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Frontiers in Endocrinology 2021Endometriosis is an estrogen-dependent chronic disease. The abnormal proliferation and invasion of ectopic stromal cells (ESCs) are important manifestations of...
OBJECTIVE
Endometriosis is an estrogen-dependent chronic disease. The abnormal proliferation and invasion of ectopic stromal cells (ESCs) are important manifestations of endometriosis, and it is necessary to find safer and more effective treatments. Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (UC-MSCs) have been shown to be promising for the treatment of many diseases, except endometriosis. The main purpose of this study was to explore the effect of EVs derived from UC-MSCs on ESCs and evaluate the therapeutic value of EVs on endometriosis.
STUDY DESIGN
Following the successful culture and identification of UC-MSCs, we collected the medium of UC-MSCs and extracted EVs by ultracentrifugation. Then, 120 μg/mL EVs were used to stimulate ESCs, which were collected to evaluate cell proliferation and invasion and expression of the estrogen-related proteins steroidogenic factor-1 (SF-1), estrogen receptors β (ERβ), and aromatase.
RESULTS
Compared with the control group treated with isodose phosphate buffered saline (PBS), 120 μg/mL EVs exposure significantly decreased the expression of cyclin D1 (mRNA: n = 6, P = 0.02; protein: n = 6, P = 0.000) and matrix metalloproteinase (MMP) 9 (mRNA: n = 6, P = 0.04; protein: n = 6, P = 0.000) of ESCs, which were consistent with Cell Counting Kit-8(CCK-8) results (day 0: NC: 0.29 ± 0.04, 120 μg/mL EVs: 0.28 ± 0.04; day 1: NC: 0.42 ± 0.08, 120 μg/mL EVs: 0.32 ± 0.01; day 2: NC: 0.64 ± 0.07, 120 μg/mL EVs: 0.50 ± 0.05, P = 0.000; day 3: NC: 0.82 ± 0.09, 120 μg/mL EVs: 0.65 ± 0.07, P = 0.000; day 4: NC: 0.95 ± 0.11, 120 μg/mL EVs: 0.76 ± 0.07, P = 0.012; n = 6) and Transwell experiments (n = 6, P = 0.000). In addition, the expression of SF-1 (encoded by NR5A1; mRNA: n = 6, P = 0.000; protein: n = 6, P = 0.000), ERβ (encoded by ESR2; mRNA: n = 6, P = 0.000; protein: n = 6, P = 0.000), and aromatase (encoded by CYP19A1; mRNA: n = 6, P = 0.04; protein: n = 6, P = 0.000) in ESCs decreased significantly.
CONCLUSION
Taken together, the results show that 120 μg/mL EVs derived from UC-MSCs can effectively inhibit the proliferation and invasion of ESCs, as well as their expression of SF-1, ERβ and aromatase, and thus may lead to the alleviation of endometriosis.
Topics: Adult; Aromatase; Case-Control Studies; Cell Proliferation; Cells, Cultured; Endometriosis; Endometrium; Estrogen Receptor beta; Extracellular Vesicles; Female; Humans; Mesenchymal Stem Cells; Ovary; RNA Splicing Factors; Stromal Cells; Umbilical Cord; Young Adult
PubMed: 34531822
DOI: 10.3389/fendo.2021.666195 -
European Review For Medical and... Dec 2023In patients with breast cancer and positive hormone receptors, aromatase inhibitors are effective in reducing the risk of recurrences and are active in progressing the...
OBJECTIVE
In patients with breast cancer and positive hormone receptors, aromatase inhibitors are effective in reducing the risk of recurrences and are active in progressing the disease in this setting. On the other hand, fatigue and painful musculoskeletal side effects can significantly reduce treatment compliance. With no further treatment options to control these symptoms, non-pharmaceutical interventions, such as oxygen-ozone therapy, may play a role in managing rheumatologic symptomatology inasmuch. We have previously reported evidence on the effectiveness of oxygen-ozone in the treatment of pain and fatigue in chronic fatigue syndrome and fibromyalgia patients and in oncological patients as well.
PATIENTS AND METHODS
In this study, we reported 6 cases of patients (mean age 64 yrs, all Caucasian females) with breast cancer upon treatment with anastrozole (Arimidex®), suffering from musculoskeletal pain, weakness and fatigue, and therefore treated with oxygen-ozone major autohemotherapy according to the Italian Scientific Society of Oxygen Ozone Therapy (SIOOT) protocol. Pain was measured with a 10-item Numerical Rating Scale (NRS) and fatigue with a 7-item Fatigue Scoring Scale (FSS).
RESULTS
A reduction of at least 66% of pain (from 9.43 ±0.54 SD to 2.36 ±1.32 SD, p<0.001) and 66.26% of fatigue were obtained for all the cases. Pain and fatigue disappeared within one month from ozone therapy, and a healthy painless state lasted for many months following the oxygen-ozone therapy.
CONCLUSIONS
The oxygen-ozone therapy is a sound opportunity for breast cancer patients to reduce anti-aromatase-induced pain, fatigue, and musculoskeletal symptoms.
Topics: Female; Humans; Middle Aged; Aromatase Inhibitors; Breast Neoplasms; Musculoskeletal Pain; Ozone; Quality of Life; Oxygen; Anastrozole
PubMed: 38095411
DOI: 10.26355/eurrev_202312_34602 -
The Journal of Comparative Neurology Mar 2021Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through...
Estrogen receptor alpha, G-protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region-specific differences across the rat caudate-putamen, nucleus accumbens core and shell.
Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through differential production via the enzyme aromatase. ERs and aromatase are expressed across the nervous system, including in the striatal brain regions. These regions, comprising the nucleus accumbens core, shell, and caudate-putamen, are instrumental for a wide-range of functions and disorders that show sex differences in phenotype and/or incidence. Sex-specific estrogen action is an integral component for generating these sex differences. A distinctive feature of the striatal regions is that in adulthood neurons exclusively express membrane but not nuclear ERs. This long-standing finding dominates models of estrogen action in striatal regions. However, the developmental etiology of ER and aromatase cellular expression in female and male striatum is unknown. This omission in knowledge is important to address, as developmental stage influences cellular estrogenic mechanisms. Thus, ERα, GPER1, and aromatase cellular immunoreactivity was assessed in perinatal, prepubertal, and adult female and male rats. We tested the hypothesis that ERα, GPER1, and aromatase exhibits sex, region, and age-specific differences, including nuclear expression. ERα exhibits nuclear expression in all three striatal regions before adulthood and disappears in a region- and sex-specific time-course. Cellular GPER1 expression decreases during development in a region- but not sex-specific time-course, resulting in extranuclear expression by adulthood. Somatic aromatase expression presents at prepuberty and increases by adulthood in a region- but not sex-specific time-course. These data indicate that developmental period exerts critical sex-specific influences on striatal cellular estrogenic mechanisms.
Topics: Animals; Caudate Nucleus; Estrogen Receptor alpha; Female; Male; Nucleus Accumbens; Putamen; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sex Characteristics
PubMed: 32632943
DOI: 10.1002/cne.24978 -
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 -
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 -
Journal of Geriatric Oncology Apr 2020Suboptimal adherence with endocrine treatment for breast cancer is influenced by a number of factors but remains poorly understood. We sought to describe the prior...
OBJECTIVE
Suboptimal adherence with endocrine treatment for breast cancer is influenced by a number of factors but remains poorly understood. We sought to describe the prior knowledge about and expectations of breast cancer treatments among older women retrospecting on their diagnosis and treatment.
METHODS
Thematic analysis was used to systematically analyze data obtained with face-to-face, open-ended interviews conducted with 54 women who had filled at least one prescription for an aromatase inhibitor. The average age was 71.9 (65-93) years at diagnosis.
RESULTS
Three salient themes were described: the sources of information on which preknowledge and expectations surrounding treatment were founded, and two phases of treatment, primary (surgery, chemotherapy and radiation therapy) and anti-hormonal. The main source of information was from family and friends who had been treated for cancer. These peers reported both positive and negative experiences and in many cases contributed to the women having some degree of misinformation. A foundational knowledge of primary treatments was evident (necessity, duration, intensity, side-effects) and that receiving one or more treatments was needed. Compared to primary treatments, anti-hormonal treatment (AHT) was unexpected, the women knew less about it, and felt comparatively under-prepared for this treatment.
CONCLUSIONS
The transition from primary treatments to adjuvant AHT therapy with receiving a prescription for an aromatase inhibitor caught many participants off guard. Our findings elucidate areas to enhance clinical practice, expand the research agenda to more thoroughly explore AHT information and design of an age-appropriate supportive intervention to improve continuation with AHT.
Topics: Aged; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans
PubMed: 31471170
DOI: 10.1016/j.jgo.2019.07.024 -
International Journal of Women's... Dec 2021As of January 2021, there are more than 3.8 million women in the United States with a history of breast cancer. The current standard of care for breast cancer involves... (Review)
Review
As of January 2021, there are more than 3.8 million women in the United States with a history of breast cancer. The current standard of care for breast cancer involves surgical resection, radiation therapy, adjuvant endocrine therapy, and/or adjuvant chemotherapy. Aromatase inhibitors (AIs) are the gold standard for endocrine therapy in postmenopausal women. Dermatologic adverse events (dAEs) associated with AIs are rare but have been reported in the literature. Commonly reported dAEs include unspecified rash, pruritus, alopecia, vulvovaginal atrophy, vasculitis, and autoimmune/connective tissue disorders. Appropriate preventative strategies and careful management considerations have the potential to optimize the comprehensive care of patients with cancer and improve quality of life. Furthermore, prevention of dAEs can lead to a reduction in cancer treatment interruptions and discontinuations. Herein, we characterize dAEs of AIs and discuss preventative management to reduce the incidence of AI therapy interruption.
PubMed: 35028380
DOI: 10.1016/j.ijwd.2021.07.002 -
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 -
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