Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects. Taxifolin is an effective ?OH scavenger that may protect bone marrow-derived mesenchymal stem cells (bmMSCs) from injury caused by ?OH.

Synthesis of Taxifolin

General procedure: Sugar identification was conducted according to a previously reported procedure (Luecha et al., 2009). Compound 1 (2 mg) was heated to 100 °C with dioxane (0.05 mL) and 5% H2SO4 (0.05 mL) for 1 h. After dilution with H2O, the reaction mixture was extracted twice with EtOAc. The EtOAc layer was evaporated to give (+)-taxifolin (18) as an amorphous solid, and 18 was identified by direct comparison with an authentic sample. The aqueous layer was passed through an Amberlite IRA-60E column. The H2O eluate was then concentrated, and the residue was treated with d-cysteine (0.05 mg) in H2O (0.03 mL) and pyridine (0.015 mL) at 60 °C for 1 h with stirring. After the solution had been concentrated and the reaction mixture dried, pyridine (0.015 mL), hexamethyldisilazane (0.015 mL), and trimethylsilyl chloride (0.015 mL) were added to the residue. The reaction mixture was then heated at 60 °C for 30 min, and the supernatant was analyzed by GC. GC conditions: column GL Sciences TC-l, 0.25 mm x 30 m; column temp: 235 °C; carrier gas: N2; tR (min): D-rhamnose (11.4), L-rhamnose (11.6). The tR of l-rhamnose was detected from 1. Acid hydrolysis of other compounds was performed in the same manner as used for 1, and the tR of L-rhamnose was detected in these compounds.[1]

Taxifolin attenuates inflammation

Taxifolin is a natural flavonoid compound that can be isolated from onions, grapes, oranges and grapefruit. It also acts as a medicine food homology with extraordinary antioxidant and anti-inflammatory activity. This study aims to explain the protective effects and potential mechanisms of taxifolin against inflammatory reaction. Flavonoids are the plant-derived polyphenol components in most traditional Chinese medicine and possess remarkable anti-inflammation capacity. Taxifolin is one of natural plant flavonoids that has been discovered in various plants including grapes, oranges. As a single compound, taxifolin is an important dietary supplement and used as functional food in general. It exhibits the anti-inflammation and protection effects by scavenging over production of reactive oxygen species (ROS) against oxidative stress. Taxifolin can promote the differentiation of osteoblast and prevent the forming of osteoclasts in vitro and in vivo models (Cai et al., 2018). In this study, taxifolin inhibited the nuclear factor-κB (NF-κB) activation, mitogen activated protein kinase (MAPK), and decreased Trap, MMP-9, Cathepsin K, C-Fos, Nfatc1, and RANK expression; Taxifolin suppressed the osteoclast activity by improving the bone loss and decreased the levels of interleukin-6 (IL-6), IL-1β, receptor activator of nuclear factor-κB ligand (RANKL) in ovariectomized-induced mice, and the protection effects of taxifolin in LPS-induced bone lysis mouse model have been verified via NF-κB signaling pathway. Additionally, Teselkin et al (2000) founds that taxifolin is more antioxidant effective in rats with tetrachloromethane hepatitis.[2]

The MAPK signaling pathway is closely associated with the progression of inflammation. The p38 MAPK family members consist of p38α, p38β, p38γ and p38δ, which share approximately 60% identical in their amino acid sequence. And Victoria with her colleagues found that p38α MAPK is a major subtype involved in immune and inflammatory responses. Further, taxifolin’s mitigatory effect on the phosphorylation levels of ERK, JNK and p38 pathways were showed. However, through the current experimental results with MAPK pathway inhibitors, we found that taxifolin did not rely completely on the MAPK pathway to suppress the gene expression of iNOS, VEGF, COX-2 and TNF-α. Taken together, the results indicate that the downregulation of phosphorylated ERK, JNK and p38 levels in the MAPK signaling pathway is a possible mechanism for taxifolin. And of course, taxifolin also exerts anti-inflammatory effects on LPS-activated inflammatory response through other signaling pathways.

This study investigated the anti-inflammation of taxifolin, as well as the reduction of phosphorylation of MAPK signaling pathway. We found taxifolin decreased the expression of pro-inflammatory cytokines and the phosphorylation of MAPK signaling pathway. Whereas, taxifolin downregulated the expression of iNOS, VEGF, COX-2 and TNF-α partly relying on the MAPK signaling pathway. The scientific explanation of the theory of taxifolin will certainly further promote the reasonable, effective application in daily diet and health protection. Therefore, a healthy consumption of onions, grapes and others including taxifolin may be favor of the reduction of inflammation in the human body.

The anti-tumor effect of taxifolin on lung cancer

Taxifolin (3,5,7,3’,4’-pentahydroxyflavanone or dihydroquercetin), a member of the flavonoid family, has been shown to possess antioxidant, anti-inflammatory, hepatoprotective, anti-Alzheimer’s disease, and anti-angiogenic properties. Recently, taxifolin has also attracted attention for its antitumor activity. The antitumor mechanism of taxifolin mainly includes the inhibition of angiogenesis, cytochrome P450 enzymes, P-glycoprotein, reactive oxidative species (ROS), and cell cycle regulators, as well as the induction of apoptosis. These multiple effects in a single compound present taxifolin as a possible therapeutic agent or an adjuvant in cancer therapy.[3]

The inhibition of stemness and EMT of taxifolin has been directly or indirectly indicated in several tumors. Taxifolin modifies bioactive biomaterials to promote the differentiation of human umbilical cord-derived mesenchymal stem cells to osteoblasts. Osteogenic differentiation, which is enhanced by taxifolin, was shown to be a result of the inhibition of the NF-κB signaling pathway. Other signaling pathways involved in the stemness of tumors include the Janus family tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT), Notch, PI3K/AKT serine/threonine kinase, SHH, and Wnt/β-catenin pathways. The involvement of taxifolin in most of these signaling pathways has been demonstrated in recent studies. Remarkably, Li et al. recently found that taxifolin enhanced MET of highly aggressive breast cancer cells via β-catenin signaling, which directly supported the EMT regulating role of taxifolin. Taxifolin has been used in health products, and different formulations of taxifolin have been developed. Taxifolin has even been proved to be effective in suppressing amyloid-beta production and beneficially modulating proinflammatory microglial phenotypes, to block PD-1/PD-L1 CTLA-4/CD80 immune checkpoint and to inhibit the activity of carbohydrate-hydrolyzing enzymes, reducing dietary carbohydrate absorption. Many structures that are similar to taxifolin have been reported to harbor hepatoprotective and anti-tumor effects. For example, silybin, which can be synthesized from coupling of taxifolin and coniferyl alcohol, has been used in a clinical setting for hepatoprotective purposes. As most clinical therapeutic agents are harmful to the liver, the co-administration of taxifolin or its analogs/derivatives could potentially be beneficial. However, there are possibilities these previous reports contain bias, and whether or not flavonoids including taxifolin could compete receptors with targeted therapies requires further investigation.

There are some limitations to this study. As the mechanisms of action of almost all flavonoids, including taxifolin, are complicated, we only tested its effects on lung cancer cells in relation to the regulation of stemness. Of course, the mechanism of action for taxifolin in inhibiting lung cancer encompasses much more than stemness regulation. Furthermore, the outcome of taxifolin therapy can be affected by liver toxicity, oxidative stress, immune checkpoints, and even the absorption of nutrients. Therefore, the specific health benefits of taxifolin, especially for cancer patients require much more investigation. In conclusion, taxifolin inhibits the viability, stemness, and EMT of lung cancer in vitro and in vivo. The inhibition of viability and EMT in both A549 and H1975 cells could be a result of stemness suppression. These results highlight the possible beneficial effects of taxifolin as a lung cancer treatment, either alone or as an adjuvant, and support further anticancer drug development based on taxifolin and other flavonoids.

References

[1]Wungsintaweekul, Boonsong; Umehara, Kaoru; Miyase, Toshio; Noguchi, Hiroshi[Phytochemistry, 2011, vol. 72, # 6, p. 495 - 502]

[2]Zhang X, Lian X, Li H, Zhao W, Li X, Zhou F, Zhou Y, Cui T, Wang Y, Liu C. Taxifolin attenuates inflammation via suppressing MAPK signal pathway in vitro and in silico analysis. Chin Herb Med. 2022 Sep 1;14(4):554-562.

[3]Wang R, Zhu X, Wang Q, Li X, Wang E, Zhao Q, Wang Q, Cao H. The anti-tumor effect of taxifolin on lung cancer via suppressing stemness and epithelial-mesenchymal transition in vitro and oncogenesis in nude mice. Ann Transl Med. 2020 May;8(9):590.