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Phytochemistry, Pharmacology, and Applications of Phytoecdysteroids
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Overall, the metabolizations described above weaken substantially the
position of the plant ecdysteroids as exogenous pest control agents and
distract the attention to probable therapeutic applications in the higher
species.
5.6. AGROCHEMICAL APPLICATIONS
5.6.1. Deterrent and Toxic Effects on Invertebrates
Invertebrates display a broad spectrum of responses to exogenous
ecdysteroids. Non-adapted species are very sensitive and stop growing
normally on diets comprising only 2 to 5 ppm 20E. The adapted species are
capable to cope under the conditions of a laboratory with diets comprising
500 to 1,000 parts per million 20E. Conversely, in realism, there is an entire
spectrum amongst these extremes, as there are particular species that grow
normally on diets comprising reasonable levels of ecdysteroids, which might
be sufficient to kill non-adapted insects, but generally which yield at higher
concentrations, which would not be sufficient to affect adapted species
(Blackford and Dinan, 1997a). The multiplicity of responses is feasible in
the non-adapted species, varying from an entire rejection of the ecdysteroidcomprising food, through premature metamorphosis and molting, to
imperfect or fail death and molting in soil nematodes and insects (Kubo
et al., 1983). One shouldn’t consider that the ecdysteroids do not affect the
adapted species, as it has been established that specific species which possess
the outstanding capacity to metabolize consumed ecdysteroids will select the
ecdysteroid-free diet in selection tests, and there exits high metabolic price
in detoxifying consumed ecdysteroids by esterification with the fatty acids
which might not be obvious in the developing terms when food is abundant
under the laboratory conditions but might have an important effect in wild
if the food is rare (Kubo et al., 1987; Robinson et al., 1987). Therefore,
it is possible that phytoecdysteroids are capable to decrease predation by
most of the phytophagous species and that the broadly different profiles and
concentrations of the ecdysteroids discovered in ecdysteroid-comprising
plants associates with the sensitivity and susceptibility of the species
of phytophagous they are being and have been exposed to. This is vital
conceptually for utilizing endogenous phytoecdysteroids for the protection
of crops, but equally numerous phytophagous species already have the
prospective to overcome higher ecdysteroid levels, and extensive utilization
of such kind of crops will give the strong assortment pressure in favor of
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adapted pests, as they have established at least two diverse approaches to
avoid this mechanism of defense. Adapted species of insect have developed
effective mechanisms of detoxification, and their midgut signifies the very
effective barrier; as an outcome, a small fraction of the ingested ecdysteroids
enters the hemolymph of insect. Other insect species (e.g., Acherontia
atropos;) quickly excrete the consumed ecdysteroid unmodified. The further
defense mechanism is dependent on the discovery of ecdysteroids in the diet
of the insect through taste receptors, which outcomes in the circumvention
of ecdysteroid-comprising diet (Blackford and Dinan, 1997b; Marion-Poll
and Descoins, 2002). Therefore, insects are capable to choose host plants
that are ecdysteroids free, or parts of the ecdysteroid-comprising species
that comprise lower concentrations (even though these might have a lower
quality of nutrition, and therefore there is the trade-off that aids the plant
while permitting the insect to feed, as the insect is normally directed away
from the developmentally significant plant parts). Feeding deterrence can
be noticed in species that have effective mechanisms of detoxification, and
it is significant to underline that the effect can be perceived with lower
concentrations of ecdysteroids. The taste receptors are existent on the
legs of adult females of as a minimum some species of insect, which can
perceive the existence of ecdysteroids on a phylloplane, and will outcome in
oviposition deterrence (Calas et al., 2006, 2007).
Natural Compounds: An Introduction
5.6.2. Ecdysteroids as Main Compounds for Pesticides
Ecdysteroids per se are not appropriate for the arthropod pest control,
as they do not possess suitable environmental or chemical properties for
external utilization to crop plants or insects (Dinan, 1989). They are not
metabolically or environmentally stable enough, as they might break down
on prolonged exposure to the conditions of the field or consumption by an
insect. As an outcome of the polarity, they would not penetrate the cuticle
of the insect well but would be washed readily from the crop plants through
the rain. Chemically, they are too costly to contemplate synthesis on a large
scale. Conversely, the commercial price of at least 1 ecdysteroid detachable
from plants has decreased dramatically over the current years, which has
simplified its feasibility for pharmaceutical productions, but it has possibly
not dropped to a level to make the crops spraying a feasible option.
Therefore, the best viewpoint in this eld to exploit the vulnerability of
the ecdysteroid receptors to disturbance is to seek particular non-steroidal
compounds which hinder with ecdysteroid action mode. This might be done
by the discovery of serendipitous or by the long-term approach centered on
Phytochemistry, Pharmacology, and Applications of Phytoecdysteroids
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understanding the interaction and shape requirements of a ligand-binding
pocket of the receptor, which can be advanced by characterization of a
receptor itself (by NMR or X-ray crystallography), or by dening the binding
similarities of an important number of the ligand analogs, which are being
presently followed (Billas and Moras, 2005; Dinan and Hormann, 2005). For
the latter approach, nature has been exceptionally kind in giving the large
array of structurally different analogs in the shape of phytoecdysteroids.
These can give a wide data set of SAR for the establishment of the binding
specicity of particular receptors and recognition of differences amongst
species before the molecular modeling of data to develop an understanding
of the charge and spatial necessities of the LBD and in giving information
about how the binding pocket and ligand interact with one another. The
models generated can be utilized to recognize novel high-afnity steroidal
ligands, impact chemical synthesis approaches, and even to develop virtual
screens for isolated chemistries to recognize prospective non-steroidal
ligands.
5.6.3. Uses in Apiculture/Sericulture/Aquaculture
It has been discovered that ecdysteroids can normally be utilized to improve
the culture of silk moths (Trivedy et al., 2006; Changrakala et al., 1998)
and honeybees (Kholodova, 2001). When exposed to large quantities of
the exogenous ecdysteroids, these particular species, like other species of
insect, experience detrimental effects. Conversely, when uncovered to low
amounts at specific times during growth, certain advantages are observed,
like enhanced synchrony of the cocoon creation and higher silk produce in
B. mori, or enhancement of fecundity in the honeybees. The action mode
of ecdysteroids under these given circumstances is not known yet, but
it is feasible that experience to low levels of the ecdysteroids lowers the
influence of stress, occasioning in improved fitness. Owing to the extensive
occurrence of certain species of plant which comprise comparatively large
quantities of phytoecdysteroids, this strategy lends itself to donating to
honey and silk production in various parts around the globe, where they
are followed as the industries of a cottage by farmers who utilize them as
minor cash earners moreover to the normal crops. Various studies have
been carried out to identify appropriate ecdysteroid-comprising plant
species native to the silkworm-rearing parts around the globe (India, China,
Thailand). The phytoecdysteroid-comprising plants can be grown up by
the farmer and merely extracted to produce solutions appropriate for insect
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application. This has the benefit of simplicity, but the control of quality is
restricted in terms of quantities of the ecdysteroid applied and of the other,
probably detrimental, compounds existent in the extract. Almost nothing is
presently known regarding the structure-activity association of ecdysteroids
for the treatment of silkworms. As this can be anticipated to be impacted by
several factors, comprising metabolism on consumption, rate of excretion,
and sequestration besides the nuclear receptor binding similarity, it could
be dissimilar from the ligand-binding particularity of the receptor only.
Therefore, there is ample scope for further comprehension of the scientific
basis of the useful applications, for optimization of treatment, and the
control of the quality of a product. Conversely, if the process is to stay in the
farmer’s control, it must be kept very simple and forthright to remain within
the resources and means of the farmer. Likewise, feasibility studies have
generally been carried out for utilizing food pellets mixed with the rough
extracts of phytoecdysteroid-comprising plants to decrease the period of
molting and enhance synchrony in shrimps/prawns (Kanazawa et al., 1972;
Cho and Itami, 2004).
Natural Compounds: An Introduction
5.6.4. Quantitative and Qualitative Alteration of Ecdysteroid
Levels in the Crop Plants
One approach for utilizing ecdysteroids to guard crop plants is to improve
the phytoecdysteroids levels existent in the plants. As phytoecdysteroids
seem to have few harmful effects on vertebrates and might have substantial
positive pharmaceutical advantages, but can deter non-adapted invertebrate
phytophagous predators, appears as an attractive idea. Conversely, amongst
the very few crop plants (spinach, quinoa) of the world gather substantial
quantities of ecdysteroids, but there exits an increasing circumstantial
proof that most of the plant species preserve the genetic capacity to yield
ecdysteroids, but in the majority of the species’ activity or expression of
biosynthetic genes is intimidated (Dinan et al., 2001a–c). Therefore,
understanding the mechanisms of regulation involved might lead to the
simple approach of dismissing the repression and improving ecdysteroid
all over the plant, or in particular parts of the plant. Such kind of variation
in regulation may be accomplished by recognition of natural alternates,
where the repression does not occur, or by genetic adjustment of the plant.
Moreover, to altering levels in the crop plants, there might be a benefit in
directing the synthesis of the ecdysteroids towards specific analogs, as some
of these may avert the metabolic procedures of phytophagous invertebrates
or have the greater inherent disruptive capability. Therefore, clarification of
Phytochemistry, Pharmacology, and Applications of Phytoecdysteroids
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phytoecdysteroid biosynthetic paths and their regulation must be the main
concern for research. If there are higher levels of ecdysteroid in the parts
of a plant to be ingested, this might bring nutraceutical advantages with
it, but might also disturb the taste or some other properties significant to
consumers and it stays to be observed if this sort of strategy can contest with
the utilization of exogenous insecticides in cost-effectiveness and efficiency.
5.6.5. Gene Switches in Plants
The most appropriate properties of the systems of gene-switch in plants are
(a) high specificity; (b) low activity in absence of the elicitor; (c) a robust,
quick, and response dependent on dose in the existence of elicitor; (d)
functionality in a broad variety of species of plant and (e) the necessity for
environmentally safe and non-phytotoxic elicitors (Wang et al., 2003). Also,
the activator must be active at the nanomolar concentrations, the large-scale
field uses to become a viable option at which point. Controlled transgene
expression in the plants might be utilized to control leaf abscission and
flowering, enhance disease resistance, in bio farming, and the creation of
the male sterility systems (Gatz and Lenk, 1998; Gurr and Rushton, 2005).
Ecdysteroid receptor systems of gene-switch have been examined
far less for the regulation of a gene in the systems of the transgenic plant
as compared to the vertebrate cells. The 1
monopartite system comprising the LBD of Heliothis virescens EcR, merged
with the DBD of VP16 and GR activation domain, which was triggered by
10 to 100 μM concentrations of the RH5992 (Jepson et al., 1998; Martinez
et al., 1999a, b). The performance of gene-switch has been substantially
enhanced by utilizing the two-hybrid system comprising of RXR and EcR
with methoxyfenozide as an activator, which is more sensitive (needing
elicitor’s nanomolar concentrations) and providing low background
expression with elevated induced levels of expression (Tavva et al., 2007a,
b). Particular DAHs (including methoxyfenozide and RH5992) are already
specialized for utilization on crops as an insecticide, and they might have
been exhibited to be environmentally well-suited chemicals. Therefore, most
of the anticipated criteria have been integrated into a system, but most of the
work till now has utilized in vitro systems like protoplasts or assessment in
the limited plants’ range; therefore, demonstration of the eld-scale use is
still lacking. Regulation of the single transgenic genes might not be rened
enough for commercial utilization, where corresponding control of various
genes might be required. Struggle so far has, comprehensibly, engrossed on
switching on a gene. Conversely, for effective application, the switching-off
st
system described was the
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Natural Compounds: An Introduction
expression might be just as signicant (Gurr and Rushton, 2005). Moreover,
it stays to be observed if the public will readily admit crops with more rmly
controlled transgene expression. However, the projections for this kind of
strategy are potentially great.
5.7. MEDICAL APPLICATIONS
5.7.1. Pharmaceutical Effects on the Vertebrates
Ecdysteroids can be categorized as adaptogenic substances, i.e., compounds
that aid the equilibrium of the body functions and enhance resistance to
several diseases (but do not cure diseases, once established). Various
reviews dealing with pharmacological effects of the ecdysteroids have been
documented (Syrov, 2000; Sláma and Lafont, 1998; Kholodova, 2001;
Lafont and Dinan, 2003; Báthori, 2002; Dinan and Lafont, 2006; Báthori and
Pongrácz, 2005), so this topic will not be discussed broadly here. The main
effects concern several physiological functions, and most of the classical
ones are given in Table 5.1.
Only one example will be described here, i.e., effects of the ecdysteroids
on skin. Application of the ecdysteroids in liposomes quickens skin repair
after apparent wounding (Lin and Lin, 1989), and the 20-hydroxyecdysone
encourages in vitro keratinocyte differentiation (Detmar et al., 1994).
Table 5.1: Some of the Ecdysteroids Pharmacological Effects on the Mammals
Effect References
Stimulation of protein synthesis Okui et al. (1968); Otaka et al. (1968)
Hypocholesterolemic Lupien et al. (1969); Syrov et al. (1983)
Immunomodulatory Kuzmitsky et al. (1990)
Vitamin D synergistic Levitsky et al. (1993)
Antiinammatory Kurmukov and Syrov (1988)
Anabolic Chermnykh et al. (1988); Koudela et al. (1995)
Antiradical/antioxidative properties Osynskaya et al. (1992)
Source: Báthori and Pongracz (2005); Lafont and Dinan (2003); Dinan and
Lafont (2006).
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Generally, ecdysteroids display wound-healing (Darmograi et al., 1998;
Syrov and Khushbaktova, 1996), psoriasis-constraining effects (Inaoka et
al., 1997), and they might even encourage regrowth of hair (Ishida et al.,
1999). Indeed, numerous patents concern the utilization of ecdysteroids in
the cosmetics (e.g., Meybeck and Bonté, 1990; Lin and Lin, 1989; Tsuji et
al., 1995a, b; Dumas et al., 2001; Darmograi et al., 1998; Hoshino et al.,
2003), and ecdysteroid-comprising preparations are available commercially.
It was currently claimed that ecdysteroids might have the effects of skin
protection against ultraviolet harm when taken orally (Meybeck and Yang,
2007); this supposition appears to be the extrapolation from the data of in
vitro, and in vivo, experimental proof is lacking. This is amongst the several
medicinal uses recommended for ecdysteroids, which also have been
exhibit to display useful effects on several organs, comprising the heart and
circulatory system, kidneys, liver, and lungs, and the CNS (central nervous
system). Ecdysteroids seem also to encourage repair of bone fracture and
decrease glycemia in diabetics (Dinan and Lafont, 2003). Methods are
starting to be established for implantation and the slow-discharge of 20E
from the biodegradable devices (Dittrich et al., 2000).
Even if they are not as spectacular as claimed occasionally, effects of the
ecdysteroids on humans and mammals cannot be overlooked, and the best
proof is that of undesirable effects in the control of animals’ cells perceived
when utilizing natural ecdysteroids for encouraging ecdysteroid-inducible
systems centered on the insect ecdysteroid receptors (Lafont and Dinan,
2006). More comprehensive studies need to be carried out as these studies
are the prerequisite for the development of the gene therapy centered on
the ecdysteroid-inducible gene switches. In mammals, the determination
of the ecdysteroid targets is a very difcult task, since numerous diverse
effects have been dened, concerning isolated physiological functions. An
extra difculty will arise from the intricate metabolism of the molecules in
humans/mammals.
5.7.2. Are Ecdysteroids Poisonous to Mammals?
5.7.2.1. Acute Toxicity Values
Revolutionary work was carried out in the 1960s by Burdette, who
established the concept of hormonal heterophylly (summarized in Burdette,
1974a). This particular topic was more broadly addressed after the finding
of phytoecdysteroids, which seemed to the promising molecules for the
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Natural Compounds: An Introduction
control of insects. Even if this concept has been less or more abandoned
in favor of the inexpensive synthetic agonistic molecules, the growth
of inducible gene systems centered on the insect ecdysteroid receptors
raises this question again. For such kind of purposes, probable injurious
effects of the ecdysteroids on vertebrates must be concluded, and the
molecules have exhibited very low toxicity when consumed by mammals:
acute poisonousness value of the 20-hydroxyecdysone for mice after oral
administration could not be determined, while that after the intraperitoneal
injections LD
was 6.4 g kg–1 (Ogawa et al., 1974b).
50
5.7.2.2. Ecdysteroids and Cancer
The stated effects of ecdysteroids on tumorous cell induction are contradictory.
Experiments are hard to compare, as the experiments vary in the molecules
utilized (20-hydroxyecdysone, ecdysone, or some other ecdysteroids), their
purity, their concentrations, the assays utilized (in vivo/in vitro), and their
duration. Therefore, Burdette and Richards (1961) perceived proliferation/
inhibitory effects on the sarcoma cells in vitro, but the scientists used the
semi-purified extract from the silkworm pupae. Later examinations with
crystalline ecdysteroids attained from plants exhibited no effects (Burdette,
1974b). Lagova and Valueva (1981) discovered that 20-hydroxyecdysone
was unsuccessful in the development of various tumor types, while it
stimulated that of the mammary gland carcinomas. It was reported by ElMofty et al. (1987, 1994) that ecdysone was capable to tempt neoplastic
lesions in mice and toads; surprisingly, these outcomes were attained with
low amounts of ecdysone, and they are thus hard to merge with the data
of some other authors who utilized amounts various orders of magnitude
higher without perceiving any contrary effects (e.g., Ogawa et al., 1974b).
5.7.2.3. Ecdysteroids and Embryotoxicity
Probable embryotoxicity was verified by the injections of polypodine B
or 20E into rising chicken eggs: the effects were unimportant and only
perceived with the highest dosages (Kosar et al., 1997).
5.7.2.4. Conclusions Regarding the Ecdysteriods Pharmacological Effects
Therefore, most available data exhibit that ecdysteroids are not toxic to
mammals, even though standard tests with the pure molecules are required
to fully develop the absence of poisonousness after daily administration
Phytochemistry, Pharmacology, and Applications of Phytoecdysteroids
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over a long period (90-day test). Such kind of experiments would permit the
elimination of ecdysone from the carcinogenic Potency Database. Anyway,
the absence of toxicity does not mean an absence of pharmacological effects.
5.7.3. Existence of Ecdysteroids in the Human Food
and Numerous Medicinal Plants
Even though ecdysteroids are existent in seeds of ca. 6% of all examined
plant species (Dinan, 2001), substantial amounts of ecdysteroids have been
perceived in only the few food plants, probably as the cultivated plants
have been nominated for output and have thus lost their capability to yield
secondary metabolites. Till now, only quinoa, spinach, button mushrooms,
and yam have been exhibited to contain substantial amounts of ecdysteroids;
most of the other human foods tried so far comprise small amounts of the
ecdysteroids (Findeisen, 2004).
Conversely, various plants utilized for customary medicine belong to
the ecdysteroidrich species (Lafont, 1998; Sláma and Lafont, 1995; Báthori,
2002). Some instances are provided in Table 5.2. Such kinds of plants
normally contain complex ecdysteroid cocktails, for instance, Serratula
tinctoria/wolfi (Rudel et al., 1992) or Leuzea carthamoides (Vokác et al.,
2002). Currently (Ho et al., 2008), a fern utilized for the customary medicine
in the Society Islands, Microsorum membranifolium, has been exhibited to
comprise huge amounts of complex conjugates and simple ecdysteroids.
Therefore, either within the food or when utilizing medicinal plants,
humans have numerous opportunities to consume ecdysteroids in quantities
that might yield a great diversity of effects, bestowing to the literature
available.
5.7.4. Anabolic Effects, Bodybuilding, and Doping
Anabolic effects of the ecdysteroids are reported in various articles (Lafont
and Dinan, 2003); improved protein synthesis and reduced protein catabolism
would outcome in spectacular upsurges in lean mass over the short period,
given that the supply of dietary amino-acid is sufficient. Stimulation of the
protein synthesis would continue at the translational level, instead of at the
transcriptional level (Uchiyama and Otaka, 1974). The anabolic effects were
st
described in rats/mice and occasioned in augmented physical endurance/
1
performance (Syrov, 2000). They have been perceived in humans, conferring
to some clinical experiments, the information of which isn’t available readily
(Figure 5.14) (Lafont and Dinan, 2003).
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Natural Compounds: An Introduction
Table 5.2: Ecdysteroid Existence in Some Medicinal Plants or Food Plants
Plant Species Organ Concentration References
Food plants
Spinacia oleracea
(spinach)
Growing tips
Seeds
Leaves
Up to 10 mg/g dw
1–2.5 mg/g
2 mg/g dw
Grebenok and Adler (1991)
Dinan (1995)
Findeisen (2004)
Chenopodium
quinoa (quinoa)
Agaricus bisporus
(button mushroom)
Dioscorea dumetorum (yam)
Some medicinal
plan
Achyranthes
fauriei (niu xi)
Cyanotis vaga
(que che hong)
Ajuga iva (chend-
gourâ)
Diploclisia
glaucescens
Lamium maculatum
Ipomoea calonyction (kaladana)
Leuzea carthamoides (maral)
Aerial parts
Seeds
Growing tips
Open owers
Immature ow-
ers
Green fruits
Fruiting bodies 0.02–0.09 mg/g dw Findeisen (2004)
Rhizomes 0.3 mg/g dw Sautour et al. (2008)
TS Roots
Leaves 7 mg/g dw Santos et al. (1970)
Aerial parts 4.5 mg/g dw Wessner et al. (1992)
Stems
Seeds
Aerial parts 0.29 mg/g dw Cui et al. (2003)
Seeds 6 mg/g Canonica et al. (1975)
Leaves
Roots
Flowers
0.3 mg/g dw
0.45–1.3 mg/g
0.6 mg/g dw 1.1
mg/g dw 1.9 mg/g
dw
1.4 mg/g dw
0.4–1.2 mg/g dw Ogawa et al. (1974a)
32 mg/g dw
4.6 mg/g
6.7 mg/g dw
5.1 mg/g dw
15.1 mg/g dw
Clément and Dinan (1991)
Dinan et al. (1998)
Dinan (1992)
Dinan (1995)
Dinan (1998)
Dinan (2001)
Bandara et al. (1989)
Vereskovskii et al. (1983)
Paris polyphylla
Microsorum
membranifolium
(metuapua’a)
Tubers 1 mg/g dw Singh and Thakur (1982)
Rhizomes
Fronds
2.0 mg/g dw
16.6 mg/g dw
Ho et al. (2007)
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