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Vascular Protection of TPE-CA on Hyperhomocysteinemia-induced Vascular Endothelial Dysfunction through AA Metabolism
Hui Li1, Zhenli Liu2, Linlin Liu1
1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
Insights
Total phenolic extracts from Citrus aurantium (TPE-CA) effectively treat hyperhomocysteinemia (HHcy) and vascular dysfunction. TPE-CA offers superior vascular protection compared to B vitamins by regulating homocysteine metabolism and arachidonic acid pathways.
Area of Science:
- Biochemistry
- Pharmacology
- Vascular Biology
Background:
- Elevated plasma homocysteine (Hcy) causes vascular endothelial dysfunction, contributing to cardiovascular diseases (CVDs).
- Current treatments for hyperhomocysteinemia (HHcy) using B vitamins have limitations in therapeutic efficacy.
- Novel therapeutic strategies are needed to improve HHcy treatment outcomes and prevent CVDs.
Purpose of the Study:
- To elucidate the multi-targeted synergistic mechanism of Total Phenolic Extracts from Citrus Aurantium L. (TPE-CA) in addressing HHcy-induced vascular endothelial dysfunction.
- To compare the therapeutic efficacy of TPE-CA with traditional B vitamin treatments for HHcy.
- To identify the key compounds, targets, and pathways involved in TPE-CA's vascular protective effects.
Main Methods:
- Network pharmacology was utilized to identify potential compound-target-pathway interactions.
- Experimental validation was performed to confirm the effects of TPE-CA on Hcy levels and vascular function.
- Analysis of Hcy metabolism via the transsulfuration pathway and arachidonic acid (AA) metabolism involving cytochrome P450 (CYP) enzymes.
Main Results:
- TPE-CA demonstrated superior efficacy in treating HHcy and associated vascular dysfunction compared to B vitamins.
- TPE-CA treatment significantly reduced plasma Hcy levels by up-regulating the transsulfuration pathway.
- TPE-CA restored vascular endothelial function by modulating AA metabolism, specifically activating CYP epoxygenase and inhibiting CYP hydroxylase pathways.
Conclusions:
- TPE-CA presents a promising therapeutic agent for HHcy and cardiovascular disease prevention due to its multi-targeted synergistic mechanism.
- The study highlights the potential of natural phenolic compounds in addressing complex metabolic and vascular disorders.
- TPE-CA's ability to regulate both Hcy and AA metabolism offers a novel therapeutic avenue for vascular protection.
Abstract:
A high concentration of homocysteine (Hcy) in plasma induces vascular endothelial dysfunction, and it may ultimately accelerate the development of cardiovascular diseases (CVDs). Although several B vitamins have been clinically applied for hyperhomocysteinemia (HHcy) treatment, the outcomes are not satisfied due to their limited therapeutic mechanism. Hence, in order to improve the curative effect, development of new effective therapeutic strategies should be put on the agenda. Total phenolic extracts of Citrus aurantium L. (TPE-CA) is a naturally obtained phenolic mixture, mainly containing flavones, flavanones and their glycosyl derivatives, flavonols, polymethoxyflavones and coumarins. Previous reports indicated that bioactive phenolic compounds possessed potent vascular protective effects and regarded as a protective agent against CVDs. Intriguingly, the exact mechanism underlying the suppressed effects of TPE-CA on HHcy could assist in revealing their therapy on CVDs. Here, the multi-targeted synergistic mechanism of TPE-CA on HHcy-induced vascular endothelial dysfunction was uncovered in a deduced manner. TPE-CA treatment exhibited an obvious superiority than that of B vitamins treatment. Network pharmacology was employed to identify the interrelationships among compounds, potential targets and putative pathways. Further experimental validation suggested that the treatment of TPE-CA for HHcy could not only effectively reduce the Hcy level in plasma through up-regulating transsulfuration pathway in Hcy metabolism, but also restore the HHcy-induced vascular endothelial dysfunction by activating cytochrome P450 enzymes (CYPs) epoxygenase signal cascades and inhibiting CYPs hydroxylase signal cascades in arachidonic acid (AA) metabolism.
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