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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 -
The Journal of Allergy and Clinical... Feb 2021Bisphenol A (BPA) has been linked with pediatric asthma development and allergic airway inflammation in animal models. Whether exposure to BPA or its structural analogs...
BACKGROUND
Bisphenol A (BPA) has been linked with pediatric asthma development and allergic airway inflammation in animal models. Whether exposure to BPA or its structural analogs bisphenol S (BPS) and bisphenol F (BPF) is associated with asthma morbidity remains unknown.
OBJECTIVE
We examined associations between bisphenols and morbidity due to pediatric asthma.
METHODS
We quantified concentrations of BPA, BPS, and BPF in 660 urine samples from 148 predominantly low-income, African American children (aged 5-17 years) with established asthma. We used biobanked biospecimens and data on symptoms, health care utilization, and pulmonary function and inflammation that were collected every 3 months over the course of a year. We used generalized estimating equations to examine associations between concentrations or detection of urinary bisphenols and morbidity outcomes and assessed heterogeneity of associations by sex.
RESULTS
We observed consistent positive associations between BPA exposure and measures of asthma morbidity. For example, we observed increased odds of general symptom days (adjusted odds ratio [aOR] = 1.40 [95% C = 1.02-1.92]), maximal symptom days (aOR = 1.36 [95% CI = 1.00-1.83]), and emergency department visits (aOR = 2.12 [95% CI =1.28-3.51]) per 10-fold increase in BPA concentration. We also observed evidence of sexually dimorphic effects; BPA concentrations were associated with increased odds of symptom days and health care utilization only among boys. Findings regarding BPS and BPF did not consistently point to associations with asthma symptoms or health care utilization.
CONCLUSION
We found evidence to suggest that BPA exposure in a predominantly low-income, minority pediatric cohort is associated with asthma morbidity and that associations may differ by sex. Our findings support additional studies, given the high pediatric asthma burden and widespread exposure to BPA in the United States.
Topics: Adolescent; Black or African American; Asthma; Baltimore; Benzhydryl Compounds; Child; Child, Preschool; Cohort Studies; Female; Humans; Male; Morbidity; Phenols; Sulfones; Urban Population
PubMed: 32736870
DOI: 10.1016/j.jaci.2020.05.031 -
Environmental Health : a Global Access... May 2021Exposure to bisphenols may affect fetal growth and development. The trimester-specific effects of bisphenols on repeated measures of fetal growth remain unknown. Our...
BACKGROUND
Exposure to bisphenols may affect fetal growth and development. The trimester-specific effects of bisphenols on repeated measures of fetal growth remain unknown. Our objective was to assess the associations of maternal bisphenol urine concentrations with fetal growth measures and birth outcomes and identify potential critical exposure periods.
METHODS
In a population-based prospective cohort study among 1379 pregnant women, we measured maternal bisphenol A, S and F urine concentrations in the first, second and third trimester. Fetal head circumference, length and weight were measured in the second and third trimester by ultrasound and at birth.
RESULTS
An interquartile range increase in maternal pregnancy-averaged bisphenol S concentrations was associated with larger fetal head circumference (difference 0.18 (95% confidence interval (CI) 0.01 to 0.34) standard deviation scores (SDS), p-value< 0.05) across pregnancy. When focusing on specific critical exposure periods, any detection of first trimester bisphenol S was associated with larger second and third trimester fetal head circumference (difference 0.15 (95% CI 0.05 to 0.26) and 0.12 (95% CI 0.02 to 0.23) SDS, respectively) and fetal weight (difference 0.12 (95% CI 0.02 to 0.22) and 0.16 (95% CI 0.06 to 0.26) SDS, respectively). The other bisphenols were not consistently associated with fetal growth outcomes. Any detection of bisphenol S and bisphenol F in first trimester was also associated with a lower risk of being born small size for gestational age (Odds Ratio 0.56 (95% CI 0.38 to 0.74) and 0.55 (95% CI 0.36 to 0.85), respectively). Bisphenols were not associated with risk of preterm birth.
CONCLUSIONS
Higher maternal bisphenol S urine concentrations, especially in the first trimester, seem to be related with larger fetal head circumference, higher weight and a lower risk of being small size for gestational age at birth.
Topics: Adult; Benzhydryl Compounds; Birth Weight; Endocrine Disruptors; Female; Femur; Fetal Development; Head; Humans; Infant, Newborn; Male; Phenols; Pregnancy; Prospective Studies; Sulfones
PubMed: 33992119
DOI: 10.1186/s12940-021-00747-6 -
Stem Cell Research & Therapy Jun 2021Methylsulfonylmethane (MSM) is a nutraceutical compound which has been indicated to counteract osteoarthritis, a cartilage degenerative disorder. In addition, MSM has...
BACKGROUND
Methylsulfonylmethane (MSM) is a nutraceutical compound which has been indicated to counteract osteoarthritis, a cartilage degenerative disorder. In addition, MSM has also been shown to increase osteoblast differentiation. So far, few studies have investigated MSM role in the differentiation of mesenchymal stem cells (MSCs), and no study has been performed to evaluate its overall effects on both osteogenic and chondrogenic differentiation. These two mutually regulated processes share the same progenitor cells.
METHODS
Therefore, with the aim to evaluate the effects of MSM on chondrogenesis and osteogenesis, we analyzed the expression of SOX9, RUNX2, and SP7 transcription factors in vitro (mesenchymal stem cells and chondrocytes cell lines) and in vivo (zebrafish model). Real-time PCR as well Western blotting, immunofluorescence, and specific in vitro and in vivo staining have been performed. Student's paired t test was used to compare the variation between the groups.
RESULTS
Our data demonstrated that MSM modulates the expression of differentiation-related genes both in vitro and in vivo. The increased SOX9 expression suggests that MSM promotes chondrogenesis in treated samples. In addition, RUNX2 expression was not particularly affected by MSM while SP7 expression increased in all MSM samples/model analyzed. As SP7 is required for the final commitment of progenitors to preosteoblasts, our data suggest a role of MSM in promoting preosteoblast formation. In addition, we observed a reduced expression of the osteoclast-surface receptor RANK in larvae and in scales as well as a reduced pERK/ERK ratio in fin and scale of MSM treated zebrafish.
CONCLUSIONS
In conclusion, our study provides new insights into MSM mode of action and suggests that MSM is a useful tool to counteract skeletal degenerative diseases by targeting MSC commitment and differentiation.
Topics: Animals; Cell Differentiation; Cells, Cultured; Chondrocytes; Chondrogenesis; Dimethyl Sulfoxide; Humans; Osteoblasts; Osteogenesis; Sulfones; Zebrafish
PubMed: 34090529
DOI: 10.1186/s13287-021-02396-5 -
Nature Communications Jun 2021Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in...
Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.
Topics: Binding Sites; Biological Transport; Calcium-Binding Proteins; Cryoelectron Microscopy; Guanidines; Humans; Models, Molecular; Multiprotein Complexes; Protein Binding; Protein Conformation; Protein Multimerization; Sodium-Hydrogen Exchanger 1; Sulfones
PubMed: 34108458
DOI: 10.1038/s41467-021-23496-z -
Xenobiotica; the Fate of Foreign... Feb 2021We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of...
We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of adult male rats and mice following exposure via feed for 7 days to BPS (338, 1125, and 3375 ppm) or BPAF (338, 1125, and 3750 ppm). In rats, the exposure concentration-normalized maximum concentration [C/D (ng/mL)/(ppm)] and area under the concentration time curve [AUC/D (h × ng/mL)/(ppm)] for free was higher for BPS (C/D: 0.476-1.02; AUC/D: 3.58-8.26) than for BPAF (C/D: 0.017-0.037; AUC/D:0.196-0.436). In mice, the difference in systemic exposure parameters between free BPS (C/D: 0.376-0.459; AUC/D: 1.52-2.54) and free BPAF (C/D: 0.111-0.165; AUC/D:0.846-1.09) was marginal. Elimination half-lives for free analytes (4.41-10.4 h) were comparable between species and analogues. When systemic exposure to free analyte was compared between species, in rats, BPS exposure was slightly higher but BPAF exposure was much lower than in mice. BPS and BPAF were highly conjugated; total BPS AUC values (rats ≥18-fold, mice ≥17-fold) and BPAF (rats ≥127-fold, mice ≥16-fold) were higher than corresponding free values. Data demonstrated that there are analogue and species differences in the kinetics of BPS and BPAF.
Topics: Animals; Benzhydryl Compounds; Hazardous Substances; Kinetics; Male; Mice; Phenols; Rats; Sulfones; Toxicity Tests; Toxicokinetics
PubMed: 32985913
DOI: 10.1080/00498254.2020.1829171 -
Materials Science & Engineering. C,... Sep 2020The aim of this study was to investigate the monomer absorption behavior of decellularized dermis and prepare a gradient-type decellularized dermis-polymer complex....
The aim of this study was to investigate the monomer absorption behavior of decellularized dermis and prepare a gradient-type decellularized dermis-polymer complex. Decellularized dermis was prepared using sodium dodecyl sulfate, and its monomer absorption behavior was investigated using three types of hydrophobic monomer with different surface free energies. The results show that monomer absorption depends strongly on the tissue structure, regardless of the surface free energy, and the amount of absorbed monomer can be increased by sonication. Based on these results, we prepared a gradient-type decellularized dermis-poly(methyl methacrylate) complex by controlling the permeation time of the methyl methacrylate monomer and polymerization initiator into the decellularized dermis. The mechanical strength of this complex gradually increased from the dermis side to the polymer side, and combined the physical characteristics of the dermis and the polymer.
Topics: Polymerization; Polymers; Polymethyl Methacrylate; Sodium Dodecyl Sulfate
PubMed: 32993989
DOI: 10.1016/j.msec.2020.111017 -
Carbohydrate Polymers May 2021The manifold array of saccharide linkages leads to a great variety of polysaccharide architectures, comprising three conformations in aqueous solution: compact sphere,...
The manifold array of saccharide linkages leads to a great variety of polysaccharide architectures, comprising three conformations in aqueous solution: compact sphere, random coil, and rigid rod. This conformational variation limits the suitability of the commonly applied molecular weight cut-off (MWCO) as selection criteria for polysaccharide ultrafiltration membranes, as it is based on globular marker proteins with narrow M and hydrodynamic volume relation. Here we show the effect of conformation on ultrafiltration performance using randomly coiled pullulan and rigid rod-like scleroglucan as model polysaccharides for membrane rejection and molecular weight distribution. Ultrafiltration with a 10 kDa polyethersulfone membrane yielded significant different recoveries for pullulan and scleroglucan showing 1% and 71%, respectively. We found deviations greater than 77-fold between nominal MWCO and apparent M of pullulan and scleroglucan, while recovering over 90% polysaccharide with unchanged M. We anticipate our work as starting point towards an optimized membrane selection for polysaccharide applications.
Topics: Glucans; Membranes, Artificial; Molecular Conformation; Molecular Weight; Polymers; Polysaccharides; Sulfones; Ultrafiltration
PubMed: 33712169
DOI: 10.1016/j.carbpol.2021.117830 -
Acta Biomaterialia Aug 2019Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides...
Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ± 3 and 24 ± 3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.
Topics: Age Factors; Animals; Cross-Linking Reagents; Disease Models, Animal; Elasticity; Electroretinography; Glaucoma; Hyaluronic Acid; Hydrogels; Injections; Injections, Intraocular; Intraocular Pressure; Kinetics; Magnetic Resonance Imaging; Mice, Inbred C57BL; Neurodegenerative Diseases; Optic Nerve; Retinal Ganglion Cells; Sulfhydryl Compounds; Sulfones; Viscosity
PubMed: 31176841
DOI: 10.1016/j.actbio.2019.06.005 -
Environmental Toxicology and... Nov 2023Freshwater animals are exposed to anthropogenic contaminants and are biomonitors of water quality and models of the deleterious impacts of exposure. Sponges, such as...
Freshwater animals are exposed to anthropogenic contaminants and are biomonitors of water quality and models of the deleterious impacts of exposure. Sponges, such as Ephydatia muelleri, constantly pump water and are effective indicators of water-soluble contaminants. Zebrafish (Danio rerio), native to Southeast Asia, live in the water column and feed at the water-sediment interface and are exposed to both water-soluble and insoluble contaminants. While sponges and zebrafish diverged ∼700 million years ago, they share common genetic elements, and their response to contaminants can be predictive to a wide-range of animals. An emerging contaminant, bisphenol S, was tested to evaluate its toxicity during development. The toxicity and mechanism(s) of action of BPS is not well known. Water-borne exposures to BPS caused differing hatching rates, morphological changes, and shared gene expression changes of toxicologically-relevant genes. This study shows that BPS causes similarly adverse developmental impacts pointing to some overlapping mechanisms of action.
Topics: Animals; Zebrafish; Water Pollutants, Chemical; Phenols; Sulfones
PubMed: 37939749
DOI: 10.1016/j.etap.2023.104311