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.

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.

Sensitive fluorescence detection of glyphosate and glufosinate ammonium pesticides by purine-hydrazone-Cu2+ complex.

Organophosphorus pesticides play an important role as broad-spectrum inactivating herbicides in agriculture. Developing a method for rapid and efficient organophosphorus pesticides detection is still urgent due to the increasing concern on food safety. An organo-probe (ZDA), synthesized by purine hydrazone derivative and 2,2'-dipyridylamine derivative, was applied in sensitive recognition of Cu2+ with detection limit of 300 nM. Mechanism study via density functional theory (DFT) and job's plot experiment revealed that ZDA and Cu2+ ions form a 1:2 complex quenching the fluorescence emission. Moreover, this fluorescent complex ZDA-Cu2+ was applicable for detecting glyphosate and glufosinate ammonium following fluorescence enhancement mechanism, with detection limits of 11.26 nM and 11.5 nM, respectively. Meanwhile, ZDA-Cu2+ was effective and sensitive when it is used for pesticide detection, reaching the maximum value and stabilizing in 1 min. Finally, the ZDA-Cu2+ probe could also be tolerated in cell assay environment, implying potential bio-application.

Exposure to chlorpyrifos interferes with intercellular communication in cumulus-oocyte complexes during porcine oocyte maturation.

Chlorpyrifos (CPF), a widely used organophosphorus pesticide (OP) to control pests has been verified reproductive toxicity on mammalian oocytes. However, limited information exists on its correlation with the dysfunction of the intercellular communication in cumulus-oocyte complexes (COCs). Herein, our study utilized porcine COCs as models to directly address the latent impact of CPF on the communication between cumulus cells (CCs) and oocytes during in vitro maturation. The results demonstrated that CPF exposure decreased the rate of the first polar body (PB1) extrusion and blocked meiosis progression. Notably, the cumulus expansion of CPF-exposed COCs was suppressed significantly, accompanied by the down-regulated mRNA levels of cumulus expansion-related genes. Furthermore, the early apoptotic level was raised and the expression of BAX/BCL2 and cleaved caspase 3 was up-regulated in the CCs of CPF-exposed COCs (p < 0.05). Moreover, CPF exposure impaired mRNA levels of antioxidant enzyme-related genes, induced higher levels of reactive oxygen species (ROS) and reduced the levels of mitochondrial membrane potential (MMP) in CCs (p < 0.05). Additionally, the integrated optical density (IOD) rate (cumulus/oocyte) of calcein and the expression of connexin 43 (CX43) was increased in CPF treatment groups (p < 0.05). As well, CPF exposure reduced the expression levels of FSCN1, DAAM1 and MYO10, which resulted in a significant decrease in the number and fluorescence intensity of transzonal projections (TZPs). In conclusion, CPF inhibited the expansion of cumulus and caused oxidative stress and apoptosis as well as disturbed the function of gap junctions (GJs) and TZPs, which eventually resulted in the failure of oocyte maturation.

Association analysis between organophosphorus flame retardants exposure and the risk of depression: Data from NHANES 2017-2018.

BACKGROUND: Organophosphorus flame retardants (OPFRs) can damage the brain and may cause abnormal behaviors. There was no population-based study to reveal the relationship between OPFRs and the occurrence of depression. This study utilized a publicly available database to investigate the correlation between OPFRs exposure and the risk of depression, and the mediation effect of inflammation on the correlation. METHODS: Data in this study was from the database of the National Health and Nutrition Examination Survey. Multifactorial logistic regression was used to estimate the relationship between OPFRs exposure and the risk of depression, and a mediation effect model was constructed to explore the impact of inflammation on the correlation. RESULTS: Data of 1273 participants was included in the study. It was found that individuals with high urinary concentration of bis-(2-chloroethyl) phosphate had an increased risk of developing depression (OR = 1.217, 95 % CI: 1.032-1.435). Combined exposure to OPFRs was significantly associated with the increased risk of depression than single OPFRs exposure. Subgroup analyses based on inflammatory levels in the body revealed that inflammation might exert the mediation effect on the association between OPFRs exposure and the risk of depression, with the contribution proportion of 8.23 %. LIMITATIONS: Cross-sectional data and rapid metabolism of OPFRs lead to uncertainty in revealing long-term exposure in the body. CONCLUSIONS: There was a correlation between OPFRs exposure and the risk of depression, which may be mediated by inflammation in the body to some extent.

Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters.

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.

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.

Organophosphate toxicity patterns: A new approach for assessing organophosphate neurotoxicity.

Organophosphorus compounds or organophosphates (OPs) are widely used as flame retardants, plasticizers, lubricants and pesticides. This contributes to their ubiquitous presence in the environment and to the risk of human exposure. The persistence of OPs and their bioaccumulative characteristics raise serious concerns regarding environmental and human health impacts. To address the need for safer OPs, this study uses a New Approach Method (NAM) to analyze the neurotoxicity pattern of 42 OPs. The NAM consists of a 4-step process that combines computational modeling with in vitro and in vivo experimental studies. Using spherical harmonic-based cluster analysis, the OPs were grouped into four main clusters. Experimental data and quantitative structure-activity relationships (QSARs) analysis were used in conjunction to provide information on the neurotoxicity profile of each group. Results showed that one of the identified clusters had a favorable safety profile, which may help identify safer OPs for industrial applications. In addition, the 3D-computational analysis of each cluster was used to identify meta-molecules with specific 3D features. Toxicity was found to correspond to the level of phosphate surface accessibility. Substances with conformations that minimize phosphate surface accessibility caused less neurotoxic effect. This multi-assay NAM could be used as a guide for the classification of OP toxicity, helping to minimize the health and environmental impacts of OPs, and providing rapid support to the chemical regulators, whilst reducing reliance on animal testing.

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.

Contamination of dairy products with tris(2,4-di-tert-butylphenyl) phosphite and implications for human exposure.

Tris(2,4-di-tert-butylphenyl) phosphite (AO168), an organophosphite antioxidant, can be oxidized to tris(2,4-di-tert-butylphenyl) phosphate (AO168 = O) during the production, processing, and application of plastics. AO168 = O can be further transformed to bis(2,4-di-tert-butylphenyl) phosphate and 2,4-di-tert-butylphenol. Here, we discovered the contamination of AO168 and its transformation products in dairy products for the first time. More samples contained AO168 (mean concentration: 8.78 ng/g wet weight [ww]), bis(2,4-di-tert-butylphenyl) phosphate (mean:11.1 ng/g ww) and 2,4-di-tert-butylphenol (mean: 46.8 ng/g ww) than AO168 = O (mean: 40.2 ng/g ww). The concentrations of AO168 and its transformation products were significantly correlated, and differed with the packaging material and storage conditions of the product. Estimated daily intakes (EDIs) of AO168 and its transformation products were calculated. Although the overall dietary risks were below one, transformation products accounted for 96.7% of the total hazard quotients. The high-exposure EDIs of total AO168 were above the threshold of toxicological concern (300 ng/kg bw/day), and deserve continual monitoring.

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.

Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.

Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms.

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%.

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.

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.

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.

Structural elucidation and anti-psoriasis activity of a novel polysaccharide from Saussurea Costus.

PSCP, a novel water-soluble polysaccharide, was extracted from the root of Saussurea costus and subsequently purified using DEAE-52 cellulose and Sephadax G-50 columns. The elucidation of its structure involved various techniques including HPGPC, FT-IR, HPLC-ELSD, GC-MS, NMR, AFM, and SEM. The results show that PSCP was a homogeneous heteropoly saccharide having molecular weight of 4131 Da and mainly composed of 1-α-D-Glcp-(-2-ß-D-Fruf-1-)23-2-ß-D-Fruf. The anti-psoriasis activity of PSCP was evaluated in imiquimod-induced psoriasis in Balb/C mice. This study revealed that treatment with PSCP resulted in a significant improvement in the pathological morphology of the skin and a reduction in the PASI score. Analysis of liver RNA-Seq data indicated that the MAPK signaling pathway may play a crucial role in the ability of PSCP to ameliorate psoriasis. PSCP was found to effectively inhibit the phosphorylation of JNK, ERK, and p38, as well as down-regulate the expression of the transcription factor AP-1 (c-fos and c-jun) in the nucleus, thereby reducing the expression of inflammatory factors. These findings suggest that PSCP holds promise as a novel therapeutic approach for the treatment of psoriasis.

Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

Recent Advances in the Application of P(III)-Nucleophiles to Create New P-C Bonds through Michaelis-Arbuzov-Type Rearrangement.

Organophosphorus compounds have long been considered valuable in both organic synthesis and life science. P(III)-nucleophiles, such as phosphites, phosphonites, and diaryl/alkyl phosphines, are particularly noteworthy as phosphorylation reagents for their ability to form new P-C bonds, producing more stable, ecofriendly, and cost-effective organophosphorus compounds. These nucleophiles follow similar phosphorylation routes as in the functionalization of P-H bonds and P-OH bonds. Activation can occur through photocatalytic, electrocatalytic, or thermo-driven reactions, often in coordination with a Michaelis-Arbuzov-trpe rearrangement process, to produce the desired products. As such, this review offers a thorough overview of the phosphorylated transformation and potential mechanisms of P(III)-nucleophiles, specifically focusing on developments since 2010. Notably, this review may provide researchers with valuable insights into designing and synthesizing functionalized organophosphorus compounds from P(III)-nucleophiles, guiding future advancements in both research and practical applications.