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Phytochemicals – biomolecules for prevention and treatment of

human diseases-a review

Abstract:

Manas Kumar Mukhopadhyay; Pratyusha Banerjee and Debjani Nath*

Department of Zoology, University of Kalyani, Nadia,West Bengal, India

* Corresponding author

Email Address: nath_debjani@yahoo.co.in
Ayurveda is the most ancient healthcare system describes thousands of medicinal plants with their medicinal properties. In recent times, developed countries are turning to the use of traditional medicinal systems because the phytochemicals are potent in different therapeutic applications as they show defensive mechanism of action against a number of chronic diseases including cancer, cardiovascular disease, diabetes, neurodegenerative disease. Plant biomolecules are also involved in anti viral as well as antimicrobial activity and also show efficacy in radioprotection. But still there are some difficulties in proper therapeutic administration of phytochemicals due to their low water solubility, low absorptivity and bioavailability. So a strategy of engineered phytochemicals has been developed to enhance solubility, cellular permeability, proteolytic stability and half-life of plant biomolecules. Still further research is required to ensure high yield as well as viability and bioavailibity of the plant biomolecules in different therapeutic application.

Key words: Medicinal plants and herbs, Plant biomolecules, Therapeutic application, Engineered phytochemicals.

1. Introduction:

Ayurveda is the most ancient health care system and is practiced widely in India, Srilanka and other countries. Atharvveda (around 1200 BC), Charak Samhita and Sushrut Samhita (100 - 500 BC) are the main classics that given detailed descriptions of over 700 herbs. In 78 A.D Dioscorides wrote “De Mater ia Medica”, describing thousands of medicinal plants. This treatise included descriptions of many medicinal plants that remain important in modern medicine, not because they continue to be used as crude drug preparations, but because they serve as the source of important pure chemicals that have important use in modern therapy. The physicians of today continue to use many substances and products derived from natural sources, usually for the same
therapeutic benefit as the crude drug. These single chemical entities, i.e., drugs, form the basis for much of our

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ability to control disease. In recent times, there have been increased waves of interest in the field of research in chemistry of natural Products. This level of interest can be attributed to several factors, including unmet therapeutic needs, the remarkable diversity of both chemical structure and biological activities of naturally occurring secondary metabolites, the utility of novel bioactive natural products as biochemical probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constituents, in solving the demand for supply of complex natural products. The R & D thrust is focused on development of new innovative/indigenous plant based drugs from the traditional system of medicine. The World Health Organization has also recognized the importance of traditional medicine and has created strategies, guidelines and standards for botanical medicines. Over the past decade, there has been a resurgence of interest in the investigation of natural materials as a source of potential drug substance. This article is aimed at highlighting the invaluable role of plant biomolecules in different therapeutic applications.

2. Importance of phytochemicals:

In recent times, developed countries are turning to the use of traditional medicinal systems that involve the use of herbal drugs and remedies and according to the World Health Organization (WHO), almost 65% of the world’s population has incorporated the value of plants as a methodology of medicinal agents into their primary modality of health care. It is often noted that 25% of all drugs prescribed today come from plants. This estimate suggests that plant-derived biomolecules make up a significant segment of natural product – based pharmaceuticals. Out of many families of secondary metabolites, nitrogen-containing alkaloids have contributed the largest number of drugs ,ranging in effects from anticholinergics (atropine) to analgesics (opium alkaloids) and from antiparasitics (quinine) to anticholinesterases (galantamine) to antineoplastics (vinblastine/vincristine), terpenoids (including steroids) have made an equally important contribution to human health. They range from Na+/K+ pump-inhibiting cardiac glycosides from Digitalis spp., to antineoplastic paclitaxel , antimalarial artemisinin, anti-inflammatory triptolide. The goals of using plants as sources of therapeutic agents are, a) to isolate bioactive compounds for direct use as drugs, e.g., digoxin, digitoxin, morphine, reserpine, taxol, vinblastine, vincristine; b) to produce bioactive compounds of novel or known structures as lead compounds for semisynthesis to produce patentable entities of higher activity and/or lower toxicity, e.g., metformin, nabilone, oxycodon (and other narcotic analgesics), taxotere, teniposide, verapamil, and amiodarone, which are based, respectively, on galegine, morphine, taxol, podophyllotoxin, khellin, and khellin; c) to use agents as
pharmacologic tools, e.g., lysergic acid diethylamide, mescaline, yohimbine; and d) to use the whole plant or

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part of it as a herbal remedy, e.g., cranberry, echinacea, feverfew, garlic, ginkgo biloba, St. John’s wort, saw
palmetto.

Table1. Numbers of medicinal species documented in different countries and regions:

Table2. Indian medicinal plants and their medicinal property:

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Table 3. Indian medicinal herbs and their property:

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3. List of phytochemical based therapeutic approaches:

Table 4: Phytochemicals and their chemopreventive activity:

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Table.5 plants and their antiviral activity:

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Table.6. phytochemicls and their antimicrobial activity:

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Table 7.Phytochemicals with their radioprotective activity:

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4.

Potential therapeutic applications of phytochemicals:

4.1. Therapeutic application in cancer:

Several proteins have been identified as specific targets of some phytochemicals (TABLE 4). Representative signalling pathways targeted by various phytochemicals include the MAPK pathways, the oncogenic AKT pathway and proteins involved in cell cycle progression [12,17,24,32].

4.1.1 Interfering with the MAPK signaling pathways:

MEK1 is an important downstream component of oncogenic RAS signalling and potentially a good target for disrupting MAPK signalling. The development of pharmacological inhibitors of MEK1, such as PD [37] [29], has shown that MEK1 possesses a unique binding pocket adjacent to its ATP-binding site,and computer modelling has indicated that several phytochemicals, including quercetin[37], myricetin[33] and equol[24], could dock with this allosteric pocket. An analogue of resveratrol (RSvL2) was shown to strongly bind MEK1. The mechanism of allosteric inhibition of MEK is attributed to the inhibitor being able to stabilize the inactive conformation of the activation loop and deform the catalytic site.

4.1.2 Suppressing AKT signaling:

AKT and mTOR mainly reprogramme metabolic pathways in cancer cells, it is also thought to be involved in pathways that control the availability of nutrients acting through AMP activated protein kinase (AMPK), which controls glucose and lipid metabolism by sensing changes in nutrient and extracellular energy levels. This suggests that the AKT-mediated oncogenic pathway could be regulated by nutrients. PI3K is an upstream regulator of AKT–mTOR signalling and also interacts with several phytochemicals. Based on X-ray crystallography, quercetin and myricetin have been shown to directly bind and suppress PI3K activity [39,45].

4.1.3 Intervening with cell cycle progression:

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Regulating cancer cell proliferation is crucial for chemoprevention. Cyclin-dependent kinases (CDKs), the essential proteins for cell cycle progression, bind with cyclins to form CDK–cyclin complexes [68]. Many CDK inhibitors (CDKIs), such as the p21 and p27 proteins, attenuate formation of these complexes and block cell cycle progression [19]. Several phytochemicals can function as CDKIs. Such as metabolite of the soybean isoflavone daidzein, is a direct inhibitor of CDK2 and CDK4 [51].

4.2. Therapeutic application in Diabetes:

Tea and several plant polyphenols were reported to inhibit a-amylase and sucrase activity, decreasing postprandial glycemia[69]. Individual polyphenols, such as β-catechin,epicatechin [70] ,epigallocatechin, epicatechin gallate, isoflavones from soyabeans, tannic acid, glycyrrhizin from licorice root, chlorogenic acid and saponins also decrease S-Glut-1 mediated intestinal transport of glucose [ 45]. Saponins delay the transfer of glucose from stomach to the small intestine.The water-soluble dietary fibres, guar gum, pectins and polysaccharides slow the rate of gastric emptying and thus absorption of glucose. The α-glucosidase inhibitors (acarbose and the others) are presently recommended for the treatment of obesity and diabetes. Phytochemicals have been shown to demonstrate such activity [71]. Plant phenols induce vasorelaxation by the induction of endothelial nitric oxide synthesis or increased bioavailability and the NO-cGMP pathway [30, 29].

4.3. Therapeutic application in Cardiovascular Disease:

The link between flavonoids and atherosclerosis is based partly on the evidence that some flavonoids possess antioxidant properties and have been shown to be potent inhibitors of LDL oxidation in vitro. For example, the phenolic substances in red wine inhibit oxidation of human LDL [40]. Flavonoids have also been shown to inhibit platelet aggregation and adhesion [72] which may be another way they lower the risk of heart disease. Isoflavones in soy foods have been reported to lower plasma cholesterol and also to have estrogenlike effects [73]. Garlic oil or garlic has been shown to be hypolipidemic in humans, with a recent meta-analysis suggesting that one half clove of garlic per day lowered serum cholesterol by approximately 9%.[74]. The same amount of garlic was shown to reduce cholesterol levels and severity of atherosclerosis in cholesterol-fed rabbits. Garlic contains a number of compounds, but those thought to be the most active are diallyl disulfide and its mono S oxide (allicim). The mechanism of hypercholesterolemia may be the inhibition of cholesterol synthesis [19].

4.4. Therapeutic application in neurodegenerative diseases:

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As is the case with major diseases of other organ systems (cardiovascular disease, diabetes and cancers), data from epidemiological studies of human populations suggest that phytochemicals in fruits and vegetables can protect the nervous system against disease. For example, phytochemicals reduced risk for Alzheimer's disease [75].Because of their beneficial effects on the cerebral vasculature, phytochemicals may also reduce the risk of stroke [76] .Dietary supplementation with blueberries protected dopaminergic neurons against dysfunction and degeneration in a rat model of Parkinson's disease [77], improved learning and memory without affecting amyloid pathology in a mouse model of Alzheimer's disease[78] and reduced brain damage and improved functional outcome in a rat model of stroke [79].Apple juice concentrate prevented age-related impairment of cognitive function in mice [80]. Moderate consumption of red wine reduced amyloid pathology in a mouse model of Alzheimer's disease [81].Considerable effort has been aimed at identifying specific molecules responsible for the health benefits conferred by plants. Four different phytochemicals (sulforaphane, resveratrol, curcumin and the cannabinoid THC) which considerable evidence suggests have neuroprotective properties that likely involve a hormetic mechanism of action.

5. Challenges of phytochemical therapy:

Despite the benefits, many phytochemicals have poor water solubility, low absorptivity and bioavailability. The intended therapeutic role of ingested phytochemicals might be different than their in vivo activity once the food matrix is disrupted [46] due to variation in their metabolism and disposition [Fig 1].

5.1 Sources of variation in phytochemical metabolism and disposition

Researchers investigation on the pharmacokinetics of phytochemicals in humans have shown substantial variation .Circulating concentrations of phytochemicals, such as psoralens, lignans, and the flavonoids naringenin and hesperitin, can vary widely among individuals [46, 82]. The process of phytochemical disposition, like that of disposition of drugs and other xenobiotics, involves absorption, metabolism, distribution, and excretion, and each of these parts may contribute to pharmacokinetic variability.

5.1.1 Phytochemical metabolism by gut bacteria

Gut bacteria can hydrolyze glycosides, glucuronides, sulfates, amides and esters [82]. They also carry out reduction, ring-cleavage, demethylation and dehydroxylation reactions.The hydrolysis of glycosides and glucuronides typically results in metabolites that are more biologically active than the parent compounds. In contrast, further bacterial degradation and transformation of aglycones can lead to production of more or less
active compounds, depending on the substrate being metabolized and the products formed. Plant polyphenols,

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including phytoestrogens such as the isoflavones and lignans, are extensively metabolized in the gut by intestinal bacteria.

5.1.2 Phytochemical metabolism by polymorphic phase II conjugating enzymes

Phytochemicals are metabolized in vivo by biotransformation enzymes in a manner similar to that of other xenobiotics. Many classes of phytochemicals are rapidly conjugated with glutathione, glucuronide, and sulfate moieties and excreted in urine and bile. Thus, in theory, polymorphisms in biotransfo rmation enzymes, such as the glutathione S-transferases (GST), UGT, and SULT, have the capacity to affect phytochemical metabolism in the same fashion as they do carcinogens and other xenobiotics
Figure 1: Schematic diagram presenting sources of variation in phytochemical metabolism and disposition.

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6. Approaches in engineering phytochemicals for conjugation:

Novel antioxidant loaded drug delivery systems such as polymeric nanoparticles have been identified as alternatives that should provide longterm delivery at the therapeutic level, prevent antioxidant degradation, and increase pharmacological activity of such antioxidants [82].

6.1. Delivery of phytochemical thymoquinone using molecular micelle modified poly(D, L lactideco- glycolide) (PLGA) nanoparticles:

Thymoquinone (TQ) is a quinone-based phytochemical present in Nigella sativa (Ranunculaceae) black seed oil is a powerful antioxidant and anticancer drug, but its administration is limited due to poor water solubility .In addition, administration of high dosages to rats has resulted in hypoactivity and difficulty in respiration associated with reduced glutathione in the liver and kidney [41]. Another report has shown that TQ was capable of reducing blood glucose levels and inducing allergic dermatitis [83]. To overcome these disadvantages, biodegradable and biocompatible polymeric nanoparticles would be attractive alternatives for TQ delivery as it provides improved TQ solubility, controlled delivery, and enhanced therapeutic properties.

6.2. Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin") for human cancer therapy:

Though curcumin have widespread clinical application in cancer and other diseases, it has limited activity due to poor aqueous solubility, and consequently, minimal systemic bioavailability. Nanoparticle-based drug delivery approaches have the potential for rendering hydrophobic agents like curcumin dispersible in aqueous media. Polymeric nanoparticle encapsulated formulation of curcumin – nanocurcumin have been synthesized – utilizing the micellar aggregates of cross-linked and random copolymers of N- isopropylacrylamide (NIPAAM), with N-vinyl-2-pyrrolidone (VP) and poly (ethyleneglycol)monoacrylate (PEG-A). Nanocurcumin, unlike free curcumin, is readily dispersed in aqueous media and show therapeutic efficacy to free curcumin against a panel of human pancreatic cancer cell lines [84].

Discussion and Conclusion:

Phytochemicals are potentially involved as protective compounds for a number of chronic diseases. Reactive oxygen species (ROS) or oxidants formed in our body due to exogenous and endogenous factors are found to be responsible for many diseases such as cancer, cardiovascular disease, neurodegenerative diseases, inflammatory disease, ischemia-reperfusion injury and aging. The phytochemicals have the ability to neutralize the free radicals or reactive oxygen species or oxidants responsible for the onset of the diseases. The mechanisms by which the plant biomolecules provide defense against ROS mediated diseases are ROS
scavenging, reduction of peroxides and repair of peroxides membrane, utilization of dietary lipids and

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alternative biological pathways that occur in different type of cancer, multiple system organ failure and diabetes. Synthetic antioxidants are found to be harmful to the health, so as alternative natural antioxidants from plant source are safer to health and have better antioxidant activity. Considerable evidences suggest that plant biomolecules such as 6-gingerol ,Caffeic acid, Cyanidin ,Equol, Fisetin ,Myricetin ,Quercetin have anticancer property[10.11,12,24,25,30,37]. Plant flavonoids show efficacy against cardiovascular disease by inhibiting platelet aggregation and adhesion [68].Some phytochemicals have been shown to be hypolipidemic thus control the plasma cholesterol [21,19].On the other hand few plant biomolecules such as polyohenols (β-catechin, epicatechchin ,tannic acid, saponins etc.) demonstrated to have antidiabetic activity as they decrease or delay the transport of glucose to intestine by a variety of parthways [29,30,45,71]. phytochemicals like sulforaphane, resveratrol, curcumin and the cannabinoid THC show hormetic mechanism of action to prevent a number of neurodegenerative diseases[74-78]. Despite the importance of phytochemicals in prevention of diseases there are some challenges regarding its proper administration in the body because of their low water solubility, low absorptivity, low bioavailability and half life of oral phytochemicals are poor. To deal with such problem a strategy of engineered phytochemicals such as PEG-curcumin, nanocurcumin has developed. Engineered phytochemicals are with improved cellular permeability, proteolytic stability and enhanced half-life of cells. Thus by increasing effective size, solubility in aqueous medium and thereby increasing circulation half life; without disturbing rather enhancing bioactivity engineered phytochemicals are now of immense interest in the area of targeted phytochemical delivery. The latest trend of rethinking the natural sources for health and medicine has created a lot of development but still there is much to be learnt about their metabolism, bioavailability, mode of action and dose-response effect, physical, chemical properties such as solubility, diffusion and temperature effects of the phytochemicals of interest and in some cases the actual compound responsible for health effects are still unknown. So, further research is needed to ensure high yield as well as viability and bioavailibity of the plant biomolecules.

Acknowledgement: Authors are grateful to the Vice-Chancellor, University of Kalyani, Kalyani, Nadia, for his interest and support in this work.

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