11. therapeutic approaches for diabetes with natural...

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Medicinal Plants as Antioxidant Agents: Understanding Their Mechanism of Action and Therapeutic

Efficacy, 2012: 237-266 ISBN: 978-81-308-0509-2 Editor: Anna Capasso

11. Therapeutic approaches for diabetes with

natural antioxidants

Palanisamy Arulselvan1

, Arthanari Umamaheswari2

and Sharida Fakurazi1,3

1Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia

43400 UPM Serdang, Selangor, Malaysia; 2Department of Botany, Bharathi Women’s College

Chennai, Tamilnadu, India; 3Department of Human Anatomy, Faculty of Medicine and Health

Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

Abstract. Diabetes mellitus is more associated with an increased

production of reactive oxygen species and a reduction in natural

antioxidant defense systems. This leads to oxidative stress/damage,

which is partly responsible for diabetes and its complications.

Tight control of glycemic is the most efficient approach of

preventing and/or decreasing these complications. Nevertheless,

antioxidant micronutrients can be proposed as alternative therapy

in patients with severe diabetes. Antioxidants from natural foods

neutralize the effects of free radicals that damage the small energy

generating mitochondria found in all cells and other vital tissues as

well. This leads to cellular dysfunction and ultimately to cell death

when the damage becomes too much to sustain normal cellular

function. Free radicals are the primary vehicle driving and

initiation of most disorder/disease processes. Nutritional important

vegetables/fruits including colorful berries, grapes, tomatoes,

carrots, spinach, broccoli, nuts and seeds to naturally combat the

damage caused by normal metabolic activity/tissue damages.

Indeed, some of the essential minerals and vitamins are able to

indirectly participate in the reduction of oxidative stress in diabetic

Correspondence/Reprint request: Dr. Arthanari Umamaheswari, Assistant Professor, Department of Botany

Bharathi Women‘s College, Chennai 600 108, Tamilnadu, India. E-mail: [email protected]

Palanisamy Arulselvan et al. 238

patients by improving glycemic control and/or are able to exert antioxidant activity.

The use of important minerals (vanadium, chromium, magnesium, zinc, selenium,

copper) and vitamins or co-factors in diabetes, with a particular focus on the

prevention/treatment of diabetic complications. Scientific reports show that dietary

supplementation with micronutrients may be a complement to classical therapies for

preventing and treating diabetic complications. Based on the available scientific

evidence, several natural products with anti-oxidant nature in common use can lower

blood glucose in patients with diabetes. Frequently used natural products often have a

long history of traditional use, and pharmacists who have a stronger medical

knowledge of these products are better positioned to counsel patients on their

appropriate use.

Introduction

Antioxidant is a molecule capable of slowing or preventing the oxidation

of other important molecules. Oxidation is a chemical reaction that transfers

electron from a substance to an oxidizing agent. Oxidation reactions can

generate toxic metabolite including free radicals, which start chain reactions

that damage tissues/cells. Antioxidants terminate these chain reactions by

removing free radicals intermediates/derivatives, and inhibit other oxidation

reactions by being oxidized themselves. Although oxidation reactions are

essential for human daily life, they can also be damaging; hence, plants and

animals maintain complex systems of multiple types of antioxidants, such as

glutathione, natural vitamins including vitamin C, and vitamin E as well as

enzymes such as superoxide dismutase, catalase and various peroxidases.

Low levels of these antioxidants, or inhibition of the antioxidants enzymes,

cause oxidative stress and may cumulative damage cells. As oxidative stress

might be an important cycle/part of many human disorders/diseases, the use

of antioxidants in pharmacology is intensively studied, particularly as

treatments for inflammation caused metabolic disorder and its complications

like diabetes, cardio stroke and other neurodegenerative diseases.

Role of free radicals and disorders/diseases

Free radicals are one of the natural by‐products of our own essential body

metabolism. These are electrically charged molecules that attack our body

tissues/cells, tearing through cellular membranes to react and create havoc

with the nucleic acids, proteins, and enzymes present in the living system.

These attacks by free radicals, collectively known as oxidative stress, are

capable of causing cells to modify their structure as well as function and can

eventually destroy them. They are continuously produced by our body‘s use

of oxygen such as in respiration and some cell‐mediated/regulated immune

Therapeutic efficacy of natural antioxidants for diabetes 239

functions. They are also generated through various environmental pollutants,

cigarette smoke, automobile exhaust, radiation, air‐pollution, pesticides, etc

[1]. Normally, there is a balance between the amount of free radicals

generated in the body and the antioxidant defense systems that scavenge/

quench these free radicals preventing them from causing deleterious effects

in the body [2]. The antioxidant defense systems in the body can only

protect the body when the amount of the free radicals is within the adequate

physiological level. But when this balance is shifted towards more of free

radicals, increasing their burden in the body either due to environmental

condition or produced within the body, it leads to oxidative stress, which

may result in vital tissue injury and subsequent diseases/disorders [3]. Since

free radicals play such an important role in the disease scenario of an

individual, a systematic understanding of the various physiologically

significant free radicals is of paramount importance before the search of the

radical scavengers or the antioxidant principles to treat the physiological

disorders caused by them. Free radicals may be designated as molecular

sharks that damage molecules in cell membranes, mitochondria the cell‘s

energy plants), DNA (the cell‘s intelligence) and are very unstable, tend to

rob electrons from the molecules in the immediate surroundings in order to

replace their own losses. Reactive oxygen species (ROS) is a collective term,

Figure 1. Generation and sources of free radicals and its various implications.


which includes not only the oxygen radicals but also some non‐radical

derivatives of oxygen. These include hydrogen peroxide (H2O2), hypochlorous

acid and ozone [4]. Over about 100 disorders/diseases like rheumatoid

arthritis, hemorrhagic shock, cardiovascular disorders, cystic fibrosis, metabolic

disorders, neurodegenerative diseases, gastrointestinal ulcerogenesis and AIDS

have been reported as ROS mediated pathways. Some very specific examples

of ROS mediated diseases include Diabetes, Alzheimers disease, Parkinson‘s

disease, Atherosclerosis, Cancer, Down‘s syndrome and ischemic reperfusion

injury in different tissues including heart, liver, brain, kidney and

gastrointestinal tract.

Oxidative stress

Oxidative stress is defined in general as excess formation and/or

insufficient removal of highly reactive molecules/intermediates including

reactive oxygen species (ROS) and reactive nitrogen species (RNS) [5,6].

ROS include free radicals such as superoxide, hydroxyl, peroxyl,

hydroperoxyl as well as non-radical species such as hydrogen peroxide

(H2O2) and hydrochlorous acid [5,7]. RNS include free radicals like nitric

oxide and nitrogen dioxide, as well as non-radicals such as peroxynitrite,

nitrous oxide and alkyl peroxynitrates [7]. Based on these highly reactive

molecules, superoxide, nitric oxide, and peroxy-nitrite are the most widely

studied species and play vital roles in the diabetes and its associated

complications. Thus, these reactive species are discussed in more detail.

Nitric oxide is normally produced from L-arginine by endothelial nitric

oxide synthase (eNOS) in the vasculature [5]. It mediates endothelium-

dependent vasorelaxation by its action on guanylate cyclase in vascular

smooth muscle cells (VSMC), initiating a cascade that leads to

vasorelaxation. Nitric oxide also displays anti-proliferative properties and

inhibits platelet and leukocyte adhesion to vascular endothelium [5].

Therefore, it is considered a vasculoprotective molecule. However, nitric

oxide easily reacts with superoxide, generating the highly reactive molecule,

and triggering a cascade of harmful events [5,7]. Therefore, its chemical

environment, i.e. presence of superoxide, determines whether nitric oxide

exerts protective or harmful effects against living system.

Production of one reactive species like ROS or RNS may lead to the

production of other species through radical chain reactions. Superoxide is

produced by one electron reduction of oxygen by several different oxidases

including NAD(P)H oxidase, xanthine oxidase, cyclooxygenase and even

eNOS under certain conditions as well as by the mitochondrial electron

transport chain during the course of normal oxidative phosphorylation, which


is essential for generating ATP [8,9,10]. Under normal conditions, superoxide

is quickly eliminated by antioxidant defense systems. It is dis-mutated to

H2O2 by manganese superoxide dismutase (Mn-SOD) in the mitochondria

and by copper (Cu)-SOD in the cytosol [8]. H2O2 is converted to H2O and O2

by glutathione peroxidase (GSH-Px) or catalase in the mitochondria and

lysosomes, respectively. H2O2 can also be converted to the highly reactive

hydroxyl radical in the presence of transition elements like iron and copper.

Oxidative stress and its role in human health

Oxidative stress is a harmful condition that occurs when there is an

excess of ROS and/or a decrease in antioxidant levels, this may cause tissue

damage by physical, chemical, psychological factors that lead to tissue injury

in human and causes different diseases. Living creatures have evolved a

highly complicated defense system and body act against free radical-induced

oxidative stress involved by various defense mechanisms such as preventative

mechanisms, repair mechanisms, physical defenses and antioxidant defenses

[11].

Oxygen derived free radical reactions have been implicated in the

pathogenesis of many human diseases/disorders including [11-18]:

Neurodegenerative disorders like alzheimer‘s disease, parkinson‘s

disease, multiple sclerosis, amyotrophic lateral sclerosis, memory loss

and depression.

Cardiovascular diseases like atherosclerosis, ischemic heart disease,

cardiac hypertrophy, hypertension, shock and trauma.

Pulmonary disorders like inflammatory lung diseases such as asthma and

chronic obstructive pulmonary disease.

Diseases associated with premature infants, including broncho

pulmonary, dysplasia, and periventricular leukomalacia, and

intraventricular hemorrhage, retinopathy of prematurity and necrotizing

enterocolitis.

Autoimmune disease like rheumatoid arthritis.

Renal disorders like glomerulonephritis and tubulointerstitial nephritis,

chronic renal failure, proteinuria, uremia.

Gastrointestinal diseases like peptic ulcer, inflammatory bowel disease

and colitis.

Cancers like lung cancer, leukemia, breast, ovary, rectum cancers etc.

Eye diseases like cataract and age related of retina, maculopathy and

ageing process.

Diabetes.


Figure 2. Classification of free radicals and various disorders/diseases induced by free

radicals.

Skin lesions and Immunodepression.

Liver disease, pancreatitis, AIDS and Infertility.

Diabetes mellitus and oxidative stress

Diabetes is a chronic metabolic or hormonal disorder that continues to

present a most important worldwide health problem. It is characterized by

absolute or relative deficiencies in insulin secretion and/or insulin action

associated with chronic hyperglycemia and disturbances of series of

metabolism including carbohydrate, lipid, and protein metabolism. As a

consequence of the metabolic derangements in diabetes, various

complications develop including both macro and micro-vascular dysfunctions

[19]. It is well accepted that oxidative stress results from an imbalance

between the generation of oxygen derived radicals and the organism‘s

antioxidant potential [20]. Various researches have shown that diabetes

mellitus is associated with increased formation of free radicals and decrease

in antioxidant potential. Due to these various events, the balance normally

present in cells between radical formation and protection against them is

disturbed. This leads to oxidative damage of cell components such as


proteins, lipids, and nucleic acids. Increased oxidative stress can induce both

type 1 and type 2 diabetes as well as its complications [21].

Conflicting results have been reported for the role of free radical induced

oxidative stress in diabetes. F2-isoprostanes are prostaglandin like

compounds formed in-vivo from free radical catalyzed peroxidation of

arachidonic acid and have emerged as novel and direct measures of oxidative

stress. F2-isoprostane levels have been reported to be increased in the plasma

of type 2 diabetes mellitus and in the urine of type 2 and type 1 diabetic

subjects [22,23]. A correlation between impaired glycemic control and

enhanced lipid peroxidation has been reported [23]. It was shown that

oxidative stress exists in diabetic patients as evidenced by increased total

antioxidant capacity in saliva and blood sample of patients [24]. Oxidative

stress is increased in diabetes because of multiple factors. Dominant among

these factors is glucose auto-oxidation leading to the production of free

radicals. Other factors include cellular oxidation/reduction imbalances and

reduction in antioxidant defenses (including decreased cellular antioxidant

levels and a reduction in the activity of enzymes that disposes free radicals).

In addition, levels of some pro-oxidants such as ferritin and homocysteine are

elevated in diabetes. Another important factor is the interaction of advanced

glycation end products (AGEs) with specific cellular receptors called AGE

receptors (RAGE). Elevated levels of AGE are formed under hyperglycemic

conditions. Their formation is initiated when glucose interacts with specific

amino acids on proteins forming a compound which undergoes further

chemical reactions. Glycation of protein alters protein and cellular/immune

function, and binding of AGEs to their receptors can lead to modification in

cell signaling pathways and further production of free radicals [25].

Sources of oxidative stress in diabetes

Substantiation of oxidative stress in diabetes is based on researches that

focused on the measurement of oxidative stress specific markers such as

plasma and urinary iso-prostane, plasma and tissue levels of nitrotyrosine and

superoxide [26-29]. There are different sources of oxidative stress in diabetes

including non-enzymatic, enzymatic and mitochondrial signaling pathways.

Thus, these mechanisms are to be discussed and to conclude with the recently

available scientific evidence for the initiation of oxidative stress and related

to diabetes associated complications.

Non-enzymatic sources of oxidative stress originate from the oxidative

biochemistry of glucose. Hyperglycemia can directly cause increased free

radicals/ROS generation. Glucose can undergo auto-oxidation and generate

hydroxyl radicals [5]. In addition, glucose reacts with proteins in a non-


enzymatic manner leading to the development of amadori products followed

by formation of AGEs. ROS is generated at multiple steps during this

biological process. In hyperglycemia, there is enhanced metabolism of

glucose through the polyol (sorbitol) pathway, which also results in enhanced

production of superoxide.

Enzymatic sources of augmented generation of reactive species in

diabetes include NOS, NAD(P)H oxidase and xanthine oxidase [28,29]. All

iso-forms of NOS require five cofactors/prosthetic groups such as flavin

adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, BH4 and

Ca2+-calmodulin. If NOS lacks its substrate L-arginine or one of its

cofactors, NOS may produce superoxide instead of nitric oxide and this is

referred to as the uncoupled state of NOS [6,28,30]. NAD(P)H oxidase is a

membrane associated enzyme that consists of five subunits and is a major

source of superoxide production [31,32]. Guzik et al. [28] investigated

superoxide levels in vascular specimens from diabetic patients and probed

sources of superoxide using inhibitors of NOS, NAD(P)H oxidase, xanthine

oxidase and mitochondrial electron transport chain. The study shows that

there is enhanced production of superoxide in diabetes and this is

predominantly mediated by NAD(P)H oxidase.

In addition, the NOS-mediated component is greater in patients with

diabetes than in normal patients [28]. Previous research findings showed that

NAD(P)H oxidase activity is significantly higher in vascular tissue

(saphenous vein and internal mammary artery) sample obtained from diabetic

patients [33]. There is plausible evidence that protein kinase C, which is

stimulated in diabetes via multiple mechanisms, i.e. polyol pathway and Ang 2,

activates NAD(P)H oxidase [34]. The mitochondrial respiratory chain is

another source of non-enzymatic generation of reactive species. During the

oxidative phosphorylation process, electrons are transferred from electron

carriers NADH and FADH2, through four complexes in the inner

mitochondrial membrane, to oxygen, generating ATP in the process [35].

Under normal conditions, superoxide is immediately eliminated by natural

defense mechanisms. Various studies showed that hyperglycemia-induced

generation of superoxide at the mitochondrial level is the initial trigger of

vicious cycle of oxidative stress in diabetes [36,37]. When endothelial cells

are exposed to hyperglycemia at the levels relevant to clinical diabetes, there

is increased generation of ROS and especially superoxide, which precedes the

activation of four major pathways involved in the development of diabetic

complications. Nishikawa and colleagues [36] elegantly demonstrated that

generation of excess pyruvate via accelerated glycolysis under hyperglycemic

conditions floods the mitochondria and causes superoxide generation at the

level of Complex II in the respiratory chain.


More important is that blockade of superoxide radicals by three kind

approaches using either a small molecule un-coupler of mitochondrial

oxidative phosphorylation (CCCP), overexpression of uncoupling protein-1

(UCP1) or overexpression of Mn-SOD, prevented changes in NF-kB as well

as polyol pathway, AGE formation and PKC activity. Based on this

information, it has been postulated by several groups that mitochondrial

superoxide is the initiating snowball that turns oxidative stress into an

avalanche in diabetes by stimulating more ROS and RNS production via

downstream activation of NF-kB-mediated cytokine production, PKC and

NAD(P)H oxidase. Thus, inhibition of intracellular free radical formation

would provide a better therapeutic approach in the prevention of oxidative

stress and related diseases especially diabetes and its complications.

Natural protection against free radical induced oxidative

stress and role of antioxidants

Reactive species can be eliminated by a number of enzymatic and non-

enzymatic antioxidant defense mechanisms. In enzymatic antioxidant system,

SOD immediately converts superoxide to H2O2, which is then detoxified to

water either by catalase in the lysosomes or by glutathione peroxidase in the

mitochondria. Another important enzyme is glutathione reductase, which

regenerates glutathione that is used as a hydrogen donor by glutathione

peroxidase during the elimination of H2O2. Maritim and colleagues reviewed

in brief detail that diabetes has multiple effects on the protein levels and

activity of these kind antioxidant enzymes, which further augment oxidative

stress by causing a suppressed defense response [6]. For example, in the

heart, which is an important target organ in diabetes and prone to diabetic

cardiomyopathy leading to chronic heart failure, SOD and glutathione

peroxidase expression as well as activity are decreased whereas catalase is

increased in various experimental models of diabetes [6,38]. In patients with

chronic heart failure, all these important enzymes are decreased in the smooth

muscle [39] and exercise training can up-regulate the expression and activity

of antioxidant enzymes. Increased iso-prostane levels in diabetic patients

with chronic heart failure are correlated with antioxidant status and disease

severity [40]. Thus, modulation of these enzymes in target organs prone to

diabetic complications such as heart and kidney may prove beneficial in the

prevention and management of heart and kidney related dysfunctions.

Non-enzymatic antioxidants include vitamins A, C and E, glutathione,

α-lipoic acid, carotenoids, trace elements like copper, zinc and selenium,

coenzyme Q10 (CoQ10), and cofactors like folic acid, uric acid, albumin, and


vitamins B1, B2, B6 and B12. Alterations in the antioxidant defense system

in diabetes have been reviewed [26]. Glutathione (GSH) acts as a direct

scavenger as well as a co-substrate for GSH peroxidase. It is a major

intracellular redox tampon system. Vitamin E is a fat-soluble vitamin that

prevents lipid peroxidation. It exists in 8 different forms, of which α -tocopherol

is the most active form in humans. Hydroxyl radical reacts with tocopherol

forming a stabilized phenolic radical which is reduced back to the phenol by

ascorbate and NAD(P)H dependent reductase enzymes [41]. CoQ10 is an

endogenously synthesized compound that acts as an electron carrier in the

Complex II of the mitochondrial electron transport chain. Brownlee et al

reported that this is the site of superoxide generation under hyperglycemic

conditions [36,37]. CoQ10 is a lipid soluble antioxidant, and in higher

concentrations, it scavenges superoxide and improves endothelial dysfunction

in diabetes [42,43]. Vitamin C (ascorbic acid) increases NO production in

endothelial cells by stabilizing NOS cofactor BH4 [44]. α-Lipoic acid is a

hydrophilic antioxidant and can therefore exert beneficial effects in both

aqueous and lipid environments. α -lipoic acid is reduced to another active

compound dihydrolipoate. Dihydrolipoate is able to regenerate other

antioxidants such as vitamin C, vitamin E and reduced glutathione through

redox cycling [44]. Thus, both experimental and clinical studies summarized

in the next sections utilized these naturally occurring antioxidants, especially

vitamins C, E and α -lipoic acid, in order to delineate the role of oxidative

stress/damage in the development of complications of diabetes.

Antioxidants

Antioxidants are substances that may protect/prevent cells from the

damage caused by unstable molecules known as free radicals. Antioxidants

interact/react with and stabilize free radicals and may prevent/manage some

of the damage free radicals otherwise might cause. Free radical damage may

lead to diabetes, inflammatory disorders and cancer etc. Examples of

antioxidants include beta-carotene, lycopene, vitamins A, C, E, and other

related natural substances [45]. An antioxidant is a molecule capable of

slowing or preventing the oxidation of other molecules. Oxidation is a

chemical reaction that transfers electrons from a substance to an oxidizing

agent. Oxidation reactions can produce free radicals, which start chain

reactions that damage tissues/cells. Antioxidants complete these specific

chain reactions by removing free radical intermediates and inhibit other

oxidation reactions by being oxidized themselves. As a result, antioxidants

are often reducing important agents such as this, ascorbic acid or polyphenols

[45]. Although oxidation reactions are crucial for human life, they can also be


damaging; hence, living systems maintain complex systems of multiple types

of antioxidants, such as glutathione, vitamin C and vitamin E as well as

enzymes such as superoxide dismutase, catalase and various peroxidases.

Decreased level of antioxidants, or inhibition of the antioxidant enzymes,

causes oxidative stress and may damage tissues/cells. As oxidative stress

might be an important part of many human disorders/diseases, the use of

antioxidants in pharmacology is intensively studied, particularly as treatments

for diabetes, and its complication specifically stroke and other

neurodegenerative diseases. Antioxidants are also widely used as ingredients

in dietary supplements in the hope of maintaining health, enhancing immune

defense systems and preventing diseases such as cancer, diabetes and

coronary heart disease.

In addition to these uses of natural antioxidants in medicine, natural

compounds have many industrial uses, such as preservatives in food,

cosmetics and preventing the degradation of rubber and gasoline. For many

years chemists have known that free radicals cause oxidation which can be

controlled or prevented by a range of natural/synthetic antioxidants

substances [46]. It is vital that lubrication oils should remain stable and liquid

should not dry up like paints. For this reason, such oil usually has small

quantities of antioxidants such as phenol or amine derivatives, added to them.

Although plastics are often formed by free radical action, they can also be

broken down by the same process, so they too, require protection by

antioxidants like phenols or naphthol etc [45].

Figure 3. Classification of anti-oxidants and its role in human health.


Sources and origin of antioxidants

Antioxidants are abundant in colorful fruits and leaf vegetables, as well

as in other important functional foods including nuts, grains and some meats,

poultry and fish. Here we describe some food sources of common bio-active

antioxidants. Beta-carotene is found in many foods that are orange in color,

including sweet potatoes, carrots, cantaloupe, squash, apricots, pumpkin and

mangoes. Some of green leafy vegetables, including collard greens, spinach,

and kale, are also rich in beta-carotene. Lutein, best known for its association

with healthy eyes, is abundant in green, leafy vegetables such as collard

greens, spinach, and kale [47].

Lycopene is a potent natural antioxidant found in tomatoes, watermelon,

guava, papaya, apricots, pink grapefruit, blood oranges and other functional

foods. Estimates suggest 85% of American dietary intake of lycopene comes

from tomatoes and tomato related products [48]. Selenium is an important

mineral, not an antioxidant nutrient. However, it is a component of

antioxidant enzymes. Plant foods like rice and wheat are the major dietary

sources of selenium in most developing and developed countries. The amount

of selenium in soil, which varies by region, determines the amount of

selenium in the foods grown in that specific soil. Animals that eat grains or

plants grown in selenium-rich soil have higher levels of selenium in their

body muscle. In the United States, meats and bread are common sources of

dietary selenium. Brazil nuts also contain large quantities of selenium.

Vitamin A is found in three main forms: retinol (Vitamin A1), 3,

4-didehydroretinol (Vitamin A2), and 3-hydroxyretinol (Vitamin A3). Foods

rich in vitamin A include liver, sweet potatoes, carrots, milk, egg yolks and

mozzarella cheese [49]. Vitamin C is also called ascorbic acid and can be

found in high abundance in many fruits and vegetables and is also found in

cereals, beef, poultry, and fish (Antioxidants and Cancer Prevention, 2007).

Vitamin E, also known as alpha-tocopherol, is found in almonds, in many oils

including wheat germ, safflower, corn and soybean oils, and is also found in

mangoes, nuts, broccoli, and other nutrient foods [50].

Classification of antioxidants

Antioxidants are grouped/classified into two namely;

1) Primary or natural antioxidants. 2) Secondary or synthetic antioxidants.


Natural antioxidants

They are the chain breaking antioxidants which react with lipid radicals

and convert them into more stable products. Antioxidants of this group are

mainly phenolic in structures and include the following [51]:

1. Antioxidants minerals

These are co-factor of important enzymatic antioxidants. Their absence

will definitely affect metabolism of many macromolecules such as

carbohydrates and nucleic acids etc. Examples of antioxidant minerals

include selenium, copper, iron, zinc and manganese.

2. Antioxidants vitamins

It is needed for most of the body essential metabolic regulations. They

include - vitamin C, vitamin E, vitamin B and its subtype.

3. Phyto-chemicals

These are mostly phenolic compounds that are neither essential vitamins

nor minerals. These include: i) Flavonoids: These are phenolic compounds

that give vegetables, functional fruits, grains, seeds leaves, flowers and bark

their colours. ii) Catechins are the most bio-active antioxidants in green and

black tea and sesamol. iii) Carotenoids are fat soluble colour in fruits and

vegetables. iv) Beta carotene, which is rich in carrot and converted to vitamin

A when the body lacks enough of the vitamin. v) Lycopene, one of the

important phyto-constituents of tomatoes and vi) zeaxantin is high in spinach

and other dark greens. Herbs and spices a rich source include diterpene,

rosmariquinone, thyme, nutmeg, clove, black pepper, ginger, garlic and

curcumin and related derivatives.

Synthetic antioxidants

These are phenolic group of compounds that perform the essential

function of capturing free radicals/decreasing oxidative stress and stopping

the chain reactions through various biological actions, the compounds include

[51]:

Butylated hydroxyl anisole (BHA),

Butylated hydroxyrotoluene (BHT),

Propyl gallate (PG) and metal chelating agent (EDTA),


Tertiary butyl hydroquinone (TBHQ),

Nor dihydro guaretic acid (NDGA) etc.

Antioxidant defense

It is evident through the reactions of oxygen, that it is toxic; still only the

aerobes survive its presence, primarily because they have evolved an inbuilt

antioxidant defense. Antioxidant defenses comprise:

Antioxidant agents that catalytically remove free radicals and other

reactive species like SOD, CAT, peroxidase and thio specific agents.

Proteins that minimize the availability of peroxidase such as iron ions,

copper ions and haem etc.

Proteins that protect important bio-molecules for immune functions

against oxidative damage including heat shock proteins.

Low molecular mass agents including natural anti-oxidants that scavenge

ROS and RNS, example GSH, ascorbic acid, tocopherol.

The antioxidants may be defined as ―any substance, when present at

below basal level compared with that of an oxidizable substrate that

significantly delays or prevents oxidations of that substrate‖.

The term oxidizable substrate includes every type of reactive molecule

found in vivo experimental model. Antioxidant defense systems include the

non-enzymatic and enzymatic antioxidants including SOD, CAT, GSH‐px,

low molecular agents and dietary nutritional antioxidants [52].

Antioxidants and its protection against various disorders/

diseases

Numerous epidemiological studies that have shown inverse correlation

between the levels of established antioxidants/phyto-nutrients present in

tissue/blood samples and occurrence of diabetes, cardiovascular disease,

cancer or mortality due to these diseases. However, some of the meta-

analysis show that supplementation with mainly single antioxidants may not

be that biologically effective [53], a view that contrasts with those of

preclinical and epidemiological studies on consumption of antioxidant‐rich

functional foods. Based on the epidemiological and case control studies

recommendations were made for the daily dietary intake of some clinically

proved antioxidants like vitamin E and C as well as others nutrients.

Requirement for effective antioxidants in Asian conditions differ from that of

industrialized western countries due to the various nutritional differences.


There are also a number of dietary supplements rich in antioxidants tested for

their clinical beneficiary efficacy. There are many research laboratories and

research institutions from India and worldwide working on the antioxidant

effect of plant derived phyto-compounds, mainly from natural sources that

are capable of protecting against oxidative damage. Different studies prove

that compounds with potent antioxidant activity include carotenoids,

curcumin from turmeric, flavonoids, caffeine present in coffee, tea, etc.,

orientin, vicenin, glabridin, glycyrrhizin, emblicanin, punigluconin,

pedunculagin, 2‐hydroxy‐4‐methoxy benzoic acid, dehydrozingerone,

picroliv, withaferin, yakuchinone, gingerol, chlorogenic acid, vanillin (food

flavoring agent) and chlorophyllin [54].

Antioxidants and diabetes

Antioxidants counter the various actions of free radicals by several

molecular mechanisms. These mechanisms include: (1) enzymes that degrade

free radicals reactions, (2) proteins such as transferrin that can bind metals

which stimulate the production of free radicals, and (3) antioxidants including

vitamins C and E that act as effective free radical scavengers. To combat

oxidative stress, the administration of exogenous antioxidants has been

investigated in a number of trials to balance antioxidants and pro-oxidants.

The theoretical framework for this comes from several clinical studies which

have found that individuals with reduced plasma antioxidant status are at

elevated risk for diabetic complication specifically cardiovascular events

[55]. In addition individuals with type 2 diabetes have lower basal levels of

antioxidants than age-matched controls [56]. Indeed, a low lipid standardized

plasma vitamin E or vitamin C concentration has been proposed as a highly

risk factor for subsequent development of type 2 diabetes and its

complication [57]. Various antioxidant supplementation studies have

demonstrated conflicting results in endothelial function, retinal blood flow

and renal function outcomes [58-60].

Therefore, we have undertaken a focused review of those experimental

clinical studies that have demonstrated glycaemic control outcome measures

in type 2 diabetes patients following natural vitamin supplementation in order

to understand any significant of antioxidant-based therapy in diabetes and its

various complications.

Antioxidants and diabetes: Clinical evidence

Researches using animal models of diabetes indicate that antioxidants,

especially α-lipoic acid (LA), improve insulin sensitivity [61]. There are


several available natural antioxidants that hold promise as new approaches

for the treatment of insulin resistance, including N-acetyl cysteine, α-lipoic

acid (LA), and flavanols. A number of researchers have found that the

antioxidants LA, glutathione, vitamin E, and vitamin C increase insulin

sensitivity in patients with insulin resistance, Type 2 diabetes, and/or

cardiovascular disease.

In patients with diabetes, both acute and chronic administration of LA

improves insulin resistance as measured by both the euglycaemic hyper-

insulinaemic clamp and the Bergman minimal model [62-64]. Furthermore,

the short-term (6 wk) oral administration of a novel controlled release

formulation of LA lowered plasma fructosamine levels in patients with type 2

diabetes [65].

α -lipoic acid

LA is an eight-carbon fatty acid that functions naturally as a cofactor in

several mitochondrial enzyme complexes responsible for oxidative glucose

metabolism and cellular energy production [63]. LA has been prescribed in

Germany as a pharmacological antioxidant for over 30 years for the treatment

of diabetes-induced neuropathy, and this compound is naturally safe, well

tolerated and more efficacious [59]. Interestingly, several clinical studies

have demonstrated an improvement in insulin sensitivity and whole-body

glucose metabolism in patients with type 2 diabetes after intravenous infusion

of LA [63]. Oral administration of LA (enteric-coated tablet) exerts a smaller

(~20%) but significant effect [63]. To overcome the abbreviated half-life of

LA (~30 min), a controlled release, orally available formulation of LA

(CRLA) has been developed, and significantly reduced plasma fructosamine

in patients with T2 diabetes [65].

Although the exact mechanism of action of LA is unknown, in vitro data

have indicated that LA pretreatment maintains the intracellular level of

reduced glutathione (the major intracellular antioxidant) in the presence of

oxidative stress, and blocks the activation of serine kinases that are associated

with insulin resistance [66,67]. Thus, LA may preserve the intracellular redox

balance (acting either directly or through other endogenous antioxidants such

as glutathione), thereby blocking the activation of inhibitory inflammatory

serine kinases including IKKβ [68].

Glutathione

In patients with type 2 diabetes, there is a significant inverse correlation

between fasting plasma FFA concentration and the ratio of reduced/oxidized


glutathione (a major endogenous antioxidant) [69]. In normal healthy

subjects, infusion of FFA (as intralipid) causes increased oxidative stress

induced damage as judged by increased malondialdehyde concentrations and

a decline in the plasma reduced/oxidized glutathione ratio [69].

Malondialdehyde, a highly toxic byproduct generated in part by lipid

oxidation and ROS, is increased in diabetes mellitus and other

disorders/diseases [70]. In both normal individuals and in subjects with

diabetes, restoration of redox balance by infusing glutathione improves

insulin sensitivity along with β-cell function [71].

N-acetylcysteine (NAC)

N-acetylcysteine (NAC), a thiol-containing antioxidant that elevates

intracellular glutathione concentrations, is receiving growing attention for

potential use as a therapeutic agent in experimentally clinical models in

which there is evidence of increased oxidative stress [72,73].

Vitamins and supplements

Numerous studies have proved that antioxidant vitamins and supplements

can help lower the markers indicative of oxidant stress and lipid peroxidation in

diabetic subjects and experimental animals as well. A number of research

studies have reported vitamin C and E and beta-carotene deficiency in diabetic

patients and experimental animals [21,28]. The most frequently studied natural

antioxidant vitamins are C and E. Vitamin E is a lipophilic antioxidant that

interferes with the chain reaction of lipid peroxidation. Vitamin C is a

hydrophilic molecule that can scavenge radicals, among them the hydroxyl

radical. It is likely that vitamins C and E act in a synergistic manner, vitamin E

primarily being oxidized to the tocopheroxyl radical and then being reduced

back to tocopherol by vitamin C and glutathione. Vitamin C is the strongest

physiological antioxidant acting in the organism‘s aqueous environment. It has

been shown to be an important natural antioxidant, to regenerate vitamin E

through redox cycling, and to raise intracellular glutathione levels. Thus,

vitamin C plays an important role in protein thiol group protection against

oxidation [21]. In contrast to vitamin A, the vitamin C and E combination can

also be safely used in high doses to help prevent diabetes and other diseases.

Vitamin C

In addition to playing a major role in the aetiology of diabetic macro-

angiopathy, endothelial dysfunction could promote insulin resistance [79].


It is possible that oxidative stress-mediated blunting of nitric oxide action

indirectly affects insulin sensitivity (e.g., reduced peripheral blood flow,

increased peroxynitrite formation, and others) consequently reducing insulin-

stimulated glucose transport in skeletal muscle.

Cigarette smoking impairs endothelial function, and is one of the major

risk factors for hypertension, atherosclerosis, and coronary heart disease. The

effects of vitamin C (infusion) on insulin sensitivity and endothelial function

[measured by flow-mediated dilation (FMD) of Brachial artery] were evaluated

in smokers, non smokers with impaired glucose tolerance, and non smokers

with normal glucose tolerance [75]. Both insulin sensitivity and FMD were

blunted in smokers and nonsmokers with IGT, compared with controls. In

smokers and in non smokers with impaired glucose tolerance, vitamin C

significantly improved FMD, increased insulin sensitivity, and decreased

plasma thiobarbituric acid-reactive substances, an index of oxidative stress. In

contrast, vitamin C had no effect on these parameters in non smokers with

normal glucose tolerance. In patients with coronary spastic angina and

endothelial dysfunction, vitamin C infusion augmented FMD and increased

insulin sensitivity [76]. In contrast, vitamin C had no effect in healthy controls.

Natural products

The word natural is an adjective referring to something/some material

that is present in and/or produced by natural sources and not artificial or man-

made. The term natural products today is quite commonly understood to refer

to herbs, herbal concoctions, natural dietary supplements, traditional Chinese

medicine, or alternative medicine [77].

Modern drugs discovery and development may have been based on

herbs, folklore, or traditional or alternative medicine, the research and

discovery of, along with the development of, herbal remedies or dietary

supplements typically present different challenges with different goals

[78,79]. So while the various stories of herbs and drugs are very much

intertwined, it needs to be fully appreciated that the use of herbs as natural

product therapy is different than the use of herbs as a platform for drug

discovery and further drug development.

Natural products as therapeutic agents

Natural products are generally either of prebiotic origin or originate from

microbes, plants, or animal sources [80,81]. As chemicals, natural products

include different classes of phyto-compounds as terpenoids, amino acids,

peptides, proteins, carbohydrates, lipids, nucleic acid bases, ribonucleic acid


(RNA), deoxyribonucleic acid (DNA), and so forth. Natural products are not

just products of convenience of nature. More than likely they are a natural

expression of the increase in complexity of organisms [82]. Interest in natural

sources to provide treatments for pain, palliatives, or curatives for a variety of

maladies or recreational use reaches back to the earliest points of history.

Nature has provided many different things for humankind over the years,

including the tools for the first attempts at therapeutic intervention [80,81].

Neanderthal and others have been found to contain the remnants of medicinal

herbs [77]. The Nei Ching is one of the earliest health science anthologies

ever produced and dates back to the thirtieth century BC [80,81]. Some of the

first evidences on the use of natural products in medicine were written in

cuneiform in Mesopotamia on clay tablets and date to approximately 2600

BC [83,84]. Indeed, many of these natural agents continue to exist in one

form or another to this day as treatments for inflammation, influenza,

coughing, and parasitic infestation. Chinese herb guides document the use of

herbaceous plants as far back in time as 2000 BC [77]. In fact, The Chinese

Materia Medica has been repeatedly documented over centuries starting at

about 1100 BC [83,84].

Egyptians have been found to have documented uses of various herbs in

1500 BC [77,83,84]. The best known of these documents is the Ebers

Papyrus, which documents nearly 1000 different substances and

formulations, most of which are plant-based medicines [80,81]. Asclepius (in

1500 BC) was a famous physician in ancient Greece who achieved fame in

part because of his use of plants in medicine [77]. A collection of Ayurveda

hymns in India from 1000 BC and earlier describes the uses of over 1000

different herbs. This work served as the basis for Tibetan Medicine translated

from Sanskrit during the eighth century [83,84]. Theophrastus, a philosopher

and natural scientist in approximately 300 BC, wrote a History of Plants in

which he addressed the medicinal qualities of herbs and the ability to

cultivate them. The Greek botanist Pedanious Dioscorides in approximately

ad 100 produced a work entitled De Materia Medica, which today is still a

very well-known European document on the use of herbs in medicine system.

Galen (ad 130–200) practiced and taught pharmacy and medicine in Rome

and published over two dozen books on his areas of interest. Galen was well-

known for his complex formulations containing multiple ingredients. Monks

in monasteries in the Middle Ages copied manuscripts about herbs and their

uses [77,83,84].

Such a lack of conventional medicine and physicians in early America

spawned the production of various types of almanacs and other publications

that contained various natural product-based recipes and assorted tidbits of

medical information. Indeed, in an effort to curry favor with commoners,


physicians themselves turned to the production of self-treatment guides for the

general public. Various types of societies and botanical clubs held meetings and

published different types of communiqués to educate the public with regard to

the availability of natural products and how they could be helpful to an

individual‘s health. Samuel Thompson‘s Thompson‘s New Guide to Health

was one very popular publication. For a variety of different reasons, the interest

in natural products continues to this very day [77,85-88]. The first commercial

pure natural product introduced for therapeutic use is generally considered to be

the narcotic morphine, marketed by Merck in 1826 [89]. The first semi-

synthetic pure drug discovered based on a natural product, aspirin, was

introduced after successful translational studies by Bayer in 1899.

Plants and their active ingredients

Nowadays, there has been a considerable interest in finding natural

antioxidants from plant materials to replace synthetic ones. Data from both

scientific reports and laboratory studies show that plants contain a large

variety of substances that possess antioxidant and other biological activities

[90]. Phyto-chemicals with antioxidant effects include some cinnamic acids,

coumarins, diterpenes, flavonoids, lignans, monoterpenes, phenylpropanoids,

tannins and triterpenes [91]. Natural antioxidants occur in all higher plants

and in all parts of the plant (wood, bark, stems, pods, leaves, fruit, roots,

flowers, pollen, and seeds) [90]. Injury or damage of plant cells, as well as

mammalian cells, is associated with the activation of lipoxygenases, which

catalyze the formation of hydroperoxides of polyunsaturated fatty acids;

hydroperoxide radicals may react with fatty acids to produce dioxoenes,

which are regarded as plant defense compounds.

The occurrence of oxidative mechanisms in plants may explain why an

abundance of antioxidant compounds have been identified in plant tissue

[91]. Therefore it seems that plants particularly those with high levels and

strong antioxidant compounds have an important role in improvement of

disorders/diseases involving oxidative stress such as diabetes mellitus. There

are many clinical investigations which have studied the biological effects of

these plants and their effective antioxidant ingredients on diabetes and its

complications and achieved good results.

Bioactive phyto-constituents as effective antioxidants

Human body system is enriched with natural antioxidants and can

prevent the onset as well as treat diseases caused and/or fostered due to free-

radical mediated oxidative stress. Human also takes antioxidants through


various kind of nutritional diet. In foods, antioxidants found in small

quantities but capable to prevent or greatly retard the oxidation of easily

oxidizable materials [92].

Recent investigations have shown that the antioxidants of plant origin

with free-radical scavenging properties could have great importance as

therapeutic agents in several diseases/disorders caused due to oxidative stress

[93]. Phyto-extracts and phyto-constituents found effective as radical

scavengers and inhibitors of lipid peroxidation [94,95]. Many synthetic

antioxidant compounds have shown toxic and/or mutagenic effects, which

have stimulated the interest of many researchers to search natural antioxidant.

Herbal medicine is still the mainstay of about 75-80% of the world

population, mainly in developing countries, for primary health care because of

better cultural acceptability, better compatibility with the human body and

lesser side effects. The chemical constituents present in the herbal medicine or

medicinal plant are a part of the physiological functions of living flora and

hence they are believed to have better compatibility with human body. Natural

products from plants are a rich resource used for centuries to cure various

ailments. The use of bioactive plant-derived compounds is on the rise, because

the main preoccupation with the use of synthetic drugs is the side effects which

can be even more dangerous than the diseases they claim to cure. In contrast,

plant derived medicines are based upon the premise that they contain natural

substances that can promote health and alleviate illness and proved to be safe,

better patient tolerance, relatively less expensive and globally competitive. So,

in respect of the healing power of plants and a return to natural remedies is an

absolute requirement of our period [93,96]. Even synthetic drugs used to treat

various disorders can capable of produce free radical which leads oxidative

stress and caused tissue/cell damage. For example, non steroidal anti-

inflammatory drugs (NSAIDs) are used widely in the treatment of pain, fever,

inflammation, rheumatic and cardiovascular disease but chronic administration

of those drugs leads the generation of free radicals which may results gastric

erosions, gastric or duodenal ulceration and severe complications such as

gastrointestinal hemorrhage and perforation [96]. The use of phyto-constituents

as drug therapy to scavenge free radicals and to treat disorders leads due to

oxidative stress has proved to be clinically effective and relatively less toxic

than the existing drugs. Therefore it is demand of time to uses drugs from plant

sources or phyto-constituents to prevent and/or treat oxidative stress.

Therapeutic strategies of medicinal plants

The management either prevention or treatment of diabetes without any

side effects are still a challenge to the biomedical field. Herbal drugs are


prescribed widely because of their effectiveness, fewer side effects and

relatively low cost. Wide array of plant derived active principles have

demonstrated anti-diabetic activity. The main active constituents of these

plants include alkaloids, glycosides, galactomannan gum, polysaccharides,

peptidoglycan, hypoglycans, guanidine, steroids, carbohydrates,

glycopeptides, terpenoids, amino acids and inorganic ions. These affect

various metabolic cascades, which directly or indirectly affect the level of

glucose in the human body [97].

Medicinal plants research and drug development

The World Health Organization estimates that approximately 80 percent

of the world‘s population relies primarily on traditional medicines as sources

for their primary health care [98]. Over 100 chemical substances that are

considered to be important drugs that are either currently in use or have been

widely used in one or more countries in the world have been derived from a

little under 100 different plants. Approximately 75 percent of these

substances were discovered as a direct result of phytoconstituents studies

focused on the isolation of active substances from plants used in traditional

medicine [83,84]. More current statistics based on prescription data from

1993 in the United States show that over 50 percent of the most prescribed

drugs had a natural product either as the drug or as the starting point in the

synthesis or design of the actual end chemical substance [89]. Thirty-nine

percent of the 520 new drugs approved during the period 2000 were either

natural products or derivatives of natural products [95]. Indeed, if one looks

at new drugs from an indication perspective over the same period of time,

over 60 percent of anti-bacterial and anti-neoplastic were again either natural

products themselves or based on structures of natural products. Of the 20 top-

selling drugs on the market in the year 2000 that are not proteins, 7 of these

were either derived from natural products or developed from leads generated

from natural products. These selected group of drugs generates over 20

billion U.S. dollars of revenue on an annual basis [99,100].

Drug development over the years has relied only on a small number of

molecular prototypes to produce new medicines [99]. Indeed, only

approximately 250 discrete chemical structure prototypes have been used, but

most of these chemical platforms have been derived from natural sources.

While recombinant proteins and peptides are gaining market share, low

molecular-weight compounds still remain the predominant pharmacologic

choice for therapeutic intervention [100]. Just a small sampling of the many

available examples of the commercialization of modern drugs from natural

products along with their year of introduction, indication, and company are:


Orlistat, 1999, obesity, Roche; Miglitol, 1996, anti-diabetic (Type 2

diabetes), Bayer; Topotecan, 1996, anti-neoplastic, SmithKline Beecham;

Docetaxel, 1995, anti-neoplastic, Rhône-Poulenc Rorer; Tacrolimus, 1993,

immunosuppressant, Fujisawa; Paclitaxel, 1993, anti-neoplastic, Bristol-

Myers Squibb. The overwhelming concern today in the pharmaceutical

industry is to improve the ability to find new drugs and to accelerate the

speed with which new drugs are discovered and developed. This will only be

successfully accomplished if the procedures for drug target elucidation and

lead compound identification and optimization are themselves optimized. The

process of high-throughput screening enables the testing of increased

numbers of targets and samples to the extent that approximately 100,000

assay points per day are able to be generated. However, the ability to

accelerate the identification of pertinent lead compounds will only be

achieved with the implementation of new ideas to generate varieties of

structurally diverse test samples [99,100]. Experience has persistently and

repeatedly demonstrated that nature has evolved over thousands of years a

diverse chemical library of compounds that are not accessible by commonly

recognized and frequently used synthetic approaches.

Natural products have revealed the ways to new therapeutic approaches,

contributed to the understanding of numerous biochemical/molecular

pathways and have established their worth as valuable tools in biological

medicinal chemistry, molecular and cellular biology. Some examples of

natural products that are currently being evaluated as potential drugs are

(natural product, source, target, indication, status): manoalide, marine

sponge, phospholipage-A2 Ca2+-release, anti-inflammatory, clinical trials;

dolastatin 10, sea hare, microtubules, antineoplastic, nonclinical; staurosporine,

streptomyces, protein kinase C, antineoplastic, clinical trials; epothilone,

myxobacterium, microtubules, antineoplastic, research; calanolide A, B, tree,

DNA polymerase action on reverse transcriptase, acquired immunodeficiency

syndrome (AIDS), clinical trials; huperzine A, moss, cholinesterase,

alzheimer‘s disease, clinical trials [100].

The costs of drug discovery and development continue to increase at

astronomical rates, yet despite these expenditures, there is a decrease in the

number of new medicines introduced into the world market. Despite the

successes that have been achieved over the years with natural products, the

interest in natural products as a platform for drug discovery has waxed and

waned in popularity with various pharmaceutical companies. Natural

products today are most likely going to continue to exist and grow to

become even more valuable as sources of new drug leads. This is because

the degree of chemical diversity found in natural products is broader than that

from any other source, and the degree of novelty of molecular structure found


Figure 4. Schematic representation of process of natural products drug discovery

against different ailments.

in natural products is greater than that determined from any other source

[99,101].

Examples of such biological activity profiles would include, but are not

limited to, nootropics, psychoactive agents, dependence attenuators,

anticonvulsants, sedatives, analgesics, anti-inflammatory agents, antipyretics,

neurotransmission modulators, autonomic activity modulators, autacoid

activity modulators, anticoagulants, hypo-lipidemics, anti-hypertensive

agents, cardioprotectants, positive ionotropes, antitussives, anti-asthmatics,

pulmonary function enhancers, anti-allergens, hypoglycemic agents, anti-

fertility agents, fertility-enhancing agents, wound healing agents, dermal

healing agents, bone healing agents, compounds useful in the prevention of

urinary calculi as well as their dissolution, gastrointestinal motility

modulators, gastric ulcer protectants, immuno-modulators, hepato-protective

agents, myelo-protective agents, pancreato-protective agents, oculo-

protective agents, membrane stabilizers, hemato-protective agents,

antioxidants, agents protective against oxidative stress, anti-neoplastic,

antimicrobials, antifungal agents, anti-protozoal agents, anti-helminthics, and

nutraceuticals [102]. Many frontiers remain within the field of natural

products that can provide opportunities to improve our quality of life.


Increasing numbers of people are receiving immunomodulatory

treatment for an organ transplant or some underlying chronic systemic

pathology, anti-neoplastic chemotherapy for cancer, or have been the

recipients of proper or improper use of powerful antibiotics. Additionally

there are a number of individuals within society that are infected with the

human immunodeficiency virus (HIV) [103]. Furthermore, in this

armamentarium, there are problems with dose-limiting nephro-toxicity, the

rapid development of resistance, drug–drug interactions of concern, and a

fungistatic mechanism of action. Thus, there is an urgent need for the

development of more efficacious antifungal agents with fewer limitations and

less side effects. Ideally such compounds should possess good distribution

characteristics, a novel mechanism of action, and a broad-spectrum cidal

antifungal activity. The discovery and isolation of an echinocandin-type

lipopeptide and lipopeptidolactone from microbes has been a significant

achievement. These compounds are water soluble and inhibit the synthesis of

1, 3-b-glycan, a key component of the fungal cell wall.

Newer therapeutic/preventive approaches with natural

antioxidants

Antioxidant‐based drugs/formulations for prevention and treatment of

complex diseases like atherosclerosis, stroke, diabetes, Alzheimer‘s disease

(AD), Parkinson‘s disease, cancer, etc. appeared over the past three decades.

Free radical theory has greatly stimulated interest in the role of dietary

antioxidants in preventing many human diseases, including cancer,

atherosclerosis, stroke, rheumatoid arthritis, neuro-degeneration and diabetes.

Dietary antioxidants may have promising therapeutic potential in delaying the

onset as well as in preventing the ageing population and its related

complications. Two neuro-protective clinical trials are available with

antioxidants: Deprenyl and tocopherol antioxidant therapy of Parkinson‘s

disease study. It has embarked on a fast track programme to discover new

drugs by building on traditional medicines and screening the diverse plants

and microbial sources [104].

Free radicals have been implicated in the etiology of large number of

major diseases. They can adversely alter many crucial biological molecules

leading to loss of form and function. Antioxidants can protect against the

damage induced by free radicals acting at various levels. Dietary and other

components of plants form major sources of antioxidants. The relation

between free radicals, antioxidants and functioning of various organs and

organ systems is highly complex and the discovery of ‗redox signals‘ is a


milestone in this crucial relationship. Recent research focus on various

strategies to protect crucial tissues and organs against oxidative damage

induced by free radicals. Many novel approaches are made and significant

findings have come to light in the last few years. The traditional functional

diet, spices and medicinal plants are rich sources of natural antioxidants.

Higher intake of foods with functional attributes including high level of

antioxidants in functional foods is one strategy that is gaining importance in

advanced countries. Coordinated research involving biomedical scientists,

nutritionists and physicians can make significant difference to human health

in the coming decades. Research on free radicals and antioxidants involving

these is one such major effort in the right direction [54].

Conclusion and future development of natural antioxidants

Technology-based economic growth rate has been one of the key factors

in creating the wealth of a nation. The most developed countries are

characterized by their wealth creation based on pursuing high quality

research, output and development investments and translating their

innovations into commercial products [105]. These criteria appear tough for

the developing nations specifically Asia region, as they are poorly prepared

to invest large sums of money for advanced research and development.

Therefore, developing countries like India may find a solution by looking

back into their glorious past of traditional medicinal practice like Ayurveda,

Unani and Siddha for alternative therapeutic options.

Traditional system like Ayurveda and Siddha, discovered, nurtured and

perfected in India as science of longevity, are not just a collection of

therapeutic recipes, but also frameworks that define the condition of sickness

and connect them with healing practices. In olden days these scientific

disciplines not only thrived in India but also influenced healing practices in

many other developing countries. That period of intense creativity was a

glorious one and every Indian has the reason to remember it with pride [106].

As an alternative approach therefore, they may rely on the traditional medical

knowledge and biodiversity as springboards. By fusing ancient wisdom and

modern science, India can create world-class products [104]. Therefore, it has

embarked on a fast track programme to discover new drugs by building on

traditional medicines and screening the diverse plants and microbial

resources of the country. Identification of antioxidant rich natural resources,

preparing molecular fingerprints of their bioactive constituents and studying

the multiple preventive/therapeutic properties in this programme may help

make India self-reliant in antioxidant based drug discovery in future.


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