Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Metaverse for mental health disorders:Opportunities and challenges

Several articles on the mental health impact of the metaverse and the need to balance its potential benefits with the risks of metaverse use has recently published.The metaverse consists of a combination of immersive technologies and artificial intelligence algorithms.The metaverse differs from the preceding digital psychiatric interventions due to its complex structure and interactions between components.The diverse functions of the metaverse ensure that it may have a substantial impact on mental health.However,the evidence for its efficacy in treating mental health disorders is limited to a few trials.The mental health benefits of immersive technologies are well-documented and suggest that metaverse-based psychiatric treatment may be similarly efficacious.The mental health risks of the metaverse are largely unknown,and it is not clear whether they will be greater than other digital psychiatric interventions.Much more research is needed to determine whether metaverse-based psychiatric treatment will meet the standards of appropriate mental healthcare.

Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

Microglia lactylation in relation to central nervous system diseases

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Lipid droplets in the nervous system:involvement in cell metabolic homeostasis

Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Heterogeneity of mature oligodendrocytes in the central nervous system

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

High mobility group box 1 in the central nervous system:regeneration hidden beneath inflammation

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.

Experimental Podophyllotoxin (Bajiaolian) Poisoning:——Ⅰ. Effects on the Nervous System

Bajiaolian, one of the species in the Mayapple family ( Podophyllum pelatum ), has been widely used as a traditional Chinese herbal medicine for the remedies of snake bites, general weakness, poisons, condyloma accuminata, lymphadenopathy, and certain tumors in China. In Western medicine, Podophyllum was first used medically as a laxative in the early 19th century. Since 1940, the resin of podophyllum has also been used topically for various skin lesions, such as warts and condyloma. Human poisonings have been reported.An animal model was established to investigate the neurotoxic effects of Bajiaolian. Podophyllotoxin, the major active ingredient in Podophyllum, was injected (ip) to young adult male rats at doses of 0, 5, 10, or 15 mg-kg-1 b.w.. The animals were sacrificed 72 h after injection.Neuronal changes were readily observable in animals treated with 10 or 15 mg-kg-1 of the toxin. Edematous changes of the anterior horn motoneurons were observed in the spinal cord. No neuronal necrosis was found. The type of neuronal swelling is believed to be only a transient change and would probably subside with time if no further assaults occur. More serious and perhaps longer term of changes were found in the dorsal ganglion neurons and the nerve fibers (axons) in the central and peripheral nervous system. Severe depletion of the Nissl substance (RNA/polyribosomes) was observed in the dorsal root ganglion neurons. Alterations in these sensory neurons would give rise to and correlate with the sensory disturbances experienced by the patients. Bodian staining also revealed a dose-related increase in the coarseness (thickness) of the nerve fibers (axons) in the cerebellum, cerebral cortex, brainstem, and spinal cord.This is the first scientific study showing the neurotoxicity of Bajiaolian, a commonly used Chinese herbal medicine. Toxicities on other organ systems by this drug certainly exist. Caution should be exercised in the dispensing and usage of this medicine.

Detrimental impact of hyperlipidemia on the peripheral nervous system A novel target of medical epidemiological and fundamental research study

Recently, epidemiological studies on the etiology of peripheral neuropathies have revealed that hyperlipidemia is a novel risk factor. Plasma lipid levels were confirmed to be associated with the incidence of many peripheral neuropathies including axonal distal polyneuropathy, vision and hearing loss, motor nerve system lesions and sympathetic nerve system dysfunction. Moreover, different lipid components such as cholesterol, triacylglycerols and lipoprotein are involved in the pathogenesis of these neuropathies. This review aimed to discuss the effect of hyperlipidemia on the peripheral nervous system and its association with peripheral neuropathies. Furthermore, a detailed discussion focusing on the explicit mechanisms related to hyperlipidemia-induced peripheral neuropathies is presented here. These mechanisms, including intracellular oxidative stress, inflammatory lesions, ischemia and dysregulation of local lipid metabolism, share pathways and interact mutually. In addition, we examined current information on clinical trials to prevent and treat peripheral neuropathies caused by hyperlipidemia, with a predictive discussion regarding the orientation of future investigations.

VEGF in the nervous system: an important target for research in neurodevelopmental and regenerative medicine

Vascular endothelial growth factor（VEGF）in neurodevelopment and regeneration：VEGF is a well-known factor that promotes vascularization and angiogenesis.Besides this it participates in the pathogenesis of several diseases,such as colorectal carcinoma,lung cancer or diabetic retinopathy.Within the last decade,VEGF has been successfully integrated into the treatment of such diseases,for example as a therapy for colorectal cancer with the VEGF-receptor （VEGFR）-inhibitor axitinib.

Experimental Study of the Effect of Autonomic Nervous System on the Transmural Dispersion of Ventricular Repolarization under Acute Myocardial Ischemia in Vivo

The effect of the autonomic nerves on the transmural dispersion of ventricular repolarization(TDR)under acute myocardial ischemia in intact canine was investigated.Using the monophasic action potential(MAP)recording technique,MAPs of the epicardium(Epi),midmyocardium(Mid)and endocardium(Endo)were recorded simultaneously by specially designed plunge-needle electrodes at the left ventricular free wall under acute myocardial ischemia in 12 open-chest dogs.MAPD 90 and TDR among three myocardial layers as well as the incidence of the early afterdepolarization(EAD)before autonomic nervous stimulation and during autonomic nervous stimulation were compared.It was found that 10 min after acute myocardial ischemia,TDR was increased from 55±8 ms to 86±15 ms during sympathetic stimulation(P<0.01).The TDR(53±9 ms)during parasympathetic stimulation was not significantly different from that of the control(55±8 ms)(P>0.05).The EAD was elicited in the Mid of 2 dogs(16%)10 min after acute myocardial ischemia,but the EAD were elicited in the Mid of 7 dogs(58%)during sympathetic stimulation(P<0.01).It was concluded that:(1)Sympathetic stimulation can increase the transmural dispersion of repolari-zation and induce early afterdepolarizations in the Mid under acute myocardial ischemia,which provide the opportunity for the ventricular arrhythmia developing;(2)Parasympathetic stimulation has no significant effect on the transmural dispersion of repolarization under myocardial ischemia.

Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

Mental health in the virtual world:Challenges and opportunities in the metaverse era

Current rates of mental illness are worrisome.Mental illness mainly affects females and younger age groups.The use of the internet to deliver mental health care has been growing since 2020 and includes the implementation of novel mental health treatments using virtual reality,augmented reality,and artificial intelligence.A new three dimensional digital environment,known as the metaverse,has emerged as the next version of the Internet.Artificial intelligence,augmented reality,and virtual reality will create fully immersive,experiential,and interactive online environments in the metaverse.People will use a unique avatar to do anything they do in their“real”lives,including seeking and receiving mental health care.In this opinion review,we reflect on how the metaverse could reshape how we deliver mental health treatment,its opportunities,and its challenges.

Crosstalk among mitophagy,pyroptosis,ferroptosis,and necroptosis in central nervous system injuries

Central nervous system injuries have a high rate of resulting in disability and mortality;however,at present,effective treatments are lacking.Programmed cell death,which is a genetically determined fo rm of active and ordered cell death with many types,has recently attra cted increasing attention due to its functions in determining the fate of cell survival.A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage.In this review,we provide an ove rview of the role of programmed cell death in central nervous system injuries,including the pathways involved in mitophagy,pyroptosis,ferroptosis,and necroptosis,and the underlying mechanisms by which mitophagy regulates pyroptosis,ferroptosis,and necro ptosis.We also discuss the new direction of therapeutic strategies to rgeting mitophagy for the treatment of central nervous system injuries,with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury.In conclusion,based on these properties and effects,interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.

Therapeutic effect of the metaverse on mental health

López del Hoyo et al collections reported the meta verse based on the virtual reality,augmented reality and artificial intelligence could be used in the therapy of mental health,although there were still some challenges.This manuscript reported that the meta verse is a prospective method to improve the prognosis of mental health problems.

Shifting the Paradigm:A Fresh Look at Physical Activity Frequency and Its Impact on Mental Health,Life Satisfaction,and Self-Rated Health in Adolescents

As adolescent mental health problems are becoming a more serious issue globally,this paper explores the relationship of physical activity in adolescents and its frequency on mental health as well as examines the mediating effects of life satisfaction and self-rated health in order to provide a reference for the promotion of mental health in adolescents.A sample of 3578 Chinese high school students completed questionnaires assessing their mental health,physical activity frequency,life satisfaction,and self-rated health.The mean SCL-90 value for adolescents was found to be 1.629%,and 24.73%of adolescents had varying degrees of mental health issue.Increased physical activity frequency is positively associated with improved mental health(p<0.001).Additionally,life satisfaction and self-rated health were found to play significant mediating roles in the relationship between physical activity frequency and mental health.Specifically,low-frequency physical activity had the most pronounced mediating effect on mental health through life satisfaction,while high-frequency physical activity exerted the most significant mediating effect on mental health through self-rated health.These findings underscore the importance of promoting physical activity among adolescents and highlight the distinct pathways through which physical activity frequency can influence mental health outcomes.Further research is needed to explore these relationships in diverse populations and settings,as well as to develop targeted intervention.

Oligodendrocytes in central nervous system diseases:the effect of cytokine regulation

Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.

Whole-process case management effects on mental state and selfcare ability in patients with liver cancer

BACKGROUND Regarding the incidence of malignant tumors in China,the incidence of liver cancer ranks fourth,second only to lung,gastric,and esophageal cancers.The case fatality rate ranks third after lung and cervical cancer.In a previous study,the whole-process management model was applied to patients with breast cancer,which effectively reduced their negative emotions and improved treatment adherence and nursing satisfaction.METHODS In this single-center,randomized,controlled study,60 randomly selected patients with liver cancer who had been admitted to our hospital from January 2021 to January 2022 were randomly divided into an observation group(n=30),who received whole-process case management on the basis of routine nursing mea-sures,and a control group(n=30),who were given routine nursing measures.We compared differences between the two groups in terms of anxiety,depression,the level of hope,self-care ability,symptom distress,sleep quality,and quality of life.RESULTS Post-intervention,Hamilton anxiety scale,Hamilton depression scale,memory symptom assessment scale,and Pittsburgh sleep quality index scores in both groups were lower than those pre-intervention,and the observation group had lower scores than the control group(P<0.05).Herth hope index,self-care ability assessment scale-revision in Chinese,and quality of life measurement scale for patients with liver cancer scores in both groups were higher than those pre-intervention,with higher scores in the observation group compared with the control group(P<0.05).CONCLUSION Whole-process case management can effectively reduce anxiety and depression in patients with liver cancer,alleviate symptoms and problems,and improve the level of hope,self-care ability,sleep quality,and quality of life,as well as provide feasible nursing alternatives for patients with liver cancer.