Abstract
It has been well claimed that herbal medicines (HMs) elicit effects via a multi-compounds and multi-targets synergistic mode. However, it lacks appropriate strategies to uncover the combinatory compounds that take effect together and contribute to a certain pharmacological effect of an herb as a whole, which represents a major bottleneck in providing sound evidence in supporting the clinic benefits of HMs. Here, we proposed a strategy to the identification of combinatory compounds contributing to the anti-inflammatory activity of Cardiotonic Pill (CP). The strategy proposed herein contains four core steps, including the identification of bioequivalent combinatorial compounds, chemical family classification-based combinatorial screen, interactive mode evaluation, and activity contribution index assay. Using this strategy, we have successfully identified six compounds in combination responsible for the anti-inflammatory effect of CP, whose anti-inflammatory activities were found comparable to that of the whole CP. Additionally, these six compounds take effect via an additive mode but little synergism. This study, together with our recent work in the identification of bioactive equivalent compounds combination, provides a widely applicable strategy to the identification of combinatory compounds responsible for a certain pharmacological activity of HMs.
Highlights
Our laboratory has proposed a strategy called “bioactive equivalent combinatorial components (BECCs)” to uncover pharmacologically active compounds in combination that are representative of the holistic effect of the whole HMs14
We have successfully discovered a combination of 18 compounds (Supplementary Figure S1) as BECCs of Cardiotonic Pill (CP), which has been used for the therapy of cardiovascular disease (CVD) for decades of years in China and has recently been approved to enter Phase III clinical trials by the FDA22–24
CP significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-6 (IL-6) in a dose-dependent manner (Fig. 2a–c, p < 0 .01)
Summary
Our laboratory has proposed a strategy called “bioactive equivalent combinatorial components (BECCs)” to uncover pharmacologically active compounds in combination that are representative of the holistic effect of the whole HMs14. Many pharmacological activities of CP or the compounds contained have been reported in supporting its clinical therapeutic effect towards CVD, which mainly include anti-inflammatory, scavenging free radical, improving microcirculatory, lipid-lowering, vasodilatory, anti-coagulant, anti-thrombotic, anti-ischemia, anti-apoptotic, endothelium-protective, and mitochondria-protective effects[25,26,27,28,29] It still remains a critical question of what compounds in combination, acting in a synergistic and/or additive mode, contribute to what pharmacological activities, which is a key step to uncovering the multiple-compounds and multiple-targets holistic mode of HMs. Systems biology has revealed a complex array of pathological processes underlying CVD, such as inflammation, oxidative stress, accumulation of lipids, coagulation, endothelial cell injury, ischemic injury, apoptosis and mitochondrial dysfunction[30,31,32].
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