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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 -
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 -
Environmental Research Aug 2023Although some studies report that exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy and early life stages of a child could adversely impact...
BACKGROUND
Although some studies report that exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy and early life stages of a child could adversely impact neurodevelopment, literature shows mixed evidence.
OBJECTIVES
Using an ecological framework for human development, we assessed the association of risk factors for environmental PFAS exposure and childhood PFAS concentrations with behavioral difficulties among school-age children exposed to PFAS from birth, while also controlling for the important influence of the parenting and familial environment.
METHODS
The study participants included 331 school-age children (6-13 years) born in a PFAS-contaminated area in the Veneto Region (Italy). We study the associations between environmental risk factors of maternal PFAS exposure (residential time, consumption of tap water, residence in Red zone A or B), and breastfeeding duration with parent assessments of children's behavioral problems (using the Strengths and Difficulties Questionnaire [SDQ]), adjusting for socio-demographic, parenting and familial variables. The direct relationships between serum blood PFAS concentrations and SDQ scores was evaluated in a subset of children (n = 79), both with single PFAS and weighted quantile sum (WQS) regressions.
RESULTS
Poisson regression models reported positive associations between high consumption of tap water and externalizing SDQ scores (Incidence Rate Ratio [IRR]: 1.18; 95% confidence interval [CI]: 1.04-1.32) and total difficulty scores (IRR: 1.14; 95% CI: 1.02-1.26). Childhood perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were associated with higher internalizing SDQ scores (4th vs. 1st quartile, PFOS IRR: 1.54, 95% CI: 1.06-2.25), externalizing scores (4th vs. 1st quartile, PFHxS IRR: 1.59, 95% CI: 1.09-2.32), and total difficulty scores (4th vs. 1st quartile, PFOS IRR: 1.37, 95% CI: 1.05-1.71; PFHxS IRR: 1.54, 95% CI: 1.09-1.90). The WQS regressions confirmed the associations reported by single-PFAS analyses.
CONCLUSIONS
We observed cross-sectional associations of tap water consumption and childhood PFOS, and PFHxS concentrations with greater behavioral difficulties.
Topics: Pregnancy; Female; Humans; Child; Cross-Sectional Studies; Environmental Exposure; Alkanesulfonic Acids; Alkanesulfonates; Fluorocarbons; Water; Environmental Pollutants
PubMed: 37207732
DOI: 10.1016/j.envres.2023.116049 -
BMC Pediatrics May 2022Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation - no study has been done in the past to compare the two forms. Each has its own benefits - but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension.
METHODS
An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects.
RESULTS
Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00-8.00) and 9.00 (8.00-9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group.
CONCLUSION
Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate.
TRIAL REGISTRATION
Trial was registered in the clinical trials registry of India [ CTRI/2019/04/018781 ][25/04/2019].
Topics: Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents
PubMed: 35624452
DOI: 10.1186/s12887-022-03366-3 -
Antiviral Chemistry & Chemotherapy 2018Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity... (Review)
Review
Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5'-dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length. IAS derivatives look like promising drug candidates for the treatment of AIDS and related infections in combination with other antiretroviral agents.
Topics: Anti-HIV Agents; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Microbial Sensitivity Tests; Molecular Structure; Reverse Transcriptase Inhibitors; Sulfones
PubMed: 29417826
DOI: 10.1177/2040206617753443 -
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 -
Bioorganic & Medicinal Chemistry Letters May 2018A series of natural products-based phenyl sulfone derivative and their property-based analogues were investigated as potential growth inhibitors of Trypanosoma brucei....
A series of natural products-based phenyl sulfone derivative and their property-based analogues were investigated as potential growth inhibitors of Trypanosoma brucei. Trypanosoma brucei is a kinetoplastid protozoan parasite that causes trypanosomiasis. In this work, we found that nopol- and quinoline-based phenyl sulfone derivative were the most active and selective for T. brucei, and they were not reactive towards the active thiol of T. brucei's cysteine protease rhodesain. A thiol reactive variant of the quinoline-based phenyl sulfone was subsequently investigated and found to be a moderate inhibitor of rhodesain. The quinoline-based compound that is not reactive towards rhodesain can serve a template for phenotypic-based lead discovery while its thiol-active congener can serve as template for structure-based investigation of new antitrypanosomal agents.
Topics: Biological Products; Dose-Response Relationship, Drug; Drug Discovery; Molecular Structure; Parasitic Sensitivity Tests; Quinolines; Structure-Activity Relationship; Sulfones; Trypanocidal Agents; Trypanosoma brucei brucei
PubMed: 29609908
DOI: 10.1016/j.bmcl.2018.03.039 -
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