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ABSTRACT: Transplantation of bone marrow stromal cells (BMSCs) reduces astrogliosis, decreases scar thickness and improves neurological functional recovery after brain damage. It is believed that transplanted BMSCs have a profound influence on astrocytes. To obtain the possible mechanism in their interaction, a co-culture system between BMSCs and astrocytes were set to investigate whether BMSCs could modulate cell cycle machinery in reactive astrocytes. The results obtained showed cell cycle regulatory proteins, cdk4 along with its activator cyclin D1, and PCNA increased while p27, an endogenous cyclin-dependent kinase inhibitor, deceased in glutamate-treated astrocytes in vitro. However, BMSCs influenced cell cycle elements in the cocultured astrocytes: cyclin D1, cdk 4 and PCNA were downregulated, while p27 was unregulated. Flow cytometry showed astrocytes in the S phase after glutamate incubation increased to 17.4±2.0% while restored to a level of 7.8±1.1% when cocultured with BMSCs. l-Canavanine, an inhibitor of inducible nitric oxide synthase, partially reversed the S phase to 11.3±0.4% in the cocultured astrocytes. These data indicated that BMSCs might inhibit the cell cycle control system in reactive astrocytes and nitric oxide signaling was involved in this process. The decline of astrogliosis conferred by BMSCs may derive from their effect of inhibiting the cell cycle progression in astrocytes.
Neuroscience Letters 06/2012; 522(1):62-6. · 2.11 Impact Factor
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ABSTRACT: Stress and various stress hormones, including catecholamines and glucocorticoids, have recently been implicated in the pathogenesis of Alzheimer's disease (AD), which represents the greatest unresolved medical challenge in neurology. Angiotensin receptor blockers have shown benefits in AD and prone-to-AD animals. However, the mechanisms responsible for their efficacy remain unknown, and no studies have directly addressed the role of central angiotensin II (Ang II), a fundamental stress hormone, in the pathogenesis of AD. The present study focused on the role of central Ang II in amyloidogenesis, the critical process in AD neuropathology, and aimed to provide direct evidence for the role of this stress hormone in the pathogenesis of AD.
Increased central Ang II levels during stress response were modeled by intracerebroventricular (ICV) administration of graded doses of Ang II (6 ng/hr low dose, 60 ng/hr medium dose, and 600 ng/hr high dose, all delivered at a rate of 0.25 µl/hr) to male Sprague Dawley rats (280-310 g) via osmotic pumps. After 1 week of continuous Ang II infusion, the stimulation of Ang II type 1 receptors was accompanied by the modulation of amyloid precursor protein, α-, β-and γ-secretase, and increased β amyloid production. These effects could be completely abolished by concomitant ICV infusion of losartan, indicating that central Ang II played a causative role in these alterations.
Central Ang II is essential to the stress response, and the results of this study suggest that increased central Ang II levels play an important role in amyloidogenesis during stress, and that central Ang II-directed stress prevention and treatment might represent a novel anti-AD strategy.
PLoS ONE 01/2011; 6(1):e16037. · 4.09 Impact Factor
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ABSTRACT: Transplantation of bone marrow stromal cells (BMSCs) improves animal neurological functional recovery after stroke. But the mechanism remains unclear. As cell cycle machinery plays an important role in stroke, we investigated the dynamic changes of cell cycle elements in a rat model of middle cerebral artery occlusion. We found the cell cycle markers, cdk4 along with its activator cyclin D1, and proliferating cell nuclear antigen (PCNA), increased after brain ischemia-reperfusion. Phosphorylation of the retinoblastoma protein (pRb, on ser-795), the cyclin D/cdk4 complex mutual target, was upregulated accordingly. However, intravenously administrated BMSCs facilitated cyclin D1, cdk4, and PCNA decrease in the ischemic cortex. Meanwhile, phospho-pRb (ser-795) was completely inhibited. On the contrary, endogenous cdk inhibitor p27 reduced before but enhanced after BMSCs treatment. These findings suggested BMSCs might modulate cell cycle progression in injured brain via downregulation of the cyclin D1/cdk4/pRb pathway as well as upregulation of p27 level. These results provide another way by which BMSCs may contribute to the recovery from stroke.
Neuroscience Letters 10/2009; 467(1):15-9. · 2.11 Impact Factor
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ABSTRACT: Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3'-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Abeta) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Abeta(25-35)-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Abeta(25-35)-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Abeta(25-35)-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.
Neuroscience Letters 12/2008; 450(2):142-6. · 2.11 Impact Factor
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ABSTRACT: To explore the re-expression of cell cycle related proteins and delayed neuronal death after chronic cerebral hypoperfusion in rats and to investigate the relationship between aberrant expression of cell cycle proteins and apoptotic cell death.
Rat model of chronic cerebral hypoperfusion was established by permanent bilateral common carotid arteries occlusion (2VO) in the retired rats. The apoptotic cells were assessed by TUNEL method. The expression of cell cycle related proteins, i.e. CDK4 and cyclin B1, were detected by immunohistochemical staining and Western blotting. A cyclin-dependent kinases (CDKs) inhibitor, roscovitine, was intracerebroventricularly administered 1 day before 2VO insult. Spatial learning behavior was assessed by the Morris water maze 7, 14 and 21 days after the surgery.
Aberrant expression of CDK4 and cyclin B1 became present 7 days after 2VO insult surgery and last for a long period. On the other hand, TUNEL positive cells appeared as early as 14 days after the surgery and peaked at day 21. Furthermore, roscovitine significantly improve behavioral deficit in the Morris water maze test 7 and 14 days after the surgery.
These findings indicated that aberrant expression of CDK4 and cyclin B1 takes place in the brain after chronic cerebral hypoperfusion in retired rat, and aberrant expression of cell cycle proteins preceded neuronal death in this model. Our data also suggest that the CDK inhibitor, roscovitine, has therapeutic potential for the treatment of dementia caused by chronic cerebral hypoperfusion.
Neurological Research 10/2008; 30(9):932-9. · 1.52 Impact Factor
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ABSTRACT: Accumulating evidence suggests that the angiotensin-(1-7) [Ang-(1-7)], is an active member of the brain renin-angiotensin system (RAS). We evaluated the possibility that intracerebroventricular (ICV, lateral ventricle) infusion of exogenous Ang-(1-7) could participate in the potentiation of bradykinin (BK) release and the kinin receptor expression in ischemic brain parenchyma after focal cerebral ischemia-reperfusion in rats. The middle cerebral artery occlusion (MCAO) and sham-operated models were prepared, continuously administrated with Ang-(1-7) or artificial cerebrospinal fluid (aCSF) by implanted Alzet osmotic minipumps into lateral cerebral ventricle after reperfusion in male Sprague-Dawley (SD) rats. Experimental animals were divided into sham-operated group (sham+aCSF), aCSF treatment group (MCAO+aCSF) and Ang-(1-7) treatment groups [MCAO+Ang-(1-7)] at low (1 pmol/0.5 microl/h), medium (100 pmol/0.5 microl/h) or high (10 nmol/0.5 microl/h) dose levels. Cerebral infarction resulted in a significant increase of BK formation from 3 h to 6 h compared with sham-operated group after reperfusion, whereas medium- and high-dose Ang-(1-7) infusion markedly enhanced BK levels from 6 h to 48 h after reperfusion. Medium- and high-dose Ang-(1-7) infusion markedly increased kinin B(2) receptor mRNA and protein expression, whereas only high-dose Ang-(1-7) infusion induced upregulating the expression of B(1) receptor. Low-dose Ang-(1-7) infusion did not modify both the kinin B(1) and B(2) receptor expression compared with aCSF treatment group after focal cerebral ischemia-reperfusion at each time point. The finding might indicate complex interactions between Ang-(1-7) and kallikrein-kinin system in the CNS after focal cerebral ischemia-reperfusion in rats.
Brain Research 08/2008; 1219:127-35. · 2.73 Impact Factor
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ABSTRACT: Recent reports suggest that bone marrow stromal cells may be induced into neural cells both in vivo and in vitro. The factors that regulate the neural differentiation and the mechanism involved, however, remains unclear. Here we demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF), a potent hematopoietic factor, was able to enhance the neural differentiation of bone marrow stromal cells. Moreover, we found that GM-CSF receptors are abundantly distributed in the bone marrow stromal cells and GM-CSF significantly upregulated the phosphorylation of cAMP-responsive element binding protein in bone marrow stromal cells. These findings suggest that GM-CSF may activate its receptor and then enhance neural differentiation of bone marrow stromal cells by upregulating phosphorylation of cAMP-responsive element binding protein.
Neuroreport 08/2007; 18(11):1113-7. · 1.66 Impact Factor
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a good model for human multiple sclerosis (MS) research. However, there are some defects in the traditional models. Here, we improved the model by using the human myelin basic protein (MBP) as antigen. EAE was induced by immunization of female Wistar rats with human MBP. Compared with the traditional models, the new model was evaluated by clinical signs to pathological changes. The immune state of the model was assessed by the lymphocyte infiltrative response and levels of TNF-alpha, IFN-gamma, IL-10. It was found that most of rats exhibited tail tone loss and hind-limb paralysis, also there were demyelination, infiltrative lymphocyte foci, "neuronophagia" in the cortex of cerebra and the white matter of spinal cords. PBMCs and spleen lymphocytes were strongly responsive to the stimulation of MBP and PHA. The levels of TNF-alpha and IFN-gamma were altered with the severity of EAE. In the remitting phase, IL-10 was increased significantly. This study demonstrates that the animal model of EAE induced by human MBP bears resemblance to the features of human multiple sclerosis and promises to be a better model than ever before for the study of MS.
Cellular & molecular immunology 11/2004; 1(5):387-91. · 2.99 Impact Factor
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ABSTRACT: Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide of the renin-angiotensin system with several beneficial effects that are often opposite to those attributed to angiotensin II (Ang II). Since there are no data available so far on the role of Ang-(1-7) after cerebral ischemia/reperfusion, in this paper, we investigated the central administration of Ang-(1-7) modulates in vivo the nitric oxide(NO) release and the endothelial NO synthase (eNOS) expression following focal cerebral ischemia/reperfusion in rats. Cerebral ischemia-reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. The levels of NO in ischemic tissues were measured by NO detection kits. Reverse transcription (RT)-PCR and western blot were used to determine messenger RNA (mRNA) and protein levels of the eNOS in ischemic tissues. The cerebral ischemic lesion resulted in a significant increase of NO release at 3 and 6h compared with sham operation group in our model after reperfusion, whereas both medium and high doses Ang-(1-7) markedly enhanced NO levels at 3-24h, and 3-72h after reperfusion, respectively. In addition, NO release increased was significantly induced by high-dose Ang-(1-7) compared with medium-dose Ang-(1-7) at 24-72 h after reperfusion. Medium and high-dose Ang-(1-7) significantly stimulated eNOS activation when compared with artificial cerebrospinal fluid (aCSF) treatment group at 3, 6, 12, 24, and 48h after reperfusion, however, no significant changes in eNOS expression were found between medium and high-dose Ang-(1-7) at different times after the ischemic insult. These findings indicate that medium and high-dose Ang-(1-7) stimulate NO release and upregulate eNOS expression in ischemic tissues following focal cerebral ischemia/reperfusion in rats.
Neuropeptides 42(5-6):593-600. · 1.55 Impact Factor
