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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 -
Toxics Oct 2021Animal poisoning is one of the greatest conservation threats facing wildlife. In a preliminary study in the oceanic archipelago of the Canary Islands, we showed that the...
Animal poisoning is one of the greatest conservation threats facing wildlife. In a preliminary study in the oceanic archipelago of the Canary Islands, we showed that the degree of threat from this circumstance was very high-even higher than that reported in other regions of continental Europe. Consequently, a legal framework for the effective prosecution of the crime of wildlife poisoning came into force in 2014 in this region. We present the results of the investigation of 961 animals and 84 baits sent to our laboratory for the diagnosis of animal poisonings during the period 2014-2021. We were able to identify poison as the cause of death in 251 animals and 61 baits. Carbofuran stands out as the main agent used in this archipelago. We have also detected an increasing tendency to use mixtures of several pesticides in the preparation of baits. The entry into operation of two canine patrols has led to the detection of more dead animals in the wild and a greater number of poisoned animals. The percentage of poison positives is significantly higher in areas with lower population density, corresponding to rural environments, as well as in areas with greater agricultural and livestock activity.
PubMed: 34678963
DOI: 10.3390/toxics9100267 -
Human Molecular Genetics Mar 2022Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement...
Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.
Topics: Acetylcholinesterase; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Caffeine; Drug Evaluation, Preclinical; Dyskinesias; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Proteins; Mutation; Neurotransmitter Agents
PubMed: 34622282
DOI: 10.1093/hmg/ddab296 -
IUBMB Life Jul 2022Riboflavin (Rf), or vitamin B2, is the precursor of FMN and FAD, redox cofactors of several dehydrogenases involved in energy metabolism, redox balance and other cell...
Riboflavin (Rf), or vitamin B2, is the precursor of FMN and FAD, redox cofactors of several dehydrogenases involved in energy metabolism, redox balance and other cell regulatory processes. FAD synthase, coded by FLAD1 gene in humans, is the last enzyme in the pathway converting Rf into FAD. Mutations in FLAD1 gene are responsible for neuromuscular disorders, in some cases treatable with Rf. In order to mimic these disorders, the Caenorhabditis elegans (C. elegans) gene orthologue of FLAD1 (flad-1) was silenced in a model strain hypersensitive to RNA interference in nervous system. Silencing flad-1 resulted in a significant decrease in total flavin content, paralleled by a decrease in the level of the FAD-dependent ETFDH protein and by a secondary transcriptional down-regulation of the Rf transporter 1 (rft-1) possibly responsible for the total flavin content decrease. Conversely an increased ETFDH mRNA content was found. These biochemical changes were accompanied by significant phenotypical changes, including impairments of fertility and locomotion due to altered cholinergic transmission, as indicated by the increased sensitivity to aldicarb. A proposal is made that neuronal acetylcholine production/release is affected by alteration of Rf homeostasis. Rf supplementation restored flavin content, increased rft-1 transcript levels and eliminated locomotion defects. In this aspect, C. elegans could provide a low-cost animal model to elucidate the molecular rationale for Rf therapy in human Rf responsive neuromuscular disorders and to screen other molecules with therapeutic potential.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disease Models, Animal; Flavin-Adenine Dinucleotide; Humans; Neuromuscular Diseases; Nucleotidyltransferases; Riboflavin; Vitamins
PubMed: 34558787
DOI: 10.1002/iub.2553 -
Ecotoxicology and Environmental Safety Aug 2021Carbaryl is the representative of carbamate insecticide. As an acetylcholinesterase inhibitor, it poses potential threat to humans and other non-target organisms....
Carbaryl is the representative of carbamate insecticide. As an acetylcholinesterase inhibitor, it poses potential threat to humans and other non-target organisms. Agrobacterium sp. XWY-2, which could grow with carbaryl as the sole carbon source, was isolated and characterized. The carH gene, encoding a carbaryl hydrolase, was cloned from strain XWY-2 and expressed in Escherichia coli BL21 (DE3). CarH was able to hydrolyze carbamate pesticides including carbaryl, carbofuran, isoprocarb, propoxur and fenobucarb efficiently, while it hydrolyzed oxamyl and aldicarb poorly. The optimal pH of CarH was 8.0 and the optimal temperature was 30 ℃. The apparent K and k values of CarH for carbaryl were 38.01 ± 2.81 μM and 0.33 ± 0.01 s, respectively. The point mutation experiment demonstrated that His341, His343, His346, His416 and D437 are the key sites for CarH to hydrolyze carbaryl.
PubMed: 34416635
DOI: 10.1016/j.ecoenv.2021.112666 -
Ecotoxicology and Environmental Safety Aug 2021Studies investigating the association between pesticide exposure and colorectal cancer (CRC) risk have been inconclusive.
BACKGROUND
Studies investigating the association between pesticide exposure and colorectal cancer (CRC) risk have been inconclusive.
OBJECTIVES
Investigate the association between pesticide exposure and CRC risk through a systematic literature review.
METHODS
CRC has the fourth-highest rate of cancer-caused death in the US after lung cancer, breast cancer in women, and prostate cancer in men. Here we have conducted a systematic literature search on studies examining the association between any pesticide exposure and CRC risk using PubMed, MEDLINE via EBSCO host, and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.
RESULTS
Following the review, 139 articles were included for qualitative evaluation. Study participants were farmers, pesticide applicators, pesticide manufacturers, spouses of pesticide applicators, farm residents, Korean veterans of the Vietnam War, rural communities, and those who consumed food with pesticide residues. The studies' results were split between those with significant positive (39 significant results) and inverse (41 significant results) associations when comparing pesticide exposure and CRC risk.
DISCUSSION
From our literature review, we have identified a similar number of significant positive and inverse associations of pesticide exposure with CRC risk and therefore cannot conclude whether pesticide exposure has a positive or inverse association with CRC risk overall. However, certain pesticides such as terbufos, dicamba, trifluralin, S-ethyl dipropylthiocarbamate (EPTC), imazethapyr, chlorpyrifos, carbaryl, pendimethalin, and acetochlor are of great concern not only for their associated elevated risk of CRC, but also for the current legal usage in the United States (US). Aldicarb and dieldrin are of moderate concern for the positive associations with CRC risk, and also for the illegal usage or the detection on imported food products even though they have been banned in the US. Pesticides can linger in the soil, water, and air for weeks to years and, therefore, can lead to exposure to farmers, manufacturing workers, and those living in rural communities near these farms and factories. Approximately 60 million people in the US live in rural areas and all of the CRC mortality hotspots are within the rural communities. The CRC mortality rate is still increasing in the rural regions despite the overall decreasing of incidence and mortality of CRC elsewhere. Therefore, the results from this study on the relationship between pesticide exposure and CRC risk will help us to understand CRC health disparities.
Topics: Adult; Colorectal Neoplasms; Farmers; Female; Herbicides; Humans; Incidence; Male; Middle Aged; Occupational Exposure; Pesticide Residues; Pesticides
PubMed: 34029839
DOI: 10.1016/j.ecoenv.2021.112327 -
Genetics Aug 2021The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels....
The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole Caenorhabditis elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 colocalizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68 RyR calcium channel, and is required for animal movement. In neurons, JPH-1 colocalizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in the soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell nonautonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and with unc-68 for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68 is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Membrane Proteins; Neuromuscular Junction; Neuronal Outgrowth; Neurons; Protein Transport; Ryanodine Receptor Calcium Release Channel; Synaptic Transmission; Synaptotagmins
PubMed: 33871019
DOI: 10.1093/genetics/iyab063 -
Journal of Nematology 2020The last decade has seen a sharp increase in nematicide research in the agricultural industry. As a result, several new synthetic nematicides have become available to...
The last decade has seen a sharp increase in nematicide research in the agricultural industry. As a result, several new synthetic nematicides have become available to growers, and several more are expected in the near future. This new interest in nematicides is directly related to the growing demand for safer and more selective products, and the increasing regulatory pressure on many of the traditional nematicides. This has led to a ban of several widely used fumigant (e.g. methyl bromide) and non-fumigant (e.g. aldicarb) nematicides. The loss of traditional nematicides, combined with a lack of replacement products and awareness of the damage that nematodes can cause, has not only raised concern among growers, but has also created new opportunities for the crop protection industry. Nematicides have become a priority, and many companies are now allocating significant research dollars to discover new nematicides. The new nematicides are very different from previous products: (i) they are more selective, often only targeting nematodes, and (ii) they are less toxic, and safer to use. This review article describes these new developments by discussing the challenges that are associated with finding new nematicides, reviewing the nature, characteristics, and efficacy of new nematicides, and discussing the impact they could have on future nematode management.
PubMed: 33829179
DOI: 10.21307/jofnem-2020-091 -
Nutrients Jan 2021Recent human cohort studies reported positive associations between organic food consumption and a lower incidence of obesity, cancer, and several other diseases....
Feed Composition Differences Resulting from Organic and Conventional Farming Practices Affect Physiological Parameters in Wistar Rats-Results from a Factorial, Two-Generation Dietary Intervention Trial.
Recent human cohort studies reported positive associations between organic food consumption and a lower incidence of obesity, cancer, and several other diseases. However, there are very few animal and human dietary intervention studies that provide supporting evidence or a mechanistic understanding of these associations. Here we report results from a two-generation, dietary intervention study with male Wistar rats to identify the effects of feeds made from organic and conventional crops on growth, hormonal, and immune system parameters that are known to affect the risk of a number of chronic, non-communicable diseases in animals and humans. A 2 × 2 factorial design was used to separate the effects of contrasting crop protection methods (use or non-use of synthetic chemical pesticides) and fertilizers (mineral nitrogen, phosphorus and potassium (NPK) fertilizers vs. manure use) applied in conventional and organic crop production. Conventional, pesticide-based crop protection resulted in significantly lower fiber, polyphenol, flavonoid, and lutein, but higher lipid, aldicarb, and diquat concentrations in animal feeds. Conventional, mineral NPK-based fertilization resulted in significantly lower polyphenol, but higher cadmium and protein concentrations in feeds. Feed composition differences resulting from the use of pesticides and/or mineral NPK-fertilizer had a significant effect on feed intake, weight gain, plasma hormone, and immunoglobulin concentrations, and lymphocyte proliferation in both generations of rats and in the second generation also on the body weight at weaning. Results suggest that relatively small changes in dietary intakes of (a) protein, lipids, and fiber, (b) toxic and/or endocrine-disrupting pesticides and metals, and (c) polyphenols and other antioxidants (resulting from pesticide and/or mineral NPK-fertilizer use) had complex and often interactive effects on endocrine, immune systems and growth parameters in rats. However, the physiological responses to contrasting feed composition/intake profiles differed substantially between the first and second generations of rats. This may indicate epigenetic programming and/or the generation of "adaptive" phenotypes and should be investigated further.
Topics: Agriculture; Animal Feed; Animals; Cadmium; Crop Production; Crops, Agricultural; Diet; Eating; Farms; Female; Fertilizers; Food, Organic; Humans; Male; Manure; Nitrogen; Pesticides; Phenotype; Phosphorus; Potassium; Rats, Wistar; United Kingdom; Rats
PubMed: 33530419
DOI: 10.3390/nu13020377 -
Frontiers in Veterinary Science 2020Nowadays the intentional poisoning of domestic and wild animals is a crime in the European Union (EU), but as in the past the poison is still used in rural areas of a...
Nowadays the intentional poisoning of domestic and wild animals is a crime in the European Union (EU), but as in the past the poison is still used in rural areas of a number of European countries to kill animals that were considered harmful for human activities. From January 2014 up until October 2020, the Laboratory of Pharmacology and Toxicology of the Faculty of Veterinary Medicine (LFT-FMV) has done the analytical detection of poisoning substances in 503 samples of wildlife and domestic animals and pesticides residues were found in 239 of the samples analyzed. In this retrospective study, toxicology results from domestic species (dog, cat, sheep, cows, and horses), wildlife species (red foxes, birds of prey, lynx, and wild boar), and food baits, are presented. During this period the samples analyzed at the LFT-FMV, were received from all over the country. Analytical detections were performed via solvent extraction followed by thin layer chromatography. Molluscicides (47%, = 109) and Carbamates (24%, = 57) were found to be the first category of pesticides involved in intoxications, in both domestic and wild animals, followed by rodenticides (13%, = 30)-in this group second and third generation, were the most represented; Strychnine is the third (11%, = 26) even though this pesticide has been banned in Portugal since 1988 and in the European Union since 2006 and finally Organophosphates (5%, = 11) in the small number. This study allowed to realize that a great number of positive samples involved banned pesticides (i.e., Aldicarb and Strychnine) but, at the same time, many positives cases were due to the exposure to commercially available products (i.e., Methiocarb and Anticoagulant rodenticides). Also, it's possible to identify the areas where domestic species are the most affected (i.e., Setubal and Lisboa) and the areas where the wild animals are the mainly affected species (i.e., Faro, Castelo Branco, and Bragança).
PubMed: 33521089
DOI: 10.3389/fvets.2020.616293