Abstract:Pyridostigmine bromide (PB) has been used to protect soldiers from the toxic effects of soman, a chemical warfare agent. Recent research shows that pyridostigmine bromide protects a significant percentage of acetylcholinesterase in isolated human intercostal muscle. Findings presented here indicate that red blood cell acetylcholinesterase is similarly protected by pyridostigmine bromide from the action of diisopropyl fluorophosphate and several organophosphate pesticides including chlorpyrifos-oxon, diazinon-o… Show more
“…Prior research focused on PB and PHYS protecting AChE from the chemical warfare agent soman . Our previous research showed that PB protected AChE from other selected OP pesticides . This research extends the finding of protection by the CBs ALD and CARB against the OPs DZO and CPO.…”
Section: Discussionsupporting
confidence: 73%
“…Previous work showed that pretreatment with PB interferes with inhibition of human muscle and red blood cell (RBC) AChE by the nerve agent soman. Pretreatment with PB also protects against inhibition by OP pesticides . Here bovine RBC AChE was used to investigate whether other CBs will protect AChE against OP pesticides.…”
The carbamate pyridostigmine bromide has been used as a pretreatment to protect individuals from the nerve agent soman. Previous research showed that pyridostigmine significantly protected human muscle acetylcholinesterase in vitro from soman and bovine red blood cell acetylcholinesterase from some organophosphorous pesticides. Research presented here demonstrates that pretreatment with other carbamates also protects acetylcholinesterase from inhibition by the pesticides chlorpyrifos-oxon and diazinon-oxon, but not from malaoxon.
“…Prior research focused on PB and PHYS protecting AChE from the chemical warfare agent soman . Our previous research showed that PB protected AChE from other selected OP pesticides . This research extends the finding of protection by the CBs ALD and CARB against the OPs DZO and CPO.…”
Section: Discussionsupporting
confidence: 73%
“…Previous work showed that pretreatment with PB interferes with inhibition of human muscle and red blood cell (RBC) AChE by the nerve agent soman. Pretreatment with PB also protects against inhibition by OP pesticides . Here bovine RBC AChE was used to investigate whether other CBs will protect AChE against OP pesticides.…”
The carbamate pyridostigmine bromide has been used as a pretreatment to protect individuals from the nerve agent soman. Previous research showed that pyridostigmine significantly protected human muscle acetylcholinesterase in vitro from soman and bovine red blood cell acetylcholinesterase from some organophosphorous pesticides. Research presented here demonstrates that pretreatment with other carbamates also protects acetylcholinesterase from inhibition by the pesticides chlorpyrifos-oxon and diazinon-oxon, but not from malaoxon.
“… 59 , 60 , 61 We also listed the top 15 ranked drugs that decreased the N_Ptbp2 / F_Ptbp2 , N_Hnrnpl / F_Hnrnpl , and N_Tra2b / F_Tra2b ratio ( Figures 4 D–4F). Annotations of these drugs from PubChem indicate a wide range of actions from cellular enzyme inhibitors (bestatin, naproxen sodium, pyridostigmine bromide, and pravastatin sodium), 62 , 63 , 64 , 65 inflammatory response regulators (triamcinolone acetonide, naproxen sodium, cortisone acetate, and diflunisal), 66 , 67 , 68 , 69 to antibiotic reagents (sulfacetamide, cefixime trihydrate, mafenide acetate, and ampicillin sodium). 70 , 71 , 72 , 73 Figure 4 Top 15 ranked drugs based on the NMD/non-NMD ratios of each reporter gene (A–C) Top 15 ranked drugs with possible NMD inhibition activity.…”
Nonsense-mediated mRNA decay (NMD) degrades transcripts with premature stop codons. Given the prevalence of nonsense single nucleotide polymorphisms (SNPs) in the general population, it is urgent to catalog the effects of clinically approved drugs on NMD activity: any interference could alter the expression of nonsense SNPs, inadvertently inducing adverse effects. This risk is higher for patients with disease-causing nonsense mutations or an illness linked to dysregulated nonsense transcripts. On the other hand, hundreds of disorders are affected by cellular NMD efficiency and may benefit from NMD-modulatory drugs. Here, we profiled individual FDA-approved drugs for their impact on cellular NMD efficiency using a sensitive method that directly probes multiple endogenous NMD targets for a robust readout of NMD modulation. We found most FDA-approved drugs cause unremarkable effects on NMD, while many elicit clear transcriptional responses. Besides several potential mild NMD modulators, the anticancer drug homoharringtonine (HHT or omacetaxine mepesuccinate) consistently upregulates various endogenous NMD substrates in a dose-dependent manner in multiple cell types. We further showed translation inhibition mediates HHT's NMD effect. In summary, many FDA drugs induce transcriptional changes, and a few impact global NMD, and direct measurement of endogenous NMD substrate expression is robust to monitor cellular NMD.
Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted to assess the influence of acute DEET (10-100μM) on muscle and vascular nociceptor K7, K, Na1.8 and Na1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5-12weeks post-exposure and persisted through weeks 21-24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor K7, K, Na1.8 or Na1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of K7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role.
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