Spatiotemporal variations and the ecological risks of organophosphate esters in Laizhou Bay waters between 2019 and 2021: Implying the impacts of the COVID-19 pandemic.

Organophosphate esters (OPEs) are a group of synthetic chemicals used in numerous consumer products such as plastics and furniture. The Coronavirus Disease 2019 (COVID-19) pandemic significantly slowed anthropogenic activities and reduced the emissions of pollutants. Meanwhile, the mismanagement of large quantities of disposable plastic facemasks intensified the problems of plastic pollution and leachable pollutants in coastal waters. In this study, the joint effects of the COVID-19 outbreak on the occurrence of 12 targeted OPEs in the waters of Laizhou Bay (LZB) were investigated. The results showed that the median total OPE concentrations were 725, 363, and 109 ng L-1 in the sewage treatment plant effluent, river water, and bay water in 2021, decreased significantly (p < 0.05) by 67%, 68%, and 70%, respectively, compared with those before the COVID-19 outbreak. The release potential of targeted OPEs from disposable surgical masks in the LZB area was ∼0.24 kg yr-1, which was insufficient to increase the OPE concentration in the LZB waters. The concentrations of most individual OPEs significantly decreased in LZB waters from 2019 to 2021, except for TBOEP and TNBP. Spatially, a lower concentration of OPEs was found in the Yellow River estuary area in 2021 compared with that before the COVID-19 pandemic due to the high content of suspended particulate matter in the YR. A higher total OPE concentration was observed along the northeastern coast of LZB, mainly owing to the construction of an artificial island since 2020. The ecological risks of the OPE mixture in LZB waters were lower than those before the COVID-19 outbreak. However, TCEP, TNBP, and BDP should receive continuous attention because of their potential ecological risks to aquatic organisms.

Synergistic action of organophosphates and COVID-19 on inflammation, oxidative stress, and renin-angiotensin system can amplify the risk of cardiovascular maladies.

Organophosphates (OPs) are ubiquitous environmental contaminants, widely used as pesticides in agricultural fields. In addition, they serve as flame-retardants, plasticizers, antifoaming or antiwear agents in lacquers, hydraulic fluids, and floor polishing agents. Therefore, world-wide and massive application of these compounds have increased the risk of unintentional exposure to non-targets including the human beings. OPs are neurotoxic agents as they inhibit the activity of acetylcholinesterase at synaptic cleft. Moreover, they can fuel cardiovascular issues in the form of myocardities, cardiac oedema, arrhythmia, systolic malfunction, infarction, and altered electrophysiology. Such pathological outcomes might increase the severity of cardiovascular diseases which are the leading cause of mortality in the developing world. Coronavirus disease-19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. Similar to OPs, SARS-CoV-2 disrupts cytokine homeostasis, redox-balance, and angiotensin-II/AT1R axis to promote cardiovascular injuries. Therefore, during the current pandemic milieu, unintentional exposure to OPs through several environmental sources could escalate cardiac maladies in patients with COVID-19.

Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.

Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. SIGNIFICANCE STATEMENT: Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.

Dynamic variation and inhalation exposure of organophosphates esters and phthalic acid esters in face masks.

The coronavirus pandemic (COVID-19) has posed a huge global health threat since December 2019. Wearing face masks is known as an effective measure for controlling the wide spread of COVID-19 and its variants. But on the other hand, face masks could be a potential source of organophosphate esters (OPEs) and phthalic acid esters (PAEs) as they are extensively added in masks. However, knowledge associated with the occurrence as well as inhalation risks of OPEs and PAEs in masks is limited. In this study, OPEs and PAEs were determined in different types of mask samples collected from the local market. OPEs and PAEs were detected in mask samples ranging from 36.7 to 855 ng/g, and from 251 to 3830 ng/g, respectively. Relatively lower OPEs and PAEs concentrations were observed in disposable mask for toddlers. Simulated inhalation experiment indicated that the mass loss of OPEs and PAEs was 136 and 3910 ng/mask in disposable masks, 71.9 and 763 ng/mask in disposable mask for toddlers, 924 and 1020 ng/mask in N95 mask after 12 h, respectively. Significantly negative correlations were exhibited between the decrement of OPEs in masks and the increment of OPEs in corresponding polyurethane foams (PUFs) during the course, elucidating OPEs released from masks could be well captured by PUFs. With regard to the variation over time, predominant OPE and PAE analogues showed semblable release and absorption tendency in mask and corresponding PUF. Inhalation exposure risk of OPEs and PAEs was estimated based on the increment of pollutants in PUF. The estimated daily intakes (EDIs), hazard index (HI) and carcinogenic risk (CR) were also calculated and they were within the threshold levels. This study provides the evidence of OPEs and PAEs releasing from the face masks during wearing and unveiled a potential source of OPEs and PAEs exposure to humans.

Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

Profiling of phthalates, brominated, and organophosphate flame retardants in COVID-19 lockdown house dust; implication on the human health.

In this study, brominated flame retardants (BFRs), phthalates, and organophosphate flame retardants (PFRs) were analyzed in indoor household dust collected during the COVID-19 related strict lockdown (April-July 2020) period. Floor dust samples were collected from 40 households in Jeddah, Saudi Arabia. The levels of most of the analyzed chemicals were visibly high and for certain chemicals multifold high in analyzed samples compared to earlier studies on indoor dust from Jeddah. Bis (2-ethylhexyl) phthalate (DEHP) was the primary chemical in these dust samples, with a median concentration of 769,500 ng/g of dust. Tris (2-butoxy ethyl) phosphate (TBEP) and Decabromodiphenyl ether (BDE 209) contributed the highest among PFRs and BFRs with median levels of 5990 and 940 ng/g of dust, respectively. The estimated daily exposure in the worst case scenario (23,700 ng/kg bw/day) for Saudi children was above the reference dose (20,000 ng/kg bw/day) for DEHP, and the hazardous index (HI) was also >1. The long-term carcinogenic risk was above the 1 × 10-5, indicating a risk to the health of Saudi young children from getting exposed to DEHP from indoor dust. This study draws attention to the increased indoor pollution during the lockdown period when all of the daily activities by adults and children were performed indoors, which negatively impacted human health, as suggested by the calculated risk. However, the current study has limitations and warrants more monitoring studies from different parts of the world to understand the phenomenon. At the same time, this study also highlights another side of COVID-19 related to our lives.

Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes.

Lysine-selective molecular tweezers are promising drug candidates against proteinopathies, viral infection, and bacterial biofilm. Despite demonstration of their efficacy in multiple cellular and animal models, important questions regarding their mechanism of action, including cell penetrance and intracellular distribution, have not been answered to date. The main impediment to answering these questions has been the low intrinsic fluorescence of the main compound tested to date, called CLR01. Here, we address these questions using new fluorescently labeled molecular tweezers derivatives. We show that these compounds are internalized in neurons and astrocytes, at least partially through dynamin-dependent endocytosis. In addition, we demonstrate that the molecular tweezers concentrate rapidly in acidic compartments, primarily lysosomes. Accumulation of molecular tweezers in lysosomes may occur both through the endosomal-lysosomal pathway and via the autophagy-lysosome pathway. Moreover, by visualizing colocalization of molecular tweezers, lysosomes, and tau aggregates we show that lysosomes likely are the main site for the intracellular anti-amyloid activity of molecular tweezers. These findings have important implications for the mechanism of action of molecular tweezers in vivo, explaining how administration of low doses of the compounds achieves high effective concentrations where they are needed, and supporting the development of these compounds as drugs for currently cureless proteinopathies.

Chemical, biological, radiological, and nuclear mass casualty medicine: a review of lessons from the Salisbury and Amesbury Novichok nerve agent incidents.

On March 4, 2018, two casualties collapsed on a park bench in Salisbury, Wiltshire, UK. They were later discovered to have been the victims of an attempted murder using the Soviet-era Novichok class of nerve agent. The casualties, along with three further critically ill patients, were cared for in Salisbury District Hospital's Intensive Care Unit. Before the COVID-19 pandemic, the Salisbury and Amesbury incidents were the longest-running major incidents in the history of the UK National Health Service. This narrative review seeks to reflect on the lessons learned from these chemical incidents, with a particular focus on hospital and local organisational responses.

New Drugs 2021, Part 2.

ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.

COVID-19 face masks: A new source of human and environmental exposure to organophosphate esters.

For the first time, organophosphate ester (OPE) content was studied in different types of surgical, self-filtering (KN95, FFP2, and FFP3) and reusable face masks used for COVID-19 prevention. OPEs were detected in all mask samples, although in highly variable amounts which ranged from 0.02 to a maximum of 27.7 µg/mask, with the highest mean concentrations obtained for KN95 masks (11.6 µg/mask) and the lowest for surgical masks (0.24 µg/mask). Twelve out of 16 tested analytes were detected, with TEP, TPHP, TNBP, TEHP and TClPP being the most common OPEs as well as present at the highest concentrations. The non-carcinogenic and carcinogenic risks of OPE inhalation were calculated as being always several orders of magnitude lower than threshold levels, indicating that the use of face masks is safe with regard to OPE contamination. However, given the wide range of OPEs observed in different masks, it can be concluded that some masks (e.g. reusable) are less OPE-contaminated than others (e.g. KN95). With regard to environmental pollution, the disposal of billions of face masks is adding to the already substantial levels of microplastics and associated toxic additives worldwide, an impact that is lessened by use of reusable masks, which also have the lowest economic cost per user. However, in situations of relatively high risk of viral inhalation, such as poorly ventilated indoor public spaces, we recommend the use of FFP2 masks.

Immunotoxic role of organophosphates: An unseen risk escalating SARS-CoV-2 pathogenicity.

Consistent gathering of immunotoxic substances on earth is a serious global issue affecting people under pathogenic stress. Organophosphates are among such hazardous compounds that are ubiquitous in nature. They fuel oxidative stress to impair antiviral immune response in living entities. Aside, organophosphates promote cytokine burst and pyroptosis in broncho-alveolar chambers leading to severe respiratory ailments. At present, we witness COVID-19 outbreak caused by SARS-CoV-2. Infection triggers cytokine storm coupled with inflammatory manifestations and pulmonary disorders in patients. Since organophosphate-exposure promotes necroinflammation and respiratory troubles hence during current pandemic situation, additional exposure to such chemicals can exacerbate inflammatory outcome and pulmonary maladies in patients, or pre-exposure to organophosphates might turn-out to be a risk factor for compromised immunity. Fortunately, antioxidants alleviate organophosphate-induced immunosuppression and hence under co-exposure circumstances, dietary intake of antioxidants would be beneficial to boost immunity against SARS-CoV-2 infection.

Methods and Applications of In Silico Aptamer Design and Modeling.

Aptamers are nucleic acid analogues of antibodies with high affinity to different targets, such as cells, viruses, proteins, inorganic materials, and coenzymes. Empirical approaches allow the design of in vitro aptamers that bind particularly to a target molecule with high affinity and selectivity. Theoretical methods allow significant expansion of the possibilities of aptamer design. In this study, we review theoretical and joint theoretical-experimental studies dedicated to aptamer design and modeling. We consider aptamers with different targets, such as proteins, antibiotics, organophosphates, nucleobases, amino acids, and drugs. During nucleic acid modeling and in silico design, a full set of in silico methods can be applied, such as docking, molecular dynamics (MD), and statistical analysis. The typical modeling workflow starts with structure prediction. Then, docking of target and aptamer is performed. Next, MD simulations are performed, which allows for an evaluation of the stability of aptamer/ligand complexes and determination of the binding energies with higher accuracy. Then, aptamer/ligand interactions are analyzed, and mutations of studied aptamers made. Subsequently, the whole procedure of molecular modeling can be reiterated. Thus, the interactions between aptamers and their ligands are complex and difficult to understand using only experimental approaches. Docking and MD are irreplaceable when aptamers are studied in silico.

Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.