New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity

Błaszczak-Świątkiewicz, Katarzyna

doi:10.3390/molecules25061321

Cited by 5 publications

(5 citation statements)

References 23 publications

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“…But, the potency was approximately only 13% of that of Mifepristone. The clinical consequences of this shift in the PRA/ PRB-quotient including progesterone resistance in endometriosis still need to be clarified (7,8,(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

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Next step in the development of mesoprogestins: the preclinical profile of EC313

Błaszczak-Świątkiewicz,

Krupa,

Mnich

et al. 2023

Front. Endocrinol.

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IntroductionThe pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule.MethodsThe suitable in vivo-model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment. ResultsThe EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors in vitro with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some in vitro-receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent in vivo. The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated. DiscussionFor an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.

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Section: Discussionmentioning

confidence: 99%

“…Since then several SPRMs have been developed. Two of them are in current clinical use: Mifepristone for pregnancy interruption and Ulipristal acetate (CDB-2914) for managing abnormal uterine bleeding (AUB) in women with uterine leiomyomas (fibroids) and as an emergency contraceptive in higher dose ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Next step in the development of mesoprogestins: the preclinical profile of EC313

Błaszczak-Świątkiewicz,

Krupa,

Mnich

et al. 2023

Front. Endocrinol.

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“…Although knockdown of BRCA1, PTGS2, and PGR did not induce the change of BMP‐2 and β‐catenin in BMSCs, these targets may be regulated by IPRN in other cell lines, such as the osteoclast like cells. Such as PGR, which was reported to be closely related to the RANK/RANKL axis, is an important signal path of osteoclasts (Blaszczak‐Swiatkiewicz, 2020; Wozniczka & Blaszczak‐Swiatkiewicz, 2021).…”

Section: Discussionmentioning

confidence: 99%

Anti‐Postmenopausal osteoporosis effects of Isopsoralen: A bioinformatics‐integrated experimental study

Wang

Jin

et al. 2022

Phytotherapy Research

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Isopsoralen (IPRN), which comes from the fruit of Psoralea corylifolia, has been identified as a kind of phytoestrogen and has been proven to be effective for the treatment of osteoporosis (OP). However, the mechanisms underlying IPRN's anti‐OP effects, especially the anti‐postmenopausal osteoporosis (PMOP) effects, remain indistinct. Thus, this study aimed to investigate the effects and mechanisms of IPRN's anti‐PMOP activity. In this study, the bioinformatics results predicted that IPRN could resist PMOP by targeting EGFR, AKT1, SRC, CCND1, ESR1 (ER‐α), AR, PGR, BRCA1, PTGS2, and IGF1R. An ovariectomized (OVX) mice model and a H2O2‐induced bone marrow mesenchyml stem cells (BMSCs) model confirmed that IPRN could inhibit the bone loss induced by OVX in mice and promote the osteogenic differentiation in H2O2‐induced BMSCs by inhibiting oxidative stress and apoptosis. Moreover, IPRN could significantly produce the above effects by upregulating ESR1. IPRN might be a therapeutic agent for PMOP by acting as an estrogen replacement agent and a natural antioxidant.

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“…This condition is accompanied by decreased expression of V-ATPase-d2, cathepsin K, and calcitonin receptors which results in inhibition of the process of osteoclastogenesis. [27][28][29][30] The reduction of ROS by anthocyanin ternatin accompanied by the application of HA/β-TCP corraline induced the release of Ca 2+ and PO4 3− ions causing increased activation of sarcoendoplasmic reticulum calcium ATPase (SERCA), a pump that acts to transport Ca 2+ ion from the cytoplasm into the sarcoendoplasmic reticulum, that is generated by p53. This resulted in an increase in phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) expression so that Wnt expression increased.…”

Section: Discussionmentioning

confidence: 99%

Combination of anthocyanin ternatin and hydroxyapatite/β-tricalcium phosphate coralline as a socket preservation biomaterial in dental implant: A narrative review

Nugraha¹,

Sosiawan²,

Anwar³

et al. 2022

World J. Adv. Res. Rev.

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Background: Tooth extraction is surgical treatment with clinical manifestation is alveolar bone resorption of 11-63% which potentially fails dental implant treatment. Socket preservation is bone regeneration treatment to minimize bone morphological changes in post-extraction using bone graft. Anti-inflammatory biomaterial is needed to modulate inflammatory cascade in the lesion. Anthocyanin ternatin is a flavonoid derived from butterfly pea (Clitoria ternatea) as an anti-inflammatory and antioxidants agent. Hydroxyapatite/β-Tricalcium Phosphate coralline (HA/β-TCP coralline) is a combination of bioceramic material from calcium carbonate heating of Porites spp. coral which has potential to induce osteogenesis, osteoinduction, and osteoconduction. Combination of Anthocyanin ternatin and HA/β-TCP coralline applied to the defect area in dried powder form to induce hard tissue regeneration. Purpose: To describe the potential of combination of Anthocyanin ternatin and HA/β-TCP coralline as a socket preservation biomaterial in dental implant. Review: Combination of Anthocyanin ternatin and dried powder HA/β-TCP coraline is applied in dental socket. Anthocyanin ternatin suppresses ROS and iNOS then inhibit NF-kB signaling pathway. Downregulation of the pathway decreases TNF-α and IL-1β/6 expression so the expression of RANKL is inhibited. Lowering of ROS followed by upregulated Ca2+ level from HA/β-TCP coralline causes the increase in DKK1 and PTEN expression so Akt and Wnt expression is induced. Upregulation of the proteins induces the BMP2/TGF-β/Smad1/5/8 signaling pathway activation manifest in the increase of Runx2, OCN, and Osx then the preosteoblast differentiation to osteoblast is increased. Conclusion: Combination of Anthocyanin ternatin and HA/β-TCP coralline is potential as socket preservation biomaterial in dental implant.

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New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity

Cited by 5 publications

References 23 publications

Next step in the development of mesoprogestins: the preclinical profile of EC313

Next step in the development of mesoprogestins: the preclinical profile of EC313

Anti‐Postmenopausal osteoporosis effects of Isopsoralen: A bioinformatics‐integrated experimental study

Combination of anthocyanin ternatin and hydroxyapatite/β-tricalcium phosphate coralline as a socket preservation biomaterial in dental implant: A narrative review

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