Guidelines derived from biomineralized tissues for design and construction of high-performance biomimetic materials: from weak to strong.

Living organisms in nature have undergone continuous evolution over billions of years, resulting in the formation of high-performance fracture-resistant biomineralized tissues such as bones and teeth to fulfill mechanical and biological functions, despite the fact that most inorganic biominerals that constitute biomineralized tissues are weak and brittle. During the long-period evolution process, nature has evolved a number of highly effective and smart strategies to design chemical compositions and structures of biomineralized tissues to enable superior properties and to adapt to surrounding environments. Most biomineralized tissues have hierarchically ordered structures consisting of very small building blocks on the nanometer scale (nanoparticles, nanofibers or nanoflakes) to reduce the inherent weaknesses and brittleness of corresponding inorganic biominerals, to prevent crack initiation and propagation, and to allow high defect tolerance. The bioinspired principles derived from biomineralized tissues are indispensable for designing and constructing high-performance biomimetic materials. In recent years, a large number of high-performance biomimetic materials have been prepared based on these bioinspired principles with a large volume of literature covering this topic. Therefore, a timely and comprehensive review on this hot topic is highly important and contributes to the future development of this rapidly evolving research field. This review article aims to be comprehensive, authoritative, and critical with wide general interest to the science community, summarizing recent advances in revealing the formation processes, composition, and structures of biomineralized tissues, providing in-depth insights into guidelines derived from biomineralized tissues for the design and construction of high-performance biomimetic materials, and discussing recent progress, current research trends, key problems, future main research directions and challenges, and future perspectives in this exciting and rapidly evolving research field.

Adenoid cystic carcinoma of the Bartholin's gland is underpinned by MYB- and MYBL1- rearrangements.

OBJECTIVE: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize the molecular underpinning of AdCC-BGs. METHODS: AdCC-BGs (n = 6) were subjected to a combination of RNA-sequencing, targeted DNA-sequencing, reverse-transcription PCR, fluorescence in situ hybridization (FISH) and MYB immunohistochemistry (IHC). Clinicopathologic variables, somatic mutations, copy number alterations and chimeric transcripts were assessed. RESULTS: All six AdCC-BGs were biphasic, composed of ductal and myoepithelial cells. Akin to salivary gland and breast AdCCs, three AdCC-BGs had the MYB::NFIB fusion gene with varying breakpoints, all of which were associated with MYB overexpression by IHC. Two AdCC-BGs were underpinned by MYBL1 fusion genes with different gene partners, including MYBL1::RAD51B and MYBL1::EWSR1 gene fusions, and showed MYB protein expression. Although the final AdCC-BG studied had MYB protein overexpression, no gene fusion was identified. AdCC-BGs harbored few additional somatic genetic alterations, and only few mutations in cancer-related genes were identified, including GNAQ, GNAS, KDM6A, AKT1 and BCL2, none of which were recurrent. Two AdCC-BGs, both with a MYB::NFIB fusion gene, developed metastatic disease. CONCLUSIONS: AdCC-BGs constitute a convergent phenotype, whereby activation of MYB or MYBL1 can be driven by the MYB::NFIB fusion gene or MYBL1 rearrangements. Our observations further support the notion that AdCCs, irrespective of organ site, constitute a genotypic-phenotypic correlation. Assessment of MYB or MYBL1 rearrangements may be used as an ancillary marker for the diagnosis of AdCC-BGs.

3.73 W all-solid-state dual-wavelength Nd:Lu2O3 crystal laser.

The laser output characteristics of N d:L u 2 O 3 crystals were investigated in detail to obtain a dual-wavelength all-solid-state laser. Using 806 nm LD end-face pumped N d:L u 2 O 3 crystals with lengths of 6 mm, a 1076 & 1080 nm laser outputs with a maximum output power of 3.73 W were obtained, with a slope efficiency of 30.4%, an optical-to-optical conversion efficiency of 28.5%, and a power stability of 0.41% for 4 h of continuous measurement. Furthermore, by suppressing the higher-order modes, a high beam quality laser output with beam quality factors of 2.092 and 1.589 in the x and y directions, respectively, and a maximum output power of 1.27 W were obtained. In addition, it was experimentally verified that both wavelengths of the output laser were elliptically polarized.

Association between life's essential 8 and frailty status among cancer survivors in the United States: a cross-sectional analysis.

BACKGROUND: Frailty not only affects disease survival but also impacts the long-term function and quality life of all adults diagnosed with and/or treated for cancer.The American Heart Association has introduced Life's Essential 8 (LE8) as a novel metric for assessing cardiovascular health. Currently, LE8's application in evaluating the frailty of cancer survivors remains unreported. This research seeks to explore the connection between LE8 scores and frailty levels in cancer survivors across the United States, thereby addressing a significant void in existing studies. METHODS: This study analyzed data from cancer survivors enrolled in the National Health and Nutrition Examination Surveys (NHANES) spanning the years 2005 to 2018, providing a comprehensive dataset. Multivariable logistic regression models were used to examine the linkage between LE8 rankings and frailty condition in cancer survivors. Furthermore, the study delved deeper into this correlation using restricted cubic spline (RCS) curves and subgroup analyses. RESULTS: In the fully adjusted model, an increased LE8 level was closely associated with a reduced odds ratio of frailty among cancer survivors, with an OR of 0.95 (95% CI: 0.94-0.96, p < 0.0001).This pattern persisted across different categorizations of LE8 into low, moderate, and high groups, demonstrating a consistent trend. The analysis revealed a non-linear relationship between LE8 scores and frailty status, further supporting a straightforward association (p-value for non-linearity = 0.0729). CONCLUSION: Studies have found that the higher the LE8 score, the less likely a cancer patient is to develop debilitating symptoms.This indicates that the LE8 scores may provide an opportunity for interventions aimed at improving the prognosis of cancer patients.

Ultralong Nanowires of Cadmium Phosphate Hydroxide Synthesized Using a Cadmium Oleate Precursor Hydrothermal Method and Sulfidation Conversion to Ultralong CdS Nanowires.

Ultralong nanowires with ultrahigh aspect ratios exhibit high flexibility, and they are promising for applications in various fields. Herein, a cadmium oleate precursor hydrothermal method is developed for the synthesis of ultralong nanowires of cadmium phosphate hydroxide. In this method, water-soluble cadmium salt is used as the cadmium source, water-soluble phosphate is used as the phosphorus source, and sodium oleate is adopted as a reactant to form cadmium oleate precursor and as a structure-directing agent. By using this method, ultralong nanowires of cadmium phosphate hydroxide are successfully synthesized using CdCl2, sodium oleate, and NaH2PO4 as reactants in an aqueous solution by hydrothermal treatment at 180 °C for 24 h. In addition, a new type of flexible fire-resistant inorganic paper with good electrical insulation performance is fabricated using ultralong nanowires of cadmium phosphate hydroxide. As an example of the extended application of this synthetic method, ultralong nanowires of cadmium phosphate hydroxide can be converted to ultralong CdS nanowires through a convenient sulfidation reaction. In this way, ultralong CdS nanowires are successfully synthesized by simple sulfidation of ultralong nanowires of cadmium phosphate hydroxide under mild conditions. The as-prepared ultralong nanowires of cadmium phosphate hydroxide are promising for applications as the precursors and templates for synthesizing other inorganic ultralong nanowires and have wide applications in various fields.

Channel semantic mutual learning for visible-thermal person re-identification.

Visible-infrared person re-identification (VI-ReID) is a cross-modality retrieval issue aiming to match the same pedestrian between visible and infrared cameras. Thus, the modality discrepancy presents a significant challenge for this task. Most methods employ different networks to extract features that are invariant between modalities. While we propose a novel channel semantic mutual learning network (CSMN), which attributes the difference in semantics between modalities to the difference at the channel level, it optimises the semantic consistency between channels from two perspectives: the local inter-channel semantics and the global inter-modal semantics. Meanwhile, we design a channel-level auto-guided double metric loss (CADM) to learn modality-invariant features and the sample distribution in a fine-grained manner. We conducted experiments on RegDB and SYSU-MM01, and the experimental results validate the superiority of CSMN. Especially on RegDB datasets, CSMN improves the current best performance by 3.43% and 0.5% on the Rank-1 score and mINP value, respectively. The code is available at https://github.com/013zyj/CSMN.

Inactivation of cGAS signaling pathway mediated by TDP-43 deficiency protects microglia from hypoxia/reoxygenation induced injury.

BACKGROUND: Microglia are damaged during cerebral ischemia-reperfusion (I/R). This study was performed to investigate the regulatory effect of tAR DNA-binding protein-43 (TDP-43) on microglia after cerebral I/R in vitro and in vivo. METHOD: The hypoxia/reoxygenation (H/R) treated microglia and rats with middle cerebral artery occlusion surgery were constructed respectively. The TDP-43 expression in brain tissues and microglia of each group was evaluated by qPCR and western blotting methods. Cell viability and cell apoptosis were combined to evaluate the degree of cell injury. As for animal experiments, neurological score and infarct volume were obtained to evaluate neurological injury. RESULTS: The levels of TDP-43 in the brain tissues of I/R group were higher than that in sham group. Both TDP-43 and Iba1, a typical microglia marker, were expressed in the brain tissues. TDP-43 was also elevated in microglia with H/R treatment. Inhibition of TDP-43 significantly down-regulated neurological deficit scores of rats after I/R surgery, and weakened the H/R treatment induced injury by promoting cell viability, inhibiting cell apoptosis, down-regulating IL-6 and iNOS levels, and up-regulating Arg-1 and IL-10 levels. Inactivation of cGAS pathway mediated by TDP-43 knockdown protects microglia from H/R treatment induced injury. CONCLUSION: The highly expressed TDP-43 level is associated with cerebral I/R, and inhibition of TDP-43 protects microglia from H/R induced injury through cGAS pathway in vitro and in vivo.

Geriatric nutritional risk index and mortality from all-cause, cancer, and non-cancer in US cancer survivors: NHANES 2001-2018.

Background: Malnutrition is strongly correlated with worsened treatment outcomes, reduced standard of living, and heightened mortality rates among individuals with cancer. Our research explores how the Geriatric Nutritional Risk Index (GNRI), a measure of nutritional status, relates to all-cause mortality, cancer-specific, and non-cancer mortality among middle-aged and older adult cancer patients. Methods: We enrolled 3,253 participants aged 40 and above who were diagnosed with cancer. The data was obtained from the National Health and Nutrition Examination Survey (NHANES) dataset covering the period from 2001 to 2018, with a median follow-up duration of 83 months. According to the GNRI levels, patients in the study were classified into two distinct groups: the group with a low GNRI (<98) and the group with a high GNRI (≥ 98). We conducted a Kaplan-Meier survival analysis to assess how survival rates vary with different nutritional conditions. Multivariable Cox regression analyses were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality, as well as cancer-specific and non-cancer-related mortality. Restricted cubic spline (RCS) analyses and subgroup evaluations were performed to augment the robustness and validity of our findings. Results: A total of 1,171 deaths were documented, with 383 attributed to cancer, and 788 from other causes. After adjusting for potential confounders, the analysis demonstrated that, within a specified range, an elevation in the GNRI is inversely associated with mortality from all causes, cancer-specific, and non-cancer causes. Moreover, Kaplan-Meier survival curves for all-cause, cancer-specific, and non-cancer mortality distinctly showed a more pronounced decrease in survival rates among individuals in the low GNRI group (<98). Notably, the restricted cubic spline regression model (RCS) revealed statistically significant non-linear associations between GNRI scores and mortality rates. The P-values were ≤0.001 for both all-cause and non-cancer mortality, and 0.024 for cancer-specific mortality. Conclusion: Our study conclusively demonstrated a robust correlation between GNRI scores and mortality rates among cancer patients, encompassing all-cause mortality as well as specific mortality related to both cancerous and non-cancerous causes. The GNRI may be a valuable prognostic tool for predicting cancer mortality outcomes, offering insights that may inform nutritional management and influence the clinical treatment strategies for cancer survivors.

The secondary visual cortex mediated the enhancement of associative learning on methamphetamine self-administration behaviors.

RATIONALE: Methamphetamine addiction is a persistent and intractable pathological learning and memory, whereas no approved therapeutics is available. However, few attentions have been paid to how associative learning participates in the formation of intractable memory related to drug addiction OBJECTIVES AND METHODS: To investigate the role of associative learning in methamphetamine addiction and the underlying neurobiological mechanism, methamphetamine self-administration, oral sucrose self-administration, chemogenetic neuromanipulation, and fiber photometry in mice were performed in this study. RESULTS: We reported that associative learning increased methamphetamine-induced self-administration, but not oral sucrose self-administration. In addition, the enhancement of methamphetamine-induced self-administration was independent of more methamphetamine consumption, and remained with higher drug-taking and motivation in the absence of visual cues, suggesting the direct effects of the associative learning that enhanced methamphetamine-induced self-administration. Moreover, chemogenetic inactivation of the secondary visual cortex (V2) reduced the enhancement of the drug-taking induced by associative learning but did not alter sucrose-taking. Further fiber photometry of V2 neurons demonstrated that methamphetamine-associative learning elicits V2 neuron excitation, and sucrose-associative learning elicits V2 neuron inhibition. CONCLUSIONS: Therefore, this study reveals the neurobiological mechanism of V2 excitability underlying how associative learning participates in the formation of intractable memory related to drug addiction, and gives evidence to support V2 as a promising target for stimulation therapy for methamphetamine addiction.

Salt-rejecting 3D cone flowing evaporator based on bilayer photothermal paper for high-performance solar seawater desalination.

Solar energy-driven water evaporation technology is a promising, low-cost and sustainable approach to alleviate the global clean water shortage, but usually suffers from low water evaporation rate and severe salt deposition on the water evaporation surface. In this work, a hydrophilic bilayer photothermal paper-based three-dimensional (3D) cone flowing evaporator was designed and prepared for stable high-performance seawater desalination with excellent salt-rejecting ability. The as-prepared bilayer photothermal paper consisted of MXene (Ti3C2Tx) and HAA (ultralong hydroxyapatite nanowires, poly(acrylic acid), and poly(acrylic acid-2-hydroxyethyl ester)). The accordion-like multilayered MXene acted as the efficient solar light absorber, and ultralong hydroxyapatite (HAP) nanowires served as the thermally insulating and supporting skeleton with a porous networked structure. A siphon effect-driven unidirectional fluid transportation unit in the 3D cone flowing evaporator could guide the concentrated saline flowing away from the evaporating surface to prevent salt deposition on the evaporation surface, avoiding severe deterioration of the performance in solar water evaporation. Furthermore, combining high solar light absorption and high photothermal conversion efficiencies, low water evaporation enthalpy (1838 ±â€¯11 J g-1), and additional energy taken from the ambient environment, the as-prepared cone flowing evaporator exhibited a high water evaporation rate of 3.22 ±â€¯0.20 kg m-2 h-1 for real seawater under one sun illumination (1 kW m-2), which was significantly higher than many values reported in the literature. This study provides an effective approach for designing high-performance solar energy-driven water evaporators for sustainable seawater desalination and wastewater purification.

Synergistically regulating the separator pore structure and surface property toward dendrite-free and high-performance aqueous zinc-ion batteries.

As an emerging electrochemical device, aqueous zinc-ion batteries (ZIBs) present promising potential in safe and large-scale energy storage. However, the large pores of commercial glass fiber (GF) separators result in uneven Zn2+ ion flux, leading to severe dendrite growth issues of Zn metal anodes. Herein, we integrated a multifunctional layer on the GF separator that can synergistically regulate the pore feature and surface property of commercial GF separators. Such modification layer, composed of nanocellulose and SiO2 nanoparticles, exhibited uniform nanoporous structure and abundant negatively charged polar functional groups. These features allow regulating the distribution of Zn2+ ions at the separator-anode interface, facilitating stable and uniform Zn nucleation and growth. Moreover, the electrostatic interaction between the negatively charged functional groups and Zn2+ ions enhanced the Zn2+ ion transport kinetics, preventing the Zn dendrites formation and adverse reactions. Consequently, the modified electrolyte-filled GF separator showed an increased Zn2+ ion transference number of 0.65. The symmetric Zn//Zn batteries utilizing such a separator achieved an impressive cycling life of 500 h at a high current density/capacity of 10 mA cm-2/4 mAh cm-2, nearly nine times longer than the battery using the unmodified GF separator (<55 h). The superior electrochemical performance was verified in both Zn//AC and Zn//LiMn2O4 full battery evaluations. This work presents a novel synergistic modification strategy for developing advanced separators for aqueous ZIBs.

Neuronal activity in the anterior paraventricular nucleus of thalamus positively correlated with sweetener consumption in mice.

Although the brain can discriminate between various sweet substances, the underlying neural mechanisms of this complex behavior remain elusive. This study examines the role of the anterior paraventricular nucleus of the thalamus (aPVT) in governing sweet preference in mice. We fed the mice six different diets with equal sweetness for six weeks: control diet (CD), high sucrose diet (HSD), high stevioside diet (HSSD), high xylitol diet (HXD), high glycyrrhizin diet (HGD), and high mogroside diet (HMD). The mice exhibited a marked preference specifically for the HSD and HSSD. Following consumption of these diets, c-Fos expression levels in the aPVT were significantly higher in these two groups compared to the others. Utilizing fiber photometry calcium imaging, we observed rapid activation of aPVT neurons in response to sucrose and stevioside intake, but not to xylitol or water. Our findings suggest that aPVT activity aligns with sweet preference in mice, and notably, stevioside is the sole plant-based sweetener that elicits an aPVT response comparable to that of sucrose.

Simulating PDT of port-wine stains in the in vivo chicken wattle model using Hemoporfin and radiation at 532 nm: Comparison of a LED and a laser source.

Port-wine stain (PWS) birthmarks are congenital capillary malformations occurring in 0.3 %∼0.5 % of newborns. Hemoporfin-mediated vascular-acting photodynamic therapy (Hemoporfin PDT) is an emerging option for treating PWS. This in vivo study aimed to compare laser and light-emitting diodes (LED) as light source for Hemoporfin PDT. Chicken wattles were used as the animal model. Color and histopathological changes were evaluated after combining Hemoporfin with KTP laser or LED light source of 532 nm at the same doses. Both PDT approaches could induce significant vascular injury and color bleaching. Although the use of the laser resulted in a greater vascular clearance, the LED showed more uniform distribution both in the beam profiles and tissue reaction and exhibited better safety. This in vivo study suggests that the LED is a favorable choice for larger PWS lesion.

Identification and Functional Characterization of Oxidosqualene Cyclases from Medicinal Plant Hoodia gordonii.

Oxidosqualene cyclases (OSCs) are the key enzymes accountable for the cyclization of 2,3-oxidosqualene to varied triterpenoids and phytosterols. Hoodia gordonii (from the family Apocynaceae), a native of the Kalahari deserts of South Africa, Namibia, and Botswana, is being sold as a prevalent herbal supplement for weight loss. The appetite suppressant properties are attributed to P57AS3, an oxypregnane steroidal glycoside. At the molecular level, the enzymes involved in the biosynthesis of triterpenes and phytosterols from H. gordonii have not been previously reported. In the current study, predicted transcripts potentially encoding oxidosqualene cyclases were recognized first by searching publicly available H. gordonii RNA-seq datasets. Two OSC-like sequences were selected for functional analysis. A monofunctional OSC, designated HgOSC1 which encodes lupeol synthase, and HgOSC2, a multifunctional cycloartenol synthase forming cycloartenol and other products, were observed through recombinant enzyme studies. These studies revealed that distinct OSCs exist for triterpene formation in H. gordonii and provided opportunities for the metabolic engineering of specific precursors in producing phytosterols in this plant species.

Littoral cell angioma of the spleen: A study of 10 cases case series and literature review.

BACKGROUND: Current study aimed to investigate the clinical characterization, differential diagnosis, and treatment of splenic littoral cell angioma (LCA). METHODS: A retrospective analysis was performed for 10 LCA cases admitted to Huzhou Central Hospital from 2007 to 2023, for clinical manifestations, hematological tests, imaging features, pathological features, treatment methods, and prognosis along with the relevant literature was also reviewed. RESULTS: During examinations, no specific clinical manifestations and hematological abnormalities were seen in all 10 cases of LCA. Imaging observations depicted single or even multiple spherical lesions in the spleen. Plains shown by computed tomography (CT) were found somewhat equal or slightly lower in density. On the other hand, magnetic resonance imaging (MRI) plain scans viz. T1 weighted image showed equal low and mixed signals while T2-weighted showed high and low mixed signals. Moreover, punctate low signals could be seen in high signals named "freckle sign" in MRI scans. On contrast-enhanced CT scans, the enhancement of the lesions was not obvious in the arterial phase, and some of the lesions showed edged ring-like enhancements and "filling lake" progressive enhancement during the venous phase and delayed phase. In multiple lesions, the number of enhanced scan lesions showed a variable changing pattern "less-more-less." MRI-enhanced scan showed the characteristics of "fast in and slow out." Microscopic examinations identified tumor tissue actually composed of sinus-like lacunae that anastomosed with each other in the form of a network. Furthermore, cystic expansion and pseudopapillary protrusions were also seen in the dilated sinus cavity which was lined with single-layer endothelial cells having conspicuous cytoplasmic hemosiderin. High immunophenotypic expressions of vascular endothelial cell phenotype (CD31, CD34, FVIII) and tissue cell phenotype (CD68) were also seen. Total and partial splenectomy were performed in 8 and 2 patients, respectively, and follow-up examinations showed survival in all patients with no recurrence. CONCLUSION: LCA is a rare splenic benign lesion with atypical clinical manifestations. CT and MRI imaging are important tools in preoperative diagnosis based on pathomorphological and immunohistochemical examinations. Splenectomy is a superior therapeutic choice with significant impacts and prognosis.

Functionalized chitosan hydrogel promotes osseointegration at the interface of3D printed titanium alloy scaffolds.

Autogenous bone transplantation is a prevalent clinical method for addressing bone defects. However, the limited availability of donor bone and the morbidity associated with bone harvesting have propelled the search for suitable bone substitutes. Bio-inspired scaffolds, particularly those fabricated using electron beam melting (EBM) deposition technology, have emerged as a significant advancement in this field. These 3D-printed titanium alloy scaffolds are celebrated for their outstanding biocompatibility and favorable elastic modulus. Thermosensitive chitosan hydrogel, which transitions from liquid to solid at body temperature, serves as a popular carrier in bone tissue engineering. Icariin (ICA), known for its efficacy in promoting osteoblast differentiation from bone marrow mesenchymal stem cells (BMSCs), plays a crucial role in this context. We developed a system combining a 3D-printed titanium alloy with a thermosensitive chitosan hydrogel, capable of local bone regeneration and integration through ICA delivery. Our in vitro findings reveal that this system can gradually release ICA, demonstrating excellent biocompatibility while fostering BMSC proliferation and osteogenic differentiation. Immunohistochemistry and Micro-CT analyses further confirm the effectiveness of the system in accelerating in vivo bone regeneration and enhancing osseointegration. This composite system lays a significant theoretical foundation for advancing local bone regeneration and integration.

Correction: Steam turbine power prediction based on encode-decoder framework guided by the condenser vacuum degree.

[This corrects the article DOI: 10.1371/journal.pone.0275998.].

Zona incerta mediates early life isoflurane-induced fear memory deficits.

The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.

Highly sensitive and accurate measurement of underivatized phosphoenolpyruvate in plasma and serum via EDTA-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry.

Phosphoenolpyruvate (PEP) is an essential intermediate metabolite that is involved in various vital biochemical reactions. However, achieving the direct and accurate quantification of PEP in plasma or serum poses a significant challenge owing to its strong polarity and metal affinity. In this study, a sensitive method for the direct determination of PEP in plasma and serum based on ethylenediaminetetraacetic acid (EDTA)-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry was developed. Superior chromatographic retention and peak shapes were achieved using a zwitterionic stationary-phase HILIC column with a metal-inert inner surface. Efficient dechelation of PEP-metal complexes in serum/plasma samples was achieved through the introduction of EDTA, resulting in a significant enhancement of the PEP signal. A PEP isotopically labelled standard was employed as a surrogate analyte for the determination of endogenous PEP, and validation assessments proved the sensitivity, selectivity, and reproducibility of this method. The method was applied to the comparative quantification of PEP in plasma and serum samples from mice and rats, as well as in HepG2 cells, HEK293T cells, and erythrocytes; the results confirmed its applicability in PEP-related biomedical research. The developed method can quantify PEP in diverse biological matrices, providing a feasible opportunity to investigate the role of PEP in relevant biomedical research.

Combination of biotransformation and metabolomics reveals tolfenpyrad-induced hepatocytotoxicity.

Tolfenpyrad (TFP) is an extensively used pesticide that inevitably leads to human exposure to both TFP and its transformation product residues. However, the biotransformation of TFP in humans has not been elucidated, and the toxicity of TFP along with its biotransformation products remains largely unknown. In this study, the biotransformation process of TFP was investigated using human liver microsomes and human hepatic cells. Endogenous metabolic changes in the cells were studied to investigate the hepatocytotoxicity of TFP at environmentally relevant concentrations. Fourteen phase I biotransformation products and four phase II TFP products were characterized, among which twelve products were identified for the first time. The oxidative product tolfenpyrad-benzoic acid (PT-CA) was particularly abundant and stable. Further hepatotoxicity assessments and metabolic studies demonstrated comparable metabolic profiles for TFP and PT-CA in HepG2 cells, with both significantly disrupting purine and glutathione metabolism. These processes are closely associated with oxidative stress, mitochondrial damage, and cell death. Our results provide novel perspectives on the biotransformation, metabolism, and hepatotoxicity of TFP, thereby highlighting the non-negligible toxicity of its crucial biotransformation product PT-CA in environmental risk assessments.