摘要：Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARα plays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.

摘要：Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells.Pericytes play a vital role in nervous system development,significantly influencing the formation,maturation,and maintenance of the central nervous system.An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes,microglia,and astrocytes.These communications govern numerous critical brain processes,including angiogenesis,neurovascular unit homeostasis,blood-brain barrier integrity,cerebral blood flow regulation,and immune response initiation.Glial cells and pericytes participate in dynamic and reciprocal interactions,with each influencing and adjusting the functionality of the other.Pericytes have the ability to control astrocyte polarization,trigger differentiation of oligodendrocyte precursor cells,and initiate immunological responses in microglia.Various neurological disorders that compromise the integrity of the blood-brain barrier can disrupt these communications,impair waste clearance,and hinder cerebral blood circulation,contributing to neuroinflammation.In the context of neurodegeneration,these disruptions exacerbate pathological processes,such as neuronal damage,synaptic dysfunction,and impaired tissue repair.This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system.It highlights their essential roles in neurovascular function and disease progression,providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.

摘要：Stem cell proliferation is tightly regulated in developing and adult tissues through the coordinated action of cell-intrinsic and extracellular signals.Although many extracellular cues were identified,the cell-intrinsic mechanisms underlying the decision of a stem cell to proliferate,enter a dormant quiescent state or differentiate into a specific cell type remains incompletely understood.

摘要：Numerous pathological states of the nervous system involve alterations in neuronal excitability and synaptic dysfunction,which depend on the function of ion channels.Due to their critical involvement in health and disease,the search for new compounds that modulate these proteins is still relevant.Traditional medicine has long been a rich source of neuroactive compounds.For example,the indigenous Mapuche people have used the leaves and bark of the Drimys winteri tree for centuries to treat various diseases.Consequently,several studies have investigated the biological effects of compounds in Drimys winteri,highlighting sesquiterpenes such as α-humulene,drimenin,polygodial,and α-,β-,γ-eudesmol.However,there is currently no literature review focusing on the ability of these sesquiterpenes to modulate ion channels.This review summarizes the current knowledge about neuroactive compounds found in Drimys winteri,with special emphasis on their direct actions on neuronal ion channels.Several Drimys winteri sesquiterpenes modulate a diverse array of neuronal ion channels,including transient receptor potential channels,gamma-aminobutyric acid A receptors,nicotinic acetylcholine receptors,and voltage-dependent Ca2+and Na+channels.Interestingly,the modulation of these molecular targets by Drimys winteri sesquiterpenes correlates with their therapeutic actions.The promiscuous pharmacological profile of Drimys winteri sesquiterpenes suggests they modulate multiple protein targets in vivo,making them potentially useful for treating complex,multifactorial diseases.Further studies at the molecular level may aid in developing multi-targeted drugs with enhanced therapeutic effects.

摘要：GNAO1-associated disorder is a rare disease and an example of developmental and epileptic encephalopathies.Caused by ca.150 different dominant missense mutations in the gene encoding the major neuronal G protein Gαo,it spans a wide range of neurological clinical manifestations,that may include epileptic seizures,motor dysfunctions,developmental and intellectual delay,and other symptoms(Sáez González et al.,2023).

摘要：Ischemia-reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia-reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia-reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia-reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltage-dependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia-reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia-reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.

摘要：Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type Ⅶ collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.

摘要：Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.

摘要：Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons,resulting in a substantial accumulation of myelin debris that can persist for years.The abnormal buildup of myelin debris at sites of injury greatly impedes nerve regeneration,making the clearance of debris within these microenvironments crucial for effective post-spinal cord injury repair.In this review,we comprehensively outline the mechanisms that promote the clearance of myelin debris and myelin metabolism and summarize their roles in spinal cord injury.First,we describe the composition and characteristics of myelin debris and explain its effects on the injury site.Next,we introduce the phagocytic cells involved in myelin debris clearance,including professional phagocytes(macrophages and microglia)and non-professional phagocytes(astrocytes and microvascular endothelial cells),as well as other cells that are also proposed to participate in phagocytosis.Finally,we focus on the pathways and associated targets that enhance myelin debris clearance by phagocytes and promote lipid metabolism following spinal cord injury.Our analysis indicates that myelin debris phagocytosis is not limited to monocyte-derived macrophages,but also involves microglia,astrocytes,and microvascular endothelial cells.By modulating the expression of genes related to phagocytosis and lipid metabolism,it is possible to modulate lipid metabolism disorders and influence inflammatory phenotypes,ultimately affecting the recovery of motor function following spinal cord injury.Additionally,therapies such as targeted mitochondrial transplantation in phagocytic cells,exosome therapy,and repeated trans-spinal magnetic stimulation can effectively enhance the removal of myelin debris,presenting promising potential for future applications.

摘要：The rise of the aging population parallels the rapidly increasing cases of neurological disorders.This puts pressure on scientists and physicians to find novel methods that can prevent and treat neurodegeneration.The brain is made up of a complex network of different cell types that work in tandem to maintain systemic homeostasis.These cells include vascular cells(endothelial cells,pericytes,and smooth muscle cells),glial cells(astrocytes,microglia,and oligodendrocytes),and neurons that have different functions to complement each other and form the neuro-glial-vascular unit(NVU).These elements act in concert to orchestrate neurovascular coupling and maintain blood-brain barrier(BBB)integrity.Unlike other systems in the human body,the brain has limited regenerative capacity.To overcome this limitation,novel approaches in stem cell biology,immune cell engineering,and bioengineering work in tandem to repair,replace,and restore function in the central nervous system.Due to the diverse cell types of the central nervous system,cell therapy allows cell type-specific modifications to precisely target neural circuitries and advance personalized medicine.This puts cell therapy at the forefront as a potential treatment to rejuvenate the cerebral landscape.This perspective focuses on the impact of cell therapy through the lens of the NVU.

摘要：Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a life-threatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappaB is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappaB contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell type-specific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.

摘要：The mechanistic target of rapamycin(mTOR)is a serine/threonine kinase that plays a pivotal role in cellular growth,proliferation,survival,and metabolism.In the central nervous system(CNS),the mTOR pathway regulates diverse aspects of neural development and function.Genetic mutations within the mTOR pathway lead to severe neurodevelopmental disorders,collectively known as"mTORopathies"(Crino,2020).Dysfunctions of mTOR,including both its hyperactivation and hypoactivation,have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions,highlighting its importance in CNS health.Molecularly,mTOR functions as the catalytic subunit of two distinct complexes:mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).These two complexes are defined by their unique components and substrate specificities,which in turn activate distinct downstream signaling cascades that underpin their diverse roles in the CNS.mTORC1,characterized by the presence of RPTOR(Regulatory Associated Protein of MTOR complex 1),is known to govern protein synthesis and autophagy.In contrast,mTORC2,which contains RICTOR(RPTOR Independent Companion of MTOR complex 2),is less understood but is known to regulate the actin cytoskeleton and metabolism.

摘要：Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the mGluR I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr9Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr9Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr9Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr9Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the mRNA and protein levels of pro-inflammatory factors,including interleukin-1β and tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr9Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1β mRNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr9Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr9Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr9Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor-mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.

摘要：Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9％)and 0.759(with an accuracy of 65.3％),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3％).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.

摘要：Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mortality.Although organism-wide deterioration is observed during aging,organs with high metabolic demand,such as the brain,are more vulnerable.Consequently,most neurodegenerative diseases occur in the aged population.Even in the healthy brain,the normal aging process is associated with several features of the neurodegenerative process,including neuroinflammation,and brain shrinkage,with a progressive decline in physiological functions(Lee and Kim,2022).

摘要：Spinal cord injury(SCI)often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage)is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.Yet,current neuroprotective therapeutic efficiency is limited(Anjum et al.,2020).To develop effective neuroprotective interventions for SCI patients,a deeper understanding of SCI pathophysiology is undoubtedly required.

摘要：Ischemic stroke,a frequently occurring form of stroke,is caused by obstruction of cerebral blood flow,which leads to ischemia,hypoxia,and necrosis of local brain tissue.After ischemic stroke,both astrocytes and the blood-brain barrier undergo morphological and functional transformations.However,the interplay between astrocytes and the blood-brain barrier has received less attention.This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood-brain barrier in ischemic stroke.Post-stroke,the structure of endothelial cells and peripheral cells undergoes alterations,causing disruption of the blood-brain barrier.This disruption allows various pro-inflammatory factors and chemokines to cross the blood-brain barrier.Simultaneously,astrocytes swell and primarily adopt two phenotypic states:A1 and A2,which exhibit different roles at different stages of ischemic stroke.During the acute phase,A1 reactive astrocytes secrete vascular endothelial growth factor,matrix metalloproteinases,lipid carrier protein-2,and other cytokines,exacerbating damage to endothelial cells and tight junctions.Conversely,A2 reactive astrocytes produce pentraxin 3,Sonic hedgehog,angiopoietin-1,and other protective factors for endothelial cells.Furthermore,astrocytes indirectly influence blood-brain barrier permeability through ferroptosis and exosomes.In the middle and late(recovery)stages of ischemic stroke,A1 and A2 astrocytes show different effects on glial scar formation.A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein,chondroitin sulfate proteoglycans,and transforming growth factor-β.In contrast,A2 astrocytes facilitate axon growth through platelet-derived growth factor,playing a crucial role in vascular remodeling.Therefore,enhancing our understanding of the pathological changes and interactions between astrocytes and the blood-brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke.These insights may pave the way for innovative therapeutic strategies for ischemic stroke.

摘要：Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial cells,mainly microglia and astrocytes.Microglia are the resident immune cells of the central nervous system,while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses.Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances;these can be pathology-associated abnormal structures,such as amyloid β proteins,or damage-associated molecular patterns released from injured cells,including their mitochondria.Once in the extracellular space,damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses.This review considers the following mitochondrial damage-associated molecular patterns:heme,cytochrome c,cardiolipin,adenosine triphosphate,mitochondrial DNA,mitochondrial transcription factor A,N-formyl peptides,and the tricarboxylic acid cycle metabolites:succinate,fumarate,and itaconate.We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system.We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate.Our review demonstrates that some mitochondrial damage-associated molecular patterns,such as cytochrome c,adenosine triphosphate,and mitochondrial transcription factor A,have already demonstrated significant effects on the central nervous system.In contrast,others including cardiolipin,mitochondrial DNA,N-formyl peptides,succinate,fumarate,and itaconate,will require additional studies corroborating their roles as damage-associated molecular patterns in the central nervous system.For all of the reviewed mitochondrial damage-associated molecular patterns,there is a shortage of studies using human cells and tissues,which is identified as a significant knowledge gap.We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied.Such studies could identify novel treatment strategies for multiple neurodegenerative diseases,which are characterized by chronic neuroinflammation and currently lack effective therapies.

摘要：Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown,suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets.Apolipoprotein E(APOE)genotypes and their corresponding protein(ApoE)isoforms may influence the biophysical properties of the cell membrane lipid bilayer.However,the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function.In the present review article,we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases.APOE genotypes(APOE ε2,APOE ε3,and APOE ε4)were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases,including sporadic Alzheimer's disease,synucleinopathies such as Parkinson's disease and Lewy body disease,stroke,and traumatic brain injury.These shared pathways often involved neuroinflammation,abnormal protein accumulation,or responses to acute detrimental events.Across these conditions,APOE variants are believed to contribute to the modulation of inflammatory responses,the regulation of amyloid and tau pathology,as well as the clearance of proteins such as α-synuclein.The bidirectional interactions among ApoE,amyloid and mitochondrial metabolism,immunomodulatory effects,neuronal repair,and remodeling underscored the complexity of ApoE's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment.Besides ApoE-specific isoforms'link to increased neuropsychiatric symptoms in Alzheimer's disease(depression,psychosis,aberrant motor behaviors,and anxiety,not apathy),the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes.Conversely,the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases.Specifically,in Lewy body disease,this variant may delay disease onset,paralleling its protective role in Alzheimer's disease,although its role in frontotemporal dementia is uncertain.The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions.In Parkinson's disease,the APOE ε4 allele significantly impacted cognitive performance,increasing the risk of developing dementia,even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease.Similarly,in traumatic brain injury,recovery rates varied,with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms.Furthermore,APOE ε4 influenced the age of onset and severity of stroke,as well as the likelihood of developing stroke-associated dementia,potentially due to its role in compromising endothelial integrity and promoting blood-brain barrier dysfunction.

摘要：Nerve trauma commonly results in chronic neuropathic pain.This is by triggering the release of pro-inflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability.Even without apparent inflammation,injury sites are associated with increased inflammatory markers.This review focuses on how it might be possible to reduce neuropathic pain by reducing inflammation.Physiologically,pain is resolved by a combination of the out-migration of pro-inflammatory cells from the injury site,the down-regulation of the genes underlying the inflammation,up-regulating genes for anti-inflammatory mediators,and reducing nociceptive neuron hyperexcitability.While various techniques reduce chronic neuropathic pain,the best are effective on＜50％of patients,no technique reliably or permanently eliminates neuropathic pain.This is because most techniques are predominantly aimed at reducing pain,not inflammation.In addition,while single factors reduce pain,increasing evidence indicates significant and longer-lasting pain relief requires multiple factors acting simultaneously.Therefore,it is not surprising that extensive data indicate that the application of platelet-rich plasma provides more significant and longer-lasting pain suppression than other techniques,although its analgesia is neither complete nor permanent.However,several case reports indicate that platelet-rich plasma can induce permanent neuropathic pain elimination when the platelet concentration is significantly increased and is applied to longer nerve lengths.This review examines the primary triggers of the development and maintenance of neuropathic pain and techniques that reduce chronic neuropathic pain.The application of platelet-rich plasma holds great promise for providing complete and permanent chronic neuropathic pain elimination.