Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Clinical significance of elevated soluble T-cell immunoglobulin and mucin domain 1 and soluble P-selectin in individuals with obstructive sleep apnea-hypopnea syndrome.

OBJECTIVES: To assess the serum concentrations of soluble T-cell immunoglobulin and mucin domain 1 (sTIM-1) and soluble P-selectin (sP-selectin) in individuals who had obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Between December 2020 and November 2022, 134 participants from the Sleep Monitoring Center of the Branch Hospital of Huai'an First People's Hospital, Jiangsu, China, engaged in this cross-sectional study. Participants were categorized as mild OSAHS (n=19), moderate OSAHS (n=22), severe OSAHS (n=57), and non-OSAHS (n=36) groups. Serum levels of sTIM-1, sP-selectin, and interleukin (IL)-6, as well as baseline clinical characteristics and polysomnography outcomes were assessed in each participant. RESULTS: Compared to the non-OSAHS group, sTIM-1 and sP-selectin levels were considerably elevated in people who had moderate or severe OSAHS (all p<0.05), but there were no notable changes between those who had mild OSAHS and non-OSAHS participants (p>0.05). The sTIM-1 and sP-selectin levels showed positive associations with the apnea-hypopnea index, body mass index (BMI), and IL-6 levels (all p<0.001). While elevated sTIM-1 was independently related to OSAHS (odds ratio [OR]=1.134, p=0.001), sP-selectin was not associated with OSAHS after adjusting for BMI (OR=1.013, p=0.467). CONCLUSION: People with moderate or severe OSAHS had higher serum sTIM-1 and sP-selectin levels, and elevated sTIM-1 is an independently related factor for OSAHS.

Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion.

Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue (cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.

Promotion of Momordica Charantia polysaccharides on neural stem cell proliferation by increasing SIRT1 activity after cerebral ischemia/reperfusion in rats.

The deacetylase SIRT1 has been reported to play a critical role in regulating neurogenesis, which may be an adaptive processes contributing to recovery after stroke. Our previous work showed that the antioxidant capacity of Momordica charantia polysaccharides (MCPs) could protect against cerebral ischemia/reperfusion (I/R) after stroke. However, whether the protective effect of MCPs on I/R injury is related to neural stem cell (NSC) proliferation remains unclear. In the present study, we designed invivo and invitro experiments to elucidate the underlying mechanisms by which MCPs promote endogenous NSC proliferation during cerebral I/R. Invivo results showed that MCPs rescued the memory and learning abilities of rats after I/R damage and enhanced NSC proliferation in the rat subventricular zone (SVZ) and subgrannular zone (SGZ) during I/R. Invitro experiments demonstrated that MCPs could stimulate the proliferation of C17.2 cells under oxygen-glucose deprivation (OGD) conditions. Further studies revealed that the proliferation-promoting mechanism of MCPs relied on increasing the activity of SIRT1, decreasing the level of acetylation of ß-catenin in the cytoplasm, and then triggering the translocation of ß-catenin into the nucleus. These data provide experimental evidence that the up-regulation of SIRT1 activity by MCPs led to an increased cytoplasmic deacetylation of ß-catenin, which promoted translocation of ß-catenin to the nucleus to participate in the signaling pathway involved in NSC proliferation. The present study reveals that MCPs function as a therapeutic drug to promote stroke recovery by increasing the activity of SIRT1, decreasing the level of acetylated ß-catenin, promoting the nuclear translocation of ß-catenin and thereby increasing endogenous NSC proliferation.

KAP1 silencing relieves OxLDL-induced vascular endothelial dysfunction by down-regulating LOX-1.

KRAB domain-associated protein 1 (KAP1) is highly expressed in atherosclerotic plaques. Here, we studied the role of KAP1 in atherosclerosis development using a cell model of endothelial dysfunction induced by oxidative low-density lipoprotein (OxLDL). The phosphorylation and protein levels of KAP1 were similar between OxLDL-treated and non-treated endothelial cells (ECs). KAP1 depletion significantly inhibited the production of OxLDL-enhanced reactive oxygen species and the expression of adhesion molecules in ECs. Treatment with OxLDL promoted the proliferation and migration of ECs, which was also confirmed by the elevated levels of the proliferative markers c-Myc and PCNA, as well as the migratory marker MMP-9. However, these effects were also abrogated by KAP1 depletion. Moreover, the depletion of KAP1 in OxLDL-treated ECs resulted in decreases in the LOX-1 level and increases in eNOS expression. Generally, the data suggest that strategies targeting KAP1 depletion might be particularly useful for the prevention or treatment of atherosclerosis.

Automatic segmentation of dermoscopy images using saliency combined with Otsu threshold.

Segmentation is one of the crucial steps for the computer-aided diagnosis (CAD) of skin cancer with dermoscopy images. To accurately extract lesion borders from dermoscopy images, a novel automatic segmentation algorithm using saliency combined with Otsu threshold is proposed in this paper, which includes enhancement and segmentation stages. In the enhancement stage, prior information on healthy skin is extracted, and the color saliency map and brightness saliency map are constructed respectively. By fusing the two saliency maps, the final enhanced image is obtained. In the segmentation stage, according to the histogram distribution of the enhanced image, an optimization function is designed to adjust the traditional Otsu threshold method to obtain more accurate lesion borders. The proposed model is validated from enhancement effectiveness and segmentation accuracy. Experimental results demonstrate that our method is robust and performs better than other state-of-the-art methods.

Melanoma Classification on Dermoscopy Images Using a Neural Network Ensemble Model.

We develop a novel method for classifying melanocytic tumors as benign or malignant by the analysis of digital dermoscopy images. The algorithm follows three steps: first, lesions are extracted using a self-generating neural network (SGNN); second, features descriptive of tumor color, texture and border are extracted; and third, lesion objects are classified using a classifier based on a neural network ensemble model. In clinical situations, lesions occur that are too large to be entirely contained within the dermoscopy image. To deal with this difficult presentation, new border features are proposed, which are able to effectively characterize border irregularities on both complete lesions and incomplete lesions. In our model, a network ensemble classifier is designed that combines back propagation (BP) neural networks with fuzzy neural networks to achieve improved performance. Experiments are carried out on two diverse dermoscopy databases that include images of both the xanthous and caucasian races. The results show that classification accuracy is greatly enhanced by the use of the new border features and the proposed classifier model.