Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1b, and tumor necrosis factor (TNF)-a. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD.
Neurodegenerative diseases (NDs) are disorders characterized by degenerative degeneration of neurons and loss of their function. NDs have a complicated pathophysiology, of which neuroinflammation and neuronal death are significant factors. The inflammatory process known as pyroptosis (“fiery death”) is caused by a family of pore-forming proteins called Gasdermins (GSDMs), which appears downstream from the activation of the inflammasome. Clear evidence of enhanced pyroptosis-related proteins activity in common NDs has coincided with abnormal aggregation of pathological proteins (such as Aβ, tau, α-synuclein et al.), making pyroptosis an attractive direction for the recent study of NDs. The purpose of this review is to provide an overview of the molecular mechanisms driving pyroptosis, the mechanistic links between pyroptosis and NDs, and emerging therapeutic strategies in Traditional Chinese Medicine (TCM) to inhibit pyroptosis for the treatment of NDs.
Background: Osthole, a natural coumarin, found in many medicinal plants. Previous studies have shown its neuroprotective effects, whereas the effect and fundamental mechanism of Osthole for alleviating AD-associated dysmnesia is still not fully clear.
Purpose: This study aimed to examine the neuroprotection of Osthole against cognitive impairment in the D-galactose-induced rats and its pharmacological mechanism.
Method: The rat was constructed by subcutaneous injection of D-galactose at a dose of 150 mg/kg/day for 56 days as a model. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to determine the underlying mechanisms of Osthole against Alzheimer's disease, while to verify the network-based predictions, western blot, Nissl staining, and immunofluorescence were applied.
Result: Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rat. Endophenotype-based network approach highlight several AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, neuroinflammationand endoplasmic reticulum stress. Among them, the proapoptotic markers (Bax), antiapoptotic protein (Bcl-2), moreover, the microgliosis (Iba-1), Astrocytosis (GFAP), and inflammatory cytokines (TNF-α1), levels of ER stress-associated proteins (BIP, p-PERK/PERK, Caspase12, CHOP and XBP1s) were evaluated in both hippocampus and cortex. And the results indicated that Osthole significantly ameliorated neuronal apoptosis, neuroinflammation and ER stress in D-galactose induced rats.
Conclusion: This study explored the pharmacological mechanism of Osthole against D-galactose induced memory impairment and identified Osthole as a potential anti-AD drug candidate targeting multiple signaling pathways by endophenotype network-based.
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