An analysis of stimulation methods used in rehabilitation equipment for children with cerebral palsy.

Objective: This paper summarizes the research progress into stimulation methods used in rehabilitation equipment for pediatric cerebral palsy (CP) for the past 20 years from 2003 to 2023. We also provide ideas for innovative research and development of artificial intelligence-based rehabilitation equipment. Methods: Through a certain search strategy, Keywords are searched in the China National Knowledge Network Database (CNKI), the Wanfang Database knowledge service platform, the Chongqing VIP information service, PubMed, Web of Science, Cochrane, ScienceDirect, Medline, Embase, and IEEE database. A total of 3,049 relevant articles were retrieved, and 49 articles were included that mentioned research and development of rehabilitation equipment. We excluded articles that were not specific to children with CP, were duplicated or irrelevant literature, were missing data, the full article was not available, the article did not describe the method of stimulation used with the rehabilitation equipment on children with CP, were not Chinese and English, and were the types of reviews and commentaries. Results: Physical stimulation is the main stimulation method of rehabilitation equipment for children with CP. Force stimulation is the main mode of physical stimulation, and there are 17 articles that have verified the clinical efficacy of force stimulation-based equipment. Conclusion: Research on the stimulation mode of pediatric cerebral palsy rehabilitation equipment is likely to focus on simulating the force of the Chinese medicine called "tuina manipulation." When this method is combined with artificial intelligence and personalized direction we believe this will lay the foundation for future development of a novel therapy for children with CP.

Enhancing the Development and Growth of Infant Cerebral Palsy Rats Using Selective Spinal Manipulations.

Cerebral palsy (CP) is a refractory pediatric disease with a high prevalence, high disability rate, and difficult treatment. A variety of treatments are currently used for CP. The treatment involves drug and non-drug therapy. Traditional Chinese medicine external therapy is a very distinctive treatment method in non-drug therapy. As one of the external therapies of traditional Chinese medicine, massage is used in treating cerebral palsy and has good efficacy, small side effects, and strong operability. As a part of TCM external therapy, selective spinal manipulation can effectively promote the growth and development of infant rats with cerebral palsy.The operation was mainly divided into four steps: first, the rubbing method was applied to the spine and both sides of the spine for 1 min. The pressing and kneading method was applied to the spine for 5 min, and the muscles on both sides of the spine for 5 min. Second, pressing and kneading the sensitive local acupoints in the spine for 2 min were performed. Thirdly, the affected limb was treated by twisting method for 1 min. Fourth, the rubbing method was applied to a midline from the forehead to the back of the brain for 1 min. This study aimed to use selective spinal manipulation to treat infant rats with cerebral palsy. The weight, Rotarod test, Foot-fault score, and growth hormone of infant rats with cerebral palsy were detected to understand the effect of selective spinal manipulation on the growth and development of infant rats with cerebral palsy. The results showed that it can promote weight gain, improve balance ability and motor function, promote growth and development of infant cerebral palsy rats, promote growth hormone secretion, and increase the temperature of sensitive parts of the back.

Effect and Mechanism of Traditional Chinese Medicine Exercise Therapy on Stroke Recovery.

Stroke is currently the second largest contributor to disability-adjusted life years (DALYs) in developing countries, and it is the third largest contributor to DALYs in developed countries. It requires a large number of resources from the health care system every year, which places a great burden on society, families, and individuals. The treatment of traditional Chinese medicine exercise therapy (TCMET) during stroke recovery has become a hot topic of current research due to its few adverse events and high efficiency. This article sorts out the latest progress of TCMET on the recovery of stroke through the review method and explores its role and mechanism based on existing clinical and experimental studies. TCMET treatment of stroke recovery mainly includes Tai Chi, Baduanjin, Daoyin, Yi Jin Jing, five-fowl play, and six-character tips, which can effectively improve motor function, balance and coordination ability, cognitive dysfunction, nerve function, depression or emotional state, daily living ability, and so on after stroke. The mechanisms of stroke treated by TCMET are discussed, and deficiencies in the literature are discussed and analyzed. It is hoped that some guiding suggestions will be provided for future clinical treatment and experimental studies.

A bibliometric analysis of traditional Chinese non-pharmacological therapies in the treatment of knee osteoarthritis from 2012 to 2022.

Objective: The benefits of traditional Chinese non-pharmacological therapies in the treatment of Knee osteoarthritis (KOA) are receiving increasing attention. Therefore, this study aims to systematically analyze the global research on the treatment of KOA by Chinese traditional non-pharmacological therapies using bibliometric analysis and present the results with a knowledge map form. Methods: Literature related to traditional Chinese non-pharmacological therapies used in the treatment of KOA from 2012 to 2022 was searched from the Web of Science core database and PubMed database. CiteSpace, SCImago Graphica and VOSviewer were used to extract nations, institutions, journals, authors, references, keywords, as well as the most widely used acupoints, therapies and evaluation indexes. Results: A total of 375 literature have been included. 32 countries around the world have participated in the research. China, the United States, and Europe were at the center of the global cooperation network. The most prolific institutions and authors were from China represented by Cun-zhi Liu and Jian-feng Tu of Beijing University of Chinese Medicine, the institution with the highest cited frequency was University of York, and "Osteoarthritis Cartilage" was the most frequently cited journal. The most frequently cited literature was "OARSI guidelines for the non-surgical management of knee, hip, and poly articular osteoarthritis." 22 kinds of Chinese non-pharmacological therapies were used to treat KOA, among which acupuncture was the most commonly used one, and ST36 (Zusanli) and WOMAC were the most commonly selected acupoint and evaluation index. Conclusion: In the past decade, the value of Chinese non-pharmacological therapies in the treatment of KOA has received widespread attention. It was a common concern of global researchers to relieve the pain of KOA patients and restore the quality of life. Under the background that acupuncture accounts for a relatively high proportion, the next step may consider how to make the balanced development of a variety of Chinese non-pharmacological therapies. In addition, the problem of how to eliminate the placebo effect maybe the direction of future research.

A bibliometric analysis of research trends of artificial intelligence in the treatment of autistic spectrum disorders.

Objective: Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder that has become the leading cause of disability in children. Artificial intelligence (AI) is a potential solution to this issue. This study objectively analyzes the global research situation of AI in the treatment of ASD from 1995 to 2022, aiming to explore the global research status and frontier trends in this field. Methods: Web of Science (WoS) and PubMed databese were searched for Literature related to AI on ASD from 1995 to April 2022. CiteSpace, VOSviewer, Pajek and Scimago Graphica were used to analyze the collaboration between countries/institutions/authors, clusters and bursts of keywords, as well as analyses on references. Results: A total of 448 literature were included, the total number of literature has shown an increasing trend. The most productive country and institution were the USA, and Vanderbilt University. The authors with the greatest contributions were Warren, Zachary, Sakar, Nilanjan and Swanson, Amy. the most prolific and cited journal is Journal of Autism and Developmental Disorders, the highest cited and co-cited articles were Dautenhahn (Socially intelligent robots: dimensions of human-robot interaction 2007) and Scassellati B (Robots for Use in Autism Research 2012). "Artificial Intelligence", "Brain Computer Interface" and "Humanoid Robot" were the hotspots and frontier trends of AI on ASD. Conclusion: The application of AI in the treatment of ASD has attracted the attention of researchers all over the world. The education, social function and joint attention of children with ASD are the most concerned issues for global researchers. Robots shows gratifying advantages in these issues and have become the most commonly used technology. Wearable devices and brain-computer interface (BCI) were emerging AI technologies in recent years, which is the direction of further exploration. Restoring social function in individuals with ASD is the ultimate aim and driving force of research in the future.

Pediatric Tuina for functional constipation in children: study protocol for a randomized controlled trail.

BACKGROUND: Functional constipation (FC) is a common functional gastrointestinal disorder, which brings many negative impacts to the children's daily life. Pediatric Tuina has been proved to be a potential therapy for FC. However, the evidence for its effectiveness and safety is insufficient due to the lack of high-quality study. This study aims to evaluate the efficacy and safety of pediatric Tuina for children with FC. METHODS/DESIGN: This study is a randomized, controlled, multicentre, clinical trial. We will include 176 children with FC from five hospitals. The participants will be randomly allocated into two groups: the pediatric Tuina group and the Medilac-Vita group. This study will include a 1-week actual treatment period and a 2-week follow-up period. Primary outcomes are weekly spontaneous bowel movements and weekly complete spontaneous bowel movements. The secondary outcomes are effective rate, stool form, distress sensation, and glycerine enema rate. The assessment will be performed each week. Adverse event will be monitored in the treatment period and follow-up period. DISCUSSION: This study is designed to evaluate the efficacy and safety of pediatric Tuina for children with FC, and we hypothesize that pediatric Tuina is more effective than probiotics. It will provide reliable evidence and support for the treatment of FC by pediatric Tuina. TRIAL REGISTRATION: This protocol was registered in the Chinese Clinical Trial Registry (ChiCTR2100046485). .

A multicenter, randomized controlled trial of massage in children with pediatric cerebral palsy: Efficacy of pediatric massage for children with spastic cerebral palsy.

BACKGROUND: Cerebral palsy is 1 of the diseases critically affecting the health of children. The spasmodic type is the most common, characterized by the increased muscular tension. It often leads to lifelong disability, bringing a heavy economic burden to families and society. As a key treatment in traditional Chinese medicine, pediatric massage has a significant clinical effect on cerebral palsy in children; however, high-quality randomized controlled studies are lacking. The main objective of this study was to evaluate the efficacy of pediatric massage for children with spastic cerebral palsy. METHODS/DESIGN: The study will be a multicenter, single-blinded, randomized-controlled pilot trial. During the period from June 2019 to December 2020, 182 children with spastic cerebral palsy will be randomly divided into experimental and control groups in a 1:1 ratio. The experimental group will undergo the modified selective spinal massage method combined with the basic rehabilitation treatment, while only the basic rehabilitation treatment would be performed for the control group. The intervention period of the study will last 12 weeks, 5 days weekly on weekdays. The primary outcomes include a modified Ashworth scale assessment and gross motor function test. The secondary outcomes include the 4-diagnostic scale of Chinese medicine and children's intelligence. The observation index will be measured during the complete 12 weeks duration after the treatment of the child, that is, before treatment, after 4 weeks of treatment, after 8 weeks, and after 12 weeks of treatment. DISCUSSION: This study aims to evaluate the efficacy of pediatric massage on children with spastic cerebral palsy; if the outcome is positive, it can provide a reference for the further promotion and application of pediatric massage in the treatment of spastic cerebral palsy. TRIAL REGISTRATION: Chinese ClinicalTrials.gov, ID: ChiCTR1900021666. Acupuncture-Moxibustion Clinical Trial Registry, AMCTR: (AMCTR-IPR-19000260) Registered on 04 March 2019.

Chinese Tuina Protects against Neonatal Hypoxia-Ischemia through Inhibiting the Neuroinflammatory Reaction.

Aim. Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of perinatal morbidity and mortality. Chinese Tuina is an effective treatment for HIE, but the molecular mechanisms are yet unknown. This study investigated the effect and mechanisms of Chinese Tuina on the inflammatory response in neonatal HIE rats. Main Methods. 30 male neonatal rats were divided randomly into 3 groups: sham, HIE, and HIE with Chinese Tuina (CHT) groups. The HIE and CHT groups were subjected to left common carotid occlusion and hypoxia at 3 days postnatal (P3). The pups in the CHT group received Chinese Tuina treatment on the next day for 28 days. The weight was measured at P4, P9, P13, P21, and P31. The behavioral functions were determined at P21. The protein expression and the methylation level in promoter regions of TNF-α and IL-10 were determined by Western blotting, immunohistochemistry, and pyrosequencing, respectively, at P33. Key Findings. The weight gain in the HIE group was slow compared with that of the CHT group. The rats in the CHT group performed better both in the balance beam and hang plate experiment. Chinese Tuina inhibited the expression of TNF-α and upregulated the expression of IL-10. Neonatal hypoxic-ischemic injury downregulated the methylation level in promoter regions of TNF-α at all CpG points but not IL-10. However, Chinese Tuina did not change the methylation level in promoter regions of TNF-α and IL-10. Significance. Chinese Tuina protected against HIE through inhibiting the neuroinflammatory reaction. While HIE markedly downregulated the methylation level of TNF-α, the protective effects of Chinese Tuina were independent of the regulation of the methylation level of TNF-α and IL-10.

Pediatric Tuina for promoting growth and development of preterm infants: A protocol for the systematic review of randomized controlled trail.

BACKGROUND: Preterm infants are babies born alive before 37 weeks. Many survived infants concomitant with defects of growth and development, a lifetime of disability usually as following when insufficient intervention. In early intervention of preterm infants, pediatric Tuina shows good effect in many Chinese and some English clinical trials. This systematic review is aimed to evaluate the efficacy and safety of pediatric Tuina for promoting growth and development of preterm infants. METHODS: The electronic databases of Cochrane Library, MEDLINE, EBASE, Web of Science, Springer, World Health Organization International Clinical Trials Registry Platform, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wan-fang database, Chinese Scientific Journal Database, and other databases will be searched from establishment to April 1, 2018. All published randomized controlled trials (RCTs) about this topic will be included. Two independent researchers will operate article retrieval, screening, quality evaluation, and data analyses by Review Manager (V.5.3.5). Meta-analyses, subgroup analysis, and/or descriptive analysis will be performed based on included data conditions. RESULTS: High-quality synthesis and/or descriptive analysis of current evidence will be provided from weight increase, motor development, neuropsychological development, length of stay, days of weight recovery to birthweight, days on supplemental oxygen, daily sleep duration, and side effects. CONCLUSION: This study will provide the evidence of whether pediatric Tuina is an effective early intervention for preterm infants. ETHICS AND DISSEMINATION: There is no requirement of ethical approval and informed consent, and it will be in print or published by electronic copies. TRAIL REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42018090563).

Tuina for children with cerebral palsy: A protocol for a systematic review.

BACKGROUND: Cerebral palsy (CP) describes a group of permanent disorders of movement and posture causing activity limitations, leading the most common movement disorder to children. On recovery of various aspects of CP, massotherapy has a good effect in a great many of Chinese clinical trials. Therefore, we plan to conduct a protocol of systematic review aimed at systematically reviewing all the clinical evidence on the effectiveness of massotherapy for treating CP in children. METHODS: The following electronic databases will be searched from inception to October 1, 2017: Cochrane Library, Web of Science, EBASE, Springer, World Health Organization International Clinical Trials Registry Platform, China National Knowledge Infrastructure, Wan-fang database, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and other sources. All published English and Chinese articles randomized controlled trials (RTCs) will be included. All types of CP of children in the trials will be included in this study and these individuals will be involved as coresearchers to evaluate the efficacy of massothreapy. RevMan V.5.3.5 software will be implemented for the assessment of bias risk, data synthesis, subgroup analysis, and meta-analyses if inclusion conditions are met. Continuous outcomes will be presented as mean difference (MD) or standard mean difference (SMD), while dichotomous data will be expressed as a relative risk. RESULTS: A high-quality synthesis of current evidence of massothreapy for children with CP will be provided from several aspects, including motor function improvement, intellectual development, improvement of self-care ability, and daily living. CONCLUSION: This protocol will present the evidence of whether Tuina threapy is an effective intervention for children with CP. ETHICS AND DISSEMINATION: There is no requirement of ethical approval and it will be in print or disseminated by electronic copies. PROSPERO REGISTRATION NUMBER: CRD42017080342.

Circular RNAs: Isolation, characterization and their potential role in diseases.

Circular RNA (circRNA) generated by alternative splicing represents a special class of non-coding RNA molecule. CircRNAs are abundant in the eukaryotic cell cytoplasm and have a characteristic organization, timing of action and disease specificity. In contrast to linear RNA, circRNAs are resistant to RNA exonuclease. Consequently, circRNA escapes normal RNA turnover and this improves circRNA stability. CircRNAs can be degraded by microRNA (miRNA) and this results in linearization of the circRNA, which can then act as competitor to endogenous RNA. Through interactions with disease-related miRNA, circRNA can play an important regulatory role in specific diseases. Furthermore, circRNAs have significant potential to become new clinical diagnostic markers.

Acupuncture for Children with Cerebral Palsy: A Systematic Review Protocol.

BACKGROUND: Cerebral palsy (CP), a childhood disease of high morbidity and serious harmfulness, has no effective therapies to completely relieve the associated pain. Acupuncture has been used widely in China to alleviate several CP symptoms, such as pain and motion disorders, despite the deficiency of high-quality evidence related to this practice. OBJECTIVE: The aim of this systematic review protocol is to assess the efficacy and safety of acupuncture for the treatment of children with CP. METHODS: The following electronic databases will be searched: Cochrane Library, Web of Science, EBASE, Springer, World Health Organization International Clinical Trials Registry Platform, China National Knowledge Infrastructure, Wan-fang database, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and other sources. All published randomized controlled trials from inception to December 2016 will be included. RevMan V.5.3 software will be implemented for the assessment of bias risk, data synthesis, subgroup analysis, and meta-analyses if inclusion conditions are met. Individuals recruited into the trials will include children with all types of CP, and these individuals will be involved as coresearchers to develop and evaluate the efficacy and safety of acupuncture for the treatment of children with CP. Due to language barriers, only English and Chinese articles will be retrieved. RESULTS: The systematic review will synthesize the available knowledge surrounding acupuncture for children with CP. The findings will be synthesized to determine the efficacy and safety of acupuncture for children with CP. CONCLUSIONS: The review has not been completed. This protocol presents a proper method to implement the systematic review, and ensures transparency for the completed review. Findings from the systematic review will be disseminated in a peer-reviewed journal and results will be presented at relevant conferences. The data of individual patients will not be included, so ethical approval is not required. TRIAL REGISTRATION: PROSPERO registration number: CRD42016038275, http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016038275 (Archived by WebCite at http://www.webcitation/6nGxoJrqm.

Space-time acupuncture for intractable cough after lupus nephropathy: A case report and literature review.

RATIONALE: Some intractable chronic cough remains a common complaint for seeking medical care. Unexplained cough in lupus nephropathy patient is rare and therapeutic options are limited. PATIENT CONCERNS: A 57 year-old woman with a 7-year history of lupus nephropathy. She has suffered from chronic cough for 3 years accompanied with chronic low back pain and fatigue, as the conventional therapy cannot relieve the symptoms. DIAGNOSES: The woman is diagnosed as intractable cough after lupus nephropathy. INTERVENTIONS: 9 times space-time acupuncture (STA) treatment was performed. OUTCOMES: The cough, as well as other uncomfortable symptoms like chronic low-back pain and fatigue have resolved, and no relapse for one year follow-up. LESSONS: STA may be an effective therapy to treat intractable chronic cough.

Acupuncture for osteoporosis: a systematic review protocol.

BACKGROUND: Osteoporosis is a global high prevalence of chronic metabolic disease with serious disability-adjusted life years losing. Acupuncture is used to treat osteoporosis broadly in China and other countries although the evidence on effectiveness cannot give a certain answer. The aim of this systematic review protocol is to appraise the efficacy and safety of acupuncture for osteoporosis. METHODS: A literature search of randomized controlled trials focusing on acupuncture for osteoporosis will be performed in the databases of Medline, Cochrane Library, Web of Science, EBASE, Springer, WHO International Clinical Trials Registry Platform (ICTRP), China National Knowledge Infrastructure (CNKI), Wan fang, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP), and other possible resources with a valid search strategy. Outcomes of pain, bone mineral density, fracture, mortality, improvement proportion, biochemical indicators, quality of life, adverse event, and other valid will be extracted and merged for quantitative analysis using Review Manager software (V.5.3.5) or descriptive analysis correspondingly. DISCUSSION: This is the first systematic review to estimate the effect of acupuncture on osteoporosis, and the result may provide evidence to clinical doctor. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037829.

An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment.

Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer's disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression.

The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation.

Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP.

Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases.

Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are permeating many sectors of disease research. Patient sample-derived iPSCs can be used to construct patient-specific disease models to elucidate the pathogenic mechanisms of disease development and to test new therapeutic strategies. Accordingly, the present review will focus on recent progress in iPSC research in the modeling of neurodegenerative disorders and in the development of novel therapeutic options.

Oleanolic Acid Induces Differentiation of Neural Stem Cells to Neurons: An Involvement of Transcription Factor Nkx-2.5.

Neural stem cells (NSCs) harbor the potential to differentiate into neurons, astrocytes, and oligodendrocytes under normal conditions and/or in response to tissue damage. NSCs open a new way of treatment of the injured central nervous system and neurodegenerative disorders. Thus far, few drugs have been developed for controlling NSC functions. Here, the effect as well as mechanism of oleanolic acid (OA), a pentacyclic triterpenoid, on NSC function was investigated. We found OA significantly inhibited neurosphere formation in a dose-dependent manner and achieved a maximum effect at 10 nM. OA also reduced 5-ethynyl-2'-deoxyuridine (EdU) incorporation into NSCs, which was indicative of inhibited NSC proliferation. Western blotting analysis revealed the protein levels of neuron-specific marker tubulin-ßIII (TuJ1) and Mash1 were increased whilst the astrocyte-specific marker glial fibrillary acidic protein (GFAP) decreased. Immunofluorescence analysis showed OA significantly elevated the percentage of TuJ1-positive cells and reduced GFAP-positive cells. Using DNA microarray analysis, 183 genes were differentially regulated by OA. Through transcription factor binding site analyses of the upstream regulatory sequences of these genes, 87 genes were predicted to share a common motif for Nkx-2.5 binding. Finally, small interfering RNA (siRNA) methodology was used to silence Nkx-2.5 expression and found silence of Nkx-2.5 alone did not change the expression of TuJ-1 and the percentage of TuJ-1-positive cells. But in combination of OA treatment and silence of Nkx-2.5, most effects of OA on NSCs were abolished. These results indicated that OA is an effective inducer for NSCs differentiation into neurons at least partially by Nkx-2.5-dependent mechanism.

Aß(1-42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins.

Accumulating evidence indicates that abnormal deposition of amyloid-ß (Aß) peptide in the brain is responsible for endothelial cell damage and consequently leads to blood-brain barrier (BBB) leakage. However, the mechanisms underlying BBB disruption are not well described. We employed an monolayer BBB model comprising bEnd.3 cell and found that BBB leakage was induced by treatment with Aß(1-42), and the levels of tight junction (TJ) scaffold proteins (ZO-1, Claudin-5, and Occludin) were decreased. Through comparisons of the effects of the different components of Aß(1-42), including monomer (Aß(1-42)-Mono), oligomer (Aß(1-42)-Oligo), and fibril (Aß(1-42)-Fibril), our data confirmed that Aß(1-42)-Oligo is likely to be the most important damage factor that results in TJ damage and BBB leakage in Alzheimer's disease. We found that the incubation of bEnd.3 cells with Aß(1-42) significantly up-regulated the level of receptor for advanced glycation end-products (RAGE). Co-incubation of a polyclonal antibody to RAGE and Aß(1-42)-Oligo in bEnd.3 cells blocked RAGE suppression of Aß(1-42)-Oligo-induced alterations in TJ scaffold proteins and reversed Aß(1-42)-Oligo-induced up-regulation of RAGE, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, we found that these effects induced by Aß(1-42)-Oligo treatment were effectively suppressed by knockdown of RAGE using small interfering RNA (siRNA) transfection. We also found that GM 6001, a broad-spectrum MMP inhibitor, partially reversed the Aß(1-42)-Oligo-induced inhibitor effects in bEnd.3 cells. Thus, these results suggested that RAGE played an important role in Aß-induced BBB leakage and alterations of TJ scaffold proteins, through a mechanism that involved up-regulation of MMP-2 and MMP-9.

EGb761 provides a protective effect against Aß1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model.

Alzheimer's disease (AD) is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aß) accumulation and deposition in brain parenchyma and cerebral capillaries, and leads to blood-brain barrier (BBB) disruption. Despite great progress in understanding the etiology of AD, the underlying pathogenic mechanism of BBB damage is still unclear, and no effective treatment has been devised. The standard Ginkgo biloba extract EGb761 has been widely used as a potential cognitive enhancer for the treatment of AD. However, the cellular mechanism underlying the effect remain to be clarified. In this study, we employed an immortalized endothelial cell line (bEnd.3) and incubation of Aß(1-42) oligomer, to mimic a monolayer BBB model under conditions found in the AD brain. We investigated the effect of EGb761 on BBB and found that Aß1-42 oligomer-induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS), were attenuated by treatment with EGb761. Moreover, treatment of the cells with EGb761 decreased BBB permeability and increased tight junction scaffold protein levels including ZO-1, Claudin-5 and Occludin. We also found that the Aß(1-42) oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE), which mediates Aß cytotoxicity and plays an essential role in AD progression, was significantly decreased by treatment with EGb761. To our knowledge, we provide the first direct in vitro evidence of an effect of EGb761 on the brain endothelium exposed to Aß(1-42) oligomer, and on the expression of tight junction (TJ) scaffold proteins and RAGE. Our results provide a new insight into a possible mechanism of action of EGb761. This study provides a rational basis for the therapeutic application of EGb761 in the treatment of AD.