The Thalamocortical Mechanism Underlying the Generation and Regulation of the Auditory Steady-State Responses in Awake Mice.

The auditory steady-state response (ASSR) is a cortical oscillation induced by trains of 40 Hz acoustic stimuli. While the ASSR has been widely used in clinic measurement, the underlying neural mechanism remains poorly understood. In this study, we investigated the contribution of different stages of auditory thalamocortical pathway-medial geniculate body (MGB), thalamic reticular nucleus (TRN), and auditory cortex (AC)-to the generation and regulation of 40 Hz ASSR in C57BL/6 mice of both sexes. We found that the neural response synchronizing to 40 Hz sound stimuli was most prominent in the GABAergic neurons in the granular layer of AC and the ventral division of MGB (MGBv), which were regulated by optogenetic manipulation of TRN neurons. Behavioral experiments confirmed that disrupting TRN activity has a detrimental effect on the ability of mice to discriminate 40 Hz sounds. These findings revealed a thalamocortical mechanism helpful to interpret the results of clinical ASSR examinations.Significance Statement Our study contributes to clarifying the thalamocortical mechanisms underlying the generation and regulation of the auditory steady-state response (ASSR), which is commonly used in both clinical and neuroscience research to assess the integrity of auditory function. Combining a series of electrophysiological and optogenetic experiments, we demonstrate that the generation of cortical ASSR is dependent on the lemniscal thalamocortical projections originating from the ventral division of medial geniculate body to the GABAergic interneurons in the granule layer of the auditory cortex. Furthermore, the thalamocortical process for ASSR is strictly regulated by the activity of thalamic reticular nucleus (TRN) neurons. Behavioral experiments confirmed that dysfunction of TRN would cause a disruption of mice's behavioral performance in the auditory discrimination task.

Human lung organoid: Models for respiratory biology and diseases.

The human respiratory system, consisting of the airway and alveoli, is one of the most complex organs directly interfaced with the external environment. The diverse epithelial cells lining the surface are usually the first cell barrier that comes into contact with pathogens that could lead to deadly pulmonary disease. There is an urgent need to understand the mechanisms of self-renewal and protection of these epithelial cells against harmful pathogens, such as SARS-CoV-2. Traditional models, including cell lines and mouse models, have extremely limited native phenotypic features. Therefore, in recent years, to mimic the complexity of the lung, airway and alveoli organoid technology has been developed and widely applied. TGF-ß/BMP/SMAD, FGF and Wnt/ß-catenin signaling have been proven to play a key role in lung organoid expansion and differentiation. Thus, we summarize the current novel lung organoid culture strategies and discuss their application for understanding the lung biological features and pathophysiology of pulmonary diseases, especially COVID-19. Lung organoids provide an excellent in vitro model and research platform.

Dexmedetomidine alleviates hippocampal neuronal loss and cognitive decline in rats undergoing open surgery under sevoflurane anaesthesia by suppressing CCAAT/enhancer-binding protein beta.

Dexmedetomidine (Dex) may exert neuroprotective effects by attenuating inflammatory responses. However, whether Dex specifically improves postoperative cognitive dysfunction (POCD) by inhibiting microglial inflammation through what pathway remains unclear. In this study, the POCD model was constructed by performing open surgery after 3 h of continuous inhalation of 3% sevoflurane to rats, which were intraperitoneally injected with 25 µg/kg Dex .5 h before anaesthesia. The results displayed that Dex intervention decreased rat escape latency, maintained swimming speed and increased the number of times rats crossed the platform and the time spent in the target quadrant. Furthermore, the rat neuronal injury was restored, alleviated POCD modelling-induced rat hippocampal microglial activation and inhibited microglial M1 type polarization. Besides, we administered Dex injection and/or CCAAT/enhancer-binding protein beta (CEBPB) knockdown on the basis of sevoflurane exposure and open surgery and found that CEBPB was knocked down, resulting in the inability of Dex to function, which confirmed CEBPB as a target for Dex treatment. To sum up, Dex improved POCD by considering CEBPB as a drug target to activate the c-Jun N-terminal kinase (JNK)/p-38 signaling pathway, inhibiting microglial M1 polarization-mediated inflammation in the central nervous system.

Cortical and thalamic modulation of auditory gating in the posterior parietal cortex of awake mice.

Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ.

Generalization of sequence effects from conflict to cueing tasks.

Cognitive control has been investigated in attentional conflict tasks for a long time. One representative phenomenon of adaptive cognitive control in these tasks is the congruency sequence effect (CSE), which means that a previous conflict will lead to reduced congruency effects at the current moment, reflecting increased control of attention toward the task at hand. One debating question is whether CSE can generalize between different conditions. Since a similar phenomenon (i.e., validity sequence effect, VSE) has been found in spatial cueing tasks, this study investigated whether the two sequential effects could generalize between each other. A cross-task sequence effect is found from previous flanker trials to current cueing trials when the task sets of the two tasks are either very similar or sufficiently dissimilar, and this C-VSE effect is influenced by the response mode of the experimental design. In addition, the VSE between trial n-2 and trial n is eliminated by the existence of an intermediate flanker trial, but the CSE between trial n-2 and trial n is still significant even with an intermediate cueing trial. Possible explanations of these findings are discussed. The findings suggest a close connection between orienting and executive control processes in attention networks and provide a new perspective and method for investigating the potential mechanisms of cognitive control.

Interactive modulations between congruency sequence effects and validity sequence effects.

Sequential modulations have been found in both conflict and spatial orienting tasks. The former is called congruency sequence effects (CSE) and the latter is called validity sequence effects (VSE). Although the two effects have similar phenomenon descriptions, the relationship of the cognitive control mechanisms under the two effects is still unclear. Using a modified attentional network test (ANT), a flanker task and an arrow cueing task are integrated into a single task, which enables the test of the possible interactions between CSE and VSE. Since a confound-minimized design is used, the observed sequence effects cannot be attributed to the feature integration of low-level stimulus features or the contingency learning. It was found that the CSE are only significant when the arrow cue in preceding trial is invalid, and the VSE are only significant when the target letter in preceding trial is congruent with the distractor letters. The findings suggest that the sequential modulations during orienting and executive control of attention networks are highly interacted with each other, and the sequence effects in these networks are possibly controlled by a complex and multifaceted adaptive control mechanism.

Missing-Sheds Granularity Estimation of Glass Insulators Using Deep Neural Networks Based on Optical Imaging.

Insulator defect detection is an important task in inspecting overhead transmission lines. However, the surrounding environment is complex, and the detection accuracy of traditional image processing algorithms is low. Therefore, insulator defect detection is still mainly performed manually. In order to improve this situation, we proposed an insulator defect detection method called INSU-YOLO based on deep neural networks. Overexposure points in the image will interfere with insulator detection, so we used image augment to reduce noise and extract the edge information of the insulator. Based on an attention mechanism, we introduced a structure called attention-block where the backbone extracts the feature map, and this aims to improve the ability of our method to detect insulators. Insulators have a variety of specifications, and the location and granularity of defects are also different. Therefore, we proposed an adaptive threat estimation method based on the area ratio between the entire insulator and the defect area. In addition, in order to solve the problem of data shortage, we established a dataset called InsuDetSet for model training. Experiments on the InsuDetSet dataset demonstrated that our model outperforms existing state-of-the-art models regarding both the detection box and speed.

Transmission Line Vibration Damper Detection Using Multi-Granularity Conditional Generative Adversarial Nets Based on UAV Inspection Images.

The vibration dampers can eliminate the galloping phenomenon of transmission lines caused by the wind. The detection of vibration dampers based on visual technology is an important issue. Current CNN-based methods struggle to meet the requirements of real-time detection. Therefore, the current vibration damper detection work has mainly been carried out manually. In view of the above situation, we propose a vibration damper detection-image generation model called DamperGAN based on multi-granularity Conditional Generative Adversarial Nets. DamperGAN first generates a low-resolution detection result image based on a coarse-grained module, then uses Monte Carlo search to mine the latent information in the low-resolution image, and finally injects this information into a fine-grained module through an attention mechanism to output high-resolution images and penalize poor intermediate information. At the same time, we propose a multi-level discriminator based on the multi-task learning mechanism to improve the discriminator's discriminative ability and promote the generator to output better images. Finally, experiments on the self-built DamperGenSet dataset show that the images generated by our model are superior to the current mainstream baselines in both resolution and quality.

Transmission Line Vibration Damper Detection Using Deep Neural Networks Based on UAV Remote Sensing Image.

Vibration dampers can greatly eliminate the galloping phenomenon of overhead transmission wires caused by wind. The detection of vibration dampers based on visual technology is an important issue. The current vibration damper detection work is mainly carried out manually. In view of the above situation, this article proposes a vibration damper detection model named DamperYOLO based on the one-stage framework in object detection. DamperYOLO first uses a Canny operator to smooth the overexposed points of the input image and extract edge features, then selectees ResNet101 as the backbone of the framework to improve the detection speed, and finally injects edge features into backbone through an attention mechanism. At the same time, an FPN-based feature fusion network is used to provide feature maps of multiple resolutions. In addition, we built a vibration damper detection dataset named DamperDetSet based on UAV cruise images. Multiple sets of experiments on self-built DamperDetSet dataset prove that our model reaches state-of-the-art level in terms of accuracy and test speed and meets the standard of real-time output of high-accuracy test results.

Design and Analysis of Broadband LiNbO3 Optical Waveguide Electric Field Sensor with Tapered Antenna.

The three-dimensional (3D) simulation model of a lithium niobate (LiNbO3, LN) optical waveguide (OWG) electric field sensor has been established by using the full-wave electromagnetic simulation software. The influences of the LN substrate and the packaging material on the resonance frequency of the integrated OWG electric field sensor have been simulated and analyzed. The simulation results show that the thickness of the LN substrate has a great influence on the resonant frequency of the sensor (≈33.4%). A sensor with a substrate thickness of 1 mm has been designed, fabricated, and experimentally investigated. Experimental results indicate that the measured resonance frequency is 7.5 GHz, which nearly coincides with the simulation results. Moreover, the sensor can be used for the measurement of the nanosecond electromagnetic impulse (NEMP) in the time domain from 1.29 kV/m to 100.97 kV/m.

Measurements of Excavation Damaged Zone by Using Fiber Bragg Grating Stress Sensors.

In this paper, a Fiber Bragg Grating (FBG) stress sensor is developed to measure the stress variation between the lower Excavation Damaged Zone (EDZ) and the upper undistributed rock. The disturbance brought by the environmental temperature can be differentially compensated with two FBGs mounted symmetrically on the spokes. Through finite element analysis, it can be known that the direct stress and shear stress are pointed at the angles of 45° and 60° on both sides of the coal mine roadway, respectively. The anchor ends of the sensors are installed into the upper undistributed rock and the bolt tails of the mine roadway with a depth of 700 m and fastened by nuts to secure the load sensing device on the surface of the rock. When the shallow foundation of surrounding rock is pressed and deformed toward the coal mining road, the structural modifications can be converted into the stress of rock bolt and the strain of spoke. Thus, the FBG mounted on the surface of the spoke receives the shift information of the Bragg wavelength. The monitoring results indicate that the FBG stress sensors are sensitive to the variation of the EDZ. During the blasting, the stress amplitude varies from 40.256 to 175.058 kPa, and the creep time changes from 21 to 74 min. The proposed method can be applied in the field of underground coal mines for safety condition monitoring of the EDZ and forecasting the coal mine roadway stability.

Effect of dexmedetomidine on analgesia and sedation of sufentanil during anesthesia induction period of gynecological surgery.

To observe and analyze the effect of dexmedetomidine on analgesia and sedation of sufentanil during anesthesia induction period of gynecological surgery. A total of 160 patients demanding gynecologic surgery were enrolled in the study and randomly divided into study group and control group, each containing 80 patients. The control group was treated with sufentanil and normal saline, while the study group was treated with sufentanil and dexmedetomidine. Then, the therapeutic effect of the two groups was compared. NTI of the two groups was observed at A2, which was significantly lower in the study group than that in the control group. Moreover, NTI value of the two groups was significantly lower at A2 and A4 than at A1. When the NTI value was reduced to a minimum, the application time was significantly shorter in the study group than that in the control group. PTO and PPT of the two groups were higher at A4 than those at A1. At A1 and A4, The difference between PTO and PPT was significantly higher in the study group than that in the control group, p<0.05. The rate of adverse reactions was significantly lower in the study group than that in the control group, p<0.05. Dexmedetomidine has good effect on analgesia and sedation of sufentanil during anesthesia induction period of gynecological surgery, which should be popularized in clinical application.

Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer.

Some microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression has been reported to correlate with chemoresistance of cancer cells. Therefore, the present study aims at investigating the effects of microRNA-139-5p (miR-139-5p) on cisplatin resistance of ovarian cancer (OC) with involvement of ring finger protein 2 (RNF2) and the mitogen-activated protein kinase (MAPK) signaling pathway. OC tissues were obtained from 66 primary OC patients. The cisplatin-sensitive A2780 and cisplatin-resistant A2780/DDP cell lines were collected for construction of RNF2 silencing and overexpressed plasmids. Cell vitality and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V-FITC/propidium iodide double-staining, respectively. Next, expression of RNF2, extracellular signal-related kinase, and p38 was determined by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Finally, the volume of xenograft tumors in BALB/c nude mice was detected. RNF2 and miR-139-5p were identified to be involved in OC. In addition, MAPK activation and RNF2 were related to cisplatin resistance of OC. miR-139-5p was downregulated in cisplatin-resistant OC tissues, and miR-139-5p overexpression could inhibit cell vitality, reduce cisplatin resistance, and promote apoptosis of OC cells. Furthermore, miR-139-5p combined with MAPK inhibitors more obviously reduced cisplatin resistance of OC. Taken together, this study demonstrated that miR-139-5p overexpression combined with inactivation of the MAPK signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2. Thus, miR-139-5p overexpression might be a future therapeutic strategy for OC.

MicroRNA-374b inhibits cervical cancer cell proliferation and induces apoptosis through the p38/ERK signaling pathway by binding to JAM-2.

Cervical cancer (CC) remains a highly prevalent cancer and mortality globally among women globally. The aim of the present study was to assess the ability of miR-374b to regulate CC cells through JAM-2, whilst exploring whether the underlying mechanism and its relation to the p38/ERK signaling pathway. During the study, microRNA-374b (miR-374b) was observed to have been expressed at a low level among CC tissues. Hence, a series of miR-374b mimics, miR-374b inhibitors, siRNA against JAM-2, SB202190 (an inhibitor for p38), and PD98059 (an inhibitor for ERK) were introduced to treat CC Siha cells and normal cervical Ect1/E6E7 cells. MTT, flow cytometry, scratch test, and transwell assays were applied to determine cell viability, apoptosis, migration, and invasion. The inhibitory role of the p38/ERK signaling pathway was observed in the CC cells treated with miR-374b mimics or siRNA against JAM-2. miR-374b mimic exposure was found to reduce cell viability, migration, and invasion, but induce apoptosis. MiR-374b inhibitor exposure was observed to have induced effects on the CC cells in a contrary manner to those induced by that of the miR-374b mimics. The key findings of the study demonstrated that miR-374b significantly inhibits cell proliferation, migration, and invasion through the blockade of the p38/ERK signaling pathway activation, as well as negatively binding to JAM-2, highlighting its potential as a therapeutic target for CC.

Lp-PLA2 silencing protects against ox-LDL-induced oxidative stress and cell apoptosis via Akt/mTOR signaling pathway in human THP1 macrophages.

Atherosclerosis is a disease of the large- and medium-size arteries that is characterized by the formation of atherosclerotic plaques, in which foam cells are the characteristic pathological cells. However, the key underlying pathomechanisms are still not fully elucidated. In this study, we investigated the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in ox-LDL-induced oxidative stress and cell apoptosis, and further, elucidated the potential machanisms in human THP1 macrophages. Flow cytometry and western blot analyses showed that both cell apoptosis and Lp-PLA2 expression were dose-dependently elevated after ox-LDL treatment for 24 h and also time-dependently increased after 50 mg/L ox-LDL incubation in THP1 macrophages. In addition, Lp-PLA2 silencing decreased ox-LDL-induced Lp-PLA2 and CD36 expression in THP1 macrophages. We also found that the levels of oil red O-staining, triglyceride (TG) and total cholesterol (TC) were significantly upregulated in ox-LDL-treated THP1 cells, but inhibited by Lp-PLA2 silencing. Furthermore, ox-LDL treatment resulted in significant increases of ROS and MDA but a marked decrease of SOD, effects that were reversed by Lp-PLA2 silencing in THP1 cells. Lp-PLA2 silencing reduced ox-LDL-induced cell apoptosis and caspase-3 expression in THP1 cells. Moreover, Lp-PLA2 siRNA transfection dramatically lowered the elevated levels of p-Akt and p-mTOR proteins in ox-LDL-treated THP1 cells. Both PI3K inhibitor LY294002 and mTOR inhibitor rapamycin decreased the augmented caspase-3 expression and TC content induced by ox-LDL, respectively. Taken together, these results revealed that Lp-PLA2 silencing protected against ox-LDL-induced oxidative stress and cell apoptosis via Akt/mTOR signaling pathway in human THP1 macrophages.

Predictive value of apolipoprotein for coronary atherosclerosis in asymptomatic non-diabetic population.

OBJECTIVE: To explore the potential correlation between apolipoprotein (Apo) levels and coronary atherosclerosis and investigate its predictive value for coronary artery lesions in asymptomatic population without diabetes. METHODS: We performed a retrospective analysis of data collected from 401 asymptomatic patients who took health check-ups. They were divided into atherosclerosis group (n=224)and control group (n=177) based on the outcome of CT angiography and blood biochemical findings. The risk factors, lipid profiles, and Apo levels were compared between these two groups. The best biochemical indicators for predicting the coronary atherosclerosis were explored. RESULTS: The levels of ApoB, ApoC2,ApoC3,and ApoE and ApoB/ApoA1 ratio were significantly higher in the atherosclerosis group than in the control group (all P<0.01), whereas the ApoA1,ApoA2, and lipoprotein a levels showed no such significant difference (all P>0.05). Logistic regression analysis revealed that age, male, hypertension,ApoC3(OR=1.572,95%CI 1.200-2.061) and ApoB/ApoA1 ratio (OR=1.767,95% CI 1.335-2.338) were independently correlated with coronary atherosclerosis (all P<0.01). In the prediction of the presence of plaque, ApoB had the largest area under curves, and the optimal cutoff point was 1.005 g/L. CONCLUSIONS: ApoC3 is closely associated with subclinical coronary atherosclerosis,while the decrease of ApoA1 level is not obvious during this period. Compared with other lipid indicators, ApoB is the strongest predictor for coronary atherosclerosis in asymptomatic non-diabetic population.

Correlation of creatine kinase with patency of stents using coronary computed tomography angiography.

OBJECTIVE: To explore the potential correlation between creatine kinase and the long-term patency of coronary drug eluting stents. METHODS: The clinical data of 74 patients who had undergone coronary computed tomography angiography after drug eluting stents implantation were retrospecpectively analyzed. Based on the computed tomography angiography findings,these patients were divided into patency group and non-patency group. The mean follow-up time was (20.5 ± 13.1) months. The serum levels of creatine kinase and creatine kinase isoenzyme were measured to determine the relationship of stent patency with these oxidative-related biomarkers after long-term follow-up. The T test or non-parametric test was adopted to compare the intergroup difference of measurement data,whereas chi-square test was conducted to test the difference of enumeration data. Logistic regression was adopted to analyze the biochemical indexes and clinical information. Only variables with a P value of less than 0.05 in the univariable analyses entered the multivariate Logistic regression model. RESULTS: Patients in the non-patency group had significantly higher serum creatine kinase level compared with patients in patency group [(115.5 ± 51.5)U/L vs.(75.9 ± 29.4)U/L, P=0.012] and significantly higher level of creatine kinase isoenzyme [(3.5 ± 5.3)U/L vs.(1.7 ± 1.3)U/L,P=0.034]. Furthermore,the Logistic analysis showed that serum creatine kinase level (odds ratio=1.573,95% CI=1.022-2.421, P=0.039)was an independent predictor of stent patency. CONCLUSION: Creatine kinase is an independent risk factor associated with stent non-patency.

Correlations between pathologic subtypes/immunohistochemical implication and CT characteristics of lung adenocarcinoma ≤ 1 cm with ground-glass opacity.

OBJECTIVE: To discuss the correlation of pathologic subtypes and immunohistochemical implication with CT features of lung adenocarcinoma 1 cm or less in diameter with focal ground-glass opacity (fGGO). METHODS: CT appearances of 59 patients who underwent curative resection of lung adenocarcinoma ≤ 1 cm with fGGO were analyzed in terms of lesion location, size, density, shape (round, oval, polygonal, irregular), margin (smooth, lobular, spiculated, lobular and spiculated), bubble-like sign, air bronchogram, pleural tag, and tumor-lung interface. Histopathologic subtypes were classified according to International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma. Common molecular markers in immunohistochemical study included human epidermal growth factor receptor (HER)-1,HER-2,Ki-67, vascular endothelial growth factor (VEGF) and DNA topoisomerase 2Α.Patients' age and lesions' size and density were compared with pathologic subtypes using analysis of variance or nonparametric Wilcoxon tests. Patients' gender, lesion location, shape and margin, bubble-like sign, air bronchogram, pleural tag, and tumor-lung interface were compared with histopathologic subtypes and immunohistochemical implication using ψ² test or Fisher's exact test. RESULTS: The patients' gender, age, lesion location, shape, air bronchogram, pleural tag, and tumor-lung interface were not significantly different among different histopathologic subtypes (P=0.194, 0.126, 0.609, 0.678, 0.091, 0.374, and 0.339, respectively), whereas the lesion size,density,bubble-like sign, and margin showed significant differences (P=0.028, 0.002, 0.003, 0.046, respectively). The expression of Ki-67 significantly differed among nodules with different shapes(P=0.015). Statistically significant difference also existed between tumor-lung interface and HER-1 expression (P=0.019) and between bubble sign and HER-2 expression (P=0.049). CONCLUSIONS: Of lung adenocarcinoma ≤ 1 cm with fGGO,bubble-like sign occurs more frequently in invasive pulmonary adenocarcinoma and less frequently in atypical adenomatous hyperplasia. In addition, preinvasive lesions (atypical adenomatous hyperplasia and adenocarcinoma in situ) more frequently demonstrates smooth margin,while invasive lesions (minimally invasive adenocarcinoma and invasive pulmonary adenocarcinoma) more frequently demonstrates lobular and spiculated margin. Some CT features are associated with immunohistochemical implication of lung adenocarcinoma ≤ 1 cm with fGGO.

Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression.

Blood-brain barrier (BBB) disruption occurring within the first few hours of ischemic stroke onset is closely associated with hemorrhagic transformation following thrombolytic therapy. However, the mechanism of this acute BBB disruption remains unclear. In the neurovascular unit, neurons do not have direct contact with the endothelial barrier; however, they are highly sensitive and vulnerable to ischemic injury, and may act as the initiator for disrupting BBB when cerebral ischemia occurs. Herein, we employed oxygen-glucose deprivation (OGD) and an in vitro BBB system consisting of brain microvascular cells and astrocytes to test this hypothesis. Neurons (CATH.a cells) were exposed to OGD for 3-h before co-culturing with endothelial monolayer (bEnd 3 cells), or endothelial cells plus astrocytes (C8-D1A cells). Incubation of OGD-treated neurons with endothelial monolayer alone did not increase endothelial permeability. However, when astrocytes were present, the endothelial permeability was significantly increased, which was accompanied by loss of occludin and claudin-5 proteins as well as increased vascular endothelial growth factor (VEGF) secretion into the conditioned medium. Importantly, all these changes were abolished when VEGF was knocked down in astrocytes by siRNA. Our findings suggest that ischemic neurons activate astrocytes to increase VEGF production, which in turn induces endothelial barrier disruption.

TCF2 attenuates FFA-induced damage in islet ß-cells by regulating production of insulin and ROS.

Free fatty acids (FFAs) are cytotoxic to pancreatic islet ß-cells and play a crucial role in the diabetes disease process. A recent study revealed a down-regulation of transcription factor 2 (TCF2) levels during FFA-mediated cytotoxicity in pancreatic ß-cells. However, its function during this process and the underlying mechanism remains unclear. In this study, treatment with palmitic acid (PA) at high levels (400 and 800 µM) decreased ß-cell viability and TCF2 protein expression, along with the glucose-stimulated insulin secretion (GSIS). Western and RT-PCR analysis confirmed the positive regulatory effect of TCF2 on GSIS through promotion of the key regulators pancreatic duodenal homeobox-1 (PDX1) and glucose transporter 2 (GLUT2) in ß-cells. In addition, both PI3K/AKT and MEK/ERK showed decreased expression in PA (800 µM)-treated ß-cells. Overexpression of TCF2 could effectively restore the inhibitory effect of PA on the activation of PI3K/AKT and MEK/ERK as well as ß-cell viability, simultaneously, inhibited PA-induced reactive oxygen species (ROS) generation. After blocking the PI3K/AKT and MAPK/ERK signals with their specific inhibitor, the effect of overexpressed TCF2 on ß-cell viability and ROS production was obviously attenuated. Furthermore, a protective effect of TCF2 on GSIS by positive modulation of JNK-PDX1/GLUT2 signaling was also confirmed. Accordingly, our study has confirmed that TCF2 positively modulates insulin secretion and further inhibits ROS generation via the PI3K/AKT and MEK/ERK signaling pathways. Our work may provide a new therapeutic target to achieve prevention and treatment of diabetes.