Aberrant activation of signal transducer and activator of transcription 3 (STAT3) has been documented in various malignancies including triple-negative breast cancers (TNBCs). The STAT3 transcription factor can regulate the different important hallmarks of tumor cells, and thus, targeting it can be a potential strategy for treating TNBC, for which only limited therapeutic options are available. In this study, we analyzed the possible effect of (-)-galiellalactone and its novel analogues, SG-1709 and SG-1721, and determined whether these agents exerted their antineoplastic effects by suppressing the STAT3 signaling pathway in TNBC cells. The two analogues, SG-1709 and SG-1721, inhibited both constitutive as well as inducible STAT3 phosphorylation at tyrosine 705 more effectively than (-)-galiellalactone, which indicates that the analogues are more potent STAT3 blockers. Moreover, SG-1721 not only inhibited nuclear translocation and DNA binding of STAT3 but also induced apoptosis, and decreased expression of diverse oncogenic proteins. Interestingly, SG-1721 also exhibited an enhanced apoptotic effect when combined with radiotherapy. Furthermore, in vivo administration of SG-1721 significantly attenuated breast xenograft tumor growth via decreasing levels of p-STAT3. Therefore, SG-1721 may be a promising candidate for further application as a pharmacological agent that can target STAT3 protein in treating TNBC.

A concise and scalable synthetic route for optically pure (4S) and (4R)-5-(3′,4′-dihydroxyphenyl)-γ-valerolactones (DHPVs), catechin metabolites, has been developed via the efficient construction of a γ-valerolactone moiety from hexenol. Noticeably, the different skin wrinkle-reducing activities of each metabolite were revealed via our unique syntheses of DHPVs in an enantiomerically pure form.

Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive studies have been devoted in this field. In conjunction with these results, our group focused on the anti-inflammatory effects of both enantiomers of DHPV (5-(3′,4′-dihydroxyphenyl)-γ-valerolactone), produced in the intestine by microbiota metabolism, on IEC-6 cells. Divergent and efficient enantioselective synthesis of (S)- and (R)-DHPV was efficiently achieved by cross-metathesis and Sharpless asymmetric dihydroxylation as a key reaction for four steps in 16% and 14% overall yields, respectively. The anti-inflammatory effects of two enantiomers were tested on IEC-6 cells, and we found that (S)-DHPV was more active than (R)-DHPV. This result implicates that the metabolite produced in the gut has beneficial effects on IEC-6 cells of rat intestines, and the chirality of the metabolite is important for its anti-inflammatory activity. This also provided information for the future discovery of novel small molecular therapeutics for the treatment of inflammatory bowel disease.

Fibrosis has various biological processes and affects almost every organ, especially in patients with inflammatory bowel disease, including Crohn’s disease, who experience discomfort caused by intestinal fibrosis, which is a problem that needs to be resolved. TGF-β signaling is known to act as a key regulator of intestinal fibrosis, and its modulation could be an excellent candidate for fibrosis therapy. Xanthohumol (XN) has various effects, including anti-inflammation and anti-cancer; however, the detailed mechanism of TGF-β signaling has not yet been studied. The purpose of this study was to investigate the mechanism underlying the anti-fibrotic effect of XN on TGF-β1-induced intestinal fibrosis using primary human intestinal fibroblasts (HIFs). In this study, to check the anti-fibrotic effects of XN on intestinal fibrosis, we assessed the expression of fibrosis-related genes in TGF-β1-stimulated HIFs by qPCR, immunoblotting, and immunofluorescence staining. As a result, XN showed the ability to reduce the expression of fibrosis-associated genes increased by TGF-β1 treatment in HIFs and restored the cell shape altered by TGF-β1. In particular, XN repressed both NF-κB- and Smad-binding regions in the α-SMA promoter, which is important in fibrosis. In addition, XN inhibited NF-κB signaling, including phosphorylated-IkBα and cyclooxygenase-2 expression, and TNF-α-stimulated transcriptional activity of NF-κB. XN attenuated TGF-β1-induced phosphorylation of Smad2 and Smad3, and the transcriptional activity of CAGA. Particularly, XN interfered with the binding of TGF-Receptor I (TβRI) and Smad3 by binding to the kinase domain of the L45 loop of TβRI, thereby confirming that the fibrosis mechanism did not proceed further. In conclusion, XN has an inhibitory effect on TGF-β1-induced intestinal fibrosis in HIFs, significantly affecting TGF-β/Smad signaling.

Ionic liquids (ILs) have sparked much interest as alternative solvents for plant materials as they provide distinctive properties. Therefore, in this study, the capacity of ILs to extract oxypeucedanin hydrate and byakangelicin from the roots of Angelica dahurica (A. dahurica) was investigated. The back-extraction method was examined to recover target components from the IL solution as well. Herein, [Bmim]Tf₂N demonstrated outstanding performance for extracting oxypeucedanin hydrate and byakangelicin. Moreover, factors including solvent/solid ratio, extraction temperature and time were investigated and optimized using a statistical approach. Under optimum extraction conditions (solvent/solid ratio 8:1, temperature 60 °C and time 180 min), the yields of oxypeucedanin hydrate and byakangelicin were 98.06% and 99.52%, respectively. In addition, 0.01 N HCl showed the most significant ability to back-extract target components from the [Bmim]Tf₂N solution. The total content of both oxypeucedanin hydrate (36.99%) and byakangelicin (45.12%) in the final product exceeded 80%. Based on the data, the proposed approach demonstrated satisfactory extraction ability, recovery and enrichment of target compounds in record time. Therefore, the developed approach is assumed essential to considerably reduce drawbacks encountered during the separation of oxypeucedanin hydrate and byakangelicin from the roots of A. dahurica.

Ionic liquids (ILs) have attracted significant interest because of their desirable properties. These characteristics have improved their application to overcome the shortcomings of conventional separation techniques for phytochemicals. In this study, several ILs were investigated for their capacity to extract isoimperatorin, a bioactive furanocoumarin, from the roots of Ostericum koreanum. Herein, 1-Butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF₄]) was selected as a promising IL for separating isoimperatorin. A central composite design was applied to optimize the extraction conditions. Under the optimal conditions, the yield of isoimperatorin reached 97.17 ± 1.84%. Additionally, the recovery of isoimperatorin from the [Bmim][BF₄] solution was successfully achieved (87.73 ± 2.37%) by crystallization using water as an antisolvent. The purity of the isoimperatorin was greatly enhanced, from 0.26 ± 0.28% in the raw material to 26.94 ± 1.26% in the product, in a one-step crystallization process. Namely, an enhancement of approximately 103-folds was reached. The developed approach overcomes the shortcomings of conventional separation methods applied for gaining isoimperatorin by significantly reducing the laboriousness of the process and the consumption of volatile organic solvents. Moreover, the simplicity and effectiveness of the method are assumed to be valuable for producing isoimperatorin-enriched products and for promoting its purification. This work also confirms the efficiency of ILs as a promising material for the separation of phytochemicals.