Pharmacological Studies of Insect Metamorphosing Hormone : Ponasterone A, Ecdyste-Rone, and Inokosterone, in the Rat

Masuoka, Michio; Orita, Shigeru; Shino, Akio; Matsuzawa, Tai; Nakayama, Ryo

doi:10.1254/jjp.20.142

Cited by 10 publications

(4 citation statements)

References 11 publications

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“…This is especially concerning because the doses of ecdysone used for sports or fitness purposes are remarkably high (in a range of up to 1000 mg/day) 19 . Moreover, there are studies associating the use of ecdysone with evident signs of aberrant kidney homeostasis, such as kidney growth and enlargement 24 , 25 . Therefore, provided that use of anabolic androgenic steroids poses a risk of renal impairment, it is imperative to determine the effect of ecdysone on the kidney health.…”

Section: Introductionmentioning

confidence: 99%

Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling

Wang

et al. 2018

Sci Rep

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Ecdysone is an arthropod molting hormone and has been marketed as a non-androgenic natural anabolic and adaptogen. However, the safety profile of ecdysone is largely undetermined. After ecdysone treatment for 2 weeks, mice developed albuminuria with histologic signs of glomerular injury, including hypertrophy, mesangial expansion, mild glomerulosclerosis and podocyte injury. A direct glomerulopathic activity of ecdysone seems to contribute, since addition of ecdysone to cultured glomerular cells induced cytopathic changes, including apoptosis, activation of mesangial cells, podocyte shape changes and a decreased expression of podocyte markers. To explore the molecular target responsible for the pathogenic actions, we employed an in silico modeling system of compound-protein interaction and identified mineralocorticoid receptor (MR) as one of the top-ranking proteins with putative interactions with ecdysone. The molecular structure of ecdysone was highly homologous to mineralocorticoids, like aldosterone. Moreover, ecdysone was capable of both inducing and activating MR, as evidenced by MR nuclear accumulation in glomerular cells both in vitro and in vivo following ecdysone treatment. Mechanistically, glycogen synthase kinase (GSK) 3β, which has been recently implicated in pathogenesis of glomerular injury and proteinuria, was hyperactivated in glomeruli in ecdysone-treated mice, concomitant with diverse glomerulopathic changes. In contrast, spironolactone, a selective blockade of MR, largely abolished the cytopathic effect of ecdysone in vitro and attenuated albuminuria and glomerular lesions in ecdysone treated mice, associated with a mitigated GSK3β overactivity in glomeruli. Altogether, ecdysone seems able to activate MR and thereby promote glomerular injury and proteinuria involving overactive GSK3β pathway signaling.

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Section: Introductionmentioning

confidence: 99%

Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling

Wang

et al. 2018

Sci Rep

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“…These results are consistent with our previous studies [ 14 , 15 ]. Unexpectedly, this compound is an insect metamorphosis hormone and the main component of Achyranthes bidentata Blume, another traditional Chinese herbal medicine [ 33 , 34 ]. Inokosterone from A. bidentata Blume has an antiandrogen effect, promotes protein synthesis in the liver, has anti-rheumatoid arthritis effects, and prevents osteoporosis [ 33 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Unexpectedly, this compound is an insect metamorphosis hormone and the main component of Achyranthes bidentata Blume, another traditional Chinese herbal medicine [ 33 , 34 ]. Inokosterone from A. bidentata Blume has an antiandrogen effect, promotes protein synthesis in the liver, has anti-rheumatoid arthritis effects, and prevents osteoporosis [ 33 , 35 ]. In this study, our bioassay system was also utilized to indicate whether inokosterone from A. bidentata Blume and G. rigescens Franch has the same antiaging effect on yeast and PC12 cells.…”

Section: Discussionmentioning

confidence: 99%

Inokosterone from Gentiana rigescens Franch Extends the Longevity of Yeast and Mammalian Cells via Antioxidative Stress and Mitophagy Induction

Liu

Chen

et al. 2022

Antioxidants

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In the present study, replicative lifespan and chronological lifespan assays of yeast were used to double-screen antiaging compounds from Gentiana rigescens Franch, a Chinese herb medicine. Inokosterone from G. rigescens Franch extended not only the replicative lifespan of K6001 yeast but also the chronological lifespan of YOM36 yeast. Furthermore, it can enhance the survival ability of mammalian cells. In order to understand the mechanism of action of this compound, this study focused on antioxidative stress and autophagy when performing the analysis. The increased cell survival rate under oxidative stress conditions, antioxidant enzyme activity and gene expression were observed in the inokosterone-treated groups. Meanwhile, the reactive oxygen species (ROS) and lipid peroxidation of yeast were obviously decreased. Additionally, the macroautophagy and mitophagy in YOM38-GFP-ATG8 yeast were increased upon inokosterone treatment, respectively. At the same time, the cleavage-free GFP from GFP-ATG8 in the cytoplasm and the ubiquitin of the mitochondria at the protein level were markedly enhanced after incubation with inokosterone. Furthermore, we investigated the effect of inokosterone on antioxidative stress and autophagy in mammalian cells, and the relationship between ROS and autophagy. The ROS, malondialdehyde (MDA) were significantly decreased, and the autophagosomes in mammalian cells were obviously increased after inokosterone treatment. The autophagosomes in ∆sod1 yeast with a K6001 background had no obvious changes, and the ROS and MDA of ∆sod1 yeast were increased compared with K6001 yeast. The increase of autophagosomes and the reduction of ROS and MDA in ∆sod1 yeast were observed after treatment with inokosterone. Meanwhile, the reduction of the ROS level and the increase of the SOD1 gene expression of K6001 yeast lacking autophagy were observed after treatment with inokosterone. In order to indicate whether the genes related to antioxidant enzymes and autophagy were involved in the antiaging effect of inokosterone, mutants of K6001 yeast were constructed to conduct a lifespan assay. The replicative lifespans of ∆sod1, ∆sod2, ∆uth1, ∆skn7, ∆gpx, ∆cat, ∆atg2, and ∆atg32 of K6001 yeast were not affected by inokosterone. These results suggest that inokosterone exerted an antiaging activity via antioxidative stress and increased autophagy activation; autophagy affected the ROS levels of yeast via the regulation of SOD1 gene expression.

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“…In particular, ecdysone targets the drosophila Malpighian tubules, which are equivalent to renal tubules in mammals, and regulates ionic changes and water retention in arthropods [12,13]. Recently, the use of ecdysone-containing adaptogens in mammalian has been associated with kidney growth and enlargement [14][15][16], which are evident clinical signs of disturbed kidney homeostasis. The mechanism underlying this renal side effect of ecdysone remains to be defined.…”

Section: Introductionmentioning

confidence: 99%

Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities

Wang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. Methods: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. Results: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. Conclusion: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury.

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Pharmacological Studies of Insect Metamorphosing Hormone : Ponasterone A, Ecdyste-Rone, and Inokosterone, in the Rat

Cited by 10 publications

References 11 publications

Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling

Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling

Inokosterone from Gentiana rigescens Franch Extends the Longevity of Yeast and Mammalian Cells via Antioxidative Stress and Mitophagy Induction

Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities

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