Molecular mechanism of acetylsalicylic acid in improving learning and memory impairment in APP/PS1 transgenic mice by inhibiting the abnormal cell cycle re-entry of neurons.

Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by the loss and apoptosis of neurons. Neurons abnormally enter the cell cycle, which results in neuronal apoptosis during the course of AD development and progression. However, the mechanisms underlying cell cycle re-entry have been poorly studied. Using neuroblastoma (N) 2a SW and APP/PS1 transgenic (Tg) mice as in vitro and in vivo AD models, we found that the expression of cyclin-dependent kinase (CDK)1/2/4 and cyclin A2/B1/D3/E1 was increased while the protein expression of p18 and p21 was decreased, which led to enhanced cell cycle re-entry in a ß-amyloid protein (Aß)-dependent mechanism. By preparing and treating with the temperature-sensitive chitosan-encapsulated drug delivery system (CS), the abnormal expression of CDK1/2/4, cyclin A2/B1/D3/E1 and p18/21 was partially restored by acetylsalicylic acid (ASA), which decreased the apoptosis of neurons in APP/PS1 Tg mice. Moreover, CDK4 and p21 mediated the effects of ASA on activating transcription factor (TF) EB via peroxisome proliferator-activated receptor (PPAR) α, thus leading to the uptake of Aß by astrocytes in a low-density lipoprotein receptor (Ldlr)-dependent mechanism. Moreover, the mechanisms of Aß-degrading mechanisms are activated, including the production of microtubule-associated protein light chain (LC) 3II and Lamp2 protein by ASA in a PPARα-activated TFEB-dependent manner. All these actions contribute to decreasing the production and deposition of Aß, thus leading to improved cognitive decline in APP/PS1 Tg mice.

Optimal Number of Clusters by Measuring Similarity Among Topographies for Spatio-Temporal ERP Analysis.

Averaging amplitudes over consecutive time samples (i.e., time window) is widely used to calculate the peak amplitude of event-related potentials (ERPs). Cluster analysis of the spatio-temporal ERP data is a promising tool to determine the time window of an ERP of interest. However, determining an appropriate number of clusters to optimally represent ERPs is still challenging. Here, we develop a new method to estimate the optimal number of clusters utilizing consensus clustering. Various polarity dependent clustering methods, namely, k-means, hierarchical clustering, fuzzy c-means, self-organizing map, spectral clustering, and Gaussian mixture model, are used to configure consensus clustering after assessing them individually. When a range of clusters is applied many times, the optimal number of clusters should correspond to the expectation, which is the average of the obtained mean inner-similarities of estimated time windows across all conditions and groups converge in the satisfactory thresholds. In order to assess our method, the proposed method has been applied to simulated data and prospective memory experiment ERP data aimed to qualify N2 and P3, and N300 and prospective positivity components, respectively. The results of determining the optimal number of clusters meet at six cluster maps for both ERP data. In addition, our results revealed that the proposed method could be reliably applied to ERP data to determine the appropriate time window for the ERP of interest when the measurement interval is not accurately defined.

Determination of the Time Window of Event-Related Potential Using Multiple-Set Consensus Clustering.

Clustering is a promising tool for grouping the sequence of similar time-points aimed to identify the attention blocks in spatiotemporal event-related potentials (ERPs) analysis. It is most likely to elicit the appropriate time window for ERP of interest if a suitable clustering method is applied to spatiotemporal ERP. However, how to reliably estimate a proper time window from entire individual subjects' data is still challenging. In this study, we developed a novel multiset consensus clustering method in which several clustering results of multiple subjects were combined to retrieve the best fitted clustering for all the subjects within a group. Then, the obtained clustering was processed by a newly proposed time-window detection method to determine the most suitable time window for identifying the ERP of interest in each condition/group. Applying the proposed method to the simulated ERP data and real data indicated that the brain responses from the individual subjects can be collected to determine a reliable time window for different conditions/groups. Our results revealed more precise time windows to identify N2 and P3 components in the simulated data compared to the state-of-the-art methods. Additionally, our proposed method achieved more robust performance and outperformed statistical analysis results in the real data for N300 and prospective positivity components. To conclude, the proposed method successfully estimates the time window for ERP of interest by processing the individual data, offering new venues for spatiotemporal ERP processing.

Exogenous Hydrogen Sulfide Regulates Mycoplasma pneumoniae Lipid-Associated Membrane Proteins to Induce Expression of Heme Oxygenase-1 and Proinflammatory Cytokines.

This study was designed to investigate the effect of exogenous hydrogen sulfide (H2S) on the secretion of Heme oxygenase (HO-1) and proinflammatory cytokines in human mononuclear cell line THP-1 stimulated by lipid-associated membrane proteins (LAMPs) prepared from Mycoplasma pneumoniae (M. pneumoniae) and explore its regulatory mechanism. Cultured cells were stimulated with M. pneumoniae LAMPs after pretreatment with H2S to analyze the production of proinflammatory cytokines and HO-1 by enzyme-linked immunosorbent assay (ELISA) and Western blot. The results showed that THP-1 cells, which were stimulated by LAMPs after pretreatment with H2S, had decreased production of interleukin-6 (IL-6) and interleukin-8 (IL-8) by inhibiting the mitogen-activated protein kinases (MAPKs)/nuclear factor-kappa B (NF-κB) signaling pathway and increased expression of HO-1 by activating the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. Our results indicate that H2S may play an important role in attenuating inflammation induced by M. pneumoniae LAMPs due to its ability to decrease the production of IL-6 and IL-8 and increase the expression of the HO-1. These findings support further studies for possible clinical applications.

The roles of prostaglandin F2 in regulating the expression of matrix metalloproteinase-12 via an insulin growth factor-2-dependent mechanism in sheared chondrocytes.

Osteoarthritis (OA) was recently identified as being regulated by the induction of cyclooxygenase-2 (COX-2) in response to high fluid shear stress. Although the metabolic products of COX-2, including prostaglandin (PG)E2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), and PGF2α, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2α in OA are largely overlooked. Thus, we showed that high fluid shear stress induced the mRNA expression of MMP-12 via cyclic (c)AMP- and PGF2α-dependent signaling pathways. Specifically, we found that high fluid shear stress (20 dyn/cm2) significantly increased the expression of MMP-12 at 6 h ( > fivefold), which then slightly decreased until 48 h ( > threefold). In addition, shear stress enhanced the rapid synthesis of PGE2 and PGF2α, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2α receptor (FPR)-, cAMP- and insulin growth factor-2 (IGF-2)-dependent phosphatidylinositide 3-kinase (PI3-K)/protein kinase B (AKT), c-Jun N-terminal kinase (JNK)/c-Jun, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-activating pathways. Prolonged shear stress induced the synthesis of 15d-PGJ2, which is responsible for suppressing the high levels of MMP-12 at 48 h. These in vitro observations were further validated by in vivo experiments to evaluate the mechanisms of MMP-12 upregulation during the onset of OA by high fluid shear stress. By delineating this signaling pathway, our data provide a targeted therapeutic basis for combating OA.

Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated ß-amyloid proteins (Aß) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE2) and PGD2, PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain.

Neurophysiological Evidence of Compensatory Brain Mechanisms Underlying Attentional-Related Processes in Symptomatically Remitted Patients with Schizophrenia.

A recent electrophysiological study suggests existing compensatory brain activity as a mechanism for functional recovery of visual attention detection (the capacity for detecting external cues) in symptomatically remitted schizophrenia patients. Despite such evidence, little is known about other aspects of attentional-related processes in schizophrenia during clinical remission, such as their capacity to concentrate on the task at hands without being interfered by distracting information. To this end, we recorded event-related brain potentials (ERPs) from 20 symptomatically remitted schizophrenia patients and 20 healthy controls while they engaged in a classic Stroop task. Symptomatically remitted patients showed comparable Stroop interference to healthy controls, indicating a degree of functional recovery of such a capacity in these patients. On the neural level, the N450 over the fronto-central and central regions, a component of the ERPs related to conflict detection, was found across both groups, although patients presented a reduced N450 relative to healthy controls. By contrast, the amplitude of the sustained potential (SP) (600-800 ms) over the parieto-central and parietal regions, a component of the ERPs related to conflict resolution, was significantly increased in patients relative to healthy controls. Furthermore, such increased SP amplitude correlated positively with improved behavioral accuracy in symptomatically remitted patients with schizophrenia. These findings reveal that symptomatically remitted patients with schizophrenia increasingly recruited the parietal activity involving successful conflict resolution to offset reduced conflict detection. Therefore, this provides further insight into compensatory mechanisms potentially involving a degree of functional recovery of attentional-related processes in schizophrenia during clinical remission.

Event-related brain potential correlates of prospective memory in symptomatically remitted male patients with schizophrenia.

Prospective memory (PM) refers to the ability to remember to perform intended actions in the future. Although PM deficits are a prominent impairment in schizophrenia, little is still known about the nature of PM in symptomatically remitted patients with schizophrenia. To address this issue, event-related brain potentials (ERPs) were recorded from 20 symptomatically remitted patients with schizophrenia and 20 healthy controls during an event-based PM paradigm. Behavioral results showed that symptomatically remitted patients with schizophrenia performed poorly on the PM task compared with healthy controls. On the neural level, the N300, a component of the ERPs related to PM cue detection, was reliable across these two groups, suggesting a degree of functional recovery of processes supporting cue detection in patients with symptomatically remitted schizophrenia. By contrast, the amplitude of the prospective positivity, a component of the ERPs related to PM intention retrieval, was significantly attenuated in symptomatically remitted schizophrenia patients relative to healthy controls. Furthermore, a significant positive correlation between the amplitude of the prospective positivity and accuracy on the PM task was found in those patients, indicating that patients' poor performance on this task may result from the failure to recover PM cue-induced intention from memory. These results provide evidence for the existence of altered PM processing in patients with symptomatically remitted schizophrenia, which is characterized by a selective deficit in retrospective component (intention retrieval) of PM. Therefore, these findings shed new light on the neurophysiological processes underlying PM in schizophrenia patients during clinical remission.