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Comparative experimental investigation of the anabolic activity of phytoecdysteroids and steranabols

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... Although ecdysteroids do not bind to the vertebrate steroid receptors and their mechanism of action is still unknown, many beneficial pharmacological properties are attributed to them (reviewed by Sla´ma and Lafont, 1995;Dinan and Lafont, 2006;Ba´thori et al. 2008). Increased body, organ and muscle weight and protein synthesis have been reported in case of oral or intraperitoneal administration of ecdysteroids in several animal species: Japanese quails (Sla´ma et al., 1996), mice (Stopka et al., 1999), rats (Syrov, 2000) and pigs (Kra´tky et al., 1997). There is an important difference between the effect of ecdysteroids and anabolic steroids: castration in rats sharply decreases the protein synthesis stimulating property of ecdysteroids, while steranabols (androgen steroids) still remain effective under this condition (Syrov, 2000). ...
... Increased body, organ and muscle weight and protein synthesis have been reported in case of oral or intraperitoneal administration of ecdysteroids in several animal species: Japanese quails (Sla´ma et al., 1996), mice (Stopka et al., 1999), rats (Syrov, 2000) and pigs (Kra´tky et al., 1997). There is an important difference between the effect of ecdysteroids and anabolic steroids: castration in rats sharply decreases the protein synthesis stimulating property of ecdysteroids, while steranabols (androgen steroids) still remain effective under this condition (Syrov, 2000). The nonandrogenic effect was suggested because the studied phytoecdysteroids did not produce any significant changes in the weight of ventral prostate and seminal vesicles in the tested animals (normal or castrated mature or immature rats, Syrov, 2000). ...
... There is an important difference between the effect of ecdysteroids and anabolic steroids: castration in rats sharply decreases the protein synthesis stimulating property of ecdysteroids, while steranabols (androgen steroids) still remain effective under this condition (Syrov, 2000). The nonandrogenic effect was suggested because the studied phytoecdysteroids did not produce any significant changes in the weight of ventral prostate and seminal vesicles in the tested animals (normal or castrated mature or immature rats, Syrov, 2000). Phytoecdysteroids also showed an anabolic effect in female rats (Syrov, 2000). ...
Article
20-Hydroxyecdysone (20E) is an ecdysteroid hormone that regulates moulting in insects. Interestingly, 20E is also found most abundantly in plant species and has anabolic effects in vertebrates, i.e. increasing muscle size without androgen influence. The effect of 20E on slow and fast fiber types of skeletal muscle has not been reported yet. Here we present that 20E affects the size (cross-sectional area, CSA) of the different fiber types in a muscle-specific manner. The effect on fiber size was modified by the distance from the site of the treatment and the presence of a regenerating soleus muscle in the animal. Besides the fiber size, 20E also increased the myonuclear number in the fibers of normal and regenerating muscles, suggesting the activation of satellite cells. According to our results 20E may provide an alternative for substitution of anabolic-androgenic steroids in therapeutic treatments against muscle atrophy.
... In sexually immature castrated rats the androgenic action of 20hydroxyecdysone (6) was not demonstrable in contrast to that of methandrostenolone (36). Twenty-four years later an extensive comparative study was presented in English using a number of purified ecdysteroids including turkesterone (18), 20hydroxyecdysone (6) and methandrostenolone (36) [26]. ...
... Meanwhile Syrov and coworkers consequently described non androgenic effects of ecdysteroids [25][26][27], at least one study is at variance with their conclusion. Xu et al. [30] have reported that 20hydroxyecdysone (6), the effective compound of the extract from Antherea pernyi Pas, was able to increase the weight of prostatesemina and levator ani/muscle-bubocavernosus muscles of castrated mice. ...
... Our knowledge is merely superficial of the structure-activity relationships of ecdysteroids in mammals. Only three publications deal with the protein metabolism, where structure-activity relationship studies are available for 14 [26], 22 [39] and 16 [47] ecdysteroids. Fig. (1) depicts the structures of the ecdysteroids used in these experiments. ...
Article
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Phytoecdysteroids are structural analogs of the insect molting hormone ecdysone. Plants comprise rich sources of ecdysteroids in high concentration and with broad structural diversity. Ecdysteroids have a number of proven beneficial effects on mammals but the hormonal effects of ecdysteroids have been proven only in arthropods. Their structures are somewhat similar to those of the vertebrate steroid hormones but there are several structural differences between the two steroid groups. Despite of these essential structural differences, ecdysteroids exert numerous effects in vertebrates that are similar to those of vertebrate hormonal steroids, and they may serve as effective anabolic, hepatoprotective, immunoprotective, antioxidant and hypoglycemic agents. Ecdysteroids do not bind to the cytosolic steroid receptors, instead, they are likely to influence signal transduction pathways, like the anabolic steroids, possibly via membrane bound receptors. The application of phytoecdysteroids is a promising alternative to the use of anabolic-androgenic steroids because of the apparent lack of adverse effects. The prospective use of phytoecdysteroids may extend to treatments of pathological conditions where anabolic steroids are routinely applied. One of the most cited aspects of phytoecdysteroid application (on the Internet) is the increase of muscle size. However in this field too stringent research is needed as an adequate cytological explanation is not yet available for the anabolic. This paper reports on the most important structural differences between androgenic hormones, their synthetic analogs and ecdysteroids. The anabolic/hormonal effects and the possible mechanisms of action of these compounds are also discussed as concerns the skeletal muscle.
... Ecdysteroids can be classified as "adaptogenic substances" (Brekhman and Dardymov, 1969), i.e. compounds which help the good equilibrium of body functions and improve resistance to various diseases (but do not cure them, once established). Several reviews dealing with the pharmacological effects of ecdysteroids have been published (Sláma and Lafont, 1995;Syrov, 2000;Kholodova, 2001;Báthori, 2002;Lafont and Dinan, 2003;Báthori and Pongrácz, 2005;Dinan and Lafont, 2006), so this topic will not be discussed extensively here. The major effects concern various physiological functions and the most "classical" ones are presented in Table 23.1. ...
... Stimulation of protein synthesis would proceed at the translational level ("ribosomal amplifier"), rather than at the transcriptional level (Uchiyama and Otaka, 1974). These anabolic effects were first described in mice/rats and resulted in increased physical performance/endurance (Syrov, 2000). They have also been observed in humans, according to the few clinical experiments, Dinan et al., 1998Clément and Dinan, 1991Dinan, 1992Dinan, 1992Dinan, 1992Dinan, 1992 the details of which are not readily available (Lafont and Dinan, 2003). ...
... The anabolic effects have been essentially assessed for 20E, which is by far the most common phytoecdysteroid, but some authors have compared its activity with those of other ecdysteroids, including turkesterone, polypodine B, ponasterone A, cyasterone and various (natural or synthetic) esters (acetates) (e.g. Syrov, 2000). Interestingly, anabolic effects have also been described for rubrosterone, an ecdysteroid which lacks the whole side-chain (Uchiyama and Otaka, 1974). ...
Chapter
We review the current and potential importance and applications of ecdysteroids in the areas of agriculture, medicine and ecotoxicology. Since ecdyster-oids are not only the steroid hormones of arthropods (and probably other invertbrate groups), but also have significant pharmaceutical effects on vertebrates, man's use of ecdysteroid agonists and antagonists (steroidal or non-steroidal) could potentially have considerable impact upon human health and the environment. The challenge is to maximise the benefits, while minimising the potential negative impacts. As agrochemicals, ecdysteroids themselves have little potential as exogenous pest con trol agents, but the many analogues are highly useful for determining the structural and spatial requirements for binding to nuclear and taste receptors and elevation of phytoecdysteroid levels in selected plant species could provide an environmentally benign approach to protect crop species against phytophagous predators (insects and nematodes). We briefly summarise the many attributed positive pharmaceutical effects of ecdysteroids in vertebrates (especially humans) and critically assess the reports associating ecdysteroids with cancer and embryotoxicity and the probable use of ecdysteroids as doping substances for athletes. We stress the need for much more extensive research into the metabolism and mode of action of ecdysteroids particularly in mammals. The presence of natural and, increasingly, man-made ecdysteroid agonists and antagonists may have considerable impact on the environ ment. On the one hand, non-steroidal (ant)agonists offer considerable promise as environmentally friendlier, more selective pesticides, but, on the other hand, could become endocrine disruptors of non-target species, especially in aquatic ecosystems. We consider in some depth the development of strategies for the identification and environmental monitoring of potential endocrine disruptors affecting ecdysteroid hormonal systems in invertebrates and emphasise the overwhelming need for basic research into the endocrinology of aquatic invertebrates which would be suitable as signal species.
... The enhancement of strength, stamina and muscle mass in mammals are among the main purported bioactive properties and commercial use of PE and PE-containing extracts (Báthori and Kalász, 2001). 20E stimulated protein synthesis in vitro in C2C12 murine myotubes as well as in vivo in rats given a single daily dose of 5 mg/kg for 10 days Syrov, 2000). Additionally, 20E increased the mass (tibialis anterior) and size (soleus and extensor digitorum longus) of skeletal muscle and stimulated muscle fiber growth in regenerating soleus muscles (Syrov, 2000;Tóth et al., 2008), demonstrating the potential of 20E as a therapeutic agent for muscle atrophy. ...
... 20E stimulated protein synthesis in vitro in C2C12 murine myotubes as well as in vivo in rats given a single daily dose of 5 mg/kg for 10 days Syrov, 2000). Additionally, 20E increased the mass (tibialis anterior) and size (soleus and extensor digitorum longus) of skeletal muscle and stimulated muscle fiber growth in regenerating soleus muscles (Syrov, 2000;Tóth et al., 2008), demonstrating the potential of 20E as a therapeutic agent for muscle atrophy. As a relatively new class of medicinally active compounds, comprehensive reviews of the purported biological effects of phytoecdysteroids have only been published within the past decade (Dinan, 2001;Lafont and Dinan, 2003;Báthori and Pongrácz, 2005;Báthori et al., 2008). ...
... Conversely, others have indicated no difference in body mass with 20E treatment with daily veinous injections of 20E (1 mg/kg) for 3 weeks in mice (Gao et al., 2008). An increase in the mass of triceps brachii was demonstrated in this study, and other muscle specific increases in the soleus, extensor digitorum longus and tibialis anterior have been reported for rats given daily administration of 20E orally or by subcutaneous injection (Toth et al., 2008;Syrov, 2000). Further research involving the optimization of dose, duration and route of administration of phytoecdysteroids, to demonstrate reproducible responses in vivo, would be required to show anabolic efficacy. ...
Article
Phytoecdysteroids have been attributed with numerous pharmacological properties in animals, including increasing muscle mass, and 20-hydroxyecdysone (20E) is one of the most abundant phytoecdysteroids produced by plants. In this study, the physiological and gene expression effects of 20E were analyzed in C57BL/6 mice given a continuous infusion of saline or 20E (5 mg/kg/day) for 5 or 15 days using subcutaneously implanted Alzet® osmotic pumps. The masses of the total body, muscle groups and organs were determined. There was a significant increase ( p = 0.01) in the mass of triceps brachii in mice treated with 20E for 5 days (115 ± 8 mg) compared with mice treated with saline for 5 days (88 ± 3 mg), however, there were no differences in the other measured parameters. To determine potential mechanisms of 20E in skeletal muscle, Illumina's Mouse Whole Genome-6 v2.0 Expression BeadChips were used to evaluate changes in gene expression of the triceps brachii after 20E infusion. Ingenuity Pathways Analysis was used to identify genes with the most evidence for differential expression, of which, 16 genes involved in the skeletal and muscular system were identified. Overall, the data suggest that 20E does not have potent anabolic properties, however, a muscle-specific increase was observed and genes were identified to provide an explanation for the muscle accretion. Copyright © 2012 John Wiley & Sons, Ltd.
... As concerns the anabolic activity, only three in vivo animal experiments have been reported on the weight gain of pubertal or impubertal castrated and intact rats [122], [ 14 C]labeled amino acid incorporation into the liver proteins of mice [123], and the hypoazotaemic effect (the ability to lower the blood levels of urea and residual nitrogen, which is directly related to the rate of protein synthesis) in male rats [124]. A recent study in vitro reported on the activities of four ecdysteroids (37, 51, 52 and 55) on the C2C12 cell line, where the rate of incorporation of [ 3 H]leucine into myotubes was determined at different ecdysteroid concentrations [125]. ...
... An additional OH group on C-1 (49) decreases the anabolic activity in vivo [122][123][124]. Hydroxylation at C-5 (51) exerted a negative effect on the protein metabolism, as measured by the urea and residual nitrogen in the blood, [124] and also lowered the rate of amino acid incorporation into mouse liver proteins [123]. ...
... Moreover, in vitro experiments with analogue 51 demonstrated a decreased rate of incorporation of [ 3 H]leucine into the myotubes [125]. Removal of the 2-OH group (44 and 45) resulted in a decreased weight gain and altered residual nitrogen and urea levels in the blood in rats [122,124], and decreased amino acid uptake by the mouse liver [123]. ...
Article
Phytoecdysteroids are plant steroids with identical or analogue structures to the molting hormone in arthropods. The ecdysteroids exert several beneficial effects on mammals, from which the most cited and deeply examined one is the increase of muscle size and strength. This shows similarities with the mode of action of the androgenic steroids but the ecdysteroids do not bind to the cytoplasmic/nuclear receptor of the mammalian steroids. These findings led to the hypothesis that ecdysteroids possibly bind to membrane bound receptors and they are likely to influence signal transduction pathways. Probably because of their closely related chemical structures, ecdysteroids exert some similar effects in vertebrates to those of the hormone 1 alpha,25-dihydroxyvitamin D3 (1,25D) which is produced in the kidney from 25-hydroxyvitamin D3, after being converted in the liver from Vitamin D3. 1,25D generates biological responses via both genomic and rapid, nongenomic mechanisms. Structure-activity relationship studies with different Vitamin D analogues could open the possibility to show that the two ways of action (genomic and nongenomic) can be influenced separately. The connection between the Vitamin D status and muscle function is already well-described in clinical studies, and several efforts have been made to evaluate the effect of Vitamin D deficiency or supplementation on muscle morphological changes and the underlying molecular mechanisms. This paper aims to summarize the main structural commonalities between the ecdysteroids, 1,25D and other Vitamin D analogues. The similarities in their effects and pathways that might be involved in the mechanism of action of these compounds will also be discussed.
... The enhancement of strength, stamina and muscle mass in mammals are among the main purported bioactive properties and commercial use of PE and PE-containing extracts (Báthori and Kalász, 2001). 20-Hydroxyecdysone stimulated protein synthesis in vitro in C2C12 murine myotubes as well as in vivo in rats given a single daily dose of 5 mg/kg for 10 days (Gorelick-Feldman et al., 2008;Syrov, 2000). Additionally, 20E increased the mass (tibialis anterior) and size (soleus and extensor digitorum longus) of skeletal muscle and stimulated muscle fiber growth in regenerating soleus muscles (Syrov, 2000;Tóth et al., 2008), demonstrating the potential of 20E as a therapeutic agent for muscle atrophy. ...
... 20-Hydroxyecdysone stimulated protein synthesis in vitro in C2C12 murine myotubes as well as in vivo in rats given a single daily dose of 5 mg/kg for 10 days (Gorelick-Feldman et al., 2008;Syrov, 2000). Additionally, 20E increased the mass (tibialis anterior) and size (soleus and extensor digitorum longus) of skeletal muscle and stimulated muscle fiber growth in regenerating soleus muscles (Syrov, 2000;Tóth et al., 2008), demonstrating the potential of 20E as a therapeutic agent for muscle atrophy. As a relatively new class of medicinally active compounds, comprehensive reviews of the purported biological effects of phytoecdysteroids have been published only within the past decade (Dinan, 2001;Lafont and Dinan, 2003;Báthori and Pongrácz, 2005;Báthori et al., 2008). ...
... Conversely, others have indicated no difference in body mass with 20E treatment with daily veinous injections of 20E (1 mg/kg) for 3 weeks in mice (Gao et al., 2008). An increase in the mass of triceps brachii was demonstrated in this study, and other muscle specific increases in the soleus, extensor digitorum longus and tibialis anterior have been reported for rats given daily administration of 20E orally or by subcutaneous injection (Syrov, 2000;Tóth et al., 2008). Further research involving the optimization of dose, duration and route of administration of phytoecdysteroids, to demonstrate reproducible responses in vivo, would be required to show anabolic efficacy. ...
Article
Full-text available
Phytoecdysteroids, which are structurally similar or identical to insect molting hormones, produce a range of effects in mammals, including increasing growth and physical performance. To study the mechanism of action of phytoecdysteroids in mammalian tissue, an in vitro cellular assay of protein synthesis was developed. In C2C12 murine myotubes and human primary myotubes, phytoecdysteroids increased protein synthesis by up to 20%. In vivo, ecdysteroids increased rat grip strength. Ecdysteroid-containing plant extracts produced similar results. The effect was inhibited by a phosphoinositide kinase-3 inhibitor, which suggests a PI3K-mediated mechanism.
... Our knowledge of their role in the latter has in fact been enriched by their availability from plant sources ( Dinan, 2001 ). Interests in these compounds have grown in recent years because of reported anabolic and favorable metabolic potentials in mammals, including humans ( Dinan and Lafont, 2006 ;Gorelick-Feldman et al., 2008 ;Syrov and Kurmukov, 1976 ;Syrov, 2000 ;Tóth, 2008 ), which have made them attractive to fitness enthusiasts and athletes. One other selling point for these compounds is the absence of concomitant androgenic effects ( Zwetsloot et al., 2014 ), consistent with their lack of binding affinity for the androgen receptor ( Gorelick-Feldman et al., 2008 ). ...
... One other selling point for these compounds is the absence of concomitant androgenic effects ( Zwetsloot et al., 2014 ), consistent with their lack of binding affinity for the androgen receptor ( Gorelick-Feldman et al., 2008 ). For these reasons, supplements containing these compounds are especially popular among recreational and elite athletes ( Syrov, 2000 ) who crave to improve or maintain their fitness levels. The most studied of the ecdysteroids is 20-hydroxyecdysone, which has anabolic effects often at high doses ( Todorov et al., 2000 ;Parr et al., 2015 ;Isenmann et al., 2019 ) and was added to the world anti-doping agency monitoring programme ( World Anti-Doping Agency, 2020 ) in 2020. ...
Article
Full-text available
Background : 20-hydroxyecdysone is an ecdysteroid which is abundant in plants and insects and has anabolic potentials in mammals. It was recently shown to have affinity for estrogen ER-β receptor, which could potentially make it vasodilatory. Yet this possibility has not been previously investigated. Such an activity in muscle arterioles could have huge implications for muscle blood flow and performance. Hypothesis/Purpose : We hypothesized that 20-hydroxyecdysone would dilate muscle arterioles by activating estrogen ER-β receptors. To test this, we investigated its vasodilatory properties in ovine muscle arterioles and further explored the mechanisms in human tissues and cells. Study Design : The study was carried out experimentally, employing functional recording of arteriolar reactivity in intact ovine muscle arterioles and gene and protein expression analysis in human tissues and cells. Methods : Direct effects of the compound on arteriolar tone were assessed by wire myography in abdominal muscle and mesenteric arterioles isolated from samples obtained from male sheep. The roles of endothelial nitric oxide synthase (NOS3), cyclooxygenase (COX) and estrogen ER-β receptor (ER-β), and their effects were determined with specific blockers. The NOS3 mRNA and protein expressions were analyzed in human coronary artery endothelial cells (HCAECs) and humanized liver of uPA+/+-SCID mice, before and after 20-hydroxyecdysone administration. Results : Comparable dose-dependent relaxations were recorded for 20-hydroxyecdysone in both muscle and mesenteric arterioles with maximum relaxations of 46.94±5.84% and 56.88±7.04% respectively, which were not statistically different. Similar relaxation was recorded for β-estradiol in both arterioles. NOS inhibition with 100 µM L-NAME attenuated the relaxation to 20-hydroxyecdysone (p<0.001) and β-estradiol (p<0.001) in muscle arterioles. Neither COX inhibition with 10 µM indomethacin nor ER blockade with 1 µM PHTPP or 1 µM ICI182780 had any noticeable effect on 20-hydroxyecdysone relaxation in these arterioles. Transcriptome analysis revealed elevated NOS3 gene in the humanized liver of 20-hydroxyecdysone-treated mice, and, elevation of both NOS3 mRNA and protein in HCAECs treated with 20-hydroxyecdysone. Conclusion : The data suggest that 20-hydroxyecdysone has a nitric oxide-dependent, but ERβ-independent, vasodilatory property in muscle arterioles. The benefits to muscle blood flow would however be dependent on the impact of its effects on other vascular beds.
... Based on these experiments, ecdysteroids have shown a wide array of pharmacological effects. Their pharmacological and therapeutic properties are well documented and reviewed (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). ...
... Ecdysteroids beneficially influence many physiological func-tions in mammals. Ecdysteroids stimulate the protein synthesis without thymolytic, antigonadotropic, or androgenic side-effects (1,(4)(5)(6)(7)(8)(9); they influence lipid metabolism (1,5,10,11), carbohydrate metabolism (1,5,12,13), and ion-currents (14,15). Ecdysteroids exert protective, preventive, corrective, and adaptogenic effects (16,17). ...
Article
Full-text available
A simple separation procedure is developed for the isolation of the main phytoecdysteroid 20-hydroxyecdysone from the herb Silene viridiflora. The purification in four steps uses only a simple preparative-scale separation technique (i.e., liquid-liquid extraction, precipitation, solid-phase extraction on octadecyl silica, and crystallization). This procedure is extended using classical normal-phase liquid column chromatography, rotation planar chromatography, and preparative high-performance liquid chromatography for the isolation of the minor ecdysteroids: integristerone A, 26-hydroxypolypodine B, 2-deoxy-20,26- dihydroxyecdysone, and polypodine B. 2-Deoxy-20,26- dihydroxyecdysone is isolated from this species for the first time. The isolation of these ecdysteroids in adequate amounts makes them readily available for insect physiology experiments and for structure-activity relationship studies. The preparative-scale separation work also results in a minor, as yet unknown ecdysteroid.
... In the 1980s, ecdysteroids were suspected to be used by Russian weightlifters in the Olympics [4] . This led to a study in 2000, comparing the anabolic efficacy of ecdysteroids to a group of anabolic androgenic steroids (AAS) known as steranabols [5] . Following the positive results, in 2015, 20-HE was compared for anabolic efficacy in vitro and in vivo with a range of endogenous and exogenous anabolic compounds [4] . ...
... 20-HE in vivo has equal hypertrophic potential as the steranabol Methandriol (Methylandrostenediol). The ecdysteroid turkesterone (11α-hydroxyecdysone) was more hypertrophic than the steranabols Methandriol and Nerobol (Methandrostenolone). [5] . Research Publish Journals ...
Article
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20-Hydroxyecdysone (20-HE) is currently undergoing a Phase 2 Clinical Trial for the treatment of sarcopenia. 20-HE is also currently being investigated by the World Anti-Doping Agency (WADA) as an anabolic agent. There are promising in vitro and in vivo results for 20-HE's anabolic effect on muscles. However, 20-HE is molecularly a steroid, thus having relatively poor water solubility and poor human oral bioavailability. Cyclodextrins (CDs) are being used in pharmaceutics to improve the water solubility and oral bioavailability of lipophilic compounds. This paper explores 20-HE's pharmacodynamics and pharmacokinetics, with a particular interest on how the 20-HE-CD complex can improve the oral bioavailability of 20-HE. Consequently, making 20-HE-CD a novel anabolic phytosteroid (APS).
... In mammals, accumulating evidence indicate that exogenous phytoecdysteroids could act as adaptogens, enhancing overall fitness and health. They were postulated to exert hepatoprotective and hypoglycemic effects as well as to stimulate protein synthesis, resulting in increased muscle growth [5]. The anabolic properties of ecdysteroids also became a point of interest of sport medicine as possible doping agents [6]. ...
... They possess side-chain at position 17 ( Figure 1), which is susceptible to chemical modifications during biosynthesis and metabolism. The main chemical transitions of ecdysteroids are: hydroxylation (usually at position 5,11,25,26), oxidation (position 26), βand γ-lactam ring formation (mainly side chain), alkylation (branched side chain at position 24) and conjugation (between neighboring hydroxyl groups at positions 2 and 3, 20 and 22). Hydroxyl groups could be modified by different chemical moieties, such as polar glycosides, phosphates, sulfates or nonpolar esters, ethers, acetates and benzoates [11,[28][29][30][31]. Table 1 compares values of partition coefficients between polar and non-polar organic solvents for selected polar (20-hydroxyecdysone, α-ecdysone) and less polar (2-deoxydysone and 2,22-dideoxydysone) ecdysteroids of Rhaponticum carthamoides. ...
Article
The review presents general principles for choosing optimal conditions for ecdysteroid separation, identification and isolation using HPLC / TLC techniques in RP, NP‐HILIC or NP modes. Analytics of ecdyteroids pose a still insufficiently resolved problem. Plant‐derived ecdysteroids are a point of interest of pharmaceutical industry and sport medicine due to their postulated adaptogenic and anabolic properties. In insects, ecdysteroids regulate larval transformation. Maral root (Rhaponticum carthamoides, Leuzea carthamoides), traditional Siberian folk‐medicine plant used as stimulant to boost overall health and fitness, is a particularly rich source of a wide variety of phytoecdysteroids. The similarity of molecular structures of ecdysteroids present in its extracts together with high content of unrelated compounds of similar chromatographic characteristics makes optimization of separation, identification and isolation of ecdysteroids a difficult analytical task. In that respect, two‐dimensional separations, 2D HPLC or 2D TLC could be of use. For identification, the hyphenated techniques are particularly important. Thus, comprehensive overview of MS spectral parameters of ecdysteroids is provided. Described principles could easily be applied for separation of ecdysteroids in extracts from other sources. They are also useful for development of separation procedures for isolation of ecysteroids in preparative‐scale applications. This article is protected by copyright. All rights reserved
... Since 2020, ecdysterone has been included in the World Anti-doping Agency (WADA) monitoring program [65]. According to different studies in mammals, ecdysterone has a wide variety of pharmacological effects: anabolic, anti-diabetic, anti-inflammatory, cardioprotective, hypolipidemic and others [62,[66][67][68][69][70]. ...
... Although the four plants have quite different phytochemical composition (Table 6), the future perspectives for introduction of their specific molecules/ plant extracts as medi-cines are similar [12,13,22,23]. Most of them could be included in the management of dia-betes, cardiovascular diseases, or used as nootropic agents and hepatoprotectors (Table 7) [12,18,35,62,67,132]. Rhaponticum carthamoides is the only plant among these which has the greatest potential to be used as a remedy for improvement physical performance, because of potential ergogenic activity. ...
Article
Full-text available
Background: In the 1960s, research into plant adaptogens began. Plants with adaptogenic properties have rich phytochemical compositions and have been used by humanity since ancient times. However, it is not still clear whether the adaptogenic properties are because of specific compounds or because of the whole plant extracts. The aim of this review is to compare the bioactive compounds in the different parts of these plants. Methods: The search strategy was based on studies related to the isolation of bioactive compounds from Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: This review includes data from 259 articles. The phytochemicals isolated from Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng were described and classified in several categories. Conclusions: Plant species have always played an important role in drug discovery because their effectiveness is based on the hundreds of years of experience with folk medicine in different nations. In our view, there is great potential in the near future for some of the phytochemicals found in these plants species to become pharmaceutical agents.
... Most intriguing is that 20E, unlike testosterone, elicits anabolic growth effects on tissues without androgenic side effects, e.g. increased prostate or seminal vesicle mass [22,23]. It is believed that 20E works via a G protein-coupled receptor to activate the PI3K/ Aktsignaling pathway, resulting in mTORC1-mediated protein synthesis [24]. ...
... Ecdysteroids (insect moulting hormones) display many pharmacological effects in mammals (reviewed in [1][2][3][4][5][6][7]). For instance, 20-hydroxyecdysone (20E) has anabolic effects in mice and humans. ...
Article
Ecdysteroids exert many pharmacological effects in mammals (including humans), most of which appear beneficial, but their mechanism of action is far from understood. Whether they act directly and/or after the formation of metabolites is still an open question. The need to investigate this question has gained extra impetus because of the recent development of ecdysteroid-based gene-therapy systems for mammals. In order to investigate the metabolic fate of ecdysteroids in mice, [1α,2α-(3)H]20-hydroxyecdysone was prepared and injected intraperitoneally to mice. Their excretory products (urine+faeces) were collected and the different tritiated metabolites were isolated and identified. The pattern of ecdysteroid metabolites is very complex, but no conjugates were found, in contrast to the classical fate of the (less polar) endogenous vertebrate steroid hormones. Primary reactions involve dehydroxylation at C-14 and side-chain cleavage between C-20 and C-22, thereby yielding 14-deoxy-20-hydroxyecdysone, poststerone and 14-deoxypoststerone. These metabolites then undergo several reactions of reduction involving, in particular, the 6-keto-group. A novel major metabolite has been identified as 2β,3β,6α,22R,25-pentahydroxy-5β-cholest-8(14)-ene. The formation of this and the other major metabolites is discussed in relation to the various effects of ecdysteroids already demonstrated on vertebrates.
... The pharmacological actions of ecdysteroids on vertebrates have been reviewed in several previous articles (Burdette, 1962(Burdette, , 1972Ogawa et al., 1974;Syrov, 1984Syrov, , 1994Sláma and Lafont, 1995;Xu et al., 1997;Syrov, 2000;Kholodova, 2001;Báthori, 2002). We will therefore focus on some aspects only, especially on those where recent developments have occurred. ...
Article
Ecdysteroids are widely used as inducers for gene-switch systems based on insect ecdysteroid receptors and genes of interest placed under the control of ecdysteroid-response elements. We review here these systems, which are currently mainly used in vitro with cultured cells in order to analyse the role of a wide array of genes, but which are expected to represent the basis for future gene therapy strategies. Such developments raise several questions, which are addressed in detail. First, the metabolic fate of ecdysteroids in mammals, including humans, is only poorly known, and the rapid catabolism of ecdysteroids may impede their use as in vivo inducers. A second set of questions arose in fact much earlier with the pioneering "heterophylic" studies of Burdette in the early sixties on the pharmacological effects of ecdysteroids on mammals. These and subsequent studies showed a wide range of effects, most of them being beneficial for the organism (e.g. hypoglycaemic, hypocholesterolaemic, anabolic). These effects are reviewed and critically analysed, and some hypotheses are proposed to explain the putative mechanisms involved. All of these pharmacological effects have led to the development of a wide array of ecdysteroid-containing preparations, which are primarily used for their anabolic and/or "adaptogenic" properties on humans (or horses or dogs). In the same way, increasing numbers of patents have been deposited concerning various beneficial effects of ecdysteroids in many medical or cosmetic domains, which make ecdysteroids very attractive candidates for several practical uses. It may be questioned whether all these pharmacological actions are compatible with the development of ecdysteroid-inducible gene switches for gene therapy, and also if ecdysteroids should be classified among doping substances.
... Many herbs have remained as an alternative to conventional therapy especially in poor areas where insulin is not readily available [14,32]. phytoecdysteroids exist in many plants via Ajuga iva [41], locally known as 'Chendgoura', is used as an hypocholesterolemic and anti-diabetic [8,38]. Our investigation study is a further attempt in this direction. ...
Article
In the current study, the effect of Ajuga iva extract on blood glucose, lipid profile, hepatic and renal toxicity and antioxidant enzyme activities in alloxan-induced diabetic rats was investigated. Diabetes was confirmed by measuring the glucoserua concentration 15 days after alloxan administration. Ajuga iva extract was administrated orally 3 weeks after alloxan injection. Our results investigate that Ajuga iva extract supplementation increased the levels of both enzymatic antioxidant (superoxide dismutase, catalase and gluthation peroxidase) and metals antioxidants (iron, copper, magnesium, calcuim) and decreased lipid peroxidation level (TBARs). Besides Ajuga iva ameliorated diabetes provoked hepatic and renal toxicity appeared by a lower level in total and direct bilirubin, urea, creatinine, triglyceride (TG), cholesterol and a higher level in HDL-cholesterol. Besides, the activities of phosphatase alkalines (PAL), aspartate and lactate transaminase (AST & ALT) were decreased. The benefices effects of phytoecdysteroids of Ajuga iva confirmed by histological observation in pancreatic tissues. In conclusion, Ajuga iva phytoecdysteroids supplements seem to be beneficial for correcting the hyperglycemia and preventing diabetic complications in liver, pancreas and kidneys.
... Results are presented in relative % compared to the average peak area of 1.00 mg/mL of 57 (starting concentration) in three neutral pH solutions. Measurements were done in triplicate at2,7,15,20,30, 40, and 60 min. Error bars represent standard error of mean. ...
Article
Multidrug resistance (MDR) is a major cause of failure of cancer chemotherapy. Fifty-eight ecdysteroids, herbal analogues of the insect molting hormone and their semisynthetic derivatives, were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their subcell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). The compounds showed very low antiproliferative activities but modulated the efflux of rhodamine 123 mediated by the ABCB1 transporter. Roughly depending on the polarity, mild to strong synergism or antagonism was observed by combining ecdysteroids with doxorubicin, and specific structure-activity relationships were also found. Our results show the effect of ecdysteroids on MDR cancer cells for the first time. Less polar derivatives may serve as valuable leads toward a potent and safe resistance modulator. Biological significance of the resistance-increasing activity of the most abundant phytoecdysteroids including 20-hydroxyecdysone is yet to be clarified.
... Biological investigations on phytoecdysteroids have indicated their anabolic (Syrov, 2000), adaptogenic, tonic (Syrov and Kurmukov, 1977), cardiotonic (Kurmukov and Yermishina, 1991), hypoglycemic, hypolipidemic, hepatoprotective (Kurtepova et al., 2001;Syrov et al., 1983) and other activities. Drugs derived from phytoecdysteroids can regulate mineral, carbohydrate, lipid and protein metabolism (Dinan and Lafont, 2006). ...
Article
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Silene is a genus of the Caryophyllaceae family, contains more than 700 species, which are widely distributed in Northern Hemisphere, but also in Africa, Asia and South American. Phytochemical investigations of Silene species have revealed that many components from this genus are highly bioactive. More than 400 compounds has been isolated, among them major are phytoecdysteroids. The paper reviews the biological (antitumour, antibacterial and antioxidant) activities and the phytoecdysteroids of genus Silene. We summarized the phytoecdysteroids content referring to 171 species from the genus Silene and list 93 phytoecdysteroids isolated over the past few decades. There are also reports on the mentioned folk and traditional effects of Silene plants. © 2012 Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas.
... (Lamiaceae) is rich in biologically active substances the leaves and stems contain up to 3.76% flavonoids, iridoids, phytoectisteroids and up to 0.1% of the plant leaves contain a compound called turkesterone (Baltaev 2000;Ramazanov 2005). The medicinal plant A. turkestanica contains biologically active substances with high pharmacological effects, such as ecdysterone, turkesterone, cyasterone, ajugasterone, ajugalactone, cyasterone-22 acetate and phytoecdysteroid used in the treatment of cancer, malaria, gastrointestinal, in cardiovascular problems (Mamatkhanov et al., 1998;Syrov, 2001;Abdukadirov et al., 2005;Shakhmurova et al., 2010). ...
Article
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This research work aims to isolate endophytic bacteria from the Ajuga turkestanica plant that have plant growth promoting properties. The microscopic, enzymatic and biochemical properties of the isolated endophytic bacteria are described. Twelve isolates of endophytic bacteria were isolated by standard microbiological methods. Isolated endophytic bacteria were identified by (MALDI-TOF MS). Endophytic bacteria isolated from the plant were detected in MALDI-TOF MS. Bacterial isolates were dominated by endophytic bacteria belonging to the genus Bacillus, Pseudomonas, Siccibacter. When the growth-enhancing properties of cultivated plants used in sustainable agriculture were studied, the isolated bacterial strains showed positive results in siderophor, ammonia, indole acetic acid production, and nitrogen fixation properties. Numerous endophytic bacteria have been found to have the enzymatic activity of oxidase, catalase, amylase, lecithinase and lipase. The results showed that endophytic bacteria isolated from the plant A. turkestanica are have plant stimulating properties which can be shown as a candidate for the production of bioinoculants individually or as part of a consortium.
... The antiinflammatory activity of A. bracteosa can be attributed to the presence of phytoecdysteroids and withanolides. Dinan and Lafont reported many studies which describe the wide-scale pharmacological applications of phytoecdysteroids on mammals [27,58,[66][67][68][69]. Evaluation of ethanolic extract (70 %) of A. bracteosa is reported expressing a promising anti-inflammatory activity probably mediated through inhibition of cholinesterase enzymes I and II (COX-1 and COX-2). ...
Article
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Background: Ajuga bracteosa has been extensively used traditionally for the treatment of a variety of diseases. The aim of the study was to scientifically validate the wide-scale exploitation of A. bracteosa in folk medicine various in vitro and in vivo assays. Moreover, these activities were related to the intrinsic biologically active phytoecdysteroids of A. bracteosa. Methods: Aerial and root parts of A. bracteosa were first extracted separately with chloroform (AbCA and AbCR) and the residue was again extracted with methanol (AbMA and AbMR). Total flavonoid and phenolic contents were assayed as quercetin (QE) and gallic acid equivalents (GAE), respectively. These extracts were analyzed for in vitro antioxidant assessment including DPPH and H2O2 (% inhibition of free radicals), and reducing power and phosphomolybdenum methods (ascorbic acid equivalents AAE mg/g DW). Further, these extracts were assayed in vivo in separate groups of Sprague-Dawley rats for carrageenan induced rat paw edema inhibition, hotplate antinociception, forced swim antidepression and anticoagulation. Dose of each crude extract and standard drug given to rats was 200 mg/Kg- and 10 mg/10 mL/Kg body weight respectively. Plant extracts and standard drugs were administered orally, 60 min prior to the conduction of assays. Moreover, biologically active phytoecdysteroids were screened in A. bracteosa with the help of RP-HPLC. Results: AbMA represented highest values of flavonoids (QE 1.98 % DW) and phenolic contents (GAE 5.94 % DW), significantly scavenged DPPH radicles (IC50 36.9) and reduced ferric ions with 718.4 mg ascorbic acid equivalent/g (AAE). Highest total antioxidant capacity was expressed by AbMR (927 mg AAE) with an IC50 value 19.1 μg/mL. The extracts which were found potent anti-oxidants, were also good at in vivo activities. AbMA significantly reduced edema in all the three hours of treatment (67.9, 70.3 and 74.3 %). AbMA also showed maximum nociceptor suppression in analgesic assay by delaying the time to start licking of paws in rats (57.7 ± 4.9 s). In addition, maximum anti-coagulation was also exhibited by AbMA (89.3 s), while all extracts were found strong antidepressants (≤15.66 s immobility time). Screening of biologically active phytoecdysteroids revealed the presence of 20-hydroxyecdysone (20-HE), makisterone (MKA), cyasterone (CYP) and ajujalactone (AJL). Total phytoecdysteroid content found in A. bracteosa was 1232.5 μg/g DW and 20-HE was most abundant (1232.5 μg/g DW) as compared to other phytoecdysteroids. Conclusion: Based on the tested in vitro and in vivo activities, AbMA was found to be a promising bioactive extract. These activities can be attributed to the intrinsic polyphenols and phytoecdysteroids contents of A. bracteosa.
... The most well documented and one of the most interesting therapeutic properties of ecdysteroids is their anabolic activity. Although some animal studies have already documented this effect (Stopka et al. 1999;Todorov et al. 2000;Syrov 2000; Kurmakov 1976), they were not published in widely known English journals and may have been performed under less than ideal conditions. To confirm the authenticity of all the prior research, an animal study was planned to verify the anabolic activity of ecdysteroids and ecdysteroid containing plants. ...
... The data reported in here demonstrate that ecdysterone induces hypertrophy of muscles with a comparable or even higher potency as shown for anabolic androgenic steroids, SARMs or IGF-1. Analogous findings were also reported by Syrov et al. [14]. They reported increased body weight gain and weight as well as increased protein content of the tibialis muscle in rats after ecdysterone administration (5 mg · kg -1 BW, orally, for 10 days). ...
Article
Full-text available
Increasing numbers of dietary supplements with ecdysteroids are marketed as “natural anabolic agents”. Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER) binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol), estradienedione (trenbolox), and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days). In C2C12 myotubes ecdysterone (1 μM) induced a significant increase of the diameter comparable to dihydrotestosterone (1 μM) and IGF 1 (1.3 nM). Molecular docking experiments supported the ERβ mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class “S1.2 Other Anabolic Agents” of the list of prohibited substances of the World Anti-Doping Agency.
... Phytoecdysteroids are natural compounds with various biological activities. It is well-known, these compounds possess a pronounced protein anabolic activity (Bathori et al. 2008 based on the same class of compounds (ecdysterone), within our Institute of the Chemistry of Plant substances (ICPS) was developed a drug -ecdysten that has strong stimulating effect on regenerative processes in organism, and which was isolated from plant Rhaponticum carthamoides (Syrov 1994(Syrov , 2000(Syrov , 2009. ...
Article
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A number of phytoecdysteroid compounds, such as ecdysterone, polipodin V, 2-deoxy-20-hydroxyecdysone, integristeron A and 2-deoxydizon were isolated from Stachys hissarica plant and their structures were confirmed by NMR, mass and IR spectroscopy. In addition, the biological activity of the S. hissarica plant's extract was tested on rats for wound healing activity. It was shown that the extract at repeated oral (per os) administration at a dose of 10 mg/kg speeds up the healing process of linear skin wounds in rats. The wound-healing activity of S. hissarica extract is confirmed to be effective and exceeds known drug methyluracil (2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine), especially in case of alloxan induced diabetic animals.
... The pharmacological actions of ecdysteroids on vertebrates have been reviewed in several previous articles (Burdette, 1962(Burdette, , 1972Ogawa et al., 1974;Syrov, 1984Syrov, , 1994Sláma and Lafont, 1995;Xu et al., 1997;Syrov, 2000;Kholodova, 2001;Báthori, 2002). We will therefore focus on some aspects only, especially on those where recent developments have occurred. ...
Article
Full-text available
Ecdysteroids are widely used as inducers for gene-switch systems based on insect ecdysteroid receptors and genes of interest placed under the control of ecdysteroid-response elements. We review here these systems, which are currently mainly used in vitro with cultured cells in order to analyse the role of a wide array of genes, but which are expected to represent the basis for future gene therapy strategies. Such developments raise several questions, which are addressed in detail. First, the metabolic fate of ecdysteroids in mammals, including humans, is only poorly known, and the rapid catabolism of ecdysteroids may impede their use as in vivo inducers. A second set of questions arose in fact much earlier with the pioneering "heterophylic" studies of Burdette in the early sixties on the pharmacological effects of ecdysteroids on mammals. These and subsequent studies showed a wide range of effects, most of them being beneficial for the organism (e.g. hypoglycaemic, hypocholesterolaemic, anabolic). These effects are reviewed and critically analysed, and some hypotheses are proposed to explain the putative mechanisms involved. All of these pharmacological effects have led to the development of a wide array of ecdysteroid-containing preparations, which are primarily used for their anabolic and/or "adaptogenic" properties on humans (or horses or dogs). In the same way, increasing numbers of patents have been deposited concerning various beneficial effects of ecdysteroids in many medical or cosmetic domains, which make ecdysteroids very attractive candidates for several practical uses. It may be questioned whether all these pharmacological actions are compatible with the development of ecdysteroid-inducible gene switches for gene therapy, and also if ecdysteroids should be classified among doping substances.
... With the high biological activity of polyhydroxylated steroids isolated from plants is of great interest among scientists and pharmacologists. Proved manifestation phytoecdysteroids adaptogenic, anabolic, radioprotective, anti-ischemic, and tonic action were set efficiency of their use in blocking the inflammatory and immunological processes in the healing of wounds and burns [1][2][3][4][5]. ...
Article
Objective: The main issue of this work is obtained, to researching of supramolecular complexes of 20-hydroxyecdysone (20 E) with γ-cyclodextrins (CD).Methods: The foundation of substance phytoecdysteroid 20 E was isolated from an ethanol extract plant Otites orae-syvaschicae Klok A method of the development of pharmaceutical substances was used during complexed organic relationship in the way of intense mechanical 20 E with α-, β- or γ-СD. The complexation of 20 E with α-, β-, and γ-СD was studied by nuclear magnetic resonance (NMR) method of spectrResults: In the study of the integrated intensities molecules signals steroid guest and host CD complex stoichiometric ratio 1:1 was prformation of clathrates was established after A and B nuclei ecdysterone had been arranged in the internal cavity of CD.Сonclusion: Supramolecular complexes of 20 E with α-, β-, and γ-СD were received during made works. The objects of research were analdescribed with the help of NMR spectroscopy. The developed technology will be the main device for operating and identification of pharmaceuticalsubstance OOSE-11, -12, and -13.Keywords: Substance Otites orae-syvaschicae Klok-11, -12, -13, 20-hydroxyecdysone, α-, β-, γ-cyclodextrins inclusion complex nuclear resonance spectroscopy.
... Pharmacological tests were first performed on mammals (mice, rats) in the late 1960s to detect any harmful effects of ecdysteroids on vertebrate organisms, which could have precluded their use as insecticides. This was the starting point for many experiments, which reported a wide array of pharmacological effects of ecdysteroids on mammals (Sláma & Lafont 1995, Syrov 2000, Kholodova 2001, Báthori 2002, Lafont & Dinan 2003, Klein 2004, Báthori & Pongrácz 2005. ...
Article
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Zooecdysteroids (arthropod steroid hormones) regulate the development of arthropods and probably many other invertebrates. Phytoecdysteroids are analogues occurring in a wide range of plant species, where they contribute to the deterrence of phytophagous invertebrates. The purpose of this short review is to summarise findings on the occurrence, metabolism and pharmacological effects of ecdysteroids in mammalian systems and to draw attention to their potential applications, particularly in gene-switch technology, where ecdysteroid analogues (steroidal and non-steroidal) can be used as effective and potent elicitors.
... The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.04.08.032607 doi: bioRxiv preprint Supporting Acuña et al., 2014;Cabello-Verrugio et al., 2015Cisternas et al., 2015;Abrigo et al., 2016;Morales et al., 2014Chermnykh et al., 1988Syrov, 2000;Tóth et al., 2008;Gorelick-Feldman et al., 2008, 2009Lawrence, 2012;Velders et al., 2012Tchoukouegno Ngeu, 2013;Chidi-Ogbolu & Baar, 2019 ...
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20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysone receptors (EcRs) and at least one membrane GPCR receptor (DopEcR) and displays numerous pharmacological effects in mammals. However, its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERβ receptor. The goal of our study was to better understand 20E mechanism of action. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) was used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with Angiotensin-(1-7), the endogenous ligand of Mas. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using small interfering RNA (siRNA) or pharmacological inhibitors. 17β-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin-(1-7) antagonists. A mechanism involving cooperation between Mas receptor and a membrane-bound palmitoylated estrogen receptor is proposed. The possibility to activate the Mas receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and indeed this mechanism may explain the close similarity between angiotensin-(1-7) and 20E effects. Our findings open a lot of possible therapeutic developments by stimulating the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.
... Ecdysteroids (mainly 20E, but also turkesterone) are already extensively used by certain sportsmen, bodybuilders, bouncers, etc. to increase muscle mass and stamina. 11α-Hydroxy ecdysteroids, such as turkesterone, are claimed to have higher anabolic activity than 20E (Syrov 2000). The absence of the side effects (long-term muscle degeneration, virilization, roid (as it is a contraction of steroid) rage, etc.) characteristic of androgenic-anabolic steroids is an attractive feature of ecdysteroids for these user groups. ...
... It has been suggested that the anabolic effects of 20E are mediated via a G-protein coupled cell surface receptor (29), as opposed to an intracellular androgen receptor. Thus, 20E is considered anabolic, but non-androgenic since it does not increase prostate or seminal vesicle mass in young castrated rats after 10 days of treatment (30), nor does it alter organ or testes mass in aging mice with 28 days of treatment (31). Regarding skeletal muscle, 20E has been reported to increase grip strength in young rats and stimulate protein synthesis via the PI3K/Akt pathway in C2C12 myotubes in vitro (32). ...
Article
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Background: Eccentric muscle contractions are commonly used in exercise regimens, as well as in rehabilitation as a treatment against muscle atrophy and weakness. If repeated multiple times, eccentric contractions may result in skeletal muscle injury and loss of function. Skeletal muscle possesses the remarkable ability to repair and regenerate after an injury or damage; however, this ability is impaired with aging. Phytoecdysteroids are natural plant steroids that possess medicinal, pharmacological, and biological properties, with no adverse side effects in mammals. Previous research has demonstrated that administration of phytoecdysteroids, such as 20-hydroxyecdysone (20E), leads to an increase in protein synthesis signaling and skeletal muscle strength. Methods: To investigate whether 20E enhances skeletal muscle recovery from eccentric contraction-induced damage, adult (7–8 mo) and old (26–27 mo) mice were subjected to injurious eccentric contractions (EC), followed by 20E or placebo (PLA) supplementation for 7 days. Contractile function via torque-frequency relationships (TF) was measured three times in each mouse: pre- and post-EC, as well as after the 7-day recovery period. Mice were anesthetized with isoflurane and then electrically-stimulated isometric contractions were performed to obtain in vivo muscle function of the anterior crural muscle group before injury (pre), followed by 150 EC, and then again post-injury (post). Following recovery from anesthesia, mice received either 20E (50 mg•kg ⁻¹ BW) or PLA by oral gavage. Mice were gavaged daily for 6 days and on day 7, the TF relationship was reassessed (7-day). Results: EC resulted in significant reductions of muscle function post-injury, regardless of age or treatment condition ( p < 0.001). 20E supplementation completely recovered muscle function after 7 days in both adult and old mice (pre vs. 7-day; p > 0.05), while PLA muscle function remained reduced (pre vs. 7-day; p < 0.01). In addition, histological markers of muscle damage appear lower in damaged muscle from 20E-treated mice after the 7-day recovery period, compared to PLA. Conclusions: Taken together, these findings demonstrate that 20E fully recovers skeletal muscle function in both adult and old mice just 7 days after eccentric contraction-induced damage. However, the underlying mechanics by which 20E contributes to the accelerated recovery from muscle damage warrant further investigation.
... Ajugacetalsterone C Breviflorasterone Ajugacetalsterone D performance, wound healing, enhancing immune function to prevent infection and disease, improvement in kidney and liver functions, and increased red cell production (Dinan, 2001;Syrov, 2001;Syrov et al., 2001a;Syrov et al., 2001b;Báthori and Pongrâcz, 2005;Dinan and Lafont, 2006;Cheng et al., 2008 (Takasaki et al., 1999). ...
Article
The plants of genus Ajuga are evergreen, clump-forming rhizomatous perennial or annual herbaceous flowering species, with Ajuga being one of the 266 genera of the family Lamiaceae. There are at least 301 species of the genus Ajuga with many variations. These plants, growing in Europe, Asia, Africa, Australia and North America, are used in gardens as ground cover or border for their foliage and beautiful flowers. Many of these plants have been used in traditional medicine as a remedy for fever, toothache, dysentery, malaria, high blood pressure, diabetes, gastrointestinal disorders, as anthelmintic, diuretic and antifungal, anti-inflammatory, and antimycobacterial agents. They are also used as insect growth inhibitor s. A large number of compounds have been isolated from the Ajuga plants, including phytoecdysteroids, neo-clerodane-diterpenes and diterpenoids, triterpenes, sterols, anthocyanidin-glucosides and iridoid glycosides, withanolides, flavonoids, triglycerides and essential oils. These compounds possess a broad spectrum of biological, pharmacological and medicinal properties, such as anabolic, analgesic, antibacterial, antiestrogenic, antifungal, anti-inflammatory, antihypertensive, antileukemic, antimalarial, antimycobacterial, antioxidant, antipyretic, cardiotonic, cytotoxic, hypoglycemic, and vasorelaxing activity, as well as antifeedant and insect growth-inhibitory properties. Thus, genus Ajuga has significant medicinal and economic importance.
Article
Ecdysteroids are known as insect moulting hormones. They have the basic steroid structure, although their physiological effects on mammalians do not show the thymolytic and androgenic side effects of vertebrate type steroid hormones. At the same time, phytoecdysteroids can be used utilizing their anabolic and adaptogenic effects. Ecdysteroids also have a tremendous potential in the most modern therapy. Recently, the biotechnology started to employ ecdysteroids as powerful inducers for gene-switch systems with insertion of modified insect receptor into the malignant cells. Nineteen ecdysteroids were isolated with combined chromatographic methods from the herbs of Silene italica ssp. nemoralis (Waldst. and Kit.) Nyman. The chemical structure of the isolated compounds have been elucidated using spectroscopic methods (x-ray, UV, CD, IR, MS, 1D-, 2D-NMR, HMQC, HMBC, COSY, TOCSY, NOESY, ROESY). Structural determination of two of the five new ecdysteroids is detailed here.
Article
Seven ecdysteroids have been isolated from the methanolic extract of the herb Serratula wolffii Andrae. The isolation process involved the removal of polar and apolar contaminants, and also included the separation of the target ecdysteroids from each other by using combined chromatographic methods. Isolation of the pure compounds required a minimum of 2 and a maximum of 7 consecutive chromatographic steps with different selectivity. Six of the isolated ecdysteroids showed the presence of an 11alpha-hydroxyl group on the steroidal skeleton, which structure may enhance the increasing effect of ecdysteroids on the protein synthesys of mammals, according to literature data. Ajugasterone C, one of these compounds was found to be present in remarkable amount in the plant. One ecdysteroid, 11 alpha-hydroxypoststerone was identified as a new natural compound.
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The World Health Organization reports that approximately 200 million people are infected with Giardia (G.) lamblia worldwide. Taking into account the emergence of resistance and the high toxicity of conventional drugs, research into new strategies to fight against G. lamblia is increasing. The aim of the study was to assess the antiprotozoal activity of 20-hydroxyecdysone in water sports athletes with giardiosis. A randomized, double-blinded, placebocontrolled clinical study was conducted. Seventy-six athletes with G. lamblia infection participated in the study and were divided into 20-hydroxyecdysone, metronidazole and placebo groups. Clinical, parasitological, haematological and biochemical analyses were performed. Positive results for antiprotozoal therapy were revealed in the 20-hydroxyecdysone and metronidazole groups. After therapy, elimination of G. lamblia was observed in 100.0% of the athletes included in the 20-hydroxyecdysone group. However, G. lamblia was resistant to metronidazole in 4.0% of athletes included in the metronidazole group. A positive clinical response to the therapy occurred in the 20-hydroxyecdysone and metronidazole groups. Our study reveals high antiprotozoal activity of 20-hydroxyecdysone against G. lamblia. Further clinical studies are necessary to evaluate the antiprotozoal efficacy of 20-hydroxyecdysone.
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Eleven phytoecdysteroids have been isolated and identified from the low polarity fractions of Serratula coronata juice by a combination of column chromatography and HLPC. Four of them are new, i.e. ecdysone 22-acetate 7 , (25 S )-inokosterone 26-acetate 9 , 20,22- O -( R -ethylidene)-20-hydroxyecdysone 10 and 20,22- O -( R -ethylidene)-ajugasterone C 11 . The biological activity of these new ecdysteroids in the Drosophila melanogaster B<sub>II</sub> cell bioassay is reported.
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Beside ecdysone (1), ecdysterone (2) is one of the most common 5beta-cholest-7-en-6-one (ecdysteroid) derivatives, which, besides having a hormonal effect on invertebrates, possesses a number of favorable non-hormonal biological effects on mammals. The most interesting of these is that on degenerative diseases, one of which, up to now not clarified in detail, is the so-called adaptogenic effect (protection of the organism against adverse stress factors) associated with anabolic, gastroprotective, and antioxidant effects. A second group of favorable effects is the possibility of suppression of neurodegenerative processes and protection of the cardiovascular system (metabolic syndrome symptom suppression, antidiabetic activity, and protection of heart and blood vessels). Because of these properties, ecdysterone has the potential to be developed as a medicinal agent.
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Herbs, herbal extracts or phytochemicals are broadly used as foods, drugs and as traditional medicines. These are well regulated in Europe, with thorough controls on both safety and efficacy or validity of health claims. However, the distinction between medicines and foods with health claims is not always clear. In addition, there are several cases of herbal products that claim benefits that are not scientifically demonstrated. This review details the complex EU legislative framework that regulates the approval and marketing of herbal products bearing health claims as well as the scientific evidence that is needed to support such claims. To illustrate the latter we focus on phytoecdysteroid (PE)-containing preparations, generally sold to sportsmen and bodybuilders. We review the limited published scientific evidence that supports claims for these products in humans. In addition, we model the in silico binding between different PEs and human nuclear receptors and discuss the implications of these putative bindings in terms of the mechanism of action of this family of compounds. We call for additional research to validate the safety and the health promoting properties of PEs and other herbal compounds, for the benefit of all consumers.
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The present study investigated the protective effect of phytoecdysteroids extracted from the Ajuga iva plant on body weight changes, blood glucose, insulin total protein, blood urea nitrogen (BUN), creatinine, triglycerides (TG), cholesterol, lipid peroxidation, antioxidant enzymes, pancreatic histopathology and hexokinase-I expression in the alloxan-induced diabetic rats. Experimental diabetes was induced following 15day intraperitoneal administration of alloxan. The rats were divided into four groups. Group I served as a sham group, and group II served as the diabetic control. Group III served as a treatment for phytoecdysteroids (10mg/kg), and group IV served as a treatment for phytoecdysteroids (20mg/kg). Phytoecdysteroids restored body weight loss to its antihyperglycemic effect. Blood glucose was reduced 19.2 and 52.9% in group III and IV respectively. Blood insulin (54.9 and 105.88%) and total protein (25 and 72.2%) was increased in group III and IV respectively. BUN, creatinine, TG, cholesterol and lipid peroxidation was significantly reduced following treatment. Catalase, superoxide dismutase (SOD), and glutathione peroxidase activity were significantly increased following treatment. Islet β-cells are lost in alloxan-induced diabetic rats. Regeneration of islets and reduced atrophy of acinar cells were noted. The number of insulin-secreting cells was tremendously reduced in alloxan-induced diabetic rats. Insulin-secreting cells were increased 48 and 61% in group III and IV respectively. Hexokinase-I mRNA (28.3 & 93.5%) and protein (27.9 and 55.3%) expression were significantly increased following treatment. Taking all these data together, it is suggested that the phytoecdysteroid could be a potential therapeutic agent against experimental diabetes.
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Objective: We aim to evaluate the potential interaction of two insect hemolymph peptides, MDF3 and MDF4, with the human androgen receptor, on the premise that the proliferative effects of the two peptides are (at least in part) a consequence of AR binding. Methods: We employed a bioinformatic approach for the prediction of protein-peptide interaction and peptide aggregation, using various in silico on-line tools such as docking servers, aggregation prediction servers and visualization and analysis software in order to evaluate our results. Results: Our evaluation indicates that MDF3 and MDF4 interact with the androgen human androgen receptor by binding to a helix shown to be involved the receptor dimerization. Out of the two peptides, MDF3 appears to form a more extensive bond network with the receptor. Conclusion: Our analysis indicates that MDF 3 and 4 may be able to activate the human androgen receptor and warrant further investigation of the potential effect on receptor function. MDF3 appears to be the most promising out of the two peptides and its interaction should be further evaluated by both computational and experimental methods.
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There is growing interest in the pharmaceutical and medical applications of 20-hydroxyecdysone (20E), a polyhydroxylated steroid which naturally occurs in low but very significant amounts in invertebrates, where it has hormonal roles, and in certain plant species, where it is believed to contribute to the deterrence of invertebrate predators. Studies in vivo and in vitro have revealed beneficial effects in mammals: anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, hepatoprotective, etc. The possible mode of action in mammals has been determined recently, with the main mechanism involving the activation of the Mas1 receptor, a key component of the renin–angiotensin system, which would explain many of the pleiotropic effects observed in the different animal models. Processes have been developed to produce large amounts of pharmaceutical grade 20E, and regulatory preclinical studies have assessed its lack of toxicity. The effects of 20E have been evaluated in early stage clinical trials in healthy volunteers and in patients for the treatment of neuromuscular, cardio-metabolic or respiratory diseases. The prospects and limitations of developing 20E as a drug are discussed, including the requirement for a better evaluation of its safety and pharmacological profile and for developing a production process compliant with pharmaceutical standards.
Chapter
Phytoecdysteroids are allelochemical toxins and antioxidants for non-adapted phytophage insect species. For the manifestation of hormonal activity, the structural organization of the phytoecdysteroid molecule is important. The most essential elements are the cis-junction of rings A and B, the presence of a D 7–6-conjugated keto group, and a complete sterol side chain. The presence of 14α-OH, 2β-OH, 3β-OH, and 20R-OH increases the biological activity. A very significant indicator of the manifestation of the protein-anabolic action of the compounds. However, the majority of phytoecdysteroids that have been isolated to date have a significantly lower ability to activate protein biosynthesis in mammals than steranobol. Of the other biological effects of phytoecdysteroids associated with their effect on metabolic processes in animals. No increase in insulin secretion was observed in animal experiments. Thus, the improvement in the activity of the central nervous system. Phytoecdysteroids did not show any toxic effects to the higher animals. In experiments on mice, it was found that LD50 for ecdysterone, when administered intravenously, was 6.4 g/kg, and for inocosterone –7.8 g/kg. Ecdysten which is based on ecdysteroids mental and physical performance improved, attention concentration increased, and reactive and personal anxiety normalized. In this chapter, postulates that phytoecdysteroids as metabolically active substances with the ability to increase the general nonspecific resistance of the body to various destabilizing environmental factors are of significant interest both in terms of further theoretical research and in terms of their practical use.
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Two new ecdysteroid acetonide derivatives, 5α-2-deoxy-20- hydroxyecdysone 20,22-acetonide (6) and makisterone C 2,3;20,22-diacetonide (8), were isolated from the dried herb of Silene viridiflora. The already known 5β-2-deoxy-20-hydroxyecdysone 20,22-acetonide (7) is additionally reported here as a new constituent of S. viridiflora. Five earlier described S. viridiflora ecdysteroids, integristerone A (1), 5,20,26-trihydroxyecdysone (26-hydroxypolipodine B; 2), 20,26-dihydroxyecdysone (3), 2-deoxy-20- hydroxyecdysone (4), 2-deoxyintegristerone A (5), are also included because of their improved characterization. The structures were established via spectroscopic analyses, including one- and twodimensional NMR and mass spectrometry.
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From the roots with rhizomes of the plantRhaponticum carthamoides Willd) Iljin Compositae), in addition to integristerone A, ecdysterone, polypodin B, 2-deoxyecdysterone, and 24(28)-dehydromakisterone A, we have isolated the new compounds ecdysteron3–2,3-monoacetonide (I), ecdysterone 20,22-monoacetonide (II)) and rhapisterone (III): I — C30H48O7, mp 232–233° (ethyl acetate-methanol) [α] D20 +56.4±2° (c 0.0; methanol); II — C30H48O7, mp 227–229° (ethyl acetate-methanol), [α] D20 +60.1±2° (c 1.3; methanol); III — C29H48O7, mp, 241–242° (ethyl acetate-methanol), [α] D20 +30±2° (c 0.1; dioxane). The structure of (III) was established on the basis of spectral characteristics as 2β, 3β, 14α, 20R, 22R, 23ζ-5β-stigmast-7-en-6-one. Details of the PMR, mass, and IR spectra of all the compounds and of the CD of rhapisterone are given.
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In experiments with white mice it has been established that phytoecdisteroides turkesteron, ecdisteron and 2-desoxy-alpha-ecdison in the dose of 5 mg on 1 kg of body mass stimulate the protein synthesis. Using the model of protein synthesis from mice liver it has been shown that the action of phytoecdisteroides is connected with the rise of poliribosome functional activity and rate increase of protein macromolecules formation. Preliminary administration of actinomycin D does not prevent the effect of protein synthesis stimulation. It has been concluded that the anabolic effect of phytoecdisteroides in mammals organism is connected not with induction of RNA synthesis but with the acceleration of translocation processes.
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