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Direct synthesis of organophosphorus compounds from white phosphorus represents a significant but challenging subject, especially in the context of ongoing efforts to comprehensively improve the phosphorus-derived chemical industry driven by sustainability and safety concerns. China is the world's largest producer of white phosphorus, creating a significant demand for the green transformation of this crucial feedstock. This review provides an overview of advancements in white phosphorus activation by Chinese research teams, focusing on the direct construction of P‒C/N/O/S/M bonds from white phosphorus. Additionally, we offer some insights into prospective directions for the activation and transformation of white phosphorus in the future. This review paper aims to attract more researchers to engage in this area, stimulating follow-up exploration and fostering enduring advances. [ABSTRACT FROM AUTHOR]

Background: Organophosphorous (OP) compound poisoning is a common toxological emergency in agricultural country like India, as it is easily available. Cardiac Marker (CPKMB &Trop-I) level were frequently elevated in OPC poisoning and ECG changes were observed. Fatality is mostly due to cardiovascular and respiratory failure. Aim & Objective: To study clinical severity and it's correlation to myocardial injury in respect to Troponine-I, CPK-MB and ECG changes. Material and Methods: A prospective observational study conducted among 97 patients admitted in Medicine Department, VIMSAR, Burla with history of OPC poisoning during the period of Dec 2019 to Dec 2021 after approval from institutional Ethical Committee. Changes in ECG, Serum CPK-MB, Trop-I level were estimated by IFCC and ELISA method, respectively and observed at admission, after 3 days and at discharge. Results: Mostly Chlorpyriphos (23.7%) was consumed followed by Phorate (22.7%). The most common clinical symptoms was bradycardia (49.5%) followed by hypotension (26.8%), and tachycardia (21.6%). Acetylcholine esterase level decreased (<25000IU) in 75.3 % patients. ECG showed Sinus bradycardia (44.3%), followed by QT prolongation (33%). On day3, significantly elevated Trop-I (27.80 %) and CPK-MB(29.89%) were found. Conclusion: Majority of the patients were in the age group of 45-60 with males more than females. Occurrence of cardiotoxicity was related to the type of compounds ingested. Elevated CPK-MB and Trop-I indicates severity of OPC poisoning requiring longer ICU stay and also statistically significant to predict the prognosis of poisoning. [ABSTRACT FROM AUTHOR]

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse.

The Iran-Iraq war (1980–1988) was the first modern war in which chemical weapons were used. The purpose of this work is to summarize the experience of treating victims, affected by nerve agents. The publications of Iranian authors in different scientific journals were used for the preparation of the article. The first use of chemical weapons by the Iraqi army occurred in August 1983 in Kurdistan (sulfur mustard). Nerve agent (tabun) was first used on February 29, 1984 in the battles for the Majnun Islands. In total, 140 tons of tabun and about 600 tons of sarin / cyclosarin were used against Iranian troops during the war. Around 5.5 thousand servicemen died directly from the nerve agents. For one dead from tabun, there were at least 7 poisoned people who needed qualified toxicological assistance; lethal outcomes among servicemen affected by the herd amounted to at least 15%. Military personnel without protective equipment, who received large doses of nerve agents, lost consciousness within 30 seconds and died in positions within a few minutes. The most sensitive to such agents were women, children and the elderly, who accidentally fell under a chemical attack. The use of nerve agents by the enemy was accompanied by panic in the troops and the arrival of a huge number of military personnel in critical condition at medical stations. Sweating, fasciculations and miosis were the first clinical signs by which those affected by such toxic agents were recognized. The effectiveness of antidote therapy (atropine + oxime + diazepam) depended on the time of medical care. The most effective was the use of atropine by titration (fractional intravenous drip) to achieve ease of breathing, absence of bronchospasm, disappearance of secretions from the respiratory tract and heart rate >80 beats/min. The oximes turned out to be not effective in the treatment of those poisoned by tabun. The most effective was degassing by physical removal of toxic chemical. Degassing of the affected had to be carried out by washing with sea or river water, using solutions of chlorine-containing household chemicals, and sprinkling with dry earth.

Background: Organophosphorus compounds are widely used as pesticides in agriculture practicing countries like India. Since it is readily available and accessible, it is one of the most commonly used agents for suicidal poisoning. The current study was undertaken to evaluate the performance of the SOFA score (scoring system) and the serum lactate level (laboratory parameter) as a mortality predictor in organophosphorus poisoning. Material and Methods: This prospective observational study was conducted at AIIMS, Bhubaneswar, for 17 months. The study population included all patients with an alleged history of ingestion of organophosphorus (OP) compounds reporting to the casualty. The receiver operating characteristic (ROC) curve and the logistic regression analysis were used for the analysis. Results: In our study, 75 patients with OP poisoning were studied after satisfying the inclusion criteria. OP poisoning was commonly seen in married males aged 21–40 years. Twelve (16%) patients died during the process of treatment. There was a statistically significant difference in the mean SOFA score, serum lactate level, pH value, and mean duration of hospital stay between the discharged and the deceased patients. In the current study, the ROC curve analysis used to assess the predictor of the outcome of OP poisoning showed that the area under the curve for SOFA score and serum lactate level were 0.794 (95% CI 0.641–0.948) and 0.659 (95% CI 0.472–0.847), respectively. Conclusion: Sequential Organ Failure Assessment (SOFA) score is significantly associated with the outcome of organophosphate poisoning and can be utilized to predict mortality.

Background: Organophosphorus compounds are widely used as pesticides in agriculture practicing countries like India. Since it is readily available and accessible, it is one of the most commonly used agents for suicidal poisoning. The current study was undertaken to evaluate the performance of the SOFA score (scoring system) and the serum lactate level (laboratory parameter) as a mortality predictor in organophosphorus poisoning. Material and Methods: This prospective observational study was conducted at AIIMS, Bhubaneswar, for 17 months. The study population included all patients with an alleged history of ingestion of organophosphorus (OP) compounds reporting to the casualty. The receiver operating characteristic (ROC) curve and the logistic regression analysis were used for the analysis. Results: In our study, 75 patients with OP poisoning were studied after satisfying the inclusion criteria. OP poisoning was commonly seen in married males aged 21–40 years. Twelve (16%) patients died during the process of treatment. There was a statistically significant difference in the mean SOFA score, serum lactate level, pH value, and mean duration of hospital stay between the discharged and the deceased patients. In the current study, the ROC curve analysis used to assess the predictor of the outcome of OP poisoning showed that the area under the curve for SOFA score and serum lactate level were 0.794 (95% CI 0.641–0.948) and 0.659 (95% CI 0.472–0.847), respectively. Conclusion: Sequential Organ Failure Assessment (SOFA) score is significantly associated with the outcome of organophosphate poisoning and can be utilized to predict mortality. [ABSTRACT FROM AUTHOR]

Introduction Sarin is a highly toxic organophosphorus nerve agent that irreversibly inhibits neuronal enzyme acetylcholinesterase. In the prevailing scenario, it is of paramount importance to develop early diagnosis and medical countermeasures for sarin exposure. A deeper understanding of the molecular mechanism of sarin intoxication and perturbations in the associated cellular processes is likely to provide valuable clues for the elucidation of diagnostic markers and therapeutic targets for sarin exposure. Methods Present study, uncovered the changes in phosphorylation patterns of multiple proteins in different rat brain regions after sarin intoxication using 2-DE/MS approach. It provided a holistic view of the phosphorylation-mediated changes in the cellular proteome and highlighted various signaling and response pathways affected at an early time point of sarin intoxication. Results We found total 22 proteins in the cortex, 25 proteins in the corpus striatum, and 17 proteins in the hippocampus, showed ≥1.5 fold changes (hyper- or hypo- phosphorylated) with respect to control, either at 2.5 h or 1 d after sarin exposure. These results indicated the differential expression of phosphoproteins involved in protein folding in the endoplasmic reticulum, carbon metabolism, metabolic function, and energy metabolism. Conclusion Four candidates (protein disulfide-isomerase A3, heat shock cognate 71 kDa protein, alpha-enolase, and creatine kinase B-type), hyperphosphorylated in all three brain regions, can be further studied to understand the molecular mechanism behind neurodegenerative changes mediated by sarin exposure. The study sheds light on major pathogenic processes initiated during sarin intoxication and provides putative diagnostic markers/therapeutic targets for further validation. [ABSTRACT FROM AUTHOR]

Phytates are a type of organophosphorus compound produced in terrestrial ecosystems by plants. In plant feeds, phytic acid and its salt form, phytate, account for 60%–80% of total phosphorus. Because phytate is a polyanionic molecule, it can chelate positively charged cations such as calcium, iron, and zinc. Due to its prevalence in vegetal tissues and the fact that people consume plants, phytate was first considered a potential health benefit. This updated review aims to summarize the current data on the results of clinical trials of phytates on human health, highlighting both beneficial and undesirable effects. To obtain these updated data, published papers in electronic databases such as PubMed/MedLine, TRIP database, Wiley, Google Scholar, Baidu, and Scopus were searched. Study results have shown that phytate can have beneficial health effects such as antioxidant, anticancer potential and reduction of pathological calcifications in blood vessels and organs; but also, negative effects by reducing the absorption of minerals important for maintaining the homeostasis of the human body. According to these recent results derived from recent clinical studies, phytates may be a potential natural source for health benefits. To improve clinical efficacy and human health benefits, further dose-response studies are needed to determine effective therapeutic doses and potential interactions with conventional drugs.

Organophosphorus (OP) pesticides are still widely applied but pose a severe toxicological threat if misused. For in vivo detoxification, the application of hydrolytic enzymes potentially offers a promising treatment. A well-studied example is the phosphotriesterase of Brevundimonas diminuta (BdPTE). Whereas wild-type BdPTE can hydrolyse pesticides like paraoxon, chlorpyrifos-oxon and mevinphos with high catalytic efficiencies, kcat/KM >2 × 107 M−1 min−1, degradation of malaoxon is unsatisfactory (kcat/KM ≈ 1 × 104 M−1 min−1). Here, we report the rational engineering of BdPTE mutants with improved properties and their efficient production in Escherichia coli. As result, the mutant BdPTE(VRNVVLARY) exhibits 37-fold faster malaoxon hydrolysis (kcat/KM = 4.6 × 105 M−1 min−1), together with enhanced expression yield, improved thermal stability and reduced susceptibility to oxidation. Therefore, this BdPTE mutant constitutes a powerful candidate to develop a biocatalytic antidote for the detoxification of this common pesticide metabolite as well as related OP compounds. [ABSTRACT FROM AUTHOR]

Introduction: Acute poisoning represents a real health threat in the world. It is a common cause of admission to emergency department and in intensive care unit. Periodic clinical and epidemiological studies are required to understand the pattern of poisoning. This study aims to analyze epidemiological aspect, clinical profile, and outcome of acute poisoning in a tertiary care hospital. Material and Methods: A cross sectional study was conducted at Government Medical College Hospital, Kota, Rajasthan. 102 admitted patients were taken for study from January 2020 to August 2020. Epidemiological variables age, sex, type of poison, mode of exposure, clinical presentation and outcome were studied. Results: The median age was 30.23 years with a male predominance (54.9%). The circumstances of poisoning were suicidal, accidental and unknown in 88.2%, 9.8%, and 1.96% respectively. Ingestion was the major route of exposure (98%) followed by inhalation (1.96%). The majority 33(32.4%) of cases were of Organophosphorus poisoning followed by 17(16.7%) cases of Rodenticide poisoning. The main symptoms were nausea and vomiting in 90(88.2%) cases. Convulsions were noted in 3(2.9%) patients. Gastric lavage was done for 92(90.19%). 8 patients (7.84%) were needed mechanical ventilation. 7 patients (6.86%) were needed vasoactive drugs. The rate of mortality was 8.82%. The aluminium phosphide poisoning was responsible for 44.4% deaths. Conclusion: Study revealed the high mortality associated with acute poisoning. Appropriate approach towards poisoning at tertiary care center and prevention remains the best strategy for reducing morbidity and mortality.

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri- ortho -cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time- and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mitochondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supplementation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN. • Tri- ortho -cresyl phosphate (TOCP) induced axon degeneration of chicken DRG neurons. • TOCP caused loss of nicotinamide nucleotide adenylyltransferase 2 (NMNAT2). • TOCP caused ATP deficiency of the DRG neurons by decreasing NAD+ level. • NAD+ supplement prevented TOCP-induced axon degeneration in chicken DRG neurons. [ABSTRACT FROM AUTHOR]

Soman produces excitotoxic effects by inhibiting acetylcholinesterase in the cholinergic synapses and neuromuscular junctions, resulting in soman-induced sustained status epilepticus (SSE). Our previous work showed delayed intramuscular (i.m.) treatment with A 1 adenosine receptor agonist N-bicyclo-[2.2.1]-hept-2-yl-5′-chloro-5′-deoxyadenosine (ENBA) alone suppressed soman-induced SSE and prevented neuropathology. Using this same rat soman seizure model, we tested if delayed therapy with ENBA (60 mg/kg, i.m.) would terminate seizure, protect neuropathology, and aid in survival when given in conjunction with current standard medical countermeasures (MCMs): atropine sulfate, 2-PAM, and midazolam (MDZ). Either 15- or 30-min following soman-induced SSE onset, male rats received atropine and 2-PAM plus either MDZ or MDZ + ENBA. Electroencephalographic (EEG) activity, physiologic parameters, and motor function were recorded. Either 2- or 14-days following exposure surviving rats were euthanized and perfused for histology. All animals treated with MDZ + ENBA at both time points had 100% EEG seizure termination and reduced total neuropathology compared to animals treated with MDZ (2-day, p = 0.015 for 15-min, p = 0.002 for 30-min; 14-day, p < 0.001 for 15-min, p = 0.006 for 30-min), showing ENBA enhanced MDZ's anticonvulsant and neuroprotectant efficacy. However, combined MDZ + ENBA treatment, when compared to MDZ treatment groups, had a reduction in the 14-day survival rate regardless of treatment time, indicating possible enhancement of MDZ's neuronal inhibitory effects by ENBA. Based on our findings, ENBA shows promise as an anticonvulsant and neuroprotectant in a combined treatment regimen following soman exposure; when given as an adjunct to standard MCMs, the dose of ENBA needs to be adjusted. • A 1 adenosine receptor agonist ENBA displays anticonvulsive/neuroprotective effects. • ENBA as delayed adjunct to medical therapy was evaluated following soman in rats. • ENBA enhanced the anticonvulsant/neuroprotective effect of atropine and midazolam. • Results illustrated the roles of adenosine pathway in seizure & brain pathology. [ABSTRACT FROM AUTHOR]

Recently, cloud point extraction (CPE) coupled with back extraction (BE) has been suggested as a promising alternative to liquid-liquid extraction. In CPE, non-ionic surfactants in aqueous solutions form micelles and the solution becomes turbid when heated to the cloud point temperature. Microwave- or ultrasonic-assisted BE can be performed after CPE and before injection of the sample for instrumental analysis by ultraviolet-visible spectroscopy, high-performance liquid chromatography, gas chromatography, gas chromatography-mass spectrometry, or liquid chromatography-mass spectrometry. This article reviews selected published scientific research on the application of CPE-BE to the determination of alkaloids, drugs and organophosphorus compounds from several complex matrices. This method could be scaled-up for use in forensic science.

Negatively charged groups are immobilized on the neutral inorganic surfaces of kaolinite by a reaction between interlayer hydroxyls of kaolinite and 1,3-dimethylimidazolium dimethylphosphate (DMI+DMP-), an ionic liquid. This interlayer grafting gives the product possessing covalently-bonded DMP-moieties with DMI+. The successful grafting is confined by a lack of differences in the 1.26-nm diffraction line due to expansion of the kaolinite interlayers between the reaction products before and after washing with an excess amount of methanol at 60°C for 2 days, and by the presence of upfield signal at -10.0 ppm in the solid-state 31P nuclear magnetic resonance signal with magic angle spinning (31P MAS NMR) spectrum compared to the 31P liquid NMR signal of DMI-DMP+ in CDCl3 at 0.57 ppm. When the product obtained by the interlayer grafting is treated with 1 mol/L hydrochloric acid, the Fourier-transform infrared spectrum and thermogravimetric curve of the acid-treated product reveal complete removal of DMI+. Additionally, the XRD pattern of the product displays a decrease in the basal spacing from 1.26 to 1.03 nm accompanied by the 31P MAS NMR signal at -8.0 ppm which are present upfield from the 31P NMR signal at 0 ppm of phosphoric acid. Acid treatment using hydrochloric acid thus removed DMI+ from the interlayer space, but the DMP- moieties were converted into dihydrogen phosphate moieties that remained grafted to the interlayer surfaces of kaolinite. These results demonstrate the formation of a proton-exchangeable and asymmetrical layered inorganic solid. [ABSTRACT FROM AUTHOR]

Tri-ortho-cresyl phosphate (TOCP) has been used commercially as a plasticizer and a flame retardant, which has been reported to cause multiple toxicities in humans and other animals. However, the effect of TOCP on female reproductive system is still unclear. The aim of this investigation was to evaluate the reproductive toxicity of TOCP in female avian and investigate its molecular mechanism. In the current study, 50 adult hens were given a single oral dose of TOCP (750 mg/kg). Egg laid by the hens were harvested and counted. Egg quality is assessed by determining the shell strength and thickness. Samples of ovary, shell gland, and serum were collected on day 0, 2, 7, and 21 after the administration. The morphological and pathological changes in tissues were examined. Cell death, follicular development, and steroidogenesis were determined to assess the toxicity of TOCP on laying hens. The results showed that egg production, egg weight, and eggshell strength significantly decreased after TOCP exposure. The calcium levels in serum and eggshell decreased and the expression levels of the eggshell formation-related genes calbindin-D28k (CaBP-D28k) and carbonic anhydrase 2 (CA2) were downregulated. The inhibitory effects of TOCP on follicular development and steroidogenesis were observed with changes in the levels of the related proteins such as forkhead box O1 (FoxO1) and mothers against decapentaplegic homolog 2/3 (Smad2/3). Cell death was identified, which might lead to follicular development disorder. Taken together, TOCP reduced the quantity and quality of the eggs laid by the hens through disrupting follicular development, steroidogenesis, and shell gland function.

A method for synthesizing six-membered heterocyclic compounds was developed based on the features of O , P -acetals. Sequential reactions of intramolecular cyclization between the methylene carbon atom of O , P -acetal and its electrophilic functional group (ester or protected carbamate) was followed by Horner–Wadsworth–Emmons (HWE) olefination with various aldehydes. The developed one-pot method yielded isochroman-4-one and benzoxazin-3-one derivatives with an alkylidene moiety. [ABSTRACT FROM AUTHOR]

• The phosphotriesterase from Brevundimonas diminuta can hydrolyse OP nerve agents. • BdPTE has shown less efficient breakdown of an OP in an animal model than in vitro. • We have performed inhibition studies with plasma components using PXE as substrate. • We demonstrate that BdPTE is inhibited by serum albumin via depletion of zinc ions. • Zinc ions are crucial for the active site and are a critical component of enzyme formulation. The phosphotriesterase of the bacterium Brevundimonas diminuta (BdPTE) is a naturally occurring enzyme that catalyzes the hydrolysis of organophosphate (OP) nerve agents as well as pesticides and offers a potential treatment of corresponding intoxications. While BdPTE mutants with improved catalytic efficiencies against several OPs have been described, unexpectedly, less efficient breakdown of an OP was observed upon application in an animal model compared with in vitro measurements. Here, we describe detailed inhibition studies with the high-activity BdPTE mutant 10-2C3(C59M/C227A) by human plasma components, indicating that this enzyme is inhibited by serum albumin. The inhibitory activity is mediated by depletion of crucial zinc ions from the BdPTE active site, either via the known high-affinity zinc binding site of albumin or via chemical complex formation with its free thiol side chain at position Cys34. Albumin pre-charged with zinc ions or carrying a chemically blocked Cys34 side chain showed significantly reduced inhibitory activity; in fact, the combination of both measures completely abolished BdPTE inhibition. Consequently, the available zinc ion concentration in blood plays an important role for BdPTE activity in vivo and should be taken into account for therapeutic development and application of a catalytic OP scavenger. [ABSTRACT FROM AUTHOR]

Tri- ortho -cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse. • TOCP induces hepatic steatosis through activating de novo lipogenesis. • TOCP affects lipid metabolism by the sterol regulatory element binding protein. • mTOR signals and ER stress participate in the TOCP-induced hepatic steatosis. [ABSTRACT FROM AUTHOR]

In this work, flame retarding phosphonate‐functionalized imidazolium ionic liquids (PFILs) were synthesized and employed as electrolyte additives for Li/LiFePO4 half‐cells. Physical and electrochemical properties, including ionic conductivity, electrochemical properties, electrochemical oxidation limit, electrochemical impedance spectroscopy (EIS) and lithium‐ion transference number (TLi+), were investigated. The results demonstrate that the addition of PFIL can improve the electrochemical performance of lithium‐ion batteries (LIBs). Hybrid electrolyte with 10 wt % bidentate phosphonate‐functionalized imidazolium ionic liquid (b‐PFIL) exhibits more excellent electrochemical oxidation stability (up to 4.77 V vs. Li/Li+), capacity retention (87.3 % after 400 cycles) and rate capability. These improvements can be ascribed to the enhanced lithium‐ion transference number (TLi+), which results from the stronger binding affinity between chelating b‐PFIL and LiPF6. [ABSTRACT FROM AUTHOR]

Recently, cloud point extraction (CPE) coupled with back extraction (BE) has been suggested as a promising alternative to liquid-liquid extraction. In CPE, non-ionic surfactants in aqueous solutions form micelles and the solution becomes turbid when heated to the cloud point temperature. Microwave- or ultrasonic-assisted BE can be performed after CPE and before injection of the sample for instrumental analysis by ultraviolet-visible spectroscopy, high-performance liquid chromatography, gas chromatography, gas chromatography-mass spectrometry, or liquid chromatography-mass spectrometry. This article reviews selected published scientific research on the application of CPE-BE to the determination of alkaloids, drugs and organophosphorus compounds from several complex matrices. This method could be scaled-up for use in forensic science. [ABSTRACT FROM AUTHOR]

To obtain fiber materials with pronounced chemical-biological protection, metal (Zn or Ta) nanoparticles were jointly applied with polyelectrolyte complexes of enzymes and polypeptides being their stabilizers. Computer modeling revealed the preferences between certain polyelectrolyte partners for N-acyl-homoserine lactone acylase and hexahistidine-tagged organophosphorus hydrolase (His6-OPH) possessing the quorum quenching (QQ) behavior with bacterial cells. The combinations of metal nanoparticles and enzymes appeared to function better as compared to the combinations of the same QQ-enzymes with antibiotics (polymyxins), making it possible to decrease the applied quantities by orders of magnitude while giving the same effect. The elimination of Gram-positive and Gram-negative bacterial cells from doubly modified fiber materials notably increased (up to 2.9-fold), whereas His6-OPH retained its hydrolytic activity in reaction with organophosphorus compounds (up to 74% of initially applied activity). Materials with the certain enzyme and Zn nanoparticles were more efficient against Bacillus subtilis cells (up to 2.1-fold), and Ta nanoparticles acted preferentially against Escherichia coli (up to 1.5-fold). Some materials were proved to be more suitable for combined modification by metal nanoparticles and His6-OPH complexes as antimicrobial protectants.

Background: Organophosphorus compound ingestion is one of the most common modes of deliberate self-harm in developing countries like India. Neurological complications are known in acute, intermediate and delayed phases following organophosphate poisoning. However, extrapyramidal manifestations are rarely reported. Case presentation: A 30-year-old male patient was brought to the emergency department with history of consumption of unknown amount of monocrotophos 36%. At the time of presentation, he was in cholinergic crisis. He was managed with intravenous satropine, pralidoxime and mechanical ventilatory support. By day six, he improved significantly and was extubated. On day eight of illness, he developed extrapyramidal syndrome (EPS) characterized by reduced facial expression, tremors of all four limbs, rigidity and intermittent opisthotonic posturing. In addition to supportive care, he was treated with oral amantadine and trihexyphenidyl. He was discharged on day fifteen and by eight weeks improved significantly and became independent for all activities of daily living. Discussion: Organophosphorus compounds are cholinesterase inhibitors which act primarily by blocking active site on the cholinesterase enzyme by forming a covalent bond. Extrapyramidal syndrome is a rare complication during intermediate phase. Increased susceptibility of the basal ganglia nuclei to the toxic products in the absence of efficient detoxification pathways may be responsible. Brain imaging may reveal characteristic signal changes or can be completely normal. Conclusion: This case highlights the importance of careful observation and meticulous neurological examination for the diagnosis and appropriate management of the rare extrapyramidal syndrome due to acute organophosphate poisoning.

The near-limit oscillatory behaviors on wick flames of dimethyl carbonate (DMC) with trimethyl phosphate (TMP) additions have been investigated experimentally. The experiments were conducted under a wick burner in conjunction with the limiting oxygen concentration test (wick-LOC), and the fuels were selected as typical examples of electrolyte solvents and organophosphorus compounds (OPCs) for lithium-ion batteries. The near-limit oscillating flames on the wick configuration were observed into two main characters: side-to-wake or side oscillation in for the side-stabilized flame (full flame) and wake oscillation for the wake-stabilized flame (wake flame). By tracing the flame base movement using a 240-fps camera, stable limit cycle oscillations were found in full flame cases, while the wake flame cannot sustain the oscillation for long and finally leads to global extinction. With the addition of TMP in DMC, the transition from the side-to-wake oscillation to the side oscillation was found in the unstable full flames with a linear increase in frequency and a significant drop in amplitude, while the wake oscillating flames performed increased trends for both. To clarify the dominant mechanism of TMP-added flame oscillations, laminar burning velocities of DMC+TMP mixtures were calculated at the oxygen level of each near-limit oscillating flame. The weakened flame speed with TMP addition revealed the inadequacy of buoyancy-driven mechanisms for the OPC added wick-flame. Then the wick surface temperature was measured adopting a special thermocouple arrangement to validate the thermal-diffusive promotion by TMP addition. Results showed that the heat feedback from TMP-added flames compensated for the low reactivity and provided a faster oscillation near the extinction limit. [ABSTRACT FROM AUTHOR]

• The phosphotriesterase from Brevundimonas diminuta can hydrolyze organophosphates. • Engineered BdPTE offers a catalytic bioscavenger of nerve agents and pesticides. • However, its biochemical stability needs optimization for therapeutic application. • We describe the replacement of two unpaired cysteine residues by inert side chains. • This leads both to high stability and catalytic activity towards toxic substrates. Organophosphorus (OP) 1 1 Organophosphorus Compund (OP). nerve agents pose a severe toxicological threat, both after dissemination in military conflicts and by terrorists. Hydrolytic enzymes, which may be administered into the blood stream of victims by injection and can decompose the circulating nerve agent into non-toxic metabolites in vivo , could offer a treatment. Indeed, for the phosphotriesterase found in the bacterium Brevundimonas diminuta (BdPTE), 2 2 Brevundimonas diminuta phosphotriesterase (BdPTE). engineered versions with improved catalytic efficiencies have been described; yet, their biochemical stabilities are insufficient for therapeutic use. Here, we describe the application of rational protein design to develop novel mutants of BdPTE that are less susceptible to oxidative damage. In particular, the replacement of two unpaired cysteine residues by more inert amino acids led to higher stability while maintaining high catalytic activity towards a broad spectrum of substrates, including OP pesticides and V-type nerve agents. The mutant BdPTE enzymes were produced in Escherichia coli , purified to homogeneity, and their biochemical and enzymological properties were assessed. Several candidates both revealed enhanced thermal stability and were less susceptible to oxidative stress, as demonstrated by mass spectrometry. These mutants of BdPTE may show promise for the treatment of acute intoxications by nerve agents as well as OP pesticides. [ABSTRACT FROM AUTHOR]

Pyruvate dehydrogenase complex (PDHc) is an important herbicide target enzyme. PDHc is a key oxidoreductase in organism and it catalyzes the oxidative decarboxylation of pyruvate to acetyl coenzyme A. Many organophosphorus compounds have been proven to be effective inhibitors of plant PDHc. In this review, the research progress and trend of PDHc inhibitors as herbicides were systematically introduced. Including the research work of our group, the discovery of phosphorous analogues as lead structures of PDHc inhibitors, optimization of lead compounds, and creation and derivatization of clacyfos were summarized and reviewed. [ABSTRACT FROM AUTHOR]

Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases.

The spectrum of 31 P-NMR is fundamentally simpler than that of 1 H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative 31 P-NMR ( 31 P-qNMR) than using quantitative 1 H-NMR ( 1 H-qNMR), which has been already established as an absolute determination method. We have previously reported a 31 P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using 31 P-qNMR at multiple laboratories. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d 4 were selected as the reference standards (RSs) for 31 P-qNMR and 1 H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CD 3 OH was selected as the solvent for 31 P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CD 3 OD was the solvent of choice for the 1 H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by 31 P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by 1 H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by 31 P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional 1 H-qNMR for the determination of organophosphorus compounds.

Introduction: Organophosphorus compound (OPC) poisoning undoubtedly being a major concern in cultivation sites of the developing world, including Bangladesh. Two potential biomarkers, for example, serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), are widely used in OPC poisoning severity indicators in patients. In this study, we sought to correlate the severity score of acute OPC poisoning with CPK or LDH level and subsequently explore their prognostic value., Methods: This study was performed on a total of 70 patients with OPC poisoning admitted to the inpatient care unit at a territory-based hospital in Bangladesh. Sociodemographics and poison types were recorded, and severity was assessed according to Peradeniya Organophosphorus Poisoning (POP) scale. Serum CPK and LDH levels were measured and recorded., Results: A total of seventy OPC patients were included with male to female ratio of 1.33:1, respectively, with a mean age of 28.7 ± 12.8 years. Chlorpyrifos and methylparathion were the most commonly utilized OP compounds, accounting for 42.9% and 28.6%, respectively. Among the OPC patients, the majority were married homemakers from rural areas. According to POP score, 55.7% and 37.1% of patients were categorized as mild and moderate, whereas very few were found to be severe. The mean serum CPK and LDH of OPC-patients at admission time were 235.6 ± 79.8 IU/L and 348.3 ± 154.1 IU/L, respectively. Serum CPK, atropine dose and hospital stay strongly correlated with clinical severity., Conclusion: We conclude that the serum CPK level strongly correlates with the degree of OPC poisoning and can be used as a predictor of the clinical intervention approaches., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Phosphonate‐functionalized ionic liquid (PFIL) is employed as a multifunctional additive to the base electrolyte mixture consisting of ethylene carbonate, dimethyl carbonate and LiPF6. Addition of PFIL (5 wt%) significantly improves the cyclic stability and rate capability of LiCoO2 cathode performed between 3.0 and 4.3 V (vs Li/Li+), and decreases the flammability of the base electrolyte as well. Electrochemical studies indicate that PFIL is preferentially oxidized on cathode to form robust cathode electrolyte interface (CEI), which contributes to the enhanced cyclic stability and rate capability. Morphological and surface analysis on the cycled cathodes also reveal that PFIL is a key component for the formation of thin CEI film and retention of structural integrity of cathode material. Comparison experiments verify that chemically linking between ionicity and phosphorus functionality is indispensable for the enhanced performance. Additives of individual nonfunctionalized ionic liquid, neutral phosphonate, or their mixture all fail to improve the electrochemical performances. [ABSTRACT FROM AUTHOR]

To evaluate the fire-retardant effectiveness of organophosphorus compounds (OPC) added to Li-ion battery electrolyte solvents, the limiting oxygen concentration (LOC) method is used in conjunction with a wick combustion system, called as wick-LOC method. With the wick-LOC method, two modes of stabilized flame are found, namely, wake flame and full flame. When OPC is added to the electrolyte, two distinct branches of extinction processes occur according to the different flame modes near extinction with no transition from the full flame to the wake flame in the case of higher OPC addition. The flame stability limits are measured as a function of OPC addition for both flame modes. The wake flame is shown to be consistently more stable at low levels of OPC addition. However, once the OPC addition exceeds a critical amount, the full flame shows higher stability with a lower LOC than the wake flame. These phenomena in the two regimes are also found in other cases of high OPC addition (different type of OPC and electrolyte solvent). In the most stable flame mode, the regime switches from the wake flame to the full flame with increasing OPC addition, and they are defined correspondingly as "blow-off regime" and "quenching regime". To explain the presence of these two regimes, the thermal balance effect is considered in the discussion of flame extinction mechanisms. The difference in flame volume near the extinction limit shows that the quenching mechanism dominates flame extinction under higher OPC addition. The thermal balance effect on flame stabilization or extinction can be the additional impact on the fire retardation abilities of OPC itself. [ABSTRACT FROM AUTHOR]

Abstract In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC 50 s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC 50 = 0.05 μM) followed by atropine (EC 50 = 0.07 μM). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC 50 = 3.8 μM vs obidoxime EC 50 = 197.8 μM). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model. Highlights • Human small bowel exposed to sarin resulted in an irreversible smooth muscle contraction. • All candidate and approved therapeutics displayed a dose-dependent smooth muscle relaxing effect after sarin exposure. • Scopolamine and atropine showed the most pronounced smooth muscle relaxing effect. • HI-6 and obidoxime fully restored sarin-inhibited cholinesterase activity. [ABSTRACT FROM AUTHOR]

Abstract Organophosphates' toxic effect causes covalent binding to serine-198 in the active site of human plasma butyrylcholinesterase (BChE) with loss of enzymatic function (covalent inhibition). Mass spectrometric detection of modified FGESAGAAS peptide at the active site is a powerful exposure biomarker tool. The aim of this study was to develop mass spectrometry-based method for BChE adduct formation screening, avoiding the use of standard peptides. Immunomagnetic separation of proteins from plasma was optimized. Commercially available anti-butyrylcholinesterase monoclonal antibodies, immobilized on magnetic beads, resulted in stable and reusable affinity sorbent. The method was tested on horse serum BChE and real human plasma from healthy donors, treated with Russian VX (VR). The BChE isolated from blood plasma was digested with pepsin and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The method was evaluated by using synthetic peptides and by comparison to the enzymatic activity Ellman's assay. The minimum concentration of VR exposure, resulting in detectable VR-adduct, was 0.2 ng/mL, which corresponded to the relative BChE inhibition of less than 2%. Adduct formation assessment was performed via monitoring of decrease in non-modified peptide LC-MS/MS signal and increase in VR-modified peptide signal. The designed approach was tested in a pilot study with 5 blood samples from healthy volunteers. Mass spectrometry-based method for BChE adduct formation was found to be in agreement with Ellman's inhibition assay, so the method is applicable for direct BChE inhibition assessment. Graphical abstract fx1 Highlights • A method for BChE quantification and VR-adduct formation assessment was designed. • Stable and reusable magnetic beads were proposed for the enzyme isolation. • Agreement between mass spectrometry and activity Ellman's assay was found. • The enzyme and adduct limit of detections corresponded to 2% level of inhibition. • The approach was tested in a pilot study with blood plasma of healthy volunteers. [ABSTRACT FROM AUTHOR]

Abstract Organophosphorus compound (OP)-induced delayed neuropathy (OPIDN) is characterized by distal axonal degeneration and demyelination of the central and peripheral axons, which leads to progressive muscle weakness, ataxia and paralysis in several days after OP intoxication. This study aimed to investigate the possible use of an imidazole fungicide miconazole as a novel therapy for OPIDN. Adult hens, the most commonly used animal models in OPIDN studies, were orally given tri- o -cresyl phosphate (TOCP). We showed that miconazole, which was administered daily to hens beginning on the 7th day after TOCP exposure, drastically ameliorated the neurotoxic symptoms and histopathological damages in spinal cord and sciatic nerves. Mechanistically, miconazole inhibited the TOCP-induced activation of ErbB/Akt signaling, and enhanced the myelin basic protein (MBP) expression. In a glial cell model sNF96.2 cells, miconazole restored the TOCP-inhibited MBP expression, and promoted cell differentiation as well as cell migration by inhibiting the activation of ErbB/Akt signaling pathway. In sum, miconazole, a synthetic imidazole fungicide, could ameliorate the symptoms and histopathological changes of OPIDN, probably by promoting glial cell differentiation and migration to enhance myelination via inhibiting the activation of ErbB/Akt. Thus, miconazole is a promising candidate therapy for the clinical treatment of OPIDN. Graphical abstract Image 1 Highlights • Miconazole ameliorates tri- o -cresyl phosphate-induced demyelination in vivo. • Miconazole restored the expression of myelin basic protein (MBP). • Miconazole promoted glial cell differentiation and migration. • These effects of miconazole were mediated through the inhibition of ErbB/Akt. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Rational design of novel ChE-based catalytic bioscavengers requires understanding of mechanisms. • However, there are discrepancies about mechanisms of inhibition, aging and reactivation of ChEs. • Knowledge of proton transfer pathways within active site are important for stability and reactivity. • Interplay between X-ray structure, molecular modeling and self–reactivation kinetics. Abstract Catalytic bioscavengers are the second-generation bioscavengers. These biopharmaceuticals are intended to degrade toxic organophosphorus agents on the skin for decontamination or in the bloodstream for pre-treatment and post-exposure treatment of organophosphate poisoning. Because catalytic degradation has to be fast, their catalytic efficiency has to be as high as possible (k cat /K m >106 M−1 min−1). Certain evolved mammalian paraoxonases and bacterial phosphotriesterases already fulfill this requirement. To be of interest, the catalytic activity of certain enzymes has to be increased by several orders of magnitude. This can be reached by computer-redesign or directed evolution existing enzymes, and alternatively, combinational strategies. The present paper focuses on the better understanding of catalytic mechanisms of cholinesterase inhibition, aging and reactivation and how this knowledge serves the rational design of novel catalytic bioscavengers based on cholinesterase structure. [ABSTRACT FROM AUTHOR]

Organophosphorus compound exposure remains a present threat through agricultural accidents, warfare, or terrorist activity. The primary mechanism of organophosphorus toxicity is through inhibition of the enzyme acetylcholinesterase, with current emergency treatment including anticholinergics, benzodiazepines, and oxime reactivators. However, a need for more effective and broadly acting countermeasures remains. This study aimed to develop larval zebrafish as a high-throughput model for evaluating novel therapeutics against acute organophosphorus exposure. Larval zebrafish at six days post-fertilization were exposed to acute concentrations of seven organophosphorus compounds and treated with one of three oximes. Lethality studies indicated similar relative toxicity to that seen in the established rodent model, with chemical warfare agents proving more lethal than organophosphorus pesticides. Additionally, the organophosphorus-specific response for oxime reactivation of acetylcholinesterase was comparable to what has been previously reported. Behavioral studies measuring the visual motor response demonstrated greater efficacy for centrally acting oxime compounds than for those that are contained to the peripheral tissue. Overall, these results support the use of this larval zebrafish model as a high-throughput screening platform for evaluating novel treatments following acute organophosphorus exposure.

Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme’s active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.

Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme. Second generation bioscavengers are catalytic bioscavengers capable of detoxifying OPs with a turnover. High bimolecular rate constants (kcat/Km > 106 M−1min−1) are required, so that low enzyme doses can be administered. Cholinesterases (ChE) are attractive candidates because OPs are hemi-substrates. Moderate OP hydrolase (OPase) activity has been observed for certain natural ChEs and for G117H-based human BChE mutants made by site-directed mutagenesis. However, before mutated ChEs can become operational catalytic bioscavengers their dephosphylation rate constant must be increased by several orders of magnitude. New strategies for converting ChEs into fast OPase are based either on combinational approaches or on computer redesign of enzyme. The keystone for rational conversion of ChEs into OPases is to understand the reaction mechanisms with OPs. In the present work we propose that efficient OP hydrolysis can be achieved by re-designing the configuration of enzyme active center residues and by creating specific routes for attack of water molecules and proton transfer. Four directions for nucleophilic attack of water on phosphorus atom were defined. Changes must lead to a novel enzyme, wherein OP hydrolysis wins over competing aging reactions. Kinetic, crystallographic, and computational data have been accumulated that describe mechanisms of reactions involving ChEs. From these studies, it appears that introducing new groups that create a stable H-bonded network susceptible to activate and orient water molecule, stabilize transition states (TS), and intermediates may determine whether dephosphylation is favored over aging. Mutations on key residues (L286, F329, F398) were considered. QM/MM calculations suggest that mutation L286H combined to other mutations favors water attack from apical position. However, the aging reaction is competing. Axial direction of water attack is not favorable to aging. QM/MM calculation shows that F329H+F398H-based multiple mutants display favorable energy barrier for fast reactivation without aging.

Acylpeptide hydrolases (APHs) catalyze the removal of N-acylated amino acids from blocked peptides. Like other prolyloligopeptidase (POP) family members, APHs are believed to be important targets for drug design. To date, the binding pose of organophosphorus (OP) compounds of APH, as well as the different OP compounds binding and inducing conformational changes in two domains, namely, α/β hydrolase and β-propeller, remain poorly understood. We report a computational study of APH bound to chlorpyrifosmethyl oxon and dichlorvos. In our docking study, Val471 and Gly368 are important residues for chlorpyrifosmethyl oxon and dichlorvos binding. Molecular dynamics simulations were also performed to explore the conformational changes between the chlorpyrifosmethyl oxon and dichlorvos bound to APH, which indicated that the structural feature of chlorpyrifosmethyl oxon binding in APH permitted partial opening of the β-propeller fold and allowed the chlorpyrifosmethyl oxon to easily enter the catalytic site. These results may facilitate the design of APH-targeting drugs with improved efficacy.

Acetylcholinesterase (AChE) inhibited by the organophosphorus nerve (OP) agent soman underlies a spontaneous and extremely rapid dealkylation (“aging”) reaction which prevents reactivation by oximes. However, in vivo studies in various, soman poisoned animal species showed a therapeutic effect of oximes, with the exact mechanism of this effect remaining still unclear. In order to get more insight and a basis for the extrapolation of animal data to humans, we applied a dynamic in vitro model with continuous online determination of AChE activity. This model allows to simulate the in vivo toxico- and pharmacokinetics between human and guinea pig AChE with soman and the oximes HI-6 and MMB-4 in order to unravel the species dependent kinetic interactions. It turned out that only HI-6 was able to slow down the ongoing inhibition of human AChE by soman without preventing final complete inhibition of the enzyme. Continuous perfusion of AChE with soman and simultaneous or delayed (8, 15 or 40 min) oxime perfusion did not result in a relevant reactivation of AChE (less than 2%). In conclusion, the results of the present study indicate a negligible reactivation of soman-inhibited AChE by oximes at conditions simulating the in vivo poisoning by soman. The observed therapeutic effect of oximes in soman poisoned animals in vivo must be attributed to alternative mechanisms which may not be relevant in humans. [ABSTRACT FROM AUTHOR]

Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme's active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons. [ABSTRACT FROM AUTHOR]

Density functional theory (DFT) and time-dependent DFT calculations were performed to elucidate the electronic and optical properties of 2-R-naphthol[2,3-d]oxaphospholes (R-NOPs). On the basis of the calculated results, the poor π overlap between the 3pz orbital of P atom and the 2pz orbitals of other atoms and increasing polarity of P atom result in a reduced energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital. When these two effects are considered simultaneously, the absorption energies obtained for the S1 state can be below 3.00 eV according to replace the P atom of oxaphosphole ring by As atom (increasing the poor π overlap) and change the functional groups (increasing polarity). The origin of these two effects is the inherent size of the 3p orbital of P atom. The role of P atom in the control of the electronic and optical properties of R-NOPs is clearly elucidated. [ABSTRACT FROM AUTHOR]

Certain organophosphorus esters, such as diisopropylfluorophosphate (DFP), cause delayed neuropathy by inhibition of neuropathy target esterase (NTE) keeping the neuron in normal function. In this study, effects of neurobion alone and in combination with dexamethasone on DFP-induced delayed neuropathy were evaluated. Thirty-five mice were divided into five groups, each consisting of 7 mice. Except group1 (Normal group), group 2 received normal saline and 1h later, 1 mg/kg DFP; groups 3, 4 and 5 received 150 mg/kg neurobion, 2 mg/kg dexamethasone and 150 mg/kg neurobion plus 2 mg/kg dexamethasone, respectively and 1h later 1mg/kg DFP. Twenty one days after the last injection, the mice were killed by decapitation under deep anesthesia. NTE level was determined in the brain and though there was no significant difference between the groups, neurobion and neurobion plus dexamethasone partlynot significantly (p > 0.05)- were able to prevent reduction of NTE in the brain caused by DFP. Histopathological evaluation of sciatic nerves showed that neurobion and neurobion plus dexamethasone significantly suppressed the harmful effect of DFP. We also evaluated the activity of acetylcholine esterase (AChE), concentration of glutathione (GSH), and malondialdehyde (MDA) levels in the serum. Results showed dexamethasone (p < 0.001) and dexamethasone in combination with neurobion (p < 0.01) diminished AChE activity significantly compared to the DFP group. Neurobion caused a significant increase in the GSH level (p < 0.05). No significant change was seen in MDA. It is suggested that neurobion should be added and used in the first aid equipment and techniques for exposure to organophosphorus compounds, e.g. pesticides and chemical warfare. [ABSTRACT FROM AUTHOR]