Medicinal Potentials and Toxicity Concerns of Bioactive Principles

Plants are widely used in many indigenous systems of medicine for therapeutic purposes and are increasingly becoming popular in modern society as alternatives to synthetic medicines. Herbal medicine, also called botanical medicine or phytomedicine are generally cheaper, accessible or readily available and more culturally acceptable to many because of the belief that they cause less side effects than some synthetic drugs [1,2]. Recent research efforts in drug discovery from medicinal plants involve a multifaceted approach that combines botanical, phytochemical, biological, and molecular techniques [3]. Bioactive principles are responsible for the therapeutic activities of medicinal plants such as hypoglycemic, anti-diabetic, antioxidant, anti-microbial, anti-inflammatory, anti-carcinogenic, antimalarial, anti-cholinergic, anti-leprosy activities etc. [4]. For instance, arrays of bioactive principles from diverse anti-diabetic plants have been exhaustively described elsewhere [5,6]. Thus, pure compounds or standardized extracts from medicinal plants provide unlimited opportunities for new drug leads because of the unmatched availability and chemical diversity of bioactive principles from the plant kingdom [7,8]. In same manner of chemical diversity, most effective poisonous agents to humans and animals have their origin from various classes of chemical substances from plants. Some notable noxious compounds from plants are the cyanogenic glycosides [9,10], myristicin [11], phytohaemagglutinins or lectin [12], neurotoxic amino acids e.g. N-oxalyi-L-α, β-diaminopropionic acid (ODAP) [13,14], protease inhibitors, chlorogenic acid, amylase inhibitors, gossypol, goitrogens [12,14], veratridines [15] etc.


Introduction
Plants are widely used in many indigenous systems of medicine for therapeutic purposes and are increasingly becoming popular in modern society as alternatives to synthetic medicines.Herbal medicine, also called botanical medicine or phytomedicine are generally cheaper, accessible or readily available and more culturally acceptable to many because of the belief that they cause less side effects than some synthetic drugs [1,2].Recent research efforts in drug discovery from medicinal plants involve a multifaceted approach that combines botanical, phytochemical, biological, and molecular techniques [3].Bioactive principles are responsible for the therapeutic activities of medicinal plants such as hypoglycemic, anti-diabetic, antioxidant, anti-microbial, anti-inflammatory, anti-carcinogenic, antimalarial, anti-cholinergic, anti-leprosy activities etc. [4].For instance, arrays of bioactive principles from diverse anti-diabetic plants have been exhaustively described elsewhere [5,6].Thus, pure compounds or standardized extracts from medicinal plants provide unlimited opportunities for new drug leads because of the unmatched availability and chemical diversity of bioactive principles from the plant kingdom [7,8].In same manner of chemical diversity, most effective poisonous agents to humans and animals have their origin from various classes of chemical substances from plants.Some notable noxious compounds from plants are the cyanogenic glycosides [9,10], myristicin [11], phytohaemagglutinins or lectin [12], neurotoxic amino acids e.g.N-oxalyi-L-α, β-diaminopropionic acid (ODAP) [13,14], protease inhibitors, chlorogenic acid, amylase inhibitors, gossypol, goitrogens [12,14], veratridines [15] etc.
The renewed interest in natural products research, in recent years, has led to the development of new drugs, such as the anti-cancer chemotherapies-paclitaxel (Taxol) from the Pacific Northwest, Taxus brevifolia Nutt, and the analogue, docetaxel, Vinca alkaloids vinblastine and vincristine, isolated from the Madagascar periwinkle, Catharanthus roseus (L.) G. Don., etoposide and teniposide, isolated from roots of Podophyllum species; in addition to other drugs derived from natural products, which account for over 40% of new registered drugs [16][17][18].Furthermore, earlier survey showed that about 70-80% of Asian and African populations rely on herbal remedies for their primary health care needs [6,19]; Artemisia annua gave mankind artemisinin, the current WHO recommended anti-malarial agent [20].The earliest anti-malarial agent-quinine was obtained from Cinchona officinalis bark that dates back to 1638 [21,22].Aside the therapeutic usefulness of bioactive principles, plants extracts is used as agrochemicals, flavor and fragrance ingredients, food additives and pesticides [7,23].Many databases are available to describe the complete pharmacophore analysis of active principles possessing anti-diabetic, anti-microbial, anti-cancerous and anti-oxidant properties from medicinal plants [24].The present review highlighted the chemical diversity and medicinal potentials of bioactive principles as well inherent toxicity concerns associated with the use of these plant products, which are of relevance to the clinician, pharmacist or toxicologist.available phytochemical methods.However, a more targeted approach is often preferred to random selection [25][26][27].Plant materials to be investigated are selected on the basis of some specific traditional uses; the so-called ethno-botanical bio-prospecting approach.Plant extracts used for traditional remedies for certain diseases are more likely to contain biologically active principles of medicinal interest [1,26,28].Alternatively, the plant can be selected based on chemo-taxonomical data.In the chemo-taxonomical approach, pre-knowledge that a particular group of plants contain certain classes of natural products may be used to predict that taxonomically related plant may contain structurally similar biomolecules [26].Plant species may be selected based on field observations.For instance, plant species that thrive in hostile environment replete with bacteria, fungi or virus synthesize defensive natural products against these pathogens, which may also exhibit bactericidal, fungicidal or virucidal activity in human system.Another approach known as information driven approach utilizes a combination of ethno-botanical, chemo-taxonomic and random approaches together with a database that contain all relevant information concerning a particular plant species [24].The database is used to prioritize which plant should be extracted and screened for biological activity.This approach is favoured by large organization, particularly, pharmacological companies, interested in screening thousands of samples for bioactivity; since it reduces cost by avoidable repetitions of encountering common or already known drugs.

Collection and identification of plant material
The whole plant or a particular plant part can be collected depending on where the metabolites of interest, if they are known, are accumulated and stored.Hence aerial (e.g.leaf, stem, flowering tops, fruit, seed and bark) and underground (e.g.tuber, bulb and root) parts can be collected separately.Collection of plant materials can be influenced by factors such as the age of the plant and environmental conditions (e.g.temperature, rainfall, sunlight, soil characteristics and altitude) [27].Therefore, it is important to take these factors into consideration for the purpose of ensuring reproducible profile of plant metabolites [28,29].The plant from which the bioactive principles are to be collected must be correctly identified.A plant taxonomist or a botanist should be involved in the detailed authentication of the plant.Any feature related to the collection, such as the name of the plant, identity of the plant part collected, place and date of collection the plant should be recorded as voucher deposit in the herbarium for future references.

Drying and grinding of plant material
Once the plant material has been collected, a common practice involves drying the samples on trays at ambient room temperature with adequate ventilation.Dry conditions are essential to prevent the formation of artifacts as a result of microbial fermentation and subsequent degradation of the plant metabolites.Furthermore, plant materials are cut or sliced into small pieces to facilitate homogenous drying and prevented from direct sunlight impact to minimize undesirable chemical reactions of plant metabolites resulting to the formation of artifacts [29].Oven drying facilitate faster drying rate and minimize hydrolysis or related reactions in the plant material.Dried samples are usually kept in sealed containers in a dry and cool place.Prolong storage should be discouraged to avoid decomposition of plant metabolites.
After the drying process, plant materials are ground into fine powder to give a more homogenous sample with increased surface area.Mechanical grinders such as hammer and cutting mills are employed to shred the plant material into various particle sizes.Potential draw-back of the grinding procedure is that samples rich in fats and volatile oils my clog up the sieves, which generates heat during the process that may degrade thermo-liable metabolites.

Extraction of plant materials
For scientific evaluations of medicinal plants, extraction of bioactive principles from the plant material is crucial in order to obtain the desired chemical components from the plant materials for separation and characterization.Analytical extraction ensures that potential active constituents are not lost, distorted or destroyed during the preparation of the extract from plant samples.Plant materials are commonly extracted by means of liquid solvents in what is known as the solid-liquid solvent extraction.A typical solid-liquid solvent extraction process for plant materials involve drying and grinding of the plant material, choosing a suitable extraction solvent and extraction procedure [30].
The choice of the extraction solvent depends mainly on the polarity and solubility of the bioactive principle of interest.Although water is generally used in many traditional herbal extraction protocols, organic solvents of varying polarities are often exploited to obtain bioactive principles of varying polarities and solubilities.The choice of extraction procedure depends on the nature of the source material and the compound to be isolated.Conventional solvent extraction procedures applicable to plant natural products include, but not limited to the use of maceration, heating under reflux, sonification, percolation, soxhlet extraction, steam distillation and sequential solvent extraction.Contemporary extraction techniques include ultrasound, solid-phase micro-extraction, supercritical-fluid extraction, pressurized-liquid extraction, microwave-assisted extraction, solid-phase extraction and surfactant mediated techniques [8,[31][32][33].The efficiencies of conventional and contemporary extraction methods mostly depend on the critical input parameters, understanding the nature of plant matrix, chemistry of bioactive principles and scientific expertise [33].The polarity of commonly used extraction solvents and chemical profiles of the extracts are summarized in Table 1 [34][35][36][37][38][39][40].
The recent development of cost-effective, sustainable and wellcontrolled application of tissue culture technology such as in vitro regeneration and genetic transformation/enhancement of medicinal plants serve to boost the selective mass production of bioactive principles [23,41,42].The technology is an advantage in that it provides continuous, reliable source of plant pharmaceuticals and a platform for large scale plant tissue culture from which bioactive principles could be harvested.
the broad category of alkaline secondary metabolites that constitute the pharmacologically bioactive principles that are predominant, but not exclusively present, in flowering plants [41,68].Alkaloids are synthesized from decarboxylation of amino acids to produces amines, which react with amine oxides to form aldehydes.The Mannich-type condensation of the aldehydes and amine groups yield characteristic heterocyclic rings of alkaloids.Furthermore, the chemical nature of their nitrogen ring serves as basis for the sub-classification of alkaloids: for instance, glycoalkaloids is the aglycone moiety that is glycosylated with a carbohydrate [12].However, few alkaloids occur as glycosides of sugar such as glucose, rhamnose and galactose, whereas some weak basic alkaloids (nicotine) occur freely in nature and others as amides (piperine) and esters (atropine, cocaine) of organic acids [7,69].Chemo-taxonomical survey showed that alkaloids are widely distributed in higher plants belonging to Apocyanaceae, Ranunculaceae, Papaveraceae, Solanaceae, and Rutaceae in Africa as well as in lower plants, insects, marine organisms and microorganisms [7,41,70].
Reports have showed that the exposure or ingestion of certain plant alkaloids could provoke harmful outcomes.Insects and hervibores are often repulsed by the potential toxicity and bitter taste of alkaloids.For instance, lupin alkaloids are feeding deterrents and lethal to certain species of insects, especially aphids [77].Also, quinolizidine alkaloids toxicity to insects and vertebrates is attributable to the interactions of sparteine or lupanine (alkaloids) with N-acetylcholine receptors (nAChR) (sparteine or lupanine activates nAChR), Na + /K + channels and interference with protein biosynthesis [66].The anti-nutrients attributes of alkaloids are in connection with their actions in the central nervous system, which disrupt or cause inappropriate transmission of electrochemical signals.Specifically, massive intake of tropane alkaloids elicits rapid heartbeat, paralysis and in fatal case, leads to death.Likewise, high dose of tryptamine alkaloids cause staggering gate and death [84,85].Strychinine alkaloids Chemical screening or metabolite profiling protocols of herbal extracts using hyphenated techniques, particularly, the LC/UV, LC/MS and LC/NMR serve to distinguish between novel and already known bioactive principles in the course of search for new lead compounds from medicinal plants.Furthermore, spectroscopic techniques such as UV/VIS and IR spectrophotometry, carbon and proton NMR, MS and ƛ-ray diffraction are applied for elucidation of structural conformations of bioactive principles [18,46,[55][56][57].Also, chemical techniques involving hydrolysis, formation of derivatives and hydration reaction coupled with structural modifications of bioactive principles are applied to establish structure/function relationship [18].

Biological and pharmacological screening
Biological activity of plant extracts are often demonstrated using in vitro and in vivo bioassay methods [5,43,[58][59][60][61].The combinations of vast arrays of plant compounds make it virtually experimentally unattainable to isolate bioactive principles to obtain absolute purity.Therefore, in order to elucidate the therapeutic activity as well as toxicity of bioactive principles, bioassay-guided approach involving biological and pharmacological targets are used during purification and fractionation steps.The in vivo bioassay methods involve the use of microorganisms, whole invertebrate and vertebrate animals, whereas in vitro procedures employ isolated subcellular systems such as enzymes and receptors as well as animal or human cell culture [18, 43,60,62,63].

Bioactive principles of medicinal and toxicological significance
Bioactive principles, also referred as plant secondary metabolites, are derived from the products of plant primary metabolites, which are associated with the process of photosynthesis viz.; carbohydrates, amino acids and simple lipids (Figure 1).
Although bioactive principles are generally not involved in growth and metabolism of plants, they play critical roles in the survival of plants by their functions in the defense of the plant against pathogenic organisms and predatory herbivores [64,65].Additionally, bioactive principles may serve as vehicle for the elimination of nitrogenous waste products and sustenance of plants in situation of drought [12,50,66,67].Also, plant secondary metabolites are referred to as the active principle of plants because they exert diverse range of pharmacological effects in mammalian systems.An overview of plant metabolic pathways (Figures 1 and 2) showed that bioactive principles are synthesized by two major pathways: the shikimic acid or aromatic amino acid and mevalonic acid pathways [7].

Alkaloids
They are diverse low-molecular-weight, cyclic organic compounds containing nitrogen in a negative oxidation state.Alkaloids belong to are used as rat poison [7].The molecular configurations of some common alkaloids are shown in Figure 3 [86].

Flavonoids
The bioflavonoid are collections of low molecular weight phenolic groups of phytochemicals that include the anthocyanins (eg.cyanidin, pelargonidin, petunidin), the flavonols (quercetin, kaempferol), flavones (luteolin, apigenin), flavanones (myricetin, naringin, hesperetin, naringenin), flavan-3-ols (catechin, epicatechin, gallocatechin), and, although sometimes classified separately, the isoflavones (genistein, daidzein) [87].Flavonoids are widely distributed in the plant kingdom and have been reported to exhibit strong antioxidant activity [87][88][89][90][91] and there appeared to be a structure/activity relationship in the capability of flavonoids to scavenge peroxynitrite [87,91].Phenylalanine is the precursor for the biosynthesis of flavonoids via the flavone synthase pathway (Figure 4).Flavonoids are plant pigments and for the most part, are responsible for display marvelous colours of flower petals and the emission of brilliant fluorescence when green plant cells are excited by UV light [90,92].Base on their peculiarities and distribution in plant kingdom, flavonoids are used by botanists for taxonomical classification of plants [90].The basic structural configuration of flavonoid compounds is the 2-phenyl-benzo[α]pyrane or flavane nucleus, which consists of two benzene rings (A and B) linked through a heterocyclic pyrane ring (C) (Figure 5   Some medicinal benefits attributable to the presence of flavonoids in diets include prevention oxidative cell damage (antioxidant and free radical scavengers), anti-inflammatory and anti-carcinogenic effects [91].Flavonoids have been noted to act as bactericidal to several strains of bacteria, inhibit important viral enzymes, such as reverse transcriptase and protease and kill certain pathogenic protozoans [60,90,94].In vitro studies have revealed that quercetin inhibits DNA   [94] in susceptible bacteria.Furthermore, two flavones from Artemisia giraldi, identified as 6, 7, 4′-trihydroxy-3′, 5′-dimethoxyflavone and 5, 5′-dihydroxy-8, 2′, 4′-trimethoxyflavone, together with 5, 7, 4′-trihydroxy-3′, 5′-dimethoxyflavone have been reported to exhibit anti-microbial activity against Aspergillus flavus, which causes invasive disease in immunosuppressed individuals [94].Phytoestrogens are weakly estrogenic isoflavones and lignans that bind to estrogen receptors, which function both as antioxidants and protective agents against cardiovascular disease in man [95].
Flavonoids extracted from Morus indica caused up-regulation of hepatic superoxide dismutase (SOD) activity, reduction of hepatic malondialdehyde (MDA) content, down-regulation of hepatic CYP2E1 expression and increase of glucose transporter 4 (GLUT-4) expressions in skeletal muscle of experimental rats, which were indications that M. indica flavonoids may ameliorate hyperlipidemia and hyperglycemia engendered by high fat diet [96].Likewise, flavonoids -hesperidin, boswellic acid, ellagic acid, quercetin, rutin and naringenin improved hyperlipidemia and hyperglycemia by partly regulating fatty acid and cholesterol metabolism and affecting gene expression of glucoseregulating enzymes in diabetic animals [97,98].Flavonoids prevent tumorigenesis by inhibiting DNA topoisomerase II activity and p53 down-regulation, and thereby elicit tumor cell apoptosis [91].Due to the proven ability of flavonoids to inhibit specific enzymes, to simulate some hormone secretions and neurotransmitters and to scavenge free radicals, pure flavonoids are used to treat many common diseases [90,94,99].Polymethoxylated flavones are known for their anticancer [100], anti-inflammatory [101], and neuro-protective [102] properties.Flavonoids from Theobroma cacao caused dose-dependent reduction of interleukin (IL)-2Ra (CD25) expression in activated lymphoid cell line, which suggests the potentials of the use flavonoids in counteracting immune system hyperactivity such as chronic autoimmune inflammatory disease [103].
Although chemo-preventive activity of flavonoids have been demonstrated using animal in vivo experiments, there are claims that dietary flavonoid/phenolic consumption or exposures may provoke toxic flavonoid-drug interactions, liver failure, contact dermatitis, hemolytic anaemias, and estrogenic-related toxicity outcomes such as male reproductive health and breast cancer [66,91].

Anthocyanins
The anthocyanins are the most important and widespread group of colouring matters in plants.These intensely coloured water soluble pigments are responsible for almost all the colours of petals, leaves and fruits of plants.Anthocyanins are basically composed of the aromatic rings of the cyanidin, from which several derivatives are generated by divergent insertions and positioning of substituents such as hydroxyl, methyl or glycosyl groups (Figure 6).Also, the molecular features of anthocyanins such as position, number, and type of substitutions on the cyaniding backbone dictates the level to which anthocyanins exert their bioactive properties as well as the intracellular localization of the pigments [87,104].

Saponins
Saponins are a family of amphipathic glycosides in which the varied number sugar moieties are bound to a 'sapogenin'-steroid alkaloids, steroids or triterpene resulting to structural varieties of saponins, which serves as basis for their classification [64,113,114].Soybean, lupins and several other legumes are rich sources of triterpene saponins [66].
Dietary saponins reduce protein digestibility probably by formation of sparingly digestible saponin-protein complexes and obstruct the absorption of micronutrients [115].Despite the toxicity concerns associated with the consumption of saponin containing plant materials, studies by Chan et al., [116] revealed that phenolics-saponins fraction from defatted kenaf seed meal is rich in antioxidants and therefore, could serve as a potential active ingredient for nutraceuticals, functional foods as well as natural food preservatives.Likewise, α-hederin and hederasaponin-C from Hedera helix, and hederacolchisides-E and -F from Hedera colchica exhibited antioxidant activities that were comparable with standard antioxidants such as α-tocopherol, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) [117].
The capabilities of saponins to ameliorate dyslipidemia have vastly been reported.Hypercholesterolemic rats administered with different combinations of saponins from Glycyrrhiza glabra (F.Fabaceae), Withania somnifera (F.Solanaceae), Asparagus racemosus (F.Liliaceae), Chlorophytum borivilianum (F.Liliaceae), and Sesamum indicum (F.Pedaliaceae) effectively reduced plasma and hepatic lipid profiles and increased fecal excretion of cholesterol, neutral sterol, and bile acid along with increased hepatic HMG-CoA reductase activity and bile acid content [118] Plasma cholesterol lowering activity of saponins is also connected with their capabilities to precipitate cholesterol from micelles and interference with enterohepatic circulation of bile acids making it unavailable for intestinal absorption and hence reduce plasma cholesterol levels.Saponins can precipitate cholesterol from micelles and interfere with enterohepatic circulation of bile acids, and thereby make cholesterol unavailable for intestinal absorption and eventual reduce plasma LDL-cholesterol levels [119][120][121][122][123]. Another perspective showed that anti-hyperlipidemia saponins inhibit pancreatic lipase activity and reduce plasma triacylglycerol concentrations, thereby engendering reduction in plasma VLDL-C concentration [124,125].Related study showed that saponins from Helicteres isora caused increased gene expression of adipsin, GLUT-4 and peroxisome proliferator activated receptor gamma (PPARγ) as well as reduced gene expression of glucose-6-phosphatase and fatty acid binding protein 4 (FABP4) enzymes, which improved hyperlipidemia and hyperglycemia in C57BL/KsJ-db/db mice [126].Saponins extracted from Entada phaseoloides (L.) Merr exerted hypoglycemic and hypolipidemic activities through repression of chronic inflammation responses in Type II diabetic rats [127].Also, saponins from Solanum anguivi Lam.fruits exhibited hypoglycemic, anti-peroxidative and anti-hyperlipidemic effects in Type I diabetic rats [128].Charantin (XV) isolated from Momordica charantia L. possesses an insulin-like activity with which it promotes insulin secretion, and thereby lowers hepatic glycogenesis [129].Also, diverse saponins such as β-sitosterol (XVI) present in Azadirachta indica A., andrographolide (XVII), a diterpenoid lactone, obtained from Andrographis paniculata Nees and gymnemic acid IV (XVIII) isolated from Gymnema sylvestre R., are agents of glycemic control in animal models [130,131].The roles of bioactive principles in bringing glycemic control to bear in both experimental animals and humans have been exhaustively described elsewhere [6,114] Adjuvant activities of saponins from traditional Chinese medicinal herbs such as Panax ginseng, Astragalus species, Panax notoginseng, Cochinchina momordica, Glycyrrhiza uralensis and Achyranthes bidentata have been previously described [132].The immune-stimulatory activities of Quil A (consists of a mixture of related saponins) isolated from the bark of Quillaja (a tree), which is used as an adjuvant in selected veterinary vaccines has been acknowledged [113].
More than five decades ago, Glauert et al. [133] reported that toxic levels of saponins cause lytic action on erythrocyte membranes.The amphipathic nature of saponins allows for compatible interaction between aglycone moiety of the molecule and inner membrane cholesterol molecules, whereas the hydrophilic sugar moiety freely binds to outer membrane proteins.The insertion of saponins into biomembrane structure affects its fluidity and function with resultant introduction of holes and pores, which elicits leaky cells and eventually cells death.Saponins-induced disturbances of membrane stability and functionality are non-specific and may affect wide range of organisms such as bacteria, fungi and even competing plants [66].Logically, saponins-biomembrane interactions are considered to be a resistance/ defense factor in legumes against microbial infections and herbivorous predators.

Tannins
Tannins or tannic acid are water-soluble polyphenols that are present in many plant foods [134].Tannins are bitter astringent, condensed or hydrolysable polyphenolic compounds that bind to and precipitate proteins and other various organic compounds including amino acids and alkaloids [12,[135][136][137].The astringency of tannins is what causes the dry and pucker feeling in the mouth following the consumption of unripe fruits or red wine.Likewise, the degradation or modification, which is most probably, connected with increased polymerization of tannins with time plays an important role in the ripening of fruit and the aging of wine [138].
Both in vivo and in vitro studies have revealed the antioxidant potentials of tannins [134,[139][140][141][142]. Using cyclic voltammetry, metmyoglobin assay and deoxyribose assay, Hagerman et al., [140] reported that the redox potentials of condensed and hydrolyzable tannins were similar to those of structurally related simple phenolics.They further noted that the tannins were 15-30 times more effective at quenching peroxyl radicals than simple phenolics or Trolox.Specifically, polygalloyl glucose reacted in an order of magnitude more quickly with hydroxyl radical than mannitol [140].
According to Reed [143], hydrolyzable tannins are polymers of gallic or ellagic acid esterified to a core molecule, commonly glucose or a polyphenol such as radical scavenging catechin (Figure 7).Similarly, notable condensed tannins such as procyanidins, prodelphinidins, epicatechin, epigallocatechin polymers with galloylated procyanidin or prodelphinidin from leaves, twigs and stem bark of Canarium album as well as crude tannins of canola and rapeseed hulls showed a very good 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing power [141].Also, proanthocyanidins (Figure 7) from persimmon (Diospyros kaki), which is a known member of condensed tannins of specific group of polyphenolic compounds, exhibits powerful antioxidant activity in streptozotocin (STZ)-induced diabetic model rats and db/db Type II diabetic mice [135].Tannin supplements from Ficus racemosa attenuated oxidative stress engendered vascular tissue damage and ameliorated hyperglycemia and hyperlipidemia in streptozotocin-induced hypercholestremia associated diabetic rats [144].Overall, there appeared to be a relationship between the molecular configuration of tannins and their capacity to scavenge reactive oxidants.For instance, according to Hatano et al. [145] the scavenging capacities of tannins having the ortho-trihydroxyl (pyrogallol) structure -(galloyl, hexahydrodiphenoyl (HHDP) groups in hydrolyzable tannins, galloyl group in acylated proanthocyanidins and the B-ring of some flavano-3-ol) were stronger than that of unacylated proanthocyanidins.
Using the hydroxyl radical scavenging activities by 2-deoxyribose oxidation system and salicylic acid system, superoxide anion scavenging activity, and linoleic acid lipid peroxidation inhibition activity respectively, Gu et al. [146] noted that high molecular weight condensed tannins {(epi) gallocatechin, epigallocatechin-3-O-gallate, epicatechin-3-O-gallateare} are the major antioxidant composition in D. kaki pulp.Generally, tannins in certain fruits serve as a natural defense mechanism against microbial infections [134].The mechanisms of anti-bacterial activity of tannins have been described [147].Likewise, proanthocyanidin polymers from D. kaki fruit exhibit anti-fungal properties as well as protective effect against diabetic oxidative stress with hyperlipidemia and anti-cancer activities [142,148,149].Also, proanthocyanidins from Pavetta owariensis that are structurally similar with the proanthocyanidins A2 and cinnamtannin B1 and B2) have been shown to have antiviral activity against herpes simplex virus (HSV) and coxsackie B virus [94,150].
Ingestion of tannin-rich grasses and agriculturally produced legumes and grains cause the precipitation of dietary proteins and gastrointestinal enzymes of herbivores, and thereby reduce the digestibility and availability of proteins to the animal [2,136,143,151].The anti-nutrient factor of tannins decreases feed intake, growth rate, feed efficiency, net metabolizable energy, and protein digestibility in experimental animals [134].

Phenols and phenolic acids
Phenolic compounds are generally synthesized via the shikimate pathway (Figure 1).These bioactive principles are often associated with lignin as ester groups and are extracted either as components of alcohol insoluble fractions or bound to simple glycosides as alcohol soluble fractions [7,152].Common phenolics among the angiosperms are p-hydroxyl-benzoic acids, protocatetuic acids, vanillic acid and syringic acid (Figure 8).Phenylpropanoids are phenolics, having a C 6 C 3 carbon skeleton (e.g.cinnamic acid, o-coumaric acid, p-coumaric acid, caffeic acid and ferulic acid), derived from shikimic acid pathway (Figure 1) [7].Additionally, simple phenylpropanoid forms conjugate with quinic acid to yield chlorogenic acid.Phenolic compounds having a C 6 C 3 C 6 carbon skeleton include flavonoids (including anthocyanins) and isoflavonoids [7].
Polyphenolics from T. cacao exhibited anti-ulcer activity and modulated leukocyte function as exemplified by their ameliorative potentials against ethanol-induced gastric mucosal lesion in animal models [153].There are claims by Kim et al. [154] that regular or occasional consumption of polyphenol-rich cocoa exerts beneficial effects on blood pressure, increases cerebral blood flow and possibly, for treatment of dementia.According to Hu, [155] dietary polyphenolic supplementation exert desirable outcome in complementary therapy when ingested in large quantity.From the reports of Ranneh et al. [156], experimental models confirmed that phenolics from T. cacao exhibited beneficial effects against platelet aggregation [157], high blood pressure [158], atherosclerosis [159], hyperglycemia and hypercholesterolemia [160,161], inflammation [162], hepatocarcinogenesis [160], DNA damage and clastogenic effect [163].Furthermore, flavonoids and polyphenol from T. cacao such as flavan-3-ols, epicatechin, and catechin are potential inhibitors of pro-inflammatory mediators in tumor necrosis factor-α (TNF-α)-sensitized Caco-2 cells in vitro and exhibited protective effect in colon cancer in vivo [164].Bioactive principles from T. cacao effectively down-regulated cyclo-oxygenase-2 and interleukin-8 (IL-8) as well as inducible nitric-oxide synthase activity by inhibiting nuclear factor (NF)-kB translocation and c-Jun N-terminal kinases (JNK) phosphorylation [156,164].In another study, quercetin, the active phenolic component in kiwifruit, mediated by its free radical-scavenging activity, prevented hydrogen peroxideinduced inhibition of gap-junction intercellular communication in rat liver epithelial cells that is required for cell-cell communication in order to maintain homeostasis by facilitating direct exchanges of essential cellular metabolites and messengers less than 1-2 kDa (e.g.Na + , K + , Ca 2+ , cyclic AMP and ATP) [165][166][167].Additionally, quercetin possesses chemopreventive activity against azoxymethane-induced colonic tumorigenesis in mice and pre-neoplastic lesions in rat hepatocarcinogenesis [167].
The nephrotoxicity associated with the use of anthraquinones from Rhubarb as laxatives has been successfully circumvented using rhubarb total free anthraquinone oral colon-specific drug delivery granules (RTFAOCDD-GN).The oral colon-specific drug delivery technology allowed anthraquinones to exert purgative effect devoid of intestinal absorption, which promoted their rapid excretion [168].

Glycosides
Glycosides are found in virtually every medicinal plant and have vast therapeutic efficacy and, certain cases, toxic effect depending on the plant of origin and the dose of plant product ingested.They are glycosylated bioactive principles in which the aglycone moieties are constituted of the alkaloids, vitamins, polyphenols, steroids, terpenoids or antibiotics etc. bound to a mono-or oligosaccharide or to uronic acid [64].Glycobiology has revealed that the glycosidic residue is crucial for bioactivity; in other circumstances; glycosylation improves pharmacokinetic parameters and may serve as leads to the development of new and more active drugs, as typified by the recently developed antibiotics vancomycin [76].A precise overview of physiologic role of glycosyl residue in bioactive principles as well as the structure/activity relationship has been described [169].The most encountered glycosides of medicinal and toxicological importance are the vitamins glycosides, polyphenolic glycosides (anthraquinone glycosides), alkaloid glycosides, glycosides in the group of antibiotics (streptomycin), glycopeptides, cardiac glycosides, steroid and terpenoid glycosides, cyanogenic glycosides etc. [12,66,113,114,169,170].
Anthraquinone glycosides are present in fairly limited distribution in plants.In traditional Chinese medicine, anthraquinone glycosides from Rheum palmatum (rhubarb) in the non-boiled form are administered when catharsis was the desired outcome [168,171].Aglycone anthraquinone are anti-fungal, impede renal tubular proliferation and ameliorate inflammations by partial inhibition of the cyclooxygenase pathway [172].Notable plants containing cardiac glycosides include: Dogbane (Apocynum spp.), Lily of the Valley (Convallaria spp.), Foxglove (Digitalis spp.), Oleander (Nerium oleander), Yellow Oleander (Thevetia spp.), and Milkweeds (Asclepias spp) [64].Cardiac glycosides all contain steroids as the aglycone.Cardiac glycosides from foxglove (Digitalis spp.), Rauvolfia caffra sond, as well as lanoxin derivative from number of plants in low doses serve as medication for cardiac disorders in humans [108,173,174].
Persistent use or abuse of anthraquinone glycosides medications, beside its strong anti-bacterial, antioxidant and anti-diabetic activities, could elicit fluid and electrolyte loss, rhabdomyolysis, renal failure and acute hepatic failure [175][176][177].Cardiac glycosides derivatives of digitalis and strophanthus such as ouabain are notable inhibitor of Na + /K + -ATPase activity of biomembranes [173,178].Similarly, cardiac glycosides have been linked with hyperkalaemia [179].The diterpenoid glycosides or atractylosides and other analogues from Coffea arabica beans are naturally present in many plants of ethnomedicinal importance and animal grazing forage in Europe, Africa, South America and Asia.Fatal outcomes following the consumption of diterpenoid glycosides include renal proximal tubule necrosis and/or centrilobular hepatic necrosis in man and farm animals [170].Also, acute toxicity of diterpenoid glycosides is associated with competitive inhibition of adenine nucleoside carrier and thus blocks oxidative phosphorylation in isolated mitochondria cocktail [170].
By their chemical nature, cyanogenic glycosides are β-linked glycosides of α-hydroxynitriles.Cyanogenic glycosides are biosynthesized from at least 2,650 species of plants [10].The L-amino acids are biosynthetic precursors of the cyanogenic glycosides.According to Vetter, [180] the amino acids are first hydroxylated to yield N-hydroxylamino acids, which are converted to aldoximes and subsequently to nitriles.Next, the hydroxylation of nitriles yields α-hydroxynitriles, which are then glycosylated to yield cyanogenic glycosides.Consumption of cyanogenic glycosides containing plants results to the release of hydrogen cyanide into systemic circulation, which inactivates cytochrome oxidase in the mitochondrial electron transport chain of cells, and thereby engenders decreased utilization of oxygen in peripheral tissues.Long-term exposure to cyanide toxicity causes upper motor neuron characterized by irreversible paralytic disorder, tropical ataxic neuropathy, optical atrophy, angular stomatitis; sensory gait ataxia; and neurosensory deafness, goitre and cretinism.Cyanogenic glycosides are present in species of Rosaceae (rose family) in particular in Prunus spp, cassava (Manihot esculanta Crantz), Cherry (Prunus cerasus), as well as other Prunus species such as peach (Prunus persica), plum (Prunus domestica), almond (Prunus dulcis), and apricot (Prunus armeniaca) [10,64,181].Some notable cyanogenic glycosides present in edible parts of plants include: amygdalin (almonds), dhurrin (sorghum), linamarin (cassava, lima beans), lotaustralin (cassava, lima beans), prunasin (stone fruit) and taxiphyllin (bamboo shoots) [10].

Terpenoids
Terpenoids are derived from five carbon isoprene units that are assembled in numerous combinations to generate vast arrays of terpene derivatives, collectively referred to as isopreniods.Most terpenoids are present in the glycosidic form rather than the non-polar or low polarity terpene aglycone form [63].The terpenoids encompasses other classes of bioactive principles in diverse collections of plants.Notable examples include: mono-and sesquiterpene volatile derivatives from Antirrhinum tortuosum [182], mono-and sesquiterpenes from Phlomis fruticosa [183], saponins and sapogenins from Asparagus aphyllus [184], sesquiterpene lactones from Palaeocyanus crassifolius [185] tetraterpene carotenoids from Arum italicum [186], triterpenoids from Olea europaea [187,188] and β-sitosterol; a triterpene-like compound from Acanthus mollis [189] that exhibits plasma cholesterol lowering properties.
Studies have shown that the terpenoids possesses anti-microbial, anti-fungal, anti-parasitic, anti-viral, anti-allergenic, anti-spasmodic, anti-hyperglycemic, anti-inflammatory and immune modulatory properties [173,190,191].Although early experimental data showed that the most common terpenes (D-limonene) caused increased incidence of renal tubular tumors in male rats, no evidence of any tumor was observed in female rats and mice of both sexes [192].Further evidence from a phase I clinical trial demonstrated that a patient with breast cancer showed a partial response to the chemopreventive activity of D-limonene.Additionally, D-limonene has been used clinically to dissolve cholesterol-containing gallstones and alleviation of gastroesophageal reflux (GERD) [192].

Coumarins
The coumarins display molecular/pharmacological diversities and are natural compounds found in diverse plant sources in the form of benzo[α]pyrene derivatives.Aside the medicinal properties of the coumarins, it's the first synthetic substance to be used as fragrance and aroma present in essential oils and industrially processed food products [39].Some naturally occurring coumarin derivatives include umbelliferone (7-hydroxycoumarin), aesculetin (6,7-dihydroxycoumarin), herniarin (7-methoxycoumarin), psoralen and imperatorin.Other notable coumarins are presented in Figure 9.

Conclusion
Plant materials are composed of vast array of bioactive principles of which their isolation, identification and characterization for analytical evaluation requires expertise with cutting edge analytical protocols and instrumentations.Bioactive principles are responsible for the therapeutic activities of medicinal plants and provide unlimited opportunities for new drug leads because of their unmatched availability and chemical diversity.For the most part, the beneficial or toxic outcomes of standardized plant extracts depend on the chemical peculiarities of the containing bioactive principles.The main objective of this review has been to emphasize that whereas bioactive principles display therapeutic benefits and have served as leads to the development of new drugs, studies have also shown that bioactive principles exhibit toxic outcomes; depending on the their sources, molecular and chemical peculiarities.

Figure 4 :
Figure 4: Pathway leading to the biosynthesis of diverse bioactive principles from phenylalanine [7].

Figure 5 :
Figure 5: The skeleton structure of a class of flavonoids (the flavones).

Figure 6 :
Figure 6: Molecular structures of some common anthocyanins.

Figure 8 :
Figure 8: Molecular structures of some phenols and phenolic acids.

Table 1 :
Polarity of extraction solvents and chemical profiles of extracts.