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Phytochemistry, Pharmacology, and Applications of Phytoecdysteroids
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Serratula
tinctoria (dyer’s
sawory)
Pfaffia iresinoides (Brazilian
ginseng)
Tinospora cordifolia (guduchi)
Sida rhombifolia
(mahabala)
Vitex glabrata
(kai nao)
Aerial parts 10–20 mg/g dw Rudel et al. (1992)
Roots 6.2 mg/g dw Nishimoto et al. (1987)
Aerial parts 0.25 mg/g dw Pathak et al. (1995)
Aerial parts 0.82 mg/g dw Jadhav et al. (2007)
Bark 16 mg/g dw Werawattanametin et al.
(1986)
Figure 5.14: Main metabolic paths of 20-hydroxyecdysone in mice.
Source: https://pubmed.ncbi.nlm.nih.gov/21439380/.
The anabolic effects are attained after consumption of instead low
ecdysteroid doses and an ecdysteroid-comprising extract made from the
roots of Leuzea cartha-moide (retibol or ekdisten) is being promoted. This
preparation appears to have been utilized by the high-level sportsmen
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from the Eastern European countries in the early 80s, and its utilization
was neither identied nor forbidden, as ecdysteroids weren’t on the list of
forbidden substances.
have become obtainable on the market (Lafont et al., 2002 (Ecdybase)).
They normally comprise 20E, occasionally in combination with the other
ecdysteroids and they are anticipated in specic for utilization by bodybuilders
(Lafont and Dinan, 2003). The preparations comprise ecdysteroids separated
from just a few plant species, primarily Cyanotis arachnoidea (China),
Pfafa sp. (Brazil), Leuzea carthamoides (Eastern Europe). Over time, the
quantities of ecdysteroids existent in the suggested dose have increased
continuously and now reached up to 300 mg. The preparations comprise
normally other extracts of the plants or molecules (e.g., vitamins, amino
acids, avonoids, Rogen-like steroids, and phenolics saponins) supposed to
behave in combination with ecdysteroids.
most usual phytoecdysteroid, but some of the authors have associated its
activity with some other ecdysteroids, comprising turkesterone, ponasterone
A, polypodine B, cyasterone, and several (synthetic or natural) esters
(e.g., Syrov, 2000). Fascinatingly, anabolic effects have been dened for
rubrosterone, the ecdysteroid which deciencies the entire side-chain
(Uchiyama and Otaka, 1974). From the studies, it is presently hard to draw
clear conclusions regarding dose-effect associations or SAR.
Natural Compounds: An Introduction
From that time, adequately ecdysteroid-comprising preparations
Anabolic effects have essentially been assessed for 20E, which is the
Of course, discovering anabolic effects linked with the natural
substances which usually can be legally utilized is striking, and various
efforts have been made to enhance the development or productivity of the
farmed animals. This utilization is anticipated to enhance the rate of growth
(in chickens, and quails and upsurge lean mass in pigs, wool production in
sheep or production of milk in cows, or confrontation to disease in chickens,
reduce stress, and, simultaneously, possibly also decrease intake of food.
Amongst the promoted ecdysteroid-comprising preparations, there are few
which have been designed for horses or dogs (Kratky et al., 1997).
5.7.5. Metabolism of the Ecdysteroids in Vertebrates
The understanding of metabolic paths and the chance of ecdysteroids in
mammals generally, and in humans particularly, is very inadequate and
disconnected. This area requires much more attention as (a) phytoecdysteroids
are the normal component of the diet of various mammals, comprising
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humans; (b) ecdysteroids have numerous pharmaceutical effects on the
mammals, and it isn’t clear what the action mode is, or if they are an
outcome of the consumed molecules or the metabolites; (c) if the ecdysteroid
receptor-centered gene switches need to be utilized for gene therapy with
the ecdysteroids as an activator, it is critical that the pharmacokinetics and
metabolism of the molecules are completely understood, and (d) it isn’t
known that how much variation takes place in the ecdysteroid metabolism
amongst individuals of the population or with state of the health or with age.
This topic has been previously reviewed (Lafont and Dinan, 2003; Dinan
and Lafont, 2006).
Investigations of the ecdysteroid metabolism have utilized radioactively
labeled molecules or unlabeled 20E. Previously, this allows observation
of the entire spectrum of metabolites, given that labeling is existent in the
stable positions (therefore side-chain branded ecdysteroids aren’t sufcient
if the side-chain cleavage occurs). In the second circumstance, if the
aim is to decide the half-life of the administered molecule (Albanese et
al., 2000; Simon and Koolman, 1989), the exploration for metabolites is
generally made hard, because we don’t know which of the molecules to
hunt for. Therefore, HPLC-MS or GLC-MS studies have been conducted in
the urine of human by comparison with the control samples, when none of
the ecdysteroids is administered, but only some the metabolites have been
identied so far, and their identication isn’t always certain, as the data of
MS aren’t adequate to recognize ecdysteroids, lest reference molecules are
accessible for comparison. The second method has thus taken benet of the
generated data in mice by utilizing radioactive molecules.
Ingested or injected ecdysteroids are quickly cleaned from the
blood. In mice, 20E and E undergo complex metabolism comprising
14-dehydroxylation, reduction of α,β-unsaturated ketone into the B-ring,
epimerization at the C-3, and, if the 20,22-diol is existent, cleavage of side-
chain, generating the complex metabolic prole (Kumpun et al., 2007;
Girault et al., 1988). 14-Dehydroxylation also takes place in cows and
humans.
5.7.6. Ecdysteroid Receptor-Centered Gene Switches for the
Mammalian Systems
As neither ecdysteroids nor the receptors are endogenous constituents of the
mammalian cells, they propose themselves as regulators of the transgenes if
some alternate of a receptor is co-transfected with a gene to be controlled in
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Natural Compounds: An Introduction
the construct, which allows regulation and a hormone is utilized as an elicitor.
The obvious low toxicity of DAHs and ecdysteroids in the mammalian
systems is a benefit, but the existence of ecdysteroids in a normal diet of
mammals and inadequate information regarding their metabolism in the
mammals could be severe limitations (Dinan and Lafont, 2006). Moreover,
to be an entirely effective and useful method, it is highly anticipated that it
is probable to utilize the system to control various transgenes independently
inside the same cell and the system responds delicately to the elicitors,
thus decreasing the number of elicitors needed and also the likelihood of
undesired pharmacological side-effects taking place. The system initially
developed by RheoGene approaches the previous goal by using various
receptor variants, each of them with diverse ligand binding selectivities
and identifying diverse control sequences in a DNA, such that several
elicitors can be utilized to regulate diverse sets of genes. Furthermore, the
original issue of the comparatively low affinity of the ecdysteroid receptors
in the mammalian cells is being attempted by the recognition of the point
mutants demonstrating an improved affinity for specific activators (Kumar
et al., 2002). Nearly all of the applications to date concern the utilization
of ecdysteroid-based gene switches to study the transgenes function under
temporally regulated conditions in vitro, by tempting the expression of a gene
at the needed time point or by the gene silencing utilizing the ecdysteroidbased RNAi method (Rangasamy et al., 2008). As the system becomes more
advanced, more delicate, and expression is tightly controlled, it will become
probable to envisage utilizing such kind of systems in vivo. The proof of
idea study has exhibited that it is probable to utilize ponasterone A to control
the temporal and spatial expression of the ecdysteroidregulated gene switch
explicitly in a mammary gland of mice. In the future, such kind of gene
switches will discover applications in fundamental research into the gene
function and more practical uses in the expression of the therapeutic proteins,
drug discovery assay, gene therapy, and functional genomics (Toniatti et
al., 2004; Fussenegger, 2001; Palli et al., 2005). Conversely, the criteria
which must be met are challenging; (a) highly specific; (b) low baseline
expression and the high ratio of induction; (c) good bioavailability of an
inducer; (d) reversibility of the induction; (e) low immunogenicity of the
components of a system; (f) flexibility for diverse applications and (g) dosedependent on an elicitor. Numerous of these have begun to be examined
for the ecdysteroid systems. There are various classes of the ligands, which
normally have been recognized which could be appropriate for the control
of such kind of systems; moreover, to the DAHs and ecdysteroids, there
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are tetrahydroquinolines and aminoketone (Panguluri et al., 2007; Palli et
al., 2005). Therefore, even though still in initial days the predictions for the
technology and the possibility of the possible applications are, despite the
caveats stated above, very encouraging.
5.8. PHARMACOLOGY OF PHYTOECDYSTEROIDS
5.8.1. Pharmacology of the Phytoecdysteroids
The literature stating the ecdysteroids effects on mammals has been studied
by various researchers and summarized by Lafont and Dinan (2003); and
Dinan (2001), and it can be determined that useful pharmacological activities
can trigger probable therapeutic applications. They also have a higher safety
margin than the chemical steroid derivatives.
5.8.2. Toxicology of the Phytoecdysteroids
Even though comprehensive toxicological data are deficient for the
phytoecdysteroids, their acute poisonousness to mammals appears to be very
low. In mice, LD
and i.p. injection was 9 g kg
respectively. Moreover, 20-hydroxyecdysone wasn’t embryotoxic when
injected into the developing chicken eggs.
values of the 20-hydroxyecdysone after oral application
50
–1
body weight and 6.4 g kg–1 body weight,
5.8.3. Adaptogenic Activities
The ecdysteroids are assumed to have adaptogenic, tonic, roborant, and
antidepressive properties, i.e., they improve the ability to manage stress and
improve resistance to tiredness. Particular plants (Cyathula spp., Achyranthes
spp., Leuzea carthamoides) have been utilized as tonics, adaptogens, and
diuretics in traditional Asiatic and Chinese medicines before they were
identified to comprise large quantities of ecdysteroids.
Koudela et al. (1995) examined adaptogenic activity in the Japanese
quails. These animals were nourished with a diet containing diverse
amounts of the pulverized seeds of plant species Leuzea carthamoides.
The seeds contain 1.8 to 2.1% of the 20-hydroxyecdysone and smaller
amounts of the other ecdysteroids. In another experiment, these quails were
managed whole seeds of the L. carthamoides ad libitum. The experimental
setup included testing of (a) the standard diet; (b) standard diet supplied
with 0.2% L. carthamoides seed powder; (c) standard diet supplied with
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Natural Compounds: An Introduction
1% L. carthamoides powder of seed; (d) standard diet supplied with 5%
L. carthamoides powder of seed; (e) standard diet supplied with 5% L.
carthamoides powder of seed + 5% Biostrong; (f) standard diet supplied
with 5% L. carthamoides powder of seed + 5% Ecovit, and (g) standard diet
supplied with complete seeds of the L. carthamoides ad libitum (Palli et al.,
2005).
After almost 37 days, the increase of living mass was measured and
expressed towards the control group (¼ 100%) as follows: (a) 102.8%;
(b) 109.5%; (c) 120.4%; (d) 101.9%; (e) 104.9%, and (f) 103.5%. These
outcomes exhibit the dose-dependent anabolic effects in birds. Anabolic
effects of the L. carthamoides were observed in vitro studies with provisions
from the liver and some other organs of the mice. However, it can’t be
excepted that the other minor metabolites are also backing this effect. The
outcomes of the radioimmunoassay analysis disclosed that the quantity of
20-hydroxyecdysone owing in the Japanese quails’ blood was relational to
the quantity of dietary ecdysteroid. Conversely, a direct correlation between
the anabolic effect and these circulating levels remains uncertain, as higher
concentrations were discovered in quails that ingested the entire seeds of
L. carthamoides, while this group didn’t have the highest upsurge in living
mass (Koudela et al., 1995).
The basis of green tea is Leuzea carthamoides ingested extensively in
Central Europe and is believed to enhance general well-being, improve
digestion, and increase appetite. Even though the effects have been
frequently attributed to the ecdysteroid content of a plant, there exists little
proof to directly relate them with this specic class of the compounds (Saez
et al., 2000).
5.8.4. Stimulation of the Protein Synthesis
Otaka et al. (1974) examined the 20-hydroxyecdysone effects on protein
blend in the mouse liver. The ecdysone augmented markedly the integration
14
C-chlorella hydrolysate into the hot-acid insoluble protein, two hours
of
after treatment. The effect is analogous to 4-chlorotestosterone. This effect
was applied to polysomes or microsomes. The stimulation tempted by
20-hydroxyecdysone was partially impervious to inhibitors of the DNAdependent ribonucleic acid (RNA) synthesis such as actinomycin, while
the stimulation through 4-chlorotestosterone was entirely repressed by the
similar actinomycin. This might specify other mechanisms indulged or the
incomplete shield against actinomycin.
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5.8.5. Effect on Hyperglycemia
Ecdysterone, separated from the Achyranthes fauriei, has generally been
identified to have a suppressive effect on tempted hyperglycemia. The
management of ecdysterone didn’t change the blood glucose of the normal
animals, but pre-treatment with ecdysone before hyperglycemic agents
repressed the hyperglycemia tempted by glucagon at the low levels. The
ecdysterone effect was also exhibited in the alloxan-diabetic mice, having
levels of blood glucose decreased to about 1/2 of the observed value before
the management of ecdysterone. Ecdysterone encouraged the integration
14
of
C glucose into the protein of mice liver and the glycogen of mildly
diabetic and normal mouse liver (Le Bizec et al., 2002; Tsitsimpikou et al.,
2001). Ecdysterone had a positive impact on insulin resistance tempted by
injections of the hydrocortisone or insulin inadequacy triggered by alloxan
treatment in the rats. The sensitivity towards intravenous administration of
the insulin was improved, but this improvement was indirectly measured
by the non-particular synthesis of entire proteins in cells, instead of by an
upsurge in the insulin secretion.
Sundaram et al. (2012) explicitly described the impact of 20-OHecdysone
on the hepatic main enzymes of the carbohydrate metabolism. Ecdysone
was separated from the species of plant Vitex negundo. Oral management of
ve mg ecdysone kg
rats for nearly 30 days reduced the plasma glucose by nearly 50% and the
HbA1c (glycosylated hemoglobin) by about 40%. Simultaneously, the
insulin levels doubled and hemoglobin normalized than the control rat. The
glycogen content of skeletal muscles and liver was improved, but not entirely
normalized by the 20-OH-ecdysone. There was an upsurge in the activity of
the enzyme of glucose-6-phosphate dehydrogenase and hexokinase. These
enzyme activities refer to a fascinating molecular mechanism of the 20-OHecdysone, changing hormone secretion in the circumstance of tempted
hyperglycemia (Brandt, 2003).
–1
body weight each day to the streptozotocin-diabetic
5.8.6. Cholesterol Homeostasis
The impact of phytoecdysteroids on cholesterol biosynthesis is speculative.
It is well known that the negative feedback control mechanism by
steroids is present. Probable targets are cholesterol catabolism of
hydroxymethylglutaryl-CoA reductase. The existence of hydroxyl groups
might play a significant part in the activity.
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Natural Compounds: An Introduction
Cholesterol homeostasis is an important process that must occur in
accuracy in the cellular level. A disturbed cholesterol balance may be the
cause of some cardiovascular disease and may progress to several of other
diseases such as neurodegenerative diseases and cancers. The cellular
cholesterol level reects the dynamic balance between biosynthesis, uptake,
export, and esterication — a process in which cholesterol is converted to
neutral cholesteryl esters either for storage in lipid droplets or for secretion as
constituents of lipoproteins (Luo et al., 2020). It is well documented that high
plasma cholesterol concentration increases the risk of atherosclerotic heart
disease. In the last decades, several studies have investigated the association
of plasma cholesterol concentrations and the risk of cardiovascular diseases
as well as the signaling pathways involved in cholesterol homeostasis.
In cholesterol biosynthesis, the master regulator of cholesterol synthesis
and uptake, SREBP-2, is attached to the ER membrane through the interaction
with SCAP and Insig-1. In a state of reduced levels of cholesterol, Insig-1
undergoes proteasomal degradation and the complex SCAP-SREBP is sorted
into COPII-coated vesicles, in a process mediated by a small GTPase, Sar1
and the coat proteins Sec23/Sec24 and Sec13/Sec31. COPII coat vesicles
escort the SCAP-SREBP complex from ER to Golgi, where SREBP is
cleaved by two resident proteases, site-1 (S1P) and site-2 (S2P), releasing
its NH
-active domain. In the nucleus, SREBP binds to the SRE inducing the
2
transcription of genes involved in cholesterol synthesis such as HMGCR,
HMGS, and MVK, as well as LDLR, which is responsible for cholesterol
uptake, in an attempt to restore the intracellular cholesterol concentrations.
ER: endoplasmic reticulum, SREBP-2: sterol regulatory element-binding
protein-2; SCAP: SREBP cleavage-activating protein; Insig-1: Insulininduced gene protein-1.
There is a close relationship between cholesterol absorption and
synthesis that is necessary to maintain whole-body cholesterol balance.
Compensatory mechanisms shift the pathways in opposite directions so that
when synthesis rises, absorption decreases and vice versa. As a proof of
concept, the treatment of hyperlipidemic men with a cholesterol synthesis
inhibitor (Atorvastatin) was associated with a 76% reduction in lathosterol
(marker of endogenous cholesterol synthesis) and an increase of 70% in
sitosterol (marker of cholesterol absorption). The effects of atorvastatin
included the upregulation of genes involved in cholesterol synthesis and
uptake (SREBP-2, HMG-CoA reductase, LDLR, and NPC1L1), and
downregulation of ABCG5 and ABCG8, which are responsible for the efux
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of cholesterol from the enterocytes back to the intestinal lumen (Tremblay
et al., 2011).
This compensatory mechanism promotes the balance among dietary
cholesterol, endogenous synthesis, and cholesterol excretion. However,
there will be wide variability among individuals for this process due to
diverse and compounded factors that may affect it. This variability can
be attributed to the alterations in the transcriptional and posttranslational
regulation of proteins related to cholesterol efux and uptake, as well as to
proteins involved in cholesterol synthesis.
The cholesterol present in the intestinal lumen originates from diet
or endogenous sources (bile secretion, TICE, and intestinal epithelial
sloughing). In the liver, cholesterol is converted to bile acids, which are
conjugated to amino acids (either glycine or taurine), secreted into the
bile, and further eliminated into the feces. The bile acid secreted into
the lumen is reabsorbed in the ileum and returns to the liver in a process
called enterohepatic circulation. The bile acid loss in the feces (~5%) is
compensated for by its synthesis in the liver in a tightly regulated process,
where the bile acids reabsorbed exert a negative feedback on synthesis.
5.8.7. Immunomodulatory Activity
Ecdysterone is capable to stimulate the main immune reaction. This activity
is centered on cellular activity, with improved T cell immunity and phagocyte
activity when dosages between 5–20 mg kg
the dosage is upsurged to 50 mg kg
–1
spleen of a mouse is marked. These dosages, though, are massive when
considered as the quantity of extract to be developed of the phytoecdysteroidcomprising plants.
In the Ajuga remota, they normally can contribute to the probable
antiplasmodial activity by the anabolic, immunoprotective, and adaptogenic
activities. According to Dinan (1992), the ecdysteroids might exhibit few
immunomodulatory effects in rats and mice and possess anti-inammatory
activity in the rodents.
The immunomodulatory effect of the 20-hydroxyecdysone has generally
been reviewed in humans. It behaves as a neutrophil and lymphocyte
modulator in vivo. It activates the T cell CD2 exhibition in vitro that is
repressed pharmacologically by upsurged cAMP levels and in minor
immunodecient persons.
–1
are given to the mice. When
, the number of antibody cells in the
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Natural Compounds: An Introduction
5.8.8. Antioxidative/Antiradical Properties
Studying and stating on antioxidative properties of the plants and their
constituents are very popular. It seems quite clear also to examine
phytoecdysteroids in this area. Various ecdysterone concentrations (10
3
to 10
phosphatidylcholine liposomes confronted with Fe
M) were confirmed in the photochemical system, comprising
3+
and Fe2+. The
ecdysterone’s antioxidative activity was comparable to ethylenediamine
tetra-acetate and diethyl paraphenylenediamine, both well-known as
inhibitors of the peroxide oxidation of lipids.
5.8.9. Synergism with Vitamin D
The experimental vitamin D hypovitaminosis encourages variations in
the functional and structural characteristics of the liver nuclear chromatin
portions. The DNA-polymerase activity upsurges, along with the activity of
fraction enhanced with RNA polymerase I. The free-radical lipid peroxidasefacilitated reactions are favorably altered in the chromatin portion with low
activity. Furthermore, the lipid and protein components of the chromatin
are altered. Administration of the ecdysterone preparations partly restores
the functional and structural organization of the chromatin, either it is
concomitantly or separately given. The lipid peroxidase is normalized.
Generally, management of ecdysterone imitators the vitamin D3 activity
concerning normalization of the biochemical catalogs.
6
Dittrich et al. (1998) hunted for an appropriate dosage form with a constant
discharge of 20-hydroxyecdysone from the device embedded in animals.
They made the binary mixture of ecdysone and poly-lactic acids. Discharge
of an active compound was validated in stationary in vitro circumstances,
comparable with the ones at the site of the possible implantation. Extended
drug release of almost zero-order kinetics was attained with the hollow
implants. These kinds of implants seem most suitable for challenging in
vivo.
5.8.10. Antitumoral Activity
The lipophilic root essence of Leuzea carthamoides, along with
20-hydroxyecdysone, was validated in the human breast adenocarcinoma
MCF-7 cells. The cell proliferation was repressed by the essence with the
of 30 mg mL–1; 20-hydroxyecdysone didn’t exhibit inhibitory activity. It
IC
50
isn’t clear to what degree phytoecdysteroids from the Leuzea carthamoides
were accountable for the activity. The products derived from the roots of the
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