Molecular Recognition Properties of Nicotinic Ligands Determining Selectivity Between Insect and Mammalian Receptors.

This investigation defines the roles of various amino acids, neighboring key conserved amino acids in loops C and D of the nicotinic acetylcholine (ACh) receptor (nAChR), in the selective molecular recognition of nicotinic ligands with diverse pharmacophores using ACh binding protein Y55W (-AChBP) mutants (+Q57R; + Q57R+S189 V; + Q57R+S189E; + Q57T; + Q57T+S189 V; + Q57T+S189E) and AChBP (AChBP) mutants (Q55T; Q55T+S186E; Q55R) as insect and mammalian nAChR structural surrogates, respectively. -nitro/cyanoimine insecticides show high affinity to four -AChBPs containing Arg57 or Thr57 and Ser189 or Val189, except for those with Glu189. Pyrazinoyl compound selectively interacts with the three -AChBPs containing Arg57 and Ser189, Val189, or Glu189.

Fungicide Metabolite MS2 Spectral Libraries for Comprehensive Human Biomonitoring.

Fungicides undergo rapid metabolism and are excreted in the urine. There are few methods for screening these ubiquitous compounds, which have a high potential for human exposure. High-resolution mass spectrometry (HRMS) is a suitable technique to assess fungicide exposures; however, there is a lack of spectral libraries for fungicide annotation and in particular for downstream metabolites.

Potency and Target Surface Interaction of Diazinoyl Nicotinic Insecticides.

Structure-activity relationships of diazinoyl nicotinic insecticides (diazinoyl isomers and 5- or 6-substituted pyrazin-2-oyl analogues) are considered in terms of affinity to the insect nicotinic acetylcholine receptor (nAChR) and insecticidal activity against the imidacloprid-resistant brown planthopper. Among the test compounds, 3-(6-chloropyridin-3-ylmethyl)-2-(pyrazinoyl)iminothiazoline shows the highest potency in nAChR affinity and insecticidal activity. acetylcholine binding protein (AChBP) mutants (Y55W + Q57R and Y55W + Q57T) are utilized to compare molecular recognition of nicotinic insecticides with diverse pharmacophores.

Noxious chemical discrimination by TRPA1 channel in the HEK293 cell expression system.

Nociception is the sensory perception of noxious chemical stimuli. Repellent behavior to avoid noxious stimuli is indispensable for survival, and this mechanism has been evolutionarily conserved across a wide range of species, from mammals to insects. The transient receptor potential ankyrin 1 (TRPA1) channel is one of the most conserved noxious chemical sensors.

Organophosphate agent action at the fatty acid amide hydrolase enhancing anandamide-induced apoptosis in NG108-15 cells.

Organophosphate (OP) agents are continuously utilized in large amount throughout the globe for crop protection and public health, thereby creating a potential concern on human health. OP agent as an anticholinesterase also acts on the endocannabinoid (EC)-hydrolases, i.e.

TRPA1-mediated repellency behavior in the red flour beetle Tribolium castaneum.

The sensory perception of irritant chemicals results in escape and repellency behavioral patterns in insects. Transient receptor potential channels are cation channels that function as sensor proteins for several types of signals, such as light, sound, temperature, taste, as well as chemical and physical stimuli; among these, the TRPA channel is widely conserved and activated by irritant chemicals. Certain plant-derived essential oils (EOs), produced by secondary metabolism, are mixtures of volatile compounds, which are used as repellents because they contain environmentally sustainable ingredients.

Antennal transcriptome analysis of chemosensory genes in the cowpea beetle, Callosobruchus maculatus (F.).

Olfaction, one of the most important sensory systems governing insect behavior, is a possible target for pest management. Therefore, in this study, we analyzed the antennal transcriptome of the cowpea beetle, Callosobruchus maculatus (F.) (Coleoptera: Chrysomelidae: Bruchinae), which is a major pest of stored pulses and legumes.

Deciphering the Flupyrimin Binding Surface on the Insect Nicotinic Acetylcholine Receptor.

A novel insecticide flupyrimin (FLP) with a trifluoroacetyl pharmacophore acts as an antagonist at the insect nicotinic acetylcholine receptor (nAChR). This investigation examines a hypothesis that the FLP C(O)CF moiety is primarily recognized by the β subunit-face in the ligand-binding pocket (interface between α and β subunits) of the insect nAChR. Accordingly, we evaluate the atomic interaction between a fluorine atom of FLP and the partnering amino acid side chain on the β subunit employing a recombinant hybrid nAChR consisting of aphid Mpα2 and rat Rβ2 subunits (with a mutation at T77 on the Rβ2).

Development of a strategic approach for comprehensive detection of organophosphate pesticide metabolites in urine: Extrapolation of cadusafos and prothiofos metabolomics data of mice to humans.

Objectives: The comprehensive detection of environmental chemicals in biospecimens, an indispensable task in exposome research, is advancing. This study aimed to develop an exposomic approach to identify urinary metabolites of organophosphate (OP) pesticides, specifically cadusafos and prothiofos metabolites, as an example chemical group, using an original metabolome dataset generated from animal experiments.

Methods: Urine samples from 73 university students were analyzed using liquid chromatography-high-resolution mass spectrometry.

Contact repellency by l-menthol is mediated by TRPM channels in the red flour beetle Tribolium castaneum.

Background: Among insects, beetles are one of the most destructive pests of agricultural and stored products. Researchers have been investigating alternatives to pesticides for more sustainable pest management. Here, we focused on insect transient receptor potential (TRP) channel-targeted repellency.

Bitter compounds in two Tricholoma species, T. aestuans and T. virgatum.

Lascivol was identified as the bitter compound in two Tricholoma species, T. aestuans and T. virgatum, and was previously isolated from the European mushroom T.

Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats.

Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between the OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established. The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe, which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: that is, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Cohort profile: Aichi regional sub-cohort of the Japan Environment and Children's Study (JECS-A).

Purpose: Effects of fetal, perinatal and childhood environment on the health of children at birth and during later life have become a topic of concern. The Aichi regional sub-cohort of the Japan Environment and Children's Study (JECS-A) is an ongoing birth cohort of pregnant women and their children which has been used to provide unique data, as adjunct studies of JECS, on multifaceted potential factors affecting children's health.

Participants: The JECS-A is part of the JECS which follows a total of 100 000 pairs of children and their mothers (fathers' participation is optional) across 15 regions in Japan.

Adverse pregnancy and perinatal outcome in patients with recurrent pregnancy loss: Multiple imputation analyses with propensity score adjustment applied to a large-scale birth cohort of the Japan Environment and Children's Study.

Problem: Several studies have reported the increased risk of preterm birth, premature rupture of membranes, and low birth weight in patients with recurrent pregnancy loss (RPL). There have been a limited number of large population-based studies examining adverse pregnancy and perinatal outcome after RPL. Multiple-imputed analyses (MIA) adjusting for biases due to missing data is also lacking.

Epididymal phospholipidosis is a possible mechanism for spermatotoxicity induced by the organophosphorus insecticide fenitrothion in rats.

Fenitrothion (FNT) is used worldwide in agricultural and public health settings. Spermatogenesis is a toxicological target of FNT under high-dose exposure. Although anti-androgenic action is postulated to be the mechanism associated with this toxicity, few studies have examined histopathology of androgen-dependent male accessory sex organs.

Flupyrimin: A Novel Insecticide Acting at the Nicotinic Acetylcholine Receptors.

A novel chemotype insecticide flupyrimin (FLP) [N-[(E)-1-(6-chloro-3-pyridinylmethyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide], discovered by Meiji Seika Pharma, has unique biological properties, including outstanding potency to imidacloprid (IMI)-resistant rice pests together with superior safety toward pollinators. Intriguingly, FLP acts as a nicotinic antagonist in American cockroach neurons, and [H]FLP binds to the multiple high-affinity binding components in house fly nicotinic acetylcholine (ACh) receptor (nAChR) preparation. One of the [H]FLP receptors is identical to the IMI receptor, and the alternative is IMI-insensitive subtype.

Isolation of botulinolysin, a thiol-activated hemolysin, from serotype D Clostridium botulinum: A species-specific gene duplication in Clostridia.

Botulinolysin (BLY) is a toxin produced by Clostridium botulinum that belongs to a group of thiol-activated hemolysins. In this study, a protein exhibiting hemolytic activity was purified from the culture supernatant of C. botulinum serotype D strain 4947.

Construction of "Toxin Complex" in a Mutant Serotype C Strain of Clostridium botulinum Harboring a Defective Neurotoxin Gene.

A non-toxigenic mutant of the toxigenic serotype C Clostridium botulinum strain Stockholm (C-St), C-N71, does not produce the botulinum neurotoxin (BoNT). However, the original strain C-St produces botulinum toxin complex, in which BoNT is associated with non-toxic non-hemagglutinin (NTNHA) and three hemagglutinin proteins (HA-70, HA-33, and HA-17). Therefore, in this study, we aimed to elucidate the effects of bont gene knockout on the formation of the "toxin complex.

Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats.

Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro.

Organophosphate agents induce plasma hypertriglyceridemia in mouse via single or dual inhibition of the endocannabinoid hydrolyzing enzyme(s).

Diverse serine hydrolases including endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been suggested as secondary targets for organophosphate (OP) agents to exert adverse toxic effects such as lipid homeostasis disruption. The goal of this investigation is to verify that a major OP insecticide fenitrothion (FNT) induces plasma hypertriglyceridemia through the inhibition of FAAH and/or MAGL in comparison with that elicited by isopropyl dodecylfluorophosphonate (IDFP), a potent FAAH/MAGL inhibitor. Fasted mice were treated intraperitoneally with FNT or IDFP and were subsequently sacrificed for evaluations of plasma triglyceride (TG) levels and liver FAAH/MAGL activities.

A potential target for organophosphate insecticides leading to spermatotoxicity.

Organophosphate (OP) insecticides as an anticholinesterase also act on the diverse serine hydrolase targets, thereby revealing secondary or unexpected toxic effects including male reproductive toxicity. The present investigation detects a possible target molecule(s) for OP-induced spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) from a chemical standpoint. The activity-based protein profiling (ABPP) approach with a phosphonofluoridate fluorescent probe pinpointed the molecular target for fenitrothion (FNT, a major OP insecticide) oxon (bioactive metabolite of FNT) in the mouse testicular membrane proteome, i.

Anticholinesterase insecticide action at the murine male reproductive system.

The present report describes for the first time that anticholinesterase type insecticides specifically inhibit the fatty acid amide hydrolase and/or monoacylglycerol lipase, as secondary target(s), in the murine male reproductive system (testis and epididymis cauda), thereby presumably being involved with spermatotoxicity such as deformity, underdevelopment, and reduced motility.

N-haloacetylimino neonicotinoids: potency and molecular recognition at the insect nicotinic receptor.

This structure-activity relationship study for neonicotinoids with an N-haloacetylimino pharmacophore identifies several candidate compounds showing outstanding insecticidal potency and consequently leads to establishing their molecular recognition at an insect nicotinic receptor structural model, wherein the neonicotinoid halogen atoms (fluorine, chlorine, bromine, and iodine) variously interact with the receptor loops C-D interfacial niche via H-bonding and/or hydrophobic interactions.

Unique neonicotinoid binding conformations conferring selective receptor interactions.

Neonicotinoid agonists selectively act on the insect nicotinic acetylcholine receptor (nAChR). The molecular basis for this specificity is deciphered by comparisons of two acetylcholine binding proteins (AChBPs) with distinct pharmacological profiles that serve as structural homologues for the nAChR subtypes. Aplysia AChBP has high neonicotinoid sensitivity, whereas Lymnaea AChBP has low neonicotinoid sensitivity, pharmacologies reminiscent of insect and vertebrate nAChR subtypes, respectively.

Neonicotinoid insecticides: highlights of a symposium on strategic molecular designs.

Neonicotinoids are the newest of the five major classes of insecticides (the others are chlorinated hydrocarbons, organophosphorus compounds, methylcarbamates, and pyrethroids), and they make up approximately one-fourth of the world insecticide market. Nithiazine was the lead compound from Shell Development Co. in California later optimized by Shinzo Kagabu of Nihon Tokushu Noyaku Seizo to increase the potency and photostability, resulting in imidacloprid and thiacloprid.