Isoliquiritigenin from licorice flavonoids attenuates NLRP3-mediated pyroptosis by SIRT6 in vascular endothelial cells.

ETHNOPHARMACOLOGIC RELEVANCE: Licorice is a traditional Chinese medicine that has been used for cardiovascular diseases. Recent studies found that supplementation with licorice extracts attenuated the development of atherosclerosis (AS) in hypercholesterolemic patients. Many studies have shown that licorice flavonoids, the main active components of licorice, have a variety of pharmacological effects, including anti-inflammation, regulation of lipid metabolism, and antioxidation. However, the key active components against AS in licorice flavonoids are still unclear. AIM OF THE STUDY: The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms. MATERIALS AND METHODS: Network pharmacology was used to screen the active components of licorice flavonoids that have anti-atherosclerotic effects. Combining bioinformatics analysis and in vitro studies, the effects and underlying mechanisms of the active component isoliquiritigenin (ISL) on cell pyroptosis were further investigated in tumor necrosis factor (TNF)-α-treated human umbilical vein endothelial cells (HUVECs). RESULTS: We constructed a compound-target network and screened 3 active components, namely, ISL, glabridin, and naringenin in licorice flavonoids. The half maximal effective concentration values of these 3 components suggested that ISL was the key active component against TNF-α-induced endothelial cell injury. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that ISL could potentially treat AS via the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway. An in vitro study verified that ISL suppressed TNF-α-induced NLRP3 activation and pyroptosis in HUVECs. The molecular docking and cellular thermal shift assay showed good compatibility between ISL and class III histone deacetylase sirtuin 6 (SIRT6). Moreover, we found that ISL upregulated the expression of SIRT6 in TNF-α-treated HUVECs. Further study found that SIRT6 knockdown reduced the inhibitory effect of ISL on pyroptosis, whereas the NLRP3 inhibitor reversed this process in TNF-α-treated HUVECs. CONCLUSIONS: Our results demonstrate that ISL is a key active component of licorice flavonoids. ISL attenuates NLRP3-mediated vascular endothelial cell pyroptosis via SIRT6, and SIRT6 may be a potential target of ISL for the treatment of AS.

Quantitative Determination of p-Cymene, Thymol, Neryl Acetate, and ß-Caryophyllene in Different Growth Periods and Parts of Eupatorium fortunei Turcz. by GC-MS/MS.

Eupatorium fortunei Turcz. is a widely used Chinese herbal medicine in China. In this study, a gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) method was developed and validated to simultaneously determine the contents of p-cymene, thymol, neryl acetate, and ß-caryophyllene in roots, stems, and leaves of Eupatorium fortunei Turcz. harvested at different growth periods. All four constituents could be detected in leaves, three could be detected in stems except ß-caryophyllene, and only thymol could be detected in roots. The order of the total contents of four constituents in different parts was leaves > stems > roots. It indicated that the leaves could be the proper medicinal parts of Eupatorium fortunei Turcz. The content of four constituents in leaves varied a lot among different growth periods and showed an M-shaped change trend with the growth of Eupatorium fortunei Turcz. The four constituents accumulated to the highest values in early July followed by mid-September. Accordingly, the best harvest time of Eupatorium fortunei Turcz. is early July and mid-September.

Uptake and Distribution Characteristic and Health Risk Assessment of Heavy Metal(loid)s in Platycodon Grandiflorum (Jacq.) A.DC. with Growth from a Medicinal Herb Garden of Xi'an, China.

The different parts of Platycodon grandiflorum were collected from a medicinal herb garden to determine five heavy metal(loid)s (Pb, Cd, As, Hg, and Cu) contents at different growth stages. The data showed that the plant accumulated varying amounts of metal(loid)s in the order Cu > Hg > Pb > As > Cd. Five heavy metal(loid) concentrations decreased in the early growth stage and then increased in the flowering season. The contents of heavy metal(loid)s except Hg in the stem were relatively lower than other tissues. The flower of Platycodon grandiflorum can highly accumulate heavy metal(loid)s, especially for Cu in the flowering period. Pb, Cd, and Cu contents in stem generally increased with growth time, while Cd and Cu in root decreased during growth time. The average daily intake doses of five heavy metal(loid)s in the root of Platycodon grandiflorum were all below the safety guideline and the target hazard quotient was less than 1.

Fractionation analysis and health risk assessment of heavy metals in six traditional Chinese medicines.

Traditional Chinese medicines (TCMs) are widely used to treat various diseases in China and some countries, and TCM products are becoming increasingly available and popular worldwide. But TCMs are facing the challenge of heavy metal pollution. In this work, we examined the total contents and fractionations of Pb, Cd, Hg, and Cu in six TCMs (Angelicae Sinensis Radix (ASR), Chuanxiong Rhizoma (CR), Polygonati Rhizoma (PR), Astragali Radix (AR), Carthami Flos (CF), and Paeoniae Radix Rubra (PRR)) and evaluated the health risk of four heavy metals in these TCMs. The results showed that Cd, Pb, and Cu contents were considerably high and the amount of Cd in six TCMs, Pb in CR, ASR, AR, and CF, and Hg in ASR, PR, and PRR exceeded the limit values. The predominant fractions of Pb, Cd, and Cu were exchangeable and carbonate fractions in six TCMs; Hg mainly existed in organic and residual fractions. The average daily intake dose (ADD) and target hazard quotient (THQ) of Pb based on total content and total THQ of four heavy metals based on bioaccessible fractions in AR and PRR exceeded the safety guideline. These results indicated that the potential health risk could occur by taking these TCMs.

Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis.

Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis in vivo. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer. SIGNIFICANCE: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis.