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See detailDevelopment of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies.
Palazzo, Claudio; Laloy, Julie; Delvigne, Anne Sophie et al

in European Journal of Pharmaceutical Sciences (2019), 9(127), 52-59

Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies ... [more ▼]

Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies prematurely born. No efficacy treatment is available to the present day. Estetrol (E4), a major estradiol metabolite, has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Liposome and DCL formulations were prepared and were physiochemically characterized. Stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells, as well as hemocompatibility of the nanovectors were performed in vitro. In vitro BBB passage was evaluated using human BBB cell line (hCMEC/D3). All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Therefore, the formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. [less ▲]

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See detailEstetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE)
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; VIELLEVOYE, Renaud ULiege et al

Poster (2018, November 13)

Estetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE) Ekaterine Tskitishvili1*, Christel Pequeux1, Renaud Viellevoye2, Michelle Nisolle3, Agnes Noël1 ... [more ▼]

Estetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE) Ekaterine Tskitishvili1*, Christel Pequeux1, Renaud Viellevoye2, Michelle Nisolle3, Agnes Noël1 and Jean-Michel Foidart1 1Laboratory of Development Biology and Tumor, University of Liege, Liege, Belgium; 2Department of Pediatrics, University of Liege, Liege, Belgium; 3Department of Ob/Gyn, University of Liege, Liege, Belgium Estetrol (E4) is a fetal estrogen synthesized only during human pregnancy. We aimed to study its role in attenuation of neonatal HIE. In vitro we defined antioxidative and cell viability effects of E4 on primary hippocampal cell cultures in oxidative stress condition by using lactate dehydrogenase (LDH) activity and cell survival (MTS) assays. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for gray and white matter (MAP-2 and MBP), neurogenesis (DCX) and angiogenesis (VEGF) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and GFAP) were measured by ELISA. Our results demonstrate that E4 has significant antioxidative and cell survival properties along with neuroprotective and therapeutic effects. It decreases the early gray and white matter loss and promotes neuro- and angiogenesis in vivo. Combined use of E4 with other steroids does not have priority over the single use of E4. We also defined that E4's antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Treatment by E4 has no effects on body weight, brain weight or body temperature. E4 might become an important safe and physiological substance to treat neonatal HIE. Based on our data EMA granted orphan drug designation to E4. References 1.Tskitishvili E, Nisolle M, Munaut C, Pequeux C, Gerard C, Noel A, Foidart JM.Estetrol attenuates Neonatal Hypoxic-Ischemic brain injury. Exp Neurol 2014; 261:298-307. 2. Tskitishvili E , Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noel A, Foidart JM. Use of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury: to combine or not to combine? Oncotarget 2016; 7(23):33722-43. 3. Tskitishvili E,Viellevoye R, Gerard C, Pequeux C, Munaut C, Nisolle M, Noel A, Foidart JM. Neonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem. Références en Gynécologie Obstetrique. 2016 17;1-4 4. Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, Foidart JM. Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study. J Endocrinol. 2017; 232(1):85-95. 5.Foidart JM, Tskitishvili E. International patent application. Estrogenic components for use in the treatment of neurological disorders. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailAnalyse détaillée de la seconde version de l’avant-projet de Code du bien-être animal wallon. Lecture commentée au 21/03/2018 du Chapitre 8 (Expérimentation animale)
Drion, Pierre ULiege; Corhay, Albert ULiege; Haubruge, Eric ULiege et al

Report (2018)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984 et ses modifications, aujourd’hui, le projet de code pour la Région wallonne). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la Directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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See detailHeterogeneity of estrogen receptor alpha and progesterone receptor distribution in lesions of deep infiltrating endometriosis of untreated women or during exposure to various hormonal treatments.
BRICHANT, Géraldine ULiege; NERVO, Patricia ULiege; Albert, Adelin ULiege et al

in Gynecological Endocrinology (2018)

Deep infiltrating endometriosis (DIE) responds variably to hormonal therapy. Mutations in cancer driver genes have been identified in a fraction of the ectopic endometrial epithelial cells, suggesting a ... [more ▼]

Deep infiltrating endometriosis (DIE) responds variably to hormonal therapy. Mutations in cancer driver genes have been identified in a fraction of the ectopic endometrial epithelial cells, suggesting a functional heterogeneity of these lesions. To evaluate the phenotype heterogeneity of cells in DIE, we measured the expression of estrogen receptor alpha (ERalpha) and of progesterone receptor (PR) in DIE of untreated women or under various treatments. We analyzed the luminal epithelial height (LEH), immunoreactive epithelial staining (IRS) and stromal staining intensity (SSI) of ERalpha and PR. We observed a high variability in the same gland, among distinct glands in the same sample and among distinct patients receiving the same treatment. LEH variability was primarily due to epithelial cells heterogeneity in a gland, secondarily to the glands randomly evaluated on the same section, and tertiary to the patient category. Variability in IRS and SSI scores was primarily the consequence of their heterogeneity in the same woman and to a lesser extent to variability among patients. LEH and SSI were not modified according to treatment. IRS for PR was lower in treated patients. This heterogeneity of ERalpha and PR distribution could explain why endocrine treatments are unable to cure this condition. [less ▲]

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See detailERα- and dose-dependent effect of estetrol on angiogenesis and tumor growth
Gallez, Anne ULiege; BLACHER, Silvia ULiege; Gérard, Céline et al

Poster (2017, November 07)

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See detailESTROGEN RECEPTORS AND ESTETROL-DEPENDENT NEUROPROTECTIVE ACTIONS: A PILOT STUDY
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; Munaut, Carine ULiege et al

Conference (2017, October 20)

Context: Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic–ischemic encephalopathy. Objective: We aimed to define ... [more ▼]

Context: Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic–ischemic encephalopathy. Objective: We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. Methods: In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERα (MPP dihydrochloride), ERβ (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic–ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic–ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Results: Our results show that LDH activity is significantly upregulated in cell cultures where the E4’s effect was completely blocked by concomitant treatment either with ERα and ERβ inhibitors (MPP and PHTPP, respectively), or ERα and ERβ inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERβ inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. Conclusions: E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. [less ▲]

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See detailDose-Dependant effect of Estetrol on Angiogenesis and Tumor growth
Gallez, Anne ULiege; BLACHER, Silvia ULiege; Lenfant, Françoise et al

Conference (2017, May 19)

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See detailDose-dependent effect of Estetrol on Angiogenesis and Tumor Growth
Gallez, Anne ULiege; Blacher, Silvia ULiege; Lenfant, Françoise et al

Poster (2017, April 24)

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and ... [more ▼]

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and they sustain the development of Estrogen Receptor α-positive tumors (ERα+). In addition, we have previously observed that estradiol (E2) can promote the growth of ERα-negative (ERα-) tumors, by increasing tumor angiogenesis that subsequently improves oxygen and nutrients delivery, thereby preventing hypoxia and necrosis. To identify new and safe drugs for the development of HRT presenting a better benefit/risk ratio, it is therefore necessary to evaluate the potential impact of new candidates on both ERα+ and ERα- tumors. In this context, estetrol (E4), a natural estrogen exclusively produced by the fetal liver, is a promising candidate. [less ▲]

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See detailImproved computer-assisted analysis of the global lymphatic network in human cervical tissues.
BALSAT, Cédric ULiege; Signolle, N; Goffin, Frédéric ULiege et al

in Modern Pathology (2017), 30(2), 313

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See detailEstrogen receptors and estetroldependent neuroprotective actions: a pilot study
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; Munaut, Carine ULiege et al

in Journal of Endocrinology (2017), 232(1), 85-95

Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen ... [more ▼]

Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERalpha (MPP dihydrochloride), ERbeta (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic-ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic-ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Our results show that LDH activity is significantly upregulated in cell cultures where the E4's effect was completely blocked by concomitant treatment either with ERalpha and ERbeta inhibitors (MPP and PHTPP, respectively), or ERalpha and ERbeta inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERbeta inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. E4's antioxidative actions mostly depend on ERalpha and ERbeta, whereas neurogenesis and possibly promyelinating activities might be realized through ERbeta. [less ▲]

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See detailNEW INJECTABLE LIPOSOME AND DRUG-IN-CYCLODEXTRIN-IN LIPOSOME SYSTEMS ENCAPSULATING ESTETROL FOR THE TREATMENT OF ISCHEMIA DISEASES IN PREMATURE BABIES
Palazzo, Claudio ULiege; Laloy, Julie; Delvigne, Anne-Sophie et al

Poster (2016, December)

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies ... [more ▼]

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies with motor, vision, hearing or mental deficiencies is still constant along the last twenty years. Moreover, no efficacy treatment is available to the present day. The estetrol (E4) has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Methods: Cyclodextrins (CD) were used to increase E4 aqueous solubility. Liposome and DCL (E4-CD complex) formulations were prepared by thin-film hydration technique. The formulations were physicochemical characterized. LDH and MTS tests on endothelial, neuronal and BBB model cells were performed in vitro on the liposome formulation. Hemocompatibility of the formulations was evaluated on red blood cells, platelet aggregation and coagulation. BBB passage tests were performed using human BBB cell line (hCMEC/D3). Results: E4-CD complexes proportionally increased the solubility of the hormone. Liposomes and DCL encapsulating E4 were prepared. All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. Moreover, the formulations are capable to release 80 % (liposome) and 90 % (DCL) of encapsulated E4 after 3 h at 37°C. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Conclusions: New non-toxic, hemocompatible liposome and DCL formulations encapsulating E4 were prepared. The formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. [less ▲]

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See detailA membrane-type- matrix metalloproteinase (MT1-MMP) - discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells
Assent, Delphine; Bourgot, Isabelle ULiege; Hennuy, Benoit et al

Poster (2016, October)

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and proapoptotic properties. To ... [more ▼]

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and proapoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. A transcriptomic analysis was performed to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering drastic alterations of the transcriptome of MCF-7 cells. [less ▲]

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See detailINNOVATIVE INJECTABLE LIPOSOME AND DRUG-IN-CYCLODEXTRIN-IN LIPOSOME SYSTEMS ENCAPSULATING ESTETROL FOR THE TREATMENT OF ISCHEMIA DISEASES IN PREMATURE BABIES
Palazzo, Claudio ULiege; Laloy, Julie; Delvigne, Anne-Sophie et al

Conference (2016, September 28)

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies ... [more ▼]

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies with motor, vision, hearing or mental deficiencies is still constant along the last twenty years. Moreover, no efficacy treatment is available to the present day. The estetrol (E4) has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Methods: Hydroxypropyl-β-cyclodextrins (degrees of substitution 0.87 and 0.63) (HPβCD 0.87 and HPβCD 0.63) were used to increase E4 aqueous solubility. Liposome and DCL (E4-HPβCD 0.63 complex) formulations were prepared by thin-film hydration technique. The formulations were physicochemical characterized and stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells were performed in vitro on the liposome formulation. Hemocompatibility of the formulations was evaluated on red blood cells, platelet aggregation and coagulation. BBB passage tests were performed using human BBB cell line (hCMEC/D3). Results: E4-HPβCD complexes proportionally increased the solubility of the hormone. Due to the lower solubility obtained with HPβCD ds 0.87, only HPβCD ds 0.63 was retained for future tests. Liposomes and DCL encapsulating E4 were prepared. All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. Moreover, the formulations are capable to release 80 % (liposome) and 90 % (DCL) of encapsulated E4 after 3 h at 37°C. The formulations, incubated in FBS at 37°C under gentle stirring, keep the same size and do not form protein corona up to 6 h. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. Preliminary BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Conclusions: New non-toxic, hemocompatible liposome and DCL formulations encapsulating E4 were prepared. The formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. Aknowledgment : The authors thank Estetra SPRL for providing Estetrol. [less ▲]

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See detailEstetrol Attenuates Neonatal Hypoxic-Ischemic Encephalopathy: Preclinical Studies
Tskitishvili, Ekaterine ULiege; Nisolle, Michelle ULiege; Noël, Agnès ULiege et al

Poster (2016, June 17)

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter ... [more ▼]

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter injuries occurring in neonates. Perinatal HIE still remains a challenge in perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may have importance for the development of new compounds and treatment strategies for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and anti-estrogenic properties on mammary gland and breast cancer
Gallez, Anne ULiege; Gérard, Céline ULiege; Blacher, Silvia ULiege et al

Poster (2016, May 30)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (0.08 mg/kg/day). E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While ERα is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathways are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailUse of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury:to combine or not to combine?
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; Munaut, Carine ULiege et al

in Oncotarget (2016)

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal ... [more ▼]

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated. The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival. In vivo pretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and antiestrogenic properties on mammary gland and breast cancer
Gérard, Céline ULiege; Gallez, Anne ULiege; Blacher, Silvia ULiege et al

Conference (2016, May 09)

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety profile would provide useful advances for patient care. Estretrol (E4) appears as a promising candidate for HRT. Indeed, in contrast to current treatment containing ethinyl estradiol or estradiol (E2), E4 has a minimal impact on liver cells activity supporting a decreased incidence on thromboembolic events. In preclinical studies, E4 has been effective against the main symptoms of menopause such as hot flushes, vaginal atrophy, and osteoporosis, from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development when it is used at concentrations effective for menopause symptom relief. We report preclinical data showing that E4 is less efficient than E2 to induce mammary gland growth. Treatment of estrogen receptor (ER)-positive breast cancer with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development. However, at 3mg/kg/day, E4 increased the growth of hormone-dependent tumors and their metastatic dissemination in ovariectomized and intact mice. This effect was similar to the one observed with E2 used at 0.08 mg/kg/day. E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While ERα is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extranuclear signaling pathways are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailNeonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem
Tskitishvili, Ekaterine ULiege; VIELLEVOYE, Renaud ULiege; Gérard, Céline et al

in Références en Gynécologie Obstétrique (2016), 17(1-1),

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation ... [more ▼]

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation, seizures and cerebral palsy, and mortality in newborns. This paper reviews the pathophysiology and current concepts of the management of neonatal HIE as well as the future potential neuroprotective strategies for attenuation of this disease. [less ▲]

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