Abstract
Application of traditional Chinese drug, artemisinin, originally derived from Artemisia annua L., in malaria therapy has now been globally accepted. Artemisinin and its derivatives, with their established safety records, form the first line of malaria treatment via artemisinin combination therapies (ACTs). In addition to its antimalarial effects, artemisinin has recently been evaluated in terms of its antitumour, antibacterial, antiviral, antileishmanial, antischistosomiatic, herbicidal and other properties. However, low levels of artemisinin in plants have emerged various conventional, transgenic and nontransgenic approaches for enhanced production of the drug. According to WHO (2014), approximately 3.2 billion people are at risk of this disease. However, unfortunately, artemisinin availability is still facing its short supply. To fulfil artemisinin’s global demand, no single method alone is reliable, and there is a need to collectively use conventional and advanced approaches for its higher production. Further, it is the unique structure of artemisinin that makes it a potential drug not only against malaria but to other diseases as well. Execution of its action through multiple mechanisms is probably the reason behind its wide spectrum of action. Unfortunately, due to clues for developing artemisinin resistance in malaria parasites, it has become desirable to explore all possible modes of action of artemisinin so that new generation antimalarial drugs can be developed in future. The present review provides a comprehensive updates on artemisinin modes of action and strategies for enhanced artemisinin production at global level.
Similar content being viewed by others
References
Aftab T, Khan MMA, Idrees M, Naeem M, Ram M (2010) Boron induced oxidative stress, antioxidant defence response and changes in artemisinin content in Artemisia annua L. J Agron Crop Sci 196:423–430. doi:10.1111/j.1439-037X.2010.00427.x
Ahlawat S, Saxena P, Alam P, Wajid S, Abdin MZ (2014) Modulation of artemisinin biosynthesis by elicitors, inhibitor, and precursor in hairy root cultures of Artemisia annua L. J Plant Interact 9(1):811–824. doi:10.1080/17429145.2014.949885
Akhurst RJ, Hata A (2012) Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 11(10):790–811. doi:10.1038/nrd3810
Alam P, Abdin MZ (2011) Over-expression of HMG-CoA reductase and amorpha-4,11-diene synthase genes in Artimisia annua L. and its influence on artimisinin content. Plant Cell Rep 30(10):1919–1928. doi:10.1007/s00299-011-1099-6
Aquil S, Husaini AM, Abdin MZ, Rather GM (2009) Overexpression of HMG-CoA reductase gene leads to enhanced artimisinin biosynthesis in transgenic Artemisia annua plants. Planta Med 75(13):1453–1458. doi:10.1055/s-0029-1185775
Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N et al (2014) A molecular marker of artemisinin resistant Plasmodium falciparum malaria. Nature 505(7481):50–55. doi:10.1038/nature12876
Arsenault PR, Vail DR, Wobbe KK, Weathers PJ (2010a) Effect of sugars on artemisinin production in Artemisia annua L.: transcription and metabolite measurements. Molecules 15:2302–2318
Arsenault PR, Vail DR, Wobbe KK, Erickson K, Weathers PJ (2010b) Reproductive development modulates gene expression and metabolite levels with possible feedback inhibition of artemisinin in Artemisia annua L. Plant Physiol 154:958–968
Asawamahasakda W, Ittarat I, Chang C-C, McElroy P et al (1994) Effects of antimalarials and protease inhibitors on plasmodial hemozoin production. Mol Biochem Parasitol 67:183–191
Ba Q, Zhou N, Duan J, Chen T, Hao M et al (2012) Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1. PLoS ONE 7(8):e42703. doi:10.1371/journal.pone.0042703
Banyai W, Kirdmanee C, Mii M, Supaibulwatana K (2010) Overexpression of farnesyl pyrophosphate synthase(FPS) gene affected artemisinin content and growth of Artemisia annua L. Plant Cell Tiss Org Cult 103:255–265. doi:10.1007/s11240-010-9775-8
Bhisutthibhan J, Pan XQ, Hossler PA, Walker DJ, Yowell CA, Carlton J et al (1998) The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem 273:16192–16198
Bommer UA, Thiele BJ (2004) The translationally controlled tumour protein (TCTP). Int J Biochem Cell Biol 36:379–385
Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89(4):1341–1378. doi:10.1152/physrev.00032.2008
Brown GD (2010) The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao). Molecules 15:7603–7698. doi:10.3390/molecules15117603
Caretto S, Quarta A, Durante M, Nisi R, de Paolis A, Blando F, Mita G (2011) Methyl jasmonate and miconazole differently affect arteminisin production and gene expression in Artemisia annua suspension cultures. Plant Biol 13:51–58
Cazelles J, Robert A, Meunier B (2001) Alkylation of heme by artemisinin, an antimalarial drug. C R Acad Sc Se Li Fascicule C Chim 4:85–89
Chen D, Ye H, Li G (2000) Expression of a chimeric farnesyl diphosphate synthase gene in Artemisia annua L. Plant via Agrobacterium tumefaciens – mediated transformation. Plant Sci 155(2):179–185. doi:10.1016/S0168-9452(00)00217-X
Chen JL, Fang HM, Ji YP, Pu GB, Guo YW, Huang LL, Du ZG, Liu BY, Ye HC, Li GF, Wang H (2011) Artemisinin biosynthesis enhancement in transgenic Artemisia annua plants by downregulation of the beta-caryophyllene synthase gene. Planta Med 77:1759–1765
Chen Y, Shen Q, Wang Y, Wang T et al (2012) The stacked over-expression of FPS, CYP71AV1 and CPR genes leads to the increase of artimisinin level in Artimisia annua L. Plant Biotechnol Rep 7:287–295. doi:10.1007/s11816-012-0262-z
Chen J, Chen X, Wang F, Gao H, Hu W (2014) Dihydroartemisinin suppresses glioma proliferation and invasion via inhibition of the ADAM17 pathway. Neurol Sci. doi:10.1007/s10072-014-1963-6
Chugh M, Sundararaman V, Kumar S, Reddy VS et al (2013) Protein complex directs haemoglobin to hemozoin formation in Plasmodium falciparum. Proc Natl Acad Sci 110:5392–5397. doi:10.1073/pnas.1218412110
Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K Pathway As Drug Target in Human Cancer. J Clin Oncol 28(6):1075–1083. doi:10.1200/JCO.2009.25.3641
Covello PS (2008) Making artemisinin. Phytochemistry 69(17):2881–2885. doi:10.1016/j.phytochem.2008.10.001
Creek DJ, Ryan E, Charman WN, Chiu FCK et al (2009) Stability of peroxide antimalarials in the presence of human haemoglobin. Antimicrob Agents Chemother 53(8):3496–3500. doi:10.1128/AAC. 00363-09
Dixon RA, Paiva N (1995) Stressed induced phenyl propanoid metabolism. Plant Cell 7:1085–1097. doi:10.1105/tpc.7.7.1085
Eckstein-Ludwig U, Webb RJ, Van GID, East JM et al (2003) Artimisinin target the SERCA of Plasmodium falciparum. Nature 424:957–961. doi:10.1038/nature01813
Edikpo N, Ghasi S, Elias A, Oguanobi N (2013) Artemisinin and biomolecules: The continuing search for mechanism of action. Mol Cell Pharmacol 5:75–89
Eichhorn T, Winter D, Büchele B, Dirdjaja N, Frank M et al (2013) Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum. Biochem Pharmacol 85:38–45. doi:10.1016/j.bcp.2012.10.006
Elfawal MA, Towler MJ, Reich NG, Weathers PJ, Rich SM (2015) Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance toartemisinin. Proc Natl Acad Sci 112(3):821-826. doi: 10.1073/pnas1413127112
Favero Fde F, Grando R, Nonato FR, Sousa IM, Queiroz NC, Longato GB, Zafred RR, Carvalho JE, Spindola HM, Foglio MA (2014) Artemisia annua L.: evidence of sesquiterpene lactones’ fraction antinociceptive activity. BMC Complement Alternat Med 14(1):266. doi:10.1186/1472-6882-14-266
Ferreira JF (2007) Nutrient deficiency in the production of artemisinin, dihydroartemisinic acid, and artemisinic acid in Artemisia annua L. J Agric Food Chem 55(5):1686–1694
Geldre EV, Vergauwe A, Eekhout EV (1997) state of the art of production of antimalarial compound artemisinin in plants. Plant Mol Biol 33:199–209
Gopalakrishnan AM, Kumar N (2014) Anti-malarial action of Artesunate involves DNA damage mediated by Reactive Oxygen Species. Antimicrob Agents Chemother. doi:10.1128/AAC. 03663-14
Graham IA, Besser K, Blumar S, Branigan CA et al (2010) The genetic map of Artemisia annua L. Identifies loci affecting yield of the antimalarial drug artemisinin. Science 327(5963):328–331. doi:10.1126/science.1182612
Guillon S, Tremouillaux GJ, Pati PK, Rideau M, Gantet P (2006) Hairy root research: recent scenario and exciting prospects - Commentary. Curr Opin Plant Biol 9:341–346
Guo XX, Yang XQ, Yang RY, Zeng QP (2010) Salicylic acid and methyl jasmonate but not Rose Bengal enhance artemisinin production through involving burst of endogenous singlet oxygen. Plant Sci 178:390–397
Guo L, Dong F, Hou Y, Cai W, Zhou X, Huang AL, Yang M, Allen TD, Liu J (2014) Dihydroartemisinin inhibits vascular endothelial growth factor-induced endothelial cell migration by a p38 mitogen-activated protein kinase-independent pathway. Exp Ther Med 8(6):1707–1712. doi:10.3892/etm.2014.1997
Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR (2011) Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem 286(8):6587–6601. doi:10.1074/jbc.M110.210047
Han J, Wang H, Lundgren A, Brodelius PE (2014) Effects of overexpression of AaWRKY1 on artemisinin biosynthesis in transgenic Artemisia annua plants. Phytochemistry 102:89–96. doi:10.1016/j.phytochem.2014.02.011
Hartwig CL, Rosenthal AS, Dangelo J, Griffin CE, Posner GH, Cooper RA (2009) Accumulation of artemisinintrioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochem Pharmacol 77(3):322–336
Haynes RK, Chan WC, Lung CM, Uhlemann AC et al (2007) The Fe 2+ mediated decomposition, PfATP6, binding and antimalarial activities of artimisone and other artemisinins: The unlikelihood of C- centered radicals as bioactive intermediates. ChemMedChem 2(10):1480–1497. doi:10.1002/cmdc.200700108
He Q, Shi J, Shen XL, An J, Sun H, Wang L, Hu YJ, Sun Q, Fu LC, Sheikh MS, Huang Y (2010) Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells. Cancer Biol Ther 9:819–824. doi:10.4161/cbt.9.10.11552
Ho WE, Peh HY, Chan TK, Wong WS (2013) Artemisinins: Pharmacological actions beyond anti-malarial. Pharmacol Ther 142(1):126–139. doi:10.1016/j.pharmthera.2013.12.001
Hou L, Block KE, Huang H (2014) Artesunate abolishes germinal center B cells and inhibits autoimmune arthritis. PLoS One 9(8):e104762. doi:10.1371/journal.pone.0104762
Hsu E (2006) Reflections on the ‘discovery’ of the antimalarial qinghao. Br J Clin Pharmacol 61(6):666–670. doi:10.1111/j.1365-2125.2006.02673.x
Huang M, Lu JJ, Huang MQ, Bao JL et al (2013) Terpenoids: natural products for cancer therapy. Expert Opin Investig Drug 21:1801–1818. doi:10.1517/13543784.2012.727395
Ji Y, Xiao J, Shen Y, Ma D, Li Z, Pu G, Li X, Huang L, Liu B, Ye H, Wang H (2014) Cloning and characterization of AabHLH1, a bHLH transcription factor that positively regulates artemisinin biosynthesis in Artemisia annua. Plant Cell Physiol 55(9):1592–1604. doi:10.1093/pcp/pcu090
Jing F, Zhang L, Li M, Tang Y, Wang Y, Wang Y, Wang Q, Pan Q, Wang G, Tang K (2009) Abscisic acid(ABA) treatment increases artemisinin content in Artemisia annua by enhancing the expression of genes in artemisinin biosynthesis pathway. Biologia 64:319–323
Kannan R, Kumar K, Sahal D, Kukreti S et al (2005) Reaction of artemisinin with haemoglobin: implication for antimalarial activity. Biochem J 385(2):409–418. doi:10.1042/BJ20041170
Kapoor RR, Chaudhary V, Bhatnagar AK (2007) Effects of arbuscular mycorrhiza and phosphorus application on artemisinin concentration in Artemisia annua L. Mycorrhiza 17:581–587. doi:10.1007/s00572-007-0135-4
Krungkrai SR, Yuthawang Y (1987) The antimalarial action of Plasmodium falciparum of quinghaoso and artesunate in combination with agents which modulate oxidant stress. Trans R Soc Trop Med Hyg 81:710–714
Laughlin JC (2002) Post-harvest drying treatment effects on antimalarial constituents of Artemisia annua L. Acta Horticult 576:315–320
Lee SH, Cho YC, Kim KH, Lee IS, Choi HJ, Kang BY (2014) Artesunate inhibits proliferation of naïve CD4+ T cells but enhances function of effector T cells. Arch Pharm Res. doi:10.1007/s12272-014-0491-5
Li W, Mo W, Shen D, Sun L et al (2005) Yeast model uncovers dual roles of mitochondria in the action of artemisinin. PLoS Genet 1:329–334. doi:10.1371/journal.pgen.0010036
Li X, Zhao M, Guo L, Huang L (2012) Effect of cadmium on photosynthetic pigments, lipid peroxidation, antioxidants, and artemisinin in hydroponically grown Artemisia annua. J Environ Sci (China) 24(8):1511–1518
Liu C, Zhao Y, Wang Y (2006) Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug. Appl Microbiol Biotechnol 72:11–20
Lu JJ, Meng LH, Cai YJ, Chen Q, Tong LJ, Lin LP, Ding J (2008) Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species. Cancer Biol Ther 7:1017–1023. doi:10.4161/cbt.7.7.6035
Lu X, Zhang L, Zhang F, Jiang W, Shen Q, Zhang L, Lv Z, Wang G, Tang K (2013) AaORA, a trichome-specific AP2/ERF transcription factor of Artemisia annua, is a positive regulator in the artemisinin biosynthetic pathway and in disease resistance to Botrytis cinerea. New Phytol 198:1191–1202
Lu M, Sun L, Zhou J, Yang J (2014) Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway. Tumour Biol 35(6):5307–5314. doi:10.1007/s13277-014-1691-9
Lulu Y, Chang Z, Ying H, Ruiyi Y, Qingping Z (2008) Abiotic stress-induced expression of artemisinin biosynthesis genes in Artemisia annua L. Chin J Appl Environ Biol 14:001–005
Ma DM, Pu GB, Lei CY, MaLQ WHH, Guo YW, Chen JL, Du ZG, Wang H, Li GF, Ye HC, Liu BY (2009) Isolation and characterization of AaWRKY1, an Artemisia annua transcription factor that regulates the amorpha-4,11-diene synthase gene, a key gene of artemisinin biosynthesis. Plant Cell Physiol 50:2146–2161
Maes L, Van Nieuwerburgh FC, Zhang Y, Reed DW, Pollier J, Vande Casteele SR, Inze D, Covello PS, Deforce DL, Goossens A (2011) Dissection of the phytohormonal regulation of trichome formation and biosynthesis of the antimalarial compound artemisinin in Artemisia annua plants. New Phytol 189(1):176–189
Marchese J, Ferreira JFS, Rehder VLG, Rodrigues O (2010) Water deficit effect on the accumulation of biomass and artemisinin in annual wormwood (Artemisia annua L., asteraceae). Braz J Plant Physiol 22(1):1–9
Mercer AE, Copple IM, Maggs JL, O’Neil PM et al (2011) The role of heme and the mitochondrion in the chemical and molecular mechanism of mammalian cell death induced by the artemisinin antimalarials. J Biol Chem 286(2):987–996. doi:10.1074/jbc.M110.144188
Messori L, Gabbiani C, Casini A, Siraqusa M et al (2006) The reaction of artemisinins with haemoglobin: A unified picture. Bioorg Med Chem 14(9):2972–2977. doi:10.1016/j.bmc.2005.12.038
Meunier FA, Nguyen TH, Colasante C, Luo F et al (2010) Sustained synaptic vesicle recycling by bulk endocytosis contribute to the maintenance of high rate neurotransmitter release stimulated by glycerotoxin. J Cell Sci 123:1131–1140. doi:10.1242/jcs.049296
Mok S, Ashley EA, Ferreira PE, Zhu L et al (2015) Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 347(6220):431–435. doi:10.1126/science.1260403
Muccioli M, Sprague L, Nandigam H, Pate M, Benencia F (2012) Toll-like receptors as novel therapeutic targets for ovarian cancer. ISRN Oncol 2012: Article ID 642141, 8 pages doi:10.5402/2012/642141
O’Neill PM, Barton VE, Ward SA (2010) The Molecular Mechanism of Action of Artemisinin—The Debate Continues. Molecules 15:1705–1721. doi:10.3390/molecules15031705
Olofsson L, Engström A, Lundgren A, Brodelius PE (2011) Relative expression of genes of terpene metabolism in different tissues of Artemisia annua L. BMC Plant Biol 11:45. doi:10.1186/1471-2229-11-45
Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Microbiol 12(5):355–367. doi:10.1038/nrmicro3240
Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A et al (2013) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496(7446):528–532. doi:10.1038/nature12051
Pandey N, Pandey-Rai S (2014a) Short-term UV-B radiation-mediated transcriptional responses and altered secondary metabolism of in vitro propagated plantlets of Artemisia annua L. Plant Cell Tiss Organ Cult 116:371–385. doi:10.1007/s11240-013-0413-0
Pandey N, Pandey-Rai S (2014b) Modulations of physiological responses and possible involvement of defense-related secondary metabolites in acclimation of Artemisia annua L. against short-term UV-B radiation. Planta 240(3):611–627. doi:10.1007/s00425-014-2114-2
Patra NK, Kumar B (2005) Improved varieties and genetic research in medicinal and aromatic plants (MAPs). In: Kumar A, Mathur AK, Sharma A, Singh AK, Khanuja SPS (eds) Proceeding of second national interactive meet on medicinal and aromatic plants. CSIR-CIMAP, Lucknow, pp 53–61
Patra N, Srivastava AK, Sharma S (2013) Study of various factors for enhancement of artemisinin in Artemisia annua hairy roots. Int J Chem Eng Appl 4:157–160
Paul S, Shakya K (2013) Arsenic, chromium and NaCl induced artemisinin biosynthesis in Artemisia annua L.: a valuable antimalarial plant. Ecotoxicol Environ Saf 98:59–65
Ponka P, Lok CN (1999) The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 31:1111–1137. doi:10.1016/S1357-2725(99)00070-9
Pu GB, Ma DM, Chen JL, Ma LQ, Wang H, Li GF, Ye HC, Liu BY (2009) Salicylic acid activates artemisinin biosynthesis in Artemisia annua L. Plant Cell Rep 7:1127–1135
Putalun W, Luealon W, De-Eknamkul W, Tanaka H, Shoyama Y (2007) Improvement of artemisinin production by chitosan in hairy root cultures of Artemisia annua L. Biotechnol Lett 29:1143–1146
Qian Z, Gong K, Zhang L, Lv J, Jing F, Wang Y, Guan S, Wang G, Tang K (2007) A simple and efficient procedure to enhance artemisinin content in Artemisia annua L. by seeding to salinity stress. Afr J Biotechnol 6(12):1410–1413
Qureshi MI, Israr M, Abdin MZ, Iqbal M (2005) Responses of Artemisia annua L. to lead and salt-induced oxidative stress. Environ Exp Bot 53:185–193
Rai R, Pandey S, Rai SP (2011a) Arsenic-induced changes in morphological, physiological, and biochemical attributes and artemisinin biosynthesis in Artemisia annua, an antimalarial plant. Ecotoxicology 20(8):1900–1913. doi:10.1007/s10646-011-0728-8
Rai R, Meena RP, Smita SS, Shukla A, Rai SK, Pandey-Rai S (2011b) UV-b and UV-C pre-treatments induce physilogical changes and artemisinin biosynthesis in Artemisia annua L.- An antimalarial plant. J Photochem Photobiol B 105:216–225
Ro DK, Paradise EM, Ouellet M, Fisher KJ et al (2006) Production of the antimalarial drug precursor artimisinic acid in engineered yeast. Nature 440:940–943. doi:10.1038/nature04640
Schramek N, Wang HH, RÖmisch-Margl W, Keil B, Radykewicz T, WinzenhÖrlein B et al (2009) Artemisinin biosynthesis in growing plants of Artemisia annua. a CO study. Phytochemitry 71:179–187
Selmeczi K, Robert A, Claparols C, Meunier B (2004) Alkylation of human haemoglobin A0 by the antimalarial drug artemisinin. FEBS Lett 556:245–248
Shandilya A, Chacko S, Jayaram B, Ghosh I (2013) A plausible mechanism for the anti- malarial activity of artimisinin: A computational approach. Sci Rep 3:251. doi:10.1038/srep02513
Simonnet X, Quennoz M, Carlen C (2008) New Artemisia annua hybrids with high artemisinin content. Acta Horticult 769:371–373
Straimer J, Gnädig NF, Witkowski B, Amaratunga C, Duru V et al (2015) Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347(6220):428–431. doi:10.1126/science.1260867
Sun C, Li J, Cao Y, Long G, Zhou B (2015) Two distinct and competitive pathways confer the cellcidal actions of artemisinins. Microb Cell 2(1):14–25. doi:10.15698/mic2015.01.181
Tang KX, Jing FY, Zhang L, Wang GF (2008) Method for increasing artemisinin content by co-transferring genes HMGR and FPS into Artemisia annua [P] Faming Zhuanli Shenqing. CN101182545A
Tang KX, Jiang WM, Lu X, Qiu B, Wang GF (2012) Overexpression AaWRYK1 gene increased artemisinin content in Artemisia annua L. Shanghai Jiao Tong University, China. Patent CN201210249469.X, 14 Novemb 2012
Telerman A, Amson R (2009) The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 9:206–216
Towler MJ, Weathers PJ (2007) Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways. Plant Cell Rep 26:2129–2136
Townsend T, Segura V, Chigeza G, Penfield T, Rae A (2013) The Use of Combining Ability Analysis to Identify Elite Parents for Artemisia annua F1 Hybrid Production. PLoS ONE 8(4):e61989
Uhlemann AC, Ramharter M, Lell B, Kremsner PG, Krishna S (2005) Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis 192:1830–1835
Wallaart TE, Pras N, Beekman AC, Quax WJ (2000) Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes. Planta Med 66:57–62
Wang YY, Weathers PJ (2007) Sugars proportionately affect artemisinin production. Plant Cell Rep 26:1073–1081
Wang JW, Zheng LP, Tan RX (2006) The preparation of an elicitor from a fungal endophyte to enhance artemisinin production in hairy root cultures of Artemisia annua L. Sheng Wu Gong Cheng Xue Bao 22:829–834
Wang JW, Zheng LP, Zhang B, Zou T (2009) Stimulation of artemisinin synthesis by combined cerebroside and nitric oxide elicitation in Artemisia annua hairy roots. Appl Microbiol Biotechnol 85(2):285–292
Wang J, Huang L, Li J, Fan Q et al (2010) Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS One 5:e 9582. doi:10.1371/journal.pone.0009582
Watanabe M, Moon KD, Vacchio MS, Hathcock KS, Hodes RJ (2014) Downmodulation of Tumor Suppressor p53 by T Cell Receptor Signaling Is Critical for Antigen-Specific CD4+ T Cell Responses. Immunity 40(5):681–691. doi:10.1016/j.immuni.2014.04.006
Weathers PJ, Elfawal MA, Towler MJ, Acquaah-Mensah GK, Rich SM (2014) Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice. J Ethnopharmacol 153(3):732–736
White NJ (2008) Qinghaosu (Artemisinin) The price of success. Science 320:331–334. doi:10.1126/science.1155165
WHO (2014) Facts sheet on the world malaria report 2013. http://www.who.int/malaria/media/world_malaria_report_2013/en/
WHO (2015) WHO updates on artemisinin resistance (February 2015). http://www.who.int/malaria/media/artemisinin_resistance_qa/en/
Xiang L, Zeng L, Yuan Y, Chen M et al (2012) Enhancement of artimisinin biosynthesis by overexpressing dxr, cyp71av1 and cpr in the plants of Artemisia annua L. Plant Omics 5:503–507
Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, Yang X, Lian F, Sun L (2007) Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology 46:920–926. doi:10.1093/rheumatology/kem014
Yang RY, Zeng XM, Lu YY, Lu WJ, Feng LL, Yang XQ, Zeng QP (2010) Senescent leaves ofArtemisia annua are one of the most active organs for overexpression of artemisinin biosynthesis responsible genes upon burst of singlet oxygen. Planta Med 76:734–742
Yuan Y, Liu W, Zhang Q, Xiang L, Liu X, Chen M, Lin Z, Wang Q, Liao Z (2014) Overexpression of artemisinic aldehyde Δ11 (13) reductase gene-enhanced artemisinin and its relative metabolite biosynthesis in transgenic Artemisia annua L. Biotechnol Appl Biochem. doi:10.1002/bab.1234
Zarn JA, Brüschweiler BJ, Schlatter JR (2003) Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14-α-demethylase and aromatase. Environ Health Perspect 111:255–261
Zhang S, Gerhard G (2008) Heme activates artemisinin more efficiently than hemin, inorganic iron or haemoglobin. Bioorg Med Chem 16:7853–7861. doi:10.1016/j.bmc.2008.02.034
Zhang L, Jing FY, Li FP, Li MY, Wang YL, Wang GF, Sun XF, Tang KX (2009) Development of transgenic Artemisia annua (Chinese wormwood) plants with an enhanced content of artemisinin, an effective anti-malarial drug, by hairpin-RNA-mediated gene silencing. Biotechnol Appl Biochem 52:199–207
Zheng LP, Guo YT, Wang JW, Tan RX (2008) Nitric oxide potentiates oligosaccharide-induced artemisinin production in Artemisia annua hairy roots. J Integr Plant Biol 50:49–55
Conflict of interest
The authors (NP and SPR) of the review article entitled “Updates on Artemisinin: an insight to mode of actions and strategies for enhanced global production” have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Handling Editor: Peter Nick
Rights and permissions
About this article
Cite this article
Pandey, N., Pandey-Rai, S. Updates on artemisinin: an insight to mode of actions and strategies for enhanced global production. Protoplasma 253, 15–30 (2016). https://doi.org/10.1007/s00709-015-0805-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00709-015-0805-6