased the density of dendritic spines.A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway.Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia,which plays an antiinflammatory role.In contrast,inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury.Dexamethasone may exe rt its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.展开更多
The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults.Whether targeting this pathway is beneficial to b...The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults.Whether targeting this pathway is beneficial to brain injury remains unclear.In this study,we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis,tauopathy,lesion size,and behavioral deficits.Pharmacological inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology domain.Mechanistically,the Citron homology domain acted as a dominant-negative mutant,impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin pathway.These findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.展开更多
The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unab...The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unable to provide a satisfactory explanation and raw data for the concerns upon request.展开更多
This study investigates the combined effects of multi-modality therapy, including mild hyperbaric therapy (mHBT), photobiomodulation (PBM), and molecular hydrogen therapy (MH), on cognitive rehabilitation in individua...This study investigates the combined effects of multi-modality therapy, including mild hyperbaric therapy (mHBT), photobiomodulation (PBM), and molecular hydrogen therapy (MH), on cognitive rehabilitation in individuals with mild-to-moderate traumatic brain injury (TBI). A total of 15 participants (7 males, 8 females, ages ranging from 20 to 78 years) diagnosed with mild-to-moderate TBI underwent 10 sessions of combined therapy. Cognitive performance was assessed using standardized neuropsychological tests before and after treatment, measuring cognitive processing speed, neural responsiveness, and executive function. The results demonstrated significant improvements across all metrics, including a 28.3 ms reduction in P300 latency, a 1.2 mV increase in P300 voltage, and reductions in completion times for the Trail-Making Tests A (14 seconds) and B (19 seconds). These findings suggest that multi-modality therapy may enhance cognitive recovery in TBI patients, with notable benefits across age and gender groups. Further research with larger sample sizes and extended follow-up is required to validate these results and explore their broader clinical applications.展开更多
Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This stud...Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This study sought to investigate:1)whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans,and 2)whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.Methods:A sample of 440 post-9/11 era U.S.veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston,MA from 2010 to 2022 was included in the study.We examined the relationship between sleep quality,as measured by the Pittsburgh Sleep Quality Index(PSQI),and cortical thickness in veterans with mTBI(n=57),PTSD(n=110),comorbid mTBI and PTSD(n=129),and neither PTSD nor mTBI(n=144).To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group,we employed a General Linear Model(GLM)at each vertex on the cortical mantle.The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.Results:There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI(n=144)or in the PTSD-only group(n=110).In the mTBI-only group(n=57),lower sleep quality was significantly associated with reduced thickness bilaterally in frontal,cingulate,and precuneus regions,as well as in the right parietal and temporal regions(β=-0.0137,P<0.0005).In the comorbid mTBI and PTSD group(n=129),significant associations were observed bilaterally in frontal,precentral,and precuneus regions,in the left cingulate and the right parietal regions(β=-0.0094,P<0.0005).Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI(n=186)compared with those without mTBI(n=254)specifically in the frontal and cingulate regions(β=-0.0077,P<0.0005).Conclusions:This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD.Thus,if directionality is established in longitudinal and interventional studies,it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.展开更多
Retraction Note to:Neurosci.Bull.(2019)35:461-470 https://doi.org/10.1007/s12264-018-00333-w The Editor-in-Chief has retracted this article.After publication,concerns were raised regarding image similarities across pu...Retraction Note to:Neurosci.Bull.(2019)35:461-470 https://doi.org/10.1007/s12264-018-00333-w The Editor-in-Chief has retracted this article.After publication,concerns were raised regarding image similarities across publications from unrelated authors.Specifically.展开更多
BACKGROUND:Post-cardiac arrest syndrome(PCAS) significantly contributes to mortality after initially successful cardiopulmonary resuscitation(CPR) in cardiac arrest(CA) patients.Effective cardiocerebral protection is ...BACKGROUND:Post-cardiac arrest syndrome(PCAS) significantly contributes to mortality after initially successful cardiopulmonary resuscitation(CPR) in cardiac arrest(CA) patients.Effective cardiocerebral protection is essential for improving post-resuscitation survival.This study investigated the mechanisms and common targets of myocardial dysfunction and brain injury after resuscitation.METHODS:The male Sprague-Dawley rats(10–12 weeks old,400–500 g) were divided into two groups:the control group(n=6),which received sham surgery,and the CA/CPR group(n=10),which received ventricular fibrillation(VF) followed by CPR.After 24 h,brain and heart tissues were collected for analysis.The sequencing was used to identify differentially expressed genes(DEGs) between control and CA/CPR rats.RESULTS:At 24 h after resuscitation,CA/CPR rats presented 217 DEGs in the hippocampus and 80 DEGs in the left ventricle(LV) compared to the control group.In the hippocampus,the most notable biological process was the positive regulation of tumor necrosis factor production,with key pathways related to inflammation and the immune response.In the LV,the Gene Ontology(GO)enrichment analysis revealed that gene alterations were primarily associated with amyloid-beta clearance,a pathway that was also relevant in the brain.Eleven common targets were identified in the DEGs of both heart and brain tissues.The reverse transcription-polymerase chain reaction(RTPCR) validation revealed significant differences in the mRNA expression of Timp1,Apln,Ccl7,and Lgals3 in both LV and hippocampus.CONCLUSION:This study identified possible key genes and underlying mechanisms involved in PCAS.The differential genes Timp1,Apln,Ccl7,and Lgals3 might serve as common biomarkers for myocardial and neurological injury following resuscitation.展开更多
BACKGROUND Traumatic brain injury(TBI)is a significant public health issue,leading to long-term neurological impairments.Current treatments offer limited recovery,particularly in restoring lost functions.Mesenchymal s...BACKGROUND Traumatic brain injury(TBI)is a significant public health issue,leading to long-term neurological impairments.Current treatments offer limited recovery,particularly in restoring lost functions.Mesenchymal stem cell-derived exosomes(MSCdE)have shown potential for promoting neuroprotection and regeneration.This study evaluates the safety and efficacy of MSCdE therapy in TBI patients.AIM To evaluate the safety and efficacy of MSCdE therapy in TBI patients.METHODS Five patients(mean age 27.00±4.06 years)with TBI from combat injuries were treated with six rounds of MSCdE therapy(3 mL intrathecally and 3 mL intramuscularly per round).The patients were followed for one year.Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0(CTCAE v5.0),and functional outcomes were evaluated with the functional independence measure(FIM),Modified Ashworth Scale(MAS),and Karnofsky Performance Scale(KPS).RESULTS No serious adverse events occurred,and only mild side effects[subfebrile fever(37.5°C-37.9°C),pain]were reported(CTCAE Grade 1).FIM motor scores improved significantly(46.20±16.39 to 64.20±18.20,P<0.01),and FIM cognitive scores also showed significant improvement(30.60±4.56 to 34.00±1.41,P<0.001).While MAS scores improved(right/left:4.60/3.60 to 2.20/1.60),these changes were not statistically significant(P>0.05),possibly due to low baseline spasticity.KPS scores significantly improved(46.00±11.40 to 72.00±8.37,P<0.001),indicating enhanced overall functional status and quality of life.CONCLUSION MSCdE therapy is safe and effective in improving motor function,cognition,and quality of life in TBI patients.Larger,controlled trials are needed to further validate these findings and optimize MSCdE therapy for TBI treatment.展开更多
文摘Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
基金supported by Open Scientific Research Program of Military Logistics,No.BLB20J009(to YZhao).
文摘Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金supported by the National Natural Science Foundation of China,No.82371399(to YY)the Natural Science Foundation of Jiangsu Province,No.BK20221206(to YY)+1 种基金the Young Elite Scientists Sponsorship Program of Jiangsu Province,No.TJ-2022-028(to YY)the Scientific Research Program of Wuxi Health Commission,No.Z202302(to LY)。
文摘Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.
基金supported by the University of Macao(MYRG2022-00054-FHS and MYRGGRG2023-00038-FHS-UMDF)the Macao Science and Technology Development Fund(FDCT0048/2021/AGJ and FDCT0020/2019/AMJ)Natural Science Foundation of Guangdong Province(EF017/FHS-YZ/2021/GDSTC).
文摘Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairments in cognition,emotion,and physical activity.Recently,near-infrared(NIR)photobiomodulation(PBM)has emerged as a promising physical intervention method for ABI,demonstrating that low-level light therapy can modulate cellular metabolic processes,reduce the in flammation and reactive oxygen species of ABI microenvironments,and promote neural repair and regeneration.Preclinical studies using ABI models have been carried out,revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages.In this review,we first inspected the possible physical and biological mechanisms of NIR-PBM,and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention.Therefore,the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications.
文摘Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
基金supported by the National Natural Science Foundation of China,No.82174112(to PZ)Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine,No.22HHZYSS00015(to PZ)State-Sponsored Postdoctoral Researcher Program,No.GZC20231925(to LN)。
文摘Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金supported by the Fundamental Research Program of Shanxi Province of China,No.20210302124277the Science Foundation of Shanxi Bethune Hospital,No.2021YJ13(both to JW)。
文摘Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
基金supported by the High-Level Public Health Technical Talent Building Program (Discipline Leader-01-01)Capital’s Funds for Health Improvement and Research (CFH 2022-1-2032)+1 种基金National Natural Science Foundation of China (82072136)Beijing Hospitals Authority’s Ascent Plan (DFL20240302)。
文摘BACKGROUND:Post-cardiac arrest brain injury remains the leading cause of mortality and longterm disability in patients following cardiac arrest(CA).However,optimizing clinical management strategies for bundled therapy after CA still faces challenges.METHODS:For this literature review,we searched PubMed,Web of Science,and SpringerLink databases for high-quality studies published between December 1982 and July 1,2024.The search included randomized clinical trials,meta-analyses,systematic reviews,and observational studies.References in included studies were also checked to identify additional sources.RESULTS:Many studies have identified potential targets for interventions to mitigate brain injury and improve outcomes for post-resuscitated patients.To optimize clinical management strategies to minimize brain injury after CA,we developed the acronym “SOOTEST-ICU” bundle,which includes “SOOTEST” therapy to optimize peripheral oxygen delivery and “ICU” intervention to optimize the cerebral oxygen cascade.The order of the “SOOTEST” treatment was organized based on the severity and importance of brain oxygen aff ecting brain injury.It includes systolic blood pressure and mean arterial pressure management,oxygenation and ventilation management,original etiological treatment,temperature control,electrolytes and acid basic status,seizure control,and targeted substrate delivery.The acronym “ICU” intervention includes intracerebral oxygen delivery,cerebral oxygen diff usion,and oxygen utilization.CONCLUSION:The “SOOTEST-ICU” therapy is developed to optimize oxygen and substrate cascades to minimize brain injury after CA.
文摘BACKGROUND:Electrolyte imbalance is common following traumatic brain injury(TBI)and can significantly impact patient outcomes.We aimed to explore the occurrence,patterns,and consequences of electrolyte imbalance in adult patients with TBI.METHODS:A retrospective study was conducted from 2016 to 2021 at a level 1 trauma center among hospitalized TBI patients.On admission,the levels of serum electrolytes,including sodium,potassium,calcium,magnesium,and phosphate,were analyzed.Demographics,injury characteristics,and interventions were assessed.The primary outcome was the in-hospital mortality.Multivariate logistic regression analysis was performed to identify independent predictors of mortality in TBI patients.RESULTS:A total of 922 TBI patients were included in the analysis,of whom 902(98%)had electrolyte imbalance.The mean age of patients with electrolyte imbalance was 32.0±15.0 years.Most patients were males(94%).The most common electrolyte abnormalities were hypocalcemia,hypophosphatemia,and hypokalemia.The overall in-hospital mortality rate was 22%in the entire cohort.In multivariate logistic analysis,the predictors of mortality included age(odds ratio[OR]=1.029,95%confidence intervals[CI]:1.013-1.046,P<0.001),low GCS(OR=0.883,95%CI:0.816-0.956,P=0.002),high Injury Severity Score(ISS)scale(OR=1.051,95%CI:1.026-1.078,P<0.001),hypernatremia(OR=2.175,95%CI:1.196-3.955,P=0.011),hyperkalemia(OR=4.862,95%CI:1.222-19.347;P=0.025),low serum bicarbonate levels(OR=0.926,95%CI:0.868-0.988,P=0.020),high serum lactate levels(OR=1.128,95%CI:1.022-1.244,P=0.017),high glucose levels(OR=1.072,95%CI:1.014-1.133,P=0.015),a longer activated partial thromboplastin time(OR=1.054,95%CI:1.024-1.084,P<0.001)and higer international normalized ratio(INR)(OR=3.825,95%CI:1.592-9.188,P=0.003).CONCLUSION:Electrolyte imbalance is common in TBI patients,with the significant prevalence of hypocalcemia,hypophosphatemia,and hypokalemia.However,hypernatremia and hyperkalemia were associated with the risk of mortality,emphasizing the need for further research to comprehend electrolyte dynamics in TBI patients.
基金supported by research grants from the Ningbo Science and Technology Plan Project,No.2022Z143hezuo(to BL)the National Natural Science Foundation of China,No.82201520(to XD)。
文摘Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-inflammato ry agents,the use of glucoco rticoids in traumatic brain injury is still controversial,and their regulatory effects on microglial polarization are not yet known.In the present study,we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action.In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization.Lipopolysaccharide,dexamethasone,RU486(a glucocorticoid receptor antagonist),and ruxolitinib(a Janus kinase 1 antagonist)were administered.RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone.The Morris water maze,quantitative reverse transcription-polymerase chain reaction,western blotting,immunofluorescence and confocal microscopy analysis,and TUNEL,Nissl,and Golgi staining were performed to investigate our hypothesis.High-throughput sequencing results showed that arginase 1,a marker of M2 microglia,was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at3 days post-traumatic brain injury.Thus dexamethasone inhibited M1 and M2 microglia,with a more pronounced inhibitory effect on M2microglia in vitro and in vivo.Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury.Additionally,glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death,and also decreased the density of dendritic spines.A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway.Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia,which plays an antiinflammatory role.In contrast,inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury.Dexamethasone may exe rt its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.
基金supported by the TARCC,Welch Foundation Award(I-1724)the Decherd Foundationthe Pape Adams Foundation,NIH grants NS092616,NS127375,NS117065,NS111776。
文摘The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults.Whether targeting this pathway is beneficial to brain injury remains unclear.In this study,we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis,tauopathy,lesion size,and behavioral deficits.Pharmacological inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology domain.Mechanistically,the Citron homology domain acted as a dominant-negative mutant,impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin pathway.These findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.
文摘The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unable to provide a satisfactory explanation and raw data for the concerns upon request.
文摘This study investigates the combined effects of multi-modality therapy, including mild hyperbaric therapy (mHBT), photobiomodulation (PBM), and molecular hydrogen therapy (MH), on cognitive rehabilitation in individuals with mild-to-moderate traumatic brain injury (TBI). A total of 15 participants (7 males, 8 females, ages ranging from 20 to 78 years) diagnosed with mild-to-moderate TBI underwent 10 sessions of combined therapy. Cognitive performance was assessed using standardized neuropsychological tests before and after treatment, measuring cognitive processing speed, neural responsiveness, and executive function. The results demonstrated significant improvements across all metrics, including a 28.3 ms reduction in P300 latency, a 1.2 mV increase in P300 voltage, and reductions in completion times for the Trail-Making Tests A (14 seconds) and B (19 seconds). These findings suggest that multi-modality therapy may enhance cognitive recovery in TBI patients, with notable benefits across age and gender groups. Further research with larger sample sizes and extended follow-up is required to validate these results and explore their broader clinical applications.
基金supported by the U.S.Department of Veterans Affairs through the Translational Research Center for TBI and Stress Disorders(TRACTS B3001-C),a VA Rehabilitation Research and Development Traumatic Brain Injury National Network Research Center,and the Boston University Chobanian&Avedisian School of Medicine’s Medical Student Summer Research Program,with funding from the Gabriel Family Foundation CTE Research Fund(MA).
文摘Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This study sought to investigate:1)whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans,and 2)whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.Methods:A sample of 440 post-9/11 era U.S.veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston,MA from 2010 to 2022 was included in the study.We examined the relationship between sleep quality,as measured by the Pittsburgh Sleep Quality Index(PSQI),and cortical thickness in veterans with mTBI(n=57),PTSD(n=110),comorbid mTBI and PTSD(n=129),and neither PTSD nor mTBI(n=144).To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group,we employed a General Linear Model(GLM)at each vertex on the cortical mantle.The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.Results:There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI(n=144)or in the PTSD-only group(n=110).In the mTBI-only group(n=57),lower sleep quality was significantly associated with reduced thickness bilaterally in frontal,cingulate,and precuneus regions,as well as in the right parietal and temporal regions(β=-0.0137,P<0.0005).In the comorbid mTBI and PTSD group(n=129),significant associations were observed bilaterally in frontal,precentral,and precuneus regions,in the left cingulate and the right parietal regions(β=-0.0094,P<0.0005).Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI(n=186)compared with those without mTBI(n=254)specifically in the frontal and cingulate regions(β=-0.0077,P<0.0005).Conclusions:This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD.Thus,if directionality is established in longitudinal and interventional studies,it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.
文摘Retraction Note to:Neurosci.Bull.(2019)35:461-470 https://doi.org/10.1007/s12264-018-00333-w The Editor-in-Chief has retracted this article.After publication,concerns were raised regarding image similarities across publications from unrelated authors.Specifically.
基金supported by the National High Level Hospital Clinical Research Funding (2022-NHLHCRF-YS-03)the National Natural Science Foundation of China (82272196)。
文摘BACKGROUND:Post-cardiac arrest syndrome(PCAS) significantly contributes to mortality after initially successful cardiopulmonary resuscitation(CPR) in cardiac arrest(CA) patients.Effective cardiocerebral protection is essential for improving post-resuscitation survival.This study investigated the mechanisms and common targets of myocardial dysfunction and brain injury after resuscitation.METHODS:The male Sprague-Dawley rats(10–12 weeks old,400–500 g) were divided into two groups:the control group(n=6),which received sham surgery,and the CA/CPR group(n=10),which received ventricular fibrillation(VF) followed by CPR.After 24 h,brain and heart tissues were collected for analysis.The sequencing was used to identify differentially expressed genes(DEGs) between control and CA/CPR rats.RESULTS:At 24 h after resuscitation,CA/CPR rats presented 217 DEGs in the hippocampus and 80 DEGs in the left ventricle(LV) compared to the control group.In the hippocampus,the most notable biological process was the positive regulation of tumor necrosis factor production,with key pathways related to inflammation and the immune response.In the LV,the Gene Ontology(GO)enrichment analysis revealed that gene alterations were primarily associated with amyloid-beta clearance,a pathway that was also relevant in the brain.Eleven common targets were identified in the DEGs of both heart and brain tissues.The reverse transcription-polymerase chain reaction(RTPCR) validation revealed significant differences in the mRNA expression of Timp1,Apln,Ccl7,and Lgals3 in both LV and hippocampus.CONCLUSION:This study identified possible key genes and underlying mechanisms involved in PCAS.The differential genes Timp1,Apln,Ccl7,and Lgals3 might serve as common biomarkers for myocardial and neurological injury following resuscitation.
文摘BACKGROUND Traumatic brain injury(TBI)is a significant public health issue,leading to long-term neurological impairments.Current treatments offer limited recovery,particularly in restoring lost functions.Mesenchymal stem cell-derived exosomes(MSCdE)have shown potential for promoting neuroprotection and regeneration.This study evaluates the safety and efficacy of MSCdE therapy in TBI patients.AIM To evaluate the safety and efficacy of MSCdE therapy in TBI patients.METHODS Five patients(mean age 27.00±4.06 years)with TBI from combat injuries were treated with six rounds of MSCdE therapy(3 mL intrathecally and 3 mL intramuscularly per round).The patients were followed for one year.Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0(CTCAE v5.0),and functional outcomes were evaluated with the functional independence measure(FIM),Modified Ashworth Scale(MAS),and Karnofsky Performance Scale(KPS).RESULTS No serious adverse events occurred,and only mild side effects[subfebrile fever(37.5°C-37.9°C),pain]were reported(CTCAE Grade 1).FIM motor scores improved significantly(46.20±16.39 to 64.20±18.20,P<0.01),and FIM cognitive scores also showed significant improvement(30.60±4.56 to 34.00±1.41,P<0.001).While MAS scores improved(right/left:4.60/3.60 to 2.20/1.60),these changes were not statistically significant(P>0.05),possibly due to low baseline spasticity.KPS scores significantly improved(46.00±11.40 to 72.00±8.37,P<0.001),indicating enhanced overall functional status and quality of life.CONCLUSION MSCdE therapy is safe and effective in improving motor function,cognition,and quality of life in TBI patients.Larger,controlled trials are needed to further validate these findings and optimize MSCdE therapy for TBI treatment.
