Zhong-Kai Fan

Liaoning Medical University, Liaonan, Jiangxi Sheng, China

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Publications (9)27.64 Total impact

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    ABSTRACT: Autophagy occurs prior to apoptosis and plays an important role in cell death regulation during spinal cord injury (SCI). This study aimed to determine the effects and potential mechanism of the glucagon-like peptide-1 (GLP-1) agonist extendin-4 (Ex-4) in SCI. Seventy-two male Sprague Dawley rats were randomly assigned to sham, SCI, 2.5 μg Ex-4, and 10 μg Ex-4 groups. To induce SCI, a 10-g iron rod was dropped from a 20-mm height to the spinal cord surface. Ex-4 was administered via intraperitoneal injection immediately after surgery. Motor function evaluation with the Basso Beattie Bresnahan (BBB) locomotor rating scale indicated significantly increased scores (p < 0.01) in the Ex-4-treated groups, especially 10 μg, which demonstrated the neuroprotective effect of Ex-4 after SCI. The light chain 3-II (LC3-II) and Beclin 1 protein expression determined via western blot and the number of autophagy-positive neurons via immunofluorescence double labeling were increased by Ex-4, which supports promotion of autophagy (p < 0.01). The caspase-3 protein level and neuronal apoptosis via transferase UTP nick end labeling (TUNEL)/NeuN/DAPI double labeling were significantly reduced in the Ex-4-treated groups, which indicates anti-apoptotic effects (p < 0.01). Finally, histological assessment via Nissl staining demonstrated the Ex-4 groups exhibited a significantly greater number of surviving neurons and less cavity (p < 0.01). To our knowledge, this is the first study to indicate that Ex-4 significantly enhances motor function in rats after SCI, and these effects are associated with the promotion of autophagy and inhibition of apoptosis.
    Molecular Neurobiology 07/2015; DOI:10.1007/s12035-015-9327-7 · 5.29 Impact Factor
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    ABSTRACT: Acetyl-l-carnitine (ALC) facilitates the entry and exit of fatty acids from mitochondria and plays an essential role in energy metabolism. Although ALC is known to exert neuroprotective effects in multiple neurological diseases, its effects on spinal cord injury (SCI)-induced mitochondrial impairments and apoptosis remain unclear. In this study, we aimed to evaluate the putative effects of ALC on mitochondrial dysfunction and apoptosis induced by SCI in a rodent model. Our results indicate that SCI elicits dynamic alternations in the expression of mitochondria-related proteins. Transmission electron microscopy analysis showed that ALC administration abrogated key ultrastructural abnormalities in mitochondria at 24h after SCI by maintaining mitochondrial length, reducing the number of damaged mitochondria, and reversing mitochondrial score (P<0.05 compared with SCI group). In addition, ALC administration maintained the mitochondrial membrane potential and mitochondrial Na(+)-K(+)-ATPase activity following SCI (P<0.05 compared with SCI group). ALC administration reversed the downregulation of mitofusin 1 (Mfn1), Mfn2, Bcl-2, and the upregulation of dynamin-related protein 1 (Drp1), mitochondrial fission 1 (Fis1), Bcl-2-associated X protein (Bax) and cytosol cytochrome c (cyto-CytC) induced by SCI (P<0.05 compared with SCI group). Finally ALC administration greatly reduced the percentage of apoptotic cells compared with the SCI group (P<0.01). In conclusion, our findings demonstrated that ALC ameliorated SCI-induced mitochondrial structural alternations, mitochondrial dysfunction, and apoptosis. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 06/2015; DOI:10.1016/j.neulet.2015.06.021 · 2.06 Impact Factor
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    ABSTRACT: Previous studies have shown that curcumin (Cur) can produce potent neuroprotective effects against damage due to spinal cord injury (SCI). However, whether Cur can preserve the function of the blood-spinal cord barrier (BSCB) is unclear. The present study was performed to investigate the mechanism underlying BSCB permeability changes, which were induced by treatment with Cur (75, 150, and 300mg/kg, i.p.) after compressive SCI in rats. BSCB permeability was evaluated by Evans blue leakage. Motor recovery of rats with SCI was assessed using the Basso, Beattie, and Bresnahan scoring system every day until the 21st days post-injury. The protein levels of heme oxygenase-1 (HO-1), tight junction protein, and inflammatory factors were analyzed by western blots. The expression of the inflammatory factors tumor necrosis factor-α (TNF-α) and nuclear factor-kappaB (NF-κB) mRNA was determined with reverse transcription-polymerase chain reactions. Treatment with Cur (150 and 300mg/kg) significantly reduced Evans blue leakage into the spinal cord tissue at 24h after SCI. Cur (150mg/kg) significantly increased HO-1 protein expression. The levels of TNF-α and NF-κB mRNA and protein greatly increased at 24h after SCI, and this increase was significantly attenuated by Cur treatment. ZO-1 and occludin expression was upregulated by Cur (150mg/kg) treatment after SCI, and this effect was blocked by the HO-1 inhibitor zinc protoporphyrin. Long-term effects of Cur on motor recovery after SCI were observed. Our results indicated that Cur can improve motor function after SCI, which could correlate with improvements in BSCB integrity.
    Journal of the Neurological Sciences 08/2014; 346(1-2). DOI:10.1016/j.jns.2014.07.056 · 2.26 Impact Factor
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    ABSTRACT: Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese medicinal herb danshen, is commonly used for the prevention and treatment of cardiovascular disease. The present study was performed to investigate the effect of Sal B on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a rat model. Sal B (1, 10, and 50 mg/kg i.v.) was administered to rats immediately following SCI. The permeability of the BSCB and spinal cord tissue water content were evaluated. Additionally, the expression levels of tight junction proteins and heme oxygenase-1 (HO-1) were monitored by Western blot analysis. Enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 24 h post-SCI to evaluate the expression of inflammation-related cytokines. In addition, the motor recovery of SCI rats was assessed using the Basso, Beattie, and Bresnahan scoring system. Compared to the SCI group, rats treated with Sal B (10, 50 mg/kg) exhibited significantly reduced spinal cord tissue water content and BSCB permeability. Further, the motor function of rats was also greatly improved by Sal B administration. The expression of pro-inflammatory factors TNF-α and NF-κB was found to be greatly increased 24 h post-SCI, and this upregulation was significantly attenuated by Sal B treatment. The expression of ZO-1 and occludin was upregulated by Sal B (10 mg/kg) treatment after SCI, and this effect was blocked by the HO-1 inhibitor ZnPP. Taken together, our results clearly indicate that Sal B attenuates SCI by promoting the repair of the damaged BSCB, demonstrating that this molecule is a novel and promising therapeutic agent for human SCI.
    Journal of Molecular Neuroscience 08/2013; 51. DOI:10.1007/s12031-013-0083-8 · 2.76 Impact Factor
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    ABSTRACT: Responsible for orchestrating cellular energy production, mitochondria are central to the maintenance of life and the gatekeepers of cell death. Its morphology is dynamic and controlled by continual and balanced fission and fusion events. In this study, we analyzed the mitochondrial dynamics and functions after spinal cord injury in rats. Further to discuss the mechanisms of the mitochondria regulate cell injury during SCI. Using adult rat spinal cord injury model, it was found that the absolute number of mitochondria per area was significantly less and the individual mitochondrial cross-sectional area was significantly greater in the neurons of rats in SCI group than in the sham-operated group at 3h and 6h after SCI, the reverse pattern at 12h and 24h after SCI. The results from Western blot and RT-PCR assays showed that the protein and mRNA levels of mitochondrial fusion-related genes (Mfn1 and Mfn2) decreased and fission-related genes (Drp1 and Fis1) increased at 3h and 6h after SCI. At 12h and 24h after SCI the reverse pattern of Mfn1, Mfn2, Drp1 and Fis1 expression was found. Taken together the results of present study showed that the mitochondrial tendency of elongation and fusion in the injured spinal cord at the 3h and 6h after SCI, the tendency of mitochondrial fission at 12h and 24h after SCI in our SCI models of rat. These findings have important implications for our understanding of the mechanisms of mitochondrial dynamics and functions after SCI injury. And mitochondrial fusion may potentially be used as a target for improving spinal cord function at the first 6h after SCI. Mitochondrial fusion may be inhibited at 12h to 24h after SCI for improving functional outcomes following SCI.
    Brain research 05/2013; 1522. DOI:10.1016/j.brainres.2013.05.033 · 2.83 Impact Factor
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    ABSTRACT: In this study, we examined whether the cigarette smoke has neuroprotective or toxicity effect on the spinal cord injury. The male Sprague-Dawley rats were included in the study and received either cigarette smoke exposure or fresh air exposure. Twenty-four hours after the last cigarette smoke or room air exposure, all rats were injured at the thoracic level 12 (T12), using an established static compression model. Our data showed that cigarette smoke group resulted in higher water content, higher permeability of blood-spinal cord barrier (BSCB), higher malondialdehyde (MDA) levels, AQP4 and HIF-1α protein expression and mRNA levels, lower glutathione (GSH) levels when compared to control group values at 12h, 24h and 48h after SCI. No significant difference on them between cigarette smoke group and control group at 0h after SCI. The results of BBB hindlimb locomotor rating scale showed that rats of cigarette smoke group had greater dysfunction in hindlimb movement than rats of control group from 2 to day 6 after SCI. The extent of recovery didn't make any difference from 7 to day 10 after SCI between cigarette smoke group and control group. These results suggest that cigarette smoke can reinforce the oxidative stress injure via HIF-1α and AQP4 in the early stage after SCI. Perhaps cigarette smoke exposure can't affect its recovery in the long run of the SCI recovery, but it can aggravate the edema and deteriorate the BSCB disruption via HIF-1α and AQP4 in the early stage after SCI. More studies will be essential to consider this hypothesis and elucidate the mechanism involved in it.
    Journal of neurotrauma 12/2012; DOI:10.1089/neu.2012.2574 · 3.97 Impact Factor
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    ABSTRACT: The study investigated the mechanism of the up-regulation of aquaporin-4 (AQP4) and aquaporin-1 (AQP1) expression induced by spinal cord injury (SCI). Using adult rat spinal cord injury model, it was found that up-regulation of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), AQP4, and AQP1 in response to spinal cord injury was greatly antagonized by 2-methoxyestradiol (2ME2), which can post-transcriptionally inhibit the expression of HIF-1α. VEGF alone significantly increased the extravasation of Evans blue and up-regulated the levels of AQP4 protein expression in the injured spinal cord issue, but the levels of AQP1 expression were not significantly changed. Taken together, our results suggest that expression of AQP4 and AQP1 is correlated with up-regulation of HIF-1α after SCI through the mechanisms that were dependent and independent of the VEGF signaling pathway, respectively. And the inhibitor of HIF-1α is a novel promising therapeutic agent for human SCI-induced edema in the future.
    Brain research 01/2011; 1370:220-6. DOI:10.1016/j.brainres.2010.11.016 · 2.83 Impact Factor
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    ABSTRACT: The current study was performed to investigate the effect of baicalin (BC) on spinal cord injury (SCI) in rat. BC (10, 30 and 100mg/kg, i.p., respectively) was administered to rats immediately and every 24h following SCI. The BC therapy (100mg/kg) dramatically decreased (1) the water content of spinal cord tissue (by dry-wet weight method), (2) the permeability of blood-spinal cord barrier (measured by Evans blue), (3) oxidant stress (malondialdehyde values and glutathione levels evaluation), (4) proinflammatory cytokines expression (tumor necrosis factor-α and NF-κB) (5) and apoptosis (measured by Bax, Bcl-2 and Caspase-3 expression). And the treatment with BC also significantly improved the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly indicate that BC possesses potent anti-inflammatory and anti-apoptotic properties, attenuates the SCI and is a new promising therapeutic agent for human SCI in the future.
    Brain research 10/2010; 1357:115-23. DOI:10.1016/j.brainres.2010.07.108 · 2.83 Impact Factor
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    ABSTRACT: The current study was performed to investigate the effect of aminoguanidine (AG) on spinal cord injury (SCI) in rat. AG (75, 150 and 300mg/kg, i.p. respectively ) was administered to rats immediately following SCI. It was found that AG (150mg/kg) significantly reduced spinal cord water content and improved motor function, however, AG at the doses of 75 and 300mg/kg had no effect. Compared to SCI group without treatment, AG at the dosage of 150mg/kg induced a reduction in the permeability of blood-spinal cord barrier (BSCB) after injury 48h (from 59.8+/-5.5microl/g to 39.8+/-3.8microl/g), a 38% decrease of Malondialdehyde (MDA) values and a 1-fold increase of the Glutathione (GSH) levels at 12h after SCI. And the expression of inducible nitric oxide synthase (iNOS) protein reached a peak at 24h after injury, which was significantly attenuated by treatment with AG (150mg/kg). In addition, the expression of AQP4 protein was down-regulated by the treatment of AG (150mg/kg) at 24h after SCI, and the changes still lasted at 48h after injury. Our results indicated that AG could induce spinal cord edema clearance and improve motor function, which could be correlated with antioxidative property, the down-regulation of iNOS and AQP4 protein expression after SCI.
    Brain research 04/2010; 1342:1-10. DOI:10.1016/j.brainres.2010.04.038 · 2.83 Impact Factor