The regulatory effects of clomiphene and tamoxifen on mTOR and LC3-II expressions in relation to autophagy in experimental polycystic ovary syndrome (PCOS)

Kuşçu, Gökçe Ceren; Gürel, Çevik; Buhur, Aylin; Oltulu, Fatih; Akman, Levent; Köse, Timur; Yavaşoğlu, Nefise Ülkü Karabay; Yavaşoğlu, Altuğ

doi:10.1007/s11033-021-06981-y

Cited by 5 publications

(2 citation statements)

References 49 publications

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“…Because bazedoxifene treatment stimulates LC3B vesicles production in LGMD R2 muscular cells and because LC3-II vesicles might be recruited to the damaged membrane site for membrane resealing process (Corkery et al, 2023), we hypothesized that its widespread protective effect might therefore be linked to this effect on autophagy rather than to the clearance of protein aggregates. This hypothesis is also supported by the fact that bazedoxifene belongs to the same class of drugs as tamoxifen, reported to improve muscle contractility in preclinical models of centronuclear myopathies (Gineste et al, 2023;Gayi et al, 2018b) and currently investigated in a phase 3 clinical trial to treat Duchenne muscular dystrophie (NCT03354039) (Gayi et al, 2018a;Dorchies et al, 2013;Nagy et al, 2019;Birnbaum et al, 2022;Kuşçu et al, 2022).…”

Section: Discussionmentioning

confidence: 90%

Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening

Bruge,

Bourg,

Pellier

et al. 2024

Preprint

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LGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. We report here the development of anin vitrohigh-throughput assay using immortalized myoblasts and monitored reallocation of an aggregated mutant form of dysferlin (DYSFL1341P). Using this assay, we screened a library of 2239 drugs and identified two autophagy inducers, namely saracatinib and bazedoxifene, as potential drugs to repurpose for LGMD R2 patients carrying theDYSFL1341Pmutation. Functional characterization of these drugs revealed that saracatinib and bazedoxifene had a protective effect on the plasma membrane in osmotic shock assay. While saracatinib restores functionality in membrane resealing through a specific rescue of L1341P dysferlin from degradation, bazedoxifene demonstrates an additional protective effect on dysferlin KO mice muscle fibers. Finally, further investigations into the molecular mechanism of action of bazedoxifene revealed an induction of autophagy flux, which may underlie the molecule’s effect on the survival of LGMD R2 myofibers.

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Section: Discussionmentioning

confidence: 90%

Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening

Bruge,

Bourg,

Pellier

et al. 2024

Preprint

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“…The present study revealed that the expression of the structural protein Desmin increased in a time-dependent manner when exposed to cadmium, indicating that MPC5 cells were damaged [ 48 , 49 ]. LC3 is a marker of cellular autophagy, and the amount of LC3-II was positively correlated with the degree of autophagy occurring [ 50 ]. The present study showed that the expression of LC3-II, a functional protein of autophagy, increased in a time-dependent manner after cadmium treatment, and the degree of autophagy was severe.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Astragaloside IV against Cadmium-Induced Damage on Mouse Renal Podocytes (MPC5)

et al. 2023

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In this study, we investigated the protective effect of Astragaloside IV (Ast) on mouse podocytes and its possible mechanism of action by constructing a cadmium-induced mouse renal podocytes model. We investigated the effects of cadmium (Cd) toxicity on cell number, morphology, the mitochondrial status of subcellular organelles, protein and gene levels, and the protective effects of Ast by constructing a model of Cd-induced damage to mouse renal podocytes (MPC5) and giving Ast protection at the same time. The results showed that exposure of MPC5 cells to CdCl2 culture medium containing 6.25 μM concentration acted with low cell mortality, but the mortality of MPC5 cells increased with the prolongation of cadmium exposure time. Given Ast, the death rate in the low dose group (12.5 μM) was significantly reduced, while the death rate in the medium dose group (25 μM) was extremely significantly reduced. In comparison to the control group, the Cd-exposed group exhibited a significant increase of 166.7% in malondialdehyde (MDA) content and a significant decrease of 17.1% in SOD activity. The mitochondrial membrane potential was also reduced to varying degrees. However, in the Ast-protected group compared to the Cd-exposed group, the MDA content significantly decreased by 20.8%, the SOD activity decreased by 7.14%, and the mitochondrial membrane potential showed a significant increase. Fluorescence staining of mitochondrial membrane potential indicated that Cd exposure caused mitochondrial apoptosis. In the 12-h cadmium-exposed group, the protein expression of Nephrin in mice significantly decreased by 33.4%. However, the expression of the Desmin protein significantly increased by 67.8%, and the expression of the autophagy protein LC3-II significantly increased by 55.5%. Meanwhile, the expression of PINK1, a mitochondrial autophagy pathway protein, was significantly increased in the 12 h and 24 h cadmium exposure groups. The mRNA level of PINK1 was significantly increased, and that of Parkin was decreased in the 48 h cadmium exposure group. Compared to the Cd-exposed group, the Ast group showed more significant improvements in the expression of podocyte structure, functional proteins, and mitochondrial autophagy pathway proteins. The immunological assay of mitochondrial autophagic pathway proteins further indicated that Cd-induced damage to MPC5 cells might be associated with the dysregulation of mitochondrial autophagy.

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Virgin coconut oil reverses behavioral phenotypes of letrozole-model of PCOS in Wistar rats via modulation of NRF2 upregulation

Akintoye

Ajibare

Omotuyi

2023

Journal of Taibah University Medical Sciences

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The regulatory effects of clomiphene and tamoxifen on mTOR and LC3-II expressions in relation to autophagy in experimental polycystic ovary syndrome (PCOS)

Cited by 5 publications

References 49 publications

Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening

Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening

Protective Effect of Astragaloside IV against Cadmium-Induced Damage on Mouse Renal Podocytes (MPC5)

Virgin coconut oil reverses behavioral phenotypes of letrozole-model of PCOS in Wistar rats via modulation of NRF2 upregulation

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