(1) This study used neural stem cell-conditioned medium, using the telencephalon of fetal rats of embryonic day 14, to induce neural differentiation from Wharton's jelly mesenchymal stem cells. As the neural stem cells were in the development phase there were no glial cells present in the cultures, thus benefiting the induction of Wharton's jelly mesenchymal stem cells.
(2) After microenvironment induction, the cells were further cultured in neural stem cell-conditioned medium supplemented with Dkk-1, a Wnt/β catenin pathway antagonist, and LeftyA, a Nodal signaling pathway antagonist.
(3) Results showed that induced Wharton's jelly mesenchymal stem cells differentiated into bulbous cells with numerous processes and expressed the retinal progenitor cell markers Rx and Pax6.
(4) Results demonstrated that Wharton's jelly mesenchymal stem cells can be induced to differentiate into retinal progenitor cells and may be used as seed cells for the clinical treatment of jury-induced visual diseases.
Human Wharton's jelly mesenchymal stem cells were isolated from fetal umbilical cord. Cells were cultured in serum-free neural stem cell-conditioned medium or neural stem cell-conditioned medium supplemented with Dkk-1, a Wnt/β catenin pathway antagonist, and LeftyA, a Nodal signaling pathway antagonist to induce differentiation into retinal progenitor cells. Inverted microscopy showed that after induction, the spindle-shaped or fibroblast-like Wharton's jelly mesenchymal stem cells changed into bulbous cells with numerous processes. Immunofluorescent cytochemical ing and reverse-transcription PCR showed positive expression of retinal progenitor cell markers, Pax6 and Rx, as well as weakly down-regulated nestin expression. These results demonstrate that Wharton's jelly mesenchymal stem cells are capable of differentiating into retinal progenitor cells in vitro.
(1) In this study, we developed an inertial sensor-based motion tracking system, a tool for evaluation of the functional rehabilitation of upper limbs after central nervous system injury. The motion ing system enabled us to analyze the complex upper limb and head movements in three dimensions according to nine degrees of freedom data from the kinematic models.
(2) The inertial sensor-based motion tracking system can be used to evaluate the functional recovery of the upper limbs after central nervous system injury accurately and stably.
Upper limb function impairment is one of the most common sequelae of central nervous system injury, especially in stroke patients and when spinal cord injury produces tetraplegia. Conventional assessment methods cannot provide objective evaluation of patient performance and the tiveness of therapies. The most common assessment tools are based on rating scales, which are inefficient when measuring small changes and can yield subjective bias. In this study, we designed an inertial sensor-based monitoring system composed of five sensors to measure and analyze the complex movements of the upper limbs, which are common in activities of daily living. We developed a kinematic model with nine degrees of freedom to analyze upper limb and head movements in three dimensions. This system was then validated using a commercial optoelectronic system. These findings suggest that an inertial sensor-based motion tracking system can be used in patients who have upper limb impairment through data integration with a virtual reality-based neuroretation system.
Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats.
(1) The growth hormone/insulin-like growth factor 1 axis is an important anabolic-conditioning tem that plays a critical role in the growth and development of the central nervous system.
(2) Enzyme-linked immunosorbent assay, western blot and reverse transcription-PCR were used to demonstrate the role of sericin in regulating the expression of hippocampal growth mone/insulin-like growth factor 1 in diabetic rats.
(3) Sericin can alleviate diabetic hippocampal damage through improving disorders in the growth hormone/insulin-like growth factor 1.
(1) The mechanism underlying the ability of thioperamide, a selective histamine H3 receptor gonist, to improve neonatal hypoxic-ischemic encephalopathy was investigated to determine if this compound could be a novel therapy for this condition.
(2) A combined application of thioperamide with H1 and H2 receptor antagonists showed that the action of increased brain histamine was mediated through postsynaptic H1 receptors.
Thioperamide, a selective histamine H3 receptor antagonist, can increase histamine content in the brain, improve brain edema, and exert a neuroprotective effect. This study aimed to examine the mechanism of action of thioperamide during brain edema in a rat model of neonatal hypoxic-ischemic encephalopathy. Our results showed that thioperamide significantly decreased brain water content and malondialdehyde levels, while significantly increased histamine levels and superoxide dismutase activity in the hippocampus. This evidence demonstrates that thioperamide could prevent oxidative damage and attenuate brain edema following neonatal hypoxic-ischemic encephalolopathy. We further observed that changes in the above indexes occurred after combined treatment of thioperamide with the H1 receptor antagonist, pyrilamine, and the H2 receptor antagonist, tidine. Experimental findings indicated that pyrilamine reversed the effects of thioperamide; however, cimetidine had no significant influence on the effects of thioperamide. Our present findings suggest that thioperamide can increase brain histamine content and attenuate brain edema and oxidative damage by acting in combination with postsynaptic H1 receptors in a rat model of neonatal ic-ischemic encephalopathy.
(1) 3-N-butylphthalide, a green botanical medicine, is a successfully synthesized and stable chemical drug used for the treatment of ischemic stroke that has independent intellectual property rights in China. Three different stereo-isomers have been identified: l-, dl-, and d-3-n-butylphthalide. The first L-isomer, originally extracted from celery seed, was artificially synthesized from racemic acid, also known as butylphthalide. L-3-n-butylphthalide has been shown to reduce β-amylase-induced neuronal apoptosis and improve cognitive function in Alzheimer's disease animal models.
(2) As a neuroprotective drug for cerebrovascular disease, 3-n-butylphthalide has been confirmed to protect nerve cells in animal experiments of stroke. Because of the significant effects of l-3-n-butylphthalide in the clinical treatment of acute ischemic stroke, this study also adopted l-3-n-butylphthalide for the treatment of vascular dementia.
(3) This is the first report that shows pretreatment with l-3-n-butylphthalide can improve cognitive deficits and neuronal loss in the hippocampus of cerebral repetitive ischemia/reperfusion mice.
(4) L-3-n-butylphthalide may be a potentially beneficial and promising drug for the treatment and prevention of vascular dementia through upregulation of Akt expression in the hippocampus.
As a neuroprotective drug for the treatment of ischemic stroke, 3-n-butylphthalide, a celery seed extract, has been approved by the State Food and Drug Administration of China as a clinical therapeutic drug for ischemic stroke patients. L-3-n-butylphthalide possesses significant efficacy in the treatment of acute ischemic stroke. The activated Akt kinase pathway can prevent the death of nerve cells and exhibit neuroprotective effects in the brain after stroke. This study provides the hypothesis that l-3-n-butylphthalide has a certain therapeutic effect on vascular dementia, and its mechanism depends on the activation of the Akt kinase pathway. A vascular dementia mouse model was established by cerebral repetitive ischemia/reperfusion, and intragastrically administered l-3-n-butylphthalide daily for 28 consecutive days after ischemia/reperfusion, or 7 consecutive days before ischemia/reperfusion. The Morris water maze test showed significant impairment of spatial learning and memory at 4 weeks after operation, but intragastric administration of l-3-n-butylphthalide, especially pretreatment with l-3-n-butylphthalide, significantly reversed these changes. Thionine staining and western blot analylsis showed that preventive and therapeutic application of l-3-n-butylphthalide can reduce loss of pyramidal neurons in the hippocampal CA1 region and alleviate nerve damage in mice with vascular dementia. In addition, phosphorylated Akt expression in hippocampal tissue increased significantly after l-3-n- butylphthalide treatment. Experimental findings demonstrate that l-3-n-butylphthalide has preventive and therapeutic effects on vascular dementia, and its mechanism may be mediated by upregulation of phosphorylated Akt in the hippocampus.
(1) The link between Braintone and pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-XS) has been previously described by Kok-Poh Loh, Wan-Hui Wong and Li-Shan Low from the Department of Pharmacology, National University of Singapore in “Mechanisms of cerebral protection of Chinese herbal extract-Braintone on middle cerebral artery occluded rats”.
(2) This study combined novel in vivo and in vitro experiments to show that Braintone dose- dependently increased the expression of hypoxia inducible factor 1α, heme oxygenase-1 and vascular endothelial growth factor in the ischemic cortex of rats with middle cerebral artery occlusion. The Chinese herbal extract Braintone is composed of Radix Rhodiolase Essence, Radix Notoginseng Essence, Folium Ginkgo Essence and Rhizoma Chuanxiong. Braintone-containing serum increased levels of hypoxia-inducible factor 1α mRNA and protein, and elevated vascular endothelial growth factor mRNA and heme oxygenase-1 protein expression in a dose-dependent manner in human umbilical vein endothelial cells after glucose-oxygen deprivation.
(3) Braintone has a neuroprotective effect, which is mediated by the up-regulation of hypoxia inducible factor 1α, heme oxygenase-1 and vascular endothelial growth factor expression.
This study used a novel combination of in vivo and in vitro experiments to show that Braintone had neuroprotective effects and clarified the molecular mechanisms underlying its efficacy. The Chinese herbal extract Braintone is composed of Radix Rhodiolase Essence, Radix Notoginseng Essence, Folium Ginkgo Essence and Rhizoma Chuanxiong. In vivo experiments showed that cerebral infarction volume was reduced, hemispheric water content decreased, and neurological deficits were alleviated in a rat model of permanent middle cerebral artery occlusion after administration of 87.5, 175 or 350 mg/kg Braintone for 7 consecutive days. Western blot analysis showed that Braintone enhanced the expression of hypoxia-inducible factor 1α, heme oxygenase-1 and vascular endothelial growth factor in the ischemic cortex of these rats. The 350 mg/kg dose of Braintone produced the most dramatic effects. For the in vitro experiments, prior to oxygen-glucose deprivation, rats were intragastrically injected with 440, 880 or 1 760 mg/kg Braintone to prepare a Braintone-containing serum, which was used to pre-treat human umbilical vein endothelial cells for 24 hours. Human umbilical vein endothelial cell injury was alleviated with this pre-treatment. Western blot and real-time PCR analysis showed that the Braintone-containing serum increased the levels of hypoxia-inducible factor 1α mRNA and protein, heme oxygenase-1 protein and vascular endothelial growth factor mRNA in oxygen-glucose deprived human umbilical vein endothelial cells. The 1 760 mg/kg dose produced the greatest increases in expression. Collectively, these experimental findings suggest that Braintone has neuroprotective effects on ischemia-induced brain damage via the up-regulation of hypoxia-inducible factor 1α, heme oxygenase-1 and vascular endothelial growth factor expression in vascular endothelial cells.
(1) Neural stem cells transplanted into tumor-bearing rats can hinder tumor cell growth and proliferation; however, the mechanism remains unclear.
(2) Glioma development and malignant biological characteristics are associated with abnormal signal transduction networks in tumor cells.
(3) This study aimed to explore neural stem cell therapy for glioma from the viewpoint of the Ras/Raf/Mek/Erk pathway. The results showed that transplantation of neural stem cells could inhibit the abnormal activation of Ras/Raf/Mek/Erk signaling, thus promoting apoptosis and potentially treating glioma.
Abnormal activation of the Ras/Raf/Mek/Erk signaling cascade plays an important role in glioma. Inhibition of this aberrant activity could effectively hinder glioma cell proliferation and promote cell apoptosis. To investigate the mechanism of glioblastoma treatment by neural stem cell transplantation with respect to the Ras/Raf/Mek/Erk pathway, C6 glioma cells were prepared in suspension and then infused into the rat brain to establish a glioblastoma model. Neural stem cells isolated from fetal rats were then injected into the brain of this glioblastoma model. Results showed that Raf-1, Erk and Bcl-2 protein expression significantly increased, while Caspase-3 protein expression decreased. After transplantation of neural stem cells, Raf-1, Erk and Bcl-2 protein expression significantly decreased, while Caspase-3 protein expression significantly increased. Our findings indicate that transplantation of neural stem cells may promote apoptosis of glioma cells by inhibiting Ras/Raf/Mek/Erk signaling, and thus may represent a novel treatment approach for glioblastoma.
(1) Hypoxia-inducible factor-1 under hypoxia is a hot topic in the field of neural regeneration research. Under hypoxia and ischemia/reperfusion, heme oxygenase-1 is upregulated by hypoxia-inducible factor-1. The available research mainly focuses on the role of hypoxia-inducible factor-1 and heme oxygenase-1 following acute cerebral ischemia and hypoxia, while very few studies have examined changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway.
(2) This is the first report showing that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is activated and sustained following chronic cerebral ischemia.
(3) Hypoxia-inducible factor-1 and heme oxygenase-1 expression was downregulated by cilostazol in rats subjected to chronic cerebral ischemia. Our findings are the first to show that cilostazol protects against apoptosis in the fontal cortex of chronic cerebral ischemic rats. Cilostazol can provide protection against vascular cognitive impairment through its anti-apoptotic effect.
Hypoxia-inducible factor-1 and its specific target gene heme oxygenase-1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol (30 mg/kg) for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative PCR and western blot analysis showed that hypoxia-inducible factor-1α and heme oxygenase-1 expression levels increased after chronic cerebral ischemia, with hypoxia-inducible factor-1α expression peaking at 3 weeks and heme oxygenase-1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxia-inducible factor-1α may upregulate heme oxygenase-1 expression following chronic cerebral ischemia and that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxia-inducible factor-1α and heme oxygenase-1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an anti-apoptotic mechanism.
(1) Synaptotagmin promotes neurotransmitter release, regulates the transfer of synaptic vesicle to synaptic active zones, and is a key factor in information transfer among neurons.
(2) A rat model of post-stroke depression was established using left middle cerebral artery occlusions in combination of chronic unpredictable stress and solitary housing during development. Experimental rats received intragastric perfusion of Xingnao Jieyu capsules dissolved in distilled water.
(3) The Xingnao Jieyu capsules upregulated synaptotagmin expression in the hippocampi of rats with post-stroke depression, and improved depression symptoms.
The Xingnao Jieyu capsule has been shown to effectively relieve neurologic impairments and lessen depression. It remains poorly understood whether this capsule can be used to treat post-stroke depression. Thus, in the present study, we established a rat model of post-stroke depression using left middle cerebral artery occlusions in combination of chronic unpredictable stress and solitary housing during development. Experimental rats received intragastric perfusion with 0.82, 0.41, and 0.20 g/kg Xingnao Jieyu capsules separately dissolved in 2 mL distilled water. Fluoxetine served as a positive control. The treatment was conducted over 28 days. Sugar water consumption test, open-field test, real-time fluorescent quantitative PCR and immunohistochemical staining results demonstrated that intragastric perfusion with various doses of Xingnao Jieyu capsules increased sugar water consumption, voluntary behaviors and synaptotagmin mRNA and protein expression in rats with post-stroke depression. These therapeutic effects were similar to those of fluoxetine. These results indicate that Xingnao Jieyu capsules upregulate synaptotagmin expression in hippocampi of rats with post-stroke depression, and exert antidepressant effects.