Exploring Artemisia annua L., artemisinin and its derivatives, from traditional Chinese wonder medicinal science

Artemisia annua L. (Chinese wormwood herb, Asteraceae) synthesizes artemisinin, which is known as qinghaosu, considers as a unique sesquiterpene endoperoxide lactone. In traditional Chinese medicine, it has been used for the treatment of fevers and haemorrhoides. More researches on Artemisia annua L. and its derivatives, especially artemisinin and other metabolites will help to increase the knowledge and value of A. annua and its constituents. Phenolics from Artemisia annua consists of coumarins, flavones, flavonols, phenolic acids, and miscellaneous. Artemisinin has attracted much attention from scientists due to its potent antimalarial properties as secondary metabolites. Moreover, more attentions are focusing on the roles of artemisinin and its derivatives in treating obesity and metabolic diseases. They also have anti-bacterial, antiinflammatory, anti-tumor, anti-protozoa, anti-helminthic, anti-fungal, anti-angiogenic and antiproliferation properties. The most important derivatives of Artemisia annua L. are arteether, artemether, artemiside, artemisinin, artemisone, artesunate, and dihydroartemisinin. Artemisinin also use against some cancers such as liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer. This important gift from ancient Chinese traditional medicine can guarantee health of people all around the world. Further researches should be done on the new advances and development of artemisinin and its derivatives as potential natural medicine in the global fight against so many diseases, malaria included.


Introduction
For thousand years, the most commonly treatment which has been widely used in different parts of the world, especially Asia was traditional herbal medicines (Shahrajabian et al., 2020a, b;Sun et al., 2020a, b), because of containing various ranges of chemical contents with different pharmacological applications. They are used by people because of effectiveness, frequently inadequate provision of modern medicine, cultural beliefs and preferences (Sun et al., 2019a, b;Shahrajabian et al., 2020c, d). Artemisia annua L., Asteraceae, has diverse biological actions from anticancer to anti-malarial activities (Beekman et al., 1998) with high drugs against strains of Plasmodium falciparum parasites (Meshnick et al., 1996). Wild or cultivated A. annua L. is a major source for artemisinin because chemical and biological synthesis of artemisinin is still under development due to poor yields (Huang et al., 2010). Tu was awarded her Nobel Prize in Physiology or Medicine in 2015 for the discovery of this important antimalarial compound as a head of a scientific group in 1967-1969(Salehi et al., 2018. Artemisinins are a family of sesquiterpene trioxane lactone bearing an endoperoxide bridge, and used artemisinins includes artemisinin (ART), artesunate (AS), artemether (AM), arteether (AE) and dihydro-artemisinin (DHA) (Asano and Iwahashi, 2017;Shi et al., 2018). Artemisinin and its derivatives are powerful and important medicine because of their ability to swiftly reduce the number of Plasmodium parasites in the blood of patients affected by malaria (Negi et al., 2018;Lv et al., 2019). However, Phyo et al., (2018) noted that reliable efficacy of artesunate for the treatment of severe malaria may no longer be assured in areas where artemisinin resistance has emerged. Rath et al. (2004) stated that one liter of an aqueous preparation of nine grams of Artemisia annua contained 94.5 milligrams of artemisinin, which is approximately 19% of the usually recommended daily dose. It can grow easily in the humid tropics though the artemisinin yield appears to be affected significantly by several factors such as seed origin, planting season, soil moisture availability and cultivation methods (Brisibe et al., 2012). Moderate salt stress has been proved to increase the artemisinin synthesis by the plant (Correa-Ferreira et al., 2019).
The biosynthesis of artemisinin was reported in the shoot cultures and genetically modified roots (hairy roots) of A. annua (Ram et al., 2014). Its derivatives such as artesunate, dihydroartemisinin and artemether are the most potential antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium flaciparum (O , Neill, 2005). Fu et al. (2016) concluded that both plant height and stem bottom diameter had the most important positive impact on artemisinin content of the leaves and herb yield. Artemether is the methylated derivatives of artemisinin.
Artemether showed anti-parasitic properties toward many protozoan parasites such as Leishmania, Toxoplasma gondii and Trypansoma spp. (Mishina et al., 2007), and also a promising drug in control of schistosomiasis mansoni due to its reductive impact on worm burden and its role in improvement of hepatic granulomatous lesions (Madbouly et al., 2015). Production of artemisinin in genetically modified microorganisms is an attractive way to enable sufficient supply of the effective antimalarial agent (Zeng et al., 2012). It can be extracted using ultrasound-assisted extraction (UAE) and then detected via HPLC (Widmer et al., 2007;Wang and Liu, 2012;Zhang et al., 2014). The biosynthetic pathway of artemisinin belongs to the isoprenoid pathway and its production pathway was divided in two stages: in the first step Acetyl-CoA make isopentenyl diphosphate (IPP) and its isomer, dimethylallyl diphosphate; in the next step IPP produces artemisinin (Mirzaee et al., 2016). There are four enzymes, namely ADS, CYP71AV1, DBR2 and ALDH1 in artemisinin biosynthetic pathway, and the artemisinin content was determined by the chemo-type of CYP71AV1 (Lv et al., 2017), and the highly active CYP71AV1 is decided by an amino acid residue (Ser479) (Komori et al., 2013). Artemisinin derivatives are effective against other parasites such as Toxoplasma gondii (De Oliveira et al., 2009), Trypanosoma cruzi (Sulsen et al., 2008), Schistosoma japonicum, Schistosoma mansoni, Fasciola hepatica, and Clonorchis sinensis (Fathy, 2011), and Acanthamoeba spp. (Derda et al. 2016). Lai et al. (2005) discovered that artemisinin and artemisinin-tagged iron-carrying compounds could be developed into powerful anticancer drugs. Njuguna et al. (2012) stated that artemisinin and its derivatives have revealed its potential use in treating other infectious and noninfectious diseases. Ivanescu et al. (2011) found artemisinin content in Romanian A. annua wild plants varies between 0.17 and 0.21% dry weight basis.
Artemisinin, artesunate and artemether are well-tolerated in both children and adults, with no evidence of serious clinical toxicity (Price, 2000). Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria (Christian et al., 2017). Wojtkowiak-Giera et al. (2018) observed that A. annua extract is a natural substance which is well tolerated in animals and may be considered as a combination therapy in treatment of acanthamoebiasis. Artesunate is the most versatile derivative of artemisinin, because it is easily soluble in water, which has facilitated the development of oral and rectal formulas (Angus et al., 2002); it is an antimalarial agent and acts cytotoxically on tumor cells (Aquino et al., 2011;Kannan et al., 2019).
Artseunate is not only an effective drug for treating tumor, but also it has been used for curing malaria, improving inflammation and protecting nerves (Noubiap, 2014;Bigoniya et al., 2015;Zhao et al., 2017;Gugliandolo et al., 2018;Wen et al., 2018). Kong et al. (2019) demonstrated that artesunate targeted activating hepatic stellate cells ferroptosis, and its effect was associated with activation of ferritinophagy. Phenolics compounds from Artemisia annua is shown in Table 1. From plant to medicine, the most important pharmacological properties of artemisinin and its derivatives Artemisinin family drugs regulate innate immune cells, regulate adaptive immune cells, and it has efficacy in treating autoimmune diseases (Hou and Huang, 2016;Shen et al., 2018). Daddy et al. (2017) suggested the use of Artemisia annua dried leaf tablets to treat resistant malaria in which the synergic role of other components with artemisinin is claimed to tackle plasmodium resistance. The most important pharmacological effects of artemisinins consist of anti-virus, anti-cancer, anti-inflammatory and anti-oxidant (Ho et al., 2014;Shi et al., 2015). Lam et al. (2018) found that Artemisinin (ART) and its derivatives are potentially effective drugs for treating various helminthic diseases of public health significance. It has been reported that ART derivatives and synthetic peroxides such as ozonides and trioxolanes maybe used as alternative or complementary drugs against schistosomes (Keiser et al., 2012;Xiao et al., 2012). Moreover, ART and its derivatives also have activities against nematodes and cestodes (Kuster et al., 2014;Abou Rayia et al., 2017). Magoulas et al. (2017) suggested that artemisinin dimmers are good candidates for the development of effective anticancer agents. Shi et al. (2018) suggested that artemisinins are capable to treat neuroinflammation-related central nerve system (CNS) diseases in both direct and indirect manners. Qiang et al. (2018) provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases. Wu et al. (2016) described the novel artemisinin derivatives in the treatment of autoimmune diseases. Lai et al. (2013) reported that artemisinin dimmers and trimers, artemisinin hybrid compounds, and tagging of aretemisnin compounds are involved in the intracellular iron-delivery mechanism, and all these compounds are promising potent anticancer compounds which may produce significantly less side effect than traditional chemotherapeutic agents. Zhao et al. (2017) noted that artemisinin enhances the stability of liver cell membrane, and reduce the damage of liver cell membrane and liver cell; it also showed a protective effect against chronic alcohol poisoning and incredible clinical potential to treat the liver injury induced by alcohol. Abba et al. (2018) also indicated that artemisinin-type drugs may be safely applied to prevent carcinogenesis and cancer metastasis in human beings. It has been reported that artemisinins possess immunoregulatory properties and modulate components of the immune system (Yao et al., 2016). Abou Rayia et al. (2017) revealed that artemisinin has the potential to be an alternative drug against trichinellosis. Yuan et al. (2019) found that ART ameliorated rosacea-like dermatitis by regulating immune reponse and angiogenesis, indicating that it could represent an effective therapeutic option for patients with rosacea. The mechanism for the antimalarial activity of artemisinin has been examined using artemisinin and its model compounds 1,2,4,5tetraoxane and 1,2,4-trioxolane derivatives (Garah et al., 2011). Chen et al. (2018 suggested that artemisinin had significant anti-tumor activities on C6 cells both in vitro and in vivo, and artemisinin might be exploited as a promising clinical anti-cancer drug in future. Leng et al. (2019) declared that an extract of an artemisinindeficient Artemisia annua herbal preparation exhibits potent anticancer activity against triple negative human breast cancer. Yao et al. (2018) also concluded that artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer. Konstat-Korzenny et al. (2018) found that both in vitro and in vivo clinical trials have shown promising activity of the artemisinin drug derivatives in treating certain types of cancer. Although, the artemisinin-based combination therapies have become more popular in the fight against malaria, resistance to artemisinin has begun to emerge (Shen et al., 2016). Lang et al. (2019) announced that an extract of an artemisinin-deficient Artemisia annua herbal preparation exhibits potent anti-cancer activity against triple negative human breast cancer. Li et al. (2018) indicated that artemisinin exhibited anti-allergic effect by inhibiting ERK activation and increasing Treg cell proportion, which subsequently decreased the expressions of allergic mediators. They have also found that artemisinin combined with neurectomy of pterygoid showed better efficacy than artemisinin alone. Artemisinin also use against liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer through reducing cell proliferation, inducing cell cycle arrest, promoting cell apoptosis, blocking tumor cell invasion, chaning the tumor microenvironment and reducing angiogenesis (Aderibigbe, 2017;Zhang et al., 2018). Munyangi et al. (2018) reported the effective treatment of schistosomiasis by using A. annua.
The plant extract of A. annua has a modulatory impact on components of the immune system such as TLR2 and TLR4 (Wojtkowiak-Giera et al., 2019). Dihydroartemisinin showed colon cancer growth by inducing apoptosis and increase the expression of PPARγ, which has made it a promising natural compound for the treatment of colon cancer . Artemisinin and its derivatives for the treatment of various diseases are shown in Table 2. The most important pharmacological properties of artemisinin are anti-malarial activity, antiviral, antibacterial, antihelminthis, antiprotozoa, antifungal, anti-inflammatory and anti-tumor properties (Zyad et al., 2017;Qiu et al., 2018). Phenolics enhance artemisinin water solubility and extraction efficiency as phenolics, mainly chlorogenic acids, are highly present in teas from A. annua (Carbonara et al., 2012). Higher artemisinin concentrations when multiplied by total leaf dry matter at the higher boron application rates may increase in total artemisinin production per plant (Davies et al., 2011). Wu et al. (2017) reported that antioxidant activity of volatile oils in the flowering and post-flowering stages were stronger than that in preflowering and initial flowering stages. Fu et al. (2020) found that geographic content differences of the components in A. annua indicate the potential differences in the health-promoting effects of its clinical application. Its essential oil extracts have a good antioxidant capacity, especially as antiradical scavengers (Gouveia and Castilho, 2013). Artesunate can compromise the repair of DNA double-strand breaks (DSBs) in ovarian cancer cells which shows its ability as a sensitizing agent in chemotherapy .
Artesunate has anti-proliferative properties in colorectal cancer (CRC) and is generally well tolerated (Krishna et al., 2015). The most important pharmaceutical benefits of Artemisia are shown in Table 3. The most important natural components and pharmaceutical benefits of Artemisia annua L is shown in Figure 2. b. The efficacy of artemisinin against malaria has promoted its use as a tea drink in endemic communities. c. Artemisia appeared to break the cycle of malaria by eliminating gametocytes. d. Artemether is co-administered with lumefantrine as part of a fixeddose combination therapy for malaria in both adult and pediatric patients.   b. α-bisabolol which is a famous antiinflammatory extract found in essential oil. c. Artemisinin may protect the aortas from atherosclerotic lesions by suppression of inflammatory reaction via AMPK/NF-κB/NLRP3 inflammasomes signaling in macrophages.
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Conclusions
Traditional Chinese medicine is a medical system based on theory, pathology, diagnosis, treatment and herbal pharmacology principles. Artemisia annua L. is a Chinese medicinal herb, which has significant efficacy against malaria with low toxicity. Artemisinin discovered and isolated by Chinese scientists in the early 1970s, as a natural peroxide drug for the treatment of malarial. Artemisinin combination therapies are used worldwide as the appropriate treatment against Plasmodium falciparum malaria. This important drug has been developed from the Chinese traditional herbal medicine and is known as Qinghaosu. Artemisinin demonstrates prominent biological activities and attracts great attention nowadays. Artemisinin and its derivatives, namely artemiside, artesunate, artemisone, arteether, artemether, and dihydroartemisinin have significant anti-malaria, anti-viral, anti-fungal, anti-cancer and anti-inflammatory properties. The artemisinin content is highly dependent on plant ecotypes, ecological interactions, seasonal and geographical variations. The discovery of artemisinin has been presented as the important example of the face of adversity, social commitment to the good of humanity, genuine esteem for past and traditional wisdom and of course a heartfelt belief in the value of science. More researchers of relationship of artemisinin and its derivatives are necessary to develop and optimize new therapeutics with significant impacts. On the basis of traditional Chinese medicine, the metabolic properties of artemisinin and its derivatives bring more hope to treat malaria, obesity and some other metabolic diseases.

Authors' Contributions
All authors read and approved the final manuscript.