Objectif Les œstrogènes endogènes, via l'activation du récepteur des œstrogènes alpha (ERα), préviennent l'obésité et l'insulinorésistance, limitant ainsi le risque de diabète de type 2. Outre les ...actions nucléaires/génomiques classiques du ERα, une fraction palmitoylée du récepteur, localisée à la membrane plasmique, induit des effets qualifiés de membranaires ou MISS (Membrane Initiated Steroid Signaling). Notre objectif était d'évaluer in vivo l'implication de cette voie MISS dans les effets bénéfiques des œstrogènes sur l'homéostasie énergétique et glucidique. Matériels et Méthodes Le phénotype métabolique de souris femelles mutées pour le site de palmitoylation du ERα (Palm°), présentant une altération de la localisation membranaire du récepteur, a été étudié en conditions de régime standard (NCD) et hyperlipidique (HFD, 45 % lipides pendant 3 mois). Résultats Les caractéristiques des souris Palm° maintenues sous NCD pendant 7 mois ne différent pas de celles des souris sauvages en dehors d'une discrète augmentation du poids du tissu adipeux péri-gonadique ( p < 0,05). En revanche, sous HFD, les femelles Palm° présentent une prise pondérale accélérée ( p < 0,001), une accumulation de tissu adipeux ( p < 0,001), une intolérance au glucose ( p < 0,001) associée à une insulinorésistance (clamp hyperinsuliné-mique euglycémique, p < 0,01) et une stéatose hépatique. L'étude en cages métaboliques révèle une diminution significative de la dépense énergétique ( p < 0,001) chez les femelles Palm° par comparaison aux animaux sauvages, malgré une activité locomotrice et des apports alimentaires similaires dans les 2 groupes. De plus, les souris Palm° présentent une hypertrophie du tissu adipeux brun ( p < 0,01), couplée à une diminution significative de l'expression de l'ARNm de PGC1α dans ce tissu (− 50 %, p < 0,01). Enfin, l'administration d'œstradiol à dose physiologique prévient les conséquences délétères du HFD sur la composition corporelle et l'homéostasie glucidique chez les souris sauvages ovariectomisées, mais cet effet est totalement aboli chez les souris Palm°. Conclusions Ces résultats démontrent que les effets MISS du ERα contribuent à l'effet préventif des œstrogènes vis-à-vis de l'obésité, de l'insulinorésistance et des anomalies de la tolérance glucidique induites par un régime hyperlipidique, notamment via le contrôle de la dépense énergétique.
A new quantification method is proposed for the determination of serum estrone (E1), estradiol (E2), and estriol (E3) based on high-performance liquid chromatography–tandem mass spectrometry combined ...with differential ion mobility separation (SelexION Technology). This approach allows determining analytes with limits of detection of 4.5, 18 and 45 fg on column for E1, E2, and E3, respectively. The lowest limits of quantification are 0.1, 0.5, and 0.5 pg mL
–1
in serum for E1, E2, and E3, respectively. The suitability of proposed method for diagnostic purposes is demonstrated in an analysis of serum from 114 patients of different genders and ages.
Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities ...including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.
Persisting acyclic hypoestrogenemia and progesterone insufficiency in the women with anovulatory syndrome and altered reproductive functions are associated with disturbed endometrial morphology, ...increased expression of receptors for estrogenes, progesterone, redistribution of NK cells with predominance of CD16+NK cells in endometrium. Meanwhile, decreased number of CD16+ NK cells and cytotoxic CD8+ T cells in blood was accompanied by increased serum IFNγ levels, and enhanced spontaneous production of TNFα. (Med. Immunol., vol. 10, N 4-5, pp 353-360).
Experimental studies have shown that the IL6/GP130/STAT3 pathway is involved in pancreatic cancer tumorigenesis and progression as well as in the development of other tumors. Bazedoxifene, a ...selective estrogene receptor modulator clinically available for the treatment of osteoporosis, has been shown to be an effective GP130/STAT3 signaling inhibitor through in vitro and small animal studies. Our aim was to investigate the effect of bazedoxifene on tumor progression in patients with advanced pancreatic and gastric tumors. We analyzed the data of 7 patients (5 suffering from pancreatic and 2 from gastric adenocarcinoma), with locally advanced and/or metastatic disease, median age 73 years old (range 48 - 86 years). Bazedoxifene was given orally at a dose of 20 mg per day for a median duration of 9 months (range 5 - 14 months). Two patients received bazedoxifene as monotherapy, 5 patients were under concomitant chemotherapy. Results showed tumor marker reduction in 5 patients, stable disease on CT in 5 patients and metabolic regression on PET-CT in 3 patients. Weight was gained in 4 patients. Two patients developed deep vein thrombosis and one pulmonary embolism, the treatment was otherwise well tolerated. An immunhistochemical study of pSTAT3 was performed in 6 patients, out of which 3 were positive. Our preliminary data indicate that bazedoxifene is a potential new therapeutic option for pancreatic and gastric cancer therapy, safe to use and at low cost. It might be administrated at an early stage with current strategies. Based on these preliminary results, we will initiate a prospective clinical study.
A new platform that can follow the movement of individual proteins inside millions of cells in a single day will help contribute to existing knowledge of cell biology and identify new therapeutics.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored ...molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III (
50; median age 39.8, range 23-65) and age-matched controls (
61; median age 36.8, range 20-69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (
and
) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E
) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that
and
were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E
-treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated
and
E
-treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E
levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E
levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy.
Current molecular understanding of estrogen action has greatly profited from advances in molecular cell biology. These advances, and their implications for clinical use, were discussed by leading ...researchers from industry and academia during an international symposium held in Berlin, 1-3 March 2006 and are featured in this volume.
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