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Molecules (Basel, Switzerland) Dec 2019Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine...
Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron-dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.
Topics: Boron Compounds; Chemistry Techniques, Synthetic; Enzyme Inhibitors; Methanol; Molecular Structure; Phosphotransferases (Alcohol Group Acceptor); Pyrrolidines; Spectrum Analysis; Structure-Activity Relationship; Sulfones
PubMed: 31810327
DOI: 10.3390/molecules24234408 -
Ecotoxicology and Environmental Safety Dec 2022Per- and polyfluoroalkyl substances (PFASs) are common environmental contaminants and are widely detected in humans. Previous studies have linked PFASs exposure to...
BACKGROUND
Per- and polyfluoroalkyl substances (PFASs) are common environmental contaminants and are widely detected in humans. Previous studies have linked PFASs exposure to adverse birth outcomes. However, the association between maternal exposure to PFASs and hemoglobin (Hb) and hematocrit (HCT) remains unclear.
OBJECTIVES
We aimed to explore the relationship between PFASs exposure with Hb and HCT during pregnancy.
METHODS
The present birth cohort study included 1044 pregnant women from Wuhan, China. Maternal HCT and Hb were measured in the first, second and third trimesters, and 13 PFASs were detected in the cord sera. Mixed linear models and general linear regression were applied to analyze the association between each single PFASs and Hb and HCT. Weighted quantile sum (WQS) regressions were used to investigate the association between PFASs mixture and Hb and HCT during pregnancy.
RESULTS
In single-PFAS models, 10 PFASs were positively associated with HCT and Hb across pregnancy (a 10-fold increase in PFASs was associated with 1.47-3.54 % change in HCT and 1.46-3.20 % change in Hb (All P-FDR < 0.05). In addition, Hb and HCT were more positively related to PFASs in the second and third trimesters rather than the first trimester. The association between PFASs exposure and maternal HCT and Hb was not significant in the iron supplementation group, whereas significant in the non-iron supplementation group. A significant interaction between iron supplementation and non-iron supplementation was also detected. WQS regressions showed that perfluorononanoic acid (PFNA) and perfluorohexane sulfonate (PFHxS) contributed most to the association between PFASs and HCT and Hb in the second and third trimesters, respectively.
CONCLUSION
Maternal PFASs exposure was positive with serum Hb and HCT. Moreover, maternal iron supplementation may play a modifying effect in influencing the relationship between PFASs and HCT and Hb.
Topics: Pregnancy; Female; Humans; Hematocrit; Fluorocarbons; Cohort Studies; Hemoglobins; Alkanesulfonates
PubMed: 36423372
DOI: 10.1016/j.ecoenv.2022.114319 -
Global Health Action 2014This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are... (Review)
Review
This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs) of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best-selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI) than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes.
Topics: Clinical Trials as Topic; Cyclooxygenase 2 Inhibitors; Drug Industry; Etoricoxib; Evidence-Based Medicine; Female; Humans; Male; Marketing; Pyridines; Sex Factors; Sexism; Spain; Sulfones
PubMed: 25498360
DOI: 10.3402/gha.v7.25484 -
Journal of the American Chemical Society Mar 2020Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable...
Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable photoprotecting groups has the potential to further expand the established utility of the photoactivation strategy in biological applications by offering higher tissue penetration, diminished phototoxicity, and compatibility with other light-dependent techniques. Nevertheless, a critical barrier to such applications remains the significant hydrophobicity of most visible-light excitable photocaging groups. Here, we find that applying the conventional 2,6-sulfonation to -methyl BODIPY photocages is incompatible with their photoreaction due to an increase in the excited state barrier for photorelease. We present a simple, remote sulfonation solution to BODIPY photocages that imparts water solubility and provides control over cellular permeability while retaining their favorable spectroscopic and photoreaction properties. Peripherally disulfonated BODIPY photocages are cell impermeable, making them useful for modulation of cell-surface receptors, while monosulfonated BODIPY retains the ability to cross the cellular membrane and can modulate intracellular targets. This new approach is generalizable for controlling BODIPY localization and was validated by sensitization of mammalian cells and neurons by visible-light photoactivation of signaling molecules.
Topics: Alkanesulfonates; Animals; Boron Compounds; Cell Membrane; Dopamine; Drug Carriers; Fluorescent Dyes; HEK293 Cells; Hippocampus; Histamine; Humans; Light; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Structure; Neurons; Rats; Solubility
PubMed: 32115942
DOI: 10.1021/jacs.9b13219 -
Advanced Science (Weinheim,... Jul 2023Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term...
Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non-specific anti-proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3-inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad-spectrum anti-inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non-specific anti-proliferative effects of PTX and SMS. Using an in vitro model of NLRP3-mediated inflammation in murine macrophages, MCC950 reduced IL-1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re-endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti-inflammatory drug-elution strategy with significant implications for cardiovascular device intervention.
Topics: Animals; Humans; Mice; Anti-Inflammatory Agents; Endothelial Cells; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfonamides; Sulfones
PubMed: 37150865
DOI: 10.1002/advs.202300521 -
Kidney & Blood Pressure Research 2018A recent alert from Spanish health authorities warned of a higher incidence of reported hypersensitivity reactions to hemodialysis membranes with polysulfone, in the... (Observational Study)
Observational Study
BACKGROUND/AIMS
A recent alert from Spanish health authorities warned of a higher incidence of reported hypersensitivity reactions to hemodialysis membranes with polysulfone, in the 2017 review of acute reactions to dialyzers found only published reports in the 21st century on polysulfone and its derivatives. The aim is to assess/evaluate the current incidence and characteristics of hypersensitivity reactions in hemodialysis patients.
METHODS
A retrospective multicentre study in 9 Spanish hospitals evaluated patients in whom a hypersensitivity reaction required a change in dialyzer membrane.
RESULTS
A total of 37 patients out of 1561 (2.37%) had hypersensitivity reactions and clinical, epidemiological and analytical data were available for 33 patients (2.11%). The membranes involved were polysulfone (n=23), polynephron (n=8), polyethersulfone (n=1) and polyacrylonitrile (n=1). This distribution reflected the frequency of use of membranes in the participating dialysis units. The reactions were described as type A in 18 cases and type B in 15 cases. There were no significant differences between the two types in clinical symptoms, the composition of the membrane involved, the method of sterilization, the season, or the time during the session in which they occurred. The most frequent symptom was dyspnea/breathlessness (64% of reactions). Eosinophilia was common (74%). 54% of the reactions occurred within the first 30 minutes of hemodialysis, 64% occurred during the first year of dialysis, and 54% required discontinuation of dialysis session. Cellulose triacetate was used as an alternative dialyzer in 78% of the cases.
CONCLUSION
The incidence of hypersensitivity reactions was in the range found in reports from 20 years ago and is observed associated with synthetic membranes, not just polysulfones. Cellulose triacetate appears to be a good alternative for these patients.
Topics: Acrylic Resins; Aged; Aged, 80 and over; Cellulose; Female; Humans; Hypersensitivity; Male; Membranes, Artificial; Middle Aged; Polymers; Renal Dialysis; Retrospective Studies; Sulfones
PubMed: 30235456
DOI: 10.1159/000493662 -
Environment International Mar 2023Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS...
Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS provided that quantitative in vitro to in vivo extrapolation (QIVIVE) can be developed. The QIVIVE ratio is the ratio of nominal (C) or freely dissolved concentration (C) in human blood to C or C in the bioassays. Considering that the concentrations of PFAS in human plasma and in vitro bioassays may vary by orders of magnitude, we tested the hypothesis that anionic PFAS bind to proteins concentration-dependently and therefore the binding differs substantially between human plasma and bioassays, which has an impact on QIVIVE. Solid phase microextraction (SPME) with C18-coated fibers served to quantify the C of four anionic PFAS (perfluorobutanoate (PFBA), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS)) in the presence of proteins and lipid, medium components, cells and human plasma over five orders of magnitude in concentrations. The C18-SPME method was used to quantify the non-linear binding to proteins, human plasma and medium, and the partition constants to cells. These binding parameters were used to predict C of PFAS in cell bioassays and human plasma by a concentration-dependent mass balance model (MBM). The approach was illustrated with a reporter gene assay indicating activation of the peroxisome proliferator-activated receptor gamma (PPARγ-GeneBLAzer). Blood plasma levels were collected from literature for occupational exposure and the general population. The QIVIVE ratios were higher than the QIVIVE ratios due to the strong affinity to proteins and large differences in protein contents between human blood and bioassays. For human health risk assessment, the QIVIVE ratios of many in vitro assays need to be combined to cover all health relevant endpoints. If C cannot be measured, they can be estimated with the MBM and concentration-dependent distribution ratios.
Topics: Humans; Biological Availability; Protein Binding; Fluorocarbons; Alkanesulfonic Acids; Alkanesulfonates; Biological Assay; Environmental Pollutants
PubMed: 36881956
DOI: 10.1016/j.envint.2023.107857 -
Genes Jan 2022Bisphenol A (BPA) and its analogs, bisphenol S (BPS) and bisphenol F (BPF), might impact fertility by altering oxidative stress pathways. Here, we hypothesize that...
Bisphenol A (BPA) and its analogs, bisphenol S (BPS) and bisphenol F (BPF), might impact fertility by altering oxidative stress pathways. Here, we hypothesize that bisphenols-induced oxidative stress is responsible for decreased gamete quality. In both female (cumulus-oocyte-complexes-COCs) and male (spermatozoa), oxidative stress was measured by CM-HDCFDA assay and key ROS scavengers (SOD1, SOD2, GPX1, GPX4, CAT) were quantified at the mRNA and protein levels using qPCR and Western blot (COCs)/immunofluorescence (sperm). Either gamete was treated in five groups: control, vehicle, and 0.05 mg/mL of BPA, BPS, or BPF. Our results show elevated ROS in BPA-treated COCs but decreased production in BPS- and BPF-treated spermatozoa. Additionally, both mRNA and protein expression of SOD2, GPX1, and GPX4 were decreased in BPA-treated COCs ( < 0.05). In sperm, motility ( < 0.03), but not morphology, was significantly altered by bisphenols. SOD1 mRNA expression was significantly increased, while GPX4 was significantly reduced. These results support BPA's ability to alter oxidative stress in oocytes and, to a lesser extent, in sperm. However, BPS and BPF likely act through different mechanisms.
Topics: Animals; Antioxidants; Benzhydryl Compounds; Cattle; Female; Free Radical Scavengers; Male; Oocytes; Oxidative Stress; Phenols; Spermatozoa; Sulfones
PubMed: 35052481
DOI: 10.3390/genes13010142 -
Drug Metabolism Letters 2018The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development... (Comparative Study)
Comparative Study
BACKGROUND
The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites.
OBJECTIVE
The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites.
METHODS
In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method.
RESULTS
CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments.
CONCLUSION
Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.
Topics: Acetates; Albendazole; Aldicarb; Biotransformation; Cyclopropanes; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Isoenzymes; Methiocarb; Microsomes, Liver; Piperazines; Quinolines; Risk Assessment; Sulfides; Sulfones; Sulfoxides; Thiazoles; Triclabendazole
PubMed: 30117405
DOI: 10.2174/1872312812666180816164626 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2020Bioactive small molecules containing α-fluoro sulfur motifs [RS(O) CH F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors....
Bioactive small molecules containing α-fluoro sulfur motifs [RS(O) CH F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors. Prominent examples include the anti-asthma drug Flovent and the phenylpyrazole insecticide pyrafluprole. Given the popularity of these structural units in bioactive small molecule design, together with the varying oxidation states of sulfur, a conformational analysis of α-fluoro sulfides, sulfoxides, and sulfones, would be instructive in order to delineate the non-covalent interactions that manifest themselves in structure. A combined crystallographic and computational analysis demonstrates the importance of hyperconjugative donor-acceptor interactions in achieving acyclic conformational control. The conformational disparity in the syn- and anti-diastereoisomers of α-fluorosulfoxides is particularly noteworthy.
Topics: Hydrocarbons, Fluorinated; Molecular Conformation; Sulfides; Sulfones; Sulfoxides; Sulfur; Sulfur Compounds
PubMed: 32735052
DOI: 10.1002/chem.202003361