The bidirectional relationship between peer relationships and bullying: Evidence from cross-lagged analyses among Chinese children.

BACKGROUND: In the digital age, bullying manifests in two distinct forms: traditional bullying and cyberbullying. Children's peer relationships are important predictors of bullying, and bullying in turn predicts peer relationships. However, few researchers have noted the bidirectional relationship between peer relationships and bullying. METHODS: The present study used a two-wave cross-lagged longitudinal design to fill this gap. The potential sex differences were also examined in this relationship. The sample consisted of 527 Chinese children aged 8 to 12 years (M = 9.69, SD = .96; 53.5% female). Participants completed peer nominations for peer acceptance, peer rejection and social dominance, as well as self-reports of traditional bullying and cyberbullying. RESULTS: Results showed that peer rejection at the first time point (T1) significantly and positively predicted traditional bullying perpetration, cyberbullying perpetration and cyberbullying victimization at the second time point (T2). Traditional bullying victimization at T1 significantly and negatively predicted peer acceptance and social dominance at T2. The results also revealed significant male and female differences. For instance, among boys, peer acceptance at T1 significantly and negatively predicted cyberbullying victimization at T2. In contrast, this relationship was not observed among girls. The present findings have important implications for understanding the cyclical relationship between peer relationships and bullying and providing practical guidance for improving peer relationships and reducing bullying.

Lead Bromide Complex in Tri-n-octylphosphine Oxide Matrix with Bright Photoluminance and Exceptional Thermoplasticity.

Metal halide materials have recently drawn increasing research interest for their excellent opto-electronic properties and structural diversity, but their resulting rigid structures render them brittle and poor formability during manufacturing. Here we demonstrate a thermoplastic luminant hybrid lead halide solid by integrating lead bromide complex into tri-n-octylphosphine oxide (TOPO) matrix. The construction of the hybrid materials can be achieved by a simple dissolution process, in which TOPO molecules act as the solvents and ligands to yield the monodispersed clusters. The combination of these functional units enables the near-room-temperature melt-processing of the materials into targeted geometry by simple molding or printing techniques, which offer possibilities for fluorescent writing inks with outstanding self-healing capacity to physical damage. The intermarriage between metal halide clusters with functional molecules expands the range of practical applications for hybrid metal halide materials.

A unique three-dimensional network double-core-shell structure S@MnO2@MXene suppresses the shuttle effect in high-sulfur-content high-performance lithium-sulfur batteries.

Lithium-sulfur (Li-S) batteries represent the most promising next-generation energy storage systems because of their high theoretical specific capacity and energy density. However, the severe shuttle effect and volume expansion of sulfur cathodes have impeded their commercial viability. Hence, accelerating the conversion of lithium polysulfides (LiPSs) is crucial for achieving efficient Li-S batteries. In this study, we employ a straightforward electrostatic self-assembly method to coat ultra-thin MXene nanosheets onto a S@MnO2 core-shell structure, resulting in a highly conductive three-dimensional network. This unique structure not only suppresses the diffusion of LiPSs but also accelerates electron and ion transfer, ensuring a rapid and efficient conversion of LiPSs. The CV curves of symmetrical cells and the Li2S deposition curves demonstrate a significant improvement in the catalytic performance of batteries with S@MnO2@MXene. The capacity of Li-S batteries achieved an impressive 842 mAh/g at the current density of 1C, with a minimal capacity decay of only 0.84 mAh/g per cycle within 500 cycles. Additionally, increasing the sulfur loading mass to 5.88 mg cm-2 resulted in an areal capacity of 6.33 mAh cm-2, demonstrating practical application potential.

A Rapid, Sensitive, and High-throughput Method for the Simultaneous Determination of Antihypertensive Drug Combinations in Dog Plasma by UHPLC-MS/MS: The Assessment of Predicable Bioequivalence of In-vitro Dissolution Condition.

BACKGROUND: Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the release in vivo and in vitro studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed. METHODS: The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10→190.10) and (m/z 408.95→294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90→268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation. RESULTS: The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracy was less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition. CONCLUSION: The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.

Microscale geometrical modulation of PIEZO1 mediated mechanosensing through cytoskeletal redistribution.

The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1's activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints.

A mapped dataset of surface ocean acidification indicators in large marine ecosystems of the United States.

Mapped monthly data products of surface ocean acidification indicators from 1998 to 2022 on a 0.25° by 0.25° spatial grid have been developed for eleven U.S. large marine ecosystems (LMEs). The data products were constructed using observations from the Surface Ocean CO2 Atlas, co-located surface ocean properties, and two types of machine learning algorithms: Gaussian mixture models to organize LMEs into clusters of similar environmental variability and random forest regressions (RFRs) that were trained and applied within each cluster to spatiotemporally interpolate the observational data. The data products, called RFR-LMEs, have been averaged into regional timeseries to summarize the status of ocean acidification in U.S. coastal waters, showing a domain-wide carbon dioxide partial pressure increase of 1.4 ± 0.4 µatm yr-1 and pH decrease of 0.0014 ± 0.0004 yr-1. RFR-LMEs have been evaluated via comparisons to discrete shipboard data, fixed timeseries, and other mapped surface ocean carbon chemistry data products. Regionally averaged timeseries of RFR-LME indicators are provided online through the NOAA National Marine Ecosystem Status web portal.

Hierarchical Self-Aggregation of Multifunctional Steviol Glycosides in Aqueous Solutions.

Steviol glycosides (SGs) are a natural sweetener widely used in the food and beverage industry, but the low solubility and stability of SG aqueous solutions greatly limit their application performance, especially in liquid formulations. In this work, we explore the solubility behavior of rebaudioside A (Reb A) in water, a major component of SGs, with the aim of clarifying the underlying mechanisms of the solubility and stability constraints of SGs, as well as the impact on their multifunctional properties. We demonstrate for the first time that Reb A exhibits hierarchical self-assembly in solutions, forming spherical micelles first when the concentration exceeds its critical micelle concentration (5.071 mg/mL), which then further assemble into large rod-like aggregates. The formation of such large Reb A aggregates is mainly dominated by hydrogen bonding and short-range Coulomb interaction energy, thus leading to the low solubility and precipitation of Reb A solutions. Surprisingly, aggregated Reb A structures display significantly improved organoleptic properties, revealing that self-aggregation can be developed as a simple, efficient, and green strategy for improving the taste profile of SGs. Additionally, the self-aggregation of Reb A at high concentrations impairs active encapsulation and also affects its interfacial and emulsifying properties.

The clinicopathological features of lung metastases of parathyroid cancinoma.

Parathyroid carcinoma(PC) is an extremely rare malignant tumor of the parathyroid glands. The lung is the most common target organ for PC distant metastases. In this study, twelve patients diagnosed with PC with lung metastases were enrolled in the study. Hematoxylin and Eosin(H&E) stained, immunohistochemical stained and next-generation sequencing (NGS) of a 425-gene panel were performed on tumor tissue samples. At the same time, we also evaluated its histopathologic characteristics. The results indicate that the microscopic examination of metastatic lesions reveals the same structure and characteristics as PC; the tumor was composed of relatively uniform cells organized in nests and separated by thin fibrous bands and abundant blood vessels. Immunohistochemical evaluation of Ki67, CyclinD1, PTH, SYN, CgA, and CD56 was useful in diagnosing PC with lung metastases. The most frequently genetic alterations were mutations of CDC73 and copy number variation (CNV) of MCL1, with a mutation rate of 25 %. In addition, the mutations of CDC73, ATM, TP53, ALK, ERBB2, MAP3K4, TSC1, CCND1 and CNV of CDK4, MCL1, SMARCB1 overlap between metastatic lesions and primary lesions. In conclusions, PC is a rare endocrine malignant tumor that is very difficult to diagnose preoperatively and prone to clinical recurrence or distant metastasis. Genetic mutations, presentation and histological characteristic were the basis for diagnosing PC with lung metastases.

Multi-objective optimization of custom implant abutment design for enhanced bone remodeling in single-crown implants using 3D finite element analysis.

The optimal configuration of a customized implant abutment is crucial for bone remodeling and is influenced by various design parameters. This study introduces an optimization process for designing two-piece zirconia dental implant abutments. The aim is to enhance bone remodeling, increase bone density in the peri-implant region, and reduce the risk of late implant failure. A 12-month bone remodeling algorithm subroutine in finite element analysis to optimize three parameters: implant placement depth, abutment taper degree, and gingival height of the titanium base abutment. The response surface analysis shows that implant placement depth and gingival height significantly impact bone density and uniformity. The taper degree has a smaller effect on bone remodeling. The optimization identified optimal values of 1.5 mm for depth, 35° for taper, and 0.5 mm for gingival height. The optimum model significantly increased cortical bone density from 1.2 to 1.937 g/cm3 in 2 months, while the original model reached 1.91 g/cm3 in 11 months. The standard deviation of density showed more uniform bone apposition, with the optimum model showing values 2 to 6 times lower than the original over 12 months. The cancellous bone showed a similar trend. In conclusion, the depth and taper have a significant effect on bone remodeling. This optimized model significantly improves bone density uniformity.

Modulating the Bader Charge Transfer in Single p-Block Atoms Doped Pd Metallene for Enhanced Oxygen Reduction Electrocatalysis.

Metallene is considered as an emerging family of electrocatalysts due to its atomically layered structure and unique surface stress. Here we propose a strategy to modulate the Bader charge transfer (BCT) between Pd surface and oxygenated intermediates via p-d electronic interaction by introducing single-atomp-block metal (M = In, Sn, Pb, Bi) into Pd metallene nanosheets towards efficient oxygen reduction reaction (ORR). X-ray absorption and photoelectron spectroscopy suggests that doping p-block metals could facilitate electron transfer to Pd sites and thus downshift the d-band center of Pd and weaken the adsorption energy of O intermediates. Among them, the developed Bi-Pd metallene shows extraordinarily high ORR mass activity of 11.34 A mgPd-1 and 0.86 A mgPd-1 at 0.9 V and 0.95 V in alkaline solution, respectively, representing the best Pd-based ORR electrocatalysts ever reported. In the cathode of a Zinc-air battery, Bi-Pd metallene could achieve an open-circuit voltage of 1.546 V and keep stable for 760 h at 10 mA cm-2. Theoretical calculations suggest that the BCT between Pd surface and *OO intermediates greatly affects the bond length between them (dPd-*OO) and Bi doping could appropriately reduce the amount of BCT and stretch the dPd-*OO, thus enhancing the ORR activity.

Roles of cerebrospinal fluid-contacting neurons as potential neural stem cells in the repair and regeneration of spinal cord injuries.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord's central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3ß inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3ß/Nrf2 pathway.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3ß (GSK-3ß), a potential target of AD treatment. PURPOSE: To investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3ß pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. METHOD: The oxidative stress of PC12 cells was induced by H2O2 (600 µM) and the effects of TFGF-18 (2 and 8 µM) or ISO (12.5 and 50 µM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3ß (Ser9), GSK-3ß, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. RESULTS: TFGF-18 inhibited neuronal damage and the expressions of Bax caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3ß (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3ß pathway. In addition, the cholinergic system (ACh， ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. CONCLUSIONS: TFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3ß/Nrf2 pathway.

Regulation of tillage on grain matter accumulation in maize.

Introduction: To address issues related to shallow soil tillage, low soil nutrient content, and single tillage method in maize production in the Western Inner Mongolia Region, this study implemented various tillage and straw return techniques, including strip cultivation, subsoiling, deep tillage, no-tillage, straw incorporation with strip cultivation, straw incorporation with subsoiling, straw incorporation with deep tillage, and straw incorporation with no tillage, while using conventional shallow spinning by farmers as the control. Methods: We employed Xianyu 696 (XY696) and Ximeng 6 (XM6) as experimental materials to assess maize 100-grains weight, grain filling rate parameters, and grain nutrient quality. This investigation aimed to elucidate how tillage and straw return influence the accumulation of grain material in different maize varieties. Results and discussion: The results indicated that proper implementation of tillage and straw return had a significant impact on the 100-grains weight of both varieties. In comparison to CK (farmer's rotary rotation), the most notable rise in 100-grains weight was observed under the DPR treatment (straw incorporation with deep tillage), with a maximum increase of 4.84% for XY696 and 6.28% for XM6. The proper implementation of tillage and straw return in the field resulted in discernible differences in the stages of improving the grain filling rates of different maize varieties. Specifically, XY696 showed a predominant increase in the filling rate during the early stage (V1), while XM6 exhibited an increase in the filling rates during the middle and late stages (V2 and V3). In comparison to CK, V1 increased by 1.54% to 27.56% in XY696, and V2 and V3 increased by 0.41% to 10.42% in XM6 under various tillage and straw return practices. The proper implementation of tillage and straw return had a significant impact on the nutritional quality of the grains in each variety. In comparison to CK, the DPR treatment resulted in the most pronounced decrease in the soluble sugar content of grains by 25.43% and the greatest increase in the crude fat content of grains by 9.67%. Conclusion: Ultimately, the proper implementation of soil tillage and straw return facilitated an increase in grain crude fat content and significantly boosted grain weight by improving the grouting rate parameters at all stages for various maize varieties. Additionally, the utilization of DPR treatment proved to be more effective. Overall, DPR is the most promising strategy to improve maize yield and the nutritional quality of grain in the long term in the Western Inner Mongolia Region.

Nanobody Mediated Atrazine Resistance in Plants.

In planta expression of recombinant antibodies has been proposed as a strategy for herbicide resistance but is not well advanced yet. Here, an atrazine nanobody gene fused with a green fluorescent protein tag was transformed to Arabidopsis thaliana, which was confirmed with PCR, ELISA, and immunoblotting. High levels of nanobody accumulation were observed in the nucleus, cytoderm, and cytosol. The nanobody expressed in the plant had similar affinity, sensitivity, and selectivity as that expressed in Escherichia coli. The T3 homozygous line showed resistance in a dose-dependent manner up to 380 g ai/ha of atrazine, which is approximately one-third of the recommended field application rate. This is the first report of utilizing a nanobody in plants against herbicides. The results suggest that utilizing a high-affinity herbicide nanobody gene rather than increasing the expression of nanobodies in plants may be a technically viable approach to acquire commercial herbicide-resistant crops and could be a useful tool to study plant physiology.

Optimized uniform sampling and validation of fiber tracts from magnetic resonance tractography for in vivo architectural measurement of human forearm muscles.

In vivo muscle architectural parameters can be calculated from the fiber tracts using magnetic resonance (MR) tractography. However, the reconstructed tracts may be unevenly distributed within the muscle volume and there lacks commonly used metric to quantitatively evaluate the validity of the tracts. Our objective is to measure forearm muscle architecture by uniformly sampling fiber tracts from the candidate streamlines in MR tractography and validate the reconstructed fiber tracts qualitatively and quantitatively. We proposed farthest streamline sampling (FSS) to uniformly sample fiber tracts from the candidate streamlines. The method was evaluated on the MR data acquired from 12 healthy subjects for 17 forearm muscles and was compared with two conventional methods through uniform coverage performance. Anatomical correctness was verified by: 1. visually assessing fiber orientation, 2. checking whether architectural parameters were within physiological ranges and 3. classifying architectural types. The proposed FSS yielded optimal uniform coverage performance among the three methods (P<0.05). FSS reduced the sampling of long tracts (10% fiber length reduction, P<0.05), and the estimated architectural parameters were within the physiological ranges (P<0.05). The tractography visually matched cadaveric specimens. The architectural types of 16 muscles were correctly classified except for the palmaris longus, which exhibited a linear arrangement of fiber endpoints (R2 = 0.95±0.02, P<0.001). The proposed FSS method reconstructed uniformly distributed fiber tracts and the anatomical correctness of the reconstructed tracts was verified. The novel methods allow for accurate in vivo muscle architectural measurement, which was demonstrated through the characterization of architectural properties in human forearm muscles.

DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma.

Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, the mechanisms underlying this lack of benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating the response to TPF therapy in NPC patients. DCAF7 promotes the cisplatin resistance and metastasis of NPC cells in vitro and in vivo. Mechanistically, DCAF7 serves as a scaffold protein that facilitates the interaction between USP10 and G3BP1, leading to the elimination of K48-linked ubiquitin moieties from Lys76 of G3BP1. This process helps prevent the degradation of G3BP1 via the ubiquitin‒proteasome pathway and promotes the formation of stress granule (SG)-like structures. Moreover, knockdown of G3BP1 successfully reversed the formation of SG-like structures and the oncogenic effects of DCAF7. Significantly, NPC patients with increased levels of DCAF7 showed a high risk of metastasis, and elevated DCAF7 levels are linked to an unfavorable prognosis. The study reveals DCAF7 as a crucial gene for cisplatin resistance and offers further understanding of how chemoresistance develops in NPC. The DCAF7-USP10-G3BP1 axis contains potential targets and biomarkers for NPC treatment.

Synthesis of 1,2,4,5-tetra-substituted benzenes via copper-catalyzed dimerization of γ,δ-unsaturated ketones.

An efficient cyclization for the synthesis of 1,2,4,5-tetra-substituted benzenes via copper catalyzed dimerization of γ,δ-unsaturated ketones has been described. This one-pot procedure employs the γ,δ-unsaturated ketones as the sole substrate with multiple C-C bond formation. This protocol features broad substrate scope and provides a facile and robust method to construct polysubstituted benzene derivatives under mild conditions.

Protein Phosphatase 2ACα Regulates ATR-Mediated Endogenous DNA Damage Response Against Microcephaly.

Protein phosphatase 2A (PP2A) is an abundant heterotrimeric holoenzyme in eukaryotic cells coordinating with specific kinases to regulate spatial-temporal protein dephosphorylation in various biological processes. However, the function of PP2A in cortical neurogenesis remains largely unknown. Here, we report that neuronal-specific deletion of Pp2acα in mice displayed microcephaly, with significantly smaller brains and defective learning and memory ability. Mechanistically, neuronal Pp2acα deficiency resulted in elevated endogenous DNA damage and activation of ATR/CHK1 signaling. It was further induced by the loss of direct interaction between PP2AC and ATR as well as the function of PP2AC to dephosphorylate ATR. Importantly, ATR/CHK1 signaling dysregulation altered both the expression and activity of several critical downstream factors including P53, P21, Bcl2, and Bax, which led to decreased proliferation of cortical progenitor cells and increased apoptosis in developing cortical neurons. Taken together, our results indicate an essential function of PP2ACα in endogenous DNA damage response-mediated ATR signaling during neurogenesis, and defective PP2ACα in neurons contributes to microcephaly.

Mechanisms of exacerbation of Th2-mediated eosinophilic allergic asthma induced by plastic pollution derivatives (PPD): A molecular toxicological study involving lung cell ferroptosis and metabolomics.

Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.

Biological Evaluation of Lysionotin: a Novel Inhibitor of 5-Lipoxygenase for Anti-glioma.

OBJECTIVE: To explore the potential mechanism of lysionotin in treating glioma. METHODS: First, target prediction based on Bernoulli Naïve Bayes profiling and pathway enrichment was used to predict the biological activity of lysionotin. The binding between 5-lipoxygenase (5-LO) and lysionotin was detected by surface plasmon resonance (SPR) and molecular docking, and the inhibitory effects of lysionotin on 5-LO and proliferation of glioma were determined using enzyme inhibition assay in vitro and cell viability analysis, respectively. Furthermore, the pharmaceutical effect of lysionotin was explored by cell survival rate analysis and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The protein expression, intracellular calcium ion concentration and cytoskeleton detection were revealed by Western blot, flow cytometry and fluorescence labeling, respectively. RESULTS: Target prediction and pathway enrichment revealed that lysionotin inhibited 5-LO, a key enzyme involved in the arachidonic acid metabolism pathway, to inhibit the proliferation of glioma. Molecular docking results demonstrated that 5-LO can be binding to lysionotin through hydrogen bonds, forming bonds with His600, Gln557, Asn554, and His372. SPR analysis further confirmed the interaction between 5-LO and lysionotin. Furthermore, enzyme inhibition assay in vitro and cell survival rate analysis revealed that 50% inhibition concentration of lysionotin and the median effective concentration of lysionotin were 90 and 16.58 µmol/L, respectively, and the results of LC-MS/MS showed that lysionotin inhibited the production of 5S-hydroperoxy-eicosatetraenoic acid (P<0.05), and moreover, the LC-MS/MS results indicated that lysionotin can enter glioma cells well (P<0.01) and inhibit their proliferation. Western blot analysis demonstrated that lysionotin can inhibit the expression of 5-LO (P<0.05) and downstream leukotriene B4 receptor (P<0.01). In addition, the results showed that lysionotin affected intracellular calcium ion concentration by inhibiting 5-LO to affect the cytoskeleton, as determined by flow cytometry and fluorescence labeling. CONCLUSION: Lysionotin binds to 5-LO could suppress glioma by inhibiting arachiodonic acid metabolism pathway.