The effect of developmental and environmental factors on secondary metabolites in medicinal plants

Journal Pre-proof The effect of developmental and environmental factors on secondary metabolites in medicinal plants Yanqun Li, Dexin Kong, Ying Fu, Michael R. Sussman, Hong Wu PII:

S0981-9428(20)30006-1

DOI:

https://doi.org/10.1016/j.plaphy.2020.01.006

Reference:

PLAPHY 5999

To appear in:

Plant Physiology and Biochemistry

Received Date: 4 June 2019 Revised Date:

12 December 2019

Accepted Date: 4 January 2020

Please cite this article as: Y. Li, D. Kong, Y. Fu, M.R. Sussman, H. Wu, The effect of developmental and environmental factors on secondary metabolites in medicinal plants, Plant Physiology et Biochemistry (2020), doi: https://doi.org/10.1016/j.plaphy.2020.01.006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Masson SAS.

Author contributions: H. Wu., conceived and designed the manuscript. Y.Q. Li., and D.X. Kong., wrote the manuscript and contributed equally. Y. Fu., edited the manuscript. M.R. Sussman., and H.Wu., performed the language editing and gave final approval of manuscript.

The Effect of Developmental and Environmental Factors on Secondary Metabolites in Medicinal Plants Yanqun Li1,2,3&, Dexin Kong1&, Ying Fu2, Michael R. Sussman4, Hong Wu1,2,3* 1

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China

Agricultural University, Guangzhou 510642, China; 2 Guangdong Key Laboratory for Innovative Development and Utilization of Forest Plant Germplasm, South China Agricultural University, Guangzhou 510642, China;

3

Guangdong Technology Research Center for Traditional Chinese Veterinary Medicine and Natural Medicine, South China Agricultural University, Guangzhou 510642, China; 4Biotechnology Center, University of Wisconsin, Madison, WI 53706, USA &

These authors contributed equally to this work. Corresponding author: E-mail address: [email protected].

Abstract Secondary metabolites (SMs) of medicinal plants are the material basis of

their clinically curative effects. They are also important indicators for evaluating the quality of medicinal materials. However, the synthesis and accumulation of SMs are very complex, which are affected by many factors including internal developmental genetic circuits (regulated gene, enzyme) and by external environment factors (light, temperature, water, salinity, etc.). Currently, lots of literatures focused on the effect of environmental factors on the synthesis and accumulation of SMs of medicinal plants, the effect of the developmental growth and genetic factors on the synthesis and accumulation of SMs still lack systematic classification and summary. Here, we have given the review base on our previous works on the morphological development of medicinal plants and their secondary metabolites, and systematically outlined the literature reports how different environmental factors affected the synthesis and accumulation of SMs. The results of our reviews can know how developmental and environmental factors qualitatively and quantitatively influence SMs of medicinal plants and how these can be integrated as tools to quality control, as well as on the improvement of clinical curative effects by altering their genomes, and/or growth conditions. 1

Key words medicinal plant, secondary metabolites, growth and development, environmental factors

Introduction Plants are living chemical factories for the biosynthesis of a huge array of the secondary metabolites (SMs) and in fact, it is these metabolites that form the basis for many commercial pharmaceutical drugs, as well as herbal remedies derived from medicinal plants. The different chemical constituents in medicinal plants possess biological activities that can improve human health via the pharmaceutical and food industries, but they also represent important value in perfume, agrochemical, cosmetic industries (Hassan, 2012). Many SMs such as alkaloids, terpenoids, and phenylpropanoids are being considered for drug development (Sanchita and Sharma, 2018). Before discussing how the plant regulates its secondary metabolites, a few brief more general comments are in order concerning new technologies that are being used and are needed, to advance the science of medicinal plants. First, the word ‘metabolome’ is now being used to describe ALL of the small molecules in a cell, and is the fourth component of a ‘systems’ approach towards biology, i.e., with genomics (DNA), transcriptomics (RNA) and proteomics being the other three. Thus, in this context secondary metabolites are a subset of the metabolome of plants, and are generally considered to be that group of small molecules separate from the many common metabolites required for life in all organisms (e.g., mitochondrial TCA cycle or glycolysis, etc). Second, mass spectrometry has emerged as the workhorse of all studies aimed at identifying and quantifying the metabolome, including secondary metabolites, and the reader is referred to recent reviews on this very powerful technology in current use (Wang et al., 2019). Finally, a key and often the most challenging aspect of research on medicinal plants is the assay used to quantitatively measure the bioactivity of the extracts. Since these extracts are incredibly complicated and most assays are not sufficiently high throughput to bio-analyze more than a few 2

dozen fractions at a time, it is clear that if more than one compound is needed to elicit an effect, our current capabilities are severely limited in terms of connecting a particular chemical structure with a particular clinical effect. For example, while recent developments in high throughput model organisms with brain like neural structures (e.g., Drosophila) may provide the best opportunity for such comprehensive analyses, there is no guarantee that the results are relevant to human effects observed from ingesting medicinal plants. This latter limitation, of a high throughput assay that can be coupled to state of the art chemical analyses, represents a particularly imposing bottleneck in research on medicinal plants that will require the creativity and hard work of future scientists to solve. Biosynthesis of SMs starts from basic pathways, such as the glycolysis or shikimic acid pathways, and subsequently diversifies, largely depending on cell type, developmental stage and environmental cues (Patra et al., 2013), these compounds are widely distributed in different plants cells, tissues and organs. However, different cells, tissues and organs of medicinal plants may possess different medicinal properties at different developmental stages (Bartwal et al., 2013). Because the developmental factors influence the initiation and subsequent differentiation of particular cellular structures involved in the biosynthesis and storage of SMs (Broun et al., 2006). In addition, the plant growth and development are usually elicited or inhibited by different environmental conditions. Therefore, the adaptation of plant morphology, anatomy, and physiological functions to the changes in biotic and abiotic may influence the accumulation of secondary metabolites (Ma et al. 2010). The SM pathways and their regulation are highly susceptible to environmental variations because the expression of genes involved in SM pathways are altered by different stresses (Borges et al., 2017; Sanchita and Sharma, 2018). The SMs exert long-term effects on plant growth and survival under stressful environments (Kurepin et al., 2017). About 100,000 SMs are present in the plant kingdom confined to specific taxonomic groups. There are three major groups of SMs in plants based on their biosynthetic

pathway

including

nitrogen-containing

compounds

(cyanogenic

glycosides, alkaloids, and glucosinolates), phenolic compounds (flavonoids and 3

phenylpropanoids), and terpenes (isoprenoids) (Fang et al., 2011). Currently, although the SMs biosynthesis and accumulation research are progressed, the reports on the developmental and environmental factors influenced on the synthesis and accumulation of SMs of medicinal plants still rarely. Here, we have given the review base on our previous works and recent progress reports on different environmental factors affected the synthesis and accumulation of SMs. and discussing how some developmental and environmental factors qualitatively and quantitatively influence SMs of medicinal plants and how these can be integrated as tools to quality control, as well as on the improvement of clinical curative effects by altering their genomes, and/or growth conditions. The stimulating of biosynthesis on SMs in medicinal plants by control and optimization of external and internal factors may be applied to develop the biotechnologies of high quality drug production.

1 Growth and development of plants influences the production of secondary metabolites According to the mainly synthesis, accumulation and distribution patterns of secondary metabolites products in medicinal plants, the medicinal parts could be classified into 4 different types: (1) roots and stems, (2) leaves, (3) flowers, (4) fruits and seeds. In addition, because the SMs are complex and diversity in different parts of medicinal plants, the different SMs may synthesize through special regulatory path way and special transport route in certain organs, tissues, and cells (Belkheir et al., 2016). Therefore, the SMs biosynthesis and accumulation are show the organ or tissue specificity. The following parts we will detailly review the recent progress of SMs biosynthesis and accumulation in different parts in medicinal plants. 1.1 Root and stem Plant roots and stems are the main organs responsible for the accumulation of active components with important medicinal value. In root and stem herbs, the accumulation of active components is mainly affected by growth periods, growth seasons and growth years. Some medicinal plants accumulate abundant of SMs mainly during their reproductive growth period. For example, the root and rhizome of 4

2-year-old Echinacea purpurea have higher yields of cichoric acid in the fruiting stage (Xu et al., 2014). During fruiting, Astragalus compactus Lam. (Fabaceae) have a higher total phenolic content than during vegetative and flowering stages of (Naghiloo et al., 2012b). The main flavonoids in the roots of Scutellaria baicalensis Georgi accumulate rapidly before the full-bloom stage (Xu et al., 2018). However, there are also some medicinal plants with higher SMs content in vegetative growth period than in reproductive growth period. For example, oleanolic acid and ecdysterone in the root of Achyranthes bidentata are both higher in the vegetative growth period than in reproductive growth period (Li and Hu, 2009). In addition to quantitative changes, variations in the quality of different components in the same plant are also obviously different. For example, the content of total flavonoids in the root of Scutellaria baicalensis Georgi is stable during the whole growth stage, but the content of baicalin increases and then gradually decreases (Hu et al., 2012). Due to the obvious difference in life cycle of different plants, a large number of SMs often occur at a certain stage of plant growth. In general, with the growth of perennial herbs, the content and yield of SMs are higher and higher. For example, saponins have the highest content in the root of three year old Panax notoginseng (Hong et al., 2005). The saponin content of 1-5 year-old Panax ginseng also increases with the increase of growth years (Shi et al., 2007). However, the opposite situation has also been reported, e.g., the content of triterpene decreases when Codonopsis pilosula is older (Zhu et al., 2014). In perennial woody medicinal plants, the SMs generally increase with ages, or stop increasing and then decrease after reaching a certain degree. For example, Geng et al. (2011) studied 5-12 year-old Cinnamomum cassia stem bark essential oils and found that the content of essential oil increased with increased years, and the oil content of C. cassia stem bark was the highest (2.61%, w/w) in 12 year old plants. In contrast, the content of trans-cinnamaldehyde in 1-12 year-old plant stem bark showed a trend of increasing first and then decreasing. Moreover, different components in the same plant also show different time courses. Chlorogenic acid, hyperin and quercetin are the highest in 13-year-old plants, rutin and quercitrin are the highest in 7-year-old plants, and magnolol is in 5

10-year-old plants of Magnolia officinalis bark (Yang et al., 2012). Much of SMs are derivatives of primary metabolites produced by plants because of diverse physiological changes (Zandalinas et al., 2017). Therefore, both species and tissue specificity determined by genetic factors are all affected the synthesis and accumulation of SMs in medicinal plants. If we want to obtain better medicinal parts and optimal harvest time in a certain organ, we need to study the organs and tissues specificity of certain medicinal components in medicinal plants, discussing the relationship between the morphogenesis and the synthesis and accumulation of these components in medicinal plants. It is appropriate to choose a longer growth period for the harvest of perennial herbs and woody medicinal plants, because plants at these growth period show more vigorous growth and metabolism, as well as increased plant height, stem diameter, root diameter and biomass all increase with the increasing growth period, concurrent with the increased content and yield of effective components. However, for medicinal plants that contain special components, the biomass and compositions should be comprehensively studied to determine the optimal harvesting period for those specific compounds. In addition, the planting and production costs in agriculture and the curative effects in the medical clinic should be primary considerations. In addition, although more chemical component biosynthesis path way have been already revealed, the SMs synthesis are very complex, which were affected by organs and tissues specificity of medicinal plants. In other words, the synthesis and accumulation patterns of different component in different organs or even in same organ were showed the differences. This phenomenon was closely related to the differences in biosynthetic metabolic pathways of different medicinal components and the expression patterns of key regulated genes in metabolic pathways (Dey et al., 1998). Currently, lots of SMs biosynthesis path ways are lacking and should be pursued in details. 1.2 Leaf Leaves are the main organs of plants for photosynthesis and play an important role in the life of plants. Leaves can also be used as a synthetic and storage organ for SMs. Leaf age (Vazquez-Leon et al., 2017), harvesting season (Gomes et al., 2019), and 6

growth stage (Li et al., 2016c), all affect the content of SMs in medicinal plant leaves. It has been reported that the biosynthesis of some monoterpenes and sesquiterpenoids (such as pinene) has begun as early as in the first cotyledon of Melaleuca alternifolia (Southwell and Russell, 2002). Synthesis and accumulation of the highest eugenol of essential oil of Cinnamomum verum are mainly in young 1-year-old leaf (Li et al., 2016c). However, the synthesis of some other compounds begin in the mature leaves. For example, compounds associated with the sabinene hydrate–terpinen-4-ol– γ-terpinene pathways seem to be formed at later stages of development (Southwell and Russell, 2002). Secretory structures, such as nectaries, resin ducts, secretory vesicles, salt glands, oil cells and secretory trichomes, are usually differentiated on the surface or inside of leaves (Fahn, 1988). Secretory structures are often one of the main sites for the synthesis and accumulation of SMs (Figueiredo et al., 2008). There are obvious differences in the secretions of different secretory structures, and the developmental state also often affects the yield and quality of medicinal materials (Verma and Shukla, 2015). Oil cells are the main sites for the synthesis and accumulation of the essential oils in leaves, and the distribution density and degree of development was significantly different with the leaf age (Li et al., 2013), thus resulting in variations in the essential oil yields. For example, the leaves of a 2-year-old branch had the highest density of oil cells (6.91 n/mm2) and the maximum percentage of oil cells at the oil saturation stage (48.05%), which coincided with the highest oil yield (2.12%). The oils were less accumulated in the 1–4 leaves of annual branch and were mostly disintegrated in the leaves of 4 year old branches, therefore the lower percentages of oil cells at oil saturation stage (6.72 and 33.71%, respectively) resulted in the lower oil yields (1.01 and 0.54%, respectively) (Li et al., 2013, 2016c). This indicates that the yield of the essential oils is directly correlated with the density of the oil cells and the degree of development of the oil cells. Indeed, developmental factors influence the initiation and subsequent differentiation of particular cellular structures involved in the biosynthesis and storage of SMs (Broun et al., 2006). Furthermore, the particular tissues as well as the developmental stages, influence the expression pattern of genes 7

related to SMs biosynthesis (Sanchita and Sharma, 2018). Understanding which genes they target will also be important to obtain further information on the pathway and on cellular mechanisms leading to the production and accumulation of metabolites in plant cells. This will also be useful in order to link aspects of plant differentiation such as the development of oil cells to the downstream metabolic events leading to metabolite accumulation. So a study of changes in the expression pattern of genes especially responsible for the regulation of secondary metabolism in medicinal plants is necessary to understand the ontogenic factors. 1.3 Flower Most of the flowers of plants have an aromatic smell mainly composed of terpenes and aromatic compounds, whose synthesis and accumulation dynamics are mainly regulated by different development stages, circadian rhythm, biological and abiotic factors (Figueiredo et al., 2008). There were apparent differences in the contents of the volatile oils among the flower buds of Magnolia zenii at different growth stages. The yields of volatile oil first increased and later decreased with the growth of flower buds. The highest oil yield was obtained from the buds in October (Hu et al., 2015). In contrast, Magnolia biondii flowers had a higher dry weight, volatile oil yield and total content of medicinal ingredients in January and February, which was the best time for harvesting high-quality raw materials (Hu et al., 2018). However, there are also great differences of the variations in different components during the growth of plants. The amounts of azulene decreased, while the content of camphor and 1,8-cineole increased, with the development of the flowers of Achillea millefolium (Figueiredo et al., 2008). The contents of elemene and ocimene rapidly increased on the 2nd day after flowering, and decreased after reaching the peak on the 6th day of Antirrhinum majus (Dudareva et al., 2003). These variations may be directly related to the developmental characteristics of flower organs, the spatio-temporal expression characteristics of volatile chemical

composition

biosynthesis regulatory genes and their encoded proteins (Lepelley et al., 2007; Gupta et al., 2011). Because of the specific expression of regulatory enzymes and related genes of SMs in plant tissues and cells, SMs in plants are usually synthesized and 8

released in specific plant tissues and organs at specific times (Belkheir et al., 2016). For example, in the flower of Antirrhinum majus, myrcene and ocimene synthase mRNA first appeared in mature flower buds, then increased continuously, reaching a peak on the 4th day of flowering. In addition, mRNA levels of myrcene and ocimene synthase genes show rhythmic expression, indicating that biosynthesis of SMs is regulated by developmental stages and by circadian rhythms (Nagegowda et al., 2008). Recently, some reports about the accumulation dynamics of chlorogenic acid and luteolin at different growth stages in Lonicera japonica Thunb. indicate that the accumulation of main components first increased and then decreased throughout the growth of L. japonica. Further analysis reveals that the accumulation dynamics of chlorogenic acid during flower organ development of L. japonica are directly controlled by the spatio-temporal expression characteristics of a key regulatory gene (HQT) and enzymatic protein encoded by HQT (Li et al., 2019). The content of luteolin is closely related to the expression characteristics of its regulatory enzyme CHI during flower organ development (Kong et al., 2017a). In addition, the accumulation of CGA and luteoloside at different growth stages in L.japonica correlated with variations in the initial activities of several other regulatory enzymes in the phenylalanine metabolic pathway, including phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H) and 4-coumarate CoA ligase (4CL) (Kong et al., 2017b). Regulation of secondary metabolism can be achieved at different levels, starting with the transport and metabolism of extracellular nutrients, through precursor formation and accumulation. This may occur via the onset of transcription and post-transcriptional processes as well as translational and posttranslational 9

controls, and of course, targeting the enzymes involved in their biosynthesis (Rokem et al., 2007). This leads to the fact that sometimes the expression characteristics of genes can only affect the synthesis and accumulation of metabolites through direct changes in the activity of the enzyme protein encoded by the genes (Navarre et al., 2013). Thus, synthesis-related SM enzymes are not only regulated at the transcription level, but also regulated by post-transcriptional and post-translational control mechanisms (Patra et al., 2013). Post-translational control mechanisms have been implicated in terpenoid indole alkaloid, anthocyanin, nicotine and camalexin biosynthesis in plants (Patra et al., 2013). The miRNAs (microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression) have also been demonstrated to play an active role in SM regulation (Singh and Sharma, 2017). In addition, the two major post-transcriptional regulators Hfq and RsmA in the Gram‐negative bacterium, Serratia 39006 were found to play a major role in regulating prodigiosin production, and RsmA was investigated by performing RNA-seq on an rsmA mutant (Wilf et al., 2011). Tobias et al. (2016) demonstrated that the lack of Hfq impaired production of many of the SM in vitro, thus revealing a global regulation of SM synthesis at the post-transcriptional level.

Moreover,

Valverde

(2017)

revealed

that

interplay

between

the

post-transcriptional (Hfq-dependent) and transcriptional (HexA-dependent) control of SM production in Photorhabdus luminiscens. These works opens a new avenue of future work in the field of natural bioactive products, provided that derivative mutants affected in control of SM production, may be a source of novel SM or of higher levels 10

for their production in vitro. 1.4 Fruits and seed The fruits and seeds are important medicinal materials of many plants, whose developmental stages also have a significant influence on the content and composition of components. Liang et al. (2006) reported that volatile oils, which are the main active ingredient in Citrus fruits, are affected by the developing secretory cavity of fruit. Usually, when the fruit is light yellow, the volatile oil content is the highest, which can be used as a morphological index for harvesting. Wu et al. (2013) found that essential oils yields showed significantly increase during maturation process, and the content of α-thujone, carene, β-pinene and γ-terpinene in Citrus medica L. var. sarcodactylis, varied significantly during maturation stages. Similarly, the contents of morphine, codeine and thebaine were highest in capsules. Maximum morphine content in capsule is reached at maturity of Papaver somniferum L roots (Shukla and Singh, 2001). Thus again, the content and composition of SMs are affected by the developmental stages of plant (Verma and Shukla, 2015). Similarly, the synthesis and accumulation of SMs were closely associated with the developmental stage of the medicinal plant seeds. The content of coffee quinic acids is relatively stable in coffee, but the content of dicoffee quinic acids obviously decreases with the developmental stage of the seeds. The content of quinic acid (precursor substance of chlorogenic acid synthesis) is high at the early developmental stage of seeds, and obviously decreases at the later stage. These variations are related to the expression characteristics of HQT gene, a key enzyme regulating phenolic acid biosynthesis (Lepelley et al., 2007). Table 1. Developmental stages change on the content of various plant SMs. Metabolite

Metabolite Name

Class Phenols

Concentration

Developmental stages

Plant Species

Parts

Refences

Change Cichoric acid

Higher

Fruiting stage

Echinacea purpurea

Root

Xu et al., 2014

Total phenolic

Higher

Fruiting stage

Astragalus compactus

Root

Naghiloo et al., 2012b

Chlorogenic acid,

Highest

13-year-old

Magnolia officinalis

Bark

Yang et al., 2012

Magnolol

Highest

10-year-old

Magnolia officinalis

Bark

Yang et al., 2012

Eugenol

Highest

1-year-old

Cinnamomum verum

Leaf

Li et al., 2016c

Chlorogenic acid

Increasing first and

Whole growth stage

Lonicera japonica

Flower

Kong et al., 2017a; Li

11

then decreasing

et al., 2019

Coffee quinic acids

Stable

Whole growth stage

coffee

Seed

Lepelley et al., 2007

Dicoffee quinic acids

Decrease

with the developmental

coffee

Seed

Lepelley et al., 2007

coffee

Seed

Lepelley et al., 2007

Scutellaria baicalensis

Root

Xu et al., 2018

stage Quinic acid

High

Early

developmental

stage Flavonoids

Flavonoids

Strong increase

Total flavonoids

Stable

Whole growth stage

Scutellaria baicalensis

Root

Hu et al., 2012

Baicalin

Increases and then

Whole growth stage

Scutellaria baicalensis

Root

Hu et al., 2012

compounds

Before the full-bloom stage

gradually decreases Hyperin and quercetin

Highest

13-year-old

Magnolia officinalis

Bark

Yang et al., 2012

Rutin, Quercitrin

Highest

7-year-old

Magnolia officinalis

Bark

Yang et al., 2012

Luteolin

Increasing first and

Whole growth stage

Lonicera japonica

Flower

Kong et al., 2017a; Li

then decreasing

et al., 2019

Terpenoids

Triterpene

Low

Older tree

Codonopsis pilosula

Root

Zhu et al., 2014

/Essential

Essential oils

Increase

Increased years

Cinnamomum cassia

Stem

Geng et al., 2011

Oils

bark Essential oils

Highest

2-year-old branch

Cinnamomum cassia;

Leaf

Li et al., 2013

Flower

Hu et al., 2015

Cinnamomum verum Essential oils

Highest

October

Magnolia zenii

bud Camphor, 1,8-cineole

Increase

With the development of

Achillea millefolium

Flower

Figueiredo et al., 2008

Antirrhinum majus

Flower

Nagegowda

the flowers Myrcene, Ocimene

Highest

4th day of flowering

et

al.,

2008

Others

Essential oils

Highest

Fruit is light yellow

Citrus

Fruit

Liang et al., 2006

Essential oils

Significant increase

Maturation process

Citrus medica

Fruit

Wu et al., 2013

Trans-cinnamaldehyde

Increasing first and

1-12 year-old

Cinnamomum cassia

Stem

Geng et al., 2011

then decreasing Saponins

Oleanolic

acid,

Highest

3 year old

Panax notoginseng

Root

Hong et al., 2005

Increase

1-5 year old

Panax ginseng

Root

Shi et al., 2007

High

Vegetative

Achyranthes bidentata

Root

Li and Hu, 2009

Achillea millefolium

Flower

Figueiredo et al., 2008

Ecdysterone Azulene

bark

growth

period Decrease

With the development of the flowers

2 Environmental factors influence the production of secondary metabolites The synthesis and proper accumulation of SMs are strictly controlled in a spatial and temporal manner and influenced by the changing abiotic and biotic environment. In general, abiotic stress is responsible for the decrease of production and yield of 12

medicinal plants. During growth and development, plants interact with the surrounding environment, where they come in contact with different abiotic components like water, light, temperature, soil and chemicals. Negative abiotic factors, such as drought or flooding, extremes of light and temperature and the presence of poor soil or toxic chemicals generate secondary stresses, and these trigger variation in the biosynthesis of SMs (Verma and Shukla, 2015). Thus, environmental factors are crucial determinants for the biosynthesis and fluctuations in plant SMs (Verma and Shukla, 2015). 2.1 Light and ultraviolet radiation 2.1.1 Light Irradiance with photons of different wavelengths and intensity is an essential abiotic component required by the plants for photosynthesis, growth, and secondary metabolic product accumulation (Zhang et al., 2015; Li et al., 2018). Excessive irradiance may inactivate or impair the photosynthetic reaction centres of the chloroplasts and cause photoinhibition and may reduce plant growth (Szymańska et al., 2017). However, lack of sunlight may reduce the absorption of light energy and inhibit plant growth and yield by affecting net photosynthetic rate (Gregoriou et al., 2007). There were the conspicuous effects of photoperiod and light intensity on the biosynthesis and storage of SMs for different chemical components (Verma and Shukla, 2015; Zhang et al., 2015; Kong et al, 2016; Li et al, 2018). Plants require an appropriate intensity of light for photosynthesis, and this affects the quality and accumulation of total alkaloids yields, hexadecanoic acid, total flavonoids, phenolic acids and spermine (Lavola et al., 2000; Kong et al., 2016; Li et al., 2018). In some cases, the higher irradiance is helpful for plant growth and SMs production (Zhang et al., 2015). For instance, the amount of scutellarin (flavone glycoside) was higher in sun-developed leaves than in shade-developed leaves of Erigeron breviscapus (Zhou et al., 2016). Similarly, the yield of essential oil is also increased in response to high light intensities (Figueiredo et al., 2008; Kong et al., 2016; Li et al., 2018). Occasionally, the opposite situation is reported. For example, concentrations of camphene, sabinene, b-pinene, borneol, bornyl acetate, and Z-jasmone were higher 13

for plants grown under partial shade than fully irradiated control plants of Flourensia cernua (Estell et al. 2016). Thus, the light intensity and photoperiod have different effects on the accumulation of plant SMs in different plants. These studies indicated that improving the yield and medicinal properties of plants might be achieved by appropriate adjustments of light quality and quantity. Different plant species have their own optimal light sets (quality and quantity), which manage to elicit maximal yield of SMs (Zhou et al., 2016). 2.1.2 Ultraviolet Radiation The effect of ultraviolet (UV) light exposure on SMs is common in medicinal plants. For example, the concentrations of flavonoids and phenolic acids increased in response to increased UV-B radiation of Chrysanthemum (Ma et al., 2016). Reifenrath and Müller (2007) reported that compared to old leaves, young leaves were efficiently protected from UV light due to high flavonoid and glucosinolate amounts in Sinapis alba, or enhanced flavonoid levels and myrosinase activities in Nasturtium officinale. An increase of total phenolic content could be due to an increase in the amount of UV radiation associated with an increase in solar radiation received by the plants (Naghiloo et al., 2012b). Spitaler et al. (2006) demonstrated that the induction of phenolics is a major factor in the reactive oxygen species (ROS) scavenging system in genetically homogenous populations grown along an altitudinal gradient, and most probably is linked with augmented UV-B light. Takshak and Agrawal (2014) reported a similar study that the UV solar radiation induces the production of ROS, and instigates protective effects that promote the biosynthesis of UV-B absorbing alkaloids, anthocyanins, carotenoids, flavonoids, lignin, phytosterols, saponins, and tannins. However, plant SMs have not been fully studied with respect to their relevant functions in plants under environmental stress. How plant SMs enable plants to avoid oxidative damage is an area of research that must be studied in detail. The expression and transcriptional level of SM-regulated genes in plants are affected by UV. For instance, Eichholz et al. (2012) reported that the concentration of flavonol quercetin-4′-O-monoglucoside increased with UV-B dose, which was accompanied with a rise in activity of polyphenol-related enzymes (phenylalanine ammonialyase 14

and peroxidase) in Asparagus officinalis L. cv. Gijnlim. Moreover, higher artemisinin accumulation under low dose UV-B exposure (3-4 h, 2.8 Wm-2) was shown to be a result of significant up-regulation of HMGR, DXR, IPPi, FPS, ADS, CYP71AV1 and RED1 gene transcripts (Pan et al., 2014), and the transcription levels of amorpha-4,11-diene synthase (ADS) and cytochrome P450 monooxygenase (CYP71AV1) genes were upregulated when compared with control plants under UV light in Artemisia annua (Yin et al., 2008). In most case, the effect of UV light exposure on SMs biosynthesis is positive, however, high doses of UV-B and UV-C radiation negatively affect growth, development, photosynthesis, and other important processes in plants (Katerova et al., 2017). SMs accumulation is highly important from pharmacological point of view and researchers face the necessity to study them including qualities of light exposure are essential in order to obtain higher yield of these valuable compounds. The effect of light on the content of SMs in plants is displayed in Table 2. Table 2. Light quality change on the content of various plant SMs. Metabolite Class Phenols

Alkaloids

Metabolite Name Anthocyanins, tannins Phenolic acids

lignin,

Concentrati on Change

Plant Species

Parts

Refences

UV-B

Increase

Root and leaf

UV-B

Increase Increase

Takshak and Agrawal, 2014 Ma et al., 2016 Naghiloo et al., 2012b

Increase

Withania somnifera Chrysanthemum Astragalus compactus Arnica montana

No effect

Tarbush

Spitaler et al., 2006

Chrysanthemum Nasturtium officinale Erigeron breviscapus Asparagus officinalis

Flower Leaf Leaf

Ma et al., 2016 Reifenrath and Müller, 2007 Zhou et al., 2016

Whole plant

Eichholz et al., 2012

Root and leaf Whole plant,

Takshak and Agrawal, 2014 Kong et al., 2016

Root, stem

Li et al., 2018

Leaf

Estell et al., 2016

Leaf

Li et al., 2018

Root and leaf

Takshak and Agrawal, 2014 Takshak and Agrawal, 2014

Full sunlight

Increase

Flavonol quercetin-4′-O-monogluc oside Alkaloids

UV-B

Increase

UV-B

Increase

30 and 50% Full sunlight

Increase

Withania somnifera Mahonia bodinieri

Sabinene, b-pinene, Borneol, Bornyl acetate, Z-jasmone Essential oil

50% shade

Increase

Mahonia breviracema Flourensia cernua

Full sunlight

Increase

Saponins,

UV-B

Increase

Phytosterols

UV-B

Increase

15

Flower Leaf Flowering heads Leaf

Scutellarin

Alkaloids

Others

Environment Factor

Mahonia breviracema Withania somnifera Withania somnifera

Root and leaf

Estell et al., 2016

Hexadecanoic acid Glucosinolate

50% Full sunlight UV

Increase

Mahonia bodinieri

Leaf

Li et al., 2018

Increase

Nasturtium officinale

Leaf

Reifenrath and Müller, 2007

2.2 Temperature stress Plant growth and development are directly linked with temperature ranges at which the plants are present. Low and high temperature ranges may have a negative impact on plant growth and productivity (Yadav, 2010). Plants growing at elevated temperatures exhibit a decline in the photochemical efficiency of photosystem II, indicating increased stress (Maxwell and Johnson, 2000). The biosynthesis of SMs is also correlated with high temperature in plants (Verma and Shukla, 2015). High-temperature stress usually increased the production of SMs (Naghiloo et al., 2012a), whereas some studies reported that SMs were decreased in plants under high-temperature stress (Shibata et al., 1988). Thus, the SMs increase or decrease in response to elevated temperatures and this is dependent on the species and multiple factors. High temperature downregulates or upregulates the responding genes and affects the growth and development of plants (Li et al., 2016b). In such conditions of heat stress, modification of physiological and biochemical processes by gene expression changes slowly leads to the development of heat tolerance in the form of acclimation or adaptation of a plant to high temperature (Hasanuzzaman et al., 2017). Plant growth and the biosynthesis and the storage of SMs are also significantly hampered as a result of low-temperature stress (Verma and Shukla, 2015). Plants grown under low temperature exhibit significant alterations in various physiochemical and molecular processes (cellular dehydration, water uptake, and metabolic reactions) that enable plants to survive low temperature stress, a phenomenon known as cold acclimation (Ashraf et al., 2018). On the basis of global gene regulation of unsaturated fatty acid biosynthesis and jasmonic acid biosynthesis-related genes, unsaturated fatty acid biosynthesis and jasmonic acid biosynthesis pathways were deduced to be involved in the low temperature responses in C. japonica (Li et al., 2016a). In response to temperature stresses, plants have shown a coordinated change at the transcriptional level. Thus transcriptional regulation plays an essential role in 16

the adaptation of cells against environmental challenges. In Artemisia annua, upon exposure to chilling and heat shock, the transcription levels of amorpha-4,11-diene synthase (ADS) and cytochrome P450 monooxygenase (CYP71AV1) genes were upregulated when compared with control plants (Yin et al., 2008). These are mostly the genes responsible for the expression of osmoprotectants, detoxifying enzymes, transporter, and regulatory proteins. These studies indicated that the concentration of SMs of different plants is associated with the metabolic pathway of the particular SMs and temperature conditions, and a plant’s ability to function in a stressful environment depends to a large extent on their genetic program (Dodd et al., 2006). The precise mechanisms, however, need to be further demonstrated and need to explore the functions of various plant SMs in plants grown under stressful conditions. Temperature factors that influence production of plant SMs should be studied. Unraveling the involvement of the SMs in stress signaling can help in enhancing the selective metabolites for their exploitation in stress tolerance. Strategies must be developed to improve the potential of plants for SM production. The effect of temperature on the content of plant SMs is shown in Table 3. Table 3 Temperature change on the content of various plant SMs. Metabolite Class Sesquiterpene lactone Phenols

Fatty acid

Metabolite Name

Environment Factor

Concentration Change Increase

Artemisinin Phenolics

A transient pre-chilling treatment High-temperature

Increase

Anthocyanins

High temperature

Decrease

α-linolenic acid, Jasmonic acid

Low temperature

Increase

Plant Species

Parts

Refences

Artemisia annua Astragalus compactus Chrysanthemum

Whole plant

Yin et al., 2008

Roots, leaf and flowers Whole plant

Naghiloo et al., 2012a Shibata et al., 1988 Li et al., 2016a

Camellia japonica

Leaf

2.3 Drought stress Drought stress decreases water absorption and water potentials in plants, which thereby negatively influence various physiological processes and can alter SM biosynthesis (Ashrafia et al., 2018). There are many reports relating to the effect of drought stress on SMs of medicinal plants. For example, the content of flavonoids and phenolics is elevated under severe drought stress condition in plants (De Abreu and 17

Mazzafera, 2005; Azhar et al., 2011). The elevation of phenolic and flavonoid compounds is highly related to the balance between carbohydrate sources and sinks. It was reported that the accumulation of soluble carbohydrates in plant cells is affected by the reduced transport of soluble sugars under water stress (Jaafar et al., 2012). When stresses act upon plants, changes in gene expression also take place (Kilian et al., 2007). In low to moderate drought stress condition, the expression of many genes contributing in the synthesis pathway of phenolic compounds such as phenylalanine ammonialyase (PAL) are elevated and this requires high energy inputs, while in moderating to severe stress condition these energy-intensive processes are more limited (Król et al., 2014). Also, an appropriate degree of drought stress may promote baicalin accumulation by stimulating the expression and activities of the key enzymes (PAL), (C4H), (4CL) and (CHS) involved in baicalin biosynthesis of Scutellaria baicalensis Georgi (Cheng et al., 2018). In another study, imposition of drought stress resulted in improved quality of key SMs such as rutin, quercetin, and betulinic acid in Hypericum brasiliense, and that of artemisinin in Artemisia (Verma and Shukla, 2015). The sterol C-4 methyl oxidase gene (SMO1) gene, which has been identified in Artemisia annua, is responsible for the enhanced production of sterols and tolerance against dehydration/drought stress (Singh et al., 2002). Drought promoted the synthesis of glycyrrhizin, as indicated by the increases in the expression of the glycyrrhizin biosynthesis pathway genes SQS1, SQS2, bAS, CYP88D6, CYP72A154 and UGT73, and increased the root concentrations of glycyrrhizin with drought in some genotypes of licorice (Glycyrrhiza glabra L.) (Hosseini et al., 2018). These studies indicated that drought responsive metabolites are produced/consumed by different pathways/cycles; new technological approaches such as transcriptomics and proteomics could help us to identify and manipulate of drought-responsive pathways/cycles involved in establishment of enhanced drought tolerance (Ashrafia et al., 2018). More research is needed to completely understand the regulatory proteins and genes involved in the biosynthesis of plant SMs so that these may be manipulated for improving plant tolerance to drought stresses. Moreover, the concentrations of SMs are significantly increased under drought stress conditions in the present 18

literature. It may be a reduced production of biomass in the stressed plants and the rate of biosynthesis of SMs is not changed, resulting in their concentration on dry or fresh weight basis simply will be elevated. So much more data on the biomass is required and thus the yields of SMs per plant are available. The effect of drought on the content of SMs in plants is displayed in Table 4. Table 4 Drought stress increases the concentration of various plant SMs Metabolite Class Phenols

Pentacyclic triterpenoid Sesquiterpene lactone

Metabolite Name

Plant Species

Parts

Refences

Total phenolics

Baicalin Rutin, Quercetin, Anthocyanins Betulinic acid

Hypericum brasiliense Trachyspermum ammi Labisia pumila Scutellaria baicalensis Hypericum brasiliense Labisia pumila Hypericum brasiliense

Shoots and roots Leaf Leaf Whole plant

De Abreu and Mazzafera, 2005 Azhar et al., 2011 Jaafar et al., 2012 Cheng et al., 2018 Verma and Shukla, 2015 Jaafar et al., 2012 Verma and Shukla, 2015

Artemisinin

Artemisia

Whole plant

Leaf

Verma and Shukla, 2015

2.4 Salinity Stress Soils with elevated levels of salt induce nutritional imbalances, hyper-osmotic stress and exhibit declines in photosynthesis, growth, and uptake of nutrients in plants (Banerjee and Roychoudhury, 2017). Plant SMs may undergo an increase or decrease in their concentration in response to salinity-induced osmotic stress or specific ion toxicity (Akula and Ravishankar, 2011). Plants growing under salinity stress increase alkaloid and tannin concentration (Abd EL-Azim and Ahmed, 2009), phenolics (Verma and Shukla, 2015), saponins, flavonoids and proline in Plantago ovata (Haghighi et al., 2012). A decrease in oil yields during salt stress was reported in recent researches (Ali et al., 2008). Moreover, many articles reported that the levels of the main compounds in essential oils of plants were differentially affected by salt stress (Neffati and Marzouk, 2008; Baatour et al., 2010). Salt stress tolerance in plants is induced by multilevel changes in molecular responses accompanied with alterations in the plant transcriptome, metabolome and proteome (Banerjee and Roychoudhury, 2018). These transcription factors include various families, like AP2, ERF, bZIP, NAC, MYB and WRKY which exhibit higher correlations with salinity (Kumar et al., 2017). Plant salt tolerance is controlled by a complex network involving plant organ, tissue, 19

physiology and molecule, and the changes of stress-induced metabolites are also too complex. The biosynthesis of SMs are undoubtedly influenced by different regulatory genes, enzymes, transcription factors and stresses caused by salinity leads to unstability of accumulation or production of different SMs. The level of these SMs changes according to their need by the plants as defense molecules to survive them in unfavorable conditions. Moreover, the key factor, receptor and mechanism of salinity stress should be pursued in more details. Much more related research is required to elucidate the molecular coherences of this fascinating issue. Although transformation of salt-tolerant gene have been done of some plants, the improvement of salt tolerance of transgenic plants is not very ideal and limited. On the transgenic frontline, it should focus upon developing salt-tolerance in susceptible plant species and facilitate the introgression of salt-tolerant genes in susceptible species of medicinal plants. The effect of salinity on the content of plant SM is shown in Table 5. Table 5 Soil salinity change on the content of various plant SMs. Metabolite Class Phenolics

Metabolite Name Tannin

Concentrati on Change Increase

Environment Factor Salinity

Alkaloids

Recinine alkaloids Alkaloid

Increase Increase

NaCl Salinity

Flavonoids compounds Monoterpene s /Essential Oils

Flavonoids

Increase

NaCl

Oil contents

Increase

Oil contents

Decrease

NaCl 25 and 50 mM NaCl High salinity

Others

Octanal; Borneol; (E)-2-Nonenal α-Pinene; (Z)-Myroxide Trans-sabinene Hydrate; γ-Terpinene cis-Sabinene Hydrate; Linalyl acetate; Terpinene-4-ol Saponins, Proline

Plant Species

Parts

Refences

Achillea fragratissima

Abd EL-Azim and Ahmed, 2009 Ali et al., 2008 Abd EL-Azim and Ahmed, 2009 Haghighi et al., 2012

Ricinus communis Coriandrum sativum

Whole plant Shoot Whole plant Root and shoot Shoot Leaf

Coriandrum sativum

Leaf

100 Mm NaCl

Origanum majorana

Shoots

Increase

Salinity

Coriandrum sativum

Leaf

Decrease

Salinity

Coriandrum sativum

Leaf

Decrease

NaCl

Origanum majorana

Aerial part

Increase

NaCl

Origanum majorana

Aerial part

Baatour et al., 2010

Increase

NaCl

Plantago ovata

Root and shoot

Haghighi et al., 2012

Ricinus communis Achillea fragratissima Plantago ovata

2.5 Other factors.

20

Ali et al., 2008 Neffati and Marzouk, 2008 Neffati and Marzouk, 2008 Baatour et al., 2010 Neffati and Marzouk, 2008 Neffati and Marzouk, 2008 Baatour et al., 2010

The synthesis and accumulation of SMs are also obviously influenced by other environmental stresses such as soil type and composition, wounding, metal ions, circadian rhythm, geography (Verma and Shukla, 2015). In recent years, there have been many reports on the effect of chemical stress (Verma and Shukla, 2015), nutrients (Dar et al., 2016), metal ions (Ma et al., 2018) and geographical origins (Li et al., 2013) on SMs. In most cases, several environmental stresses jointly cause drastic changes in the growth, physiology, and metabolism of plants leading to the increased accumulation of SMs (Debnath et al., 2011). The response of plants to multiple abiotic stresses is unique and cannot be directly speculated from simply studying one stress applied individually. Plants with different genotypes might behave differentially under drought stress. Moreover, the differences in plant SM content are often difficult to interpret as many abiotic conditions usually interfere with complex internal factors. These studies may have a significant role in developing plants that are tolerant to multiple stresses. Hence, the optimum environmental conditions for plant growth are very complex. There is a need for the development of broad-spectrum resistance (i.e., resistance to multiple stresses) in medicinal plants. Additionally, recent studies showed that the soil microbial community plays an important role in promoting plant growth and health. Studying the relationship between the composition of the soil microbial community and the synthesis and accumulation of active constituents of medicinal plants is expected to provide scientific guidance for the cultivation and management of medicinal plants with the highest active ingredient content. SMs accumulation in plants in the course of plant-soil microbial interaction definitely impels the development of attractive strategies to bring medicinal plants cultivation into new era for pharmaceutical purpose.

3 Conclusions and future prospects The content and composition of effective components, i.e., the SMs in medicinal plants are vary with changes in the growth seasons, growth years and environment. The SM content increases or decreases under developmental process or stress 21

conditions in medicinal plants with the same genetic background, because the gene expression or their encoded protein activity involved in secondary metabolic pathways are modified at different growth stages or in the presence of different stresses. Therefore, to achieve a more precise understanding of the temporal and spatial patterns of synthesis and accumulation of active ingredients in specific organs, tissues and cells in plants, new technologies used to study genomics, transcriptomics and metabolomics will need to be applied. These can be used to reveal the molecular regulatory mechanisms of synthesis and metabolism of active constituents of medicinal plants at different growth stages and stress conditions. Specifically, these may reveal changes in metabolic pathways of the main active constituents of medicinal plants, which can provide important theoretical foundations and technical support for the improvement of medicinal plant varieties, protection of germplasm resources, selection of suitable planting regions and synthesis of secondary metabolites.

Contributions H. Wu., conceived and designed the manuscript. Y.Q. Li., and D.X. Kong., wrote the manuscript and contributed equally. Y. Fu., edited the manuscript. M.R. Sussman., and H.Wu., performed the language editing and gave final approval of manuscript.

Acknowledgements This study was supported by the Science and Technology Innovation Fund Project on Forestry of Guangdong Province (2017KJ-CX006), the Nature Science Foundation of China (31870172), Technology and Development Project of Finance Department of Guangdong Province, China ([2015]639).

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Highlights: The secondary metabolites (SMs) of plant can be especially affected by developmental and environmental factors The review reveal the dynamic accumulation of SMs in medicinal plants Developmental and environmental factors has influence on the expression of SMs biosynthesis genes The review suggest regulation at post-transcriptional/translational levels on SMs.

Conflict of interest The authors declare that they have no competing interests.