Trace Amount of Bi-Doped Core-Shell Pd@Pt Mesoporous Nanospheres with Specifically Enhanced Peroxidase-Like Activity Enable Sensitive and Accurate Detection of Acetylcholinesterase and Organophosphorus Nerve Agents.

The urgent need for sensitive and accurate assays to monitor acetylcholinesterase (AChE) activity and organophosphorus pesticides (OPs) arises from the imperative to safeguard human health and protect the ecosystem. Due to its cost-effectiveness, ease of operation, and rapid response, nanozyme-based colorimetry has been widely utilized in the determination of AChE activity and OPs. However, the rational design of nanozymes with high activity and specificity remains a great challenge. Herein, trace amount of Bi-doped core-shell Pd@Pt mesoporous nanospheres (Pd@PtBi2) have been successfully synthesized, exhibiting good peroxidase-like activity and specificity. With the incorporation of trace bismuth, there is a more than 4-fold enhancement in the peroxidase-like performance of Pd@PtBi2 compared to that of Pd@Pt. Besides, no significant improvement of oxidase-like and catalase-like activities of Pd@PtBi2 was found, which prevents interference from O2 and undesirable consumption of substrate H2O2. Based on the blocking impact of thiocholine, a colorimetric detection platform utilizing Pd@PtBi2 was constructed to monitor AChE activity with sensitivity and selectivity. Given the inhibition of OPs on AChE activity, a biosensor was further developed by integrating Pd@PtBi2 with AChE to detect OPs, capitalizing on the cascade amplification strategy. The OP biosensor achieved a detection limit as low as 0.06 ng mL-1, exhibiting high sensitivity and anti-interference ability. This work is promising for the construction of nanozymes with high activity and specificity, as well as the development of nanozyme-based colorimetric biosensors.

Relationship of Cytotoxic and Antimicrobial Effects of Triphenylphosphonium Conjugates with Various Quinone Derivatives.

Quinone derivatives of triphenylphosphonium have proven themselves to be effective geroprotectors and antioxidants that prevent oxidation of cell components with participation of active free radicals - peroxide (RO2·), alkoxy (RO·), and alkyl (R·) radicals, as well as reactive oxygen species (superoxide anion, singlet oxygen). Their most studied representatives are derivatives of plastoquinone (SkQ1) and ubiquinone (MitoQ), which in addition to antioxidant properties also have a strong antibacterial effect. In this study, we investigated antibacterial properties of other quinone derivatives based on decyltriphenylphosphonium (SkQ3, SkQT, and SkQThy). We have shown that they, just like SkQ1, inhibit growth of various Gram-positive bacteria at micromolar concentrations, while being less effective against Gram-negative bacteria, which is associated with recognition of the triphenylphosphonium derivatives by the main multidrug resistance (MDR) pump of Gram-negative bacteria, AcrAB-TolC. Antibacterial action of SkQ1 itself was found to be dependent on the number of bacterial cells. It is important to note that the cytotoxic effect of SkQ1 on mammalian cells was observed at higher concentrations than the antibacterial action, which can be explained by (i) the presence of a large number of membrane organelles, (ii) lower membrane potential, (iii) spatial separation of the processes of energy generation and transport, and (iv) differences in the composition of MDR pumps. Differences in the cytotoxic effects on different types of eukaryotic cells may be associated with the degree of membrane organelle development, energy status of the cell, and level of the MDR pump expression.

Portal vein gas is a sign of intestinal necrosis after pesticide poisoning: a case report.

Portal vein gas accumulation and intestinal pneumatosis are uncommon signs indicating a high mortality risk in cases of intestinal ischemic necrosis. However, the widespread use of computed tomography has led to an increase in detection of benign lesions. We report a case of portal vein gas accumulation resulting from organophosphorus pesticide poisoning. A male patient was brought to the hospital in a comatose state with bilateral pupils that measured 1.0 mm, and he showed shortness of breath and wet rattles in the lungs. A cholinesterase concentration of 214 U/L was detected on an auxiliary examination. The patient was diagnosed with organophosphorus pesticide poisoning and underwent mechanical ventilation, hemoperfusion, and continuous renal replacement therapy according to the poisoning guidelines. On the fifth day, considerable abdominal distension was observed. An abdominal computed tomography scan revealed dilation of the small bowel and ascending colon with fluid and gas accumulation, as well as gas within the intestinal wall and hepatic veins. Although portal vein gas and intestinal pneumatosis are a sign of mortality requiring immediate surgical intervention, an increasing number of benign cases suggests potential benefits of conservative treatment approaches.

Ambient long-term exposure to organophosphorus pesticides and the human gut microbiome: an observational study.

BACKGROUND: Organophosphorus pesticides (OP) have been associated with various human health conditions. Animal experiments and in-vitro models suggested that OP may also affect the gut microbiota. We examined associations between ambient chronic exposure to OP and gut microbial changes in humans. METHODS: We recruited 190 participants from a community-based epidemiologic study of Parkinson's disease living in a region known for heavy agricultural pesticide use in California. Of these, 61% of participants had Parkinson's disease and their mean age was 72 years. Microbiome and predicted metagenome data were generated by 16S rRNA gene sequencing of fecal samples. Ambient long-term OP exposures were assessed using pesticide application records combined with residential addresses in a geographic information system. We examined gut microbiome differences due to OP exposures, specifically differences in microbial diversity based on the Shannon index and Bray-Curtis dissimilarities, and differential taxa abundance and predicted Metacyc pathway expression relying on regression models and adjusting for potential confounders. RESULTS: OP exposure was not associated with alpha or beta diversity of the gut microbiome. However, the predicted metagenome was sparser and less evenly expressed among those highly exposed to OP (p = 0.04). Additionally, we found that the abundance of two bacterial families, 22 genera, and the predicted expression of 34 Metacyc pathways were associated with long-term OP exposure. These pathways included perturbed processes related to cellular respiration, increased biosynthesis and degradation of compounds related to bacterial wall structure, increased biosynthesis of RNA/DNA precursors, and decreased synthesis of Vitamin B1 and B6. CONCLUSION: In support of previous animal studies and in-vitro findings, our results suggest that ambient chronic OP pesticide exposure alters gut microbiome composition and its predicted metabolism in humans.

Occurrence of organophosphorus flame retardants in Xiangjiang River: Spatiotemporal variations, potential affecting factors, and source apportionment.

The environmental occurrence of organophosphorus flame retardants (OPFRs) is receiving increasing attention. However, their distribution in the Xiangjiang River, an important tributary in the middle reaches of the Yangtze River, is still uncharacterized, and the potential factors influencing their distribution have not been adequately surveyed. In this study, the occurrence of OPFRs in the Xiangjiang River was comprehensively investigated from upstream to downstream seasonally. Fourteen OPFRs were detected in the sampling area, with a total concentration (∑OPFRs) ranging from 3.16 to 462 ng/L, among which tris(1-chloro-2-propyl) phosphate was identified as the primary pollutant (ND - 379 ng/L). Specifically, ∑OPFRs were significantly lower in the wet season than in the dry season, which may be due to the dilution effect of river flow and enhanced volatilization caused by higher water temperatures. Additionally, Changsha (during the dry season) and Zhuzhou (during the wet season) exhibited higher pollution levels than other cities. According to the Redundancy analysis, water quality parameters accounted for 35.7% of the variation in the occurrence of OPFRs, in which temperature, ammonia nitrogen content, dissolved oxygen, and chemical oxygen demand were identified as the potential influencing factors, accounting for 28.1%, 27.2%, 24.1%, and 11.5% of the total variation, respectively. The results of the Positive Matrix Factorization analysis revealed that transport and industrial emissions were the major sources of OPFRs in Xiangjiang River. In addition, there were no high-ecological risk cases for any individual OPFRs, although tris(2-ethylhexyl) phosphate and tributoxyethyl phosphate presented a low-to-medium risk level. And the results of mixture risk quotients indicated that medium-risk sites were concentrated in the Chang-Zhu-Tan region. This study enriches the global data of OPFRs pollution and contributes to the scientific management and control of pollution.

Impact of circadian clock protein Bmal1 on experimentally-induced periodontitis-associated renal injury.

OBJECTIVES: To investigate the mechanism of circadian clock protein Bmal1 (Bmal1) on renal injury with chronic periodontitis, we established an experimental rat periodontitis model. METHODS: Twelve male Wistar rats were randomly divided into control and periodontitis groups (n=6, each group). The first maxillary molars on both sides of the upper jaw of rats with periodontitis were ligated by using orthodontic ligature wires, whereas the control group received no intervention measures. After 8 weeks, clinical periodontal parameters, including probing depth, bleeding index, and tooth mobility, were evaluated in both groups. Micro-CT scanning and three-dimensional image reconstruction were performed on the maxillary bones of the rats for the assessment of alveolar bone resorption. Histopatholo-gical observations of periodontal and renal tissues were conducted using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Renal function indicators, such as creatinine, albumin, and blood urea nitrogen levels, and oxidative stress markers, including superoxide dismutase, glutathione, and malondialdehyde levels, were measured using biochemical assay kits. MitoSOX red staining was used to detect reactive oxygen species (ROS) content in the kidneys. The gene and protein expression levels of Bmal1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in rat renal tissues were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining. RESULTS: Micro-CT and HE staining results showed significant bone resorption and attachment loss in the maxillary first molar region of the periodontitis group. Histological examination through HE and PAS staining revealed substantial histopathological damage to the renal tissues of the rats in the periodontitis group. The findings of the assessment of renal function and oxidative stress markers indicated that the periodontitis group exhibited abnormal levels of oxidative stress, whereas the renal function levels showed abnormalities without statistical significance. MitoSOX Red staining results showed that the content of ROS in the renal tissue of the periodontitis group was significantly higher than that of the control group, and RT-qPCR and immunohistochemistry results showed that the expression levels of Bmal1, Nrf2, and HO-1 in the renal tissues of the rats in the periodontitis group showed a decreasing trend. CONCLUSIONS: Circadian clock protein Bmal1 plays an important role in the oxidative damage process involved in the renal of rats with periodontitis.

Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

Clinical Profile and Outcome of Organophosphorus Poisoning in a Tertiary Hospital.

Organophosphorus compound (OPC) poisoning is common in Bangladesh. The toxicity of the agent and paucity of appropriate medical services has resulted in high mortality rates. To find out the clinical profile and outcome of OPC poisoning patients is the main aim of my study. This descriptive cross-sectional study was conducted in the Department of Medicine, Mymensingh Medical College Hospital, Bangladesh from September 2016 to November 2018. In this study, mean age of the study subjects was 25.90±11.24 years. Males (70.8%) were predominant than female (29.2%). In this study, most of the poisoning was done by ingestion (98.3%) and only two (1.7%) by inhalation. Regarding features, most muscarinic effect was constricted pupil and bronchospasm (65.0%). Common nicotinic effect was fasciculation (25.0%) and central effect was headache (61.67%). Mean amount of OPC ingestion was 26.30±17.24 ml in this study. Regarding circumstances of poisoning, familial disharmony (38.3%) and quarrel with other family members (37.5%) were the major reason followed by failure of personal affairs (15.0%) and other reasons (9.2%). Regarding complications, aspiration pneumonia was found in 6.7% cases, cardiac arrhythmia was in 6.7% cases and intermediate syndrome was in 1.7% cases. Most of the study subjects (95.0%) recovered fully. Most of the patients were from rural area. Suicidal was the common motive and familial disharmony and quarrel with other family members are the common circumstances of poisoning. Mortality rate was 5.0%.

A pyrene-based chromo-fluorogenic probe for specific detection of sarin gas mimic, diethylchlorophosphate.

Nerve agents are becoming serious issues for the healthy and sustainable environment of modern civilization. Therefore, its detection and degradation are of paramount importance to the scientific community. In the present contribution, we have introduced a chromo-fluorogenic pyrene-based  probe, (E)-2-methoxy-3-(pyren-1-ylimino)-3,8a-dihydro-2H-chromen-4-ol (PMCO) to detect sarin stimulant diethylchlorophosphate (DCP) in solution and gaseous phases. On inserting DCP in PMCO solution, a visual colorimetric change from yellow to clear colourless in daylight and highly intensified blue fluorescence was observed instantly under a 365 nm portable UV lamp light. PMCO has outstanding selectivity and high sensitivity with a limit of detection of 1.32 µM in dimethyl sulfoxide (DMSO) medium and 77.5 nM in 20% H2O-DMSO. A handy strained paper strip-based experiment was demonstrated to recognize DCP in a mixture of similar toxic analytes. A dip-stick experiment was performed to identify DCP vapour, and may be used as an effective photonic tool. We also demonstrated real sample analysis utilizing different DCP-spiked water samples and validating DCP detection even in various types of soils such as sand, field, and mud. Therefore, this present study provides an effective chemosensor for instant and on-site detection of toxic nerve agents in dangerous circumstances.

Cascade reaction triggered colorimetric array for identification of organophosphorus pesticides congeners.

A modern agriculture uses alternative pest control methods to boost productivity, leading to an accumulation of organophosphorus (OPPs) congeners. This necessitates an intuitive and quick way to identify OPPs congeners. A colorimetric sensor for detecting OPPs congeners using a double-enzyme cascade reaction has been successfully designed and constructed in this study. The OPPs regulate the color changes induced by manganese dioxide nanoflowers (MnO2 NFs) and specific alkaline phosphatases (ALP) during the etching of gold nanopyramids (Au NBPs). The ascorbic acid (AA) produced by ALP hydrolysis inhibits Au NBPs etching by MnO2 NFs oxidized 3, 3', 5, 5'-tetramethylbenzidine (TMB). By inhibiting ALP catalytic activity, OPPs prevent AA formation. In this process, Au NBPs will undergo further etching, resulting in various colors so they can be analyzed semi-quantitatively with the naked eye. It has been found that different types of OPPs inhibit enzymes differently and therefore result in varying degrees of etching of Au NBPs. Principal Component Analysis (PCA) is performed by smart devices that convert R, G, and B signals into digital signals. This colorimetric array tests various foods (tea, apple, and cabbage). Colorimetric visualization sensors combined with data analysis will be used in real-life product development.

Evaluation of multiple organophosphate insecticide exposure in relation to altered thyroid hormones in NHANES 2007-2008 adult population.

The thyroid gland is susceptible to chemical exposure such as organophosphate insecticides (OPIs). With the ubiquitous nature of these products, humans are simultaneously exposed to a multitude of chemicals. This study aimed to evaluate the association between an individual and a mixture of OPI metabolites and changes in serum thyroid hormone (TH) concentrations. The analyzed data were 1,434 participants from the United States National Health and Nutrition Examination Surveys (NHANES) cycle 2007-2008. Generalized linear model (GLM) regression, weighted quantile sum (WQS), and adaptive least absolute shrinkage and selection operator (adaptive LASSO) regression were used to investigate the associations between urinary OPI metabolites and altered serum THs. In GLM, all of the five urinary OPI metabolites were inversely associated with free triiodothyronine (FT3) among the male subjects; meanwhile, higher thyroglobulin (Tg) was related to dimethylphosphate (DMP). Moreover, in WQS models, the metabolite mixture induced FT3 down-regulation (ß = -0.209 (95% CI: -0.310, -0.114)), and caused an increased Tg concentration (ß = 0.120 (95% CI: 0.024, 0.212)), however, any significant association was observed among female participants. Consistently, the weighted index and LASSO coefficient demonstrated dimethylthiophosphate (DMTP) as the strongest metabolite in the FT3 model (mean weight= 3.449e-01 and ß =-0.022, respectively), and dimethylphosphate (DMP) represented the highest association in the Tg model (mean weight= 9.873e-01 and ß =-0.020, respectively). Further research is required to confirm our results and investigate the clinical impacts of these disruptions.

Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.

Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.

Molecular cloning and characterization of farnesyl diphosphate synthase from Rosa rugosa Thunb associated with salinity stress.

Rosa rugosa, a renowned ornamental plant, is cultivated for its essential oil containing valuable monoterpenes, sesquiterpenes, and other compounds widely used in the floriculture industry. Farnesyl diphosphate synthase (FPPS) is a key enzyme involved in the biosynthesis of sesquiterpenes and triterpenes for abiotic or biotic stress. In this study, we successfully cloned and characterized a full-length FPPS- encoding cDNA identified as RrFPPS1 using RT-PCR from R. rugosa. Phylogenetic analysis showed that RrFPPS1 belonged to the angiosperm-FPPS clade. Transcriptomic and RT-qPCR analyses revealed that the RrFPPS1 gene had tissue-specific expression patterns. Subcellular localization analysis using Nicotiana benthamiana leaves showed that RrFPPS1 was a cytoplasmic protein. In vitro enzymatic assays combined with GC-MS analysis showed that RrFPPS1 produced farnesyl diphosphate (FPP) using isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) as substrates to provide a precursor for sesquiterpene and triterpene biosynthesis in the plant. Additionally, our research found that RrFPPS1 was upregulated under salt treatment. These substantial findings contribute to an improved understanding of terpene biosynthesis in R. rugosa and open new opportunities for advancements in horticultural practices and fragrance industries by overexpression of the RrFPPS1 gene in vivo increased FPP production and subsequently led to elevated sesquiterpene yields in the future. The knowledge gained from this study can potentially lead to the development of enhanced varieties of R. rugosa with improved aroma, medicinal properties, and resilience to environmental stressors.

Association between organophosphate flame retardant exposure and lipid metabolism: data from the 2013-2014 National Health and Nutrition Examination Survey.

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants that can be detected in water, dust, and biological organisms. Certain OPFRs can disrupt lipid metabolism in animal models and cell lines. However, the effects of OPFRs on human lipid metabolism remain unclear. We included 1,580 participants (≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between OPFR exposure and lipid metabolism biomarkers. After adjusting for confounding factors, results showed that one-unit increases in the log levels of diphenyl phosphate (DPhP) (regression coefficient = -5.755; S.E. = 2.289; p = 0.023) and log bis-(1-chloro-2-propyl) phosphate (BCPP) (regression coefficient = -4.637; S.E. = 2.019; p = 0.036) were negatively associated with the levels of total cholesterol (TC) in all participants. One-unit increases in the levels of DPhP (regression coefficient = -2.292; S.E. = 0.802; p = 0.012), log bis (1,3-dichloro-2-propyl) phosphate (BDCPP) (regression coefficient = -2.046; S.E. = 0.825; p = 0.026), and log bis-2-chloroethyl phosphate (BCEP) (regression coefficient = -2.604; S.E. = 0.704; p = 0.002) were negatively associated with the levels of high-density lipoprotein cholesterol (HDL-C). With increasing quartiles of urine BDCPP levels, the mean TC levels significantly decreased in all participants (p value for trend = 0.028), and quartile increases in the levels of DPhP (p value for trend = 0.01), BDCPP (p value for trend = 0.001), and BCEP (p value for trend<0.001) were negatively corelated with HDL-C, with approximately 5.9, 9.9, and 12.5% differences between the upper and lower quartiles. In conclusion, DPhP, BDCPP, and BCEP were negatively related to HDL-C concentration, whereas DPhP and BCPP levels were negatively associated with TC level. Thus, exposure to OPFRs may interfere with lipid metabolism.

Highly specific and sensitive chromo-fluorogenic detection of sarin, tabun, and mustard gas stimulants: a multianalyte recognition approach.

Nerve agents are the most notorious substances, which can be fatal to an individual because they block the activity of acetylcholinesterase. Fighting against unpredictable terrorist assaults and wars requires the simple and quick detection of chemical warfare agent vapor. In the present contribution, we have introduced a rhodamine-based chemosensor, BDHA, for the detection of nerve gas-mimicking agents diethylchlorophosphate (DCP) and diethylcyanophosphonate (DCNP) and mustard gas-mimicking agent 2-chloroethyl ethyl sulfide (CEES), both in the liquid and vapor phase. Probe BDHA provides the ability for detection by the naked eye in terms of colorimetric and fluorometric changes. It has been revealed that the interaction between nerve agents mimics and probe BDHA facilitates spirolactam ring opening due to the phosphorylation process. Thus, the highly fluorescent and colored species developed while probe BDHA is colorless and non-fluorescent due to the intramolecular spirolactam ring. Moreover, probe BDHA can effectively recognize DCP, DCNP, and CEES in the µM range despite many toxic analytes and could be identified based on the response times and quantum yield values. Inexpensive, easily carried paper strips-based test kits were developed for the quick, on-location solid and vapor phase detection of these mustard gas imitating agents (CEES) and nerve gas mimicking agents (DCP and DCNP) without needing expensive equipment or skilled personnel. More remarkably, the test strips' color and fluorescence can be rapidly restored, exposing them to triethyl amine (TEA) for cyclic use, suggesting a potential application in the real-time identification of chemical warfare agents. To accomplish the on-location application of BDHA, we have experimented with soil samples to find traces of DCP. Therefore, the chromo-fluorogenic probe BDHA is a promising, instantaneous, and on-the-spot monitoring tool for the selective detection of DCP, DCNP, and CEES in the presence of others.

Mitoquinone mesylate as post-exposure prophylaxis against SARS-CoV-2 infection in humans: an exploratory single center pragmatic open label non-randomized pilot clinical trial with matched controls.

BACKGROUND: An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice. METHODS: In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure). FINDINGS: Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant. INTERPRETATION: This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted. FUNDING: This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

Co-delivery of siBcl-2 and PTX with mitochondria-targeted functions to overcoming multidrug resistance.

Multidrug resistance (MDR) poses a significant impediment to the efficacy of chemotherapy in clinical settings. Despite Paclitaxel (PTX) being designated as the primary pharmaceutical agent for treating recurrent and metastatic breast cancer, the emergence of PTX resistance frequently results in therapeutic shortcomings, representing a substantial obstacle in clinical breast cancer management. In response, we developed a delivery system exhibiting dual specificity for both tumors and mitochondria. This system facilitated the sequential administration of small interfering B-cell lymphoma-2 (siBcl-2) and PTX to the tumor cytoplasm and mitochondria, respectively, with the aim of surmounting PTX resistance in tumor cells through the activation of the mitochondrial apoptosis pathway. Notably, we employed genetic engineering techniques to fabricate a recombinant ferritin containing the H-subunit (HFn), known for its tumor-targeting capabilities, for loading siBcl-2. This HFn-siBcl-2 complex was then combined with positively charged Triphenylphosphine-Liposome@PTX (TL@PTX) nanoparticles (NPs) to formulate HFn/siBcl-2@TL/PTX. Guided by HFn, these nanoparticles efficiently entered cells and released siBcl-2 through the action of triphenylphosphine (TPP)-mediated "proton sponge," thereby precisely modulating the expression of Bcl-2 protein. Simultaneously, PTX was directed to the mitochondria through the accurate targeting of TL@PTX, synergistically initiating the mitochondrial apoptosis pathway and effectively suppressing PTX resistance both in vitro and in vivo. In conclusion, the development of this dual-targeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer.

Impact of combined alpha-lipoic acid and mitoquinone supplementation on myocardial infarction in aged rats: Heart performance and molecular mechanisms.

BACKGROUND: This study aimed to investigate the effects of combined alpha-lipoic acid (ALA) and mitoquinone (Mito Q) supplementation on cardiac function and the underlying mechanisms in aged rats with myocardial infarction (MI). METHODS: The aged rats underwent left anterior descending artery (LADA) occlusion for 30 min, followed by reperfusion for 24 h. ALA (100 mg/kg, gavage) and Mito Q (10 mg/kg, IP) were administered daily for two weeks before ischemia. Cardiac function, inflammatory, and apoptotic markers were evaluated 24 h after ischemia. RESULTS: The results of this study indicated that the administration of the combination of ALA and Mito Q significantly improved cardiac function. This improvement was linked to a reduction in the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß (P < 0.001) and apoptotic markers (Bax, caspase-3, and Cyt-c), as well as a decrease in the percentage of TUNEL-positive cells (P < 0.001). CONCLUSION: The study revealed that combined intervention synergistically mitigated cardiac dysfunction by suppressing inflammatory and apoptotic pathways in aged rats with MI. Further research is needed to validate the potential of ALA and Mito Q as therapeutic options for elderly people at risk of heart attacks.

Facile extraction and determination of organophosphorus pesticides using poly (8-hydroxyquinoline) functionalized magnetic multi-walled carbon nanotubes nanocomposite in water, fruits, and vegetables samples.

This study presents a dispersive micro-solid phase extraction (D-µ-SPE) approach for extracting and determining of two organophosphorus pesticides (OPPs), including diazinon and chlorpyrifos as model analytes in various samples. For this purpose, we synthesized, characterized, and utilized magnetic multi-walled carbon nanotubes coated with poly 8-hydroxyquinoline (MWCNTs/Fe3O4@PHQ) as a novel sorbent. The impact of various parameters, including sorbent type, sample pH, sample volume, sorbent amount, desorption solvent (type and volume), extraction time, and ionic strength on the extraction efficiency was investigated and optimized. Following the extraction, the desorbed pesticides in acetone were analyzed using gas chromatography with an FID detector. Under the optimized experimental conditions, the proposed method showed excellent linearity in the range of 3-1000 µg/L, low detection limit (0.9-1.5 µg/L), good relative recoveries (86-101.5 %), and high precision (RSD < 6.5 %). Finally, the applicability of this method was evaluated by analyzing the target OPPs in a variety of real samples, and obtained satisfactory results.

Discovering Novel Organophosphorus Compounds in Wastewater Treatment Plant Effluents through Suspect Screening and Nontarget Analysis.

Limited knowledge on the structure of emerging organophosphorus compounds (OPCs) hampers our comprehensive understanding of their environmental occurrence and potential risks. Through suspect and nontarget screening, combining data-dependent acquisition, data-independent acquisition, and parallel reaction monitoring modes, we identified 60 OPCs (17 traditional and 43 emerging compounds) in effluents of 14 wastewater treatment plants (WWTPs) in Beijing and Qinghai, China. These OPCs comprise 26 organophosphate triesters, 17 organophosphate diesters, 6 organophosphonates, 7 organothiophosphate esters, and 4 other OPCs. Notably, 14 suspect OPCs were newly identified in WWTP effluents, and 16 nontarget OPCs were newly discovered in environmental matrices. Specifically, the cyclic phosphonate, (5-ethyl-2-methyl-1,3,2-dioxaphosphorinan-5-yl)methyl dimethyl phosphonate P-oxide (PMMMPn), consistently appeared in all WWTP effluents, with semiquantitative concentrations ranging from 44.4 to 282 ng/L. Its analogue, di-PMMMPn, presented in 93% of wastewater samples. Compositional differences between the WWTP effluents of two cities were mainly attributed to emerging OPCs. Hazard and ecological risk assessment underscored the substantial contribution of chlorinated organophosphate esters and organothiophosphate esters to overall risks of OPCs in WWTP effluents. This study provides the most comprehensive OPC profiles in WWTP effluents to date, highlighting the need for further research on their occurrence, fate, and risks, particularly for chlorinated OPCs.