[Show abstract][Hide abstract] ABSTRACT: Background
Endoplasmic reticulum (ER) stress-induced apoptosis plays a major role in various diseases, including spinal cord injury (SCI). Nerve growth factor (NGF) show neuroprotective effect and improve the recovery of SCI, but the relations of ER stress-induced apoptosis and the NGF therapeutic effect in SCI still unclear.
Young adult female Sprague-Dawley rats’s vertebral column was exposed and a laminectomy was done at T9 vertebrae and moderate contusion injuries were performed using a vascular clip. NGF stock solution was diluted with 0.9% NaCl and administered intravenously at a dose of 20 μg/kg/day after SCI and then once per day until they were executed. Subsequently, the rats were executed at 1d, 3 d, 7d and 14d. The locomotor activities of SCI model rats were tested by the 21-point Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test and footprint analysis. In addition, Western blot analysis was performed to identify the expression of ER-stress related proteins including CHOP, GRP78 and caspase-12 both in vivo and in vitro. The level of cell apoptosis was determined by TUNEL in vivo and Flow cytometry in vitro. Relative downstream signals Akt/GSK-3β and ERK1/2were also analyzed with or without inhibitors in vitro.
Our results demonstrated that ER stress-induced apoptosis was involved in the injury of SCI model rats. NGF administration improved the motor function recovery and increased the neurons survival in the spinal cord lesions of the model rats. NGF decreases neuron apoptosis which measured by TUNEL and inhibits the activation of caspase-3 cascade. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 are inhibited by NGF treatment. Meanwhile, NGF administration also increased expression of growth-associated protein 43 (GAP43). The administration of NGF activated downstream signals Akt/GSK-3β and ERK1/2 in ER stress cell model in vitro.
The neuroprotective role of NGF in the recovery of SCI is related to the inhibition of ER stress-induced cell death via the activation of downstream signals, also suggested a new trend of NGF translational drug development in the central neural system injuries which involved in the regulation of chronic ER stress.
Journal of Translational Medicine 05/2014; 12(1):130. DOI:10.1186/1479-5876-12-130 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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-3β and ERK1/2, especially in the ER stress cell model.
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.
[Show abstract][Hide abstract] ABSTRACT: Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth-suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5-bis(2-methoxyphenyl) penta-1,4-dien-3-one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non-small cell lung cancer (NSCLC) cells in a dose-responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress-mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63-induced cell apoptosis, indicating that the apoptotic pathway is ER stress-dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.
International Journal of Cancer 09/2012; 131(6):1455-65. DOI:10.1002/ijc.27406 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the apoptosis of human ovarian cancer cell lines, A2780 and CP70, induced by a novel curcumin analogue, B19. The proliferation of cells was detected with methyl thiazolyl tetrazolium (MTT) assay and apoptosis was examined by flow cytometry. Reactive oxygen species (ROS) were assessed by the fluorescent indicator DCF-DA. The protein expression of the endoplasmic reticulum (ER) stress pathways, GRP78, XBP-1, ATF-4 and CHOP, was examined with Western blotting. A growth inhibitory effect was observed after treatment with B19 in a dose-dependent manner and with more potential than curcumin. At 20 µM, B19 induced significant apoptosis in CP70 cells. Furthermore, B19 induced the ER stress response, while curcumin had no effect on ER stress. These results suggest that B19 has more effective antitumor properties than curcumin, and is associated with the activation of ER stress and ROS in ovarian cancer cells.
Molecular Medicine Reports 12/2011; 5(3):739-44. DOI:10.3892/mmr.2011.700 · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The basic fibroblast growth factor (bFGF) has a very short half-life in vivo, and this limits its therapeutic value for frequent administration. Liposome technology was used to improve the stability of bFGF and to prolong its effects in vivo.
bFGF-encapsulated liposomes (bFGF-lip) were prepared using the pH gradient method. Four critical factors were investigated including concentration of citric acid solution, incubation time of blank liposomes, incubation temperature and sonication time. The pharmacodynamics of bFGF-lip was investigated by establishing a deep second-degree burns model in rats.
The optimal bFGF-lip were characterised by high entrapment efficiency (79.88 ± 3.37%), good physical stability (K(E): 1.02 ± 0.413%) and high bioactivity ((6.147 ± 0.769) × 10(5) IU ml(-1)). The middle dose of bFGF-lip (60 IU ml(-1)) demonstrated the fastest tissue collagen generation as well as the earliest and highest tumour growth factor (TGF)-β1 and dermal cell proliferation (proliferating cell nuclear antigen (PCNA)) expression as compared with other treatments.
Results of the present study imply that bFGF-lip have promising prospects for application in wound-healing therapies.
Burns: journal of the International Society for Burn Injuries 03/2011; 37(5):886-95. DOI:10.1016/j.burns.2011.01.018 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is a leading cause of morbidity and mortality worldwide. Cyclooxygenase-2 (COX-2) expression is upregulated in lung carcinomas and is considered an attractive therapeutic target. In this study, the effect of curcumin and curcumin analogues on COX-2 expression induced by phorbol 12-myristate 13-acetate (PMA) were investigated. We found that a novel curcumin analogue (GL63) inhibited PMA-induced COX-2 mRNA and protein levels in H460 cells to a greater degree than curcumin. To understand the molecular mechanisms governing COX-2 regulation, the effect on COX-2 mRNA degradation was examined; we found that GL63 significantly decreased COX-2 mRNA stability by reducing cytoplasmic localization and protein abundance of human antigen R (HuR). The 3'-untranslated region (3'-UTR) report gene assay also showed GL63 substantially reduced the 3'-UTR green fluorescent protein values, indicating that the destabilizing effect on COX-2 mRNA may be couple with the posttranscriptional inhibition of COX-2. Taken together, our results provide evidence that the novel curcumin analogue can effectively inhibit PMA-induced COX-2 expression in H460 cells, a mechanism associated with COX-2 mRNA stability and post-transcriptional regulation.