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.

https://bioone.org/journals/Journal-of-Insect-Science/volume-3/issue-7/031.003.0701/Practical-uses-for-ecdysteroids-in-mammals-including-humans--and/10.1673/031.003.0701.pdf

Practical uses for ecdysteroids in mammals including humans: an update

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.

/pdf/effects-and-applications-of-arthropod-steroid-hormones-3s5z3wf0t4.pdf

Effects and applications of arthropod steroid hormones (ecdysteroids) in mammals.

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 ER 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. 17-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.

/pdf/20-hydroxyecdysone-activates-the-protective-arm-of-the-renin-2vdjxamwkz.pdf

20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor

On the model of focal ischemia-reperfusion of the brain investigated the induction of nitrosative stress in mitochondria of rats hearts and possible mechanisms of protective action of ecdysterone. It is shown that focal ischemia-reperfusion of the brain induced in myocardial mitochondria the activation of constitutive and inducible de novo synthesis of NO by oxidation of L-arginine and not oxidative synthesis of NO through the recovery of oxidized stable metabolites of NO. Strong evidence of induction of nitrosative stress in heart mitochondria by focal ischemia-reperfusion of the brain, was a significant increase in mitochondrial pool of nitrate- and nitrite-anions and pools of nitrosothiols, that is proof of the formation and decay of peroxynitrite--a key marker of nitrosative stress. Also was observed increase in heart mitochondria by focal ischemia-reperfusion of the brain, content key regulator of de novo synthesis of NO-hydrogen sulfide and activity of inducible arginase II and, as a result, the pool of carbamide, which is also a regulator of the synthesis of NO. Previous introduction for animals herbal extract Serratsula coronata, enriched ecdysterone, reduces induction nitrosative stress in mitochondria of rats hearts under conditions of focal ischemia-reperfusion of the brain.

/pdf/induction-of-nitrosative-stress-in-mitochondria-of-rats-4v1l38ljtm.pdf

[Induction of nitrosative stress in mitochondria of rats hearts in experimental ischemia-reperfusion of the brain and its correction by ecdysterone].

L'obesite est une maladie complexe dont la prevalence est en constante augmentation a travers le monde. A l'instar de nombreux medicaments qui ont pour origine des molecules vegetales, de nouveaux principes actifs ont ete recherches dans les plantes. Parmi eux, les phytoecdysteroides, notamment la 20-hydroxyecdysone presente dans le quinoa, ont montre des effets pharmacologiques benefiques, et seraient donc des candidats potentiellement efficaces contre l'obesite. L'objectif de cette these est de mettre en evidence les proprietes d'un extrait de quinoa enrichi en 20-hydroxyecdysone sur le surpoids et l'obesite et d'en caracteriser les effets.Dans un premier temps, un apport alimentaire d'extrait de quinoa enrichi en 20-hydroxyecdysone chez la souris soumise a un regime hyperlipidique a permis de limiter le developpement du tissu adipeux, sans modifier la prise alimentaire. Dans le tissu adipeux, ces effets ont ete associes a une diminution de la quantite de transcrits de genes impliques dans le stockage lipidique et l'inflammation. L'analyse du bilan energetique a mis en evidence un effet de l'extrait de quinoa sur l'augmentation de la depense energetique liee a une augmentation de l'oxydation des glucides, ainsi que sur la diminution de l'absorption intestinale des lipides. Ensuite, chez le sujet en surpoids ou obese, l'extrait de quinoa a montre une tendance a la prevention de la reprise de poids et de masse adipeuse suite a une restriction energetique. Cet effet s'est accompagne d'un maintien de l'amelioration de l'insulino-sensibilite. Enfin, des mesures de biodisponibilite de la 20-hydroxyecdysone chez la souris ont permis de quantifier sa teneur circulante et de suivre l'apparition de certains de ses metabolites dont le role reste a identifier. Ces resultats montrent un benefice potentiel de l'extrait de quinoa et de son principe actif, la 20-hydroxyecdysone, sur la stabilisation du poids et de la masse adipeuse suite a une reduction ponderale. D'autres etudes seront necessaires afin de poursuivre la caracterisation de ces effets.

https://pastel.archives-ouvertes.fr/pastel-00998299/document

Effets d'un extrait de quinoa enrichi en 20-hydroxyecdysone dans un modèle d'obésité nutritionnelle : application clinique

It is established that ecdysterone (20-hydroxyecdysone) in concentration of 10(-8) M and calcitriol (1 alpha, 25-dihydroxyvitamin D3) in concentration 10(-12) M evoke in the studied tissues-targets of rats (brain, heart, liver, intestine mucosa) rapid (0.5-2 min) transit (2.5-4 times) increase of the intracellular pools of arachidonic acid, eicosanoid--total peptidoleukotrienes C4/D4/E4 (2.5-6 times), and, especially prostaglandins--stable metabolite prostacyclin 6-ketoprostaglandin F1 alpha (10-400 times). Ecdysterone in concentration 10(-11)-10(-9) inhibits arachidonic cascade in the brain and heart. Activation of arachidonic cascade and further increase of biosynthesis of cGMP are considered as a single negative link of autoregulation of activity of phospholipid-dependent signal system of cells and ecdysterone as a possible efficient modulator intracellular pools of eicosanoid in the tissues of warm-blooded animals.

[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Modulation of intracellular pools of arachidonic acid and products of its oxidative metabolism].

Variations of sphingomyelin metabolism in the tissue of brain, liver, heart and mucosa of small intestine of healthy rats were studied in the in vivo experiments using L-[methyl-3H]methionine for 1h after administration of 10(-8)-10(-12) M of biologically active hydroxysterols--steroid hormones: ecdysterone (20-hydroxyecdysone) and calcitriol (1 alpha, 25-dihydroxy vitamin D3) Considerable activation (5-10 times) of sphingomyelin hydrolysis is observed 1-2 min after peroral administration of hydroxysterols An essential increase of the pools of sphingosin is observed Sphingosin is a modulator of activity of protein kinase C taking part in the transfer of the external signal to the cell It is supposed that sphingomyelin metabolism modulation can be one of the effector mechanisms of early (pregenom) action of steroid hormones--ecdysterone and calcitriol

[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Identification of sphingomyelin as the effector mechanism of the early effect].

Tuhanova Av

Papers

[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Modulation of intracellular pools of arachidonic acid and products of its oxidative metabolism].

[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Identification of sphingomyelin as the effector mechanism of the early effect].