Onopordopicrin from the new genus Shangwua as a novel thioredoxin reductase inhibitor to induce oxidative stress-mediated tumor cell apoptosis.

Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus Shangwua, e.g. onopordopicrin (ONP), C2, and C3, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C2 and C3, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.

Identification of a Sesquiterpene Lactone from Arctium lappa Leaves with Antioxidant Activity in Primary Human Muscle Cells.

Many pathologies affecting muscles (muscular dystrophies, sarcopenia, cachexia, renal insufficiency, obesity, diabetes type 2, etc.) are now clearly linked to mechanisms involving oxidative stress. In this context, there is a growing interest in exploring plants to find new natural antioxidants to prevent the appearance and the development of these muscle disorders. In this study, we investigated the antioxidant properties of Arctium lappa leaves in a model of primary human muscle cells exposed to H2O2 oxidative stress. We identified using bioassay-guided purification, onopordopicrin, a sesquiterpene lactone as the main molecule responsible for the antioxidant activity of A. lappa leaf extract. According to our findings, onopordopicrin inhibited the H2O2-mediated loss of muscle cell viability, by limiting the production of free radicals and abolishing DNA cellular damages. Moreover, we showed that onopordopicrin promoted the expression of the nuclear factor-erythroid-2-related factor 2 (Nrf2) downstream target protein heme oxygenase-1 (HO-1) in muscle cells. By using siRNA, we demonstrated that the inhibition of the expression of Nrf2 reduced the protective effect of onopordopicrin, indicating that the activation of the Nrf2/HO-1 signaling pathway mediates the antioxidant effect of onopordopicrin in primary human muscle cells. Therefore, our results suggest that onopordopicrin may be a potential therapeutic molecule to fight against oxidative stress in pathological specific muscle disorders.

Phytotoxic activity of crop residues from Burdock and an active substance.

Problems related to weed management such as outbreaks of herbicide-resistant weeds have recently increased. An interesting approach to such problems is to use plant materials with phytotoxic activity. Burdock (Arctium lappa L.) is a biennial herb belonging to Asteraceae and is cultivated in several countries. The present study investigated the phytotoxic activity of burdock and its active substances. Extracts of both burdock leaves and roots inhibited the shoot and root growth of cress and barnyard grass, where the level of inhibition increased with increasing extract concentration. The leaf extracts had 2.0-2.5 times higher activity than the root extracts. Bioassay-guided separations of the leaf extracts led to isolation of a phytotoxic substance, onopordopicrin. Onopordopicrin significantly inhibited the shoot and root growth of cress and barnyard grass. The concentrations of the substance required for 50% growth inhibition were 0.27 and 0.26 mM for cress shoots and roots, respectively, and 1.86 and 0.35 mM for barnyard grass shoots and roots, respectively. The present results suggest that burdock leaves have high phytotoxic activity and onopordopicrin may play a major role in the activity. Burdock leaves may be a good resource for weed management.

Antiallergic activities of Japanese leaf burdock extract in a rat basophilic leukemia cell line.

Although primarily cultivated for its edible root, the leaves and stems of "Japanese leaf burdock (Arctium lappa L)" are also edible. This study determined the antiallergic activity of root, leaf, and stem extracts of Japanese leaf burdock using the rat basophilic leukemia cell line. We demonstrate that the hot water extract of Japanese leaf burdock stems has a strong inhibitory effect on antigen-stimulated degranulation. This extract was further fractionated into five fractions using a glass column. The fraction obtained with 99% ethanol extracts (99% EtEx) elicits a concentration-dependent increase in degranulation inhibition. One of antiallergic compounds from the separation of components of the 99% EtEx fraction using high-performance liquid chromatography and mass spectrometry analyses had a value of m/z 393.16. From these results and those of previous studies, one of the antiallergic components was hypothesized to be onopordopicrin. Our findings demonstrate that the extract of Japanese leaf burdock exerts a strong antiallergic activity. PRACTICAL APPLICATIONS: "Japanese leaf burdock (Arctium lappa L)" is a traditional Japanese vegetable with edible leaves and stems. The antiallergic activity of the hot water extracts has been shown in vitro. One of the antiallergic components was hypothesized to be onopordopicrin. Therefore, "Japanese leaf burdock" could serve as a functional food for patients with allergic disorders, such as allergic rhinitis.

Vibrational and structural study of onopordopicrin based on the FTIR spectrum and DFT calculations.

In the present work, the structural and vibrational properties of the sesquiterpene lactone onopordopicrin (OP) were studied by using infrared spectroscopy and density functional theory (DFT) calculations together with the 6-31G(∗) basis set. The harmonic vibrational wavenumbers for the optimized geometry were calculated at the same level of theory. The complete assignment of the observed bands in the infrared spectrum was performed by combining the DFT calculations with Pulay's scaled quantum mechanical force field (SQMFF) methodology. The comparison between the theoretical and experimental infrared spectrum demonstrated good agreement. Then, the results were used to predict the Raman spectrum. Additionally, the structural properties of OP, such as atomic charges, bond orders, molecular electrostatic potentials, characteristics of electronic delocalization and topological properties of the electronic charge density were evaluated by natural bond orbital (NBO), atoms in molecules (AIM) and frontier orbitals studies. The calculated energy band gap and the chemical potential (µ), electronegativity (χ), global hardness (η), global softness (S) and global electrophilicity index (ω) descriptors predicted for OP low reactivity, higher stability and lower electrophilicity index as compared with the sesquiterpene lactone cnicin containing similar rings.

Screening and HPLC-Based Activity Profiling for New Antiprotozoal Leads from European Plants.

Based on a survey of remedies used in Renaissance Europe to treat malaria, we prepared and screened a library of 254 extracts from 61 plants for antiplasmodial activity in vitro. HPLC-based activity profiling was performed for targeted identification of active constituents in extracts. One of the most remarkable results was the identification of onopordopicrin, a germacranolide sesquiterpene lactone isolated from Arctium nemorosum as a potent inhibitor of P. falciparum with an IC(50) of 6.9 µM. It was tested similarly against Trypanosoma brucei rhodesiense, the parasite which causes African sleeping sickness. With an IC(50) of 0.37 µM, onopordopicrin was one of the most potent natural products reported so far. Cytotoxicity was determined against rat myoblast L6 cells (IC(50): 3.06).