DanHong injection dose-dependently varies amino acid metabolites and metabolic pathways in the treatment of rats with cerebral ischemia.

AIM: To determine how the relative amino acid contents and metabolic pathways regulate the pharmacological phenotypes in rats with cerebral ischemia after treatment with varying doses of DanHong injection (DHI). METHODS: Adult male rats underwent middle cerebral artery occlusion (MCAO), and were injected with DHI (DH-1: 1 mL/kg; DH-2: 2.5 mL/kg; DH-3: 5 mL/kg, and DH-4: 10 mL/kg, iv) daily for 3 d. The neurological deficit score, body weights and infarct volume were assessed. Serum levels of 20 free amino acids were determined using HPLC, and the values were transformed through the quantitative analysis of the amino acids in the serum metabolic spectrum. Multivariate statistical analysis methods (PCA and PLS-DA) and web-based metabolomics tools (MetPa and MetaboAnalyst) were used to analyze the biological data sets for the amino acids. RESULTS: Administration of DHI dose-dependently decreased cerebral infarct volume, and ameliorated neurological deficits. A total of 5, 6, 7 and 7 non-overlapping metabolites were identified in the DH-1, DH-2, DH-3, and DH-4 groups, respectively. Eight metabolites were shared between the DHI groups and the vehicle group. In addition, the serum levels of glutamic acid, aspartic acid and serine increased with increasing DHI dose. A total of 3, 2, 2 and 5 non-overlapping metabolic pathways were identified in the DH-1, DH-2, DH-3 and DH-4 groups, respectively, and glycine, serine, threonine and histidine metabolism were identified as overlapping pathways among the 4 dose groups. CONCLUSION: Overlapping and non-overlapping amino acid metabolites and metabolic pathways are associated with the dose-dependent neuroprotective effect of DHI.

Deciphering potential pharmacological mechanisms of Danhong injection to treat chronic stable angina based on drug response-related modules and genes.

ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI), a traditional Chinese medicine (TCM) injection that has been widely used to treat coronary heart disease and angina pectoris. However, its underlying pharmacological mechanisms have not been fully elucidated. Not all patients benefit from DHI to the same extent. We attempted to explore the characteristics of potential therapeutic targets in different responsive populations. AIM OF THE STUDY: This study aimed to reveal the potential molecular mechanisms of DHI in treating chronic stable angina and identify potential therapeutic targets for DHI. MATERIALS AND METHODS: Based on a previous phase IV clinical trial of DHI in treating chronic stable angina, drug response modules were identified through structural entropy and similarity. Drug response-related genes were screened out based on the correlations between drug response module/module-related genes and clinical features and were assessed using a random forest model. Further validation was conducted using a hypoxia/reoxygenation (H/R) model. RESULTS: Seven DHI-related response modules were identified. Eight drug response-related genes were screened out, and principal component analysis showed that DHI responders were distinguished from responders in the control group based on their expression values. The combination of the two most important genes, SHC4 and PIP5K1P1, discriminated between responders and nonresponders with an area under the receiver operating characteristic curve (AUC) of 0.714; however, no significant difference was found in the AUC between the combination and a single gene. Reverse transcription-polymerase chain reaction showed that middle-dose DHI treatment significantly decreased SHC4 mRNA expression compared with that in the H/R group (P = 0.026), a finding consistent with our previous analysis of differentially expressed genes. CONCLUSIONS: DHI comprehensively exerted a therapeutic effect by acting on multiple response modules related to angina pectoris and drug response-related genes. Our findings indicate that the dimensionality reduction strategy based on the target network-drug response module-therapeutic targets can contribute to revealing the mechanism of action of TCM compounds and guiding precise clinical medication.