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1.  Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat 
Background
Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates many processes, including cell growth and the immune response. mTOR is also dysregulated in several neurological diseases, such as traumatic brain injury (TBI), stroke, and neurodegenerative disease. However, the role of mTOR in intracerebral hemorrhage (ICH) remains unexplored. The aims of our study were to determine whether inhibiting mTOR signaling could affect the outcome after ICH and to investigate the possible underlying mechanism.
Methods
A rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and mTOR activation was inhibited by administration of rapamycin. mTOR signaling activation was determined by western blotting. Neurobehavioral deficit after ICH was determined by a set of modified Neurological Severity Scores (mNSS). The levels of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and cytokines were examined using flow cytometry and ELISA, respectively.
Results
Our results demonstrated thatmTOR signaling was activated 30 minutes and returned to its basal level 1 day after ICH. Increased p-mTOR, which mean that mTOR signaling was activated, was predominantly located around the hematoma. Rapamycin treatment significantly improved the neurobehavioral deficit after ICH, increased the number of Tregs, increased levels of interleukin-10 and transforming growth factor-β and reduced interferon-γ both in peripheral blood and brain.
Conclusions
Our study suggests that mTOR improves ICH outcome and modulates immune response after ICH.
doi:10.1186/1742-2094-11-44
PMCID: PMC3975837  PMID: 24602288
ICH; mTOR; Rapamycin; Outcome; Immune response
2.  Glial Scar Formation Occurs in the Human Brain after Ischemic Stroke 
Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.
doi:10.7150/ijms.8140
PMCID: PMC3936028  PMID: 24578611
glial scar; reactive gliosis; ischemic stroke; human; patients
3.  17β-Estradiol Attenuates Poststroke Depression and Increases Neurogenesis in Female Ovariectomized Rats 
BioMed Research International  2013;2013:392434.
Studies have linked neurogenesis to the beneficial actions of specific antidepressants. However, whether 17β-estradiol (E2), an antidepressant, can ameliorate poststroke depression (PSD) and whether E2-mediated improvement of PSD is associated with neurogenesis are largely unexplored. In the present study, we found that depressive-like behaviors were observed at the first week after focal ischemic stroke in female ovariectomized (OVX) rats, as measured by sucrose preference and open field test, suggesting that focal cerebral ischemia could induce PSD. Three weeks after middle cerebral artery occlusion (MCAO), rats were treated with E2 for consecutive 14 days. We found that E2-treated rats had significantly improving ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test, compared to vehicle-treated group. In addition, we also found that BrdU- and doublecortin (DCX)-positive cells in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) were significantly increased in ischemic rats after E2 treatment, compared to vehicle-treated group. Our data suggest that focal cerebral ischemia can induce PSD, and E2 can ameliorate PSD. In addition, newborn neurons in the hippocampus may play an important role in E2-mediated antidepressant like effect after ischemic stroke.
doi:10.1155/2013/392434
PMCID: PMC3838842  PMID: 24307996
4.  Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus 
Aging (Albany NY)  2012;4(9):606-619.
Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells. Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew. By grafting young wild-type (WT) BM progenitors into aged IL-7R−/− hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation. Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.
PMCID: PMC3492225  PMID: 23047952
Hematopoiesis; bone marrow; T-lineage cells; niche cells; microenvironment; thymic stromal cells; aging; competitive repopulation
5.  Notch-1 signalling is activated in brain arteriovenous malformations in humans 
Brain  2009;132(12):3231-3241.
A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.
doi:10.1093/brain/awp246
PMCID: PMC2792368  PMID: 19812212
Notch-1; AVM; human; brain; signalling; angiogenesis

Results 1-5 (5)