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Environmental Science and Pollution... Sep 2021The ban and restriction of polychlorinated biphenyls (PCBs) and major brominated flame retardants (BFRs), including hexabromocyclododecane (HBCD) and polybrominated... (Review)
Review
The ban and restriction of polychlorinated biphenyls (PCBs) and major brominated flame retardants (BFRs), including hexabromocyclododecane (HBCD) and polybrominated diphenyl ethers (PBDEs), due to their confirmed detrimental effects on wildlife and humans have paved the way for the wide application of organophosphate esters (OPEs). OPEs have been extensively used as alternative flame retardants, plasticizer, and antifoaming agents in various industrial and consumer products, which leads to an increase in production, usage, and discharge in the environment. We compile recent information on the production/usage and physicochemical properties of OPEs and discussed and compared the available sample treatment and analysis techniques of OPEs, including extraction, clean-up, and instrumental analysis. The occurrence of OPEs in sediment, aquatic biota, surface, and drinking water is documented. Toxicity, human exposure, and ecological risks of OPEs were summarized; toxicological data of several OPEs shows different adverse health effects on aquatic organisms and humans. Much attention was given to document evidence regarding the bioaccumulation and biomagnification potential of OPEs in aquatic organisms. Finally, identified research gaps and avenues for future studies are forwarded.
Topics: Bioaccumulation; Environmental Monitoring; Esters; Flame Retardants; Humans; Organophosphates
PubMed: 34378126
DOI: 10.1007/s11356-021-15861-8 -
Pharmacological Reviews Mar 2023Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the... (Review)
Review
Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. SIGNIFICANCE STATEMENT: Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.
Topics: Animals; Organophosphates; SARS-CoV-2; COVID-19; Amyloidogenic Proteins; Biological Products; Mammals
PubMed: 36549866
DOI: 10.1124/pharmrev.122.000654 -
Proceedings of the National Academy of... Apr 2022As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as...
As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs.
Topics: Colitis, Ulcerative; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Immunosuppressive Agents; Multiple Sclerosis; Organophosphates; Protein Binding; Protein Conformation, alpha-Helical; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors
PubMed: 35412894
DOI: 10.1073/pnas.2117716119 -
Endocrinology Jun 2023Organophosphate esters (OPEs) are used extensively as flame retardants and plasticizers and are found ubiquitously in the environment and human matrices. Previous...
Organophosphate esters (OPEs) are used extensively as flame retardants and plasticizers and are found ubiquitously in the environment and human matrices. Previous studies suggested that exposure to some of these chemicals may disrupt the homeostasis of female sex hormones and have detrimental effects on female fertility. Here, we determined the effects of OPEs on the function of KGN ovarian granulosa cells. We hypothesized that OPEs alter the steroidogenic ability of these cells by dysregulating the expression of transcripts involved in steroid and cholesterol biosynthesis. KGN cells were exposed for 48 hours to 1 of 5 OPEs (1-50μM): triphenyl phosphate (TPHP), tris(methylphenyl) phosphate (TMPP), isopropylated triphenyl phosphate (IPPP), tert-butylphenyl diphenyl phosphate (BPDP), and tributoxyethyl phosphate (TBOEP), or to a polybrominated diphenyl ether flame retardant, 2,2',4,4' tetrabromodiphenyl ether (BDE-47), in the presence or absence of Bu2cAMP. OPEs increased the basal production of progesterone (P4) and 17β-estradiol (E2) and had either no effect or inhibited Bu2cAMP-stimulated P4 and E2 synthesis; exposure to BDE-47 had no effect. Quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed that OPEs (≥5μM) increased the basal expression of critical genes (STAR, CYP11A1, CYP19A1, HSD3B2, and NR5A1) involved in steroidogenesis; upon stimulation, the expression of all genes tested was downregulated. An overall inhibition in cholesterol biosynthesis was induced by OPEs, characterized by a downregulation in HMGCR and SREBF2 expression. TBOEP consistently showed the least effect. Therefore, OPEs perturbed steroidogenesis in KGN granulosa cells by targeting the expression of steroidogenic enzymes and cholesterol transporters; these effects may have an adverse impact on female reproduction.
Topics: Humans; Female; Esters; Organophosphates; Granulosa Cells; Flame Retardants; Environmental Monitoring
PubMed: 37288667
DOI: 10.1210/endocr/bqad089 -
Organic Letters Jun 2022A general methodology allowing the preparation of phosphonylated 1-spirocyclopropyl analogues of glycosyl-1-phosphates is reported. The scope of this reaction has been...
A general methodology allowing the preparation of phosphonylated 1-spirocyclopropyl analogues of glycosyl-1-phosphates is reported. The scope of this reaction has been assessed using various -glycals easily obtained from the corresponding pyranoses and furanoses. The cyclopropanation was found to be stereospecific, and the selectivity only depends on the / configuration of the starting -glycal. The four possible isomers of spirocyclopropyl ribose-1-phosphonate could thus be prepared in a controlled manner, protected and deprotected.
Topics: Organophosphates; Phosphates; Ribose
PubMed: 35666228
DOI: 10.1021/acs.orglett.2c01422 -
Current Environmental Health Reports Dec 2019Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and... (Review)
Review
PURPOSE OF REVIEW
Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and are consequently prevalent in the environment and frequently detected in human biomonitoring studies. Exposure during pregnancy is of particular concern as OPEs have recently been detected in placental tissues, suggesting they may be transferred to the developing infant. Also, studies have now shown that children typically experience higher exposure to several OPEs compared with adults, indicating they may be disproportionately impacted by these compounds. This review summarizes the current literature on reproductive and child health outcomes of OPE exposures and highlights areas for future research.
RECENT FINDINGS
Experimental animal studies demonstrate potential for OPEs to adversely impact health, and a limited number of epidemiologic studies conducted in adult cohorts suggest that OPEs may interfere with the endocrine system. Neurodevelopment is perhaps the most well studied of children's health endpoints, and several studies indicate that prenatal and early life OPE exposures impact both cognitive and behavioral development. Associations have also been reported with reproductive outcomes (e.g., fertilization and pregnancy loss) and with the timing of parturition and preterm birth. Cross-sectional studies also demonstrate associations between OPEs and respiratory health outcomes, allergic disease, and measures of adiposity. An expanding body of research demonstrates that OPEs are associated with adverse reproductive health and birth outcomes, asthma and allergic disease, early growth and adiposity, and neurodevelopment. Still, additional research is urgently needed to elucidate the full impact of OPEs on children's health.
Topics: Adult; Child; Cross-Sectional Studies; Environmental Exposure; Environmental Monitoring; Esters; Female; Flame Retardants; Humans; Maternal Exposure; Organophosphates; Plasticizers; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 31755035
DOI: 10.1007/s40572-019-00258-0 -
International Journal of Molecular... Nov 2020Aptamers are nucleic acid analogues of antibodies with high affinity to different targets, such as cells, viruses, proteins, inorganic materials, and coenzymes.... (Review)
Review
Aptamers are nucleic acid analogues of antibodies with high affinity to different targets, such as cells, viruses, proteins, inorganic materials, and coenzymes. Empirical approaches allow the design of in vitro aptamers that bind particularly to a target molecule with high affinity and selectivity. Theoretical methods allow significant expansion of the possibilities of aptamer design. In this study, we review theoretical and joint theoretical-experimental studies dedicated to aptamer design and modeling. We consider aptamers with different targets, such as proteins, antibiotics, organophosphates, nucleobases, amino acids, and drugs. During nucleic acid modeling and in silico design, a full set of in silico methods can be applied, such as docking, molecular dynamics (MD), and statistical analysis. The typical modeling workflow starts with structure prediction. Then, docking of target and aptamer is performed. Next, MD simulations are performed, which allows for an evaluation of the stability of aptamer/ligand complexes and determination of the binding energies with higher accuracy. Then, aptamer/ligand interactions are analyzed, and mutations of studied aptamers made. Subsequently, the whole procedure of molecular modeling can be reiterated. Thus, the interactions between aptamers and their ligands are complex and difficult to understand using only experimental approaches. Docking and MD are irreplaceable when aptamers are studied in silico.
Topics: Anti-Bacterial Agents; Aptamers, Nucleotide; Computer Simulation; Directed Molecular Evolution; Drug Design; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Organophosphates; Proteins; SELEX Aptamer Technique
PubMed: 33182550
DOI: 10.3390/ijms21228420 -
Harmful Algae Feb 2020Anatoxin-a(S) is the most potent natural neurotoxin produced by fresh water cyanobacteria. It is also the least understood and monitored. Although this potent...
Anatoxin-a(S) is the most potent natural neurotoxin produced by fresh water cyanobacteria. It is also the least understood and monitored. Although this potent cholinesterase inhibitor was first reported in the 1970s and connected with animal poisonings, the lack of chemical standards and identified biosynthetic genes together with limited diagnostics and acute reactivity of this naturally-occurring organophosphate have limited our understanding of its environmental breadth and human health implications. Anatoxin-a(S) irreversibly inhibits acetylcholinesterase much like other organophosphate agents like paraoxon. It is however often confused with the similarly named anatoxin-a that has a completely different chemical structure, mechanism of action, and biosynthesis. Herein we propose renaming of anatoxin-a(S) to clarify its distinct structure and mechanism and to draw renewed attention to this potent natural poison. We propose the new name guanitoxin (GNT) to emphasize its distinctive guanidino organophosphate chemical structure.
Topics: Animals; Cholinesterase Inhibitors; Cyanobacteria; Fresh Water; Humans; Neurotoxins; Organophosphates
PubMed: 32113603
DOI: 10.1016/j.hal.2019.101737 -
Journal of the American Mosquito... Sep 2022Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos,...
Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos, malathion, and pirimiphos-methyl were performed with 3rd-stage larvae and adult females of Cx. quinquefasciatus from the municipalities of Soledad and Puerto Colombia, following the methods of the World Health Organization and Centers for Disease Control and Prevention, respectively. The median lethal concentration (LC50) and 90% lethal concentration (LC90) resistance ratios (RRLC50 and RRLC90) were determined for each insecticide in the field populations evaluated, using the Cartagena strain as the susceptible control. Relative to LC50 and LC90 of the Cartagena strain, the population from Puerto Colombia was moderately resistant to temephos (RRLC50 5.7-fold) and malathion (RRLC50 8.6-fold, RRLC90 9-fold) and susceptible to pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold). The population from Soledad was susceptible to temephos and pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold) and showed moderate resistance to malathion (RRLC50 7.5-fold). It is important to emphasize that routine monitoring of insecticide resistance in Cx. quinquefasciatus helps us detect resistance early and improve the effectiveness of control strategies.
Topics: Animals; Colombia; Culex; Female; Insecticide Resistance; Insecticides; Larva; Malathion; Organophosphates; Temefos
PubMed: 35839258
DOI: 10.2987/22-7058 -
Molecular Biology Reports Jun 2023Organophosphate pesticides (OPs) are widely used in agriculture, healthcare, and other industries due to their ability to kill pests. However, OPs can also have... (Review)
Review
Organophosphate pesticides (OPs) are widely used in agriculture, healthcare, and other industries due to their ability to kill pests. However, OPs can also have genotoxic effects on humans who are exposed to them. This review summarizes the research on DNA damage caused by OPs, the mechanisms behind this damage, and the resulting cellular effects. Even at low doses, OPs have been shown to damage DNA and cause cellular dysfunction. Common phenomena seen in cells that are exposed to OPs include the formation of DNA adducts and lesions, single-strand and double-strand DNA breaks, and DNA and protein inter and intra-cross-links. The present review will aid in comprehending the extent of genetic damage and the impact on DNA repair pathways caused by acute or chronic exposure to OPs. Additionally, understanding the mechanisms of the effects of OPs will aid in correlating them with various diseases, including cancer, Alzheimer's, and Parkinson's disease. Overall, knowledge of the potential adverse effects of different OPs will help in monitoring the health complications they may cause.
Topics: Humans; Pesticides; Organophosphates; Insecticides; Organophosphate Poisoning; DNA Repair; DNA Damage
PubMed: 37155010
DOI: 10.1007/s11033-023-08424-2