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Alzheimer’s disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation Refereed/Peer-reviewed

To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippocampus after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippocampus of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippocampus. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats. Refereed/Peer-reviewed

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of lifelong disabilities worldwide, without effective therapies and clear regulatory mechanisms. MicroRNAs (miRNAs) act as a significant regulator in neuroregeneration and neuronal apoptosis, thus holding great potential as therapeutic targets in HIE. In this study, we established the hypoxia-ischemia (HI) model in vivo and oxygen-glucose deprivation (OGD) model in vitro. Zea-longa score and magnetic resonance imaging were applied to verify HI-induced neuronal dysfunction and brain infarction. Subsequently, a miRNA microarray analysis was employed to profile miRNA transcriptomes. Down-regulated miR-124 was found 24 h after HIE, which corresponded to the change in PC12, SHSY5Y, and neurons after OGD. To determine the function of miR-124, mimics and lentivirus-mediated overexpression were used to regulate miR-124 in vivo and in vitro, respectively. Our results showed that miR-124 overexpression obviously promoted cell survival and suppressed neuronal apoptosis. Further, the memory and neurological function of rats was also obviously improved at 1 and 2 months after HI, indicated by the neurological severity score, Y-maze test, open field test, and rotating rod test. Our findings showed that overexpression of miR-124 can be a promising new strategy for HIE therapy in future clinical practice. Refereed/Peer-reviewed

Staphylococcal biofilms cause many infectious diseases and are highly tolerant to the effects of antimicrobials;this is partly due to the biofilm matrix, which acts as a physical barrier retarding the penetration and reducing susceptibility to antimicrobials, thereby decreasing successful treatment outcomes. In this study, both single and mixed micellar systems based on poly vinyl caprolactam (PCL)-polyethylene glycol (PEG) copolymers were optimised for delivery of chlorhexidine (CHX) to S. aureus, MRSA and S. epidermidis biofilms and evaluated fortheir toxicity using Caenorhabditis elegans. The respective polyethylene glycol (PEG) and poly vinyl caprolactam(PCL) structural components promoted stealth properties and enzymatic responsive release of CHX inside biofilms,leading to significantly enhanced penetration (56%) compared with free CHX and improving the efficacy against Staphylococcus aureus biofilms grown on an artificial dermis (2.4 log reduction of CFU). Mixing Soluplus-based micelles with Solutol further enhanced the CHX penetration (71%) and promoted maximumr eduction in biofilm biomass (> 60%). Nematodes-based toxicity assay showed micelles with no lethal effects as indicated by their high survival rate (100%) after 72 h exposure. This study thus demonstrated that bio-responsivecarriers can be designed to deliver a poorly water-soluble antimicrobial agent and advance the controlof biofilm associated infections. Refereed/Peer-reviewed

Background: Suitable exercise can promote development of cognitive function and improve learning and memory ability of the hippocampus. Nevertheless, mechanisms that elicit these positive effects of exercise are yet needing to be elucidated. IGF2 is known to act as a potent memory and cognitive enhancer, whereas the mechanism by which IGF2 regulates cognitive function related to moderate treadmill exercise remained largely vague.Methods: In the study, rats were subjected to slight, moderate and high intensity treadmill training for 6 weeks. Then, Morris Water maze test was employed to investigate hippocampus-dependent spatial learning and memory ability in rats subjected to different intensity treadmill exercise. Subsequently, the gene chip and Gene Ontology were used for analysis to explore the expression level of IGF2. Furthermore, The TargetScan_7.1, miRDB, and microRNA.org. databases was used to predict the target gene of IGF2. Results: After Morris Water maze test, we found that middle intensity treadmill training could obviously enhance learning and memory function of rats. The qRT-PCR and western blot confirmed that the expression of IGF2 was significantly upregulated in hippocampus after moderate treadmill exercise. Through databases, miRNA-483 was screened and predicted as the target gene of IGF2. Moreover, silencing IGF2 inhibited the neurite growth in the hippocampus of rats, while, miRNA-483-inhibitor ameliorated the silencing IGF2 induced hippocampal neurons impairment to promote the neurite outgrowth.Conclusions: These findings suggested that the treadmill training could enhance the cognitive function, in which the underlying mechanism is involving in elevating the expression level of IGF2 and associated with downregulated miRNA-483. This therefore provide a reliable theoretical explanation on improving cognitive function induced by moderate exercise.

The interplay between mesenchymal stem cells (MSCs) and immune cells has been studied for MSCs isolated from different tissues. However, the immunomodulatory capacity of urine stem cells (USCs) has not been adequately researched. The present study reports on the effect of USCs on peripheral blood lymphocytes. USCs were isolated and characterized before coculture with resting and with anti‐CD3/CD28 bead stimulated lymphocytes. Similarly to bone marrow mesenchymal stem cells (BM‐MSCs), USCs inhibited the proliferation of activated T lymphocytes and induced their apoptosis. However, they also induced strong activation, proliferation, and cytokine and antibody production by B lymphocytes. Molecular phenotype and supernatant analysis revealed that USCs secrete a range of cytokines and effector molecules, known to play a central role in B cell biology. These included B cell‐activating factor (BAFF), interleukin 6 (IL‐6) and CD40L. These findings raise the possibility of an unrecognized active role for kidney stem cells in modulating local immune cells., Kidney derived urine stem cells are equipped to provide B cells survival signals, promoting their activation, proliferation, and antibody production. Molecular phenotype and supernatant analysis revealed that USCs express the adhesion molecule ICAM‐1 and secrete B cell‐activating factor (BAFF), interleukin 6 (IL‐6) and CD40L, raising the possibility of an unrecognized active role for these cells in modulating local immune cells.

Alzheimer's disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation.

Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4–8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a time-dependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity. Refereed/Peer-reviewed

Neural stem/progenitor cells (NSPCs) have a potential to treat various neurological diseases, such as Parkinson's Disease, Alzheimer's Disease, and Spinal Cord Injury. However, the limitation of NSPC sources and the difficulty to maintain their stemness or to differentiate them into specific therapeutic cells are the main hurdles for clinical research and application. Thus, for obtaining a therapeutically relevant number of NSPCs in vitro, it is important to understand factors regulating their behaviors and to establish a protocol for stable NSPC proliferation and differentiation. Coating materials for cell culture, such as Matrigel, laminin, collagen, and other coating materials, can significantly affect NSPC characteristics. This article provides a review of coating materials for NSPC culturing in both two dimensions and three dimensions, and their functions in NSPC proliferation and differentiation, and presents a useful guide to select coating materials for researchers. Refereed/Peer-reviewed

Background Neonatal hypoxic-ischemic encephalopathy (HIE) represents as a major cause of neonatal morbidity and mortality. However, the underlying molecular mechanisms in brain damage are still not fully elucidated. This study was conducted to determine the specific potential molecular mechanism in the hypoxic-ischemic induced cerebral injury. Methods Here, hypoxic-ischemic (HI) animal models were established and primary cortical neurons were subjected to oxygen–glucose deprivation (OGD) to mimic HIE model in vivo and in vitro. The HI-induced neurological injury was evaluated by Zea-longa scores, Triphenyte-trazoliumchloride (TTC) staining the Terminal Deoxynucleotidyl Transferased Utp Nick End Labeling (TUNEL) and immunofluorescent staining. Then the expression of Cytochrome c oxidase subunit 5a (COX5A) was determined by immunohistochemistry, western blotting (WB) and quantitative real time Polymerase Chain Reaction (qRT-PCR) techniques. Moreover, HSV-mediated COX5A over-expression virus was transducted into OGD neurons to explore the role of COX5A in vitro, and the underlying mechanism was predicted by GeneMANIA, then verified by WB and qRT-PCR. Results HI induced a severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats, in corresponding to the decrease on the expression of COX5A in both sides of the brain. What’s more, COX5A over-expression significantly promoted the neuronal survival, reduced the apoptosis rate, and markedly increased the neurites length after OGD. Moreover, Triosephosephate isomerase (TPI) was predicted as physical interactions with COX5A, and COX5A over-expression largely increased the expressional level of TPI. Conclusions The present findings suggest that COX5A plays an important role in promoting neurological recovery after HI, and this process is related to TPI up-regulation.

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family, best characterized for its survival and differentiative effects in the central nervous system. Pro-BDNF, known as the precursor of BDNF, is believed to have opposite functions to mature BDNF (mBDNF). The opposing effects of Pro-BDNF and mBDNF have led researchers to propose a ‘yin’ (Pro-BDNF) and ‘yang’ (mBDNF) model of which, the specific mechanism of its opposing functions is unclear and requires further investigation. In order to elucidate pro-BDNF's explicit role, we established a pro-BDNF knockout (KO) mouse model. This BDNF pro-domain KO mouse model showed significant weight loss, impaired righting reflex, abnormal motor behaviours and short lifespan (less than 22 days), mimicking a Huntington's disease (HD)-like phenotype. ELISA results showed BDNF pro-domain KO not only blocked pro-BDNF, but also significantly affected the level of mBDNF. Abnormal morphologic changes were found in the dentate gyrus (DG) of the hippocampus in pro-BDNF KO mice, and western blot confirmed significant cell apoptosis in pro-BDNF KO mice brains. Furthermore, the expression of glutamic acid decarboxylase 65/67 (GAD65/67) was significantly reduced in pro-BDNF KO mice, indicating impaired inhibitory neurotransmission. Heterozygous (Het) mice showed impaired learning and memory capability and depressive-like behaviours, compared with wild type (WT) mice. Overall, these results support that pro-domain of BDNF is an indispensable part of the BDNF gene; without the proper formation of pro-BDNF, mBDNF cannot be produced successfully and function correctly on its own. Our study also supports the BDNF hypothesis in the pathogenesis of HD Refereed/Peer-reviewed

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of lifelong disabilities worldwide, without effective therapies and clear regulatory mechanisms. MicroRNAs (miRNAs) act as a significant regulator in neuroregeneration and neuronal apoptosis, thus holding great potential as therapeutic targets in HIE. In this study, we established the hypoxia-ischemia (HI) model in vivo and oxygen-glucose deprivation (OGD) model in vitro. Zea-longa score and magnetic resonance imaging were applied to verify HI-induced neuronal dysfunction and brain infarction. Subsequently, a miRNA microarray analysis was employed to profile miRNA transcriptomes. Down-regulated miR-124 was found 24 h after HIE, which corresponded to the change in PC12, SHSY5Y, and neurons after OGD. To determine the function of miR-124, mimics and lentivirus-mediated overexpression were used to regulate miR-124 in vivo and in vitro, respectively. Our results showed that miR-124 overexpression obviously promoted cell survival and suppressed neuronal apoptosis. Further, the memory and neurological function of rats was also obviously improved at 1 and 2 months after HI, indicated by the neurological severity score, Y-maze test, open field test, and rotating rod test. Our findings showed that overexpression of miR-124 can be a promising new strategy for HIE therapy in future clinical practice.