Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 µM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

Synthesis and properties of the kojic acid dimer and its potential for the treatment of Alzheimer's disease.

The kojic acid dimer (KAD) is a metabolite derived from developing cottonseed when contaminated with aflatoxin. The KAD has been shown to exhibit bright greenish-yellow fluorescence, but little else is known about its biological activity. In this study, using kojic acid as a raw material, we developed a four-step synthetic route that achieved the gram-scale preparation of the KAD in approximately 25% total yield. The structure of the KAD was verified by single-crystal X-ray diffraction. The KAD showed good safety in a variety of cells and had a good protective effect in SH-SY5Y cells. At concentrations lower than 50 µM, the KAD was superior to vitamin C in ABTS+ free radical scavenging assay; the KAD resisted the production of reactive oxygen species induced by H2O2 as confirmed by fluorescence microscopy observation and flow cytometry analysis. Notably, the KAD could enhance the superoxide dismutase activity, which might be the mechanism of its antioxidant activity. The KAD also moderately inhibited the deposition of amyloid-ß (Aß) and selectively chelated Cu2+, Zn2+, Fe2+, Fe3+, and Al3+, which are related to the progress of Alzheimer's disease. Based on its good effects in terms of oxidative stress, neuroprotection, inhibition of Aß deposition, and metal accumulation, the KAD shows potential for the multi-target treatment of Alzheimer's disease.

Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aß deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimer's disease.

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aß1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30, had IC50 values of 11.15 µM and 6.87 µM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aß1-42 fibril aggregation and promoted fibril disaggregation with IC50 of 3.69 µM and 3.35 µM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aß1-42, and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease.

MEG-based Classification and Grad-CAM Visualization for Major Depressive and Bipolar Disorders with Semi-CNN.

Major depressive disorder (MDD) and bipolar disorder (BD) are two major mood disorders with partly overlapped symptoms but different treatments. However, their misdiagnosis and mistreatment are common based on the DSM-V criteria, lacking objective and quantitative indicators. This study aimed to develop a novel approach that accurately classifies MDD and BD based on their resting-state magnetoencephalography (MEG) signals during euthymic phases. A revisited 3D CNN model, Semi-CNN, that could automatically detect brainwave patterns in spatial, temporal, and frequency domains was implemented to classify wavelet-transformed MEG signals of normal controls and MDD and BD patients. The model achieved a test accuracy of 96.05% and an average of 95.71% accuracy for 5-fold cross-validation. Furthermore, saliency maps of the model were estimated using Grad-CAM++ to visualize the proposed classification model and highlight disease-specific brain regions and frequencies. Clinical Relevance - Our model provides a stable pipeline that accurately classifies MDD, BD, and healthy individuals based on resting-state MEG signals during the euthymic phases, opening the potential for quantitative and accurate brain-based diagnosis for the highly misdiagnosed MDD/BD patients.

Updated evidence of Dengzhan Shengmai capsule against ischemic stroke: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is the most common type of stroke, with high mortality, disability and recurrence rate, which brings a heavy burden to individuals, families and the medical system. Therefore, the intervention and treatment of ischemic stroke are of great significance. Chinese herbal medicine is widely used in treating stroke, for example, Dengzhan shengmai (DZSM) capsule. The current systematic review aims to comprehensively evaluate the efficacy and safety of the DZSM capsule in treating ischemic stroke. MATERIALS AND METHODS: Eligible randomized controlled trials (RCTs) were included to evaluate the efficacy and safety of Chinese herbal medicine DZSM capsule in treating ischemic stroke. Eight electronic databases were searched up to January 27, 2021. The risk ratio (RR), standardized mean difference (SMD), or weighted mean difference (WMD) with 95% confidence interval (CI) were used to assess DZSM capsule treatment outcomes. RESULTS: A total of 28 RCTs involving 6683 participants were included in the systematic review and meta-analysis. Compared with conventional therapy group, DZSM capsule plus conventional therapy improved Barthel Index scores (WMD: 8.97, 95%CI: 5.88-12.05) and reduced modified Rankin Scale (WMD: -0.75, 95%CI: -1.02∼ -0.48), reduced neurological functional deficit scores (WMD: -2.81, 95%CI: -4.17∼ -1.44), recurrence rate (RR: 0.57, 95%CI: 0.44-0.73) and mortality (RR: 0.54, 95%CI: 0.31-0.95), improved clinical effect (RR: 1.18, 95%CI: 1.12-1.24) and quality of life (WMD: 21.67, 95%CI: 6.74-36.61), exhibited a beneficial effect on hemorheology such as elevated levels of APTT (SMD: 1.17, 95%CI: 0.87-1.47) and INR (SMD: 1.12, 95%CI: 0.82-1.42), and on lipid metabolism such as levels of TC (SMD: -0.62, 95%CI: -1.04 âˆ¼ -0.20), TG (SMD: -0.72, 95%CI: -1.18∼ -0.26), LDL (SMD: -1.14, 95%CI: -1.57∼ -0.71) and HDL (SMD: 0.93, 95%CI: 0.36-1.50). No trials reported severe adverse events. CONCLUSION: DZSM capsule appears to be safe and effective in clinical applications for ischemic stroke. Based on conventional therapy, adding the DZSM capsule could reduce the mortality, recurrence rate, and neurological functional deficit scores, improve clinical effect and quality of life. In addition, compared with conventional therapy, the addition of the DZSM capsule played a beneficial role in hemorheology and lipid metabolism, which may attribute to the potential mechanism.