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European Journal of Medicinal Chemistry Feb 2022The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives...
The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives were synthesized starting from 6-methoxy-2-naphthaldehyde. All of the synthesized compounds were investigated in terms of their monoamine oxidase (MAO) inhibitory effects and significant results were found. The results showed that compound 2j potently inhibited MAO-A and MAO-B, while compound 2t strongly and selectively inhibited MAO-B compared to standard drugs. Compounds 2k and 2q exhibited selective and satisfying inhibition on MAO-B. In the aromatase inhibition studies of the compounds, it was determined that compounds 2q and 2u had high inhibitory properties. Molecular docking studies on MAO-A, MAO-B, and aromatase enzymes were carried out for the aforementioned compounds. Additionally, molecular dynamics simulation was studied for compound 2q on MAO-B and aromatase complexes. Finally, the Field-based QSAR study was developed and the structure-activity relationship (SAR) was explained. For the first time, dual inhibitors on MAO and aromatase enzyme were investigated together. The aim of this approach is for finding the potential agents that do not cause the cognitive disorders and may even treat neurodegenerative symptoms, thus, the aim was reached successfully.
Topics: Aromatase; Aromatase Inhibitors; Drug Evaluation, Preclinical; Humans; Hydrazones; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 34998057
DOI: 10.1016/j.ejmech.2021.114097 -
Comprehensive Psychiatry May 2023Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine...
BACKGROUND
Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain.
METHODS
The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [C]cetrozole non-displaceable binding potential.
RESULTS
The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = -0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend.
CONCLUSIONS
These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.
Topics: Animals; Humans; Female; Male; Nicotine; Aromatase; Cotinine; Tobacco Use Disorder; Brain; Positron-Emission Tomography
PubMed: 36905856
DOI: 10.1016/j.comppsych.2023.152381 -
Environmental Pollution (Barking, Essex... Nov 2020Triazoles are used as antifungal agents, they mostly inhibit two enzymes: 14α-demethylase and aromatase. These enzymes are utilised also in other species and therefore...
Triazoles are used as antifungal agents, they mostly inhibit two enzymes: 14α-demethylase and aromatase. These enzymes are utilised also in other species and therefore the affection in non-target species in the environment is expected as well. Besides, triazoles are often being applied in a mixture and they can also interact with other substances present. This study clarifies how three selected representative triazoles (tebuconazole, penconazole and cyproconazole) interact with each other (group effect) and in mixtures (cocktail effect) with copper, essential/toxic for all organisms. Within the experiments on electrospray and collision-induced dissociations (both ESI-MS), it has been found that the fragments correspond to typical triazole metabolites. For their formation, the presence of copper ions is crucial. The inhibitory effect of Cu cocktails on aromatase enzymatic activity has been studied. The presence of Cu ions together with triazole(s) significantly increases the inhibitory effect on aromatase activity. The highest inhibitory effect (more than 60%) on aromatase activity is produced by cocktails containing penconazole and Cu ions, namely by penconazole/Cu and penconazole/tebuconazole/Cu. The reactivity of triazoles in groups is not significantly affected by the interactions among them. Additionally, the role of triazoles in copper Fenton reaction regulation has been observed and described. These changes may be attributed to the formation and stabilization of the complexes with the central Cu ion, with usually one, two or three triazolic ligands, depending on the mixture. The study demonstrates that the interaction of triazoles and Cu ions is a complex process; their impact on metabolism seems to be rather extensive and must be evaluated in the context of biochemical reactions.
Topics: Antifungal Agents; Aromatase; Copper; Oxidation-Reduction; Triazoles
PubMed: 32693302
DOI: 10.1016/j.envpol.2020.115201 -
Frontiers in Neuroendocrinology Jan 2020Aromatase is the requisite and limiting enzyme in the production of estrogens from androgens. Estrogens synthesized centrally have more recently emerged as potent... (Review)
Review
Aromatase is the requisite and limiting enzyme in the production of estrogens from androgens. Estrogens synthesized centrally have more recently emerged as potent neuroprotectants in the vertebrate brain. Studies in rodents and songbirds have identified key mechanisms that underlie both; the injury-dependent induction of central aromatization, and the protective effects of centrally synthesized estrogens. Injury-induced aromatase expression in astrocytes occurs following a broad range of traumatic brain damage including excitotoxic, penetrating, and concussive injury. Responses to neural insult such as edema and inflammation involve signaling pathways the components of which are excellent candidates as inducers of this astrocytic response. Finally, estradiol from astrocytes exerts a paracrine neuroprotective influence via the potent inhibition of inflammatory pathways. Taken together, these data suggest a novel role for neural aromatization as a protective mechanism against the threat of inflammation and suggests that central estrogen provision is a wide-ranging neuroprotectant in the vertebrate brain.
Topics: Animals; Aromatase; Astrocytes; Brain; Brain Edema; Brain Injuries; Estradiol; Female; Humans; Inflammation; Male; Nerve Degeneration; Neuroprotection; Songbirds; Up-Regulation
PubMed: 31786088
DOI: 10.1016/j.yfrne.2019.100816 -
Molecular Human Reproduction Mar 2021Preeclampsia (PE) is a gestational disease, which seriously impairs maternal and infant health. However, the pathogenesis of PE remains unclear. The aromatase (CYP19A1)...
Preeclampsia (PE) is a gestational disease, which seriously impairs maternal and infant health. However, the pathogenesis of PE remains unclear. The aromatase (CYP19A1) in placenta converts androgens from maternal and fetal adrenal glands to estrogen. Therefore, this change in the aromatase expression or function and the subsequent change of steroids in the placenta could be related to the pathophysiology of PE. In this study, we first analyzed the expression of CYP19A1 in clinical placental tissues as well as the level of sex hormones in corresponding serum samples. The results showed that the expression of aromatase in the placenta of PE patients was relatively low and accompanied by a sex hormone imbalance. Subsequently, animal experiments showed that ischemia and hypoxia lead to a low expression of CYP19A1, and that PE-like symptoms appear in pregnant mice following decreased or inhibited CYP19A1 expression. It was also found that, with the downregulation of CYP19A1 expression, the invasion and migration abilities of trophoblast cells were enhanced, which benefited placental implantation. However, alongside this, apoptosis and the inflammatory response were also increased, which was detrimental to placental development. Phosphoproteomic analyses revealed that the activation of the PI3K/AKT signaling pathway may play a key role in these processes. In conclusion, the downregulation of aromatase has a dual role in PE, among which the induction of the disease is the main role. Our study provides a potential novel method for the early prediction and treatment of PE.
Topics: Animals; Aromatase; Down-Regulation; Female; Humans; Mice; Phosphatidylinositol 3-Kinases; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts
PubMed: 33624796
DOI: 10.1093/molehr/gaab013 -
Journal of Genetics and Genomics = Yi... Apr 2022Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy. The transcription factor gene...
Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy. The transcription factor gene heart and neural crest derivatives expressed 1 (Hand1) promotes differentiation of mouse trophoblast giant cells. However, the role of HAND1 in human trophoblasts remains unknown. Here, we report that HAND1 inhibits human trophoblastic progesterone (P4) and estradiol (E2) from cholesterol through downregulation of the expression of steroidogenic enzymes, including aromatase, P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1). Mechanically, although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter, it restrains transcription of P450scc by upregulation of the methylation status of P450scc gene promoter through its binding to ALKBH1, a demethylase. Unlike aromatase and P450scc, HAND1 decreases 3β-HSD1 mRNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein HuR. Finally, HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2. Thus, our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts, which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.
Topics: AlkB Homolog 1, Histone H2a Dioxygenase; Animals; Aromatase; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cholesterol; Cholesterol Side-Chain Cleavage Enzyme; Female; Humans; Mice; Placenta; Pregnancy; Steroids; Trophoblasts
PubMed: 34391879
DOI: 10.1016/j.jgg.2021.07.014 -
Biochemical Pharmacology Apr 2024Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women,...
Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.
Topics: Female; Humans; PPAR gamma; Aromatase; Adipose Tissue; Estrogens; Breast Neoplasms; Adipogenesis
PubMed: 38423186
DOI: 10.1016/j.bcp.2024.116095 -
The Journal of Maternal-fetal &... Dec 2022Placental cytochrome p450 (CYP450) enzymes and efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are critical for transfer of drugs...
BACKGROUND
Placental cytochrome p450 (CYP450) enzymes and efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are critical for transfer of drugs from the placenta to maternal circulation. (aromatase) is the enzyme responsible for metabolizing methadone and buprenorphine in the human placenta.
OBJECTIVE
We sought to determine if differences exist in and efflux transporter immunostaining intensity and density within the syncytiotrophoblast in opioid-exposed and unexposed pregnancies. Additionally, we sought to investigate whether and efflux transporter expression was different in placentas of infants who developed severe neonatal opioid withdrawal syndrome (NOWS) and those who did not.
STUDY DESIGN
This was a retrospective nested case control study from 2014 to 2019 at a single tertiary care center. The opioid-exposed cohort included pregnant women aged ≥18 years on maintenance methadone or buprenorphine with non-anomalous singleton fetuses and gestational age ≥33 weeks. Controls included pregnant women with no medication exposure delivering at ≥37 weeks. De-paraffinized placental sections, inclusive of the apical syncytiotrophoblast membrane, were labeled with monoclonal antibodies for aromatase, P-gp, and BCRP. Placentas were scored for the presence and intensity of staining using the Allred scoring schema. Data were analyzed using descriptive, parametric, and nonparametric statistics. < .05 was considered significant.
RESULTS
One hundred and ten opioid-exposed neonates were included in this analysis (51 and 59 ), with 68/110 delivering at term. Ten unexposed controls delivering at term were also included. The median placental Allred scores for aromatase were significantly lower in the opioid-exposed cohort compared with the unexposed controls (exposed 6.8 ± 1.4 vs. unexposed 7.5 ± 0.7, = .03). The median placental Allred scores for aromatase were significantly lower in that developed severe NOWS compared to ( = .03) that did not develop severe NOWS. There were no differences in P-gp and BCRP scores between groups.
CONCLUSIONS
Syncytiotrophoblast aromatase immunostaining scores were reduced in compared to . Additionally, infants who developed severe NOWS had significantly lower placental aromatase in the apical syncytiotrophoblast compared with those without severe NOWS.
Topics: Adult; Female; Humans; Infant, Newborn; Pregnancy; Analgesics, Opioid; Aromatase; ATP Binding Cassette Transporter, Subfamily G, Member 2; Buprenorphine; Case-Control Studies; Methadone; Neonatal Abstinence Syndrome; Neoplasm Proteins; Placenta; Retrospective Studies; Staining and Labeling
PubMed: 34978244
DOI: 10.1080/14767058.2021.2022647 -
International Journal of Molecular... May 2023The widely used organotin compounds are notorious for their acute toxicity. Experiments revealed that organotin might cause reproductive toxicity by reversibly...
The widely used organotin compounds are notorious for their acute toxicity. Experiments revealed that organotin might cause reproductive toxicity by reversibly inhibiting animal aromatase functioning. However, the inhibition mechanism is obscure, especially at the molecular level. Compared to experimental methods, theoretical approaches via computational simulations can help to gain a microscopic view of the mechanism. Here, in an initial attempt to uncover the mechanism, we combined molecular docking and classical molecular dynamics to investigate the binding between organotins and aromatase. The energetics analysis indicated that the van der Waals interaction is the primary driving force of binding the organic tail of organotin and the aromatase center. The hydrogen bond linkage trajectory analysis revealed that water plays a significant role in linking the ligand-water-protein triangle network. As an initial step in studying the mechanism of organotin inhibiting aromatase, this work provides an in-depth understanding of the binding mechanism of organotin. Further, our study will help to develop effective and environmentally friendly methods to treat animals that have already been contaminated by organotin, as well as sustainable solutions for organotin degradation.
Topics: Animals; Aromatase; Molecular Docking Simulation; Organotin Compounds; Reproduction; Research Design
PubMed: 37240300
DOI: 10.3390/ijms24108954 -
International Journal of Molecular... Jan 2021Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology,...
Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology, aromatase is found in vertebrates and the invertebrates of the genus , where it carries out the aromatization reaction of the A-ring of androgens that produces estrogens. Here, we investigate the molecular evolution of this unique and highly substrate-selective enzyme by means of structural, sequence alignment, and homology modeling, shedding light on its key role in species conservation. The alignments led to the identification of a core structure that, together with key and unique amino acids located in the active site and the substrate recognition sites, has been well conserved during evolution. Structural analysis shows what their roles are and the reason why they have been preserved. Moreover, the residues involved in the interaction with the redox partner and some phosphorylation sites appeared late during evolution. These data reveal how highly substrate-selective cytochrome P450 has evolved, indicating that the driving forces for evolution have been the optimization of the interaction with the redox partner and the introduction of phosphorylation sites that give the possibility of modulating its activity in a rapid way.
Topics: Amino Acid Sequence; Animals; Aromatase; Catalytic Domain; Estrogens; Evolution, Molecular; Humans; Models, Molecular; Sequence Alignment; Structure-Activity Relationship; Vertebrates
PubMed: 33435208
DOI: 10.3390/ijms22020631