Abstract
Plant secondary biosynthetic pathways are exceedingly inducible by elicitors and facilitate enhanced metabolite production using plant cell tissue and organ cultures. Elicitors can regulate large number of control points and trigger the expression of key genes with increased cellular activities at biochemical and molecular level involving signal compounds. A large number of chemical elicitors viz: jasmonic acid (JA), methyl jasmonate (MeJA), salicylic acid (SA), acetyl salicylic acid (ASA), ethylene (ET) and ethrel (Ethe), heavy metals (HM), many types of chemical compounds (natural or synthetic) and their combinations are used for elicitation studies. Cell suspensions and hairy roots are commonly used culture systems followed by adventitious roots and multiple shoots for elicitation experiments. Amongst the elicitors and concentrations used 100 µM MeJA was found optimum for secondary metabolite enhancement in majority of experiments compared to SA and JA. Elicitor treatments promoted yield enhancements starting from 1.0 to maximum of 2230-fold across plant species studied. Elicitors singly with media additives, combination of elicitors and elicitors other than signal compounds along with hormones were found beneficial for enhanced secondary metabolite production. Further, a combination of target gene over expression and elicitor treatment also supported higher secondary product yield. The present communication presents information exclusively about the use of chemical elicitors for secondary metabolites production in vitro covering approximately more than a decade of research at one place in one review. Further, this extensive appraisal will be useful for the understanding and manipulation of secondary metabolites for enhanced production in vitro.
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Introduction
Plants synthesize a diversity of low molecular weight, structurally complex chemical compounds commonly known as secondary metabolites. Secondary metabolites do have a very important role in plants interaction with its environment for their existence and sustenance (Pichersky and Gang 2000; Moore et al. 2014). Higher plants with inherent non-mobile status make own self-defense strategies (structural/chemical) for their survival. Thus, as a part of chemical defense strategy, plants synthesize enormous number of chemical compounds (secondary metabolites) to meet the pressing requirements of the plants. The estimates already revealed that, plants produce more than 100,000 secondary metabolites, while the total number may exceed over 500,000 once they are structurally characterized (Hadacek 2002).
Many secondary metabolites yet need characterization in plants for future health care and pharmaceutical bioprospecting (Lee 2010; Soejarto et al. 2012; Elkington 2014; Pan 2014). Scores of chemical compounds from plant origin are in current use for medicine preparations and the fact remains that plants continue to be the principal source for many important bioactive molecules/pharmacophores (Dias et al. 2012; Pan 2014; Raomai et al. 2015). Currently, one-fourth of all prescribed pharmaceuticals across the globe contain chemical compounds (secondary metabolites) that are directly, indirectly or via semi-synthetically derived solely from plants (Song et al. 2014). Recently, research wing of British Broadcasting Corporation (BBC) has made a global ahead of its time forecast for world market of plant-derived drugs between 2013 extending up to 2020 stands at 35.4 billion US $ (http://www.bccresearch.com/market-research/biotechnology/botanical-plant-derived-drugs-report-io022g.html).
Plants grow in harsh surroundings and stay alive in a biotic and abiotic stressed environment. A wide array of defense strategies against biotic and abiotic stresses exhibited by plants through both preexisting innate (constitutive) and induced defense systems. These induced defense responses in plants generally triggered following recognition of chemical factors or molecules by cellular environment called elicitors. An elicitor probably defined as a factor, substance, molecule or an agent, which, when a minute quantity incorporated to an existing cellular background, it improves, the biosynthetic competence of specific compounds particularly secondary metabolites in the pathway (Bhalla et al. 2005; Zhao et al. 2005; Namdeo 2007; Onrubia et al. 2013; Murthy et al. 2014; Gorelick and Bernstein 2014).
In the recent past a number of reviews have been published for the production of secondary metabolites using in vitro plant tissue culture systems (Vanisree and Tsay 2004; Zhou and Wu 2006; Matkowski 2008; Karuppusamy 2009; Ramakrishna and Ravishankar 2011; Hussain et al. 2012; Murthy et al. 2014; Ramirez-Estrada et al. 2016). These reviews included collective citation and inclusion of all elicitor types (biological, chemical and physical) together in one review. Keeping in view the extensive use and potentials of chemical group of elicitors for secondary metabolite production in vitro, there is need to bring out a review dedicated exclusively to chemical elicitors. Considering the enormous existing and upcoming literature, only few selected representative examples depicting current trend of research developments covering more than one decade of approximate literature survey are included in this review.
Elicitors: mechanism of action
Elicitor cross talk with the receptors present in the plasma membrane of several plant cells by stimulating an array of defense responses. This multitasking ability of such elicitors is unique as well as multidimensional (Gorelick and Bernstein 2014). Research findings indicate that it can regulate large number of biochemical control points; trigger the expression of key genes and transcription factors too. Therefore, now it is a well-established fact that the elicitors have the ability to control array of cellular activities at biochemical and molecular level (Zhao et al. 2005; Baenas et al. 2014). Elicitor perception is able to increase the intensity of plant’s response to biotic and abiotic stresses with the enhanced synthesis of signal compounds such as JA, SA, ET, NO etc. and its subsequent influence on secondary metabolite production.
Plant’s response to wounding and in systemic resistance is an important function of JA in plant growth and development. In recent times, greater role of JA in plant defense strategy is discussed at length (Ballare 2011; Pirbalouti et al. 2014). Further, MeJA is a volatile unique molecule and has the knack to spread out interplant communication through airborne signals for defense responses (Wasternack 2014; Kazan 2015; Dar et al. 2015). JA involves signal transduction pathways with the participation of jasmonate zim domain (JAZ) proteins, which are further subjected to proteasomal degradation via Skp1/Cullin/F-box (SCF) complex. JAZ proteins degradation results in the release of MYB/MYC transcription factors, which ultimately stimulate JA-dependent gene expression in secondary metabolism (Wasternack 2014).
Endogenous signaling by salicylic acid in plants mediates defense against pathogens and initiates synthesis of both localized acquired resistance (LAR) and systemic acquired resistance (SAR). The signal can also move to nearby plants by the volatile ester, i.e. methyl salicylate a possible alert communication for pathogen attack that plants can understand (Santner and Estelle 2009; Vlot et al. 2009). In addition, the mode of action of SA and its complex interaction with other signal compounds such as JA, ET and NO has been studied in detail (Qiao and Fan 2008; Boatwright and Pajerowska-Mukhtar 2013; Caarls et al. 2015).
The fruit-ripening hormone ET is responsible for biochemical and morphological changes involved in fruit senescence. ET synthesis in plants is related to wounding, abiotic and biotic stresses (Kazan 2015). ET perception is accomplished by ET receptors. Five ET membrane-localized receptors have been identified in Arabidopsis (Wang et al. 2002; Yoo et al. 2009). Binding of ET inactivates the receptors e.g. CTR1 (Constitutive Triple Response) is inactivated which results in the suppression of the CTR1–MAPK pathway and the activation of the MKK9–MPK3 and -6 cascades, which phosphorylates Thr residues of EIN3 and EIL1 transcription factors in the nucleus. Phosphorylation of EIN3 and EIL1 probably increases stability, which finally decreases their interaction with EBF1 and -2 for subsequent gene expression (Yoo et al. 2009).
Nitric oxide (NO) a free radical identified as signaling molecule implicated in elicitor-mediated defense reactions of plants (Matsuura et al. 2014). Particularly, it was found that NO targets a number of proteins and enzymes in plants (Wilson et al. 2008). The elicitor molecule NO is also known to activate MAP kinase signaling pathways resulting in altered gene expression. Plants definitely perceive and respond to NO, but the mechanism is not clear. There are no specific plant NO receptor has been identified. Abscisic acid (ABA) induces synthesis of both NO and H2O2. Thus, NO and Ca2+ are both strongly implicated in the signaling cascade that must operate. Thus, it would seem very likely that responses to NO are accomplished by signaling through cyclic guanosine monophosphate (cGMP), cyclic adenosine diphosphoribose (cADPR) and Ca2+. NO alleviates the deleterious effect from reactive oxygen species (ROS) in establishing stress resistance responses. In addition to its signaling roles, NO may also function as a regulator for gene expression (Kopyra and Gwozdz 2004).
While discussing mode of action of elicitors, it is necessary to mention about the interaction of various signal compounds/elicitors and their role in gene regulation. As it is well-established fact that environmental stresses such as ozone, UV irradiation and wounding involve the generation of ROS and synthesis of ET. ROS related responses are influenced by the outcome of the interactions among JA, SA and ET. ASA and SA repress JA synthesis and following ET production. In the presence of UV-B stress, induction of PR-1 is dependent on ET, but not on JA suggesting that, ET is a signal required to activate the SA pathway (Wang et al. 2002; Qiao and Fan 2008). NO may directly or indirectly interact with other signaling molecules such as SA and ET and abiotic stress. A diagrammatic representation of elicitor mode of action is depicted in Fig. 1.
In vitro culture systems and elicitor treatment
Culture systems
Some of the culture systems and our own experiences such as somaclonal variation, nutrient media manipulation, precursor feeding, elicitation, hairy root culture, plant cell immobilization, biotransformation, large scale cultivation in bioreactor system and genetic manipulation are reported (Giri and Vijaya Laxmi 2000; Giri et al. 2001a, b, 2003; Vanisree and Tsay 2004; Abhyankar et al. 2005; Shyamkumar et al. 2007; Giri et al. 2009; Begum et al. 2009; Shimizu et al. 2010; Banerjee et al. 2012; Lee et al. 2015; Zaheer et al. 2016).
Callus culture system, has been used less frequently only to evaluate the effect of signal compounds for secondary metabolite production (Fig. 2). Generally, callus culture system used to detect the presence of bioactive compounds in cultured plant tissue in vitro. However, callus culture system are even used currently in elicitation studies (Pandey et al. 2015). Different experimental investigations on secondary metabolite production with few recent examples are mentioned in this review (Table 1). Another extensively used culture system for elicitor treatment and secondary metabolites production is cell suspensions compared to others for elicitation experiments (Fig. 2; Table 1). Obviously, the trend of literature on the use of cell suspension for elicitation studies is enormous and it becomes difficult to cite all of them in the present context (Table 1). However, few most recent findings are included in this assessment.
Hairy root cultures have proved to be a valuable culture system for elicitation studies due to its inherent characteristics of hormone autotrophy, uncontrolled growth, biosynthetic and genetic stability distinctiveness. Further, certain secondary metabolites are synthesized exclusively in the roots. Thus, transformed hairy root cultures have become important for secondary metabolite production in vitro (Giri et al. 2003; Guillon et al. 2006; Srivastava and Srivastava 2007; Murthy et al. 2014; Zaheer et al. 2016). Hairy root cultures are quite frequently used culture system compared to others except cell suspensions for elicitor treatment and secondary metabolite production (Fig. 2; Table 1). Literature on the use of hairy root cultures in elicitation studies for secondary metabolite production has accumulated considerably over years (Fig. 2; Table 1). Adventitious root is an appropriate culture system for production of secondary metabolites in vitro. Adventitious roots are induced with ease in vitro, incorporating low concentrations of auxin and can be cultured in large scale axenically analogous to hairy root cultures but comparatively with reduced growth rate. Being organized/differentiated culture system, adventitious roots also possess genetic and biosynthetic stability (Baque et al. 2012). Similar to other culture systems adventitious roots frequently used for elicitation but with reduced frequency (Fig. 2; Table 1).
Higher secondary metabolite content has been detected in leaves of specific plant species (Giri et al. 2009; Begum et al. 2009; Zaheer and Giri 2015). Multiple shoot culture is one such culture system, which can generate high biomass of leaves with cytokinin manipulation for secondary metabolite production and elicitor driven yield enhancement (Kikowska et al. 2015; Zaheer and Giri 2015). In this part of the review, few recent findings will be highlighted involving elicited multiple shoots for the production of secondary metabolites (Table 1).
Elicitor treatment
In general, exogenous supply of signal compounds (chemical elicitors) such as JA, SA, ET, NO and HM, synthetic chemicals etc. to different culture systems creates a plant under stress like cellular environment. The elicitors not only bring change quantitatively (yield enhancement of existing biomolecules) but also found to alter/synthesize secondary metabolites qualitatively (discovery of entirely new/novel compounds). The prime objective of incorporating elicitors artificially onto in vitro cultures is to misguide the cells or tissues for a possible biotic/abiotic attack, mimicking the external environment similar to natural conditions under stress related damage in plants. The manifestations of elicitor treatment with altered/modified/elevated genetic and biochemical activities in the cellular background is observed as enhanced yield of target chemicals, higher gene expression and discovery of entirely new/novel biomolecules (Caretto et al. 2011; Murthy et al. 2014; Ramirez-Estrada et al. 2016). The qualitative and quantitative variations in the content of bioactive natural products (secondary metabolites) are in expected direction following elicitor treatment.
Chemical elicitors such as jasmonic acid (JA), methyl jasmonate (MeJA), 2-hydroxyl ethyl jasmonate, salicylic acid (SA), acetyl salicylic acid (ASA), trifluro ethyl salicylic acid, ethylene (ET), nitric oxide (NO), sodium nitropruside (SNP), ethrel or ethephon (Ethe) are used for elicitation studies. In addition, di-methyl sulfo-oxide (DMSO), pyrazine 2-carboxylic acid, benzo (1, 2, 3) thiadiazole-7-carboxylic acid-s methyl ester (BION), eugenol, polyamines, morphactin, sodium acetate, sorbitol, benzothiadiazole, saccharin, hydrogen peroxide, silver nitrate, triton-x, copper sulphate, ancymidol, cyclodextrins, methylated cyclodextrins, cantharidin, putrescine, glutathione, heavy metal ions (HM), Ca+2 cAMP, catharidin, and many more have been employed for secondary metabolite manipulation in vitro. Different chemical elicitors used for elicitation, gene isolation and study of secondary metabolic pathway in post genomic era are carried out (Oksman-Caldentey and Inzé 2004). Let us discuss some of the recent findings on frequently used chemical elicitors and their applications using various plant in vitro culture systems.
JA and related compounds
JA and its related signal molecules in particular MeJA used extensively for elicitation studies involving in vitro culture systems (Fig. 3; Table 1). Keeping in view the enormous literature on the use of JA and its related molecules in elicitation studies, a few latest examples cited herein involving different culture systems such as callus, suspension cells, hairy roots, adventitious roots and multiple shoots. Elicitation with 0.5 μM MeJA influenced betalain pigment production in callus culture of Bougainvillea (Lakhotia et al. 2014). Recently, betulinic acid with anti-cancer property was reported involving elicitation of callus cultures of different Ocimum species (Pandey et al. 2015). MeJA at 200 µM resulted in 2-fold (5.10 ± 0.18 % DW) increase of betulinic acid compared to (2.61 ± 0.19 % DW) from untreated control callus cultures of O. basilicum. Peruvoside production at the tune of 8.93 mg/l in cell suspension cultures of Thevetia peruviana with the incorporation of 100 mg/l MeJA was achieved (Zabala et al. 2010). Elicitation and permeabilization influenced accumulation and storage profile of phytoestrogens in suspension cultures of Genista tinctoria. Maximum levels (198.3 mg/100 g DW genistein: 3.0 fold); 15.21 mg/100 g DW daidzein: 5.0-fold increase were obtained (Luczkiewicz and Kokotkiewicz 2012).
Irrespective of different plant species and culture systems used for elicitation expriments, the concentration of elicitors was vital. An analysis indicated that the concentration of JA or MeJA ranged from as low as 5.0 to 500 µM across different plant species and in vitro culture systems was studied (Fig. 4). In a real time assessment of collected literature on the concentration of elicitors revealed that 100 µM MeJA used in maximum number of experiments involving several plants and culture systems (Fig. 4; Table 1). In another report, a 2.6-fold enhancement in phytoecdysteroids (20-hydroxyecdysone); was obtained from MeJA (0.6 mM) elicited cell suspension cultures of Achyranthes bidentata (Wang et al. 2013). Enhanced shikonofuran derivatives production (12-fold) in response to 5.0 µM MeJA treatment in shikonin proficient and shikonin-deficient cell lines from suspension cultures of Arnebia euchroma was also studied (Wang et al. 2014). Elicitation of antioxidant secondary metabolites with jasmonates and gibberellic acid reported in cell suspension cultures of Artemisia absinthium (Ali et al. 2015). Cell suspension cultures of A. absinthium when treated with 1.0 mg/l MeJA resulted total phenolic content 6.7 mg GAE (Gallic Acid Equivalent)/g DW and 1.0 mg/l JA it produced 6.7 mg GAE/g DW compared to control 5.32 mg GAE/g DW. Whereas, 1.0 mg/l MeJA resulted 2.19 mg QE (Quercetin Equivalent)/g DW in total flavonoid content and 1.0 mg/l JA produced 1.89 mg QE/g compared to 1.57 mg QE/g DW in control. Recently, 150 µM MeJA elicitation promoted 15.4-fold increased gymnemic acid production in cell suspension cultures of G. sylvestre (Bhuvaneswari et al. 2015).
Addition of 200 µM MeJA promoted 11.22 mg/g DW total phenolics and 3.60 mg/g DW total flavonoids, 60.28 and 32.93 mg/g DW in hairy roots of Ginseng and Echinacea, respectively (Wu et al. 2008). Hairy root cultures are also used for enhanced Rg3 ginsenoside biosynthesis in Panax elicited by MeJA. In this study, a 7-day treatment of hairy roots with 0.1 mM MeJA leads to the detection of Rg3 by HPLC analysis contrast to its absence in untreated control (Kim et al. 2013). Recently, Matsuura et al. (2014) have reviewed the biotechnological benefits of oxidative stress and elicitation on indole alkaloid production. Daidzin content enhancement up to 7.3-fold (3.43 % DW) was obtained with 10 µM JA treatment in hairy root cultures of Psoralea corylifolia compared to 0.478 % DW in control (Zaheer et al. 2016).
Optimization of elicitors with different concentrations of JA, MeJA and SA were used to enhance the valtrate production. However, optimal production (10.58 mg/g DW) was obtained only with 100 mg/l MeJA compared to JA and SA in adventitious roots of Valeriana amurensis (Cui et al. 2012). Elicitor treatment at 50 µM MeJA and XAD-7 resulted in 3.55-fold triptolide production. Whereas, XAD-7 alone was resulted in 49.11-fold increase in wilforgine, MeJA at 100 µM promoted 10.40-fold wilforine in adventitious root fragment liquid cultures of Tripterygium wilfordii. However, there was no significant increase in alkaloid content with SA treatment alone or combined with XAD-7 when compared to control (Miao et al. 2014). Further, an exceptionally high percentage of enhancements of bioactive compound production in adventitious root cultures of Eleutherococcus koreanum Nakai by elicitation with MeJA and SA was studied (Lee et al. 2015). A detailed study in E. koreanum, optimal concentration of elicitor MeJA at 50 µM increased biomass and bioactive compounds production of five target bioactive molecules such as eleutherosides B and E, chlorogenic acid, and total phenolics and flavonoids which were on an average 37.77 % higher than the untreated control root cultures.
Shoot cultures of Eryngium planum grown in 1.0 mg/l BAP + 0.1 mg/l indole acetic acid containing medium and treated with 100 µM MeJA for 48 h resulted in 19.795 mg/g DW enhanced phenolic compounds, which was 4.5-fold higher than 4.36 mg/g DW in control (Kikowska et al. 2015). Production of increased plumbagin (3.0-fold) was also reported following 50 µM MeJA elicitation of Drosera burmanii whole plant cultures (Putalun et al. 2010). A 3.08-fold enhancement in bacoside (8.46 mg/g DW) was obtained when shoot cultures of Bacopa monnieri treated with 1.0 mg/l JA compared to 2.74 mg/g DW bacoside in control shoots (Sharma et al. 2015). JA at 25 and 50 µM promoted 3.3 and 3.0-fold increase in andrographolide content in multiple shoot cultures of Andrographis paniculata after eighth week, respectively when compared to control (Zaheer and Giri 2015).
SA and related compounds
Similar to other chemical elicitors, SA and its related compounds are used comparatively lesser than MeJA for elicitation studies (Fig. 3; Table 1). Keeping in view many research findings and the importance of salicylic as a potent elicitor, we will restrict ourselves to few recent examples on elicitation involving in vitro plant cell and tissue culture systems. Five-fold increase of capsaicinoid synthesis following SA or MeJA (500 µM) elicitation in Habanero pepper (Capsicum chinense Jacq.) cell suspension cultures was obtained (Gutierrez-Carbajal et al. 2010). Elicitation with SA promoted improved podophyllotoxin production and its correlation with lignan biosynthesis in cell cultures of Linum album with increased expression of genes (Yousefzadi et al. 2010). Treatment of L. album cell cultures with 10 µM SA for 3 days resulted in 3.0-fold increase in podophyllotoxin content compared to non-elicited control cultures. A detailed study on the influence of SA on the production of phenolic compounds e.g. salvianolic acid B and caffeic acid was reported in cell suspension cultures of Salvia miltiorrhiza. SA concentrations ranging between 6.25 and 22.5 mg/l found to enhance the phenolic compounds. Further, the biosynthetic enzymes such as phenylalanine ammonia-lyase (PAL), tyrosine aminotransferase (TAT), superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) enzymes were found upregulated by the application of SA (Dong et al. 2010). SA and MeJA promoted increased production of d-chiro-inositol compared to untreated control in cell suspension cultures of Fagopyrum esculentum (Hu et al. 2011). Observations indicated that MeJA at 0.4 mM resulted in 6.141 mg/g d-chiro-inositol, whereas, 0.6 mM SA accumulated 5.521 mg/g. However, combination of 0.2 mM MeJA and 0.6 mM SA resulted in 7.575 mg/g d-chiro-inositol production, which was 3.72-fold higher than the untreated control cultures.
Like other elicitors, it revealed that, the concentration of SA and its related compounds used in the elicitation ranged from as low as 5.0 µM to as high as 500 µM. In a realistic appraisal of literature on the concentrations of elicitors revealed that, 100 µM SA also used in majority of studies (Fig. 4). Significant increase in 10-hydroxycamptothecin (HCPT) content was obtained when callus cultures of Camptotheca acuminata were treated with 100 µM SA (Pi et al. 2010). Pueraria candollei hairy root culture treatment with SA at 100 µM resulted in 20 ± 1 mg/g dry wt isoflavonoid compared to control (14 mg/g dry wt) after 3 days of elicitation (Udomsuk et al. 2011). SA at 50 mg/l elicited saponin production up to 87.66 ± 1.66 mg/gm DW in transverse thin cell layer cultures of Paris polyphylla which was 3.6-fold higher than in vivo rhizome (Raomai et al. 2015). Maximum sanguinarine content (0.058 % DW) following 250 μM SA elicitation in cell suspension cultures of Papaver somniferum was detected (Verma et al. 2014).
Influence of 500 µM SA elicitations on accumulation of hyoscyamine (4.35 mg/g DW) and scopolamine is (0.28 mg/g DW) in adventitious root cultures of Datura metel was studied (Ajungla et al. 2009). ASA at 25 µM increased 2.3-fold (1.44 % DW) daidzin content when compared to untreated control (0.62 % DW) roots of P. corylifolia (Zaheer et al. 2016). SA at 50 µM resulted in enhanced hypericin (7.98-fold) and pseudohypericin (13.58-fold) production in H. hirsutum (Coste et al. 2011). Effect of elicitors MeJA (10 µM) and SA (200 µM) on furanocoumarin production up to 4.7 and 5.9-fold, respectively; observed and in situ product removal was studied using shoot cultures of Ruta graveolens (Diwan and Malpathak 2011). Elicitation with SA at 20 and 50 µM to multiple shoot cultures of A. paniculata accumulated 3.4 (1.654 % DW) and 3.1-fold (1.483 % DW) andrographolide content, respectively; when compared to 0.478 % DW in control (Zaheer and Giri 2015).
ET and ethrel/ethephon
A close assessment of existing literature has revealed that ET is not a widespread chemical elicitor used for secondary metabolite yield enhancement keeping in view its positive as well as negative effects. Therefore, ET: a less frequently used compared to other elicitors for elicitation studies and limited too few sporadic findings (Fig. 3; Table 1).
Further, general trend has been that the application of ET alone for secondary metabolite accumulation was not encouraging. However, combined treatment of ET along with any other signal molecule found beneficial for enhanced production of secondary metabolites indicating its interactive role. It revealed that the concentration of ET is a vital determinant for the altered biosynthesis of secondary metabolites as higher concentrations slow down and on the other hand, lower one enhances the biosynthetic ability of tissue under treatment.
Few reports are documented on ET treatments and is included here starting from recent to earlier findings. Combined application and interaction of JA and ET in Cupressus lusitanica cell cultures for the production of β-thujaplicin were investigated (Zhao et al. 2004). ET gas at 200 ppm increased β-thujaplicin production (22 mg/l) in cell suspension cultures of C. lusitanica compared to untreated control (11 mg/l). The culture systems such as cell suspension, hairy roots and rootless shoot cultures of Catharanthus roseus were used to evaluate the influence of MeJA, SA and ET on indole alkaloid accumulation (Vazquez-Flota et al. 2009). In a study it was found that, irrespective of the use of signal compounds alone or in combinations, the type of culture system was also critical in rendering helpful effect on accumulation of alkaloids. MeJA at 10 µM and 5 ppm ET was effective for enhanced vindoline production in rootless shoot cultures, which was about 6.5 times higher than the untreated control cultures. ET alone reduced catharanthine accumulation in these cultures. In Leucojum aestivum, 1-aminocyclopropane-1-carboxylic acid (ACC) synthase induced ET production and shown positive effect on galanthamine production (Ptak et al. 2010). ACC (10 µM) increased ET production up to 26.4 nl/g fresh weight, FW in callus and 2.1 nl/g FW in somatic embryos. The galanthamine content was (2 % DW) which was six times higher than control (0.34 % DW) in somatic embryos cultured on medium supplemented with ACC. In the recent times, ET is not that frequently used elicitor to be experimented for the enhancement of secondary metabolites. Use of ET as elicitor is much more of academic than practical importance. A possible involvement of ET in shikonin biosynthesis in Lithospermum erythrorhizon shoot cultures examined and it found that, ET acted for a regulatory role in shikonin biosynthesis involving L. erythrorhizon shoot cultures (Touno et al. 2005). Enhanced shikonin production up to threefold (0.23 % DW) was achieved when L. erythrorhizon shoot cultures were treated with 10 μl ET per petridish containing 25 ml of media compared to untreated control.
Ethrel or 2-chloroethylphosphonic acid commonly known as ethephon is solely marketed by Bayer Crop Science Group. Ethrel (Ethe) used not that frequently in elicitation studies compared to other leading elicitors (Fig. 3; Table 1). Elicitor treatment of SA (500 µM), MeJA (100 µM) and Ethe (500 µM) to cell suspension cultures of Cayratia trifolia after 1 week resulted in 3–6-fold [5–11 mg/l DM (dry mass)] increase in stilbenes content within 15 day of culture compared to untreated control (Roat and Ramawat 2009). Elicitation of Bupleurum falcatum transgenic adventitious roots with MeJA (5 and 20 µM), SA (1 and 5 µM) and Ethe (1 and 10 µM) induced squalene synthase gene activity upregulation and higher production of phytosterol and saikosaponins (Kim et al. 2011).
NO and related compounds
The study on the role of NO in UV-B for flavonoid production in Gingko biloba callus was reported (Hao et al. 2009). UV-B along with 0.2 mM SNP influenced PAL regulation and resulted in enhanced flavonoid production. Enhanced taxol production (11 % more than control cultures) was obtained with 20 μM SNP treatment using immobilized cell culturs of Taxus cupsidata (Xiao et al. 2009). A 2.3-fold (22.4 mg/l) increase of artemisinin was obtained with combined treatment of SNP (10 µM) and cerebroside (30 µg/ml) compared to untreated control (9.6 mg/l) in hairy root cultures of A. annua (Wang et al. 2009). Application of 0.1 mM SNP resulted in increased terpenoid catharanthine production in hairy root cultures of C. roseus (Li et al. 2011). Studies on evolution of ROS with 100 µM NO-induced tanshinone production (tanshinone I, cryptotanshinone, dihydrotanshinone I and tanshinone IIA, with increased yield by 80, 170, 60 and 180 %; respectively; compared to control) in S. miltiorrhiza hairy roots has also been carried out (Liang et al. 2012).
Combined treatments of elicitors and media additives
Research findings indicate that combined treatments of elicitors and media additives have shown positive effect on enhancement of secondary metabolite production in vitro. Influence of single elicitor no doubt has promoting effect on yield enhancement, however; elicitor combinations have shown improved results. In Boswellia serrata callus cultures four major boswellic acid isomers were found manipulated by biotic and abiotic elicitors (Ghorpade et al. 2011). Na2SO4 at 10 and 15 mg/l resulted in enhanced production of acetyl-11-keto-β-boswellic acid (AKBBA) and 11-keto-β-boswellic acid (KBBA), respectively; which was 10.0-fold compared to control callus cultures. Combined effect of increased sucrose concentration and/or elicitation using MeJA generated positive response. The rosmarinic acid (RA), chlorogenic acid content and caffeic acid was found to be increased in the callus and other culture systems compared to the leaves and roots of intact plants (Kikowska et al. 2012). In this study, a 3.0-fold (16.24 mg/g) increase of RA content in callus and 2.0-fold (3.91 mg/g) in cell suspension cultures was achieved post elicitation with 100 µM MeJA.
In addition to the combination of elicitors, a systematic treatment of Argemone mexicana cell cultures with MeJA and SA promoted sanguinarine production (Trujillo-Villanueva et al. 2012). A 9.0-fold increase in sanguinarine synthesis compared to untreated control was obtained following the sequential treatment. Vitis vinifera cell suspension cultures produced improved trans-resveratrol extracellularly using cyclodextrins and MeJA (Belchi-Navarro et al. 2012). The combination of MeJA (100 µM) and l-tyrosine (2 mM) increased the thebaine yield up to 84.62 mg l−1 at 6 days after treatment in cell suspension cultures of Papaver bracteatum (Zare et al. 2014). About 3.4–4.6 fold enhancements in anthocyanin production was achieved following combined treatment of elicitor and precursor in cell suspension cultures of V. vinifera (Qu et al. 2011). Combined application of JA and gibberellic acid favoured for enhanced antioxidant secondary metabolites production in cell suspension cultures of A. absinthium L. (Ali et al. 2015). Elicitation of A. annua cell suspension cultures with 22 µM MeJA and 200 µM miconazole promoted 2.5–3.0-fold increase in artemisinin production. Further, MeJA treatment influenced expression of genes such as CYP71AV1, CPR and DBR2 related to artemisinin biosynthesis (Caretto et al. 2011). Enhanced artemisinin production (27 μmol g/l i.e. 300-fold higher compared to untreated control) in A. annua cell suspension cultures was also obtained by combined elicitation of 50 mM [2,6-di-O-methyl)-β-cyclodextrin (DIMEB)] and 100 μM MeJA with media additive β-Cyclodextrins (Durante et al. 2011).
In hairy root cultures of P. corylifolia, increased isoflavone daidzein production up to 2.2 and 0.228 % DW genistein were obtained after 48 h of elicitation treatment. This study exploited combined application of elicitation and precursor feeding (1.0 mM SA and 2.0 mM phenylalanine), respectively resulting in 1.3-fold higher daidzein and genistein production (Shinde et al. 2009). Combined elicitation of cerebroside and NO, promoted increased artemisinin production (22.4 mg/l: 2.3-fold increase) in A. annua hairy roots (Wang et al. 2009). MeJA elicitation at 100 µM combined with sucrose and l-phenylalanine feeding to root cultures of Taxus x media var. Hicksii promoted improved taxane production (Sykłowska-Baranek et al. 2015). Citronellal at 50 mg/l was found critical and promoted 3.35 mg/g DW valtrate content compared to 2.95 mg/g DW in control without precursor in V. amurensis (Cui et al. 2012). Recently, adventitious root culture system of Echinacea purpurea was exploited for enhanced production of secondary metabolites such as caffeic acid derivatives (CADs), phenols and flavonoids (Mobin et al. 2015).
A combination of plant growth regulators and elicitors (JA, SA) on production of secondary metabolites (hypericin and pseudohypericin) involving shoot cultures of H. hirsutum and H. maculatum was studied. SA was more effective in stimulating the accumulation of hypericins. JA at 250 µM promoted 1.55-fold of hypericin in H. maculatum and 3.0-fold in H. hirsutum. SA (50 µM) resulted in increased plant growth and production of hypericins (hypericin: 7.98-fold, pseudohypericin: 13.58-fold) in shoot cultures of H. hirsutum and H. maculatum (Coste et al. 2011). Multiple shoots of D. purpurea have proved to be an ideal in vitro culture system for production of cardiotonic glycosides following elicitation and other media manipulation (Patil et al. 2013). BAP at 7.5 µM was suitable for shoot biomass and addition of 50 µM SA resulted in 2.17-fold digitoxin enhancement. Increased concentration of SA (200 µM) resulted in 7.46-fold production of digoxin over control shoot cultures (g/g DW). An addition, of media additive progesterone (200 mg/l), promoted ninefold digoxin and with 300 mg/l a 12-fold increase in digitoxin was obtained. l-tryptophan at 0.5 mM enhanced 2.0-fold cichoric acid, 1.26-fold chlorogenic acid, 39.5 mg/g DW ± 1.7 phenols and 34.2 mg/g DW ± 1.4 of flavonoids, which was 56 and 24 % more than the untreated control. SA at 100 µM along with 0.6 mg/l BAP and 20 mg/l spermidine resulted in enhanced production of withanolide A (16-fold), withanolide B (13-fold), withaferin A (15-fold) and withanone (14-fold) in multiple shoot cultures of Withania somnifera (Sivanandhan et al. 2013). In addition increase in centellosides production (2.40 and 2.44-fold increase of madecassoside and asiaticoside, respectively) resulted from 0.1 mM MeJA elicitation in Centella asiatica. However, combined treatment of thidiazuron and MeJA, a 1.8-fold increase recorded compared to only MeJA treatment (Yoo et al. 2011).
Chemical elicitors other than regular signal compounds and hormones
It is evident that signal molecules and their related compounds and hormones have been used quite frequently for elicitation studies. In this section, we will enlist and discuss the exploitation of few chemical compounds as elicitors other than regular signal compounds and hormones. Plant gum driven elicitation promoted guggulsterone synthesis in cell suspension cultures of Commiphora wightii (Dass and Ramawat 2009). Gum arabic (100 mg/l) elicited 2.4-fold (198.1 µg/l) whereas mesquite gum (50 mg/l) increased twofold (163.1 µg/l) guggulsterone production, respectively when compared to control (84.2 µg/l) in cell suspension cultures of C. wightii. Treatment of elicitor pyrazinecarboxamides revealed noticeable influence on flavonolignans synthesis in Silybum marianum callus and cell suspension cultures. Application of N-(3-iodo-4-methylphenyl) pyrazine-2-carboxamide at 2.95 × 10−4 mol/l increased production of silychristin after 6-hours of elicitation, which was 2-times higher than control sample. Enhance production of silychristin was reached after 72 h with 2.53 × 10−3 mol/l N-(3-iodo-4-methylphenyl)-5-tert-butyl-pyrazine-2-carboxamide which was 12 times more than the control in callus culture of S. marianum (Tumová et al. 2010).
Higher dipyranocoumarin production (243-fold increase in inophyllum A and 284-fold inophyllum B) was obtained in stem callus derived cell suspension cultures of Calophyllum inophyllum with 1.0 mM HM chromium treatment. Further, highest enhancement up to 2230-fold inophyllum D (dipyranocoumarin) was observed with the same (1.0 mM HM chromium) treatment (Pawar and Thengane 2011). An increase in genistin (11.60 mg/g DW) and daidzein (8.31 mg/g DW) were recorded with new synthetic substance, 2-(2-fluoro-6-nitrobenzylsulfanyl) pyridine-4-carbothioamide (1 μmol/l) treatment after 48 h in cell suspension cultures of Trifolium pratense. This enhancement was at the tune of 152 and 151 %, respectively when compared with control. In addition, a maximum content of flavonoids (5.78 mg/g DW) an increase in production by 142 % was obtained when compared to untreated control with 6-hour 100 μmol/l elicitor application (Kasparova et al. 2012). In a different finding, the effect of 10 µM N,N′-dicyclohexylcarbodiimide (DCCD) on ginsenoside biosynthesis using cell suspension cultures of Panax ginseng was investigated and the maximal content of total ginsenosides increased to 3.0-fold compared to untreated control (Huang et al. 2013). Treatment of Perovskia abrotanoides adventitious root cultures with 25 µM AgNO3 enhanced tanshinone production (12.98 µg/g DW) compared to untreated control (6.79 µg/g DW) roots (Zaker et al. 2015).
Treatment of gypsum (16 mg/l) to in vitro tissues of Allium sativum enhanced alliin production in garlic leaves and plantlets (3.74 and 3.69 µg/g dry wt) compared to control cultures (2.22 and 2.18 µg/g dry wt), respectively (Nasim et al. 2010). Increase in artemisinin and dihydroartemisinic acid in A. annua shoot cultures was obtained following dimethyl sulfoxide (DMSO) treatment and is attributed to ROS generation (Mannan et al. 2010). A treatment of 0.25 and 2.0 % (v/v) DMSO resulted in 2.26-fold enhancement in artimisinin and its precursor dihydroartimisinin synthesis, respectively in A. annua multiple shoot cultures. Bacopa monnieri shoot cultures treated with 45 mg/l of CuSO4 promoted 1.42-fold increase in bacoside content (8.73 mg/g DW) compared to untreated (6.14 mg/g DW) controls (Sharma et al. 2015).
Influence of enhanced gene expression and elicitor treatment
It is quite common in elicitation studies that the elicitors promote yield increase and simultaneous enhanced gene expression for the target secondary metabolite in the background. These studies are helpful for the isolation of unknown genes and their exploitation in engineering of secondary metabolic pathways (Oksman-Caldentey and Inzé 2004). Overexpression of isolated target gene is a common strategy for securing increased yield of secondary metabolites (Thethewey 2004). However, in the recent past, it was found that a combined strategy of gene overexpression for key (rate limiting) enzyme in a secondary biosynthetic pathway and simultaneous elicitor application is exceedingly favourable for increased product yield. MeJA and 2-hydroxyethyl jasmonate (HEJ) elicitation at 200 µM evaluated singly to study gene expression profile and ginsenoside content in Panax notoginseng cell cultures (Hu and Zhong 2008). MeJA and HEJ mediated elicitation; influenced transcription of several ginsenoside biosynthetic genes e.g. squalene synthase, squalene epoxidase and cycloartenol synthase. Amongst two elicitors, HEJ at 200 µM promoted highest ginsenoside production (2.89 ± 0.15/100 mg DW) compared to 0.65 ± 0.06/100 mg DW in untreated control cultures. Elicitation of cell cultures of V. vinifera with MeJA application alongside media additive sucrose influenced pathogenesis related protein genes (phenylalanine ammonia lyase, chalcone synthase, stilbene synthase etc.) expression and anthocyanin accumulation was quite promising (Belhadj et al. 2008). Sucrose (2 %) and MeJA at 20 µM promoted 23 and 28-fold increase in piceids (trans and cis-piceids) a major resveratrol derivative after 12 h, respectively. Combination of MeJA and sucrose produced anthocyanin of about 3.9 μmol/g FW more than sevenfold increase after 120 h compared to control.
In a significant finding, elicitation of hyoscyamine 6 β-hydroxylase (h6 h) overexpressing Atropa baetica transgenic hairy roots resulted in 25-fold increase in h6 h, 125-fold putrescine methyl transferase (pmt) with ASA and MeJA, respectively (el Jaber-Vazdekis et al. 2008). JA at 50 mg/l, elicitation stimulated ORCA3 transcriptional regulator up to a maximum of 170-fold increase in ORCA3 transcripts in C. roseus hairy roots. This JA driven elicitation triggered terpenoid indole alkaloid metabolites pathway genes in C. roseus (Peebles et al. 2009). The effect of constitutive (octadecanoid-responsive Catharanthus AP2/ERF domain) and application of MeJA and SNP to C. roseus hairy roots activated overexpression of CrORCA3 and resulted the decrease in catharanthine accumulation. However, MeJA (50 mg/l) treatment not only enhanced mRNA transcripts of pathway genes but also an increase in catharanthine content was obtained (Zhou et al. 2010).
In another report the squalene synthase (BfSS1) gene showed its overall regulatory influence on triterpene saponins biosynthesis following MeJA treatment of Bupleurum falcatum roots and enhanced saikosaponin and phytosterol production (Kim et al. 2011). In a molecular study, a number of genes for key enzymes (3-hydroxy-3-methylglutaryl-CoA reductase, 1-deoxy-d-xylulose-5-phosphate synthase, farnesyl diphosphate synthase, geranylgeranyl diphosphate synthase and copalyl diphosphate synthase) in tanshinone biosynthesis pathway were characterized in S. miltiorrhiza hairy root cultures following elicitor treatment (Kai et al. 2012). Up-regulation of several genes following 100 µM MeJA treatment of hairy roots promoted highest tanshinone production (0.931 mg/g DW) on day 9 which was 5.78-fold higher compared to 0.161 mg/g DW in control. Recently, an increase in taxane production was also reported involving 100 µM MeJA and coronatine driven elicitation of Taxus x media transgenic hairy root cultures (Sykłowska-Baranek et al. 2015).
Conclusion and future perspectives
Keeping in view the enormous nature of existing literature on chemical elicitation studies for secondary metabolite production using plant cell and tissue culture systems is uncatchable. It is in actuality becomes a huge task to document the entire progress in real time sense in one token review. However, in the present exercise, attempts are made to bestow a sky eye view selected representative projection of current trend on the influence of exclusively chemical elicitors and their profound effect on secondary metabolite production using different plant cell and tissue culture systems.
Now it is an established fact that chemical elicitors are having immense multitasking ability to drive a number of cellular functions at both biochemical and genetic level (Boatwright and Pajerowska-Mukhtar 2013; Caarls et al. 2015). Elicitor receptor perception in the plasma membrane, contribution of signals from organs such as chloroplast and mitochondria and participation of 26S proteasomal degradation pathway facilitated by JA are key control points in the mechanism of elicitor action. Further, the involvement of MAPKs in cytosol by ET, NO and Ca++ dependent regulation lead to direct gene expression or via transcription factor mediation. In addition, interaction of signal compounds (NO, JA, ET and SA) generates ROS which contribute towards gene expression and production of requisite transcripts for enzymatic synthesis of enhanced secondary metabolites.
In the present context, cell suspensions are maximum used compared to other culture systems in elicitor treatment experiments. The hairy roots have proved to be a valuable culture system for elicitation studies. Amongst the chemical elicitors, JA, SA and its related compounds; are used extensively for elicitation. Overall survey reveals that concentrations of chemical elicitors do matter for enhanced production of secondary metabolites. Quite interestingly 100 µM concentration across different chemical elicitors are used for elicitation experiments using culture systems of diverse plants. In particular, 100 µM MeJA has been used in majority of findings surveyed. It is difficult to comprehend the basis for the selection of desired elicitor concentrations. However, the choice of concentrations look arbitrary based on logistic standardization experiments and influenced by previous published literature. Adequate understanding and knowledge on the mechanism of action of eliciting signal compounds may show the way to decide on the requisite concentration of elicitors for proper experimentation and promising results.
Chemical elicitors generally used singly or in combinations with other agents for better results. The combinations can be of different permutations such as between two, between three or sometimes-single elicitor or more than one elicitor combine with essential macro or micronutrients, precursors and media additives. Further, at times it is also observed that elicitors combined with physical factors such as UV light, temperature regime and pulsed electric field yielded better results for secondary metabolite production (Hao et al. 2009; Saw et al. 2012). In addition, some unique combination strategies such as over expression of a rate limiting enzyme (key gene) combined with an elicitor e.g. MeJA can bring about multifold increase in secondary metabolite production in vitro compared to the application of elicitor alone (Peebles et al. 2009). The literature survey and overall review of data indicated that a maximum of more than 2000-fold yield enhancement could be achieved through elicitation. This is a positive indication for exploitation of elicitation driven enhanced plant secondary metabolite production in vitro using different biotechnological approaches.
The initial pre-genomic research initiatives included knowhow to understand natural product biosynthesis using biochemical and genetic approaches. Simple concept of elicitation and the use of chemical elicitors in particular have changed the basic strategy of understanding genes involved in secondary metabolite synthesis. In the post- genomic era use of chemical elicitors, in particular MeJA to study plant metabolic network demonstrated for the first time for secondary metabolism in tobacco cells (Goossens et al. 2003). The basic knowledge of elicitation mechanism at biochemical, genetic and molecular level will be helpful to manipulate secondary metabolic pathways to develop quality foods and pharmaceuticals in health care for practical applications (Baenas et al. 2014). Therefore, the chemical elicitors compared to other biotic (biological elicitors) has become unique for its multitasking role in triggering array of cellular activities which ultimately help to understand biosynthesis of secondary metabolites using molecular and genetic engineering techniques for commercial exploitation.
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Acknowledgments
Authors would like to thank sponsors University Grants Commission (UGC), Department of Science and Technology (DST), New Delhi OU-DST-PURSE Project and thank OU-UGC-CPEPA Programme UGC, New Delhi for financial support. Mr. Mohd Zaheer thanks UGC and DST, New Delhi for the Research Fellowships.
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Giri, C.C., Zaheer, M. Chemical elicitors versus secondary metabolite production in vitro using plant cell, tissue and organ cultures: recent trends and a sky eye view appraisal. Plant Cell Tiss Organ Cult 126, 1–18 (2016). https://doi.org/10.1007/s11240-016-0985-6
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DOI: https://doi.org/10.1007/s11240-016-0985-6