Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS-and Aβ-induced neuroinflam-matory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 mi-croglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proin-flammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflam-masome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroin-flammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphol-ogy, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and mor-phology. Taken together, our findings indicate that donepezil significantly downregulates LPS-and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.1

Web-based infectious disease surveillance systems and public health perspectives: a systematic review

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background Emerging and re-emerging infectious diseases are a significant public health concern, and early detection and immediate response is crucial for disease control. These challenges have led to the need for new approaches and technologies to reinforce the capacity of traditional surveillance systems for detecting emerging infectious diseases. In the last few years, the availability of novel web-based data sources has contributed substantially to infectious disease surveillance. This study explores the burgeoning field of web-based infectious disease surveillance systems by examining their current status, importance, and potential challenges. Methods A systematic review framework was applied to the search, screening, and analysis of web-based infectious disease surveillance systems. We searched PubMed, Web of Science, and Embase databases to extensively review the English literature published between 2000 and 2015. Eleven surveillance systems were chosen for evaluation according to their high frequency of application. Relevant terms, including newly coined terms, development and classification of the surveillance systems, and various characteristics associated with the systems were studied. Results Based on a detailed and informative review of the 11 web-based infectious disease surveillance systems, it was evident that these systems exhibited clear strengths, as compared to traditional surveillance systems, but with some limitations yet to be overcome. The major strengths of the newly emerging surveillance systems are that they are intuitive, adaptable, low-cost, and operated in real-time, all of which are necessary features of an effective public health tool. The most apparent potential challenges of the web-based systems are those of inaccurate interpretation and prediction of health status, and privacy issues, based on an individuals internet activity. Conclusion Despite being in a nascent stage with further modification needed, web-based surveillance systems have evolved to complement traditional national surveillance systems. This review highlights ways in which the strengths of existing systems can be maintained and weaknesses alleviated to implement optimal web surveillance systems

Trade and Welfare Compensation: The Missing Links

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Entrapment of Binaural Auditory Beats in Subjects with Symptoms of Insomnia

Binaural beat (BB) stimulation, which has two different frequencies for each ear, is reportedly effective in reducing anxiety and controlling mood. This study aimed to evaluate the brain wave entrainment effect of binaural beats and to propose an effective and safe supplementary therapy for relieving the symptoms of insomnia. Subjects between 20 and 59 years of age with subclinical symptoms of insomnia were recruited from the community. Quantitative electroencephalography was measured twice, before and two weeks after the BB intervention. Participants used the apparatus with or without 6 Hz BB for 30 min before going to bed for two weeks. When music with BB was played, the relative theta power increased (occipital, p = 0.009). After two weeks of intervention with music, the theta power increased when listening to music with BB (parietal, p = 0.009). After listening to music with BB for two weeks, the decrease in the beta power was more noticeable than after using music-only devices when participants listened to music in the laboratory (occipital, p = 0.035). When BB were played, the entrapment of the theta wave appeared. Therefore, exposure to music with BB is likely to reduce the hyper-arousal state and contribute to sleep induction

Analysis of protein levels of inflammatory cytokines in gingival tissue after treatment with fermented whey bioconversion products (WBPs) for 8 weeks.

(a) TNF-α (b) IL-6. Normal: Administration of phosphate buffered saline (PBS) without inducing periodontitis, Control: Administration of PBS after inducing periodontitis, LP-YK1 WBP: Administration of WBPs by L. plantarum SMFM2017-YK1 after inducing periodontitis, LF-NK1 WBP: Administration of WBPs by L. fermentum SMFM2017-NK1 after inducing periodontitis. *Statistically significant, compared to control group by pairwise Student’s t-test (p < 0.05).</p

Relative expression of oxidative stress cytokines in gingival tissue after treatment of fermented whey bioconversion products (WBPs) for 8 weeks.

(a) Gpx1 (b) Sod1 (c) Cat. Normal: Administration of phosphate buffered saline (PBS) without inducing periodontitis, Control: Administration of PBS after inducing periodontitis, LP-YK1 WBP: Administration of whey bioconversion product by L. plantarum SMFM2017-YK1 after inducing periodontitis, LF-NK1 WBP: Administration of whey bioconversion product by L. fermentum SMFM2017-NK1 after inducing periodontitis. *Statistically significant, compared to control group by pairwise Student’s t-test (p < 0.05).</p

Primer sequences of inflammatory and oxidative stress-related cytokines used for quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Primer sequences of inflammatory and oxidative stress-related cytokines used for quantitative reverse transcription polymerase chain reaction (RT-qPCR).</p

Histopathologic analysis of mandibular first molar tooth regions from rats administered with whey bioconversion products (WBPs) and their effects on periodontitis.

LP-YK1 WBP: Administration of WBPs produced by L. plantarum SMFM2017-YK1 after inducing periodontitis, LF-NK1 WBP: Administration of WBPs by L. fermentum SMFM2017-NK1 after inducing periodontitis. Arrow: inflammatory cell infiltration, Head of arrow: epidermal hyperplasia.</p