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Review

Antiviral and Immunomodulation Effects of Artemisia

1
College of Ayurveda, Mount Madonna Institute, 445 Summit Road, Watsonville, CA 95076, USA
2
California College of Ayurveda, 700 Zion Street, Nevada City, CA 95959, USA
*
Authors to whom correspondence should be addressed.
Medicina 2021, 57(3), 217; https://doi.org/10.3390/medicina57030217
Submission received: 23 January 2021 / Revised: 23 February 2021 / Accepted: 25 February 2021 / Published: 27 February 2021
(This article belongs to the Special Issue The Future of Medicine: Frontiers in Integrative Health and Medicine)

Abstract

:
Background and Objectives: Artemisia is one of the most widely distributed genera of the family Astraceae with more than 500 diverse species growing mainly in the temperate zones of Europe, Asia and North America. The plant is used in Chinese and Ayurvedic systems of medicine for its antiviral, antifungal, antimicrobial, insecticidal, hepatoprotective and neuroprotective properties. Research based studies point to Artemisia’s role in addressing an entire gamut of physiological imbalances through a unique combination of pharmacological actions. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes are some of the major phytochemicals of the genus. Notable among the phytochemicals is artemisinin and its derivatives (ARTs) that represent a new class of recommended drugs due to the emergence of bacteria and parasites that are resistant to quinoline drugs. This manuscript aims to systematically review recent studies that have investigated artemisinin and its derivatives not only for their potent antiviral actions but also their utility against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Materials and Methods: PubMed Central, Scopus and Google scholar databases of published articles were collected and abstracts were reviewed for relevance to the subject matter. Conclusions: The unprecedented impact that artemisinin had on public health and drug discovery research led the Nobel Committee to award the Nobel Prize in Physiology or Medicine in 2015 to the discoverers of artemisinin. Thus, it is clear that Artemisia’s importance in indigenous medicinal systems and drug discovery systems holds great potential for further investigation into its biological activities, especially its role in viral infection and inflammation.

1. Introduction

Medicinal plants, which are undervalued, have an important place in modern medicine owing to the multitude of active principles that nature provided through millions of years of evolution. These numerous plant chemicals or phytochemicals possess far reaching, biologically active, beneficial effects and provide protection to the plants from insects, bacteria, virus and other predators. These phytochemicals either alone or in combination affect multiple pathways simultaneously to produce the desired pharmacological effect. Many medicinal plants or herbs are revered by the ancient medical traditions (Chinese medicine, Ayurveda, Native Americans, etc.) due to their healing benefits and about 40% of modern medicines are derived from plants [1,2,3]. The development of antibacterial and anti-infectious agents is a major focus in modern medical research. Plant-based antiviral formulations have been studied for their therapeutic potential in the management of various viral diseases including influenza, human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis, and coxsackievirus infections [4,5,6,7].
One particular plant that has garnered a lot of attention in lieu of the COVID-19 epidemic is Artemisia which is one of the largest and most widely distributed genera of the family Astraceae (Compositae) [6,8]. Artemisia is a varied genus consisting of more than 500 diverse species and is found in the temperate zones of Europe, Asia and North America [9,10,11]. Evidence-based in vitro and in vivo studies on several species of Artemisia resulted in the identification of numerous phytochemicals with varied pharmacological activities, including terpenoids, flavonoids, coumarins, caffeoylquinic acids and sterols [12,13]. The first clinical trial of Artemisia extract in human patients with malaria was conducted in August 1972. Following that trial, the active compound in the Artemisia extract was isolated and identified as artemisinin. Several derivatives or synthetic compounds with key structures similar to artemisinin have now been developed including artesunate and piperaquine from A. annua and piperitone and trans-ethyl cinnamate from A. judaica that have potent antiviral and anti-inflammatory activities [9,14,15,16]. A combination of artemisinin and its derivatives (ARTs) is now recommended by the World Health Organization (WHO) for the treatment of malaria.

2. Methods

For the review, we conducted a search of PubMed Central, Scopus and Google scholar databases of articles published from 2000 to 2020 to include the most recent literature. The search was limited to articles in English and abstracts were reviewed for relevance to the subject matter of pharmacological perspective on Artemisia. Articles containing combinations of MeSH terms ‘Artemisia’ ‘artemisinin’, ‘artesunate’, ‘phytochemistry’, ‘diseases or conditions’, ‘in vitro or in vivo experiments’, ‘COVID-19′, ‘SARS-CoV-2′ and ‘mechanistic actions’ were collected. Boolean terms (AND/OR/NOT) were added to combine or exclude keywords in the search resulting in more focused literature.

3. Ethnopharmacology

The isolation and identification of potent compounds from the genus Artemisia, particularly artemisinin and its derivatives using novel drug discovery methods, prompted the Nobel Committee to award the Nobel Prize in Physiology or Medicine in 2015 for its impact on public health [17,18]. This spurred the interest of several researchers to study the phytochemical and pharmacological properties of other species of the genus Artemisia.
Nearly 45 different species of Artemisia grow in India and in the Indian subcontinent and is mainly used as a medicinal plant [8,19]. Ayurveda describes two species A. absinthium and A. maritima, popularly known as Mugwort that vary slightly in their qualities and actions as shown in Table 1.
In the Ayurvedic system of medicine, the term ‘prabhava’ refers to the ‘instinct intelligence’ of a plant in eliciting a wide range of medicinal effects [21,22]. A. absinthium and A. maritima are revered, owing to their prabhava and are recommended in Ayurveda for infections, inflammation, skin and liver diseases, respiratory conditions, neurological conditions and as an insecticidal (krimighna) [6,8].
The pharmacological actions and properties of the various Artemisia species from several geographic locations are listed in Table 2. Basically, the plant has been used as an anti-malarial, anti-spasmodic, anti-inflammatory, febrifuge, cardiac stimulant, anthelmintic, headaches, dyspepsia, liver and kidney tonic, to improve memory, for digestive and respiratory issues and as a hypertensive and anticoagulant.
The wide variety of actions stems from the fact that these various species of Artemisia possess high content of alkaloids, lactones, flavonoids, phenols, quinines, tannins and terpenoids all of which play a role in the growth of the plant or provide protection from pathogens or predators [6,9,44,45].

4. In Vitro and In Vivo Studies

We review some of the recent in vivo and in vitro studies of various extracts and formulations of Artemisia. The research studies utilized aqueous, methanol, chloroform or acetone extracts, essential oils or oil based extracts or dried powders of various species of Artemisia. The studies were performed on bacterial, viral or fungal cultures, cultured cells or animal models with limited studies on humans.
In the light of the COVID-19 pandemic, some species of Artemisia including but not limited to A. annua, A. absinthium, A. vulgaris, A. maritima and A. indhana are receiving greater attention from researchers as they hold great potential for their powerful anti-infectious, antiviral and anti-inflammatory activities [6,12,46,47,48]. Recent studies are now pointing to the exciting roles of artemisinin and its derivatives (ARTs) as potential drug candidates against SARS-CoV-2 owing to their potent antiviral and anti-inflammatory properties.

4.1. Anti-Carcinogenic Activity

Various species of the Artemisia plant have been shown to suppress the growth of numerous cancer cell lines including leukemia, colon cancer, renal cell carcinoma and breast cancer cells [28,49,50]. Phytochemical analysis of the various extracts revealed the presence of coumarins, flavonoids, anthocyanins, cardiac glycosides and tannins. These phytochemicals and their derivatives exhibit growth inhibitory properties through multiple actions including blocking angiogenesis, triggering apoptosis or cell cycle arrest and disrupting cell migration [51,52,53]. Researchers are now focusing their efforts on ARTs that appear to be broad-spectrum antitumor agents based on their efficacy and safety [54,55].
In a randomized, double-blind, placebo-controlled pilot trial involving 23 subjects, the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC) was determined. The primary outcome measure was the proportion of tumor cells undergoing apoptosis. Despite the fact that it was a small study size with variability in quantitating immunohistochemical markers, the results clearly indicated selective cytotoxicity of oral artesunate.
In addition to the above mentioned study, other clinical trials involving patients with solid tumors including colorectal carcinoma, breast cancer, hepatocellular carcinoma and lung cancer have been completed with encouraging results. In all these studies, ARTs inhibited growth of solid tumors with no evident toxicity and with a low incidence of adverse effects thus highlighting their role as promising anti-cancer agents [54,56,57].

4.2. Anti-Oxidant Activity

The phytochemicals and their derivatives, extracts and essential oils derived from the Artemisia plant have a unique property of being reactive oxygen species (ROS) modulators. In some cases they exhibit strong antioxidant and radical scavenging activity against hydroxyl ion and hydrogen peroxide and display excellent protective effect by strengthening the antioxidant defense system and lowering the generation of ROS [6,58].
In other situations, especially involving cancer cells, ARTs triggered ROS production leading to mitochondrial dysfunction and autophagy of leukemia cell lines. ARTs-induced ROS production triggered apoptosis in various tumor cell lines studies, including neuroblastoma, glioblastoma, T-cell lymphoma and breast cancer cells [54]. In studies using mouse models of cancer, ARTs induced ROS production leading to the inhibition of growth of ovarian cancer [54].
The mechanism of action of ARTs involves binding to ferrous iron (e.g., heme) and triggering the generation of ROS, which results in cytostatic or cytotoxic effects. The production of ROS can also trigger cellular damage through the peroxidation of membrane lipids, activation of pro-apoptotic pathways or creating genomic and mitochondrial DNA instability [59]. Thus, the ROS modulating properties exhibited by the various phytochemicals isolated from different species of Artemisia highlight the importance of exploring the therapeutic uses of these compounds in pathological conditions that feature oxidative stress.

4.3. Anti-Bacterial and Anti-Parasitic Activity

The plant extracts and compounds obtained from Artemisia species have been shown to be powerful inhibitors of bacteria and parasites [9]. Mechanistic studies demonstrate the bactericidal properties of some of these phytochemicals against Gram-negative or Gram-positive bacteria involving the destruction of the bacterial membrane [6,28,60,61]. Notable among the phytochemicals is ARTs that represent a new class of antibacterial drugs [9,14,15].
ARTs also possess potent antimalarial properties and are effective against both asexual and sexual parasite stages. In several clinical trials involving both ARTs and quinine, ARTs outperformed quinine in terms of mean parasite clearance time, fever clearance time, coma resolution times and incidence of adverse effects [14,15,16,62]. Artemisinin-based therapies are now recommended due to the resistance displayed by bacteria and parasites to quinoline drugs.

4.4. Anti-Fibrotic Effects

In addition to the above mentioned pharmacological properties, ARTs are also known for their anti-fibrotic effects [29,63,64]. The role of ARTs in blocking the development or progression of fibrotic phenotypes has been studied in animal models of pulmonary fibrosis, renal fibrosis, hepatic fibrosis, and other types of tissue fibrosis suggesting the potential utility of these compounds as anti-fibrotic agents. The effects of ARTs against profibrotic processes include induction of apoptosis, inhibition of proliferation, blocking differentiation of tissue-specific myofibroblast precursors or preventing the accumulation of tissue myofibroblasts that provoke tissue fibrosis [6,63]. In addition, ARTs block the expression of extracellular matrix (ECM) genes and pro-fibrotic genes in myofibroblasts thereby antagonizing cellular processes that promote accumulation of fibrotic tissue. ARTs also inhibit angiogenesis either through direct effects on endothelial cells or indirectly by downregulating pro-angiogenic gene expression in angiogenesis-supporting non-endothelial cells. With its anti-fibrotic role in disease models across several species and multiple tissues involving diverse mechanisms, artemisinin-based therapeutics for treatment of fibrotic diseases may prove efficacious in humans [64].

4.5. Role in Neurodegeneration

Extracts of several Artemisia species exhibit neuroprotective effects against focal ischemia-reperfusion-induced cerebral injury, microglial cytotoxicity and glutamate excitotoxicity [65]. Furthermore, Artemisia protects neurons against mitochondrial potential loss, attenuates reactive oxygen species and protects neurons against H2O2-induced death by upregulating the Nrf2 pathway [66]. ARTs improve learning and memory in mouse models of Alzheimer’s disease mice by blocking Aβ25-35-induced increase in the levels of inflammatory cytokines IL-1β, IL-6 and TNF-α and by restoring the autophagic flux and promoting the clearance of Aβ fibrils [67,68].
Recently, three different subtypes of Alzheimer’s disease (AD) have been described [69]. The type-3 AD classified as infectious or Krimi (ayurveda classification of AD) is the result of exposure to virus or biotoxins, such as mycotoxins, and features chronic inflammation [69,70]. Owing to their powerful antiviral and anti-inflammatory properties, ARTs may serve as excellent drug candidates for type-3 AD.

4.6. Anti-Inflammatory Activity

Artemisia species exhibit powerful anti-inflammatory effects. Several sesquiterpenes derived from Artemisia and their derivatives including artemisinin, artesunate, dihydroarteannuin, artemisolide, eupatilin, scoparone, capillarisin and scopoletin have received special attention due to their role in blocking inflammation. Using animal models, ARTs were found to be effective in treating inflammatory conditions including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and allergic disorders [71].
Some of the anti-inflammatory mechanisms include: (1) inhibition of the iNOS and COX-2 pathways; (2) suppression of ERK and NF-κB signaling; (3) inhibition of pathogenic T cell activation; (4) suppressing B cells activation and antibody production; and (5) inhibition of Akt phosphorylation and IκB degradation through the PI3K/Akt signaling pathway downstream of TNF-α [72,73,74,75]. Thus, the varied mechanisms through which these phytochemicals derived from Artemisia exhibit their anti-inflammatory effects warrant investigation into their role as therapeutic candidates for inflammatory conditions and autoimmune disorders.

4.7. Anti-Viral

Several phytochemicals isolated from various Artemisia species exhibit significant antiviral activity [76]. ARTs have turned out to be the most promising antiviral drug candidates with activities against hepatitis B and C viruses, human herpes viruses HSV-1 and HSV-2, HIV-1 and influenza virus A in the low micromolar range [77,78,79,80,81,82]. In most cases, ARTs inhibited the central regulatory processes of viral-infected cells (NF-κB or Sp1-dependent pathways), thus blocking the host-cell–type and metabolic requirements for viral replication [80].
Owing to their potent anti-inflammatory, immunoregulatory and antiviral properties, ARTs are being pursued for their activity against SARS-CoV-2 infection. Researchers used in silico approaches to investigate if artemisinin or its derivatives could physically bind any of the COVID-19 target proteins including SARS-CoV-2 spike glycoprotein, spike ectodomain structural protein, the main protease of the virus (MPro) or spike receptor-binding domain, thereby preventing SARS-CoV-2 from binding to the host receptor ACE2 [83,84,85,86,87,88,89]. ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis of artemisinin showed that it was non-cytotoxic, had good aqueous solubility and a good permeability through the blood–brain barrier with a promising therapeutic potential. Furthermore, molecular docking studies revealed that artemisinin bound to all four proteins and in some cases displayed better binding modes than hydroxychloroquine [85,86,87,88,89]. Thus, ARTs could serve as best leads for further drug development process for SARS-CoV-2 infection.
Several investigators have now shown that extracts from different species of Artemisia are active against SARS-CoV-2 [79,86,90,91]. Results from recent studies indicate that ARTs impair SARS-CoV-2 viral infection by modulating several host cell metabolic pathways thus making them attractive candidates for COVID-19 [85,86,92]. The mechanism of antiviral activity may be through the induction of cellular ROS, blunting the PI3K/Akt/p70S6K signaling pathway, binding to NF-κB/Sp1 or inducing a endocytosis inhibition mechanism, all of which lead to inhibition of viral replication and growth [85,93,94]. The above mentioned results have spurred the interest of few groups to embark on clinical trials to evaluate the safety and efficacy of ARTs in the treatment of subjects with SARS-CoV-2 viral infection.
In a recently published controlled clinical trial, 41 patients with confirmed COVID-19 were divided into two groups. While 18 subjects served as the control group, the experimental group (n = 23) received a combination of artemisinin-piperaquine (AP). AP was orally administrated with a loading dose of two tablets (artemisinin 125 mg and piperaquine 750 mg) on the first day, followed by a low dose of one tablet/day (artemisinin 62.5 mg and piperaquine 375 mg) for six days [95]. The primary outcome was the percentage of participants with undetectable SARS-CoV-2 on days 7, 10, 14, and 28 following the treatment. The results indicated that: (1) the average time to achieve undetectable SARS-CoV-2 RNA in the AP group was significantly less than that in the control group; (2) the elimination rate of SARS-CoV-2 RNA in the AP group was significantly higher than that in the control group; and (3) the length of hospital stay for the AP group was significantly lower than that in the control group. Although the study had insufficient sample size and trial design, nevertheless, the safe toxicity profile and immunoregulatory activities makes AP an excellent drug candidate against SARS-CoV-2 infection [95].
Transforming Growth Factor-beta (TGF-β) plays an important role in modulating the immune system and displays different activities on different types of immune cells. SARS-CoV-2 infection is accompanied by a cytokine storm together with edema and pulmonary fibrosis at the end stage of the infection. SARS-CoV-2 also up-regulates TGF-β expression which may partly explain the cytokine storm and fibrosis in the lung [94,96,97]. Efforts are underway to discover novel and specific small molecules that can potently block TGF-β expression with negligible side-effects. Artemisinin and its derivatives have been shown to be suppressors of TGF-β in several models of inflammatory diseases [64,98,99,100]. A randomized, open-label Phase IV study is underway to evaluate the safety and efficacy of a proprietary formulation of ARTs in adult COVID-19 patients with symptomatic mild-moderate COVID-19 [101]. In addition to its potent antiviral activity, the drug is expected to mitigate the TGF-β mediated inflammatory injury associated with the cytokine storm and viral sepsis in these patients. Initial results show that the ARTs-based drug has a very favorable safety profile and significantly accelerated the recovery of patients with mild-moderate COVID-19 infection [101]. Thus inhibition of TGF-β signaling by ARTs may be an attractive therapeutic strategy making them excellent drug candidates against SARS-CoV-2 infection.

5. Conclusions and Future Direction

Several phytochemical derivatives and lead molecules have been developed from medicinal plants for various significant therapeutic activities [4,5,94,102,103]. Scientists routinely investigate medicinal plants just for that one single and potent compound responsible for the therapeutic effect [104]. Studies comparing the action of whole plant extracts to the action of purified preparation show that, in many cases, the potency of the purified preparation declines at each step of fractionation [105]. Since the therapeutic effect may be the result of the combination of several compounds present in the medicinal plant, a complex mixture of compounds has a greater effect than isolated compounds [106]. The advantages of a combinatorial approach may be the synergy exhibited by the various components, enhanced bioavailability, cumulative effects and affecting an entire network of pathways in tandem [107].
Artemisia has prominence in Chinese and Ayurvedic medicinal systems for its numerous therapeutic properties. Among the phytochemicals present in the plant, the lactone derivative artemisinin and its derivatives—termed ARTs—are very promising owing to their multiple pharmacological actions [4,7,85,93,94]. Recent studies point to ARTs as attractive candidates for SARS-CoV-2 and they are a major focus in medical research [4,85,92,103]. SARS-CoV-2 infection manifests as a mild respiratory tract infection and influenza-like illness to a severe disease with accompanying lung injury (in severe cases lung fibrosis), oxidative stress, multisystem inflammatory conditions, multi-organ failure and neurological issues [108,109,110,111]. The role of ARTs as an antioxidant and anti-inflammatory and to be able to block tissues fibrosis together with its safety and low toxicity profile makes it an excellent drug candidate against SARS-CoV-2 infection [85,94].

Author Contributions

Conceptualization, S.G.K. and R.V.R.; Methodology, S.G.K. and R.V.R.; Data curation, S.G.K. and R.V.R.; Original draft preparation and Writing, R.V.R.; Reviewing and Editing, S.G.K. and R.V.R. Both authors have read and agreed to the published version of the manuscript.

Funding

The research study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

Not Applicable.

Informed Consent Statement

Not Applicable.

Data Availability Statement

Not Applicable.

Conflicts of Interest

This manuscript is not under consideration by another journal, nor has it been published. SGK is a paid consultant-at-large with Oncotelic, Inc., a wholly-owned subsidiary of Mateon Therapeutics, the sponsor for the clinical development of the proprietary formulation of ARTs for SARS-CoV-2 infection. RVR declares no competing financial interests.

References

  1. Rao, R.V.; Descamps, O.; John, V.; Bredesen, D.E. Ayurvedic medicinal plants for Alzheimer’s disease: A review. Alzheimers Res. Ther. 2012, 4, 22. [Google Scholar] [CrossRef] [PubMed]
  2. Parasuraman, S.; Thing, G.S.; Dhanaraj, S.A. Polyherbal formulation: Concept of ayurveda. Pharmacogn. Rev. 2014, 8, 73–80. [Google Scholar] [CrossRef] [Green Version]
  3. Barkat, M.A.; Goyal, A.; Barkat, H.A.; Salauddin, M.; Pottoo, F.H.; Anwer, E.T. Herbal medicine: Clinical perspective & regulatory status. Comb. Chem. High Throughput Screen. 2020. [Google Scholar] [CrossRef]
  4. Vellingiri, B.; Jayaramayya, K.; Iyer, M.; Narayanasamy, A.; Govindasamy, V.; Giridharan, B.; Ganesan, S.; Venugopal, A.; Venkatesan, D.; Ganesan, H.; et al. COVID-19: A promising cure for the global panic. Sci. Total Environ. 2020, 725, 138277. [Google Scholar] [CrossRef]
  5. Akram, M.; Tahir, I.M.; Shah, S.M.A.; Mahmood, Z.; Altaf, A.; Ahmad, K.; Munir, N.; Daniyal, M.; Nasir, S.; Mehboob, H. Antiviral potential of medicinal plants against HIV, HSV, influenza, hepatitis, and coxsackievirus: A systematic review. Phytother. Res. 2018, 32, 811–822. [Google Scholar] [CrossRef] [PubMed]
  6. Bora, K.S.; Sharma, A. The genus Artemisia: A comprehensive review. Pharm. Biol. 2011, 49, 101–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Mishra, K.P.; Sharma, N.; Diwaker, D.; Ganju, L.; Singh, S.B. Plant derived antivirals: A potential source of drug development. J. Virol. Antivir. Res. 2013, 2. [Google Scholar] [CrossRef]
  8. Koul, B.; Taak, P.; Kumar, A.; Khatri, T.; Sanyal, I. The Artemisia genus: A review on traditional uses, phytochemical constituents, pharmacological properties and germplasm conservation. J. Glycom. Lipidom. 2018, 7, 1–7. [Google Scholar] [CrossRef]
  9. Pandey, A.K.; Singh, P. The Genus Artemisia: A 2012–2017 literature review on chemical composition, antimicrobial, insecticidal and antioxidant activities of essential oils. Medicines 2017, 4, 68. [Google Scholar] [CrossRef] [Green Version]
  10. Poiata, A.; Tuchilus, C.; Ivanescu, B.; Ionescu, A.; Lazar, M.I. Antibacterial activity of some Artemisia species extract. Revista Medico Chirurgicala a Societatii de Medici si Naturalisti din Iasi 2009, 113, 911–914. [Google Scholar]
  11. Tan, R.X.; Zheng, W.F.; Tang, H.Q. Biologically active substances from the genus Artemisia. Planta Medica 1998, 64, 295–302. [Google Scholar] [CrossRef] [Green Version]
  12. Obistioiu, D.; Cristina, R.T.; Schmerold, I.; Chizzola, R.; Stolze, K.; Nichita, I.; Chiurciu, V. Chemical characterization by GC-MS and in vitro activity against Candida albicans of volatile fractions prepared from Artemisia dracunculus, Artemisia abrotanum, Artemisia absinthium and Artemisia vulgaris. Chem. Cent. J. 2014, 8, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Semwal, B.R.; Semwal, D.K.; Mishra, S.P.; Semwal, R. Chemical composition and antibacterial potential of essential oils from Artemisia capillaris, Artemisia nilagirica, Citrus limon, Cymbopogon flexuosus, Hedychium spicatum and Ocimum tenuiflorum. Nat. Prod. J. 2015, 5, 199–205. [Google Scholar] [CrossRef]
  14. Antoine, T.; Fisher, N.; Amewu, R.; O’Neill, P.M.; Ward, S.A.; Biagini, G.A. Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential. J. Antimicrob. Chemother. 2014, 69, 1005–1016. [Google Scholar] [CrossRef]
  15. Shah, N.K.; Tyagi, P.; Sharma, S.K. The impact of artemisinin combination therapy and long-lasting insecticidal nets on forest malaria incidence in tribal villages of India, 2006–2011. PLoS ONE 2013, 8, e56740. [Google Scholar] [CrossRef]
  16. WWARN Artemisinin Based Combination Therapy (ACT) Africa Baseline Study Group. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data. BMC Med. 2015, 13, 212. [Google Scholar]
  17. Tambo, E.; Khater, E.I.; Chen, J.H.; Bergquist, R.; Zhou, X.N. Nobel prize for the artemisinin and ivermectin discoveries: A great boost towards elimination of the global infectious diseases of poverty. Infect. Dis. Poverty 2015, 4, 58. [Google Scholar] [CrossRef] [Green Version]
  18. Su, X.Z.; Miller, L.H. The discovery of artemisinin and the Nobel prize in physiology or medicine. Sci. China Life Sci. 2015, 58, 1175–1179. [Google Scholar] [CrossRef] [Green Version]
  19. Joshi, R.K.; Satyal, P.; Setzer, W.N. Himalayan aromatic medicinal plants: A review of their ethnopharmacology, volatile phytochemistry, and biological activities. Medicines 2016, 3, 6. [Google Scholar] [CrossRef] [Green Version]
  20. Joshi, V.K.; Joshi, A.; Dhiman, K.S. The ayurvedic pharmacopoeia of India, development and perspectives. J. Ethnopharmacol. 2017, 197, 32–38. [Google Scholar] [CrossRef]
  21. Kumar, D.; Arya, V.; Kaur, R.; Bhat, Z.A.; Gupta, V.K.; Kumar, V. A review of immunomodulators in the Indian traditional health care system. J. Microbiol. Immunol. Infect. 2012, 45, 165–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Katiyar, C.K. Ayurpathy: A modern perspective of Ayurveda. Ayu 2011, 32, 304–305. [Google Scholar] [CrossRef]
  23. Ivanescu, B.; Miron, A.; Corciova, A. Sesquiterpene lactones from Artemisia genus: Biological activities and methods of analysis. J. Anal. Methods Chem. 2015, 2015. [Google Scholar] [CrossRef] [Green Version]
  24. Batiha, G.E.; Olatunde, A.; El-Mleeh, A.; Hetta, H.F.; Al-Rejaie, S.; Alghamdi, S.; Zahoor, M.; Magdy Beshbishy, A.; Murata, T.; Zaragoza-Bastida, A.; et al. Bioactive compounds, pharmacological actions, and pharmacokinetics of wormwood (Artemisia absinthium). Antibiotics 2020, 9, 353. [Google Scholar] [CrossRef]
  25. Kumar, S.; Kumari, R. Artemisia: A medicinally important genus. J. Complement. Med. Alt. Healthcare 2018, 7. [Google Scholar] [CrossRef]
  26. Liu, N.Q.; Van der Kooy, F.; Verpoorte, R. Artemisia afra: A potential flagship for African medicinal plants? South Afr. J. Bot. 2009, 75, 185–195. [Google Scholar] [CrossRef] [Green Version]
  27. Fu, C.; Yu, P.; Wang, M.; Qiu, F. Phytochemical analysis and geographic assessment of flavonoids, coumarins and sesquiterpenes in Artemisia annua L. based on HPLC-DAD quantification and LC-ESI-QTOF-MS/MS confirmation. Food Chem. 2020, 312, 126070. [Google Scholar] [CrossRef] [PubMed]
  28. Feng, X.; Cao, S.; Qiu, F.; Zhang, B. Traditional application and modern pharmacological research of Artemisia annua L. Pharmacol. Ther. 2020, 216, 107650. [Google Scholar] [CrossRef] [PubMed]
  29. Septembre-Malaterre, A.; Lalarizo Rakoto, M.; Marodon, C.; Bedoui, Y.; Nakab, J.; Simon, E.; Hoarau, L.; Savriama, S.; Strasberg, D.; Guiraud, P.; et al. Artemisia annua, a traditional plant brought to light. Int. J. Mol. Sci. 2020, 21, 4986. [Google Scholar] [CrossRef] [PubMed]
  30. Ahuja, A.; Yi, Y.S.; Kim, M.Y.; Cho, J.Y. Ethnopharmacological properties of Artemisia asiatica: A comprehensive review. J. Ethnopharmacol. 2018, 220, 117–128. [Google Scholar] [CrossRef]
  31. Costa, R.; Ragusa, S.; Russo, M.; Certo, G.; Franchina, F.A.; Zanotto, A.; Grasso, E.; Mondello, L.; Germano, M.P. Phytochemical screening of Artemisia arborescens L. by means of advanced chromatographic techniques for identification of health-promoting compounds. J. Pharm. Biomed. Anal. 2016, 117, 499–509. [Google Scholar] [CrossRef]
  32. Adams, J.D.; Garcia, C.; Garg, G. Mugwort (Artemisia vulgaris, Artemisia douglasiana, Artemisia argyi) in the treatment of menopause, premenstrual syndrome, dysmenorrhea and Attention Deficit Hyperactivity Disorder. Chin. Med. 2012, 3, 116–123. [Google Scholar] [CrossRef] [Green Version]
  33. Allerton, T.D.; Kowalski, G.M.; Stampley, J.; Irving, B.A.; Lighton, J.R.B.; Floyd, Z.E.; Stephens, J.M. An ethanolic extract of Artemisia dracunculus L. enhances the metabolic benefits of exercise in diet-induced obese mice. Med. Sci. Sports Exerc. 2020. [Google Scholar] [CrossRef] [PubMed]
  34. Majdan, M.; Kiss, A.K.; Halasa, R.; Granica, S.; Osinska, E.; Czerwinska, M.E. Inhibition of neutrophil functions and antibacterial effects of tarragon (Artemisia dracunculus L.) infusion-phytochemical characterization. Front. Pharmacol. 2020, 11. [Google Scholar] [CrossRef]
  35. Mokhtar, A.B.; Ahmed, S.A.; Eltamany, E.E.; Karanis, P. Anti-blastocystis activity in vitro of Egyptian herbal extracts (family: Asteraceae) with emphasis on Artemisia judaica. Int. J. Environ. Res. Public Health 2019, 16, 1555. [Google Scholar] [CrossRef] [Green Version]
  36. Cho, J.Y.; Park, K.H.; Hwang, D.Y.; Lee, S.Y.; Moon, J.H.; Ju Lee, Y.; Park, K.D.; Ham, K.S. Three new decenynol glucosides from Artemisia scoparia (Asteraceae). J. Asian Nat. Prod. Res. 2020, 22, 795–802. [Google Scholar] [CrossRef] [PubMed]
  37. Boudreau, A.; Poulev, A.; Ribnicky, D.M.; Raskin, I.; Rathinasabapathy, T.; Richard, A.J.; Stephens, J.M. Distinct fractions of an Artemisia scoparia extract contain compounds with novel adipogenic bioactivity. Front. Nutr. 2019, 6. [Google Scholar] [CrossRef]
  38. Xie, G.; Schepetkin, I.A.; Siemsen, D.W.; Kirpotina, L.N.; Wiley, J.A.; Quinn, M.T. Fractionation and characterization of biologically-active polysaccharides from Artemisia tripartita. Phytochemistry 2008, 69, 1359–1371. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Calderone, V.; Martinotti, E.; Baragatti, B.; Breschi, M.C.; Morelli, I. Vascular effects of aqueous crude extracts of Artemisia verlotorum Lamotte (Compositae): In vivo and in vitro pharmacological studies in rats. Phytother. Res. 1999, 13, 645–648. [Google Scholar] [CrossRef]
  40. De Lima, T.C.; Morato, G.S.; Takahashi, R.N. Evaluation of the central properties of Artemisia verlotorum. Planta Medica 1993, 59, 326–329. [Google Scholar] [CrossRef]
  41. Ding, Y.H.; Wang, H.T.; Shi, S.; Meng, Y.; Feng, J.C.; Wu, H.B. Sesquiterpenoids from Artemisia vestita and their antifeedant and antifungal activities. Molecules 2019, 24, 3671. [Google Scholar] [CrossRef] [Green Version]
  42. Tian, S.H.; Zhang, C.; Zeng, K.W.; Zhao, M.B.; Jiang, Y.; Tu, P.F. Sesquiterpenoids from Artemisia vestita. Phytochmistry 2018, 147, 194–202. [Google Scholar] [CrossRef] [PubMed]
  43. Ragasa, C.Y.; de Jesus, J.P.; Apuada, M.J.; Rideout, J.A. A new sesquiterpene from Artemisia vulgaris. J. Nat. Med. 2008, 62, 461–463. [Google Scholar] [CrossRef]
  44. Willcox, M. Artemisia species: From traditional medicines to modern antimalarials—And back again. J. Altern. Complement. Med. 2009, 15, 101–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Nigam, M.; Atanassova, M.; Mishra, A.P.; Pezzani, R.; Devkota, H.P.; Plygun, S.; Salehi, B.; Setzer, W.N.; Sharifi-Rad, J. Bioactive compounds and health benefits of Artemisia species. Nat. Prod. Commun. 2019. [Google Scholar] [CrossRef] [Green Version]
  46. Ekiert, H.; Pajor, J.; Klin, P.; Rzepiela, A.; Slesak, H.; Szopa, A. Significance of Artemisia vulgaris, L. (common mugwort) in the history of medicine and its possible contemporary applications substantiated by phytochemical and pharmacological studies. Molecules 2020, 25, 4415. [Google Scholar] [CrossRef]
  47. Abad, M.J.; Bedoya, L.M.; Apaza, L.; Bermejo, P. The Artemisia L. genus: A review of bioactive essential oils. Molecules 2012, 17, 2542–2566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Lee, Y.J.; Thiruvengadam, M.; Ching, I.M.; Nagella, P. Polyphenol composition and antioxidant activity from the vegetable plant Artemisia absinthium L. Aust. J. Crop Sci. 2013, 7, 1921–1926. [Google Scholar]
  49. Kiani, B.H.; Kayani, W.K.; Khayam, A.U.; Dilshad, E.; Ismail, H.; Mirza, B. Artemisinin and its derivatives: A promising cancer therapy. Mol. Biol. Rep. 2020, 47, 6321–6336. [Google Scholar] [CrossRef]
  50. Firestone, G.L.; Sundar, S.N. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev. Mol. Med. 2009, 11. [Google Scholar] [CrossRef]
  51. Ly, B.T.K.; Ly, D.M.; Linh, P.H.; Son, H.K.; Ha, N.L.; Chi, H.T. Screening of medicinal herbs for cytotoxic activity to leukemia cells. J. BUON 2020, 25, 1989–1996. [Google Scholar]
  52. Kumar, M.S.; Yadav, T.T.; Khair, R.R.; Peters, G.J.; Yergeri, M.C. Combination therapies of artemisinin and its derivatives as a viable approach for future cancer treatment. Curr. Pharm. Des. 2019, 25, 3323–3338. [Google Scholar] [CrossRef] [PubMed]
  53. Jia, L.; Song, Q.; Zhou, C.; Li, X.; Pi, L.; Ma, X.; Li, H.; Lu, X.; Shen, Y. Dihydroartemisinin as a putative STAT3 inhibitor, suppresses the growth of head and neck squamous cell carcinoma by targeting Jak2/STAT3 signaling. PLoS ONE 2016, 11, e0147157. [Google Scholar] [CrossRef] [PubMed]
  54. Slezakova, S.; Ruda-Kucerova, J. Anticancer activity of artemisinin and its derivatives. Anticancer Res. 2017, 37, 5995–6003. [Google Scholar]
  55. Pulito, C.; Strano, S.; Blandino, G. Dihydroartemisinin: From malaria to the treatment of relapsing head and neck cancers. Ann. Transl. Med. 2020, 8, 612. [Google Scholar] [CrossRef] [PubMed]
  56. Krishna, S.; Ganapathi, S.; Ster, I.C.; Saeed, M.E.; Cowan, M.; Finlayson, C.; Kovacsevics, H.; Jansen, H.; Kremsner, P.G.; Efferth, T.; et al. A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer. EBioMedicine 2015, 2, 82–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Berger, T.G.; Dieckmann, D.; Efferth, T.; Schultz, E.S.; Funk, J.O.; Baur, A.; Schuler, G. Artesunate in the treatment of metastatic uveal melanoma—First experiences. Oncol. Rep. 2005, 14, 1599–1603. [Google Scholar] [CrossRef] [PubMed]
  58. Du, L.; Chen, J.; Xing, Y.Q. Eupatilin prevents H2O2-induced oxidative stress and apoptosis in human retinal pigment epithelial cells. Biomed. Pharmacother. 2017, 85, 136–140. [Google Scholar] [CrossRef]
  59. Krishna, S.; Uhlemann, A.C.; Haynes, R.K. Artemisinins: Mechanisms of action and potential for resistance. Drug Resist. Updates 2004, 7, 233–244. [Google Scholar] [CrossRef]
  60. Yang, M.T.; Kuo, T.F.; Chung, K.F.; Liang, Y.C.; Yang, C.W.; Lin, C.Y.; Feng, C.S.; Chen, Z.W.; Lee, T.H.; Hsiao, C.L.; et al. Authentication, phytochemical characterization and anti-bacterial activity of two Artemisia species. Food Chem. 2020, 333, 127458. [Google Scholar] [CrossRef] [PubMed]
  61. Huang, J.; Qian, C.; Xu, H.; Huang, Y. Antibacterial activity of Artemisia asiatica essential oil against some common respiratory infection causing bacterial strains and its mechanism of action in Haemophilus influenzae. Microb. Pathog. 2018, 114, 470–475. [Google Scholar] [CrossRef]
  62. Cui, L.; Su, X.Z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti Infect. Ther. 2009, 7, 999–1013. [Google Scholar] [CrossRef]
  63. Dolivo, D.; Weathers, P.; Dominko, T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharmaceutica Sinica B 2021, 11, 322–339. [Google Scholar] [CrossRef]
  64. Wang, Y.; Wang, Y.; You, F.; Xue, J. Novel use for old drugs: The emerging role of artemisinin and its derivatives in fibrosis. Pharmacol. Res. 2020, 157, 104829. [Google Scholar] [CrossRef] [PubMed]
  65. Lu, B.W.; Baum, L.; So, K.F.; Chiu, K.; Xie, L.K. More than anti-malarial agents: Therapeutic potential of artemisinins in neurodegeneration. Neural Regen. Res. 2019, 14, 1494–1498. [Google Scholar]
  66. Sajjad, N.; Wani, A.; Sharma, A.; Ali, R.; Hassan, S.; Hamid, R.; Habib, H.; Ganai, B.A. Artemisia amygdalina upregulates Nrf2 and protects neurons against oxidative stress in Alzheimer disease. Cell Mol. Neurobiol. 2019, 39, 387–399. [Google Scholar] [CrossRef]
  67. Qiang, W.; Cai, W.; Yang, Q.; Yang, L.; Dai, Y.; Zhao, Z.; Yin, J.; Li, Y.; Li, Q.; Wang, Y.; et al. Artemisinin B improves learning and memory impairment in AD dementia mice by suppressing neuroinflammation. Neuroscience 2018, 395, 1–12. [Google Scholar] [CrossRef]
  68. Zhao, Y.; Long, Z.; Ding, Y.; Jiang, T.; Liu, J.; Li, Y.; Liu, Y.; Peng, X.; Wang, K.; Feng, M.; et al. Dihydroartemisinin ameliorates learning and memory in Alzheimer’s disease through promoting autophagosome-lysosome fusion and autolysosomal degradation for abeta clearance. Front. Aging Neurosci. 2020, 12. [Google Scholar] [CrossRef] [PubMed]
  69. Bredesen, D.E. Inhalational Alzheimer’s disease: An unrecognized—And treatable—Epidemic. Aging 2016, 8, 304–313. [Google Scholar] [CrossRef] [PubMed]
  70. Bredesen, D.E.; Rao, R.V. Ayurvedic profiling of Alzheimer’s disease. Altern. Ther. Health Med. 2017, 23, 46–50. [Google Scholar] [PubMed]
  71. Shi, C.; Li, H.; Yang, Y.; Hou, L. Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators Inflamm. 2015, 2015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Qin, D.P.; Li, H.B.; Pang, Q.Q.; Huang, Y.X.; Pan, D.B.; Su, Z.Z.; Yao, X.J.; Yao, X.S.; Xiao, W.; Yu, Y. Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities. Bioorg. Chem. 2020, 103, 104221. [Google Scholar] [CrossRef]
  73. Boudreau, A.; Burke, S.J.; Collier, J.J.; Richard, A.J.; Ribnicky, D.M.; Stephens, J.M. Mechanisms of Artemisia scoparia’s anti-inflammatory activity in cultured adipocytes, macrophages, and pancreatic β-cells. Obesity 2020, 28, 1726–1735. [Google Scholar] [CrossRef]
  74. Zamani, S.; Emami, S.A.; Iranshahi, M.; Zamani Taghizadeh Rabe, S.; Mahmoudi, M. Sesquiterpene fractions of Artemisia plants as potent inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 expression. Iran. J. Basic Med. Sci. 2019, 22, 774–780. [Google Scholar] [PubMed]
  75. Cheng, C.; Ho, W.E.; Goh, F.Y.; Guan, S.P.; Kong, L.R.; Lai, W.Q.; Leung, B.P.; Wong, W.S. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS ONE 2011, 6, e20932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Efferth, T. Beyond malaria: The inhibition of viruses by artemisinin-type compounds. Biotechnol. Adv. 2018, 36, 1730–1737. [Google Scholar] [CrossRef]
  77. Obeid, S.; Alen, J.; Nguyen, V.H.; Pham, V.C.; Meuleman, P.; Pannecouque, C.; Le, T.N.; Neyts, J.; Dehaen, W.; Paeshuyse, J. Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication. PLoS ONE 2013, 8, e81783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Romero, M.R.; Efferth, T.; Serrano, M.A.; Castano, B.; Macias, R.I.; Briz, O.; Marin, J.J. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an ”in vitro” replicative system. Antiviral Res. 2005, 68, 75–83. [Google Scholar] [CrossRef] [PubMed]
  79. Uzun, T.; Toptas, O. Artesunate: Could be an alternative drug to chloroquine in COVID-19 treatment? Chin. Med. 2020, 15, 54. [Google Scholar] [CrossRef]
  80. Efferth, T.; Romero, M.R.; Wolf, D.G.; Stamminger, T.; Marin, J.J.; Marschall, M. The antiviral activities of artemisinin and artesunate. Clin. Infect. Dis. 2008, 47, 804–811. [Google Scholar] [CrossRef] [Green Version]
  81. D’Alessandro, S.; Scaccabarozzi, D.; Signorini, L.; Perego, F.; Ilboudo, D.P.; Ferrante, P.; Delbue, S. The use of antimalarial drugs against viral infection. Microorganisms 2020, 8, 85. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Jang, E.; Kim, B.J.; Lee, K.T.; Inn, K.S.; Lee, J.H. A survey of therapeutic effects of Artemisia capillaris in liver diseases. Evid. Based Complement. Alternat. Med. 2015, 2015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Rolta, R.; Salaria, D.; Kumar, V.; Sourirajan, A.; Dev, K. Phytocompounds of Rheum emodi, Thymus serpyllum and Artemisia annua inhibit COVID-19 binding to ACE2 receptor: In silico approach. Res. Square 2020. [Google Scholar] [CrossRef]
  84. Sharma, S.; Deep, S. In-silico drug repurposing for targeting SARS-CoV-2 Mpro. J. Biomol. Struct. Dyn. 2020. [Google Scholar] [CrossRef]
  85. Cao, R.; Hu, H.; Li, Y.; Wang, X.; Xu, M.; Liu, J.; Zhang, H.; Yan, Y.; Zhao, L.; Li, W.; et al. Anti-SARS-CoV-2 potential of artemisinins in vitro. ACS Infect. Dis. 2020, 6, 2524–2531. [Google Scholar] [CrossRef]
  86. Sehailia, M.; Chemat, S. Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: Potential repurposing of artenimol for COVID-19. J. Biomol. Struct. Dyn. 2020. [Google Scholar] [CrossRef]
  87. Rai, K.K.; Sharma, L.; Pandey, N.; Meena, R.P.; Rai, S.P. Repurposing Artemisia annua L. flavonoids, artemisinin and its derivatives as potential drugs against novel coronavirus (SARS-nCoV) as revealed by in-silico studies. Int. J. Appl. Sci. Biotechnol. 2020, 84, 374–393. [Google Scholar] [CrossRef]
  88. Tomic, N.; Pojskic, L.; Kalajdzic, A.; Ramic, J.; Kadric, N.L.; Ikanovic, T. Screening of preferential binding affinity of selected natural compounds to SARS-CoV-2 proteins using in silico methods. EJMO 2020, 4, 319–323. [Google Scholar]
  89. Alazmi, M.; Motwalli, O. Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through docking, characterization, and molecular dynamics for natural drug candidates. J. Mol. Model. 2020, 26, 338. [Google Scholar] [CrossRef]
  90. Gilmore, K.; Zhou, Y.; Ramirez, S.; Pham, L.V.; Fahnøe, U.; Feng, S.; Offersgaard, A.; Trimpert, J.; Bukh, J.; Osterrieder, K.; et al. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. BioRxiV 2020. [Google Scholar] [CrossRef]
  91. Nair, M.S.; Huang, Y.; Fidock, D.A.; Polyak, S.J.; Wagoner, J.; Towler, M.J.; Weathers, P.J. Artemisia annua L. extracts prevent in vitro replication of SARS-CoV-2. BioRxiV 2020. [Google Scholar] [CrossRef]
  92. Gendrot, M.; Duflot, I.; Boxberger, M.; Delandre, O.; Jardot, P.; Le Bideau, M.; Andreani, J.; Fonta, I.; Mosnier, J.; Rolland, C.; et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: In vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J. Infect. Dis. 2020, 99, 437–440. [Google Scholar] [CrossRef] [PubMed]
  93. Krishna, S.; Bustamante, L.; Haynes, R.K.; Staines, H.M. Artemisinins: Their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520–527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Chen, W. A potential treatment of COVID-19 with TGF-beta blockade. Int J. Biol. Sci. 2020, 16, 1954–1955. [Google Scholar] [CrossRef]
  95. Li, G.; Yuan, M.; Li, H.; Deng, C.; Wang, Q.; Tang, Y.; Zhang, H.; Yu, W.; Xu, Q.; Zou, Y.; et al. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomized, and controlled trial. Int J. Antimicrob. Agents 2020, 18, 106216. [Google Scholar] [CrossRef] [PubMed]
  96. Evans, R.M.; Lippman, S.M. Shining light on the COVID-19 pandemic: A vitamin D receptor checkpoint in defense of unregulated wound healing. Cell Metab. 2020, 32, 704–709. [Google Scholar] [CrossRef] [PubMed]
  97. Uckun, F.M.; Hwang, L.; Trieu, V. Selectively targeting TGF-β with trabedersen/OT-101 in treatment of evolving and mild ARDS in COVID-19. Clin. Investig. 2020, 10, 167–176. [Google Scholar]
  98. Yao, Y.; Guo, Q.; Cao, Y.; Qiu, Y.; Tan, R.; Yu, Z.; Zhou, Y.; Lu, N. Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-beta signaling in breast cancer. J. Exp. Clin. Cancer Res. 2018, 37, 282. [Google Scholar] [CrossRef]
  99. Wu, X.; Zhang, W.; Shi, X.; An, P.; Sun, W.; Wang, Z. Therapeutic effect of artemisinin on lupus nephritis mice and its mechanisms. Acta Biochimica et Biophysica Sinica 2010, 42, 916–923. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Cao, Y.; Feng, Y.H.; Gao, L.W.; Li, X.Y.; Jin, Q.X.; Wang, Y.Y.; Xu, Y.Y.; Jin, F.; Lu, S.L.; Wei, M.J. Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer cells in vitro and in vivo. Int. Immunopharmacol. 2019, 70, 110–116. [Google Scholar] [CrossRef] [PubMed]
  101. Trieu, V.; Saund, S.; Rahate, P.S.; Barge, V.B.; Nalk, K.S.; Windlass, H.; Uckun, F.M. Targeting TGF-β pathway with COVID-19 drug candidate ARTIVeda/PulmoHeal accelerates recovery from mild-moderate COVID-19. MedRxiv 2020. [Google Scholar] [CrossRef]
  102. Cragg, G.M.; Newman, D.J.; Snader, K.M. Natural products in drug discovery and development. J. Nat. Prod. 1997, 60, 52–60. [Google Scholar] [CrossRef] [PubMed]
  103. Haq, F.U.; Roman, M.; Ahmad, K.; Rahman, S.U.; Shah, S.M.A.; Suleman, N.; Ullah, S.; Ahmad, I.; Ullah, W. Artemisia annua: Trials are needed for COVID-19. Phytother. Res. 2020, 34, 2423–2424. [Google Scholar] [CrossRef]
  104. Williamson, E.M. Synergy and other interactions in phytomedicines. Phytomedicine 2001, 8, 401–409. [Google Scholar] [CrossRef]
  105. Rasoanaivo, P.; Wright, C.W.; Willcox, M.L.; Gilbert, B. Whole plant extracts versus single compounds for the treatment of malaria: Synergy and positive interactions. Malar. J. 2011, 10, S4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Raskin, I.; Ripoll, C. Can an apple a day keep the doctor away? Curr. Pharm. Des. 2004, 10, 3419–3429. [Google Scholar] [CrossRef] [PubMed]
  107. Wagner, H.; Ulrich-Merzenich, G. Synergy research: Approaching a new generation of phytopharmaceuticals. Phytomedicine 2009, 16, 97–110. [Google Scholar] [CrossRef] [PubMed]
  108. Thevarajan, I.; Buising, K.L.; Cowie, B.C. Clinical presentation and management of COVID-19. Med. J. Aust. 2020, 213, 134–139. [Google Scholar] [CrossRef]
  109. Lipman, M.; Chambers, R.C.; Singer, M.; Brown, J.S. SARS-CoV-2 pandemic: Clinical picture of COVID-19 and implications for research. Thorax 2020, 75, 614–616. [Google Scholar] [CrossRef]
  110. Cecchini, R.; Cecchini, A.L. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med. Hypotheses 2020, 143, 110102. [Google Scholar] [CrossRef] [PubMed]
  111. Ritchie, K.; Chan, D.; Watermeyer, T. The cognitive consequences of the COVID-19 epidemic: Collateral damage? Brain Commun. 2020, 2, fcaa069. [Google Scholar] [CrossRef] [PubMed]
Table 1. Ayurveda describes two species A. absinthium and A. maritima that vary slightly in their qualities and actions. Both plants popularly known as Mugwort are revered in Ayurveda for their anti-infectious and insecticidal (krimighna) properties [20].
Table 1. Ayurveda describes two species A. absinthium and A. maritima that vary slightly in their qualities and actions. Both plants popularly known as Mugwort are revered in Ayurveda for their anti-infectious and insecticidal (krimighna) properties [20].
A. absinthiumA. maritima
NamesMugwort, Indian wormseed, Damanaka, Davana, Dona, Douna, DavanamuOld woman, Mugwort, worm seed, Kirmani, Chuhara, Dirmana
Qualities (guna)Light (laghu), Dry (ruksha), Hot (teekshana)Light (laghu), Dry (ruksha), Hot (teekshana)
Taste (rasa)Asringent (kashaya), Bitter (tikta)Pungent (katu), Bitter (tikta)
Potency (veerya)Hot (Ushna)Hot (Ushna)
Post-digestive effect (vipaka)Pungent (katu)Pungent (katu)
Special Intrinsic Action (prabhava)Insecticidal (krimighna), anti-pyretic (jwaraghna)Insecticidal (krimighna), anti-pyretic (jwaraghna)
UsesOptimizes kapha, pitta and vata (tridosha shamaka), anti-infectious, improves digestion, wound healing, respiratory and liver tonicOptimizes kapha and vata (Kaphavata shamaka), anti-infectious, improves digestion, wound healing
Parts of plant usedRoot, leaves, barkRoot, leaves, bark
Table 2. The pharmacological actions and properties of a subset of Artemisia species.
Table 2. The pharmacological actions and properties of a subset of Artemisia species.
SpeciesUsesPhytochemicals Isolated
A.absinthiumcardiac stimulant, anthelmintic, liver function, memory boosterSesquiterpene lactones, polyphenolic compounds, flavonoids, tannins, lignins [23,24].
A. abrotanumInsecticide, liver conditionsFlavonols, tannins, coumarins [6,8,25].
A.afracoughs, colds, malaria, diabetes, bladder and kidney disordersmonoterpenoids, sesquiterpenes, glaucolides, guaianolides; flavonoids [23,26].
A.annuaFever, malaria, fibrosisVolatile oils, sesquiterpene lactones, phenolic compounds, flavones [23,27,28,29].
A.asiaticacancer, inflammation, infections and ulcersVolatile oils, flavones, alkaloids [6,30].
A. arborescensAnti-inflammatory, Antihistaminic, Blood decongestantTerpenes, flavone, fatty acids [6,31].
A.douglasianapremenstrual syndrome and dysmenorrheaMonoterpenes, sesquiterpene lactones [23,32]
A.dracunculusantidiabetic and anticoagulantVolatile oils, coumarins, polyphenolic compounds, glucoside [33,34].
A.judaicaGastrointestinal disordersVolatile components, phenolic compounds [6,35]
A.maritimaanthelmintic, liver function, GI issuesVolatile oils, fatty acids, polyphenolic compounds, sesquiterpene lactones [6,23]
A.scopariaantibacterial, antiseptic, antipyreticVolatile oils, fatty acids, coumarins, pyrogallol tannins, cholagogic components, flavonoids, flavones [6,36,37].
A. tripartitecold, sore throats, tonsillitis, headaches and woundsGuaianolides, polysaccharides [6,38]
A.verlotorumhypertensionVolatile oils, fatty acids [6,39,40].
A.vestitainflammatory diseasesVolatile oils, flavonoids [41,42].
A.vulgarisanalgesic, anti-inflammatory, antispasmodic and liver diseaseTerpenes, coumarins [6,43].
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Kshirsagar, S.G.; Rao, R.V. Antiviral and Immunomodulation Effects of Artemisia. Medicina 2021, 57, 217. https://doi.org/10.3390/medicina57030217

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