Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The patholog...Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.展开更多
Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a s...Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.展开更多
Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities.Neuroinflammatory plaques formed through the extracellular deposition of amyloid-βproteins,a...Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities.Neuroinflammatory plaques formed through the extracellular deposition of amyloid-βproteins,as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins,comprise two typical pathological features of Alzheimer's disease.Besides symptomatic treatment,there are no effective therapies for delaying Alzheimer's disease progression.MicroRNAs(miR)are small,non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes.Indeed,miR-146a,a NF-κB-regulated gene,has been extensively implicated in the development of Alzheimer's disease through several pathways.Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder.Mi R-146a is believed to reduce amyloid-βdeposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway;however,there is also evidence supporting that it can promote these processes through many other pathways,thus exacerbating the pathological manifestations of Alzheimer's disease.It has been widely reported that miR-146a mediates synaptic dysfunction,mitochondrial dysfunction,and neuronal death by targeting m RNAs encoding synapticrelated proteins,mitochondrial-related proteins,and membrane proteins,as well as other mRNAs.Regarding the impact on glial cells,miR-146a also exhibits differential effects.On one hand,it causes widespread and sustained inflammation through certain pathways,while on the other hand,it can reverse the polarization of astrocytes and microglia,alleviate neuroinflammation,and promote oligodendrocyte progenitor cell differentiation,thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons.In this review,we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease.We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease,such as amyloid-βdeposition,tau protein hyperphosphorylation,neuronal death,mitochondrial dysfunction,synaptic dysfunction,and glial cell dysfunction,as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.展开更多
Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. T...Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly,metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore,the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood–brain barrier function.However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.展开更多
Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target no...Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.展开更多
This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor(BDNF)levels in first-episode schizophrenia patients.The study re...This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor(BDNF)levels in first-episode schizophrenia patients.The study revealed that higher levels of interleukin-6 and tumor necrosis factor-αcorrelated with reduced BDNF levels and poorer cognitive performance.Schizophrenia is a severe psy-chiatric disorder impacting approximately 1%of the global population,charac-terized by positive symptoms(hallucinations and delusions),negative symptoms(diminished motivation and cognitive impairments)and disorganized thoughts and behaviors.Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting.The findings from Cui et al’s study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes.Effective treatment approaches involve a com-bination of pharmacological and non-pharmacological interventions tailored to individual patient needs.Hence,monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life.Conse-quently,this manuscript highlights the need for an integrated approach to schizo-phrenia management,considering both clinical symptoms and underlying neuro-biological changes.展开更多
Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the ind...Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.展开更多
The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vesse...The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.展开更多
Traumatic spinal cord injury （SCI） is a detrimental condition that causes loss of sensory and motor function in an individual. Many complex secondary injury cascades occur after SCI and they offer great potential fo...Traumatic spinal cord injury （SCI） is a detrimental condition that causes loss of sensory and motor function in an individual. Many complex secondary injury cascades occur after SCI and they offer great potential for therapeutic targeting. In this study, we investigated the response of endogenous neural progenitor cells, astrocytes, and microglia to a localized thoracic SCI throughout the neuroaxis. Twenty-five adult female Sprague-Dawley rats underwent mild-contusion thoracic SCI （n = 9）, sham surgery （n = 8）, or no surgery （n = 8）. Spinal cord and brain tissues were fixed and cut at six regions of the neuroaxis. Immunohistochem- istry showed increased reactivity of neural progenitor cell marker nestin in the central canal at all levels of the spinal cord. Increased reactivity of astrocyte-specific marker glial fibrillary acidic protein was found only at the lesion epicenter. The number of activated microglia was significantly increased at the lesion site, and activated microglia extended to the lumbar enlargement. Phagocytic microglia and macrophages were significantly increased only at the lesion site. There were no changes in nestin, glial fibrillary acidic protein, microglia and macrophage response in the third ventricle of rats subjected to mild-contusion thoracic SCI compared to the sham surgery or no surgery. These findings indicate that neural progenitor cells, astrocytes and microglia respond differently to a localized SCI, presumably due to differences in inflammatory signaling. These different cellular responses may have implications in the way that neural progenitor cells can be manipulated for neuroregeneration after SCI. This needs to be further investigated.展开更多
Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial infl...Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).展开更多
Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outc...Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outcomes,particularly substantial declines in cognitive function.The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain,a disrupted blood–brain barrier,oxidative stress,neurotransmitter dysfunction,and severe microglial activation.Increasing evidence suggests that complementary and alternative medicine,especially Traditional Chinese Medicine(TCM),is favorable in alleviating cognitive decline after sepsis.Here,we summarized the studies of traditional herbal remedies,TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.展开更多
Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total ...Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.展开更多
Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia(MI),as myocardial damage and inflammatory stimuli concurrently occur.Sympathetic nerves undergo...Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia(MI),as myocardial damage and inflammatory stimuli concurrently occur.Sympathetic nerves undergo structural and functional changes after MI,leading to adverse left ventricular(LV)remodeling and heart failure(HF).The complex inflammatory response to MI,including local myocardial anti-inflammatory repair and systemic immune reactions,plays a key role in adverse LV remodeling.Here,we review the progressive structural and electrophysiological remodeling of the LV and the involvement of sympathetic tone in complex and dynamic processes that are susceptible to MI pathological conditions.Acupuncture has been reported to effectively improve cardiac function,eliminate arrhythmia,and mitigate adverse LV remodeling via somatosensory regulation after MI.Moreover,acupuncture has an anti-inflammatory effect on the pathological process of myocardial ischemia.In this Review,we aim to summarize the involvement of sympathetic nerve activation in the neuro-immune modulation of structural and functional cardiac changes after MI.As a noninvasive method for sympathetic regulation,acupuncture is an ideal option because of its anti-ischemic efficacy.A better understanding of the neural circuitry that regulates cardiac function and immune responses following MI could reveal novel targets for acupuncture treatment.展开更多
BACKGROUND The capacity of posttraumatic stress disorder(PTSD)to occur with delayed onset has been documented in several systematic reviews and meta-analyses.Neurobiological models of PTSD may provide insight into the...BACKGROUND The capacity of posttraumatic stress disorder(PTSD)to occur with delayed onset has been documented in several systematic reviews and meta-analyses.Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms.AIM To obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODS A scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed,which included 38 studies in the qualitative synthesis.RESULTS Neurobiological mechanisms underlying PTSD symptoms,onset,and course involve several interconnected systems.Neural mechanisms involve the neurocircuitry of fear,comprising several structures,such as the hippocampus,amygdala,and prefrontal cortex,that are amenable to time-dependent increases in activity through sensitization and kindling.Neural network models explain generalization of the fear response.Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses,both of which may be involved in sensitization to stress.Neuroinflammatory mechanisms are characterized by immune activation,which is sometimes due to the effects of traumatic brain injury.Finally,neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities,and these may be particularly relevant in cases of long-delayed PTSD.CONCLUSION Thus,delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.展开更多
OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative ph...OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative phos⁃phorylation to aerobic glycolysis.However,the molecular mechanism underlying the role of glycolysis in microglial activation and progres⁃sion of neuroinflammatory diseases have not yet been fully understood.METHODS The anti-inflammatory effects and its underlying mecha⁃nisms of glycolytic inhibition in vitro were exam⁃ined in lipopolysaccharide(LPS)activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay(ELISA),quantitative reverse transcriptase polymerase chain reaction(RT-PCR),Western blotting,immunoprecipitation,Flow cytometry and nuclear factor kappa B(NF-κB)luciferase reporter assays.In vivo,the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-or LPS-induced Par⁃kinson disease(PD)models were constructed to explored the anti-inflammatory and neuropro⁃tective effects of glycolytic inhibitor.RESULTS Inhibition of glycolysis by specific inhibitors[2-DG and 3-bromopyruvic acid(3-BPA)],knockdown of glucose transporter type 1(Glut-1)or hexoki⁃nase(HK)Ⅱabolished LPS-induced expres⁃sion of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glyco⁃lytic inhibitors significantly inhibited LPS-induced mTOR phosphorylation,IKKβphosphorylation,IκB phosphorylation,IκB degradation,nuclear translocation of P65 and NF-κB luciferase activity.Furthermore,LPS-induced P65 acetyla⁃tion on lysine 310,which is mediated by NAD-dependent protein deacetylase sirtuin-1 and is critical for NF-kB activation,were inhibited by glycolytic inhibitors.A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect.In vivo,2-DG significantly ameliorated MPTP or LPS induced DA neuron loss and glial cell activation.CONCLUSION Glycolysis is actively involved in microglial activation.Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.展开更多
Objective: Some studies have investigated the association between oral microbiome and mild cognitive impairment (MCI). However, there needs to be more narrative reviews synthesizing this evidence. This study aimed to ...Objective: Some studies have investigated the association between oral microbiome and mild cognitive impairment (MCI). However, there needs to be more narrative reviews synthesizing this evidence. This study aimed to bridge this gap in the current knowledge. Methods: A comprehensive search was conducted on PubMed (MEDLINE) to identify studies examining the association between the oral microbiome and MCI. Search parameters and inclusion criteria were clearly defined, encompassing terms related to the oral microbiome, MCI, and their association. Two authors independently selected relevant studies and performed data extraction. Result: Four studies were included. Two cohort studies and two case-control reported an association between the oral microbiome and MCI. Conclusion: Based on the evidence synthesized from the included studies, the review suggests an association between MCI and the oral microbiome. Specifically, all included studies identified significant differences in the abundance of specific microbial species between individuals with MCI and those with normal cognitive function, underscoring the potential role of these species in neuroinflammatory diseases.展开更多
The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-...The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.展开更多
Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinf...Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes.Despite significant progress in understanding the molecular mechanisms related to neuroinflammation,the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear.Additionally,targeted neuroprotective strategies for RIBI are currently lacking.In this study,we systematically characterized the pathophysiology of RIBI using zebrafish(larvae/adults)and murine models.We established direct associations between neuronal damage and cognitive-behavioral deficits.Mechanistically,we proposed a ROS-mitochondrialimmune axis.Specifically,radiation-induced ROS lead to mitochondrial dysfunction,resulting in the leakage of mitochondrial DNA into the cytosol.This,in turn,activated the cGAS-STING pathway,thereby driving persistent microglia-mediated neuroinflammation.Furthermore,we engineered a dual-function nanotherapeutic agent,Pep-Cu_(5.4)O@H151.This agent integrates ultrasmall copper-based nanozymes(Cu_(5.4)O)for ROS scavenging and H151(a STING inhibitor)and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia.This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades.Our research provided an in-depth analysis of radiation-induced neurotoxicity,clarifying the crucial ROS-mitochondrial-immune axis.Moreover,we have developed a precise therapeutic strategy on the basis of this mechanism.展开更多
In a recent study published in Cell,Woo et al.1 investigated the role of the immunoproteasome and the metabolic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)in neurons in the context of mult...In a recent study published in Cell,Woo et al.1 investigated the role of the immunoproteasome and the metabolic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)in neurons in the context of multiple sclerosis(MS)-related IFNγsignaling,finding new therapeutic targets for neurodegeneration in MS and possibly other related neuroinflammatory neurodegenerative disorders.展开更多
Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neu...Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons.Unfortunately,within weeks after implantation,neural recording quality from microelectrodes degrades,owing largely to a neuroinflammatory response.Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress.We developed a mechanically-adaptive,resveratrol-eluting(MARE)neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity.In this work,we demonstrate that compared to rigid silicon controls,highly-flexible MARE probes exhibit improved recording performance,more stable impedance,and a healing tissue response.With further optimization,MARE probes can serve as long-term,robust neural probes for brain-machine interface applications.展开更多
基金supported by the Helmholtz-Gemeinschaft,“Zukunft-sthema”Immunology and inflammation”(ZT-0027)supported by the Pertermax-Müller-Stiftung and the Niedersachsen Research Network on Neuroinfectiology(N-RENNT)of the Ministry of Science and Culture of Lower Saxony
文摘Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.
基金supported by the Key Research Projects of Universities of Henan Province,No.21A320064 (to XS)the National Key Research and Development Program of China,No.2021YFA1201504 (to LZ)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Science,No.XDB36000000 (to CW)the National Natural Science Foundation of China,Nos.31971295,12374406 (both to LZ)。
文摘Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.
基金supported by the National Natural Science Foundation of China,No.81970991(to GC)Program of Shanghai Academic Research Leader,No.22XD1423400(to HG)。
文摘Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities.Neuroinflammatory plaques formed through the extracellular deposition of amyloid-βproteins,as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins,comprise two typical pathological features of Alzheimer's disease.Besides symptomatic treatment,there are no effective therapies for delaying Alzheimer's disease progression.MicroRNAs(miR)are small,non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes.Indeed,miR-146a,a NF-κB-regulated gene,has been extensively implicated in the development of Alzheimer's disease through several pathways.Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder.Mi R-146a is believed to reduce amyloid-βdeposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway;however,there is also evidence supporting that it can promote these processes through many other pathways,thus exacerbating the pathological manifestations of Alzheimer's disease.It has been widely reported that miR-146a mediates synaptic dysfunction,mitochondrial dysfunction,and neuronal death by targeting m RNAs encoding synapticrelated proteins,mitochondrial-related proteins,and membrane proteins,as well as other mRNAs.Regarding the impact on glial cells,miR-146a also exhibits differential effects.On one hand,it causes widespread and sustained inflammation through certain pathways,while on the other hand,it can reverse the polarization of astrocytes and microglia,alleviate neuroinflammation,and promote oligodendrocyte progenitor cell differentiation,thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons.In this review,we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease.We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease,such as amyloid-βdeposition,tau protein hyperphosphorylation,neuronal death,mitochondrial dysfunction,synaptic dysfunction,and glial cell dysfunction,as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.
基金supported by the National Natural Science Foundation of China,Nos.31871477,32170971 (both to SQ)the Qing-Feng Scholar Research Foundation of Shanghai Medical College,Fudan University,No.QF2212 (to HT)。
文摘Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly,metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore,the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood–brain barrier function.However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.
基金supported by the National Natural Science Foundation of China,Nos. 81760247, 82171450the Scientific Research Foundation for Doctors of the Affiliated Hospital of Zunyi Medical University,No.(2016)14 (all to HH)。
文摘Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.
基金Supported by Basic Science Research Program Through the National Research Foundation of Korea(NRF)Funded By the Ministry of Education,No.NRF-RS-2023-00237287.
文摘This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor(BDNF)levels in first-episode schizophrenia patients.The study revealed that higher levels of interleukin-6 and tumor necrosis factor-αcorrelated with reduced BDNF levels and poorer cognitive performance.Schizophrenia is a severe psy-chiatric disorder impacting approximately 1%of the global population,charac-terized by positive symptoms(hallucinations and delusions),negative symptoms(diminished motivation and cognitive impairments)and disorganized thoughts and behaviors.Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting.The findings from Cui et al’s study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes.Effective treatment approaches involve a com-bination of pharmacological and non-pharmacological interventions tailored to individual patient needs.Hence,monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life.Conse-quently,this manuscript highlights the need for an integrated approach to schizo-phrenia management,considering both clinical symptoms and underlying neuro-biological changes.
基金MT received studentship from Sao Paulo Research Foundation(2017/21655-6)HSB was a Brazilian National Council for Scientific and Technological Development researcher(425838/2016-1,307252/2017-5)This work was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil(CAPES)–Finance Code 001 and FAPESP(2016/07115-6).
文摘Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.
基金supported by the Key Program of the National Natural Science Foundation of ChinaNo.82030071+1 种基金the Science and Technology Major Project of ChangshaNo.kh2103008(both to JZH)
文摘The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.
基金supported by UTS Faculty of Science Early Career Research Grant to CAG
文摘Traumatic spinal cord injury （SCI） is a detrimental condition that causes loss of sensory and motor function in an individual. Many complex secondary injury cascades occur after SCI and they offer great potential for therapeutic targeting. In this study, we investigated the response of endogenous neural progenitor cells, astrocytes, and microglia to a localized thoracic SCI throughout the neuroaxis. Twenty-five adult female Sprague-Dawley rats underwent mild-contusion thoracic SCI （n = 9）, sham surgery （n = 8）, or no surgery （n = 8）. Spinal cord and brain tissues were fixed and cut at six regions of the neuroaxis. Immunohistochem- istry showed increased reactivity of neural progenitor cell marker nestin in the central canal at all levels of the spinal cord. Increased reactivity of astrocyte-specific marker glial fibrillary acidic protein was found only at the lesion epicenter. The number of activated microglia was significantly increased at the lesion site, and activated microglia extended to the lumbar enlargement. Phagocytic microglia and macrophages were significantly increased only at the lesion site. There were no changes in nestin, glial fibrillary acidic protein, microglia and macrophage response in the third ventricle of rats subjected to mild-contusion thoracic SCI compared to the sham surgery or no surgery. These findings indicate that neural progenitor cells, astrocytes and microglia respond differently to a localized SCI, presumably due to differences in inflammatory signaling. These different cellular responses may have implications in the way that neural progenitor cells can be manipulated for neuroregeneration after SCI. This needs to be further investigated.
基金supported by the National Natural Science Foundation of China,No.81971192(to AMX)。
文摘Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).
基金Youth Project of National Natural Science Foundation of China:the Mechanism Study of Shenfuhuang Formula on Cognitive Impairment and Synaptic Plasticity in Sepsis via IL-33/ST2 Pathway-mediated Microglial Polarization(No.82004292)Special Project of National Natural Science Foundation of China:Study on the Mechanism and Material Basis of Jinhua Qinggan Granules in Regulating the Cytokine Storm of Viral Pneumonia(No.82141202)+1 种基金The National Interdisciplinary Innovation Team of TCM under the State Administration of TCM(ZYYCXTD-D-202201)The Financial project of Beijing Municipal Health Commission:Study on Pharmacodynamic Mechanism of Traditional Chinese Medicine in Treating Viral Pneumonia。
文摘Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outcomes,particularly substantial declines in cognitive function.The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain,a disrupted blood–brain barrier,oxidative stress,neurotransmitter dysfunction,and severe microglial activation.Increasing evidence suggests that complementary and alternative medicine,especially Traditional Chinese Medicine(TCM),is favorable in alleviating cognitive decline after sepsis.Here,we summarized the studies of traditional herbal remedies,TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.
基金International Cooperative Project of Traditional Chinese Medicine(GZYYG2020023)CAMS Innovation Fund for Medical Sciences(CIFMS)Grant(2021-I2M-1-034)Key Research Project of Hunan Province(222SK2018).
文摘Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.
基金National Key R&D Program of China:Research on the Specificity and Systemic Effects of Acupoints on Target Organs(No.2022YFC3500702)National Natural Science Foundation of China:Autonomic Neural Modulation underlying“One Acupoint for Multi-Organ Comorbidity”via Propriospinal Interaction(No.82330127)。
文摘Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia(MI),as myocardial damage and inflammatory stimuli concurrently occur.Sympathetic nerves undergo structural and functional changes after MI,leading to adverse left ventricular(LV)remodeling and heart failure(HF).The complex inflammatory response to MI,including local myocardial anti-inflammatory repair and systemic immune reactions,plays a key role in adverse LV remodeling.Here,we review the progressive structural and electrophysiological remodeling of the LV and the involvement of sympathetic tone in complex and dynamic processes that are susceptible to MI pathological conditions.Acupuncture has been reported to effectively improve cardiac function,eliminate arrhythmia,and mitigate adverse LV remodeling via somatosensory regulation after MI.Moreover,acupuncture has an anti-inflammatory effect on the pathological process of myocardial ischemia.In this Review,we aim to summarize the involvement of sympathetic nerve activation in the neuro-immune modulation of structural and functional cardiac changes after MI.As a noninvasive method for sympathetic regulation,acupuncture is an ideal option because of its anti-ischemic efficacy.A better understanding of the neural circuitry that regulates cardiac function and immune responses following MI could reveal novel targets for acupuncture treatment.
基金Supported by the Danish Working Environment Research Fund from Arbejdsmilj?forskningsfonden(to Bonde JP)。
文摘BACKGROUND The capacity of posttraumatic stress disorder(PTSD)to occur with delayed onset has been documented in several systematic reviews and meta-analyses.Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms.AIM To obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODS A scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed,which included 38 studies in the qualitative synthesis.RESULTS Neurobiological mechanisms underlying PTSD symptoms,onset,and course involve several interconnected systems.Neural mechanisms involve the neurocircuitry of fear,comprising several structures,such as the hippocampus,amygdala,and prefrontal cortex,that are amenable to time-dependent increases in activity through sensitization and kindling.Neural network models explain generalization of the fear response.Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses,both of which may be involved in sensitization to stress.Neuroinflammatory mechanisms are characterized by immune activation,which is sometimes due to the effects of traumatic brain injury.Finally,neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities,and these may be particularly relevant in cases of long-delayed PTSD.CONCLUSION Thus,delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.
文摘OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative phos⁃phorylation to aerobic glycolysis.However,the molecular mechanism underlying the role of glycolysis in microglial activation and progres⁃sion of neuroinflammatory diseases have not yet been fully understood.METHODS The anti-inflammatory effects and its underlying mecha⁃nisms of glycolytic inhibition in vitro were exam⁃ined in lipopolysaccharide(LPS)activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay(ELISA),quantitative reverse transcriptase polymerase chain reaction(RT-PCR),Western blotting,immunoprecipitation,Flow cytometry and nuclear factor kappa B(NF-κB)luciferase reporter assays.In vivo,the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-or LPS-induced Par⁃kinson disease(PD)models were constructed to explored the anti-inflammatory and neuropro⁃tective effects of glycolytic inhibitor.RESULTS Inhibition of glycolysis by specific inhibitors[2-DG and 3-bromopyruvic acid(3-BPA)],knockdown of glucose transporter type 1(Glut-1)or hexoki⁃nase(HK)Ⅱabolished LPS-induced expres⁃sion of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glyco⁃lytic inhibitors significantly inhibited LPS-induced mTOR phosphorylation,IKKβphosphorylation,IκB phosphorylation,IκB degradation,nuclear translocation of P65 and NF-κB luciferase activity.Furthermore,LPS-induced P65 acetyla⁃tion on lysine 310,which is mediated by NAD-dependent protein deacetylase sirtuin-1 and is critical for NF-kB activation,were inhibited by glycolytic inhibitors.A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect.In vivo,2-DG significantly ameliorated MPTP or LPS induced DA neuron loss and glial cell activation.CONCLUSION Glycolysis is actively involved in microglial activation.Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.
文摘Objective: Some studies have investigated the association between oral microbiome and mild cognitive impairment (MCI). However, there needs to be more narrative reviews synthesizing this evidence. This study aimed to bridge this gap in the current knowledge. Methods: A comprehensive search was conducted on PubMed (MEDLINE) to identify studies examining the association between the oral microbiome and MCI. Search parameters and inclusion criteria were clearly defined, encompassing terms related to the oral microbiome, MCI, and their association. Two authors independently selected relevant studies and performed data extraction. Result: Four studies were included. Two cohort studies and two case-control reported an association between the oral microbiome and MCI. Conclusion: Based on the evidence synthesized from the included studies, the review suggests an association between MCI and the oral microbiome. Specifically, all included studies identified significant differences in the abundance of specific microbial species between individuals with MCI and those with normal cognitive function, underscoring the potential role of these species in neuroinflammatory diseases.
基金supported by the National Natural Science Foundation of China,No.82471411(to ZW and TD)the Key Research and DevelopmentProgram of Shaanxi Province,No.2023-ZDLSF-12(to TD).
文摘The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.
基金supported by the National Natural Science Foundation of China(82273577,82304079)the CAMS Innovation Fund for Medical Sciences(2023-I2M-3-018,2023-I2M-2-008,2021-I2M-1-042)+2 种基金the Natural Science Foundation of Tianjin Municipal Science and Technology Commission(23JCJQJC00230,24JCZDJC00580)the Fundamental Research Funds for the Central Universities(3332023066,3332024079)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare.
文摘Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes.Despite significant progress in understanding the molecular mechanisms related to neuroinflammation,the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear.Additionally,targeted neuroprotective strategies for RIBI are currently lacking.In this study,we systematically characterized the pathophysiology of RIBI using zebrafish(larvae/adults)and murine models.We established direct associations between neuronal damage and cognitive-behavioral deficits.Mechanistically,we proposed a ROS-mitochondrialimmune axis.Specifically,radiation-induced ROS lead to mitochondrial dysfunction,resulting in the leakage of mitochondrial DNA into the cytosol.This,in turn,activated the cGAS-STING pathway,thereby driving persistent microglia-mediated neuroinflammation.Furthermore,we engineered a dual-function nanotherapeutic agent,Pep-Cu_(5.4)O@H151.This agent integrates ultrasmall copper-based nanozymes(Cu_(5.4)O)for ROS scavenging and H151(a STING inhibitor)and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia.This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades.Our research provided an in-depth analysis of radiation-induced neurotoxicity,clarifying the crucial ROS-mitochondrial-immune axis.Moreover,we have developed a precise therapeutic strategy on the basis of this mechanism.
基金supported by Spanish Ministry of Science and Innovation(MCIN/AEI/10.13039/501100011033/FEDER,UE)grants PID2021-123141OB-I00 to J.J.L.and PID2022-138813OB-I00 to J.P.B.
文摘In a recent study published in Cell,Woo et al.1 investigated the role of the immunoproteasome and the metabolic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)in neurons in the context of multiple sclerosis(MS)-related IFNγsignaling,finding new therapeutic targets for neurodegeneration in MS and possibly other related neuroinflammatory neurodegenerative disorders.
基金funded by Merit Review Award#I01RX003083(A.H.-D./J.R.C.)and a Research Career Scientist Award Grant#12635707(J.R.C.)from the United States Department of Veterans Affairs Rehabilitation Research and Development Servicesupport was provided in a pre-doctoral fellowship to N.N.M.from the Department of Defense National Defense Science and Engineering Fellowship Program。
文摘Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons.Unfortunately,within weeks after implantation,neural recording quality from microelectrodes degrades,owing largely to a neuroinflammatory response.Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress.We developed a mechanically-adaptive,resveratrol-eluting(MARE)neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity.In this work,we demonstrate that compared to rigid silicon controls,highly-flexible MARE probes exhibit improved recording performance,more stable impedance,and a healing tissue response.With further optimization,MARE probes can serve as long-term,robust neural probes for brain-machine interface applications.
