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1.
Oncotarget ; 8(60): 102067-102077, 2017 Nov 24.
Article in English | MEDLINE | ID: mdl-29254225

ABSTRACT

Cerebrovascular disease such as stroke is one of the most common diseases in the aging population, and neural stem cells (NSCs) transplantation may provide an alternative therapy for cerebral ischemia. However, a hostile microenvironment in the ischemic brain offers is challenging for the survival of the transplanted cells. Considering the neuroprotective role of basic fibroblast growth factor (bFGF), the present study investigated whether bFGF gene-modified NSCs could improve the neurological function deficit after transient middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. These rats were intravenously injected with modified NSCs (5×106/200 µL) or vehicle 24 h after MCAO. Histological analysis was performed on days 7 and 28 after tMCAO. The survival, migration, proliferation, and differentiation of the transplanted modified C17.2 cells in the brain were improved. In addition, the intravenous infusion of NSCs and bFGF gene-modified C17.2 cells improved the functional recovery as compared to the control. Furthermore, bFGF promoted the C17.2 cell growth, survival, and differentiation into mature neurons within the infarct region. These data suggested that bFGF gene-modified NSCs have the potential to be a therapeutic agent in brain ischemia.

2.
Mol Neurobiol ; 53(7): 4375-86, 2016 09.
Article in English | MEDLINE | ID: mdl-26232067

ABSTRACT

Clinical translation of growth factor therapies faces multiple challenges; the most significant one is the short half-life of the naked protein. Gelatin nanostructured lipid carriers (GNLs) had previously been used to encapsulate the basic fibroblast growth factor to enhance the functional recovery in hemiparkinsonian rats. In this research, we comparatively study the enhanced therapy between nerve growth factor (NGF) loaded GNLs (NGF-GNLs) and NGF only in spinal cord injury (SCI). The effects of NGF-GNLs and NGF only were tested by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. Western blot analysis and immunofluorescent staining were further performed to identify the expression of ER stress-related proteins, neuron-specific marker neuronal nuclei (NeuN), and growth-associated protein 43 (GAP43). Correlated downstream signals Akt/GSK-3ß and ERK1/2 were also analyzed with or without inhibitors. Results showed that NGF-GNLs, compared to NGF only, enhanced the neuroprotection effect in SCI rats. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 inhibited by NGF-GNL treatment were more obvious. Meanwhile, NGF-GNLs in the recovery of SCI are related to the inhibition of ER stress-induced cell death via the activation of downstream signals PI3K/Akt/GSK-3ß and ERK1/2.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Gelatin/chemistry , Lipids/chemistry , Nanostructures/chemistry , Nerve Growth Factor/pharmacology , Recovery of Function/drug effects , Spinal Cord Injuries/physiopathology , Animals , Cell Survival/drug effects , Disease Models, Animal , Drug Carriers/chemistry , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Nanostructures/ultrastructure , Nerve Growth Factor/therapeutic use , Neurons/drug effects , Neurons/metabolism , Neuroprotection/drug effects , PC12 Cells , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Spinal Cord Injuries/drug therapy , Up-Regulation/drug effects
3.
Mol Neurobiol ; 51(3): 1343-52, 2015.
Article in English | MEDLINE | ID: mdl-25048984

ABSTRACT

Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury, sclerosis, and diabetic neuropathy. Protein misfolding and accumulation in the ER lumen initiate unfolded protein response in energy-starved neurons which are relevant to toxic effects. In neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, ER dysfunction is well recognized, but the mechanisms remain unclear. In stroke and ischemia, spinal cord injury, and amyotrophic lateral sclerosis, chronic activation of ER stress is considered as main pathogeny which causes neuronal disorders. By targeting components of these ER signaling responses, to explore clinical treatment strategies or new drugs in CNS neurological diseases might become possible and valuable in the future.


Subject(s)
Central Nervous System Diseases/metabolism , Central Nervous System Diseases/therapy , Endoplasmic Reticulum Stress/physiology , Endoplasmic Reticulum/metabolism , Neurons/metabolism , Signal Transduction/physiology , Animals , Central Nervous System Diseases/pathology , Endoplasmic Reticulum/pathology , Humans , Unfolded Protein Response/physiology
4.
PLoS One ; 8(4): e59966, 2013.
Article in English | MEDLINE | ID: mdl-23565178

ABSTRACT

Hypertrophic scars (HTS) and keloids are challenging problems. Their pathogenesis results from an overproduction of fibroblasts and excessive deposition of collagen. Studies suggest a possible anti-scarring effect of basic fibroblast growth factor (bFGF) during wound healing, but the precise mechanisms of bFGF are still unclear. In view of this, we investigated the therapeutic effects of bFGF on HTS animal model as well as human scar fibroblasts (HSF) model. We show that bFGF promoted wound healing and reduced the area of flattened non-pathological scars in rat skin wounds and HTS in the rabbit ear. We provide evidence of a new therapeutic strategy: bFGF administration for the treatment of HTS. The scar elevation index (SEI) and epidermal thickness index (ETI) was also significantly reduced. Histological reveal that bFGF exhibited significant amelioration of the collagen tissue. bFGF regulated extracellular matrix (ECM) synthesis and degradation via interference in the collagen distribution, the α-smooth muscle actin (α-SMA) and transforming growth factor-1 (TGF-ß1) expression. In addition, bFGF reduced scarring and promoted wound healing by inhibiting TGFß1/SMAD-dependent pathway. The levels of fibronectin (FN), tissue inhibitor of metalloproteinase-1 (TIMP-1) collagen I, and collagen III were evidently decreased, and matrix metalloproteinase-1 (MMP-1) and apoptosis cells were markedly increased. These results suggest that bFGF possesses favorable therapeutic effects on hypertrophic scars in vitro and in vivo, which may be an effective cure for human hypertrophic scars.


Subject(s)
Fibroblast Growth Factor 2/pharmacology , Wound Healing/drug effects , Wound Healing/physiology , Actins/metabolism , Animals , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Apoptosis/drug effects , Cicatrix, Hypertrophic/drug therapy , Collagen Type I/biosynthesis , Collagen Type III/biosynthesis , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression , Humans , Immunohistochemistry , Male , Models, Animal , Proliferating Cell Nuclear Antigen/metabolism , Rabbits , Rats , Signal Transduction/drug effects , Transforming Growth Factor beta1/metabolism
5.
Mol Neurobiol ; 48(3): 452-64, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23516099

ABSTRACT

The role of autophagy in the recovery of spinal cord injury remains controversial; in particular, the mechanism of autophagy regulated degradation of ubiquitinated proteins has not been discussed to date. In this study, we investigated the protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and ubiquitinated protein accumulation is involved in the rat model of trauma. bFGF administration improved recovery and increased the survival of neurons in spinal cord lesions in the rat model. The protective effect of bFGF is related to the inhibition of autophagic protein LC3II levels; bFGF treatment also enhances clearance of ubiquitinated proteins by p62, which also increases the survival of neuronal PC-12 cells. The activation of the downstream signals of the PI3K/Akt/mTOR pathway by bFGF treatment was detected both in vivo and in vitro. Combination therapy including the autophagy activator rapamycin partially abolished the protective effect of bFGF. The present study illustrates that the role of bFGF in SCI recovery is related to the inhibition of excessive autophagy and enhancement of ubiquitinated protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new trend for bFGF drug development for central nervous system injuries and sheds light on protein signaling involved in bFGF action.


Subject(s)
Autophagy/drug effects , Fibroblast Growth Factor 2/therapeutic use , Neuroprotective Agents/therapeutic use , Recovery of Function/drug effects , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Ubiquitinated Proteins/metabolism , Animals , Disease Models, Animal , Female , Fibroblast Growth Factor 2/administration & dosage , Fibroblast Growth Factor 2/pharmacology , Heat-Shock Proteins/metabolism , Humans , Motor Neurons/drug effects , Motor Neurons/metabolism , Motor Neurons/pathology , Neuroprotective Agents/pharmacology , PC12 Cells , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Sequestosome-1 Protein , Signal Transduction/drug effects , Sirolimus/pharmacology , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/enzymology , TOR Serine-Threonine Kinases/metabolism
6.
CNS Neurosci Ther ; 19(1): 20-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23082997

ABSTRACT

AIM: To investigate the mechanism of endoplasmic reticulum (ER) stress-induced apoptosis as well as the protective action of basic fibroblast growth factor (bFGF) both in vivo and in vitro. METHODS AND RESULTS: ER stress-induced apoptosis was involved in the injuries of spinal cord injury (SCI) model rat. bFGF administration improved the recovery and increased the survival of neurons in spinal cord lesions in model rat. The protective effect of bFGF is related to the inhibition of CHOP, GRP78 and caspase-12, which are ER stress-induced apoptosis response proteins. bFGF administration also increased the survival of neurons and the expression of growth-associated protein 43 (GAP43), which is related to neural regeneration. The protective effect of bFGF is related to the activation of downstream signals, PI3K/Akt/GSK-3ß and ERK1/2, especially in the ER stress cell model. CONCLUSIONS: This is the first study to illustrate that the role of bFGF in SCI recovery is related to the inhibition of ER stress-induced cell death via the activation of downstream signals. Our work also suggested a new trend for bFGF drug development in central neural system injuries, which are involved in chronic ER stress-induced apoptosis.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Fibroblast Growth Factor 2/therapeutic use , Neurons/drug effects , Recovery of Function/drug effects , Spinal Cord Injuries , Animals , Caspase 12/metabolism , Disease Models, Animal , Female , GAP-43 Protein/metabolism , Heat-Shock Proteins/metabolism , In Situ Nick-End Labeling , Locomotion/drug effects , Neurons/metabolism , PC12 Cells , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Rats , Rats, Sprague-Dawley , Severity of Illness Index , Signal Transduction/drug effects , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Time Factors , Transcription Factor CHOP/metabolism , Up-Regulation/drug effects
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