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Annals of Neurosciences Jan 2021Alzheimer's disease (AD), a prevalent neurodegenerative disease with progressive dementia and neurotransmission (NT)-dysfunction-related complications in older adults,...
BACKGROUND
Alzheimer's disease (AD), a prevalent neurodegenerative disease with progressive dementia and neurotransmission (NT)-dysfunction-related complications in older adults, is known to be caused by abnormal Amyloid-β (Aβ) peptide and associated amyloid plaques in the brain. Drugs to cure AD are not in sight. Two major excitatory neurotransmitters, glutamate (Glu) and acetylcholine (ACh), and their signaling systems are implicated in AD.
OBJECTIVE
To determine the effect of various NT-altering compounds including fenobam, quisqualic acid, and dimethyl sulfoxide (DMSO) in the protection against Aβ toxicity. Further, to identify the potential mechanism through which the protection happens.
METHODS
The well-known AD model, CL4176, in which human Aβ expression is turned on upon a temperature shift to 25 °C that leads to paralysis, was screened for protection/delay in paralysis because of Αβ toxicity. While screening the compounds, dimethyl sulfoxide (DMSO), a universal solvent used to solubilize compounds, was identified to provide protection. Aldicarb and levamisole assays were performed to identify the contribution of ACh neurotransmission in Αβ toxicity protection by DMSO.
RESULTS
One percent and two percent DMSO delayed paralysis by 48% and 90%, respectively. DMSO was dominant over one of the Glu-NT pathway-related compounds, Fenobam-Group I mGluR antagonist. But DMSO provided only 30% to 50% protection against Quisqualic acid, the Glu-agonist. DMSO (2%) delayed ACh-NT, both presynaptic acetylcholine esterase inhibitor (AchEi)-aldicarb and postsynaptic-iAChR-agonst-levamisole induced paralysis, by ∼70% in CL4176. DMSO seems to be altering Ca ion permeability essential for NT as EthyleneDiamine Tetra-Acetic acid (EDTA) and DMSO provided similar aldicarb resistance either combined or alone in wildtype worms. But postsynaptic Ca depletion by EDTA could reverse DMSO-induced levamisole hypersensitivity. Surprisingly, the absence of FOrkhead boXO (FOXO) transcription factor homolog, (loss-of-function mutant), a critical transcription factor in the reduced IIS-mediated longevity in abolished DMSO-mediated Ald.
CONCLUSION
DMSO and Fenobam protect against Aβ toxicity through modulation of NT.
PubMed: 34733055
DOI: 10.1177/09727531211046369 -
Toxicological Sciences : An Official... Dec 2019Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health...
Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. Although the literature suggests that PFOS may induce neurotoxicity, neurotoxic mechanisms, and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 h and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, gamma-amino butyric acid (GABA)ergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, approximately 50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, approximately 200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, approximately 2 µM). Perfluorooctane sulfonate exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation, and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.
Topics: Alkanesulfonic Acids; Animals; Antioxidants; Caenorhabditis elegans; Cell Line; Dopamine; Environmental Pollutants; Fluorocarbons; Humans; Neurons; Neurotoxicity Syndromes; Oxidative Stress; Reactive Oxygen Species
PubMed: 31428778
DOI: 10.1093/toxsci/kfz191 -
Journal of Nematology Mar 1998Chemical and microbial degradation of the nematicides-insecticides aldicarb and ethoprop has been studied extensively in both laboratory and field studies. These studies...
Chemical and microbial degradation of the nematicides-insecticides aldicarb and ethoprop has been studied extensively in both laboratory and field studies. These studies show that temperature is the most important variable affecting the degradation rate of aldicarb and its carbamate metabolites in surface soils. Temperature and organic matter appear to be the most important variables affecting degradation rates of ethoprop in soils under normal agricultural conditions, with organic matter being inversely related to degradation, presumably due to increased binding to soil particles. Soil moisture may be important under some conditions for both compounds, with degradation reduced in low-moisture soils. The rate of degradation of aldicarb residues (aldicarb + aldicarb sulfoxide + aldicarb sulfone) does not seem to be significantly affected by depth from soil surface, except that aldicarb residues degrade more slowly in acidic, coarse sand subsoils. Degradation of ethoprop also continues in subsurface soils, although field data are limited due to its lower mobility. Both compounds degrade in groundwater. Because microbial activity decreases with depth below soil surface, chemical processes are important components of the degradation of both aldicarb residues and ethoprop. For aldicarb, transformation to carbamate oxides in surface soils is primarily microbial, while degradation to noncarbamate compounds appears to be primarily the result of soil-catalyzed hydrolysis throughout the soil profile. For ethoprop, both chemical and microbial catalyzed hydrolysis are important in surface soils, with chemical hydrolysis becoming more important with increasing depth.
PubMed: 19274198
DOI: No ID Found -
Journal of Nematology Oct 1990Yields of U.S. Size A potato tubers were increased by 1,3-dichloropropene (1,3-D) (56 liters/ha) and 1,3-D (56 liters/ha) + aldicarb (3.4 kg/ha) in 1982 and 1983 and by...
Yields of U.S. Size A potato tubers were increased by 1,3-dichloropropene (1,3-D) (56 liters/ha) and 1,3-D (56 liters/ha) + aldicarb (3.4 kg/ha) in 1982 and 1983 and by aldicarb (3.4 kg/ha) in 1982. Treatments that included aldicarb provided the best control of corky ringspot disease, whereas those including 1,3-D were more effective against bacterial wilt. The most effective nematode control (nematodes included Meloidogyne incognita, Belonolaimus longicaudatus, trichodorids, Criconemella ornata, Tylenchorhynchus claytoni, and Helicotylenchus sp.) was provided by the combination of 1,3-D + aldicarb.
PubMed: 19287795
DOI: No ID Found -
PLoS Genetics Jan 2012Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs)...
Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs) respectively. Relatively little is known about factors that differentially regulate SV and DCV secretion. Here we identify a novel protein RIC-7 that is required for neuropeptide secretion in Caenorhabditis elegans. The RIC-7 protein is expressed in all neurons and is localized to presynaptic terminals. Imaging, electrophysiology, and behavioral analysis of ric-7 mutants indicates that acetylcholine release occurs normally, while neuropeptide release is significantly decreased. These results suggest that RIC-7 promotes DCV-mediated secretion.
Topics: Acetylcholine; Aldicarb; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Diacylglycerol Kinase; Drug Hypersensitivity; Exocytosis; Muscle, Skeletal; Mutation; Nerve Tissue Proteins; Neurons; Neuropeptides; Presynaptic Terminals; Secretory Vesicles; Synaptic Vesicles; gamma-Aminobutyric Acid
PubMed: 22275875
DOI: 10.1371/journal.pgen.1002464 -
Frontiers in Molecular Neuroscience 2023mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders...
mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient's cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the gene, (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of locomotion indicates that mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype-phenotype correlations of -related disorders.
PubMed: 37324589
DOI: 10.3389/fnmol.2023.1170061 -
Journal of Nematology Feb 2023Reniform nematode () is a major pest of sweetpotato in many production regions in Southern United States. Applying soil fumigants and non-fumigant nematicides are the...
Reniform nematode () is a major pest of sweetpotato in many production regions in Southern United States. Applying soil fumigants and non-fumigant nematicides are the primary management strategies available to growers. This study compared the relative efficacy of nematicides (1,3-dichloropropene, fluopyram, oxamyl, fluazaindolizine, aldicarb, Majestene, and fluensulfone) for management of reniform nematode on sweetpotato. Fumigating soil with 1,3-dichloropropene consistently reduced soil population densities of reniform nematode at the time of planting in both trial years (31 - 36% reduction relative to the untreated control); however, the duration of suppression varied greatly by growing season. A similar trend was observed with fluopyram (56 - 67% reduction) and aldicarb (63 - 65% reduction), which provided season-long suppression of reniform nematode population development in 2021 but had no impact in 2022. In 2021, nematicide application had no impact on yield; however, in 2022, oxamyl and aldicarb increased the yield of U.S.#1 grade sweetpotato. Overall, soil fumigation with 1,3-dichloropropene and in-furrow application of fluopyram and aldicarb provided the most consistent suppression of reniform nematode on sweetpotato.
PubMed: 38283661
DOI: 10.2478/jofnem-2023-0061 -
Brain Sciences Apr 2023Organophosphate (OP) and carbamate pesticides are toxic to pests through targeted inhibition of acetylcholinesterase (AChE). However, OPs and carbamates may be harmful...
Differentiated Neurons Are More Vulnerable to Organophosphate and Carbamate Neurotoxicity than Undifferentiated Neurons Due to the Induction of Redox Stress and Accumulate Oxidatively-Damaged Proteins.
Organophosphate (OP) and carbamate pesticides are toxic to pests through targeted inhibition of acetylcholinesterase (AChE). However, OPs and carbamates may be harmful to non-target species including humans and could induce developmental neurotoxicity if differentiated or differentiating neurons are particularly vulnerable to neurotoxicant exposures. Hence, this study compared the neurotoxicity of OPs, chlorpyrifos-oxon (CPO), and azamethiphos (AZO) and the carbamate pesticide, aldicarb, to undifferentiated versus differentiated SH-SY5Y neuroblastoma cells. OP and carbamate concentration-response curves for cell viability were undertaken using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays and cellular bioenergetic capacity assessed via quantitation of cellular ATP levels. Concentration-response curves for inhibition of cellular AChE activity were also generated and the production of reactive oxygen species (ROS) was monitored using a 2',7'-dichlorofluorescein diacetate (DCFDA) assay. The OPs and aldicarb reduced cell viability, cellular ATP levels, and neurite outgrowth in a concentration-dependent fashion, from a threshold concentration of ≥10 µM. Neurotoxic potency was in the order AZO > CPO > aldicarb for undifferentiated cells but CPO > AZO > aldicarb for differentiated cells and this toxic potency of CPO reflected its more extensive induction of reactive oxygen species (ROS) and generation of carbonylated proteins that were characterized by western blotting. Hence, the relative neurotoxicity of the OPs and aldicarb in part reflects non-cholinergic mechanisms that are likely to contribute to developmental neurotoxicity.
PubMed: 37239200
DOI: 10.3390/brainsci13050728 -
Journal of Nematology Jul 1975Aqueous solutions of 5-500 mug/ml aldicarb inhibited hatching of Heterodera schachtii. Addition of hatching agents, zinc chloride, or sugarbeet root diffusate, to the...
Aqueous solutions of 5-500 mug/ml aldicarb inhibited hatching of Heterodera schachtii. Addition of hatching agents, zinc chloride, or sugarbeet root diffusate, to the aldicarb solutions did not decrease the inhibition of hatching. When cysts were removed from the aldicarb solufions and then treated for 4 wk in sugarbeet root diffusate, larvae hatched and emerged. Treatments of newly hatched larvae of H. schachtii with 5-100 mug/ml aldicarb depressed later development of larvae on sugarbeet (Beta vulgaris). Similar treatments with aldicarb sulfoxide had less effect on larval development, and aldicarb sulfone had no effect. Numbers of treated larvae that survived and developed were inversely proportional to concentration (0.1-5.0 mug/ml) and duration (0-14 days) of aldicarb treatments. Development of H. schachtii on sugarbeet grown in aldicarb-treated soil was inversely proportional to the concentration of aldicarb in the tested range of 0.75 - 3.0 mug aldicarb/g of soil. Transfer of nematode-infected plants to soil with aldicarb retarded nematode development, whereas transfer of plants first grownin treated soil to nematode-infested soil only slightly suppressed nematode development. Development of H. schachtii was inhibited in slices of storage roots of table beet (B. vulgaris), sugarbeet and turnip, (Brassica rapa), that had grown in soil treated with aldicarb.
PubMed: 19308173
DOI: No ID Found -
Journal of Nematology Jan 1981Residue dynamics in giapevine of the nematicide aldicarb (2-methyl-(metbylthio) propionaldehyde-O-(Methylcarbamoyl) oxime) and its biologically similar active...
Residue dynamics in giapevine of the nematicide aldicarb (2-methyl-(metbylthio) propionaldehyde-O-(Methylcarbamoyl) oxime) and its biologically similar active metabolites, aldicarb sulfoxide and aldicarb sulfone, were determined by gas chromatographic techniques. Residues were found in the roots, trunks, stems, and leaves of grapevine 120 d after application. Residues in leaves as high as 1.40 and 8.89 ppm resulted from 4.5 and 9 kg ai/ha respectively. In roots, trunks, and stems the residues had also declined after 180 d. No residues were detected in the newly forming immature fruit. Residues in roots, trunks, young branches, and leaves declined further after 270 d, but residues in mature fruit at harvest time were 0.03 and 0.05 ppm from application of 4.5 and 9 kg ai/ha, respectively. In other trials the amount of aldicarb toxic residues found in mature fruit at harvest time varied with grape varieties, time and rate of application, total amount of rainfall, irrigation water, and soil type.
PubMed: 19300718
DOI: No ID Found