Estrogen Receptor-1 Genetic Polymorphisms for the Risk of Premature Ovarian Failure and Early Menopause

Background: The aim of this study was to investigate the role of the estrogen receptor 1 (ESR1) genetic polymorphisms for early menopause that was classified as premature ovarian failure (POF) and early menopause (EM) and to examine whether the associations of ESR1 genetic variants are different for POF and EM. Methods: We selected 100 POF cases and matched 100 EM cases and 200 normal menopause (NM) controls from the Korean Multi-Center Cohort. Among them, we restricted idiopathic POF and EM cases vs NM controls by excluding POF/EM cases with medical/surgical causes. The XbaI (rs9340799) and PvuII (rs2234693) in the ESR1 gene were genotyped. The single-nucleotide polymorphism (SNP) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis. Also nominal polytomous logistic regression was used to find whether ESR1 genetic variants are differently associated with POF and EM. Results: The global p values for idiopathic POF and EM were 0.08 and 0.39 (SNP-based), and <0.001 and 0.12 (haplotype-based), respectively. The XbaI genetic variant containing the X allele was marginally significantly associated with a reduced risk of idiopathic POF (OR=0.6, 95% CI 0.3-1.0). The P-x haplotype and diplotypes significantly decreased the risk of idiopathic POF (OR=0.5, 95% CI 0.2-0.9; OR 0.4, 95% CI 0.2-0.9, respectively). In contrast from POF, the P-x haplotypes and diplotypes insignificantly increased the risk for both idiopathic EM (p(polytomous)=0.009 for P-x haplotype; p(polytomous)=0.02 for P-x diplotypes). Conclusion: Our results suggest that the ESR1 gene including PvuII and XbaI polymorphisms may modify the risk of idiopathic premature ovarian failure (POF) but not idiopathic early menopause (EM) risk.Bretherick KL, 2008, FERTIL STERIL, V89, P318, DOI 10.1016/j.fertnstert.2007.03.008Chang SH, 2007, MATURITAS, V58, P19, DOI 10.1016/j.maturitas.2007.04.001Kitamura I, 2007, BONE, V40, P1623, DOI 10.1016/j.bone.2007.02.016Molvarec A, 2007, HYPERTENS RES, V30, P205Hsieh YY, 2007, MOL HUM REPROD, V13, P117, DOI 10.1093/molehr/gal099Dvornyk V, 2006, MATURITAS, V54, P19, DOI 10.1016/j.maturitas.2005.08.005Onland-Moret NC, 2005, CANCER CAUSE CONTROL, V16, P1195, DOI 10.1007/s10552-005-0307-5Popat RA, 2005, NEUROLOGY, V65, P383Schuit SCE, 2005, EUR J ENDOCRINOL, V153, P327, DOI 10.1530/eje.1.01973Kok HS, 2005, HUM REPROD, V20, P536, DOI 10.1093/humrep/deh600Ioannidis JPA, 2004, JAMA-J AM MED ASSOC, V292, P2105van der Klift M, 2004, J BONE MINER RES, V19, P1172, DOI 10.1359/JBMR.040215Schuit SCE, 2004, JAMA-J AM MED ASSOC, V291, P2969Wasserman L, 2004, INT J OBESITY, V28, P49, DOI 10.1038/sj.ijo.0802481van Meurs JBJ, 2003, HUM MOL GENET, V12, P1745, DOI 10.1093/hmg/ddg176Gorai I, 2003, J CLIN ENDOCR METAB, V88, P799, DOI 10.1210/jc.2002-020353Laml T, 2002, HUM REPROD UPDATE, V8, P483Herrington DM, 2002, CIRCULATION, V105, P1879, DOI 10.1161/01.CIR.0000016173.98826.88Kobayashi N, 2002, MATURITAS, V41, P193YOO KY, 2002, ASIAN PAC J CANCER P, V3, P85de Bruin JP, 2001, HUM REPROD, V16, P2014Pelletier G, 2000, J CLIN ENDOCR METAB, V85, P4835Weiderpass E, 2000, CARCINOGENESIS, V21, P623Yan G, 2000, J WOMEN HEALTH GEN-B, V9, P275Lorentzon M, 1999, J CLIN ENDOCR METAB, V84, P4597Weel AEAM, 1999, J CLIN ENDOCR METAB, V84, P3146Drummond AE, 1999, MOL CELL ENDOCRINOL, V151, P57, DOI 10.1016/S0303-7207(99)00038-6Christin-Maitre S, 1998, MOL CELL ENDOCRINOL, V145, P75Torgerson DJ, 1997, EUR J OBSTET GYN R B, V74, P63vanderSchouw YT, 1996, LANCET, V347, P714Kobayashi S, 1996, J BONE MINER RES, V11, P306NELSON LM, 1996, REPROD ENDOCRINOLOGY, P1394KAPRIO J, 1995, HUM BIOL, V67, P739CRAMER DW, 1995, FERTIL STERIL, V64, P740EXCOFFIER L, 1995, MOL BIOL EVOL, V12, P921NELSON LM, 1994, J CLIN ENDOCR METAB, V79, P1470CAPLAN GA, 1994, J ROY SOC MED, V87, P200PALMER JR, 1992, AM J EPIDEMIOL, V136, P408BAGUR AC, 1992, CALCIFIED TISSUE INT, V51, P4FRANCESCHI S, 1991, INT J CANCER, V49, P57MEYER JM, 1991, AM J MED GENET, V39, P148TRELOAR SA, 1990, AM J HUM GENET, V47, P137SNOWDON DA, 1989, AM J PUBLIC HEALTH, V79, P709

Antiviral Activity of Two Marine Carotenoids against SARS-CoV-2 Virus Entry In Silico and In Vitro

The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, and their inhibitory activity was confirmed with SARS-CoV-2 pseudovirus on HEK293 cells overexpressing angiotensin-converting enzyme 2 (ACE2). Siphonaxanthin from Codium fragile showed significant antiviral activity with an IC50 of 87.4 μM against SARS-CoV-2 pseudovirus entry, while fucoxanthin from Undaria pinnatifida sporophyll did not. The acute toxicities were predicted to be relatively low, and pharmacokinetic predictions indicate GI absorption. Although further studies are needed to elucidate the inhibition of viral infection by siphonaxanthin, these results provide useful information in the application of these marine carotenoids for the treatment and prevention of COVID-19

Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro

Phenolic compounds and carotenoids are potential inhibitors of cytochrome P450s. Sixteen known compounds, phenolic compounds and carotenoids from seaweed were examined for potential inhibitory capacity against CYP1A2 and CYP3A4 in silico and in vitro. Morin, quercetin, and fucoxanthin inhibited the enzyme activity of CYP1A2 and CYP3A4 in a dose-dependent manner. The IC50 values of morin, quercetin, and fucoxanthin were 41.8, 22.5, and 30.3 &mu;M for CYP1A2 and 86.6, 16.1, and 24.4 &mu;M for CYP3A4, respectively. Siphonaxanthin and hesperidin did not show any significant effect on CYP1A2, but they slightly inhibited CYP3A4 activity at high concentrations. In silico modeling of CYP&rsquo;s binding site revealed that the potential inhibitors bound in the cavity located above the distal surface of the heme prosthetic group through the 2a or 2f channel of CYPs. This study presents an approach for quickly predicting CYP inhibitory activity and shows the potential interactions of compounds and CYPs through in silico modeling

Evaluation of Antiviral Effect against SARS-CoV-2 Propagation by Crude Polysaccharides from Seaweed and Abalone Viscera In Vitro

Crude polysaccharides, extracted from two seaweed species (Hizikia fusiforme and Sargassum horneri) and Haliotis discus hannai (abalone) viscera, were evaluated for their inhibitory effect against SARS-CoV-2 propagation. Plaque titration revealed that these crude polysaccharides efficiently inhibited SARS-CoV-2 propagation with IC50 values ranging from 0.35 to 4.37 μg/mL. The crude polysaccharide of H. fusiforme showed the strongest antiviral effect, with IC50 of 0.35 μg/mL, followed by S. horneri and abalone viscera with IC50 of 0.56 and 4.37 μg/mL, respectively. In addition, immunofluorescence assay, western blot, and quantitative RT-PCR analysis verified that these polysaccharides could inhibit SARS-CoV-2 replication. In Vero E6 cells, treatment with these crude polysaccharides before or after viral infection strongly inhibited the expression level of SARS-CoV-2 spikes, nucleocapsid proteins, and RNA copies of RNA-dependent RNA-polymerase and nucleocapsid. These results show that these crude marine polysaccharides effectively inhibit SARS-CoV-2 propagation by interference with viral entry

Characteristics of Hypoglycemic Diabetic Patients Visiting the Emergency Room

Introduction. Severe hypoglycemia can be life-threatening; therefore, it is important to identify the characteristics of the hypoglycemic patients. The aim of this study is to analyze the type and characteristics of diabetic patients with hypoglycemia who visited an emergency room. Methods. We included diabetic patients with hypoglycemia who visited the emergency room of St. Mary’s Hospital in Seoul from January 2009 to August 2018 in the study. Hypo_S group patients visited the emergency room once whereas Hypo_M group patients visited twice or more. We also compared the incidence of cardiovascular disease between the groups within 5 years after hypoglycemia. Results. A total of 843 patients were included in this study, with a mean age of 71±14 years and average glycated hemoglobin (HbA1c) level of 6.7±1.4%. For patients with hypoglycemia, lower body mass index, lower HbA1c, shorter diabetes duration, and lower glomerular filtration rate have a statistically significant relationship with patient characteristics in the emergency room group (all p<0.001). Hypoglycemia symptoms were most frequently observed between 6:00 and 12:00 am (p<0.001). Cardiovascular diseases within 5 years after discharge were more frequent in the Hypo_S group than in the Hypo_M group; however, there was no statistical significance. The frequency of aneurysms was significantly higher in patients with hypoglycemia than in other patients in the emergency room (p<0.05). Conclusion. Relatively thin older patients with a diabetes duration shorter than 10 years and good blood sugar control showed higher frequency of visits to the emergency room due to hypoglycemia. For these patients, medical staff should always be mindful of their susceptibility to hypoglycemia when prescribing insulin or OHA and educate them on the prevention of hypoglycemia

Onset of Hyperkalemia following the Administration of Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker

Introduction. In spite of the established importance of detecting angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker- (ARB-) induced hyperkalemia, there have not been many studies on the time of its occurrence. Methods. We retrospectively analyzed electronic medical records to determine the onset time and incidence rate of hyperkalemia (serum potassium>5.5 mEq/L or 6.0 mEq/L) among hospitalized patients newly started on a 15-day ACEI or ARB therapy. Results. Among 3101 hospitalized patients, hyperkalemia incidence was 0.5%–0.9% and 0.8%–2.1% in the ACEI and ARB groups, respectively. However, it was not significantly different among different ARB types. Hyperkalemia’s onset was distributed throughout 15 days, without any trend. Hyperkalemia incidence was 7.3 and 35.1 times higher at 5.5 mEq/L (hazard ratio HR=7.31, 95%confidence interval CI=4.19–12.76, p<0.001) and 6.0 mEq/L (HR=35.11, 95%CI=8.25–149.52, p<0.001), respectively, than the baseline creatinine level. Hyperkalemia incidence in patients with chronic renal failure was 5.7 and 9.2 times higher at 5.5 mEq/L (HR=5.72, 95%CI=3.24–10.12, p<0.001) and 6.0 mEq/L (HR=9.16, 95%CI=4.02–20.88, p<0.001), respectively. Conclusions. It is unlikely that it is necessary to monitor hyperkalemia immediately after administration of ACEI or ARB. However, when prescribed for patients with abnormal kidney function, clinicians should always consider the possibility of developing hyperkalemia

Inhibition of SARS-CoV-2 Virus Entry by the Crude Polysaccharides of Seaweeds and Abalone Viscera In Vitro

Much attention is being devoted to the potential of marine sulfated polysaccharides as antiviral agents in preventing COVID-19. In this study, sulfated fucoidan and crude polysaccharides, extracted from six seaweed species (Undaria pinnatifida sporophyll, Laminaria japonica, Hizikia fusiforme, Sargassum horneri, Codium fragile, Porphyra tenera) and Haliotis discus hannai (abalone viscera), were screened for their inhibitory activity against SARS-CoV-2 virus entry. Most of them showed significant antiviral activities at an IC50 of 12~289 μg/mL against SARS-CoV-2 pseudovirus in HEK293/ACE2, except for P. tenera (IC50 &gt; 1000 μg/mL). The crude polysaccharide of S. horneri showed the strongest antiviral activity, with an IC50 of 12 μg/mL, to prevent COVID-19 entry, and abalone viscera and H. fusiforme could also inhibit SARS-CoV-2 infection with an IC50 of 33 μg/mL and 47 μg/mL, respectively. The common properties of these crude polysaccharides, which have strong antiviral activity, are high molecular weight (&gt;800 kDa), high total carbohydrate (62.7~99.1%), high fucose content (37.3~66.2%), and highly branched polysaccharides. These results indicated that the crude polysaccharides from seaweeds and abalone viscera can effectively inhibit SARS-CoV-2 entry