enhancing-development-growth-infant-cerebral-palsy-rats-using

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 ...

Yunnan University of Traditional Chinese Medicine

Our previous studies demonstrated that the epimedium herb, when simultaneously used with GCs, counteracted suppressive effects of GCs on the HPA axis without adverse influence on the therapeutic action of GCs. Here, total flavones were extracted from the epimedium flavonoids (EFs) and then used to investigate whether EFs provide protective effects on the HPA axis. We found that GCs induced a significant decrease in body weight gain, adrenal gland weight gain, and plasma adrenocorticotropin (ACTH) and corticosterone levels. After treatment with EFs, body weight gain, adrenal gland weight gain, and plasma corticosterone level were significantly restored, whilst plasma ACTH level was partially elevated. EFs were also shown to promote cell proliferation in the outer layer of adrenal cortex and to enhance the migration of newly divided cells toward the inner layer. To elucidate the underlying mechanisms, the mRNA expression of insulin-like growth factor II (IGF-II) was measured, and EFs significantly upregulated IGF-II expression. Our results indicated that EFs counteract the suppression of the HPA axis induced by GCs. This may involve both the ACTH and IGF-II pathways and thereby promote regeneration of the adrenal cortex suggesting a potential clinical application of EFs against the suppressive effects of GCs on the HPA axis.

Epimedium flavonoids counteract the side effects of glucocorticoids on hypothalamic-pituitary-adrenal axis.

Alzheimer's disease (AD) is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aβ) 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 Aβ(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 Aβ1-42 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 Aβ(1-42) oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE), which mediates Aβ 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 Aβ(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.

EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model.

Accumulating evidence indicates that abnormal deposition of amyloid-β (Aβ) 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 Aβ(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 Aβ(1-42), including monomer (Aβ(1-42)-Mono), oligomer (Aβ(1-42)-Oligo), and fibril (Aβ(1-42)-Fibril), our data confirmed that Aβ(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 Aβ(1-42) significantly up-regulated the level of receptor for advanced glycation end-products (RAGE). Co-incubation of a polyclonal antibody to RAGE and Aβ(1-42)-Oligo in bEnd.3 cells blocked RAGE suppression of Aβ(1-42)-Oligo-induced alterations in TJ scaffold proteins and reversed Aβ(1-42)-Oligo-induced up-regulation of RAGE, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, we found that these effects induced by Aβ(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 Aβ(1-42)-Oligo-induced inhibitor effects in bEnd.3 cells. Thus, these results suggested that RAGE played an important role in Aβ-induced BBB leakage and alterations of TJ scaffold proteins, through a mechanism that involved up-regulation of MMP-2 and MMP-9.

Aβ(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.

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.

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

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-βIII (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.

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

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.

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

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.

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

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.

Acupuncture for osteoporosis: a systematic review protocol.

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.

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

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.

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

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.

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

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.

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

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.

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

. 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. . 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- and IL-10 were determined by Western blotting, immunohistochemistry, and pyrosequencing, respectively, at P33. . 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- and upregulated the expression of IL-10. Neonatal hypoxic-ischemic injury downregulated the methylation level in promoter regions of TNF- at all CpG points but not IL-10. However, Chinese Tuina did not change the methylation level in promoter regions of TNF- and IL-10. . Chinese Tuina protected against HIE through inhibiting the neuroinflammatory reaction. While HIE markedly downregulated the methylation level of TNF-, the protective effects of Chinese Tuina were independent of the regulation of the methylation level of TNF- and IL-10.

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

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.

Article	Year
Epimedium flavonoids counteract the side effects of glucocorticoids on hypothalamic-pituitary-adrenal axis. Evidence-based complementary and alternative medicine : eCAM\| PubMed ID: 24174984	2013
EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model. PloS one\| PubMed ID: 25426944	2014
Aβ(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 pro... Journal of neurochemistry\| PubMed ID: 25866188	2015
Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases. Stem cells international\| PubMed ID: 26240571	2015
Oleanolic Acid Induces Differentiation of Neural Stem Cells to Neurons: An Involvement of Transcription Factor Nkx-2.5. Stem cells international\| PubMed ID: 26240574	2015
The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation. Journal of immunology research\| PubMed ID: 27294160	2016
An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment. Journal of immunology research\| PubMed ID: 27493973	2016
Acupuncture for osteoporosis: a systematic review protocol. Systematic reviews\| PubMed ID: 27653783	2016
Acupuncture for Children with Cerebral Palsy: A Systematic Review Protocol. JMIR research protocols\| PubMed ID: 28057608	2017
Circular RNAs: Isolation, characterization and their potential role in diseases. RNA biology\| PubMed ID: 28820337	2017
Tuina for children with cerebral palsy: A protocol for a systematic review. Medicine\| PubMed ID: 29369196	2018
Space-time acupuncture for intractable cough after lupus nephropathy: A case report and literature review. Medicine\| PubMed ID: 29390501	2017
Pediatric Tuina for promoting growth and development of preterm infants: A protocol for the systematic review of randomized controlled trail. Medicine\| PubMed ID: 29718853	2018
Chinese Tuina Protects against Neonatal Hypoxia-Ischemia through Inhibiting the Neuroinflammatory Reaction. Neural plasticity\| PubMed ID: 33488693	2020
Pediatric Tuina for functional constipation in children: study protocol for a randomized controlled trail. Trials\| PubMed ID: 36064720	2022

XianTao Tai

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