Effects Of Estrogen Receptor Modulators Research Articles

Investigation of the potential effects of estrogen receptor modulators on immune checkpoint molecules

Immune checkpoints regulate the immune system response. Recent studies suggest that flavonoids, known as phytoestrogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (SERMs) as inhibiting ligands for immune checkpoint proteins (CTLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong binding energy values for quinestrol, quercetin, and bazedoxifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin and bazedoxifene, known to modulate EGFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functionality. We discuss the impact of SERMs on PD-1 and CTLA-4, suggesting that these SERMs could have therapeutic effects through immune checkpoint inhibition. This study highlights the potential of SERMs as inhibitory ligands for immune checkpoint proteins, emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating SERMs as therapeutic agents. Our findings open new avenues for cancer immunotherapy by exploring the interaction between various SERMs and immune checkpoint pathways.

Cardioprotective effects of the estrogen receptors modulators in the conditions of experimental acute myocardial infarction

According to modern ideas, in myocardial infarction a cascade of pathobiochemical reactions is triggered directly in the ischemic focus, leading to a disturbance in the metabolism of cardiomyocytes, the launch of "parasitral" energy-producing reactions, the development of mitochondrial dysfunction, the complete blockade of the macroergic compounds synthesis, and as a result, cells death. In this regard, in the acute period of myocardial infarction it is pathogenetically justified to use drugs that can affect cardiomyocytes metabolism and restore the course of bioenergetic reactions in the cell.Aim of study – to evaluate the SERM cardioprotective effects in the conditions of acute myocardial infarction modelling with the use of the ST2 marker.Materials and methods: The experimental part of the work was performed on 120 mature rats - males weighing 190–230 grams. Small-focal acute myocardial infarction was modelled by the administration of coronary artery spasm induced agents – pituitrin and β1, 2, 3 isoprenaline adrenomimetic for 3 days. The investigated drugs tamoxifen citrate (0.1 mg/kg) (reg. № EF3300), toremifene (0.1 mg/kg) (reg. № 1705834), and also comparators – tiotriazoline (50 mg/kg) (UA/2931/01/02) and capicor (6 Mg/kg) (reg. № 11114) were injected intraperitoneally 20 minutes after the injection of isadrin for 3 days in the above stated doses. The myocardial infarction development was confirmed by electrocardiographic study, as well as the appearance of troponin I in blood plasma. The directivity and severity of pathobiochemical processes in the cardiac tissue, as well as the effect of the studied drugs on them, were studied through the enzyme-linked immunosorbent assay of nitrotirozine and homocysteine concentration in the heart homogenate and ST2 in blood plasma.Results: Systematic administration of a coronary artery spasm induced agents to laboratory animals led to a gradual, progressive ischemic lesion of cardiomyocytes. Biological markers of myocardial infarction Troponin, ST2 I were registered on the 3rd day after the administration of pituitrin and isadrin in the blood plasma of the control group.Using selective receptors modulators and reference preparations (thiotriazoline, capicor) in experimental therapy of rats with experimental myocardial infarction promoted the normalization of biochemical processes in cardiomyocytes. However, the effect of the studied drugs was unidirectional with various degree of intensity. All the drugs statistically significantly reduced oxidative stress marker products. The most marked effects were displayed by the selective estrogen receptors modulators toremifene and tamoxifen, which decreased in ST2 blood plasma level (by more than 46 %) providing realization of IL 33 cardioprotective properties. In addition, SERM can limit oxidative and nitrosyl stresses development, leading to a decrease in the concentration of homocysteine and nitrotirozine in the heart. Interaction of these effects of tamoxifen citrate in conditions of acute myocardial infarction modelling resulted in a marked cardioprotective effect, increasing the percentage of animals which survived to an average of 75 %.Conclusions. The cardioprotective effects of selective estrogen receptor modulators identified by us are an experimental foundation for the relevance and viability of further research in this direction.

Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system.

Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1 (MAP1), MAP2, neurofilament 38 (NF38) by different mechanisms of action and at different levels: neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.

Effects of lorazepam and WAY-200070 in larval zebrafish light/dark choice test

Zebrafish larvae spend more time in brightly illuminated area when placed in a light/dark testing environment. Here we report that the anxiolytic drugs lorazepam and diazepam increased the time larval fish spent in the dark compartment in the light/dark test. Lorazepam did not affect the visual induced optokinetic response of larval fish. Gene expression levels of c-fos and crh were significantly increased in the hypothalamus of fish larvae underwent light/dark choice behavior, whilst lorazepam treatment alleviated the increased c-fos and crh expressions. Furthermore, we found estrogen receptor β gene expression level was increased in fish larvae underwent light/dark choice. We next examined effects of estrogen receptor modulators (estradiol, BPA, PHTPP, and WAY-200070) in the light/dark test. We identified WAY-200070, a highly selective ERβ agonist significantly altered the light/dark choice behavior of zebrafish larvae. Further investigation showed WAY-200070 treatment caused a reduction of crh expression level in the hypothalamus, suggesting activation of ERβ signaling attenuate the stress response. Interestingly, WAY-200070 treatment caused marked increase of c-fos expression in the habenula of fish larvae underwent behavior test. These results suggest WAY-200070 activation of ERβ mediated signaling may regulate anxiety related behavior in zebrafish through modulation of neuronal activity in habenula.