Effect of PCI on ophthalmic artery hemodynamics in patients with acute coronary syndrome.

Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.

Effect of cytochrome P450 2C19 (CYP2C19) gene polymorphism and clopidogrel reactivity on long term prognosis of patients with coronary heart disease after PCI.

Objective: To investigate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity and its association with long-term clinical outcome in patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). Methods: In total, 675 patients were enrolled. Based on the platelet inhibition rate, patients were categorized into two groups: clopidogrel low responsiveness (CLR) and normal clopidogrel responsiveness (NCR). The CLR group was divided into ticagrelor and clopidogrel group based on the antiplatelet drugs used in the follow-up treatment. Patients were classified into three groups (normal metabolizer, intermediate metabolizer, and poor metabolizer) based on the CYP2C19 genotype. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity. The cumulative rates of 12-month all-cause deaths, major adverse cardiovascular events (MACCEs), and bleeding events were calculated. Results: CLR was observed in 44.4% of the overall population. Significant differences were observed in the platelet inhibition rate of clopidogrel among the three metabolic genotypes (P < 0.05). At the 12-month follow-up, 13 patients (1.9%) died and 96 patients (14.2%) experienced MACCEs. Patients with CLR (9.6% vs. 11.7% vs. 22.1%, P < 0.05) or poor metabolizer (10.7% vs. 16.4% vs. 22.6%, P = 0.026) experienced a higher rate of MACCEs. A MACCEs risk score between zero and two was calculated. The highest incidence of MACCEs significantly increased with the 2-positive results, and the area under the curve (AUC) was 0.712 (95% CI: 0.650-0.774, P < 0.05). There was no significant difference between the group with a score of one and the occurrence of MACCEs (P > 0.05). Conclusions: Low response to clopidogrel in CHD patients is correlated with CYP2C19 gene polymorphism. CYP2C19 genotyping combined with platelet reactivity is an independent predictor of 12-months MACCEs in patients with clopidogrel treatment after PCI, which is better than either test alone.

Electroencephalogram findings in 10 patients with post-stroke epilepsy: A retrospective study.

BACKGROUND: Post-stroke epilepsy is a common and easily overlooked complication of acute cerebrovascular disease. Long-term seizures can seriously affect the prognosis and quality of life of patients. Electroencephalogram (EEG) is the simplest way to diagnose epilepsy, and plays an important role in predicting seizures and guiding medication. AIM: To explore the EEG characteristics of patients with post-stroke epilepsy and improve the detection rate of inter-seizure epileptiform discharges. METHODS: From January 2017 to June 2020, 10 patients with post-stroke epilepsy in our hospital were included. The clinical, imaging, and EEG characteristics were collected. The stroke location, seizure type, and ictal and interictal EEG manifestations of the patients with post-stroke epilepsy were then retrospectively analyzed. RESULTS: In all 10 patients, epileptiform waves occurred in the side opposite to the stroke lesion during the interictal stage; these manifested as sharp wave, sharp-wave complex, or spike discharges in the anterior head lead of the side opposite to the lesion. CONCLUSION: In EEG, epileptiform waves can occur in the side opposite to the stroke lesion in patients with post-stroke epilepsy.

Immune-regulatory properties of endovascular extravillous trophoblast cells in human placenta.

INTRODUCTION: Uterine spiral artery remodeling is the prerequisite for ensuring adequate blood supply to the maternal-fetal interface during human pregnancy. One crucial cellular event in this process involves the extensive replacement of the spiral artery endothelial cells by endovascular extravillous trophoblasts (enEVTs), a subtype of extravillous trophoblasts (EVTs). However, our understanding of the properties of enEVTs remains limited. METHODS: Human enEVTs in decidual tissues during early pregnancy was purified using flow sorting by specific makers, NCAM1 and HLA-G. The high-throughput RNA sequencing analysis as well as the cytokine antibody array experiments were carried out to analyze for cell properties. Gene ontology (GO) enrichment, kyoto encyclopedia of genes and genomes (KEGG) enrichment, and gene set enrichment analysis (GSEA) were performed on differentially expressed genes of enEVTs. Immunofluorescent assays were used to verify the analysis results. RESULTS: Both enEVTs and interstitial EVTs (iEVTs) exhibited gene expression patterns typifying EVT characteristics. Intriguingly, enEVTs displayed gene expression associated with immune responses, particularly reminiscent of M2 macrophage characteristics. The active secretion of multiple cytokines and chemokines by enEVTs provided partial validation for their expression pattern of immune-regulatory genes. DISCUSSION: Our study reveals the immune-regulatory properties of human enEVTs and provides new insights into their functions and mechanisms involved in spiral artery remodeling.

Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain.

Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.

Effects of posterior staphyloma on choroidal structure in myopic adults: a retrospective study.

BACKGROUND: Studies on the choroid of myopic eyes with posterior staphyloma have shown that choroidal thickness decreased. This retrospective study further analysed the effects of posterior scleral staphyloma on choroidal blood vessels and matrix components compared to non-pathological myopia. METHODS: In this cross-sectional study, ninety-one eyes were divided into pathological (posterior staphyloma) and non-pathological myopia. The latter was further divided into three groups (Group 1: 26 mm ≤ axial length; Group 2: 24 mm ≤ axial length < 26 mm; Group 3: 22 mm ≤ axial length < 24 mm). Choroidal thickness, total choroidal area, luminal area, stromal area, and choroidal vascularity index were calculated. RESULTS: The CVI in N1, N2, I1, S2 of the posterior staphyloma group were lower than those of group 1 (both P < 0.05). The mean height of posterior staphyloma was associated with mean CT (Pearson correlation: r = -0.578, P = 0.039) but not with the mean CVI in posterior staphyloma group. In all groups, the mean choroidal thickness, total choroidal area, luminal area, and stromal area were significantly associated with axial length (P < 0.001), and the mean choroidal vascularity index was significantly associated with the mean choroidal thickness (P < 0.001). CONCLUSION: The choroidal structure of pathological myopia with posterior staphyloma and non-pathological myopia with longer axial length demonstrates alterations in which choroidal vessels are more impaired than the stroma. A lower choroidal vascularity index should be alert to pathological changes for myopia with axial length > 26 mm.

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1-PKA-CREB signaling in the placenta.

Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T0 ) synthesis, reduced estradiol (E2 ), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E2 as well as elevated T0 synthesis in PE placentas. Administration of the T0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T0 production and reduced E2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E2 , but not T0 , actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17ß-HSD3 and 3ß-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

Comparison of Ophthalmic Artery Morphological Characteristics and Retinal Vessel Diameter for Identifying Ocular Ischemic Syndrome.

Purpose: To investigate the morphological characteristics of the ophthalmic artery (OA) and retinal vessels in ocular ischemic syndrome (OIS) and to compare their ability to identify OIS. Methods: This cross-sectional observational study included 21 patients with unilateral OIS and 17 controls matched for age, sex, degree of internal carotid artery (ICA) stenosis, and cerebral collateral patency. This study used a three-dimensional reconstruction based on computed tomographic angiography to measure the morphological characteristics of the OA and the ICA. Quantitative measurements of retinal vessel diameter were performed using the Integrative Vessel Analysis software. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of the OA diameter and the central retinal artery equivalent (CRAE) to identify OIS. Results: The diameter of the OA (odds ratio = 0.001; P = 0.001) and the CRAE (odds ratio = 0.951; P = 0.028) were significantly associated with the presence of OIS after adjusting for age, sex, and the degree of the ICA stenosis. The areas under the curve for the OA diameter and the CRAE were, respectively, 0.871 (P < 0.001) and 0.744 (P = 0.017) according to the ROC curves analysis. Conclusions: The OA diameter measurement identified OIS better than CRAE measurement. The OA may reflect the changes in ocular blood supply in patients with OIS earlier than retinal vessels. The OA of eyes with OIS may undergo arterial wall remodeling, leading to a decrease in OA diameter and further reduction in blood flow.

[Quality of Images Reconstructed by Deep Learning Reconstruction Algorithm for Head and Neck CT Angiography at 100 kVp].

Objective To evaluate the impact of deep learning reconstruction algorithm on the image quality of head and neck CT angiography (CTA) at 100 kVp. Methods CT scanning was performed at 100 kVp for the 37 patients who underwent head and neck CTA in PUMC Hospital from March to April in 2021.Four sets of images were reconstructed by three-dimensional adaptive iterative dose reduction (AIDR 3D) and advanced intelligent Clear-IQ engine (AiCE) (low,medium,and high intensity algorithms),respectively.The average CT value,standard deviation (SD),signal-to-noise ratio (SNR),and contrast-to-noise ratio (CNR) of the region of interest in the transverse section image were calculated.Furthermore,the four sets of sagittal maximum intensity projection images of the anterior cerebral artery were scored (1 point:poor,5 points:excellent). Results The SNR and CNR showed differences in the images reconstructed by AiCE (low,medium,and high intensity) and AIDR 3D (all P<0.01).The quality scores of the image reconstructed by AiCE (low,medium,and high intensity) and AIDR 3D were 4.78±0.41,4.92±0.27,4.97±0.16,and 3.92±0.27,respectively,which showed statistically significant differences (all P<0.001). Conclusion AiCE outperformed AIDR 3D in reconstructing the images of head and neck CTA at 100 kVp,being capable of improving image quality and applicable in clinical examinations.

13-Cis Retinoic Acid Induces Neuronal Differentiation in Daoy (Medulloblastoma) Cells Through Epigenetic Regulation of Topoisomerase IIß.

Medulloblastoma (MB) is a malignant tumor of the cerebellum that occurs in children and infants. Abnormal neuronal differentiation can lead to brain tumors, and topoisomerase IIß (Top IIß) plays an important role in neuronal differentiation. The aim of this study was to investigate the molecular mechanism of 13-cis retinoic acid (13-cis RA) promoting the expression of Top IIß and inducing neuronal differentiation in human MB Daoy cells. The results showed that 13-cis RA inhibited the cell proliferation and induced cell cycle arrest in G0/G1 phase. The cells differentiated into a neuronal phenotype, with high expression of the neuronal marker microtubule-associated protein 2 (MAP2) and abundant Top IIß, and obvious neurite growth. Chromatin immunoprecipitation (ChIP) assay showed that histone H3 lysine 27 tri-methylation (H3K27me3) modification in Top IIß promoter decreased after 13-cis RA-induced cell differentiation, while jumonji domain-containing protein 3 (JMJD3) binding in Top IIß promoter increased. These results suggest that H3K27me3 and JMJD3 can regulate the expression of Top IIß gene, which is related to inducing neural differentiation. Our results provide new insights into understanding the regulatory mechanisms of Top IIß during neuronal differentiation and imply the potential application of 13-cis RA in the clinical treatment of MB.

Impact of total cerebral small vessel disease score on ophthalmic artery morphologies and hemodynamics.

BACKGROUND: Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score. METHODS: This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations. RESULTS: The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (ß = - 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001). CONCLUSIONS: The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA.

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.

Comparison of the efficacy and safety of non-steroidal anti-inflammatory drugs and corticosteroid drugs for prevention of cystoid macular edema after cataract surgery.

INTRODUCTION: To compare the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAID), corticosteroid (CS), and a combination of both drugs to prevent cystoid macular edema (CME) after cataract surgery. METHODS: We searched Pubmed, Cochrane Library, and Embase electronic databases to assess the relevant randomized controlled trials (RCTs) up to 28 April 2021. Network meta-analysis was registered on PROSPERO (CRD42020182520). RESULTS: Twenty-four RCTs were included in this review. The NSAID and combination of both drugs were significantly reduced the risk of developing CME than CS alone in non-diabetics and mix populations. In the ranking profiles, the combination therapy showed a significant advantage over the single drugs and was less likely to develop CME. Diclofenac was the most likely to reduce the odds of developing CME compared with bromfenac and nepafenac. Dexamethasone was the most likely to reduce the odds of developing CME compared with betamethasone and fluorometholone. CONCLUSION: NSAID combination with CS has significantly reduced the risk of developing CME postoperatively than the single drug. Diclofenac was superior to bromfenac and nepafenac in preventing CME. Dexamethasone was superior to betamethasone and fluorometholone in preventing CME.

[Regulatory Effect of Vitamin D on Renin Expression at Maternal-Fetal Interface].

Objective: To investigate the regulatory effect and mechanism of vitamin D on the local renin-angiotensin system at maternal-fetal interface in the pathological process of preeclampsia (PE). Methods: The mRNA and protein expression of renin in decidua of normal pregnancy and PE placentas was determined by RT-PCR and Western blot. Normal decidual tissues were treated with active and inactive vitamin D for 48 h in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Normal decidual stromal cells and glandular epithelial cells were isolated and purified, and identified by immunocytochemical staining. RT-PCR was used to examine the mRNA of vdr, cyp27 b1, cyp24 a1, and renin in the two types of cells and in decidual tissue, and the mRNA products were subjected to gel electrophoresis. These two cell types were treated with active and inactive vitamin D in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Decidual gland epithelial cells were treated with protein kinase A (PKA) activator forskolin or inhibitor H89 to explore the interaction between PKA pathway and vitamin D in the regulation of renin expression. Results: The expression of renin in PE decidua was significantly higher than that of normal control at transcriptional and translational levels ( P<0.05). Vitamin D treatment could significantly down-regulate the expression of renin in normal decidua tissues ( P<0.05), while it significantly up-regulated CYP24A1 expression ( P<0.001). Decidual stromal cells and gland epithelial cells were successfully isolated from decidual tissue. Compared with that in decidual stromal cells, the mRNA level of vitamin D-related molecules in gland epithelial cells was more similar to that in decidual tissue. Active or inactive vitamin D treatment significantly inhibited the expression of renin in glandular epithelial cells ( P<0.05), but the expression of renin in decidual stromal cells was not affected. However, the treatment of active or inactive vitamin D in these two kinds of cells significantly increased the expression of CYP24A1 ( P<0.001). Active vitamin D could significantly inhibit the upregulation of renin by PKA agonist forskolin, and could inhibit the expression of renin through synergy with PKA inhibitor H89. Conclusion: The expression of renin in placental decidua is up-regulated in patients with PE, and the activation of local renin-angiotensin system at the maternal-fetal interface may be involved in the pathogenesis of PE. Vitamin D can specifically down-regulate renin expression in human decidual gland epithelial cells by competing with the PKA pathway. Vitamin D supplementation may have potential value for clinical intervention of PE.

Ophthalmic artery changes in type 2 diabetes with and without acute coronary syndrome.

BACKGROUND: Ocular blood flow provides a new perspective for studying the effects of diabetes and ischemic heart disease on systemic blood flow, pathological mechanisms, and prognosis. Previous studies have analyzed the hemodynamic changes of the ophthalmic artery (OA) in patients with diabetes and ischemic heart disease, but the results remain controversial due to limited observation methods. We aimed to explore the morphological and hemodynamic features in the OA in patients with type 2 diabetes (T2D) with and without acute coronary syndrome (ACS). METHODS: In total, 134 participants, including 30 control participants, 34 with ACS only, 34 with T2D only, and 36 with both ACS and T2D, undergoing computed tomography angiography were enrolled. Three-dimensional OA models were reconstructed, and morphological parameters of the OA were measured. In addition, numerical simulations using computational fluid dynamics were used to acquire hemodynamic parameters of the OA. RESULTS: In this study, 134 OA models were reconstructed. Morphological measurements revealed a smaller initial OA diameter in the T2D group than in the other two ACS groups. A hemodynamic simulation showed a significantly lower OA blood velocity in patients with ACS and T2D than that in controls (P < 0.001). The mass flow ratios in all disease groups were lower than those in the control group (P < 0.001, P = 0.020, and P < 0.001, respectively). The ACS and T2D groups had higher OA pressure levels than those of the control group (P = 0.013). The OA blood velocity and mass flow ratio were correlated with several clinical parameters. CONCLUSIONS: This study revealed morphological and hemodynamic differences in the OA between patients with T2D with and without ACS. Furthermore, the hemodynamic characteristics of the OA correlated with clinical prognostic biomarkers, suggesting the potential predictive ability of the OA.

Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice.

BACKGROUND: The laboratory mouse was domesticated from the wild house mouse. Understanding the genetics underlying domestication in laboratory mice, especially in the widely used classical inbred mice, is vital for studies using mouse models. However, the genetic mechanism of laboratory mouse domestication remains unknown due to lack of adequate genomic sequences of wild mice. RESULTS: We analyze the genetic relationships by whole-genome resequencing of 36 wild mice and 36 inbred strains. All classical inbred mice cluster together distinctly from wild and wild-derived inbred mice. Using nucleotide diversity analysis, Fst, and XP-CLR, we identify 339 positively selected genes that are closely associated with nervous system function. Approximately one third of these positively selected genes are highly expressed in brain tissues, and genetic mouse models of 125 genes in the positively selected genes exhibit abnormal behavioral or nervous system phenotypes. These positively selected genes show a higher ratio of differential expression between wild and classical inbred mice compared with all genes, especially in the hippocampus and frontal lobe. Using a mutant mouse model, we find that the SNP rs27900929 (T>C) in gene Astn2 significantly reduces the tameness of mice and modifies the ratio of the two Astn2 (a/b) isoforms. CONCLUSION: Our study indicates that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The analysis shows the positively selected genes are closely associated with behavior and the nervous system in mice. Tameness may be related to the Astn2 mutation and regulated by the ratio of the two Astn2 (a/b) isoforms.

Momordica charantia Exosome-Like Nanoparticles Exert Neuroprotective Effects Against Ischemic Brain Injury via Inhibiting Matrix Metalloproteinase 9 and Activating the AKT/GSK3ß Signaling Pathway.

Plant exosome-like nanoparticles (ELNs) have shown great potential in treating tumor and inflammatory diseases, but the neuroprotective effect of plant ELNs remains unknown. In the present study, we isolated and characterized novel ELNs from Momordica charantia (MC) and investigated their neuroprotective effects against cerebral ischemia-reperfusion injury. In the present study, MC-ELNs were isolated by ultracentrifugation and characterized. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) and MC-ELN injection intravenously. The integrity of the blood-brain barrier (BBB) was examined by Evans blue staining and with the expression of matrix metalloproteinase 9 (MMP-9), claudin-5, and ZO-1. Neuronal apoptosis was evaluated by TUNEL and the expression of apoptotic proteins including Bcl2, Bax, and cleaved caspase 3. The major discoveries include: 1) Dil-labeled MC-ELNs were identified in the infarct area; 2) MC-ELN treatment significantly ameliorated BBB disruption, decreased infarct sizes, and reduced neurological deficit scores; 3) MC-ELN treatment obviously downregulated the expression of MMP-9 and upregulated the expression of ZO-1 and claudin-5. Small RNA-sequencing revealed that MC-ELN-derived miRNA5266 reduced MMP-9 expression. Furthermore, MC-ELN treatment significantly upregulated the AKT/GSK3ß signaling pathway and attenuated neuronal apoptosis in HT22 cells. Taken together, these findings indicate that MC-ELNs attenuate ischemia-reperfusion-induced damage to the BBB and inhibit neuronal apoptosis probably via the upregulation of the AKT/GSK3ß signaling pathway.

Efficacy of comprehensive remote ischemic conditioning in elderly patients with acute ST-segment elevation myocardial infarction underwent primary percutaneous coronary intervention.

BACKGROUND: Remote ischemic conditioning (RIC) is used to protect against myocardial injury. However, there is no adequate evidence for comprehensive RIC in elderly patients with ST-segment elevation myocardial infarction (STEMI). This study aimed to test whether comprehensive RIC, started pre-primary percutaneous coronary intervention (PPCI) and repeated daily on 1-30 days post-PPCI, can improve myocardial salvage index (SI), left ventricular ejection fraction (LVEF), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and 6-min walk test distance (6MWD) in elderly patients with acute STEMI during 12 months follow-up. METHODS: 328 consenting elderly patients were randomized to receive standard PPCI plus comprehensive RIC (the treatment group) or standard PPCI (the control group). SI at 5-7 days after PPCI, LVEF, left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), KCCQ-CSS, 6MWD and adverse events rates were measured and assessed. RESULTS: SI was significantly higher in the treatment group [interquartile range (IQR): 0.38-0.66, P = 0.037]. There were no significant differences in major adverse events at 12 months. Although the differences of LVEDVI, LVESVI and LVEF between the treatment group and the control group did not reach statistical significance at 6 months and 12 months, LVEF tended to be higher, LVEDVI tended to be lower in the treatment group. The KCCQ-CSS was significantly higher in the treatment group at 1 month (IQR: 46.5-87, P = 0.001) and 12 months (IQR: 55-93, P = 0.008). There was significant difference in 6MWD between the treatment group and the control group (IQR: 258-360 vs. IQR: 250-345, P = 0.002) at 1 month and (IQR: 360-445 vs. IQR: 345-432, P = 0.035) at 12 months. A modest correlation was found between SI and LVEF (r = 0.452, P < 0.01), KCCQ-CSS ( r = 0.440, P < 0.01) and 6MWD ( r = 0.384, P < 0.01) respectively at 12 months. CONCLUSIONS: The comprehensive RIC can improve SI, KCCQ-CSS and 6MWD. It may be an adjunctive therapy to PPCI in elderly patients with STEMI.

The mystery of the life tree: the placentas†.

The placenta is the interface between the fetal and maternal environments during mammalian gestation, critically safeguarding the health of the developing fetus and the mother. Placental trophoblasts origin from embryonic trophectoderm that differentiates into various trophoblastic subtypes through villous and extravillous pathways. The trophoblasts actively interact with multiple decidual cells and immune cells at the maternal-fetal interface and thus construct fundamental functional units, which are responsible for blood perfusion, maternal-fetal material exchange, placental endocrine, immune tolerance, and adequate defense barrier against pathogen infection. Various pregnant complications are tightly associated with the defects in placental development and function maintenance. In this review, we summarize the current views and our recent progress on the mechanisms underlying the formation of placental functional units, the interactions among trophoblasts and various uterine cells, as well as the placental barrier against pathogen infections during pregnancy. The involvement of placental dysregulation in adverse pregnancy outcomes is discussed.

Healthy Serum-Derived Exosomes Improve Neurological Outcomes and Protect Blood-Brain Barrier by Inhibiting Endothelial Cell Apoptosis and Reversing Autophagy-Mediated Tight Junction Protein Reduction in Rat Stroke Model.

Blood-brain barrier (BBB) dysfunction causing edema and hemorrhagic transformation is one of the pathophysiological characteristics of stroke. Protection of BBB integrity has shown great potential in improving stroke outcome. Here, we assessed the efficacy of exosomes extracted from healthy rat serum in protection against ischemic stroke in vivo and in vitro. Exosomes were isolated by gradient centrifugation and ultracentrifugation and exosomes were characterized by transmission electron microscopy (TEM) and nanoparticle tracking video microscope. Exosomes were applied to middle cerebral artery occlusion (MCAO) rats or brain microvascular endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD) injury. Serum-derived exosomes were injected intravenously into adult male rats 2 h after transient MCAO. Infarct volume and gross cognitive function were assessed 24 h after reperfusion. Poststroke rats treated with serum-derived exosomes exhibited significantly reduced infarct volumes and enhanced neurological function. Apoptosis was assessed via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining and the expression of B-cell lymphoma-2 (Bcl-2), Bax, and cleaved caspase-3 24 h after injury. Our data showed that serum exosomes treatment strikingly decreased TUNEL+ cells in the striatum, enhanced the ratio of Bcl-2 to Bax, and inhibited cleaved caspase-3 production in MCAO rats and OGD/reoxygenation insulted bEnd.3 cells. Under the consistent treatment, the expression of microtubule-associated protein 1 light chain 3B-II (LC3B-II), LC3B-I, and Sequestosome-1 (SQSTM1)/p62 was detected by Western blotting. Autolysosomes were observed via TEM. We found that serum exosomes reversed the ratio of LC3B-II to LC3B-I, prevented SQSTM1/p62 degradation, autolysosome formation, and autophagic flux. Together, these results indicated that exosomes isolated from healthy serum provided neuroprotection against experimental stroke partially via inhibition of endothelial cell apoptosis and autophagy-mediated BBB breakdown. Intravenous serum-derived exosome treatment may, therefore, provide a novel clinical therapeutic strategy for ischemic stroke.