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.

MicroRNAs of microglia： wrestling with central nervous system disease

Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transcriptional regulation. Indeed, evidence shows that microRNAs are one of the most important regulators mediating microglial activation, polarization, and autophagy, and subsequently affecting neuroinflammation and the outcome of central nervous system disease. In this review, we provide insight into the function of microRNAs, which may be an attractive strategy and influential treatment for microglia-related central nervous system dysfunction. Moreover, we comprehensively describe how microglia fight against central nervous system disease via multiple functional microRNAs.

The Olig family affects central nervous system development and disease

Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system develop- ment and related diseases.

Glymphatic system:a gateway for neuroinflammation

The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic diseases.Systemic diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous system.This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation.In addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and neurodegeneration.Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.

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.

Clinical manifestations and gene mutation in a case of Machado-Joseph disease

This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Crania MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 （ATXN3） gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history.

Circular RNAs:Diagnostic and Therapeutic Perspectives in CNS Diseases

Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and pathology.In particular,accumulating data on circRNA functions in various central nervous system(CNS)diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders.In this review,we focus on the regulatory and functional roles of circRNAs in CNS diseases,highlighting their diagnostic and therapeutic potential,with the aim of providing new insights into CNS diseases.

Treatment outcome in children with central nervous system-positive Burkitt lymphoma using only intrathecal and systemic chemotherapy combined with rituximab

Background:With current chemotherapy treatment,>90%of survival has been obtained for Burkitt lymphoma(BL).In this study,the demographic characteristics and treatment outcomes are presented for 78 children in China with central nervous system-positive(CNS+)BL.Methods:This retrospective study consecutively enrolled 78 CNS+BL patients in Beijing Children’s Hospital(BCH)from 2007 to 2019 who received the BCH B-cell non-Hodgkin’s lymphoma regimen(modified by French-American-British mature lymphoma B-cell 96[FAB/LMB96]C1 arm±rituximab).Clinical characteristics,methods of disease detection in the CNS,and outcomes were evaluated.Univariate and multivariate analyses were used to assess prognostic factors.Results:The median age of 65 boys and 13 girls at the time of diagnosis was 5.7 years(ranging from 1 to 14 years).Patients were followed up for a median time of 34 months(ranging from 1 to 72 months).Bone marrow invasion was found in 38(48.7%)patients.There were 48(61.5%),44(56.4%),and 25(32%)patients with cranial nerve palsy,intracerebral mass(ICM),and parameningeal extension,respectively.Abnormal cerebrospinal fluid(CSF)morphology and CSF immunophenotype appeared in 15(19.2%)and 15(19.2%)patients,respectively.There were 69(88.5%)patients treated with chemotherapy combined with rituximab,and nine patients were treated solely with chemotherapy.Finally,five patients died of treatment-related infection,recurrence occurred for 13,and one developed a second tumor.The 3-year overall survival and event-free survival rates were 78.9%±4.7%and 71.4%±6.0%,respectively.Treatment with chemotherapy only,ICM positivity,and>4 organs involved at diagnosis were independent risk factors.Conclusions:Rituximab combined with a modified LMB96 regimen has greatly increased the efficacy of treatment for Chinese children with CNS+BL,and with the continuous collection of outcome data,treatment-related complications are decreasing.For further verification,a large sample multicentre randomized controlled study should be performed to explore a treatment scheme for Chinese children with even greater efficacy.

Neurocutaneous melanosis with an intracranial cystic-solid meningeal melanoma in an adult:A case report and review of literature

BACKGROUND Neurocutaneous melanosis(NCM)is a rare congenital,nonhereditary neurocutaneous syndrome that mainly occurs in children;adult NCM is very rare.Due to its rarity,the clinical features and treatment strategies for NCM remain unclear.The purpose of this study was to explore the clinical features,diagnosis,treatment and prognosis of NCM in adults.Most intracranial meningeal melanomas are solid masses,and cystic-solid malignant melanomas are very rare.Due to the lack of data,the cause of cystic changes and the effect on prognosis are unknown.CASE SUMMARY A 41-year-old woman was admitted to the hospital with intermittent headache for 1 mo.Magnetic resonance imaging(MRI)showed a 4.7 cm×3.6 cm cystic-solid mass in the left temporal lobe with peritumoral edema.The entire mass was removed,and postoperative pathology indicated malignant melanoma.CONCLUSION MRI is the first-choice imaging approach for diagnosing central nervous system diseases in NCM patients,although cerebrospinal fluid may also be used.At present,there is no optimal treatment plan;gross total resection combined with BRAF inhibitors and MEK inhibitors might be the most beneficial treatment.

Acupuncture for neurological disorders in the Cochrane reviews Characteristics of included reviews and studies

OBJECTIVE： To summarize Cochrane reviews of acupuncture for neurological disorders, and characteristics of included reviews and studies. DATA SOURCES： A computer-based online search of the Cochrane Library （Issue 7 of 12, July 2010） was performed with the key word ＂acupuncture＂ and systematic evaluations for acupuncture for neurological disorders were screened. STUDY SELECTION： Systematic reviews on acupuncture in the treatment of neurological disorders were included, and the characteristics of these reviews were analyzed based on methods recommended by the Cochrane collaboration. MAIN OUTCOME MEASURES： Basic characteristics, methodological quality, main reasons for excluding trials, results and conclusions of Cochrane reviews were assessed. RESULTS： A total of 18 Cochrane systematic reviews were included, including 13 completed reviews and five research protocols. The 13 completed reviews involved 111 randomized controlled trials, including 43 trials （38.7%） conducted in China, 47 trials （42.3%） using sham-acupuncture or placebo as control, 15 trials （13.5%） with relatively high quality, 91 trials （81.9%） reporting data on follow-up. Primary outcomes used in the Cochrane reviews were reported by 65 trials （58.6%）, and adverse events were reported in 11 trials （9.9%）. Two hundred and eighty three trials were excluded. Two reviews on headache suggested that acupuncture is a valuable non-drug treatment for patients with chronic or recurrent headache, and has better curative effects on migraine compared with preventative drug treatment. CONCLUSION： Of the Cochrane reviews on acupuncture in the treatment of neurological disorders, two reviews evaluating the efficacy of acupuncture in treating headaches drew positive conculsions, while other reviews did not obtain positive conclusions due to a small sample size or low methodological quality. The methodological quality of acupuncture trials needs further improvement.

Shuanghuanglian injection downregulates nuclear factor-kappa B expression in mice with viral encephalitis

A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.

Value of sympathetic skin response test in the early diagnosis of diabetic neuropathy

Background Diabetic neuropathy is common in diabetes mellitus. The early stage of diabetic neuropathy is often symptomless and difficult to be treated. The aim of this study was to assess the correlation between the results of the sympathetic skin response (SSR) test and the development of diabetic neuropathy, and explore the use of SSR as an objective basis for the early diagnosis of diabetic neuropathy. Methods The latencies and amplitudes of initiation and of the N and P waves were determined by SSR testing of the extremities of 80 diabetic patients and 30 healthy controls. Results The latencies of initiation and of the N and P waves were significantly (P<0.001) longer in diabetic patients than in the controls, while there was no significant difference in the amplitudes (P>0.05). All but two patients (97.5%) demonstrated abnormal SSR in at least one limb. Conclusions SSR can detect early dysfunction of the small sympathetic fibers in people affected by diabetes mellitus, and may be a useful electrophysiological test for the early diagnosis of diabetic neuropathy.