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Review
. 2020 Apr 16:11:366.
doi: 10.3389/fphar.2020.00366. eCollection 2020.

Angelicin-A Furocoumarin Compound With Vast Biological Potential

Camille Keisha Mahendra  1   2 , Loh Teng Hern Tan  2   3 , Wai Leng Lee  4 , Wei Hsum Yap  5 , Priyia Pusparajah  6 , Liang Ee Low  7   8 , Siah Ying Tang  9   10 , Kok Gan Chan  11   12 , Learn Han Lee  2 , Bey Hing Goh  1   13   14
Affiliations
Review

Angelicin-A Furocoumarin Compound With Vast Biological Potential

Camille Keisha Mahendra et al. Front Pharmacol. .

Abstract

Angelicin, a member of the furocoumarin group, is related to psoralen which is well known for its effectiveness in phototherapy. The furocoumarins as a group have been studied since the 1950s but only recently has angelicin begun to come into its own as the subject of several biological studies. Angelicin has demonstrated anti-cancer properties against multiple cell lines, exerting effects via both the intrinsic and extrinsic apoptotic pathways, and also demonstrated an ability to inhibit tubulin polymerization to a higher degree than psoralen. Besides that, angelicin too demonstrated anti-inflammatory activity in inflammatory-related respiratory and neurodegenerative ailments via the activation of NF-κB pathway. Angelicin also showed pro-osteogenesis and pro-chondrogenic effects on osteoblasts and pre-chondrocytes respectively. The elevated expression of pro-osteogenic and chondrogenic markers and activation of TGF-β/BMP, Wnt/β-catenin pathway confirms the positive effect of angelicin bone remodeling. Angelicin also increased the expression of estrogen receptor alpha (ERα) in osteogenesis. Other bioactivities, such as anti-viral and erythroid differentiating properties of angelicin, were also reported by several researchers with the latter even displaying an even greater aptitude as compared to the commonly prescribed drug, hydroxyurea, which is currently on the market. Apart from that, recently, a new application for angelicin against periodontitis had been studied, where reduction of bone loss was indirectly caused by its anti-microbial properties. All in all, angelicin appears to be a promising compound for further studies especially on its mechanism and application in therapies for a multitude of common and debilitating ailments such as sickle cell anaemia, osteoporosis, cancer, and neurodegeneration. Future research on the drug delivery of angelicin in cancer, inflammation and erythroid differentiation models would aid in improving the bioproperties of angelicin and efficacy of delivery to the targeted site. More in-depth studies of angelicin on bone remodeling, the pro-osteogenic effect of angelicin in various bone disease models and the anti-viral implications of angelicin in periodontitis should be researched. Finally, studies on the binding of angelicin toward regulatory genes, transcription factors, and receptors can be done through experimental research supplemented with molecular docking and molecular dynamics simulation.

Keywords: angelicin; biological activities; biological potential; furocoumarin; psolaren.

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Figures

Figure 1
Figure 1
(A) Furocoumarin's several different possible attachments of the furan ring on the coumarin nucleus; (B) Angular furocoumarin: Angelicin; (C) Linear furocoumarin: Psoralen.
Figure 2
Figure 2
(A) Formation of interstrand crosslinks in the DNA by psoralen when exposed to UVR; (B) Formation of monoadducts in the DNA by angelicin when exposed to UVR.
Figure 3
Figure 3
Potential bioproperties of the furocoumarin, angelicin, as an anti-cancer, anti-inflammation, anti-viral, anti-periodontitis, erythroid differentiating, and pro-osteo- and chondrogenic therapeutic agent.
Figure 4
Figure 4
The biosynthesis pathway of linear and angular furocoumarin in plants. Both psoralen and angelicin come from the same precursor, umbelliferone, which had been modified differently to form both linear and angular furocoumarin pathways. Though psoralen is able to act as a negative feedback against C2'H activity, it is not known yet if angelicin is also involved in the negative feedback loop.
Figure 5
Figure 5
The involvement of angelicin in several apoptotic pathways which promote cancer cell death. In the intrinsic pathway, angelicin increases the expression of proapoptotic proteins and decreases the expression of anti-apoptotic proteins, causing a caspase cascade of caspase 3 and 9 to occur. In the extrinsic pathway, combination treatment between TRAIL and angelicin down-regulated c-FLIP which leads to an increase in active caspase 3, inducing cell apoptosis. However, the involvement of other apoptosis-related proteins with the combination treatment in the extrinsic pathway is yet to be elucidated. The PI3K/AKT and MAPK pathways are also actively involved in angelicin-mediated cancer cell death.
Figure 6
Figure 6
The anti-inflammatory properties of angelicin. (A) Angelicin attenuates inflammation-induced-damage in acute lung injuries and asthma by lowering the cytokine production and reducing the infiltration of neutrophils and macrophages. Both MAPK and NF-κB pathway was also affected by angelicin in which angelicin inhibits the phosphorylation of IκB, p65, p38, and JNK. (B) Angelicin exerts a neuroprotective effect by inhibiting the production of nitric oxide and reducing the damage caused by hydrogen peroxide in LPS-induced inflamed mouse BV2 microglia cells and HT22 mouse hippocampal cells respectively.
Figure 7
Figure 7
Angelicin exhibits pro-osteogenic, chondrogenic differentiating properties while suppressing adipogenic differentiation. (A) Several genes and proteins were upregulated by angelicin in the osteogenic differentiation via TGF-β/BMP, Wnt/β-catenin pathway and AhR pathway. It is also able to attenuate oxidative stress by upregulating antioxidant enzymes, inhibiting bone resorption. Other markers like ERα are upregulated as well by angelicin. (B) The suppression of adipogenesis by angelicin through the regulation of the mTOR pathway. (C) The induction of angelicin in chondrogenic differentiation via the Wnt/β-catenin, MAPK, and TGF-β/BMP pathway.
Figure 8
Figure 8
Angelicin exhibits anti-periodontitis, anti-viral and erythroid differentiating properties. (A) Angelicin reduces and inhibits the thickening of P. gingivalis biofilm while inhibiting the expression of pro-inflammatory cytokines. Besides that, angelicin also promotes osteogenic differentiation and an increase in the expression of osteogenic genes in hPDLCs. (B) Angelicin inhibits murine gammaherpesvirus 68 lytic cycle at early stages of infection by affecting the expression of RTA mRNA and thus indirectly the expression of ORF45 and ORF65 proteins, decreasing the formation of plaques. (C) Erythroid differentiation increases as angelicin and its photoproduct increase the expression of fetal haemoglobin mRNA.
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