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Studying Mass Balance and the Stability of (Z)-Ligustilide from Angelica sinensis Helps to Bridge a Botanical Instability-Bioactivity Chasm.

ABSTRACT: Numerous reports assigning (Z)-ligustilide (1) the role of a major bioactive principle in Apiaceae botanicals are called into question by the recurrent demonstrations of 1 being an unstable, rapidly degrading compound, ultimately leading to dynamic residual complexity. While Angelica sinensis is recognized for its therapeutic value in (peri-)menopausal symptom management, its purported active principle, 1, represents a typical example of the instability-bioactivity chasm of botanicals. To help bridge the gap, this study used both the essential oil and purified 1 obtained from A. sinensis to investigate the factors that influence the chemical transformation of 1, the products formed, and the rationale for monitoring 1 in natural product preparations. Countercurrent separation was used to purify 1 from a supercritical fluid extract of A. sinensis, achieving 93.4% purity in a single step. Subsequent purification by preparative HPLC afforded 1 with a 98.0% purity. Providing a mass balance setting, we monitored chemical changes occurring to highly purified 1 under various conditions and at different time points, in sealed NMR tubes by quantitative 1H NMR (qHNMR). The nondestructive nature of NMR enabled a comprehensive assessment of degradation products. Moreover, in being a mole-based determination, the total intensity (integral) of all NMR signals intrinsically represents the theoretical mass balance within the sample solution. The results demonstrated that 1 is most stable while within the original plant material. Exposure to light had a profound impact on the chemical transformation of 1, leading to the formation of ligustilide dimers and trimers, as verified by both NMR and LC-HRMS studies. Moreover, the results shown for 1, augmented by other recent outcomes, have serious implications for the meaningful biological evaluation of NPs that exhibit instability/reactivity, while having a plethora of "promising" bioactivities reported in the literature and being frequently associated with unsubstantiated health claims.

SUBMITTER: Duric K

PROVIDER: S-EPMC6930006 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Studying Mass Balance and the Stability of (Z)-Ligustilide from Angelica sinensis Helps to Bridge a Botanical Instability-Bioactivity Chasm.

Duric Kemal K Liu Yang Y Chen Shao-Nong SN Lankin David C DC Nikolic Dejan D McAlpine James B JB Friesen J Brent JB Pauli Guido F GF

Journal of natural products 20190903 9

Numerous reports assigning (Z)-ligustilide (1) the role of a major bioactive principle in Apiaceae botanicals are called into question by the recurrent demonstrations of 1 being an unstable, rapidly degrading compound, ultimately leading to dynamic residual complexity. While Angelica sinensis is recognized for its therapeutic value in (peri-)menopausal symptom management, its purported active principle, 1, represents a typical example of the instability-bioacti ...[more]

PMID: 31478376

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Project description:OBJECTIVE:In developed countries with westernized diets, the excessive consumption of added sugar in beverages and highly refined and processed foods is associated with increased risk for obesity, diabetes, and cardiovascular diseases. As a major constituent of added sugars, fructose has been shown to cause a variety of adverse metabolic effects, such as impaired insulin sensitivity, hypertriglyceridemia, and oxidative stress. Recent studies have shown that ketohexokinase isoform C is the key enzyme responsible in fructose metabolism that drive's fructose's adverse effects. The objective of this study was to identify botanical ingredients with potential for inhibitory activity against ketohexokinase-C and fructose-induced metabolic effects by using a series of in vitro model systems. METHODS:Extracts from 406 botanicals and 1200 purified phytochemicals were screened (initial concentration of 50 ?g/mL and 50 ?M, respectively) for their inhibitory activity using a cell free, recombinant human ketohexokinase-C assay. Dose response evaluations were conducted on botanical extracts and phytochemicals that inhibited ketohexokinase-C by > 30% and > 40%, respectively. Two different extract lots of the top botanical candidates were further evaluated in lysates of HepG2 cells overexpressing ketohexokinase-C for inhibition of fructose-induced ATP depletion. In addition, extracts were evaluated in intact Hep G2 cells for inhibition of fructose-induced elevation of triglyceride and uric acid production. RESULTS:Among the botanical extracts, phloretin (Malus domestica) extracts were the most potent (IC50: 8.9-9.2 ?g/mL) followed by extracts of Angelica archangelica (IC50: 22.6 ?g/mL-57.3 ?g/mL). Among the purified phytochemicals, methoxy-isobavachalcone (Psoralea corylifolia, IC50 = 0.2 ?M) exhibited the highest potency against ketohexokinase isoform C activity followed by osthole (Angelica archangelica, IC50 = 0.7 ?M), cratoxyarborenone E (Cratoxylum prunifolium, IC50 = 1.0 ?M), and ?-/?-mangostin (Cratoxylum prunifolium, IC50 = 1.5 ?M). Extracts of Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis exhibited ketohexokinase inhibitory activity and blocked fructose-induced ATP depletion and fructose-induced elevation in triglyerides and uric acid. CONCLUSIONS:Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis were the top four botanical candidiates identified with inhibitory activity against ketohexokinase-C. Future studies are needed to show proof of mechanism and the efficacy of these botanical extracts in humans to blunt the negative metabolic effects of fructose-containing added sugars.

Dataset Information

Studying Mass Balance and the Stability of (Z)-Ligustilide from Angelica sinensis Helps to Bridge a Botanical Instability-Bioactivity Chasm.

Publications

Studying Mass Balance and the Stability of (<i>Z</i>)-Ligustilide from <i>Angelica sinensis</i> Helps to Bridge a Botanical Instability-Bioactivity Chasm.

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