Mechanism of Action of Artemisia and their Active Ingredients

The essential oil is extracted from the leaf, areal part, stem, and inflorescence of Artemisia by various methods, for example, hydro-distillation methods (Pandey, A.K. et al. 2014). Essential oil is composed of more than 60 different components. The concentration and the composition of the essential oil of the same species can differ, depending on the geographical origin. Essential oil contains a major component reported in Artemisia species, such as beta-pinene, thujone, 1, 8-Cineole, camphor, caryophyllene, camphene, artemisia ketone, and germacrene D (Chu S, et al.

, 2012; Khan M, et al., 2012).

However, some components are limited to specific species. For example, piperitone in A. judaica, artedouglasia oxide in A. stelleriana, capillene in A. stricta, chamazulene in A. arborescens L, and methyl chavicol has been reported in higher amounts in A. dracunculus (Shang z, et al., 2012; Cavar S, et al., 2012). Essential oil has a strong odor due to a complex mixture of monoterpenes and sequiterpenes. Artemisia has been reported to have antimalaria, cytotoxic, anti-hepatotoxic, antibacterial, antifungal, antioxidant and anticancer activities (Duffy et al. 2004).

Anti-fungal Activity:

Wormwood has inhibitory activity against fungi. Inhibitory activity depends on the composition of the essential oil. For instance, z-epoxyocimene and chrysanthenyl of France wormwood inhibited growth of candida albicans and Saccharomyces cerevisiae var (Juteau F et al., 2003). Turkish wormwood contains essential oil whose main components are camphor, 1,8-cineole, and chamazulene. These chemical components act as fungicidal at a dose of 20 ul against 34 species of fungi (Kordali S et al., 2005). F. solani and F. oxysporum were affected by es cis-epoxyocimene, chrysanthenol, and chrysanthenyl acetate (Bailen M et al., 2013).

Reactive oxygen species are highly reactive and can cause oxidative damage to different biomolecules, for example, damage in protein and lipid which lead to chronic disease (Halliwell B et al., 1997). The natural antioxidant of essential oil of wormwood protects from free radical damage and is safer than conventional therapeutics, which can lead to severe side effects (Ciesla L et al., 2012). Antioxidant activity is due to the essential oil and its components such as Artemetin (flavone) which has been described as an antioxidant that neutralizes peroxide radicals, thymol, Carvacrol, casticin which are reported as having weak radical scavenging activity, and other phenolic compounds (Bora KS et al., 2011).

Essential oil and extract components of wormwood have been reported to have antibacterial activity, especially against gram-positive bacteria (Fiamegos et al., 2011). The major (camphor, p-cymene, caryophyllene) or minor (?-pinene, ?-pinene) components of essential oil can easily enter the gram-positive bacteria because of lack of phospholipid membrane in these bacteria (Moslemi et al., 2012). Essential oil can also kill bacteria by inhibiting the synthesis of DNA, RNA, protein, and polysaccharide (Abad et al., 2012).

Wormwood and its extracts are considered to have strong antioxidant and/or immune modulatory potential and thus show hepatoprotective activity in animal-based models. For instance, caffeoyl and dicaffeoylquinic acids are hepatoprotective in nature. Aqueous-methanolic extract of wormwood exhibited hepatoprotective effect especially against acetaminophen and CCl4, both of which induce hepatic damage (Gilani AUH et al., 1995). The mechanism of action of wormwood in hepatic may be associated with inhibition of hepatic microsomal drug metabolizing enzymes, antioxidant activity, and/or blocking calcium channels (Mohammadian A et al., 2016).

Wormwood has been reported to have antimalarial activity. For instance, the aqueous and alcoholic leaf extracts of wormwood showed antimalarial activity against a strain of Plasmodium berghei in mice (Zafar MM et al., 1990). While the aqueous extract and sesquiterpene lactone fraction of wormwood have inhibited the growth of
P. falciparum, which causes malaria in humans (Valdes AFC et al., 2008), acts by reacting with the heme groups of the hemoglobin molecules digested by parasites, altering the cell structure and its functions. This is done through the free radicals derived from the iron and artemisinin reaction, thus affecting the growth and reproduction (Ferreira JFS et al., 2008; Meshnick, S.R et al., 1989).

The derivatives of artemisinin have varying effects depending on the tissue type; consequently, they show strong cancer activity against leukemia and colon cancer with an intermediate effect against melanoma, prostate, CNS, and ovarian cancers (Efferth, T. et al., 2001). The mechanism of Artemisia against cancer cells is initiated by the cleavage of the endoperoxide bridge by the high iron concentration present in cancer cells. This results in free radicals and subsequent oxidative damage, such as iron depletion in the cells and damage to biomolecules, including proteins, DNA, RNA, and lipids, which cause cancer cell death (Bustos et al., 1994).

The mechanisms of Artemisia in malarial parasites and cancer cells are similar but differ in that the cancer cell is sensitive to oxygen radicals because of a relative deficiency in antioxidant enzymes (Kelter, G. et al., 2007). Also, artemisinin concurrently causes activity, inhibitory, and attenuating effects on multiple complementary cell signaling pathways (Hou, J.et al.,2008).

Metabolites of wormwood have been discovered in a wide spectrum of localizations, such as mitochondria, ER, food vacuoles, and other membrane systems. The mechanism of action could be towards any one or several of these (Liu Y, et al., 2010; Wang J, et al., 2010; Eckstein-Ludwig U, et al., 2003). Wormwood is generally unstable in the presence of alkaline or acidic conditions, and due to the presence of the peroxide, it reacts with certain reducing agents, including Fe2+, heme, and Cu+. The endoperoxide bridge in wormwood is considered to be key to the anti-malarial and anti-cancer properties. The bridge cleavage by high concentrations of iron present in parasites and cancer cells results in a free radical, which causes cell damage (Li J, et al., 2010; Krishna S, et al., 2004; Bustos et al., 1994).

Wormwood obstructs the expression and function of specific nuclear receptors such as estrogen and androgen receptors, which are important in antiproliferative activities. Wormwood also targets genes involved in a wide range of normal and cancer cell functions, including cell proliferation, differentiation, cell survival, and apoptosis (McEwan, I.J., 2009; Kerkhofs, S., et al., 2009). Wormwood and its derivatives have been shown to inhibit the proliferation of various human cancers including breast cancer due to high ERa to ERb ratios frequently found in human breast cancer cells, such as MCF-7 and T47D cells, which are highly sensitive to the antiproliferative effects of artemisinin-related compounds (Efferth, T., et al., 2002; Sundar, S.N., et al., 2008). Artemisinin acts only on the activity of the androgen receptor, which has been reported to be critical to the development of normal prostate tissue and to the proliferation of neoplastic prostatic epithelium (Crawford, E.D., 2009).

Apoptosis

Apoptosis, also known as programmed cell death, involves cells dying and dismantling themselves at particular points during the development process (Horvitz, 1999). Apoptosis occurs normally during homeostatic mechanisms to maintain cell populations in tissues and as a defense mechanism, such as in immune reactions (Norbury and Hickson, 2001). The morphology of cells appears as a round or oval mass during apoptosis, with dark eosinophilic cytoplasm and dense purple nuclear chromatin fragments.

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