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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 -
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 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 -
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 -
British Journal of Cancer Apr 2018Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional...
BACKGROUND
Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells.
METHODS
We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents.
RESULTS
We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo.
CONCLUSIONS
These findings may lead to the development of novel therapeutic strategies targeting DGC.
Topics: Animals; Antineoplastic Agents; Cdh1 Proteins; Cell Line, Tumor; Disease Models, Animal; Drug Screening Assays, Antitumor; Male; Mice; Mice, Knockout; Mice, Nude; Stomach Neoplasms; Tumor Suppressor Protein p53
PubMed: 29527007
DOI: 10.1038/s41416-018-0008-y -
Organic Letters Sep 2016An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium...
An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium salts. The scope covers cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols as well as primary and secondary fluorinated alcohols. The methodology gives access to alkyl aryl ethers of previously unprecedented steric congestion. Furthermore, the versatility of the developed procedure was demonstrated by arylation of the pro-drug mestranol.
PubMed: 27586361
DOI: 10.1021/acs.orglett.6b01975 -
Translational Pediatrics Jan 2024Neonatal hypoxic-ischemic brain damage (HIBD) is a clinical syndrome causing brain injury in newborns with obscure etiology. Increasing evidence suggests that...
BACKGROUND
Neonatal hypoxic-ischemic brain damage (HIBD) is a clinical syndrome causing brain injury in newborns with obscure etiology. Increasing evidence suggests that ferroptosis plays a role in HIBD. This study aimed to clarify the key ferroptosis-related genes (FRGs) of HIBD, construct a long non-coding RNA-microRNA-messenger RNA (lncRNA-miRNA-mRNA) network, and further investigate the pathogenesis of HIBD.
METHODS
Gene expression data were downloaded from the Gene Expression Omnibus and FerrDb databases. The differentially expressed lncRNAs and FRGs were screened, and the related miRNAs and mRNAs were predicted. The obtained mRNA was intersected with the differentially expressed FRGs (DE-FRGs) to identify the key DE-FRGs. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts method was applied to analyze the immune cell infiltration level and the relationship between key genes and immune cells.
RESULTS
Gene differential expression analysis revealed that 1,178 lncRNAs, 207 miRNAs, and 647 mRNAs were differentially expressed in the blood of HIBD patients in comparison to healthy controls. The correlations of the lncRNAs, miRNAs, and mRNAs lead to the establishment of a competing endogenous RNA (ceRNA) network associated with ferroptosis in HIBD. Further validation using an external dataset and quantitative real-time polymerase chain reaction (PCR) analysis of brain tissues from hypoxic-ischemic encephalopathy rats confirmed the expression patterns of three key genes, including , and . Meanwhile, the three key genes were closely correlated with the infiltration of multiple immune cells and might affect the function of HIBD regulatory genes such as and . In addition, drug prediction suggested that four drugs, including cephaeline, emetine, mestranol, and sulmazole, might alleviate HIBD.
CONCLUSIONS
Our study established a ceRNA network, identified three key genes, and predicted four drugs that are associated with ferroptosis in HIBD, which provides new ideas for the investigation of the disease mechanisms and might facilitate the diagnosis and treatment of the disease.
PubMed: 38323182
DOI: 10.21037/tp-23-596