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.
Palanisamy Arulselvan et al. 240
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
Therapeutic efficacy of natural antioxidants for diabetes 241
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.
Palanisamy Arulselvan et al. 242
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
Therapeutic efficacy of natural antioxidants for diabetes 243
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-
Palanisamy Arulselvan et al. 244
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.
Therapeutic efficacy of natural antioxidants for diabetes 245
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
Palanisamy Arulselvan et al. 246
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
Therapeutic efficacy of natural antioxidants for diabetes 247
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.
Palanisamy Arulselvan et al. 248
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.
Therapeutic efficacy of natural antioxidants for diabetes 249
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),
Palanisamy Arulselvan et al. 250
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.
Therapeutic efficacy of natural antioxidants for diabetes 251
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
Palanisamy Arulselvan et al. 252
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
Therapeutic efficacy of natural antioxidants for diabetes 253
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].
Palanisamy Arulselvan et al. 254
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
Therapeutic efficacy of natural antioxidants for diabetes 255
(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,
Palanisamy Arulselvan et al. 256
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
Therapeutic efficacy of natural antioxidants for diabetes 257
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
Palanisamy Arulselvan et al. 258
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:
Therapeutic efficacy of natural antioxidants for diabetes 259
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
Palanisamy Arulselvan et al. 260
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.
Therapeutic efficacy of natural antioxidants for diabetes 261
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
Palanisamy Arulselvan et al. 262
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.
Therapeutic efficacy of natural antioxidants for diabetes 263
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