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.
Raj Kumar, Pankaj Kumar Singh, Rajesh Arora, Raman Chawla, Rakesh Kumar Sharma
PEER REVIEWED
Studies are beginning to show the ability of some plant extracts to protect against radiation. This review highlights the radioprotective effects of the Himalayan Mayapple. PEER REVIEWED
This is the second article published in the Trees
for Life Journal which deals with radioprotection (see Role of Rosemary
Leaf Extract Against Various Doses of Gamma Radiation by Sancheti and Goyal).
While it is not a major focus of this journal, radioprotection has interest for
our readership and is attracting ever more attention within the scientific
community. No synthetic radioprotective chemicals are available that are
perfectly safe and effective. While a variety of plant extracts have been
evaluated for their protective capacity, this work is still in its infancy. The
following review highlights the radioprotective effects of the Himalayan Mayapple.
It also illustrates the degree to which mechanism-based studies are beginning
to support the purely observational work that initially brought to light the radioprotective
effects of certain plant extracts.
Abstract
Radiation mediated free radical flux interferes with
oxidation/reduction-based physiological mechanisms. These free radicals react
with a number of biomolecules including Deoxyribonucleic acid (DNA), lipids and
proteins. The rate and selectivity of these free radical mediated reactions
depend upon the concentration, half-life and state of delocalization of
electrons in the free radicals and the free radicals’ oxidizing ability.
Podophyllum hexandrum Royle (Himalayan Mayapple)
was known as Aindri (“a divine drug”) in ancient times. It has been
reported to be used through the ages and in modern times as a cure for allergic
and inflammatory conditions of the skin; biliary fever; burning sensation;
cold; constipation; cancer of the brain, bladder and lung; erysipelas;
Hodgkin’s disease; insect bites; mental disorders; monocytoid leukemia;
non-Hodgkin’s lymphoma; rheumatism; septic wounds; plague; and venereal warts.
It has served as a commercial source of podophyllotoxin and related aryltetralin
lignans and several other bioactive constituents. Podophyllotoxin finds use as
a precursor for the semi-synthetic topisomerase inhibitors in the treatment of leukemias,
lung and testicular cancers, dermatological disorders like warts, rheumatoid
arthritis, psoriasis and malaria. It also has numerous applications in modern
medicine by virtue of its free radical scavenging capacity. An extract of P.
hexandrum has been shown to provide approximately 80% whole-body
radioprotection in mice.
The present review highlights the state of knowledge
about the radioprotective mechanism of P. hexandrum at different levels
of organization in living organisms. Further, an insight into its mode of
action at the molecular level, including the studies of the expression patterns
of various proteins associated with inhibition of apoptosis in the spleen of
male Swiss albino strain ‘A’ mice by immunoblotting, has been presented. In
conclusion, the studies clearly demonstrated that P. hexandrum extract provides
protection from gamma-radiation by the modulation of expression of proteins
associated with cell death attributed to its ability to modulate free radical
flux.
Introduction
Radiation is one of the most severe causes of
oxidative stress mediated by free radical flux. This flux interferes with
oxidation/reduction-based physiological mechanisms existing inside the
mammalian body system. The rate and selectivity of free radical mediated
reaction depends primarily upon several factors: the concentration of radicals,
the state of delocalization of electrons, the half-life of free radicals and
weak bonds of nearby bio-molecules. Radiation protection is an area of great
significance due to its possible applications in planned radiotherapy as well
as unplanned radiation exposure (1,2). Research in the development of radioprotectors
worldwide has focused on screening a variety of chemical and biological
compounds. Various drugs from natural or synthetic origin, i.e., antioxidant cytoprotective
agents, immuno modulators, vitamins and DNA binding molecules, have been
evaluated extensively for their radioprotective potentials in both in vitro
and in vivo models (1,3,4,5,6). However, the fact remains that there is
not a single radioprotective drug available which meets all the prerequisites
of an ideal radioprotector, i.e., produces no cumulative or irreversible
toxicity, provides effective long-term protection, remains stable for a number
of years without losing shelf life, and can be easily administered (7,8). In
view of this, the search for less toxic and more potent radioprotector drugs
continues.
Herbal drugs have been utilized since ancient times
for curing various diseases and other disorders. Even today, more than 70% of
the world’s population still depends on plant-based remedies to meet their
health care needs (9). Various plants have been reported to be beneficial for
free radical-mediated conditions in humans such as arthritis, atherosclerosis,
cancer, Alzheimer’s disease, Parkinson’s disease, aging and inflammatory
disorders. It is, therefore, logical to expect that plants may contain groups
of compounds that can protect against radiation-induced reactive oxygen species
(ROS) and reactive nitrogen species (RNS) mediated damage (7,8).
Podophyllum hexandrum
Podophyllum hexandrum Royle (Himalayan Mayapple),
is an herb that grows at about 4000 meters of altitude in the Himalayan region
(Figure 1) (10). P. hexandrum has been investigated extensively for its radioprotective
capabilities in recent years, including free radical scavenging, time and
dose-dependent inhibition of apoptosis (programmed cell death) and cell cycle
arrest-related activities in both in vitro and in vivo models
(7,8). The plant is an endangered species and included in the Red Book. In
vitro propagation for mass multiplication of P. hexandrum has been
recently reported (11). Besides its traditional uses (10), methanolic,
hydro-alcoholic and chloroform extracts of P. hexandrum have been
reported to render approximately 70-95% radioprotection in mice when
administered 1-2 hours before lethal whole-body 10Gy radiation (12,13,14). To
achieve radioprotection, recovery of damaged cells after radiation exposure and
minimization of cell death by inhibition of apoptosis is an inescapable
necessity (15,16,17,18,19). P. hexandrum has been reported to contain a
number of bioactive molecules including flavonoids and lignans (10,20,21,22).
 (Click to enlarge)
Figure 1: Podophyllum hexandrum (syn. P. emodi);
common names - Aindri, Himalayan Mayapple, Devil’s apple, and
Duck’s foot; low to the ground with glossy green, drooping, lobed
leaves on its few stiff branches, with a pale pink flower and bright red-orange
bulbous fruit; propagated by seed or by dividing the rhizome; tolerant
to cold temperatures but not to dry conditions. In Eastern Asia, it is found
from Afghanistan to China and through the Himalayan ranges.
Many flavonoids and lignans are already known for their
antioxidant action and anti-apoptotic potential, and thus contribute towards
radioprotection (21). Several mechanisms have been proposed to explain the
radiation protection observed, following administration of P. hexandrum
extract, such as free radical scavenging, stabilization of mitochondrial cell
potential, regulation of cell cycle activities and time dependent apoptosis
(12,13,14,15,16,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35).
P. hexandrum exhibited both anti-cancer
(pro-oxidant ability) and radioprotective (antioxidant ability) effects
respectively depending upon the dose administered (1,20,21,24,29). The
pro-oxidant effects are observed in the presence of metal ions by virtue of the
presence of some aryltetralin lignans (22), further supporting DNA
fragmentation ability at the in vitro level (35). At specific radioprotective
doses, it exhibited significant antioxidant effect as summarized in Table 1.
Molecular mechanism of P. hexandrum mediated radioprotection
Cytoprotective properties
We have recently reported that the mode of protection
by P. hexandrum at the molecular level includes the modulation of
protein expression [associated with cell death (apoptosis) and DNA repair)] by P.
hexandrum administration 200 mg/kg.b.wt. i.p. 2 hrs. before 10 Gy
irradiation (17,18,19). The most striking observations indicated that as a
result of P. hexandrum extract treatment in mice, the expression of heat
shock proteins, especially HSP-70 along with its transcriptional factor HSF-1
(heat shock transcription factor; a protein regulates HSP-70 synthesis) was
increased significantly as compared to the mice treated with radiation (10 Gy)
only. Heat shock proteins are cytoprotective in nature and have been reported
to be increased under various environmental stresses such as increased temperature,
ionizing radiation and chemical toxicants (17). The overexpression of HSF-1
suggested transcriptional level induction of heat shock proteins in the spleen
of mice treated with P. hexandrum extract. The expression of phosphorylating
enzymes (proteins regulating phosphate group transfer to other functional
proteins) such as PkC, MAPKAP Kinase-2 was also observed to increase in the
mice spleen after P. hexandrum treatment (with or without irradiation),
as compared to irradiated control suggesting the possible role of phosphorylating
enzymes in the signal transduction pathways that is initiated upon P. hexandrum
treatment (17,18,19).
Apoptosis inhibitory activities
A strong inhibition of Apoptosis Inducing Factor (AIF
- a cell death promoting protein) expression in the group of mice showed overexpression
of HSP-70 upon P. hexandrum treatment (17). On the basis of a previous
study (36), it was suggested that P. hexandrum treatment initiates an
antagonistic interaction between AIF and HSP-70 expression and thus suppresses
the apoptotic molecular cascade thereby protecting DNA fragmentation. The
anti-apoptotic effect of HSP-70 can be attributed to the ability of P. hexandrum
to provide protection to chromatin from proteases and nucleases, which are
well known apoptotic markers (17,18,19).
Cell proliferation activities
The role of nuclear factor kappa beta (NFkb)
has also been studied extensively in apoptotic regulation NFkb-Ikb
complex and was found to be stable in the cytoplasm. However, under radiation
stress Ikb2
gets phosphorylated by enzymes like Pkc and consequently free NF-kb
moves towards the nucleus, binds with DNA, and initiates a variety of
transcription at times leading to induced cell death (37,38). The expression of
NF-kb
was found to be induced in the cytoplasm upon P. hexandrum treatment
(+/- irradiation), but it was found to be translocated into the nucleus. Podophyllum
hexandrum treatment inhibited the translocation of free NFkb
from the cytoplasm to the nucleus and could explain its anti-inflammatory
effects. This effect may have further lead to down-regulation of p53 and up
regulation of Bcl-2 protein expression, which may have possible contributions
toward reduction of apoptosis and enhanced cell proliferation. Increased
expression of Bcl-2, and HSP70, observed following P. hexandrum
treatment (+/- irradiation), suggests a role of P. hexandrum in
stabilization of the mitochondrial membrane potential leading to inhibition of
membrane permeability (36,39). This prevents release of cytochrome C, leading
to inhibition of apoptosis and thereby offering protection against
radiation-mediated damage to the cells in conformity with the earlier
observations (40). The induced expression of Ras-GAP directly demonstrated the
activation of Ras-related protein R-Ras in the animals treated with P. hexandrum
extract (+/- irradiation), indicating enhanced cell proliferation.
DNA Repair Studies
The expression of proliferating cell nuclear antigen
(PCNA), an important cell proliferation marker in the cell system, was found to
be enhanced in the spleen of mice treated with P. hexandrum (with or
without irradiation), further demonstrating improved cell proliferation and
eventually survival. P. hexandrum treatment (with or without
irradiation) induced the molecular expression of the Poly (ADP-ribosyl) DNA
polymerase (PARP) and down-regulated the expression of caspases and their
transcription regulators (i.e., Caspase Activated DNAase), further indicating
improved DNA repair and significant inhibition of the apoptosis in the mouse
model system (17,18). A summary of the radioprotective action modulated via
modulation of expression of proteins is shown in Figure 2.
 (Click to enlarge)
Figure 2: Possible molecular mechanisms of
radioprotection provided by P. hexandrum
Future Prospects
In view of its acceptable therapeutic index and a
significant dose-reduction factor, P. hexandrum is a promising candidate
plant for development of radioprotective drugs. Since it is an endangered
plant, the interesting lead of usage of Trametes hirsuta (an endopyte)
for mass production of precursors of radioprotective formulation (41) needs to
be further pursued for upscaling. Further studies to characterize the total
profile of gene expression (up or down regulation) by cDNA micro-array and the
effects of P. hexandrum on protein expression (proteomic profiling) will
help unravel the intricate mechanisms of signal transduction pathways operating
at the molecular level. Such data will help in the development of novel radioprotectors
for human use.
Conclusion
In conclusion, P. hexandrum acts in a holistic manner
at various levels. Its administration on mice prior to irradiation leads to a
dramatic enhancement (~80%) in survival. At the molecular level, it induces
pro-survival protein and DNA repair protein expression while down-regulating
the expression of proteins associated with induction of apoptosis. These
activities are congruent with the in vitro free radical modulating ability of
rhizome extracts of P. hexandrum.
Acknowledgements
The authors express their sincere thanks to all the
past and present workers of radiation biology laboratories of INMAS and Natural
Plant Product Division, Regional Research Laboratory, Jammu who have either
originated the work quoted in this mini-review or have given them the benefits
of their experiences of studies on Podophyllum hexandrum.
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Table 1: Radioprotective Studies using Podophyllum
hexandrum
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Radioprotective Studies
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Major Inferences
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References
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Survival Study
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Serendipitously discovered while evaluating
anti-cancerous properties of Podophyllum hexandrum. More than 80%
radioprotection observed in a 30-day survival study using Strain ‘A’ Swiss
Albino mice against 10 Gy exposure with dose reduction factor of 1.33.
Radioprotective effects of podophyllotoxin, an
active constituent of Podophyllum hexandrum were reported in yeast (Sacchromyces
cerevisae).
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1, 6, 15
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Gastroprotection
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The aqueous crude extract (200mg/Kg b.wt., -2hrs)
rendered gastroprotection by:
a) threefold increase in number of surviving crypts
b) 2.7-fold increase in villi cellularity
c) limiting
the radiation-induced apoptosis in crypt cells
d) modulation
of the antioxidant defense system in jejunum and ileum at 12th
post-irradiation day
e) enhanced
levels of glutathione-S-transferase (GST) and superoxide dismutase (SOD) observed
at in vivo level.
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1, 36
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Neuroprotection
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Sub-lethal (2 Gy) dose was given to rats in utero
on day 17 of gestation and pre-irradiation treatment of extract exhibited
mitigation of neuro-physiological alternations.
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19, 38
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Hepatoprotection
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In vitro studies, using human hepato
carcinoma cell lines further revealed its ability to stabilize the state of
mitochondrial oxidative burst, decreased TBARS, time-dependent inhibition of
gamma radiation-induced leakage of electrons in the mitochondrial electron
transport chain (ETC) via reduction in ROS and NO generation and simultaneous
enhancement in the thiol status via neo-synthesis. It also
significantly inhibited the radiation-induced enhanced complex I (NADH: UQ reductase)
activity. On the other hand, the flow and leakage of electrons from complex
I/III (NADH: cytochrome C oxidoreductase) and complex II/III (succinate: cytochrome
C oxidoreductase) was maintained. The above studies are in line with
modulating ability of extract on antioxidant defense in mice.
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20, 21, 30
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Reproductive System
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Extract administration exhibited significant increases
in testis weight, repopulation of the seminiferous tubules and the resting
primary spermatocytes and the stem-cell survival index was maintained. Increased
levels of sperm counts and reduction in the abnormalities of sperm morphology
revealed its ability to protect the testicular system. The extract has also
exhibited its ability to modulate antioxidant enzymes in the male
reproductive system.
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1, 37
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Molecular level Investigations
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Studies at the molecular level revealed interesting
data, e.g., anti-inflammatory activity (reduction of interferon-gamma,
interleukin-6 and tumour necrosis factor-alpha secretion in lipopolysaccharide-induced
inflammation in isolated macrophages); enhanced MAPKAP (mitogen-activated
protein kinase-activated protein) kinase-2 activation along with HSF-1
(heat-shock transcription factor-1) leading to up-regulation of HSP-70
(heat-shock protein-70) with concomitant strong inhibition of AIF
(apoptosis-inducing factor) expression; DNA degradation, and translocation of
free NF-κβ (nuclear factor kappa beta) from cytoplasm to nucleus leading to
decreased expression of tumor suppressor protein p53 and there is a
simultaneous increase in Bcl-2 (B-cell chronic lymphocytic lymphoma 2), Ras-GAP
(Ras-GTPase-activating protein) and PCNA (proliferating cell nuclear
antigen). Such mechanisms have resulted in enhanced survival status.
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26, 27, 28
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Comparative Studies on Fractionated Extracts
of High-Altitude Podophyllum hexandrum and semi-purified extract of
Low-altitude Podophyllum hexandrum
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On the basis of antioxidant screening using radioprotective
studies of Podophyllum hexandrum, aqueous, aqua-alcoholic, chloroform
and alcoholic extracts were selected. The polarity of solvent system to be
used was established. Further, the comparative analysis with semi-purified
extract of low-altitude Podophyllum hexandrum revealed that the
semi-purified extract along with alcoholic and chloroform extract exhibited
immense potential. The semi-purified extract exhibited significant inhibitory
ability against 20 Gy induced double and single strand breaks by virtue of
its free radical scavenging potential. The extract acted as a pro-oxidant in
the presence of metal ions supported by its DNA fragmentation ability. The
extract also exhibited apoptosis induction ability at selected doses. The
selected extracts exhibited significant (p<0.05) nitric oxide scavenging
potential and antioxidant activity in the lipid phase.
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2, 9, 25, 40
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Hemopoietic Modulation
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The studies are further supported by hemopoietic modulatory
ability of the semi-purified extract. The semi-purified extract exhibited
significant recovery in hemoglobin content as compared to irradiated group.
Total leukocytes content was fairly high on 30th post-treatment
day and also the differential leukocyte count was restored to an extent. The
activity was found to be attributed to the hydroxyl ion scavenging activity
of the extract. The extract prophylactic treatment causes the recovery of the
animals on 10th day from bone-marrow aplasia caused due to lethal
exposure of gamma radiation (10Gy). In a recent study using a hydro-alcoholic
extract of Podophyllum hexandrum, the enhanced expression of
heme-oxygenase-1 and pro-survival multi domain Bcl-2 proteins revealed that
the extract-induced modulation of hemopoietic system is linked to the
expression levels of these proteins. The above studies are in coherence with
the immunostimulatory ability and cytoprotective potential of the extract. The
extract also exhibited an inherent potential to chelate iron at in vitro level
indicating its ability to reduce the amplification process.
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5, 14, 16, 24, 35
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Role of secondary metabolites of Podophyllum
hexandrum in radiation protection
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The comparative studies using the comparable levels
of aryltetralin lignans exhibited an indicative correlation between the
pro-antioxidant behavior of the extracts of Podophyllum hexandrum and
the content of individual lignans. The study was just a step towards
revealing the role of lignans in radiation protection. In addition, a novel galactoside
of quercetin was identified in aquo-alcoholic extract of High-altitude Podophyllum
hexandrum and the extract exhibited significant (p<0.05) protein
protection and peroxyl radical scavenging activity in ex vivo model.
These studies indicated the probable role of polyphenolics in addition to lignans
in radiation protection. These leads revealed that the ratio of lignans:polyphenolics
might play a critical role in providing overall radiation protection. The endophytic
Trametes hirsuta is reported as a novel alternative source of podophyllotoxin
and related aryltetralin lignans. An isolated study using endophyte Trametes
hirsuta exhibited the independent synthesis of podophyllotoxin and
related aryl-tetralin lignans. The isolated lignans, even in combinations of
two or more lignans, exhibited significant antioxidant activities relevant to
radiation protection. The studies at the compound levels are still in
infancy and require augmenting for the development of an effective radioprotective
alternative for human use.
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10, 11, 33
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