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.

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.

Role of CD36 in central nervous system diseases

CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.

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.

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.

Recent Advances for Global Perspectives on Etiology, Pathophysiology, Clinical Presentations, and Management of Moyamoya Disease

Moyamoya disease (MMD) is a condition characterized by the gradual narrowing and blockage of blood vessels in the brain, specifically those in the circle of Willis and the arteries that supply it. This results in reduced blood flow and oxygen to the brain, leading to progressive symptoms and potential complications. The underlying pathophysiological mechanism remains elucidated. However, recent studies have highlighted numerous etiologic factors: abnormal immune complex responses, susceptibility genes, branched-chain amino acids, antibodies, heritable diseases, and acquired diseases, which may be the great potential triggers for the development of moyamoya disease. Its clinical presentation has varying degrees from transient asymptomatic events to significant neurological deficits. Moyamoya disease (MMD) shows different patterns in children and adults. Children with MMD are more susceptible to ischemic events due to decreased blood flow to the brain. Conversely, adults with MMD are more prone to hemorrhagic events involving brain bleeding. Children with MMD may experience a range of symptoms including motor impairments, sensory issues, seizures, headaches, dizziness, cognitive delays, or ongoing neurological problems. Although adults may present with similar clinical symptoms as children, they are more prone to experiencing sudden onset intraventricular, subarachnoid, or intracerebral hemorrhages. One of the challenges in moyamoya disease is the potential for misdiagnosis or delayed diagnosis, particularly when physicians fail to consider MMD as a possible cause in stroke patients. This review aims to provide a comprehensive overview of recent global studies on the pathophysiology of MMD, along with advancements in its management. Additionally, the review will delve into various surgical treatment options for MMD, as well as its rare occurrence alongside atrioventricular malformations. Exciting prospects include the use of autologous bone marrow transplant and the potential role of Connexin 43 protein treatment in the development of moyamoya disease.

Targeting nuclear factor erythroid 2-related factor 2-regulated ferroptosis to treat nervous system diseases

By critically examining the work,we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2(NRF2)in nervous system diseases.We also proposed suggestions for future bibliometric studies,including the integration of multiple websites,analytical tools,and analytical approaches,The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases.Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases.Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems.In particular,nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

Vimentin as a potential target for diverse nervous system diseases

Vimentin is a major type Ⅲ intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout(GFAPVIM) mice. However, attenuated glial scar formation in post-stroke in GFAP–/– VIM–/– mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIMmice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

The complex roles of m^(6)A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases

N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.

Mesenchymal stem cell-derived extracellular vesicles therapy in traumatic central nervous system diseases:a systematic review and meta-analysis

Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the rapy.We comprehensively evaluated the efficacy of mesenchymal stem cell-de rived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies.Our meta-analysis was registered at PROSPERO(CRD42022327904,May 24,2022).To fully retrieve the most relevant articles,the following databases were thoro ughly searched:PubMed,Web of Science,The Cochrane Library,and Ovid-Embase(up to April 1,2022).The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases.The Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies.After screening 2347studies,60 studies were included in this study.A meta-analysis was conducted for spinal co rd injury(n=52) and traumatic brain injury(n=8).The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal co rd injury animals,including rat Basso,Beattie and Bresnahan locomotor rating scale scores(standardized mean difference [SMD]:2.36,95% confidence interval [CI]:1.96-2.76,P <0.01,I2=71%) and mouse Basso Mouse Scale scores(SMD=2.31,95% CI:1.57-3.04,P=0.01,I2=60%) compared with controls.Further,mesenchymal stem cell-de rived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals,including the modified N eurological Severity Score(SMD=-4.48,95% CI:-6.12 to-2.84,P <0.01,I2=79%) and Foot Fault Test(SMD=-3.26,95% CI:-4.09 to-2.42,P=0.28,I2=21%) compared with controls.Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-de rived extra cellular vesicles.For Basso,Beattie and Bresnahan locomotor rating scale scores,the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles(allogeneic:SMD=2.54,95% CI:2.05-3.02,P=0.0116,I2=65.5%;xenogeneic:SMD:1.78,95%CI:1.1-2.45,P=0.0116,I2=74.6%).Mesenchymal stem cellde rived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultra centrifugation(SMD=3.58,95% CI:2.62-4.53,P <0.0001,I2=31%) may be more effective than other EV isolation methods.For mouse Basso Mouse Scale scores,placenta-derived mesenchymal stem cell-de rived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles(placenta:SMD=5.25,95% CI:2.45-8.06,P=0.0421,I2=0%;bone marrow:SMD=1.82,95% CI:1.23-2.41,P=0.0421,I2=0%).For modified Neurological Severity Score,bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs(bone marrow:SMD=-4.86,95% CI:-6.66 to-3.06,P=0.0306,I2=81%;adipose:SMD=-2.37,95% CI:-3.73 to-1.01,P=0.0306,I2=0%).Intravenous administration(SMD=-5.47,95% CI:-6.98 to-3.97,P=0.0002,I2=53.3%) and dose of administration equal to 100 μg(SMD=-5.47,95% CI:-6.98 to-3.97,P <0.0001,I2=53.3%)showed better res ults than other administration routes and doses.The heterogeneity of studies was small,and sensitivity analysis also indicated stable results.Last,the methodological quality of all trials was mostly satisfactory.In conclusion,in the treatment of traumatic central nervous system diseases,mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery.

The Value of Traditional Medicine Should not be Underestimated-Traditional Chinese Medicine in Treatment of Autoimmune Diseases

Autoimmune diseases of the nervous system(ADNS)are characterized by the formation of a pronounced neurologic deficit and often lead to disability.The attention of doctors and researchers is increasingly attracted by complementary medicine as adjuvant or preventive therapy for various diseases,including autoimmune diseases.Traditional Chinese medicine(TCM)is a combination of treatment methods that include acupuncture,herbal medicine,dietetics,physical exercises,and other methods that are often used in conjunction with recognized approaches of official medical science.The article describes the application of TCM techniques in autoimmune diseases of the nervous system,and demonstrates clinical experience in the use of acupuncture,herbal medicine,diets and physical exercises.Traditional and complementary medicine is an important and often underestimated healthcare resource,especially in the prevention and treatment of autoimmune diseases of the nervous system.

Overview of emerging therapies for demyelinating diseases

This paper provides an overview of autoimmune disorders of the central nervous system,specifically those caused by demyelination.We explore new research regarding potential therapeutic interventions,particularly those aimed at inducing remyelination.Remyelination is a detailed process,involving many cell types–oligodendrocyte precursor cells(OPCs),astrocytes,and microglia–and both the innate and adaptive immune systems.Our discussion of this process includes the differentiation potential of neural stem cells,the function of adult OPCs,and the impact of molecular mediators on myelin repair.Emerging therapies are also explored,with mechanisms of action including the induction of OPC differentiation,the transplantation of mesenchymal stem cells,and the use of molecular mediators.Further,we discuss current medical advancements in relation to many myelin-related disorders,including multiple sclerosis,optic neuritis,neuromyelitis optica spectrum disorder,myelin oligodendrocyte glycoprotein antibodyassociated disease,transverse myelitis,and acute disseminated encephalomyelitis.Beyond these emerging systemic therapies,we also introduce the dimethyl fumarate/silk fibroin nerve conduit and its potential role in the treatment of peripheral nerve injuries.Despite these aforementioned scientific advancements,this paper maintains the need for ongoing research to deepen our understanding of demyelinating diseases and advance therapeutic strategies that enhance affected patients’quality of life.

Changes in the etiology of liver cirrhosis and the corresponding management strategies

We read with interest the article by Xing Wang,which was published in the recent issue of the World Journal of Hepatology 2023;15:1294-1306.This article focuses particularly on the prevalence and trends in the etiology of liver cirrhosis(LC),prognosis for patients suffering from cirrhosis-related complications and hepatocellular carcinoma(HCC),and management strategies.The etiology of cirrhosis varies according to geographical,economic,and population factors.Viral hepatitis is the dominant cause in China.Vaccination and effective treatment have reduced the number of people with viral hepatitis,but the overall number is still large.Patients with viral hepatitis who progress over time to LC and HCC remain an important population to manage.The increased incidence of metabolic syndrome and alcohol consumption is likely to lead to a potential exponential increase in metabolic dysfunction-associated steatotic liver disease(MASLD)-associated LC and alcoholic liver disease in the future.Investigating the evolution of the etiology of LC is important for guiding the direction of future research and policy development.These changing trends indicate a need for greater emphasis on tackling obesity and diabetes,and implementing more effective measures to regulate alcohol consumption in order to reduce the occurrence of MASLD.In an effort to help cope with these changing trends,the authors further proposed countermeasures for healthcare authorities doctors,and patients.

Emerging trends and hotspots of Nuclear factor erythroid 2-related factor 2 in nervous system diseases

BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.

Research progress of sphingosine 1-phosphate and its signal transduction in central nervous system diseases

Sphingosine 1-phosphate(S1P),as a sphingolipid metabolite,has become a key substance in regulating various physiological processes,involved in differentiation,proliferation,migration,morphogenesis,cytoskeleton formation,adhesion,apoptosis,etc.process.Sphingosine 1-phosphate can not only activate the S1P-S1PR signaling pathway by binding to the corresponding receptors on the cell membrane,but also play a role in the cell.In recent years,studies have found that there is a certain relationship between its level changes and the occurrence and development of central nervous system diseases.This article reviews the latest knowledge of sphingosine-1-phosphate in the occurrence and treatment of nervous system diseases,and further clarifies its molecular mechanism in the treatment and development of central nervous system diseases.

Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases

As a new type of nerve regulation technology, Vagus Nerve Stimulation is currently used in the treatment of nervous system diseases. Auricular Vagus Nerve Stimulation has become one of the research hotspots in this field, because there is no implantation risk. However, there is no unified standard for the treatment parameters of aVNS for nervous system diseases. In this paper, the research progress of the anatomical structure and parameters of the vagus nerve and its role in nervous system diseases are reviewed to provide basis for further research.

The effects and potential of microglial polarization and crosstalk with other cells of the central nervous system in the treatment of Alzheimer’s disease

Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.

Etiology of inflammatory bowel disease:A unified hypothesis

Inflammatory bowel disease(IBD),including both ulcerative colitis(UC) and Crohn's disease(CD),emerged and dramatically increased for about a century.Despite extensive research,its cause remains regarded as unknown.About a decade ago,a series of findings made me suspect that saccharin may be a key causative factor for IBD,through its inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and over digestion of the mucus layer and gut barrier(the Bacteria-Protease-Mucus-Barrier hypothesis).It explained many puzzles in IBD such as its emergence and temporal changes in last century.Recently I further found evidence suggesting sucralose may be also linked to IBD through a similar mechanism as saccharin and have contributed to the recent worldwide increase of IBD.This new hypothesis suggests that UC and CD are just two symptoms of the same morbidity,rather than two different diseases.They are both caused by a weakening in gut barrier and only differ in that UC is mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess,while CD is mainly due to increased infiltration of antigens and particles from gut lumen and the resultant recruitment of macrophages and formation of granulomas.It explained the delayed appearance but accelerated increase of CD over UC and many other phenomena.This paper aims to provide a detailed description of a unified hypothesis regardingthe etiology of IBD,including the cause and mechanism of IBD,as well as the relationship between UC and CD.

Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.