Download PREFACE The cell is exposed to a large variety of

PREFACE
The cell is exposed to a large variety of reactive oxygen species (ROS) and reactive
nitrogen species (RNS) from both exogenous and endogenous sources (Kohen and
Gati, 2000). The exogenous sources include various drugs, exposure to di-oxygen,
which, although a non-reactive biradical, can independently cause oxidation and
damage to proteins and enzymes, radiation etc.
Ionising and nonionising irradiation constitutes a major exogenous source of ROS
(Pentland, 1994; Shadyro et al., 2002). Exposure of the cell to γ-irradiation results in
the production of a whole range of radical and non-radical species from ionization of
intracellular water. Even exposure to non-ionizing irradiation such as UV-C (< 290
nm), UV-B (290–320 nm), and UV-A (320–400 nm) can indirectly produce a variety
of ROS including 1O2, H2O2, and O2● radicals. Radiotherapy may cause tissue injury
that is caused by free radicals. Ionizing radiation passing through living tissues
generates reactive free radicals. These free radicals can interact with critical
macromolecules, such as DNA, proteins or membranes, and can induce cell damage
and potentially cell dysfunction and death. Damage to DNA may be the most
important factor in cell death (Karbownik and Reiter, 2000). When DNA is
damaged, it is followed by altered cell division, cell death, depletion of stem cell
pools, organ system disfunction and, if the radiation dose is sufficiently high, the
organism will die. Although the cells and tissues are equipped with endogenous
enzymes (e.g. superoxide dismutase) capable of detoxification and removal of the
products of water radiolysis, when these reactive oxygen species increase in the
biological system following exposure to irradiation, the endogenous system is
incapable of protecting cells from the hazardous effects of free radicals. Exposure to
high amounts of ionising radiation results in damage to the haematopoietic,
gastrointestinal or central nervous systems, depending on radiation dose (Sandeep
and Nair 2012).
A number of drugs can increase the production of free radicals in the presence of
increased oxygen tensions and thus act as a major source of ROS (Naito et al., 1998;
Rav et al., 2001). The agents appear to act additively with hyperoxia to accelerate the
rate of damage. These drugs include antibiotics that depend on quinoid groups or
bound metals for activity (nitrofurantoin), antineoplastic agents as bleomycin,
anthracyclines (adriamycin) (Singal et al.,1998) and methotrexate, which possess
pro-oxidant activity (Gressier et al., 1994). Among this belomycine and adreamicine,
whose mechanism of activity is mediated via production of ROS, those like
nitroglycerine that are NO● donors, and those that produce ROS indirectly. The
adriamycin (doxorubicin)-induced cardiotoxicity has been shown to be mediated
through different mechanisms including free radical generation, membrane lipid
peroxidation, mitochondrial damage and iron-dependent oxidative damage to
macromolecules (Zhou a et al., 2001; Xu et al., 2001).
Another important
chemotherapeutic drug inducing oxidative stress is cisplatin. Nephrotoxicity is the
major dose limiting adverse reaction associated with cisplatin. Oxidative damage has
been proposed as a mechanism of cisplatin-induced renal cell death. Narcotic drugs
and anesthetizing gases are considered major contributors to the production of ROS
(Chinev et al., 1998).
Human body is always exposed to different environmental pollutants and
xenobiotics. Liver is the first organ to metabolize all foreign compounds and hence it
is susceptible to almost as many different diseases. Some are rare but there are a few
those are all too common, including hepatitis, cirrhosis, liver fibrosis, alcohol-related
disorders and liver cancer. The high global prevalence of these hepatopathies places
them among the most serious diseases. Although the pathogenesis of liver fibrosis is
not quite clear, there is no doubt that reactive oxygen species (ROS) play an
important role in pathological changes in the liver. The commonly used analgesic,
acetaminophen cause free radical flux and cause damage to the hepatic system
(Bessems and Vermeulen 2001).
Although the exposure of the organism to ROS is extremely high from exogenous
sources, the exposure to endogenous sources is much more important and extensive,
because it is a continuous process during the life span of every cell in the organism
(Kohen, 1999). The reduction of oxygen to water in the mitochondria for ATP
production occurs through the donation of 4 electrons to oxygen to produce water
(Fleury et al., 2002). During this process several major oxygen derivatives are
formed. In many cases there is a leakage of ROS from the mitochondria into the
intracellular environment (Ames, 1995). The mitochondrion serves as the major
organelle responsible for ROS production and many events throughout the cell cycle.
The massive production of mitochondrial ROS is increased further in the aging cell
where the function of the mitochondrion is impaired and its membrane integrity
damaged (Brunk and Terman, 2002).
Enzymes comprise another endogenous
source of ROS. O2●– is produced by one electron reduction of oxygen by several
different oxidases including nicotinamide phosphate dinucleotide (NADPH) oxidase,
xanthine oxidase, cyclooxygenase and even endothelial nitric oxide synthase (eNOS)
under certain conditions. (Evans et al., 2003; Griendling and FitzGerald; 2003a,b
Taniyama and Griendling, 2003). While most enzymes produce ROS as a by-product
of their activity, exemplified by the formation of superoxide radicals by xanthine
oxidase. There are some enzymes designed to produce ROS, such as eNOS yields NO●
radicals, those that produce H2O2, and those responsible for hydroxylation (Canas,
1999; Shaul 2002). White blood cells, including neutrophils, eosinophils, basophils,
and mononuclear cells (monocytes), and lymphocytes, with their mechanisms to
combat bacteria and other invaders are major producers of endogenous ROS.
(Forman Ginsburg and Torres, 2001; Ginsburg and Kohen, 1995).
Following
stimulation, these cells undergo a respiratory burst characterized by a 20-fold
increase in oxygen consumption, which is accompanied by an increase in glucose
utilization and production of reduced NADPH by the pentose phosphate pathway
(Babior et al., 2002). NADPH serves as a donor of electrons to an activated
enzymatic complex in the plasma membrane. This NADPH oxidase complex utilizes
electrons to produce superoxide radicals from the oxygen molecule. Numerous
pathologies and disease states serve as sources for the continuous production of ROS
(Gutteridge, 1993; Kaul et al 2001; Venditti 2002). Almost every organ or system of
the body is affected by oxidative stress. The harmful effects of reactive oxygen species
on the cell are most often include; damage of DNA, oxidations of polydesaturated
fatty acids in lipids (lipid peroxidation), oxidations of amino acids in proteins,
oxidatively inactivate specific enzymes by oxidation of co-factors.
To protect the cells and organ systems of the body against reactive oxygen species,
humans have evolved a highly sophisticated and complex antioxidant protection
system. It involves a variety of components, both endogenous and exogenous in
origin, that function interactively and synergistically to neutralize free radicals
(Jacob, 1995). The role of antioxidants is to neutralize the excess of free radicals, to
protect the cells against their toxic effects and to contribute to disease prevention.
Endogenous compounds in cells can be classified as enzymatic antioxidants and non-
enzymatic antioxidants. The major antioxidant enzymes directly involved in the
neutralization of ROS and RNS are: superoxide dismutase (SOD), catalase (CAT),
glutathione peroxidase (GPx) and glutathione reductase (GRx). (Willcox et al., 2004;
Pacher et al., 2007; Genestra, 2007; .Halliwell, 2007; Valko et al., 2006; Valko et
al., 2005). Exogenous antioxidants are agents which cannot be produced by human
body but may protect against pro-oxidant forces when administered as supplements.
The exogenous antioxidants are obtained from dietary sources, among them Vitamin
C, Vitamin E and β-carotene are the most widely studied dietary antioxidants.
Several natural agents have been used to ameliorate some toxic and carcinogenic
xenobiotics and drugs toxicity. These include Vitamin E and C, carotenoids and
extract of several medicinal plants. Among this considerable interest is focused in the
use of herbal and its phytoconstituents for therapeutic uses. These are mainly
because of their antioxidant property and are less harmful when compared to the
synthetic ones. Plant products have various pharmacological properties and have
been used for the treatment of various diseases long ago. Therefore, screening herbal
drugs offers a major focus for new drug discovery. In this way, attention over the
past 15 years has shifted towards the evaluation of plant products as radioprotectors,
hepato protectors, nephro protectors, cardioprotectors etc due to their efficacy and
low toxicity.
Medicinal plants are considered to be an important source of
antioxidant compounds and the therapeutic benefit of many medicinal plants is often
attributed to their antioxidant properties (Sandeep and Nair, 2012, Joy and Nair,
2009). Compounds with antioxidant activities can neutralize free radicals or their
reactions can be used to alleviate the side effects of xenobiotics like
chemotherapeutic drugs and radiotherapy.
Acorus calamus L., (Family: Araceae) is an important medicinal plant used in the
Ayurvedic system of medicine. This plant with its rich ethno botanical history and
pharmacological effects has been valued for its rhizome and fragrant oils which have
been used medicinally (Motley, 1994).
Alpha-asarone is one of the active
components present in the volatile oil isolated from A.calamus extract (Baxter et al.,
1960). Hemidesmus indicus R.Br. (Syn. Indian sarsaparilla) belongs to the family
Ascalepiadaceae.
Its root is widely used in Ayurvedic, Unani and traditional
medicines for the treatment of inflammation, cuts, wounds, burns, skin and blood
diseases, ulcers, immunological disorders (Verma, 2005; Das, 2003, Kotnis, 2004).
It is well known for its antioxidant and anti-inflammatory activity (Saravanan and
Nalini, 2007). Coscinium fenestratum Colebr. (Menispermaceae), commonly known
as tree turmeric, grows widely in the Western Ghats (India) and Sri Lanka. The plant
has been mainly used for treating diabetes mellitus in the traditional Ayurvedic and
Siddha systems of medicine (Varier, 1994). The present study is mainly focused to
assess the other usefulness of these selected medicinal plants,Acorus calamus and its
major
active
fenestratum.
component
We
α-asarone,
evaluated
the
Hemidesmus
antioxidant,
indicus
and
Coscinium
anti-inflammatory,
antitumor,
radioprotective, hepatoprotective, cardioprotective, nephroprotective activity of the
aqueous-ethanolic extract of this medicinal plant and the pure compound α-asarone.