Pharmacological effects and mechanisms of YiYiFuZi powder in chronic heart disease revealed by metabolomics and network pharmacology

Abstract

Introduction: YiYiFuZi powder (YYFZ) is a classical formula in Chinese medicine, which is commonly used clinically for the treatment of Chronic Heart Disease (CHD), but it’s pharmacological effects and mechanism of action are currently unclear.Methods: An adriamycin-induced CHD model rat was established to evaluate the pharmacological effects of YYFZ on CHD by the results of inflammatory factor level, histopathology and echocardiography. Metabolomic studies were performed on rat plasma using UPLC-Q-TOF/MS to screen biomarkers and enrich metabolic pathways; network pharmacology analysis was also performed to obtain the potential targets and pathways of YYFZ for the treatment of CHD.Results: The results showed that YYFZ significantly reduced the levels of TNF-α and BNP in the serum of rats, alleviated the disorder of cardiomyocyte arrangement and inflammatory cell infiltration, and improved the cardiac function of rats with CHD. The metabolomic analysis identified a total of 19 metabolites, related to amino acid metabolism, fatty acid metabolism, and other metabolic pathways. Network pharmacology showed that YYFZ acts through PI3K/Akt signaling pathway, MAPK signaling pathway and Ras signaling pathway.Discussion: YYFZ treatment of CHD modulates blood metabolic pattern and several protein phosphorylation cascades but importance specific changes for therapeutic effect require further studies.

Cardiovascular protection of YiyiFuzi powder and the potential mechanisms through modulating mitochondria-endoplasmic reticulum interactions

“…Data-mining research has demonstrated that YYFZ can affect mitochondria-ER interactions by regulating mitochondrial function and ER function ( Wang, 2019 ; Wang Y. et al, 2023 ; Wang Y. Y. et al, 2023 ). In addition, network pharmacology has shown that YYFZ can modulate the phosphoinositide 3-kinase (PI3K)/AKT, modulating mitogen-activated protein kinase (MAPK), and Ras signaling pathways ( Wang Y. et al, 2023 ), all of which potentially affect mitochondria-ER interactions. Abnormal mitochondrial-ER interactions are thought to be key mechanisms in CVD such as CHD, HF, pulmonary hypertension, and atherosclerosis ( Zhang et al, 2020 ).…”

“…Through metabolomics and network pharmacology analysis, it was found that YYFZ improves the efficiency of endoplasmic reticulum-associated protein degradation (ERAD), a process that removes misfolded proteins from the ER. By enhancing ERAD, it can reduce the accumulation of misfolded proteins and subsequently alleviate ER stress ( Wang Y. et al, 2023 ). ER stress is a cellular condition that occurs when there is an accumulation of unfolded or misfolded proteins in the ER ( Haeri and Knox, 2012 ), which triggers a cellular response known as the UPR ( Hetz, 2012 ).…”

“…A double-blind clinical trial using drugs targeting mitochondrial ROS may improve or even restore myocardial energetics, showing promise in limiting HF progression ( Daubert et al, 2017 ). Amino acid metabolomics analysis has demonstrated that YYFZ regulates the glutathione and taurine synthesis pathways as well as phenylalanine and tyrosine metabolism ( Wang Y. et al, 2023 ). Both glutathione and taurine are powerful antioxidant molecules that help protect cells from oxidative damage ( Kerksick and Willoughby, 2005 ; Schaffer and Kim, 2018 ; Kwon et al, 2019 ; Surai et al, 2021 ), thereby safeguarding mitochondria from harm.…”

“…Metabolomic and network pharmacology analyses have also shown that YYFZ indirectly contributes to antioxidant effects by reducing lipid accumulation, increasing glucose utilization and ATP production, promoting the production of intermediates, donating electrons to the electron transport chain (ETC. ), and driving ATP synthesis ( Wang Y. et al, 2023 ).…”

“…Network pharmacology analysis suggests that YYFZ may impact mitochondria-ER interactions ( Wang, 2019 ; Wang Y. et al, 2023 ). Our study reviews the cardiovascular protective effects of YYFZ by directly regulating mitochondrial and ER function and indirectly influencing cardiovascular risk factors (such as lipid and glucose metabolism), oxidative stress, inflammatory responses, cellular apoptosis, and Ca 2+ balance to impact the mitochondria-ER interactions.…”