Secondary Metabolites Based-Plant Origin: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Hazem Salaheldin Elshafie.

Natural products are compounds produced by living organisms and can be divided into two main categories: primary (PMs) and secondary metabolites (SMs). Plant PMs are crucial for plant growth and reproduction since they are directly involved in living cell processes, whereas plant SMs are organic substances directly involved in plant defense and resistance. SMs are divided into three main groups: terpenoids, phenolics and nitrogen-containing compounds. The SMs contain a variety of biological capabilities that can be used as flavoring agents, food additives, plant-disease control, strengthen plant defenses against herbivores and, additionally, it can help plant cells to be better adapted to the physiological stress response. 

  • natural products
  • metabolism
  • metabolomics
  • biological activity

1. Natural Products

For thousands of years, nature has provided medicinal agents, and an astounding number of modern medications have been developed from natural sources, many of which are used in traditional medicine [17][1]. Natural products commonly refer to herbal concoctions, dietary supplements, and traditional and alternative medicines [18][2]. Plants have been utilized for medicinal purposes since the ancient Sumerian population. Hippocrates used about 400 distinct plant species for medicinal purposes [18][2]. Particularly, NPs have been used since ancient times and civilizations, including Chinese, Ayurveda and Egyptian, for the treatment of many diseases and illnesses [3]. The vast majority of traditional institutions during the Middle Ages in Europe, such as the classical Greek, Roman and Arabic regions, had their own herbal gardens for healing patients and teaching purposes about herbal plants. About 75 percent of people worldwide still rely on plant-based traditional medicines for primary health care [19][4].
During the last century, the term ’secondary metabolites’ was first suggested by Albrecht Kossel in 1910 and then by a Polish botanist Friedrich Czapek, 30 years later, who described SMs as the end products of nitrogen metabolism [20,21][5][6]. The most historically famous NP is penicillin which is derived from the fungus Penicillium notatum and was discovered by Fleming in 1929 [22,23][7][8]. The interesting medicinal uses of plant NPs have been well-documented for thousands of years. Among the most important plant NPs are SMs which have been used as an important source of medicines for early drug discovery [24,25][9][10]. The development of significant sophisticated analytical techniques, such as chromatography, in the middle of the 20th century made it possible to learn more about SMs and their chemical structures. Paper chromatography, in particular, made it clear that some of these compounds were colored pigments. Molecular biology and the significant advancement of biochemical tools in recent years have shown that plant SMs are crucial for plants to their environment adaptation [21][6].
For the comprehension of their distribution and abundance, plant SMs were considered not only as plant waste products but as specialized single substances with specific characteristics that originated from different chemical functional groups, and they can be useful in the pharmaceutical industry for discovering new bio-drugs for different purposes. Attempts to create models of allocation to SMs were immediately met with two difficulties: (i) comprehending the development and upkeep of the astonishing diversity of chemicals produced in the plant world; (ii) identifying the patterns underlying the variance in quantities that may be seen in both inside and between plants of the same and different species.

2. Uses of Plant Natural Products

The plant NPs and their semisynthetic derivatives are the richest sources of biologically active compounds [26][11]. Primary metabolites (PMs) such as carbohydrates, amino acids, fatty acids and organic acids are involved in growth and development, respiration and photosynthesis, and hormone and protein synthesis [4,12][12][13]. Plant secondary metabolites (SMs) such as terpenoids, phenolics and nitrogen-containing compounds (alkaloids) determine the color of vegetables, protect plants against herbivores and microorganisms and act as signal molecules under stress conditions [7,16][14][15]. However, most alkaloids are usually colorless crystals and do not have an effect on the color of vegetables, and some alkaloids are colored, such as berberine (yellow) and sanguinarine (orange) [7,16][14][15]. Plant SMs have several benefits of being utilized in different fields such as nutritional, cosmetic, medical, pharmaceutical and agricultural.

2.1. Nutritional Uses and Food Industry

Recently, there has been a great interest in the benefits of a wide variety of fruits and vegetables, which provide different bioactive SMs, including phytochemicals, vitamins, essential amino acids, minerals and fibers. However, the stability of those substances can be adversely influenced by various ecological and physical factors such as light, temperature and relative humidity [31][16]. On the other hand, the essential fatty acids extracted from several fruits and seeds oils have functional properties for reducing disease risk.
Some essential amino acids (EAA), such as histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine, are very important for diet and for several bodily processes, such as protein synthesis, tissue repair and nutrient absorption [32][17]. Some EAAs can enhance post-operative recovery; improve mood, sleep and athletic performance; and prevent muscle loss [32][17]. The majority of people may achieve their daily demands by eating a healthy, balanced diet containing EAA. In addition, the use of a diet rich in fiber has been recommended as a nutritional supplement against hypertension, obesity and diabetes [31][16].
Among the main functions of plant metabolites, they can influence the physical food characteristics such as color, taste, consistency and smell [33][18]. In addition, they have several health benefits; for example, they are characterized by antioxidant, anti-carcinogenic, anti-inflammatory and antimicrobial properties. Many plant metabolites are also able to lower the cholesterol level of humans and improve poor nutrition [34][19]. For example, the β-carotene (provitamin A) content in golden rice is significantly improved, which is helpful in fighting against vitamin A deficiency [34][19]. Many other phytochemicals are also regarded as nutrients that benefit human health. These include glucosinolates, flavonoids, phytosterols, phenolic acids, carotenoids and polyunsaturated fatty acids, which are efficient at reducing the chance of developing clinical disease [35,36][20][21].

2.2. Cosmetic Uses

The use of some plant SMs in cosmetic preparations is principally due to their low mammalian toxicity [37][22]. They are used for skin care, such as dryness, eczema, acne, free-radical scavenging and other skin protection effects. In addition, they are also used as hair growth stimulants and hair colorants. Among the most important plant SMs the essential oils (EOs), which can be incorporated into some cosmetic products giving a pleasant aroma, shine and other conditioning properties [38][23]. For example, menthol is often used as a flavoring agent in toothpaste and mouthwashes, which combines antibacterial efficacy and protects the mouth, and the addition of menthol gives a great-tasting freshness and prevents the buildup of plaque that can lead to gingivitis and bad breath [39][24]. Traditional remedies based-natural products have been used for centuries for treating skin and a wide variety of dermatological disorders [40][25]. In several plant EOs, the hydrophobic liquid mixtures of volatile compounds, such as castor, coconut, sunflower and olive oils, have been used for cosmetic purposes such as dry skin, eczema, acne and spot treatments [41][26]. Plant EOs are also known as volatile oils, ethereal oils, aetheroleum or simply as plant oil from which they were extracted.

2.3. Medical/Pharmaceutical Uses

Plant SMs and their derivatives have been employed as therapeutic agents for the treatment of numerous diseases and illnesses since ancient times [42][27]. Many natural compounds based-plant origin have been utilized as the main raw materials for several drugs. Plant SMs have also been used as drug precursors, prototypes and pharmacological probes [42,43][27][28]. In particular, a reasonable percentage of drugs worldwide are based on plant origin, and several bioactive compounds are currently used in the pharmaceutical industry [44][29].
Some specific examples of plant SMs have been used as drug precursors, such as morphine, the first NPs isolated from the opium poppy (Papaver somniferum) in 1806 and used as drug precursors for several medicines [45][30]. Artemisinin isolated from Artemisia annua has been used as an antimalarial drug containing sesquiterpene lactone, which treats malignant cerebral malaria caused by Plasmodium falciparum [46][31]. Paclitaxel, isolated from Taxus brevifolia, a highly oxygenated tetracyclic diterpenoid, acts as an antimitotic agent that inhibits the polymerization of tubulin to form microtubules. The same substance has also been used as an effective drug against ovarian and breast cancers [47][32]. In addition, calanolide A, isolated from Calophyllum lanigerum, is a non-nucleoside reverse transcriptase inhibitor (NNRTi) of type-1 HIV and an inhibitor of AZT-resistant strains of HIV [48][33].
In addition, scientific research regarding the plant SMs is continuing to explore their chemical structures as possible templates for new drug developments [49][34]. On the other hand, the search for more effective anti-cytotoxic agents is still a priority in the development of new anticancer drugs. Therefore, a number of important commercialized novel anticancer treatments have been derived from plants. In particular, many plant SMs, including alkaloid, diterpenes, triterpenes and polyphenolic compounds, have already been reported as great anticancer agents in several research [50,51][35][36].

2.4. Agricultural Uses

The NPs can be used for plant protection and growth promotion. In fact, several botanical and microbial plant SMs may induce the plant systematic resistance and plant hormones, which positively enhance plant growth [52,53][37][38]. The literature reports that many plants, such as neem, citrus, sage, menth, garlic, oregano, moringa, etc., or their single bioactive constituents, have been used for controlling several bacterial and fungal diseases, pest infestation and harmful weeds [54,55,56][39][40][41]. The main applications of plant SMs for plant protection and as plant-growth promoters have been discussed as follows.

2.4.1. Plant Protection

Plant NPs have several benefits for agriculture, where they can exhibit antiviral, antibacterial and antifungal activities [57][42]. NPs have economic importance; in fact, they can be used directly as active ingredients in several commercial products used for crop protection against phytopathogens, insects, weeds and mites. Many plant SMs, such as flavones, flavonoids, quinines, tannins, terpenes and saponins, act as antifungal and/or antibacterial agents for plant diseases [58][43]. In particular, some common bioactive SMs used for plant protection have very complex structures with many stereo centers, such as flavanones extracted from several citrus plants, has antimutagenic and antibacterial effects [59][44]. Azadirachtin, extracted from Azadirachta indica, has a strong insecticidal effect. Chelerythrine, extracted from Chelidonium majus, showed an important antibacterial effect. On the other hand, a lot of vegetal extract and plant EOs have been commercialized as crop protection products for use in biological agriculture [55,59,60,61,62][40][44][45][46][47]. In particular, some plant SMs, especially root exudates, play an important role in plant protection against a wide range of phytopathogens by killing or deterring soil microbes, herbivorous insects and nematodes [5,63,64][48][49][50]. A recent study conducted by Ensley [64][50] reported that pyrethrin derived from the flowers of Pyrethrum cinerariaefolium explicated promising insecticidal effects against some harmful pests.

2.4.2. Plant Growth-Promoting Effect

Plant growth regulators are simple molecules that have important effects on plant growth and are effective even in low concentrations [65,66][51][52]. Many natural substances and their synthetic or semisynthetic derivatives have been used in agriculture as plant growth regulators or other essential processes such as germination, vegetative reproduction, maturation and senescence [67][53]. In particular, plant hormones, also defined as phytohormones, are chemical substances produced by plants that play an essential role in regulating the living plant functions such as growth (auxin indole-3-acetic acid; IAA) and reproduction, seed and bud dormancy, organizing stomatal closure, and abiotic stress responses and seed ontogeny (abscisic acid). These substances, derived mainly from SMs, are responsible for the adaptation of plants to environmental conditions. The plant response to SMs growth regulators may differ according to plant species, age, variety, environment, stage of development, physiological and nutritional status, and hormonal balance [66,68,69][52][54][55].
Many other plant-derived compounds have growth-promoting characteristics and defense functions, such as karrikins, which promote seed germination and plant growth by simulating the signaling hormone strigolactone and aid in the growth of symbiotic arbuscular mycorrhizal fungi in the soil [70][56]. In addition, melatonin is also considered an important plant NPs as a hormone and is synthesized indirectly as an intermediate product of the shikimate pathway and has some physiological functions for plant growth, reproduction and defense against oxidative stress [71][57].
On the other hand, several phytohormones play an essential role in the ability of the plant to adapt and accommodate to different abiotic and biotic stresses such as drought, salinity and temperature [72][58]. The positive effect of plant metabolites on the plant response to unfavorable external factors may help the plants to maintain optimal growth and development [73][59]. Some common plant SMs, such as abscisic acid, salicylic acid, gibberellins, cytokinin, jasmonic acid and ethylene, play major roles in plant defense responses to biotic and abiotic stresses [74][60]. On the other hand, Smolander et al. [74][60] reported that the decomposition of cultivated soil might be influenced by some plant SMs, particularly terpenes and tannins, through increasing nitrogen immobilization and C/N cycling.

3. Biological Activity of Plant SMs

3.1. Antimicrobial

Among the most common plant SMs with antimicrobial effects against different pathogenic microorganisms are saponin, flavonoids, thiosulfinates, glucosinolates, phenolics, alkaloids and organic acids. The antimicrobial activity of plant SMs depends mainly on their chemical structures, principal constituents and effective dose. In particular, some terpenoids (aliphatic alcohols, aldehydes, ketones, acids) and some phenolic compounds (isoflavonoids) are considered the main plant components demonstrating efficient antimicrobial activity [134][61]. Shan et al. [135][62] reported that the antibacterial effect of more than 40 plant extracts is correlated to the presence of phenolic constituents. In addition, some vegetables, such as red cabbage, are rich in the phenolic compound anthocyanins, which showed promising antimicrobial activity [136][63]. On the other hand, some plant EOs containing phenolic compounds, such as citrus, olive, tea tree, orange and bergamot, have interesting antimicrobial activity against several pathogenic microbes. However, other researchers reported that some non-phenolic EOs extracted from oregano, clove, rosemary, parsley and sage showed promising antibacterial effects against both G+ve and G-ve pathogenic strains [51,61,137,138][36][46][64][65]. In addition, many plant oils are rich in phenolic compounds such as thymus, verbane, menth, lemon, orange, etc. [55,56,57,61,139,140][40][41][42][46][66][67]. In particular, some nonphenolic constituents of EOs, such as allyl garlic oil, are more effective, especially against G-ve bacteria [140,141][67][68].

3.2. Antioxidant

Antioxidants are compounds able to inhibit the oxidation process, the chemical process that can produce free radicals and chain reactions and may damage the cells. Antioxidants are useful for increasing the quality of processed food and avoiding spoilage [142][69]. The sources of antioxidants can be natural or synthetic. Certain fruits and vegetables in their organs are rich in antioxidants [18][2]. The plant SMs with potential antioxidant activity can be considered natural alternatives to many chemosynthetic substances for improving food quality and increasing self-life [143,144][70][71]. Several plant families, such as Asteraceae, Rosaceae and Punicaceae, produce bioactive SMs, including flavonoids, lignans, vitamins, carotenoids and terpenoid, which are characterized by strong antioxidant activities [145][72]. The natural antioxidants from plant materials are mainly polyphenols (phenolic acids, flavonoids, anthocyanins, lignans and catechin), carotenoids (xanthophylls, lycopene and carotenes) and vitamins (vitamins E and C). In particular, pomegranate (Punica granatum L.) fruits in the family Punicaceae are rich in acids, sugars, vitamins, minerals and phenolic compounds as strong antioxidant agents [146][73]. Aqueous tea extract is one of the most common natural antioxidants used in the food industry due to its rich content of catechins, tannins and flavonoids without affecting the food flavor, as reported by Yin et al. [147][74]. In addition, broccoli, cabbage, tomatoes and lettuce produce some potential antioxidants, such as vitamins C and E, which aid in the solubility of lipid compounds and prevent cell damage originating from high oxidative stress [148][75]. On the other hand, several plant EOs extracted from oregano, marjoram, thyme, verbena, sage and rosemary are considered rich sources of natural antioxidants; however, their volatile nature affects the food flavor [149,150][76][77].

3.3. Pharmacological Activity

3.3.1. Antibiotic

Several plant SMs have antibiotic-action properties against a variety of harmful microbes interfering the essential cellular functions such as cell wall synthesis, DNA/RNA replication and protein assimilation. Between 1935 and 1968, 12 kinds of antibiotics were approved in the medicinal field [156][78]. However, from 1969 to 2000, their number significantly decreased. After that, the number of available antibiotics gradually expanded again between 2003 and 2015, when 20 new antibiotics were approved; among them, 16 were based on natural compounds and/or their derivatives [157][79]. A recent study conducted by Newman and Cragg [158][80] reported that several plant SMs had been approved to possess interesting antibacterial activity, such as plazomicin and sisomicin, which were approved in the USA as two derivatives of the aminoglycoside. In addition, the same authors reported that some modifications of aminoglycosides were carried out in 2018, forming three tetracycline-based agents: omadacycline, eravacycline, sarecycline and lefamulin [158][80].

3.3.2. Antiviral

There is no efficient therapy against viruses because they use the biological mechanism of host cells for their replication; for this reason, all possible virus treatments have serious side effects on the host cells [159][81]. Natural compounds are considered important sources for the discovery and development of novel antiviral drugs due to their availability and minimal side effects. There are few drugs based plant sources available for controlling viral diseases. Recently, several research has been conducted to find out new plant sources serving as antiviral agents [160][82]. The world annual report of medicinal chemistry between 1983 and 1994 indicated that only seven natural drugs out of ten synthetic agents had been approved by Food & Drug Administration (FDA). Many natural and synthetic compounds showed in vitro antiviral activity with less effectiveness in vivo [159][81]. Most of the work related to antiviral compounds revolved around the inhibition of various enzymes associated with the life cycle of viruses. Shu [161][83] reported that there are two effective plant-derived antiviral compounds, (+)-Calanolide A and SP-303, under clinical development. (+)-Calanolide A was isolated from the Malaysian rainforest tree Calophyllum langigerum and showed effective HIV-RT inhibitory activity [161][83]. SP-303 was isolated from the latex of a Latin American plant Croton lechleri, showing potential in vitro activity against Herpes simplex viruses (HSV) and other DNA or RNA viruses [161][83]. Several plant alkaloids such as Citrusinine I (isolated from Citrus sp.), Atropine (isolated from Atropa belladonna) and Scopolamine (isolated from Datura stramonium) illustrated antiviral activity against many viruses such as HSV [162,163][84][85]. However, some plant PMs such as carbohydrates, have also exhibited in vitro inhibitory activities against HIV, cytomegalovirus (CMV) and HSV, such as mannose (isolated from Cymbidium hybrid and Epipactis helleborine), show effective antiviral effects against HIV and CMV [162][84]. In particular, Shashank and Abhay [157][79] reported that the structure–function relationship between plant SMs and HIV enzyme inhibitory activity has also been observed.

3.3.3. Anti-Inflammatory

Inflammation is a complex biological protective response of body tissues to microbial infection, tissue damage or irritants involving immune cells, blood vessels and molecular mediators [157][79]. Several studies reported the anti-inflammatory effects of some natural herbs, such as Curcuma longa, Zingiber officinale, Rosmarinus officinalis and Borago officinalis, which have promising applications in some clinical aspects [164][86]. Natural products recently developed as anti-inflammatory drugs provide a comprehensive resource ranging from detailed explanations to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity [165,166][87][88]. Recently, the creation of anti-inflammatory substances based on plant SMs, such as polyphenols, terpenes, fatty acids and many other bioactive components, have demonstrated noteworthy efficacy. In particular, Aswad et al. [167][89] reported that many plant SMs such as moupinamide, capsaicin and hypaphorine derived from Zanthoxylum beecheyanum, chili pepper and Erythrina velutina, respectively, can be used as new promising anti-inflammatory drugs.

3.3.4. Anticancer

Several plant SMs have been reported to possess potential anticancer activity due to their capacity to prevent oxidative stress and inflammation that causes damage to DNA, which in turn leads to carcinogenesis [168][90]. Natural products, such as irinotecan, vincristine, vinblastine, etoposide and paclitaxel from plants; actinomycin D and mitomycin C from bacteria; and marine-derived bleomycin, are widely used in various cancer therapies [169][91]. Moreover, fruits and vegetables containing vitamins, minerals, folate, plant sterols, carotenoids and phytochemicals, such as flavonoids and polyphenols, are associated with reduced cancer mortality [170][92]. Herbs and spices such as ginger, capsicum, curcumin, clove, rosemary, sage, oregano and cinnamon are very rich in antioxidants due to the high content of phenolic compounds, and they have been shown to counteract reactive oxygen species (ROS)-mediated damage in different human cancers [166][88].

4. Metabolomics: Technology Development and Experimental Approaches

Metabolomics is defined as a comprehensive quantitative and qualitative analysis of all metabolites present in a specific cell, tissue or organism. Targeted and global (or unbiased) metabolite analysis are the two main metabolomics methodologies. The chemical characterization for plant metabolites, particularly SMs, is a subset of analytic techniques such as gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS), together with an estimate of quantity. Various other techniques, including thin layer chromatography (TLC), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and nuclear magnetic resonance (NMR) are also part of the metabolite analysis [171,172][93][94]. One-dimensional (1D) NMR spectrometry has shown its utility for high-throughput analysis and classification of similar chemical groups of samples; however, the large numbers of overlapping peaks generated by this method may hinder the accurate identification of specific metabolites. Recently, by replacing the 1D 1HNMR spectroscopic technology, a two-dimensional (2D) 1H–13C NMR strategy for the analysis of metabolites as multivariate statistical objects has been developed [173][95]. The new advanced techniques, including various forms of liquid chromatography with NMR, such as HPLC–SPENMR, have improved the sensitivity of NMR analyses and are capable of characterizing both the high- and low-abundance metabolites in complex crude plant extracts [174][96]. Mass spectroscopy (MS) is currently the most widely applied technology in metabolomics. Among a variety of MS techniques, GC–MS has been long used in metabolite profiling of human body fluids or plant extracts [175,176][97][98].

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