Taohong Siwu decoction reduces acute myocardial ischemia-reperfusion injury by promoting autophagy to inhibit pyroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu decoction (TSD) is a classic traditional Chinese medicine (TCM) prescription used to promote the blood circulation and alleviate blood stasis. TSD consists of Paeonia lactiflora Pall., Conioselinum anthriscoides (H. Boissieu) Pimenov & Kljuykov, Rehmannia glutinosa (Gaertn.) DC., Prunus persica (L.) Batsch, Angelica sinensis (Oliv.) Diels, and Carthamus creticus L. in the ratio of 3:2:4:3:3:2. Studies on the effects of TSD on myocardial ischemia-reperfusion injury (MIRI) from the perspective of autophagy and pyroptosis have not been reported. AIM OF THE STUDY: Investigate the effect of TSD on MIRI and explore the underlying mechanisms. MATERIALS AND METHODS: We searched the main components and corresponding potential targets of TSD on The Pharmacology of Traditional Chinese Medicine Systems database for target prediction. We identified targets for MIRI on Online Mendelian Inheritance in Man and GeneCards databases. The intersection of the compound target and disease target was obtained and a protein-protein interaction network constructed. We undertook enrichment analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. The results of network pharmacology were verified by in vivo experiments in mice. RESULTS: In mice, TSD significantly reduced the volume of the myocardial infarct, significantly reduced serum levels of cardiac troponin-nI (CTnI), creatine kinase-myocardial band (CK-MB), malonaldehyde (MDA), interleukin (IL)-6, increased the activity of superoxide dismutase (SOD) and IL-10 level, reduced the level of pyroptosis in myocardial tissue, increased the number of autophagosomes, and significantly reduced the fluorescence intensity of apoptosis-associated speck-like protein (ASC), Nod-like receptor protein 3 (NLRP3), and caspase-1. TSD administration increased the protein expression of microtubule-associated protein light chain 3 (LC3), but reduced the protein expression of p62, NLRP3, ASC, caspase-1, cleaved caspase-1, pro-caspase-1, gasdermin D (GSDMD), GSDMD-N-terminal, IL-18, and IL-1ß. Administration of 3-Methyladenin could reverse the effect of TSD in inhibiting inflammation and the release of proinflammatory factors. CONCLUSION: TSD treatment alleviated MIRI by promoting autophagy to suppress activation of the NLRP3 inflammasome and reducing the release of proinflammatory factors.

Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach.

Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.