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Beilstein Journal of Organic Chemistry 2020A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne...
A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels-Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.
PubMed: 32461769
DOI: 10.3762/bjoc.16.79 -
Gynecological Endocrinology : the... Dec 2023In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users. To... (Review)
Review
In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users. To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety. For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptives'. Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman. Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health.
Topics: Female; Humans; Contraceptives, Oral, Combined; Progestins; Latin America; Ethinyl Estradiol; Estrogens; Women's Health
PubMed: 37857350
DOI: 10.1080/09513590.2023.2271072 -
Biomolecules Mar 2022Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the...
Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more L1 is expressed, the more tumor cells migrate and increase their metastatic potential. L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy. These unfortunate features are indicated by observations that cells that normally do not express L1 are induced to express it when becoming malignant. With the aim to ameliorate the devastating functions of L1 in tumors, we designed an alternative approach to counteract tumor cell migration. Libraries of small organic compounds were screened using the ELISA competition approach similar to the one that we used for identifying L1 agonistic mimetics. Whereas in the former approach, a function-triggering monoclonal antibody was used for screening libraries, we here used the function-inhibiting monoclonal antibody 324 that reduces the migration of neurons. We now show that the L1 antagonistic mimetics anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol inhibit the migration of cultured tumor cells in an L1-dependent manner, raising hopes for therapy.
Topics: Animals; Antibodies, Monoclonal; Cell Adhesion; Cell Movement; Glioblastoma; Mice; Neural Cell Adhesion Molecule L1; Zebrafish
PubMed: 35327631
DOI: 10.3390/biom12030439 -
Genomics Sep 2020Gliomas account for 75% of the primary malignant brain tumors and a majority of lower-grade gliomas (LGG) inevitably develop into glioblastoma. The dysregulation of...
Gliomas account for 75% of the primary malignant brain tumors and a majority of lower-grade gliomas (LGG) inevitably develop into glioblastoma. The dysregulation of lncRNAs play a crucial role in LGG. In the present study, we first screened out six differentially expressed lncRNAs (AC021739.2, AL031722.1, AL354740.1, FGD5-AS1, LINC00844, and NEAT1) based on TCGA and GTEx RNA-seq databases. LncRNA prognostic signature was then established by Kaplan-Meier and multivariate Cox proportional hazards regression, with its predictive value validated by time-dependent receiver operating characteristic (ROC) curves. After lncRNA-miRNA-mRNA regulatory networks were established by Cytoscape 3.7.2, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, with results enriched in various malignancy-related functions and pathways. Finally, six putative drugs (irinotecan, camptothecin, mitoxantrone, azacitidine, mestranol, and enilconazole) were predicted by Connectivity Map. In conclusion, we identified a 6-lncRNA prognostic signature with its ceRNA networks, and six candidate drugs against LGG.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Female; Glioma; Humans; Male; MicroRNAs; Middle Aged; Prognosis; RNA, Long Noncoding; RNA, Messenger; Risk; Young Adult
PubMed: 32447005
DOI: 10.1016/j.ygeno.2020.05.016 -
The Science of the Total Environment Dec 2022An effect-directed analysis (EDA) approach was used to identify the compounds responsible for endocrine disruption in a hospital effluent (Basque Country). In order to...
An effect-directed analysis (EDA) approach was used to identify the compounds responsible for endocrine disruption in a hospital effluent (Basque Country). In order to facilitate the identification of the potentially toxic substances, a sample was collected using an automated onsite large volume solid phase extraction (LV-SPE) system. Then, it was fractionated with a two-step orthogonal chromatographic separation and tested for estrogenic effects with a recombinant yeast (A-YES) in-vitro bioassay. The fractionation method was optimized and validated for 184 compounds, and its application to the hospital effluent sample allowed reducing the number of unknowns from 292 in the raw sample to 35 after suspect analysis of the bioactive fractions. Among those, 7 of them were confirmed with chemical standards. In addition, target analysis of the raw sample confirmed the presence of mestranol, estrone and dodemorph in the fractions showing estrogenic activity. Predictive estrogenic activity modelling using quantitative structure-activity relationships indicated that the hormones mestranol (5840 ng/L) and estrone (128 ng/L), the plasticiser bisphenol A (9219 ng/L) and the preservative butylparaben (1224 ng/L) were the main contributors of the potential toxicity. Derived bioanalytical equivalents (BEQs) pointed mestranol and estrone as the main contributors (56 % and 43 %, respectively) of the 50 % of the sample's explained total estrogenic activity.
Topics: Endocrine Disruptors; Environmental Monitoring; Estrogens; Estrone; Hospitals; Mestranol; Water Pollutants, Chemical
PubMed: 35985602
DOI: 10.1016/j.scitotenv.2022.157985 -
Environmental Monitoring and Assessment Mar 2015This paper presents the study of the occurrence of 10 endocrine-disrupting compounds (EDCs) in 60 water samples using a method for simultaneous quantification and...
This paper presents the study of the occurrence of 10 endocrine-disrupting compounds (EDCs) in 60 water samples using a method for simultaneous quantification and confirmation of the presence of these emerging compounds, using ultra-performance liquid chromatography with electrospray ionization and tandem mass spectrometry (UPLC-ESI-MS/MS). All samples were previously extracted by solid-phase extraction (SPE). Several natural and synthetic hormones (17-β-estradiol, ethinylestradiol, estriol, estrone, progesterone, mestranol, and diethylstilbestrol) and some industrial products (4-n-nonylphenol, 4-tert-octylphenol, and bisphenol A) were chosen for this survey. The analytical limits were calculated for each compound and were used in the identification and quantification of these target compounds in EPAL's water supply system. In this study, several samples were taken from the main intakes of water (surface and groundwater) used for production of water for human consumption and from different sampling points of the drinking water distribution system (piping, nets, and reservoirs). Some target compounds, such as estriol, 4-tert-octylphenol, mestranol, and nonylphenol, were found in trace amounts in several water samples. However, the studied endocrine-disrupting appeared in very low concentrations when compared with the assessed analytical limits.
Topics: Benzhydryl Compounds; Chromatography, Liquid; Endocrine Disruptors; Environmental Monitoring; Estradiol; Estrone; Ethinyl Estradiol; Humans; Phenols; Solid Phase Extraction; Tandem Mass Spectrometry; Water Pollutants, Chemical; Water Supply
PubMed: 25712629
DOI: 10.1007/s10661-015-4374-0 -
Environmental Science & Technology May 2021Diverse organic compounds, many derived from consumer products, are found in sewage sludge worldwide. Understanding which of these poses the most significant...
Diverse organic compounds, many derived from consumer products, are found in sewage sludge worldwide. Understanding which of these poses the most significant environmental threat following land application can be investigated through a variety of predictive and cell-based toxicological techniques. Nontargeted analysis using high-resolution mass spectrometry with predictive estrogenic activity modeling was performed on sewage sludge samples from 12 wastewater treatment plants in California. Diisobutyl phthalate and dextrorphan were predicted to exhibit estrogenic activity and identified in >75% of sludge samples, signifying their universal presence and persistence. Additionally, the application of an estrogen-responsive cell bioassay revealed reductions in agonistic activity during mesophilic and thermophilic treatment but significant increases in antagonism during thermophilic treatment, which warrants further research. Ten nontarget features were identified (metoprolol, fenofibric acid, erythrohydrobupropion, oleic acid, mestranol, 4'-chlorobiphenyl-2,3-diol, medrysone, scillarenin, sudan I, and ,-didesmethyltramadol) in treatment set samples and are considered to have influenced the estrogenic activity observed. The combination of predictive and estrogenicity with nontargeted analysis has led to confirmation of 12 estrogen-active contaminants in California sewage sludge and has highlighted the importance of evaluating both agonistic and antagonistic responses when evaluating the bioactivity of complex samples.
Topics: Estrogens; Estrone; Sewage; Water Pollutants, Chemical; Water Purification
PubMed: 33909413
DOI: 10.1021/acs.est.0c07846 -
The Journal of Clinical Endocrinology... Nov 2022It is essential to improve the current predictive ability for type 2 diabetes (T2D) risk.
CONTEXT
It is essential to improve the current predictive ability for type 2 diabetes (T2D) risk.
OBJECTIVE
We aimed to identify novel metabolic markers for future T2D in Chinese individuals of Han ethnicity and to determine whether the combined effect of metabolic and genetic markers improves the accuracy of prediction models containing clinical factors.
METHODS
A nested case-control study containing 220 incident T2D patients and 220 age- and sex- matched controls from normoglycemic Chinese individuals of Han ethnicity was conducted within the Wuxi Non-Communicable Disease cohort with a 12-year follow-up. Metabolic profiling detection was performed by high-performance liquid chromatography‒mass spectrometry (HPLC-MS) by an untargeted strategy and 20 single nucleotide polymorphisms (SNPs) associated with T2D were genotyped using the Iplex Sequenom MassARRAY platform. Machine learning methods were used to identify metabolites associated with future T2D risk.
RESULTS
We found that abnormal levels of 5 metabolites were associated with increased risk of future T2D: riboflavin, cnidioside A, 2-methoxy-5-(1H-1, 2, 4-triazol-5-yl)- 4-(trifluoromethyl) pyridine, 7-methylxanthine, and mestranol. The genetic risk score (GRS) based on 20 SNPs was significantly associated with T2D risk (OR = 1.35; 95% CI, 1.08-1.70 per SD). The area under the receiver operating characteristic curve (AUC) was greater for the model containing metabolites, GRS, and clinical traits than for the model containing clinical traits only (0.960 vs 0.798, P = 7.91 × 10-16).
CONCLUSION
In individuals with normal fasting glucose levels, abnormal levels of 5 metabolites were associated with future T2D. The combination of newly discovered metabolic markers and genetic markers could improve the prediction of incident T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Case-Control Studies; Genetic Markers; Asian People; China
PubMed: 35977051
DOI: 10.1210/clinem/dgac487 -
Aquatic Toxicology (Amsterdam,... Jun 2016Effectively treating domestic wastewater so that it can be safely discharged or reused is critical for maintaining the integrity of freshwater resources, and for...
Effectively treating domestic wastewater so that it can be safely discharged or reused is critical for maintaining the integrity of freshwater resources, and for protecting the health of animals that rely on these systems. Amphibians are currently facing widespread population declines, so there is a particularly urgent need to investigate exposure scenarios that might result in weakened amphibian populations. Domestic sewage has received little attention as a possible factor that could influence the survival, growth and development, or general health of amphibians. However, wastewater reuse for crop irrigation and other purposes is increasing and holding ponds and constructed wetlands exist at many wastewater treatment facilities, introducing conceivable pathways that could result in the exposure of amphibians to treated wastewater. We exposed developing striped marsh frog (Limnodynastes peronii) tadpoles, to control water and 12.5, 25, 50 and 100% UV treated domestic sewage, and quantified effects on growth and development, hepatic energy reserves, and enzymatic pathways associated with detoxification and oxidative stress. Growth and development were accelerated and relative liver size was increased in exposed animals. The exposure resulted in an apparently hormetic increase in hepatic triglycerides and dose-dependent reduction in glycogen stores, as well as increased lipase and NADPH activity, indicating a general disruption to energy metabolism and/or mobilization. Contrary to expectations based on published studies with fish, we found no evidence of lipid peroxidation or induction of the detoxification enzyme Superoxide Dismutase (SOD), however, this may reflect the use of UV treatment as opposed to chlorination for disinfection. Chemical analysis and risk-based prioritization consistently identified fluoxetine, triclosan and diazinon as high-risk contaminants in the wastewater, with nonylphenol and mestranol flagged as risks during one early collection. Research is needed to explore the potential for these specific contaminants to elicit the responses identified in the present study, and to perform similar assessments using wastewater from other locations with different treatment options.
Topics: Animals; Anura; Energy Metabolism; Free Radical Scavengers; Glycogen; Larva; Lipase; Liver; NADP; Oxidative Stress; Ranidae; Sewage; Triglycerides; Ultraviolet Rays; Wastewater; Water Pollutants, Chemical; Water Purification; Wetlands
PubMed: 26991752
DOI: 10.1016/j.aquatox.2016.03.010 -
Environmental Toxicology and Chemistry Nov 2016The present study investigated the occurrence of 13 parent and conjugated estrogens and progestagens in surface water of the Santa Ana River. With the exception of the...
The present study investigated the occurrence of 13 parent and conjugated estrogens and progestagens in surface water of the Santa Ana River. With the exception of the synthetic hormones 17α-ethynylestradiol and mestranol, other compounds were detected at least twice at 10 representative sites, with the ubiquitous estrone (E1) and 17β-estradiol-3-sulfate as the dominant compounds quantified (0.24-6.37 ng/L and 0.49-9.25 ng/L, respectively). Sites near dairy farms exhibited high levels of conjugates, whereas those close to a sewage treatment plant (STP) effluent outlet displayed relatively high concentrations of E1. Principle component analysis coupled with multiple linear regression revealed dairy farms and the STP as the 2 significant contamination sources, accounting for 69.9% and 31.1% of the total hormone burden, respectively. Risk assessment results suggested E1 and 17β-estradiol (E2) as the 2 hormones with the largest risks to aquatic organisms, and which combined, contributed >90% of the total estrogenicity. Most of the sites investigated showed that E1 and E2 posed a medium risk (0.1 < risk quotient < 1), whereas each induced a high risk (risk quotient >1) at sites severely impacted by the STP and dairy farms. These results suggest that river health would benefit from effective treatment of waste at the STP and dairy farms prior to discharge. Environ Toxicol Chem 2016;35:2657-2664. © 2016 SETAC.
Topics: Estrogens; Estrogens, Conjugated (USP); Linear Models; Principal Component Analysis; Progestins; Risk Assessment; Rivers; Spectrometry, Mass, Electrospray Ionization; Water Pollutants, Chemical
PubMed: 27061433
DOI: 10.1002/etc.3447