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Toxics Aug 2023Organophosphate pesticides (OPs) are toxic substances that contaminate aquatic environments, interfere with the development of the nervous system, and induce...
Organophosphate pesticides (OPs) are toxic substances that contaminate aquatic environments, interfere with the development of the nervous system, and induce Neurodevelopmental Toxicity (NDT) in animals and humans. The canonical mechanism of OP neurotoxicity involves the inhibition of acetylcholinesterase (AChE), but other mechanisms non-AChE are also involved and not fully understood. We used network toxicology and molecular docking to identify molecular targets and toxicity mechanisms common to OPs. Targets related to diazinon-oxon, chlorpyrifos oxon, and paraoxon OPs were predicted using the Swiss Target Prediction and PharmMapper databases. Targets related to NDT were compiled from GeneCards and OMIM databases. In order to construct the protein-protein interaction (PPI) network, the common targets between OPs and NDT were imported into the STRING. Network topological analyses identified EGFR, MET, HSP90AA1, and SRC as hub nodes common to the three OPs. Using the Reactome pathway and gene ontology, we found that signal transduction, axon guidance, cellular responses to stress, and glutamatergic signaling activation play key roles in OP-induced NDT.
PubMed: 37624215
DOI: 10.3390/toxics11080710 -
Indian Journal of Pharmacology 2023Human paraoxonase 1 (PON1) enzyme protects against atherosclerosis by preventing low-density lipoprotein from oxidative modification. Upregulation of PON1 enzymatic...
Human paraoxonase 1 (PON1) enzyme protects against atherosclerosis by preventing low-density lipoprotein from oxidative modification. Upregulation of PON1 enzymatic activity is suggested to contribute to atheroprotective potential of statins. Glutamine (Q) to arginine (R) at site 192 and leucine (L) to methionine (M) substitution at site 55 polymorphisms influence the PON1 activity. The study assessed the role of PON1 polymorphisms on lipid-lowering and PON1-modulating activity of statins in a Western Indian cohort of patients with dyslipidemia. Lipid profile and PON1 activity were determined at baseline and 3 months after initiation of statin treatment. PON1 genotypes (QQ, QR, RR; LL, LM, and MM) were determined by PCR-RFLP. Paraoxon was used as a substrate for assessing PON1 activity by spectrophotometry. A total of 140 statin-naïve patients were enrolled; of them, 116 were available for final analysis. Fifty-seven (50%) had QQ, 39 (35%) had QR, and 17 (15%) had RR genotypes. Seventy-six (67%) patients had LL, 35 (31%) had LM, and 2 (2%) had MM genotypes. We observed no impact of PON1 polymorphisms on lipid parameters posttreatment. A significant increase was observed in the serum PON1 activity from a median (range) of 47.92 U/L (9.03-181.25) to 72.22 U/L (7.64-244.44) (P < 0.05) following statin treatment, which was independent from high-density lipoprotein (HDL) concentration. This increase was significantly greater in QQ compared to QR and RR genotypes (P = 0.01). To conclude, the important antioxidant properties of statins are exerted via the rise in serum PON1 activity, independent of HDL cholesterol concentrations. The increase was greater in individuals with QQ genotype. Future large-scale studies will validate the premise that QQ homozygotes see added benefits from statin treatment compared to R carriers. In the meantime, PON1 enzymatic activity remains an important marker to be measured while assessing pleotropic effects of statins in CAD.
Topics: Humans; Aryldialkylphosphatase; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antioxidants; Prospective Studies; Genotype; Lipoproteins, HDL; Phenotype
PubMed: 37555413
DOI: 10.4103/ijp.IJP_215_20 -
The Journal of Rheumatology Jul 2023This posthoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and...
Relationship Between Paraoxonase-1 Genotype and Activity, and Major Adverse Cardiovascular Events and Malignancies in Patients With Rheumatoid Arthritis Receiving Tofacitinib.
OBJECTIVE
This posthoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and malignancies in clinical studies of tofacitinib in patients with rheumatoid arthritis (RA).
METHODS
Data were pooled from 9 phase II/III studies and the associated long-term extension studies (all completed by October 2017). PON1 activities in plasma were measured using paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity), and phenylacetate (arylesterase activity) as substrates. PON1 Q192R genotype effect on baseline PON1 activity was assessed using linear regression for each study, with fixed-effects metaanalysis across studies. MACE and malignancy risk by time-varying enzyme activity was determined using Cox proportional hazards regression.
RESULTS
The analysis included 1969 patients with RA. Compared with the QQ genotype, the RR genotype had a significant positive association with baseline paraoxonase activity and a significant negative association with baseline lactonase and arylesterase activity (all < 0.001). Time-varying models demonstrated a significant association of increased paraoxonase activity over time with lower risk of MACE ( < 0.001) and malignancies (excluding nonmelanoma skin cancer [NMSC]; ≤ 0.05), even after controlling for risk factors identified in univariate analysis and RA disease activity. A similar trend was observed for lactonase and arylesterase for MACE.
CONCLUSION
Higher paraoxonase activity over time was associated with significantly reduced risk of future MACE and malignancies (excluding NMSC), but not NMSC, in patients with RA receiving tofacitinib. Further investigation of PON1 as a novel functional lipid biomarker of MACE/malignancy risk in patients with RA is warranted. (ClinicalTrials.gov: NCT01059864, NCT00550446, NCT00687193, NCT00960440, NCT00814307, NCT00856544, NCT00853385, NCT00847613, NCT01039688, NCT00413699, NCT00661661).
PubMed: 37453736
DOI: 10.3899/jrheum.2023-0112 -
ACS Applied Materials & Interfaces Jul 2023The development of bio-MOFs or MOF biocomposites through the combination of MOFs with biopolymers offers the possibility of expanding the potential applications of MOFs,...
The development of bio-MOFs or MOF biocomposites through the combination of MOFs with biopolymers offers the possibility of expanding the potential applications of MOFs, making use of more environmentally benign processes and reagents and giving rise to a new generation of greener and more bio-oriented composite materials. Now, with the increasing use of MOFs for biotechnological applications, the development of new protocols and materials to obtain novel bio-MOFs compatible with biomedical or biotechnological uses is needed. Herein, and as a proof of concept, we have explored the possibility of using short-peptide supramolecular hydrogels as media to promote the growth of MOF particles, giving rise to a new family of bio-MOFs. Short-peptide supramolecular hydrogels are very versatile materials that have shown excellent in vitro and in vivo biomedical applications such as tissue engineering and drug delivery vehicles, among others. These peptides self-assemble by noncovalent interactions, and, as such, these hydrogels are easily reversible, being more biocompatible and biodegradable. These peptides can self-assemble by a multitude of stimuli, such as changes in pH, temperature, solvent, adding salts, enzymatic activity, and so forth. In this work, we have taken advantage of this ability to promote peptide self-assembly with some of the components required to form MOF particles, giving rise to more homogeneous and well-integrated composite materials. Hydrogel formation has been triggered using Zn salts, required to form ZIF-8, and formic acid, required to form MOF-808. Two different protocols for the in situ MOF growth have been developed. Finally, the MOF-808 composite hydrogel has been tested for the decontamination of water polluted with phosphate ions as well as for the catalytic degradation of toxic organophosphate methyl paraoxon in an unbuffered solution.
Topics: Metal-Organic Frameworks; Hydrogels; Salts; Peptides; Drug Delivery Systems
PubMed: 37390355
DOI: 10.1021/acsami.3c06943 -
International Journal of Molecular... Jun 2023Herein, a novel completely green biosensor was designed exploiting both the biological and instrumental components made of eco-friendly materials for the detection of...
Herein, a novel completely green biosensor was designed exploiting both the biological and instrumental components made of eco-friendly materials for the detection of herbicides encapsulated into biodegradable nanoparticles for a sustainable agriculture. Similar nanocarriers, indeed, can deliver herbicides to the correct location, reducing the amount of active chemicals deposited in the plant, impacting the agricultural and food industries less. However, handling measurements of nanoherbicides is crucial to provide comprehensive information about their status in the agricultural fields to support farmers in decision-making. In detail, whole cells of the unicellular green photosynthetic alga UV180 mutant were immobilized by a green protocol on carbonized lignin screen-printed electrodes and integrated into a photo-electrochemical transductor for the detection of nanoformulated atrazine. Specifically, atrazine encapsulated into zein and chitosan doped poly-ε-caprolactone nanoparticles (atrazine-zein and atrazine-PCL-Ch) were analyzed following the current signals at a fixed applied potential of 0.8 V, in a range between 0.1 and 5 µM, indicating a linear relationship in the measured dose-response curves and a detection limit of 0.9 and 1.1 nM, respectively. Interference studies resulted in no interference from 10 ppb bisphenol A, 1 ppb paraoxon, 100 ppb arsenic, 20 ppb copper, 5 ppb cadmium, and 10 ppb lead at safety limits. Finally, no matrix effect was observed on the biosensor response from wastewater samples and satisfactory recovery values of 106 ± 8% and 93 ± 7% were obtained for atrazine-zein and atrazine-PCL-Ch, respectively. A working stability of 10 h was achieved.
Topics: Atrazine; Lignin; Microalgae; Zein; Herbicides; Biosensing Techniques; Electrodes
PubMed: 37373233
DOI: 10.3390/ijms241210088 -
Scientific Reports Jun 2023Agrichemicals such as organophosphorus pesticides' metabolites (OPPMs) are more hazardous and pervasive than their parent pesticides. Parental germline exposure to such...
Agrichemicals such as organophosphorus pesticides' metabolites (OPPMs) are more hazardous and pervasive than their parent pesticides. Parental germline exposure to such xenobiotics leads to an elevated susceptibility towards reproductive failures e.g. sub- or in-fertility. This study sought to examine the effects of low-dose, acute OPPM exposure on mammalian sperm function using buffalo as the model organism. The buffalo spermatozoa were briefly (2 h) exposed to metabolites of the three most prevalent organophosphorus pesticides (OPPs) viz. Omethoate (from Dimethoate), paraoxon-methyl (from methyl/ethyl parathion) and 3, 5, 6-trichloro-2-pyridinol (from chlorpyrifos). Exposure to OPPMs resulted in compromised structural and functional integrity (dose-dependent) of the buffalo spermatozoa typified by elevated membrane damage, increased lipid peroxidation, precocious capacitation and tyrosine phosphorylation, perturbed mitochondrial activity and function and (P < 0.05). This led to a decline in the in vitro fertilizing ability (P < 0.01) of the exposed spermatozoa, as indicated by reduced cleavage and blastocyst formation rates. Preliminary data indicate that acute exposure to OPPMs, akin to their parent pesticides, induces biomolecular and physiological changes in spermatozoa that compromise their health and function ultimately affecting their fertility. This is the first study demonstrating the in vitro spermatotoxic effects of multiple OPPMs on male gamete functional integrity.
Topics: Animals; Male; Buffaloes; Fertility; Methyl Parathion; Organophosphorus Compounds; Pesticides; Semen; Sperm Motility; Spermatozoa
PubMed: 37277402
DOI: 10.1038/s41598-023-35541-6 -
Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury.Biomedicines May 2023Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and...
Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse closed-head TBI model induced by a weight drop device, along with OP exposure to paraoxon. Spatial and visual memory as well as neuron loss and reactive astrocytosis were measured 30 days after exposure to mild TBI (mTBI) and/or paraoxon. Molecular and cellular changes were assessed in the temporal cortex and hippocampus. Cognitive and behavioral deficits were most pronounced in animals that received a combination of paraoxon exposure and mTBI, suggesting an additive effect of the insults. Neuron survival was reduced in proximity to the injury site after exposure to paraoxon with or without mTBI, whereas in the dentate gyrus hilus, cell survival was only reduced in mice exposed to paraoxon prior to sustaining a mTBI. Neuroinflammation was increased in the dentate gyrus in all groups exposed to mTBI and/or to paraoxon. Astrocyte morphology was significantly changed in mice exposed to paraoxon prior to sustaining an mTBI. These results provide further support for assumptions concerning the effects of OP exposure following the Gulf War. This study reveals additional insights into the potentially additive effects of OP exposure and mTBI, which may result in more severe brain damage on the modern battlefield.
PubMed: 37239152
DOI: 10.3390/biomedicines11051481 -
International Journal of Molecular... Apr 2023A cDNA encoding a novel cholinesterase (ChE, EC 3.1.1.8) from the larvae of (Linnaeus) was identified, sequenced, and expressed in insect cell culture using the...
A cDNA encoding a novel cholinesterase (ChE, EC 3.1.1.8) from the larvae of (Linnaeus) was identified, sequenced, and expressed in insect cell culture using the baculoviral expression vector pBlueBac4.5/V5-His. The open reading frame (1746 nucleotides) of the cDNA encoded 581 amino acids beginning with the initiation codon. Identical cDNA sequences were amplified from the total RNA of adult tick synganglion and salivary gland, strongly suggesting expression in both tick synganglion and saliva. The recombinant enzyme (rAaChE1) was highly sensitive to eserine and BW284c51, relatively insensitive to tetraisopropyl pyrophosphoramide (iso-OMPA) and ethopropazine, and hydrolyzed butyrylthiocholine (BuTCh) 5.7 times as fast as acetylthiocholine (ATCh) at 120 µM, with calculated values for acetylthiocholine (ATCh) and butyrylthiocholine of 6.39 µM and 14.18 µM, respectively. The recombinant enzyme was highly sensitive to inhibition by malaoxon, paraoxon, and coroxon in either substrate. Western blots using polyclonal rabbit antibody produced by immunization with a peptide specific for rAaChE1 exhibited reactivity in salivary and synganglial extract blots, indicating the presence of AaChE1 antigenic protein. Total cholinesterase activities of synganglial or salivary gland extracts from adult ticks exhibited biochemical properties very different from the expressed rAaACh1 enzyme, evidencing the substantial presence of additional cholinesterase activities in tick synganglion and saliva. The biological function of AaChE1 remains to be elucidated, but its presence in tick saliva is suggestive of functions in hydrolysis of cholinergic substrates present in the large blood mean and potential involvement in the modulation of host immune responses to tick feeding and introduced pathogens.
Topics: Animals; Rabbits; Ixodidae; Amblyomma; Cholinesterases; DNA, Complementary; Acetylthiocholine; Butyrylthiocholine; Ticks; Antibodies
PubMed: 37175388
DOI: 10.3390/ijms24097681 -
PloS One 2023Organophosphate intoxication via acetylcholinesterase inhibition executes neurotoxicity via hyper stimulation of acetylcholine receptors. Here, we use the...
Organophosphate intoxication via acetylcholinesterase inhibition executes neurotoxicity via hyper stimulation of acetylcholine receptors. Here, we use the organophosphate paraoxon-ethyl to treat C. elegans and use its impact on pharyngeal pumping as a bio-assay to model poisoning through these neurotoxins. This assay provides a tractable measure of acetylcholine receptor mediated contraction of body wall muscle. Investigation of the time dependence of organophosphate treatment and the genetic determinants of the drug-induced inhibition of pumping highlight mitigating modulation of the effects of paraoxon-ethyl. We identified mutants that reduce acetylcholine receptor function protect against the consequence of intoxication by organophosphates. Data suggests that reorganization of cholinergic signalling is associated with organophosphate poisoning. This reinforces the under investigated potential of using therapeutic approaches which target a modulation of nicotinic acetylcholine receptor function to treat the poisoning effects of this important class of neurotoxins.
Topics: Animals; Organophosphate Poisoning; Paraoxon; Cholinesterase Inhibitors; Caenorhabditis elegans; Acetylcholinesterase; Receptors, Nicotinic; Neurotoxins; Organophosphates
PubMed: 37083685
DOI: 10.1371/journal.pone.0284786 -
International Journal of Molecular... Feb 2023Combined use of various antimicrobial peptides (AMPs) with enzymes that hydrolyze the signaling molecules of the resistance mechanism of various microorganisms, quorum...
Combined use of various antimicrobial peptides (AMPs) with enzymes that hydrolyze the signaling molecules of the resistance mechanism of various microorganisms, quorum sensing (QS), to obtain effective antimicrobials is one of the leading approaches in solving the antimicrobial resistance problem. Our study investigates the lactoferrin-derived AMPs, lactoferricin (Lfcin), lactoferampin and Lf(1-11), as potential partners for combination with enzymes hydrolyzing lactone-containing QS molecules, the hexahistidine-containing organophosphorus hydrolase (His-OPH) and penicillin acylase, to obtain effective antimicrobial agents with a scope of practical application. The possibility of the effective combination of selected AMPs and enzymes was first investigated in silico using molecular docking method. Based on the computationally obtained results, His-OPH/Lfcin combination was selected as the most suitable for further research. The study of physical-chemical characteristics of His-OPH/Lfcin combination revealed the stabilization of enzymatic activity. A notable increase in the catalytic efficiency of action of His-OPH in combination with Lfcin in the hydrolysis of paraoxon, -(3-oxo-dodecanoyl)-homoserine lactone and zearalenone used as substrates was established. Antimicrobial efficiency of His-OPH/Lfcin combination was determined against various microorganisms (bacteria and yeasts) and its improvement was observed as compared to AMP without enzyme. Thus, our findings demonstrate that His-OPH/Lfcin combination is a promising antimicrobial agent for practical application.
Topics: Quorum Sensing; Lactoferrin; Molecular Docking Simulation; Peptides; Anti-Infective Agents
PubMed: 36834977
DOI: 10.3390/ijms24043566