Integrated analysis reveals effects of bioactive ingredients from Limonium Sinense (Girard) Kuntze on hypoxia-inducible factor (HIF) activation

Abstract

Limonium Sinense (Girard) Kuntze is a traditional Chinese medicinal herb, showing blood replenishment, anti-tumour, anti-hepatitis, and immunomodulation activities amongst others. However, the mechanism of its pharmacological activities remains largely unknown. Here, we investigated the effects of bioactive ingredients from Limonium Sinense using an integrated approach. Water extracts from Limonium Sinense (LSW) showed a strong growth inhibitory effect on multiple cells in both 2D and 3D cultures. Global transcriptomic profiling and further connectivity map (CMap) analysis identified several similarly acting therapeutic candidates, including Tubulin inhibitors and hypoxia-inducible factor (HIF) modulators. The effect of LSW on the cell cycle was verified with flow cytometry showing a G2/M phase arrest. Integrated analysis suggested a role for gallic acid in mediating HIF activation. Taken together, this study provides novel insights into the bioactive ingredients in Limonium Sinense, highlighting the rich natural resource and therapeutic values of herbal plants.

Integrated network pharmacology and cellular assay reveal the biological mechanisms of Limonium sinense (Girard) Kuntze against breast cancer

“…In line with these ndings, our current analysis highlights the close relationship between the biological activity of L. sinense and cancer-related pathways, suggesting a potential role of L. sinense in cancer treatment. Moreover, the signi cant enrichment of the Cell cycle pathway in our analysis further supports our previous ndings that the water extract of L. sinense leads to cell cycle arrest at the G2/M phase [13]. Additionally, the ethanol extract of L. sinense demonstrates a remarkable inhibitory effect on the growth of various breast cancer cell lines, suggesting the considerable potential of L. sinense as an adjuvant of therapeutic agent for the treatment of breast cancer.…”

“…4A). In addition, HIF-1 signalling pathway and cell cycle were also observed in the KEGG pathways, which consistent with our previous ndings that the biological properties of L. sinense were associated with G2/M cell cycle arrest and HIF activation [13]. The GO term analysis predicted that the targets of L. sinense are mainly related with protein phosphorylation (GO:0006468) in Biological Process, integral component of plasma membrane (GO:0005887) in Cellular Component, and protein tyrosine kinase activity (GO:0004713) in Molecular Function (Fig.…”

“…However, there is no direct evidence to prove the blood-enriching function of L. sinense so far. Our previous study demonstrated that the water extract of L. sinense exhibits the ability to induce hypoxia inducible factor (HIF) activation [13]. Interestingly, in our current analysis, the HIF-1 signalling pathway was also signi cantly enriched.…”

“…In our previous study, we demonstrated that the water extract of L. sinense has a signi cant inhibitory effect on the growth of multiple breast cancer cell lines [13]. Based on the network pharmacology results, we found that Apigenin may play a key role in treating cancer.…”

“…Other studies revealed signi cant anti-viral activity of L. sinense, and compounds such as gallic acid, samarangenin B and myricetin derived from L. sinense exhibited signi cant inhibitory effects against viral infections [10][11][12]. Our previous study [13] have found a signi cant inhibitory effect of the water extract of L. sinense on multiple types of human breast cancer cells. However, further underlying mechanisms of the pharmacological activities of L. sinense still remain to be elucidated.More than 40 chemical compounds have been identi ed from L. sinense, most of which are avonoids [12,14].…”