Mass spectrometry-based multi-omics analysis reveals the thermogenetic regulation of herbal medicine in rat model of yeast-induced fever.

ETHNOPHARMACOLOGICAL RELEVANCE: In the principle of traditional Chinese medicine (TCM), clinical usage is based on drug attributes of the herbal medicine. The cold and hot properties of TCM are classified accordingly to their pharmacological effects, such as temperature change. Herbal medicine has been used as food supplements in our daily life, and the thermogenetic regulation is one of their primary applications. However, the underlying mechanism of "cold" or "hot" stimulating effect of herbal medicine has not been fully identified. AIM OF THE STUDY: Thermogenetic regulation and classification of herbal medicine of hot/cold herbs were determined by rat model of yeast-induced fever. MATERIALS AND METHODS: Here, a novel method in classifying and characterizing cold- and hot-herbal medicines was established by analyses of mass spectrometry (MS)-based metabolomics and lipidomics from the serum of herbal extract-treated rats. The yeast-induced inflammatory rats were used as the model system, which were subjected to the treatments of cold- or hot-herbal medicine. RESULTS: The multi-omics approach identified the clustering of metabolites from cold and hot herb-treated rat serum by using partial least squares discriminant analysis (PLS-DA), and which subsequently identified that the 8-h treatment was the metabolic perturbation point of herb-mediated thermogenesis. Meanwhile, the levels of identified metabolites in the serum, i.e. lysoPE, lysoPC and carnitine, showed a positive relationship with the regulation of body temperature; while the levels of amino acid, fatty acid and bile acid were contrary correlated with the temperature change. In addition, the differential expressed metabolites were subjected to pathway enrichment and network analyses in revealing the possible action mechanism of herbal medicines in relating to thermogenetic regulation. CONCLUSION: The developed MS-based omics provides a new insight in characterizing the properties of cold/hot herbal medicine.

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and ß-amyloid (Aß) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aß production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aß oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aß oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aß aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.