Enriched environment alleviates neurological deficits via downregulation of Cx43 after experimental stroke.

While it has been demonstrated that enriched environment (EE) can protect against cerebral ischemia/reperfusion (I/R) injury, the underlying mechanism remains largely unknown. Connexin 43 (Cx43) is a key component of gap junctions, which may mediate cell-to-cell communication in neural cells. This study aimed to investigate the neuroprotective effects of EE against cerebral I/R injury in rats by modulating Cx43. A rat model of cerebral I/R injury was established by middle cerebral artery occlusion (MCAO)/reperfusion. Rats were randomly divided into the sham, MCAO, MCAO + EE, MCAO + Gap19, and MCAO + EE + Gap19 groups. The modified neurological severity score test and Morris water maze assay were used to assess neurological deficits. The infarct volume was measured using triphenyltetrazolium chloride (TTC) staining. Neuronal survival was detected by immunofluorescence. The indices of oxidative stress were determined using ELISA, and the reactive oxygen species levels were determined using a dihydroethidium probe. Cx43 and inflammation-related protein expression levels were also measured using western blotting and immunohistochemistry. EE and Gap19 treatment significantly improved neurological deficits, reduced infarct volumes, attenuated neuronal injury, and suppressed inflammatory cytokine expression and oxidative stress. Furthermore, EE and Gap19 treatment notably downregulated the expression of Cx43 and the inflammation-related pathway TLR4/MyD88/NF-κB in the ischemic penumbra. Gap19, a Cx43 inhibitor, markedly enhanced the neuroprotective effects of EE in rats with cerebral I/R injury. EE treatment protects against cerebral I/R injury in rats via Cx43 downregulation. Our findings may shed light on the mechanism underlying the protective efficacy of EE.

Overexpression of microRNA-202-3p in bone marrow mesenchymal stem cells improves cerebral ischemia-reperfusion injury by promoting angiogenesis and inhibiting inflammation.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) can cause brain tissue inflammation, neuronal degeneration, and apoptosis. There is increasing evidence that microRNAs (miRNA) exert neuroprotective effects by regulating the inflammatory process during cerebral ischemia-reperfusion injury. Additionally, it is increasingly acknowledged that neuroinflammation is regulated by Toll-like receptor 4 (TLR4). However, it is unclear whether miRNA can exert its neuroprotective effects by regulating TLR4-mediated inflammation. METHODS: The effects of BMSCs over-expressing miR-202-3p on CIRI, angiogenesis in midbrain tissue, and the release of inflammatory factors (IFs) in the serum were measured using in vivo rat models. We also used SH-SY5Y cells to establish an ischemia-reperfusion in vitro cell model. The interaction between miR-202-3p and TLR4 was analyzed by overexpressing miR-202-3p and knocking down TLR4. Knockdown of TLR4 was performed using siRNA. RESULTS: Overexpression of miR-202-3p in BMSCs could significantly improve brain function and reduce brain damage. Simultaneously, miR-202-3p could significantly promote angiogenesis, increase the expression of vWF and VEGF, and reduce the expression of IFs. When the expression of TLR4 was significantly reduced in SH-SY5Y cells, the expression of IFs increased. Therefore, miRNA-202-3p may interact with TLR4 to modulate inflammation. CONCLUSION: Our data indicated that miR-202-3p potentially exerts its neuroprotective effects and protects against CIRI by regulating TLR4-mediated inflammation.

Folate-targeted star-shaped cationic copolymer co-delivering docetaxel and MMP-9 siRNA for nasopharyngeal carcinoma therapy.

The co-delivery of drug and gene has become the primary strategy in cancer therapy. Based on our previous work, to co-deliver docetaxel (DOC) and MMP-9 siRNA more efficiently for HNE-1 nasopharyngeal carcinoma therapy, a folate-modified star-shaped copolymer (FA-CD-PLLD) consisting of ß-cyclodextrin (CD) and poly(L-lysine) dendron (PLLD) was synthesized, and then used for DOC and MMP-9 co-delivery. Different from commonly used amphiphilic copolymers micelles, the obtained CD derivative could be used directly for the combinatorial delivery of nucleic acid and hydrophobic DOC without a complicated micellization process. In vitro and in vivo assays are carried out to confirm the effectiveness of the target strategy and combined treatment. It was found that the conjugation of CD-PLLD with FA could enhance the DOC/MMP-9 delivery effect obviously, inducing a more significant apoptosis and decreasing invasive capacity of HEN-1 cells. In vivo assays showed that FA-CD-PLLD/DOC/MMP-9 could inhibit HNE-1 tumor growth and decrease PCNA expression effectively, indicating a promising strategy for nasopharyngeal carcinoma therapy. Moreover, the in vivo distribution of DOC and MMP-9, blood compatibility and toxicity are also explored.

Application of a paraplegic gait orthosis in thoracolumbar spinal cord injury.

Paraplegic gait orthosis has been shown to help paraplegic patients stand and walk, although this method cannot be individualized for patients with different spinal cord injuries and functional recovery of the lower extremities. There is, however, a great need to develop individualized paraplegic orthosis to improve overall quality of life for paraplegic patients. In the present study, 36 spinal cord (below T4) injury patients were equally and randomly divided into control and observation groups. The control group received systematic rehabilitation training, including maintenance of joint range of motion, residual muscle strength training, standing training, balance training, and functional electrical stimulation. The observation group received an individualized paraplegic locomotion brace and functional training according to the various spinal cord injury levels and muscle strength based on comprehensive systematic rehabilitation training. After 3 months of rehabilitation training, the observation group achieved therapeutic locomotion in 8 cases, family-based locomotion in 7 cases, and community-based locomotion in 3 cases. However, locomotion was not achieved in any of the control group patients. These findings suggest that individualized paraplegic braces significantly improve activity of daily living and locomotion in patients with thoracolumbar spinal cord injury.