Seipin overexpression attenuates cerebral ischemia-reperfusion injury via preventing apoptosis and autophagy.

BACKGROUND: Ischemic cerebrovascular disease (ICVD) is one of three fatal diseases in humans, along with heart disease and malignant tumors. Cerebral ischemia/reperfusion injury (CI/RI) is the primary cause of ICVD. Recently, seipin was reported to be crucial for lipid droplet formation, hepatic steatosis, and axonal atrophy. However, the function and mechanism of seipin in CI/RI has not been explicitly stated. METHODS: Oxygen-glucose deprivation/reoxygenation (OGD/R) hippocampal neuron cell line (HT-22) and middle cerebral artery occlusion (MCAO) in rats were established. The levels of apoptosis- and autophagy-related proteins and seipin were confirmed by western blot. Cell proliferation was assessed with CCK-8, and ischemic infarction and pathological structure were monitored by TTC and H&E staining, and tissue apoptosis was assessed through TUNEL assay. RESULTS: The proliferative activity was decreased, and apoptosis and autophagy pathways could also be induced in the OGD/R HT-22 cells. Seipin overexpression accelerated viability and inhibited apoptosis and autophagy in the OGD/R HT-22 cells. Moreover, the data revealed that seipin overexpression could also attenuate cerebral infarction, apoptosis. Autophagy pathways could be repressed by seipin in the MCAO rats. CONCLUSION: Seipin has a protective role against CI/RI in rats, and its mechanism might be relevant to the suppression of apoptosis and autophagy, suggesting that seipin might be a latent target for CI/RI.

EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice.

Neuropathic pain is a refractory disease with limited treatment options due to its complex mechanisms. Whereas erythropoietin-producing hepatocyte A1 (EphA1) mediates the production of inflammatory factors that are important in the progression of neurological diseases, its role and molecular mechanisms in neuropathic pain remain unclear. In the present study, we established a mouse model of chronic constriction injury (CCI). EphA1 expression was observed to be progressively upregulated at the mRNA and protein levels with the progression of the disease. Subsequently, knockdown of EphA1 expression levels using adenovirus short hairpin RNA (AAV-shEphA1) revealed an increase in mechanical stimulation withdrawal threshold (PWT) and withdrawal latency (PWL) when EphA1 expression was decreased, accompanied by improved dorsal root ganglion injury, increased leukocytosis, decreased microglia, and decreased levels of pro-inflammatory factors. For the underlying mechanism, it was found that EphA1 regulates the activity of the RhoA/ROCK2 pathway by modulating the level of CXCR4. Inhibition of CXCR4 and RhoA/ROCK2 could effectively alleviate the promoting effect of EphA1 upregulation on neuropathic pain. In conclusion, our study suggests that depletion of EphA1 ameliorates neuropathic pain by modulating the CXCR4/RhoA/ROCK2 signaling pathway, and targeting EphA1 may be a potential clinical treatment for neuropathic pain.

Ubiquitin­specific peptidase 53 promotes chronic constriction injury­induced neuropathic pain through the RhoA/ROCK pathway.

Neuropathic pain is associated with nervous system injury and the production of pro­inflammatory factors. Critical functions for ubiquitin­specific peptidase 53 (USP53) have been demonstrated in various diseases. However, the role and mechanism of USP53 in chronic constriction injury (CCI)­induced neuropathic remains unclear. In our current study, a model of neuropathic pain was induced by CCI in rats. Quantitative reverse transcription­polymerase chain reaction (qRT­PCR) and western blotting results demonstrated that USP53 was significantly up­regulated in CCI rats. In addition, silencing of USP53 alleviated neuropathic pain and reduced the production of pro­inflammatory factors in CCI rats according to paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) tests and enzyme­linked immunosorbent assay (ELISA), respectively. Moreover, knockdown of USP53 inhibited the activation of FK506­binding protein 51 (FKBP51)/RhoA/ROCK signaling in CCI rats. In summary, this study revealed that USP53 exacerbated CCI­induced neuropathic pain, potentially via regulation of the FKBP51/RhoA/ROCK pathway.

Application value and challenge of traditional Chinese medicine carried by ZIF-8 in the therapy of ischemic stroke.

Stroke is a group of major diseases that cause death or disability in adults, with high incidence and lack of available therapeutic strategies. Although traditional Chinese medicine (TCM) has continuously achieved good effects in the therapy of stroke while there is still not convincing due to the limitation of blood-brain permeability, as well as the individual differences in usage and dosage. With the improvement of nanotechnology, TCM nanopreparation has gradually become a research hotspot in various fields due to its advantages in permeating the blood-brain barrier, targeting delivery, enhancing sustained-release drug delivery, changing the distribution in the body, and improving bioavailability. Zeolitic imidazolate framework-8 (ZIF-8) is an ideal nano-drug delivery system for adsorption, catalysis, and drug loading, which is a biocompatible metal-organic framework framed by 2-methylimidazole and zinc ions. At present, ZIF-8 was wildly used in the treatment of ischemic stroke. However, challenges remain persists for its clinical application, such as preparation technology, detection technology in vivo, targeting specificity, safety and stability, and so forth. Therefore, more efforts need to overcome the above problems to develop the application of TCM nanopreparations in the therapy of ischemia/reperfusion in the future.