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ChemMedChem Jan 2017Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133...
Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2β-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17β-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety. The resulting compound, called RM-581 ({4-[17α-ethynyl-17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone), was synthesized efficiently in only five steps from commercially available estrone. In comparison with RM-133, RM-581 was found to be twice as metabolically stable, retains potent cytotoxic activity in breast cancer MCF-7 cell culture, and fully blocks tumor growth in a mouse xenograft model of breast cancer. Advantageously, the selectivity over normal cells has been increased with this estrane version of RM-133. In fact, RM-581 showed a better selectivity index (15.3 vs. 3.0) for breast cancer MCF-7 cells over normal breast MCF-10A cells, and was found to be nontoxic toward primary human kidney proximal tubule cells at doses reaching 50 μm.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Design; Female; Humans; MCF-7 Cells; Mestranol; Mice; Mice, Nude; Transplantation, Heterologous
PubMed: 28060448
DOI: 10.1002/cmdc.201600482 -
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 -
Environmental Pollution (Barking, Essex... Jun 2016In this work, source pollution tracing of the sediments of the Danube River and its tributaries in Serbia was performed using sterol ratios. Improved liquid...
In this work, source pollution tracing of the sediments of the Danube River and its tributaries in Serbia was performed using sterol ratios. Improved liquid chromatography-tandem mass spectrometry method, which enabled complete chromatographic separation of four analytes with identical fragmentation reactions (epicoprostanol, coprostanol, epicholestanol and cholestanol), was applied for the determination of steroid compounds (hormones, human/animal and plant sterols). A widespread occurrence of sterols was identified in all analyzed samples, whereas the only detected hormones were mestranol and 17α-estradiol. A human-sourced sewage marker coprostanol was detected at the highest concentration (up to 1939 ng g(-1)). The ratios between the key sterol biomarkers, as well as the percentage of coprostanol relative to the total sterol amount, were applied with the aim of selecting the most reliable for distinction between human-sourced pollution and the sterols originated from the natural sources in river sediments. The coprostanol/(cholesterol + cholestanol) and coprostanol/epicoprostanol ratios do not distinguish between human and natural sources of sterols in the river sediments in Serbia. The most reliable sterol ratios for the sewage pollution assessment of river sediments in the studied area were found to be coprostanol/(coprostanol + cholestanol), coprostanol/cholesterol and epicoprostanol/coprostanol. For the majority of sediments, human-derived pollution was determined. Two sediment samples were identified as influenced by a combination of human and natural biogenic sources.
Topics: Animals; Cholestanol; Cholestanols; Cholesterol; Chromatography, Liquid; Environmental Monitoring; Environmental Pollution; Estradiol; Geologic Sediments; Humans; Mestranol; Rivers; Serbia; Sewage; Tandem Mass Spectrometry
PubMed: 26874877
DOI: 10.1016/j.envpol.2015.12.036 -
Water Science and Technology : a... Apr 2017This study examined the individual and combined effects of potassium ferrate(VI) additions and freeze-thaw conditioning for the treatment and dewatering of wastewater...
This study examined the individual and combined effects of potassium ferrate(VI) additions and freeze-thaw conditioning for the treatment and dewatering of wastewater sludge in cold climates, with particular focus on the inactivation of fecal coliforms and oxidation of estrogens, androgens, and progestogens. The first phase of the study evaluated the effects of potassium ferrate(VI) pre-treatment followed by freeze-thaw at -20 °C using a low (0.5 g/L) and high (5.0 g/L) dose of potassium ferrate(VI). The results showed that pre-treatment of anaerobically digested sludge with 5 g/L of potassium ferrate(VI) reduced the concentration of fecal coliforms in the sludge cake to below 100 MPN/g DS. The second phase evaluated the ability of ferrate(VI) to oxidise selected hormones in sludge. Anaerobically digested sludge samples were spiked with 10 different hormones: estrone (E1), 17α-estradiol, 17β-estradiol (E2), estriol (E3), 17α-ethinylestradiol (EE2), equilin, mestranol, testosterone, norethindrone and norgestrel in two groups of low (3-75 ng/mL) and high (12-300 ng/L) concentration ranges of hormones. The samples were treated with either 0.5 or 1.0 g/L of potassium ferrate(VI), and hormone concentrations were measured again after treatment. Potassium ferrate(VI) additions as low as 1.0 g/L reduced the concentration of estrogens in sludge. Potassium ferrate(VI) additions of 0.5 and 1.0 g/L were less effective at reducing the concentrations of androgens and progestogens. Increasing ferrate(VI) dose would likely result in more substantial decreases in the concentrations of fecal coliforms and hormones. The results of this study indicate that the combined use of freeze-thaw and ferrate(VI) has the potential to provide a complete sludge treatment solution in cold regions.
Topics: Estradiol; Estrogens; Estrone; Ethinyl Estradiol; Feces; Freezing; Hormones; Iron Compounds; Oxidation-Reduction; Potassium Compounds; Sewage; Waste Disposal, Fluid; Wastewater
PubMed: 28402303
DOI: 10.2166/wst.2017.021 -
Ecotoxicology and Environmental Safety Jul 2024Several studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different...
Several studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different studies. We aimed to investigate the associations between serum metal concentrations and the risk of developing T2D among 8734 participants using a prospective cohort study design. We utilized inductively coupled plasmamass spectrometry (ICP-MS) to assess the serum concentrations of 27 metals. Cox regression was applied to calculate the hazard ratios (HRs) for the associations between serum metal concentrations on the risk of developing T2D. Additionally, 196 incident T2D cases and 208 healthy control participants were randomly selected for serum metabolite measurement using an untargeted metabolomics approach to evaluate the mediating role of serum metabolite in the relationship between serum metal concentrations and the risk of developing T2D with a nested casecontrol study design. In the cohort study, after Bonferroni correction, the serum concentrations of zinc (Zn), mercury (Hg), and thallium (Tl) were positively associated with the risk of developing T2D, whereas the serum concentrations of manganese (Mn), molybdenum (Mo), barium (Ba), lutetium (Lu), and lead (Pb) were negatively associated with the risk of developing T2D. After adding these eight metals, the predictive ability increased significantly compared with that of the traditional clinical model (AUC: 0.791 vs. 0.772, P=8.85×10). In the nested casecontrol study, a machine learning analysis revealed that the serum concentrations of 14 out of 1579 detected metabolites were associated with the risk of developing T2D. According to generalized linear regression models, 7 of these metabolites were significantly associated with the serum concentrations of the identified metals. The mediation analysis showed that two metabolites (2-methyl-1,2-dihydrophthalazin-1-one and mestranol) mediated 46.81% and 58.70%, respectively, of the association between the serum Pb concentration and the risk of developing T2D. Our study suggested that serum Mn, Zn, Mo, Ba, Lu, Hg, Tl, and Pb were associated with T2D risk. Two metabolites mediated the associations between the serum Pb concentration and the risk of developing T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Prospective Studies; Male; Female; Middle Aged; China; Metals; Adult; Aged; Environmental Pollutants; Cohort Studies; Metabolomics; Case-Control Studies; Thallium; Environmental Exposure; East Asian People
PubMed: 38772147
DOI: 10.1016/j.ecoenv.2024.116470 -
Pesticide Biochemistry and Physiology Sep 2023Red swamp crayfish, Procambarus clarkii, is a globally invasive species, which has caused great damage to biodiversity, agriculture, and fishing. Therefore, the...
Red swamp crayfish, Procambarus clarkii, is a globally invasive species, which has caused great damage to biodiversity, agriculture, and fishing. Therefore, the development of effective management methods, such as pheromone control, is necessary for biological control and biodiversity protection. However, the components of P. clarkii sex pheromones have not yet been explored, and the chemosensory mechanism of the P. clarkii antennae after stimulation by sex pheromone also remains unknown. In this study, we isolated and identified the candidate bioactive component of the female P. clarkii sex pheromone using ultrafiltration centrifugation, semi-preparative liquid phase separation and omics technologies and conducted bioassays to determine its attraction ability. Meanwhile, RNA-Seq technology was used to analyze the potential chemosensory mechanism of antennae. Our results indicated that the male P. clarkii were uniaxially attracted to the female crude conditioned water (FCW), medium fraction (MF, isolated by ultrafiltration centrifugation), and preparative fragment 6 of females (PFF6, isolated by semi-preparative liquid phase separation). Metabolomic analysis revealed the presence of 18 differential metabolites between the PFF6 and PFM6 samples, among which 15 were significantly upregulated in the PFF6 sample. Bioassay test also showed that mestranol, especially at concentrations of 10-10 mol∙l, could significantly attract P. clarkii males; therefore, mestranol was identified as the candidate sex pheromone component of P. clarkii females. Furthermore, RNA-Seq results showed that most differentially expressed genes (DEGs) enriched in lipid metabolism and signal transduction pathways were up-regulated in P. clarkii males. In addition, high expressions of Ca-binding protein and ion transporting ATPases may enhance the sensitivity of the antennae of P. clarkii males towards sex pheromones. Our study provides data on P. clarkii sex pheromone composition and reveals the molecular mechanism of sex pheromone response in P. clarkii. Moreover, our study provides a referable method for the isolation of candidate bioactive molecules from the P. clarkii sex pheromone.
Topics: Female; Male; Animals; Sex Attractants; Astacoidea; Mestranol; Pheromones; Adenosine Triphosphatases
PubMed: 37666605
DOI: 10.1016/j.pestbp.2023.105580 -
Archives of Toxicology Dec 2022Despite growing concern about adverse effects of bisphenol AF (BPAF) due to its endocrine disrupting properties, there is a lack of toxicity data from low-dose studies...
Despite growing concern about adverse effects of bisphenol AF (BPAF) due to its endocrine disrupting properties, there is a lack of toxicity data from low-dose studies and direct evidence linking its adverse effects to endocrine disrupting properties. Here, we investigated the effects of gestational and postnatal exposure to BPAF through drinking water (0.15-15 μg/mL, equivalent to the daily intake of ~ 50 and 5 mg/kg/day) on testis development in mice. We found that like mestranol, 5 mg/kg/day BPAF resulted in remarkable decreases in multiple male reproductive parameters in adulthood, such as the sperm number and serum testosterone level. Notably, 50 μg/kg/day BPAF also caused significant decreases in anogenital distance (AGD), the luteinizing hormone level and spermatocyte number, along with declining trends in sperm number and the serum levels of testosterone and follicle-stimulating hormone. In line with the adverse outcomes observed in adulthood, on postnatal day (PND) 9, we also observed BPAF-caused dose-dependent alterations, including reduced AGD, seminiferous tubule area and numbers of total germ cells, spermatocytes and Leydig cells, coupled with down-regulated expression of male-biased genes in testes. Even when exposure to 5 mg/kg/day BPAF as well as MES was initiated from PND 0, similar alterations in male reproductive parameters were also found on PND 9, along with a decrease in the GnRH content in the hypothalamus; moreover, testicular alterations and the reduction in AGD were partly antagonized by the estrogen receptor (ER) antagonist ICI 182,780, but the reduction of GnRH production was not done, showing that the effects of BPAF on testis development may be partially mediated by ER signaling. In conclusion, all the findings demonstrate that low-dose BPAF can partly disrupt mammal testis development and cause adverse testicular outcomes in adulthood, indicating a potential reproductive risk to mammals including humans. Importantly, our finding that developmental alterations elicited by BPAF have been detectable on PND 9 provides important motivation for the development of effective methods for early detection of adverse effects of estrogenic chemicals on testis development.
Topics: Humans; Male; Animals; Mice; Adult; Testis; Drinking Water; Mestranol; Fulvestrant; Receptors, Estrogen; Semen; Benzhydryl Compounds; Follicle Stimulating Hormone; Testosterone; Luteinizing Hormone; Mammals; Gonadotropin-Releasing Hormone
PubMed: 36098747
DOI: 10.1007/s00204-022-03377-0 -
European Journal of Epidemiology Aug 2021Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC...
Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses' Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65-0.91]; >10 years of use, 0.43 [0.32-0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41-0.67]) and second-generation progestins (0.43 [0.30-0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50-0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49-0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.
Topics: Adult; Aged; Cohort Studies; Contraceptives, Oral, Hormonal; Endometrial Neoplasms; Estrogens; Ethinyl Estradiol; Female; Humans; Mestranol; Middle Aged; Progestins; Prospective Studies
PubMed: 33331993
DOI: 10.1007/s10654-020-00705-5 -
Obesity (Silver Spring, Md.) Nov 2014To assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity.
OBJECTIVE
To assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity.
METHODS
Using data from the Collaborative Perinatal Project (1959-1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (≥85th percentile) or obesity (≥95th percentile) in the offspring according to exposure during different months of pregnancy were used.
RESULTS
Oral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3-4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3).
CONCLUSIONS
Pharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear.
Topics: Adult; Body Weight; Child; Child, Preschool; Cohort Studies; Contraceptives, Oral, Hormonal; Diethylstilbestrol; Female; Humans; Male; Odds Ratio; Overweight; Pediatric Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Young Adult
PubMed: 24760473
DOI: 10.1002/oby.20778 -
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