Shuang-Xin-Tong-Tiao formula from Menghe medicine exerts dual cardioprotective and antidepressant effects associated with the suppression of Toll-like receptor 4 / nuclear factor kappa-B / hypoxia-inducible factor-1 alpha signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuang-Xin-Tong-Tiao formula (SXTTF) is a characteristic traditional Chinese medicine (TCM) prescription developed within the Menghe medical lineage, traditionally used for cardioprotective and antidepressant. Increasing clinical and experimental evidence suggests a close interplay between heart and depression, however, the underlying mechanisms remain poorly understood.

AIM OF THE STUDY: This study aimed to elucidate the active components and molecular mechanisms of SXTTF in cardioprotective and antidepressant by integrating network pharmacological and in vivo experimental validation.

MATERIALS AND

METHODS

The active compounds and putative targets of SXTTF were retrieved from TCM-related databases. CHD-associated genes were gathered from the GeneCards database. Common targets between SXTTF and CHD were identified through target intersection. A component-target network was established using Cytoscape, and Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed via the DAVID database. A rat model of comorbid myocardial injury and depression was constructed by subcutaneous injection of isoproterenol combined with chronic unpredictable mild stress (CUMS). Echocardiography and histopathological staining were performed to assess cardiac function and myocardial injury. Western blotting was applied to evaluate the expression of proteins in the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway.

RESULTS

Compared with the control group, rats subjected to isoproterenol and CUMS - referred to hereafter as the rat model of ISO-induced myocardial injury combined with CUMS-induced depression - exhibited significantly impaired cardiac function, increased myocardial fibrosis, apoptotic cardiomyocytes, enlarged cardiomyocyte cross-sectional area, and elevated expression of TLR4-NF-κB-HIF-1α pathway-related proteins. Behavioral tests including the open field test, sucrose preference test, and forced swimming test confirmed the presence of depression-like symptoms. SXTTF treatment significantly ameliorated both cardiac and behavioral abnormalities in a dose-dependent manner.

CONCLUSIONS

Collectively, SXTTF exerts dual cardioprotective and antidepressant effects, potentially through coordinated modulation of neuroinflammation and myocardial injury associated with the TLR4-NF-κB-HIF-1α axis. This study provides a pharmacological basis for the clinical use of SXTTF in cardio-psychiatric comorbidities.