Design and synthesis of new alfa-naphthoflavanones as potent and selective CYP1B1 inhibitors.

Natural Flavanones are abundant in human diet and a few of them exhibited chemopreventive effects against xenobiotic procarcinogens through the inhibition of tumour specific CYP1B1 enzyme. Herein, a series of new alfa-naphthoflavanones were synthesised and evaluated for their enzymatic inhibitory potency and selectivity of CYP1B1 over its isoenzyme CYP1A1. The most active compound 8c displayed highest inhibitory potency against CYP1B1 with the IC50 value of 0.1 nM. The structure activity relationship studies implied that the methoxy groups on the core scaffold of naphthalene ring significantly influenced CYP1B1 inhibition efficacy, while B-ring substitutions played important roles in activity. Molecular docking studies were conducted to provide a better understanding on the key structural features involved in CYP1B1 inhibitory activity. The results of the study implied that these naphthoflavanones could be considered as new leads and further investigation be conducted to explore the flavanone scaffold as skeleton for inhibiting CYP1B1.

Quantitative urinary proteome analysis reveals potential biomarkers for disease activity of Behcet's disease uveitis.

PURPOSE: Behçet's disease-associated uveitis (BDU) is a severe, recurrent inflammatory condition affecting the eye and is part of a systemic vasculitis with unknown etiology, making biomarker discovery essential for disease management. In this study, we intend to investigate potential urinary biomarkers to monitor the disease activity of BDU. METHODS: Firstly, label-free data-dependent acquisition (DDA) and tandem mass tag (TMT)-labeled quantitative proteomics methods were used to profile the proteomes of urine from active and quiescent BDU patients, respectively. For further exploration, the remaining fifty urine samples were analyzed by a data-independent acquisition (DIA) quantitative proteomics method. RESULTS: Twenty-nine and 21 differential proteins were identified in the same urine from BDU patients by label-free DDA and TMT-labeled analyses, respectively. Seventy-nine differentially expressed proteins (DEPs) were significantly changed in other active BDU urine samples compared to those in quiescent BDU urine samples by IDA analysis. Gene Ontology (GO) and protein-protein interaction (PPI) analyses revealed that the DEPs were associated with multiple functions, including the immune and neutrophil activation responses. Finally, seven proteins were identified as candidate biomarkers for BDU monitoring and recurrence prediction, namely, CD38, KCRB, DPP4, FUCA2, MTPN, S100A8 and S100A9. CONCLUSIONS: Our results showed that urine can be a good source of biomarkers for BDU. These dysregulated proteins provide potential urinary biomarkers for BDU activity monitoring and provide valuable clues for the analysis of the pathogenic mechanisms of BDU.

The safety and efficacy of the re-administration of gilteritinib in a patient with FLT3-mutated R/R AML with CNS relapse: a case report.

FLT3-ITD is a type of poor prognostic factors in acute myeloid leukemia (AML) disease. Gilteritinib, the second-generation FLT3 tyrosine kinase inhibitor, improved the overall survival of patients with relapsed/refractory FLT3-mutated AML in the ADMIRAL phase III trial. However, few data are available on the efficacy and safety of gilteritinib-based therapy for FLT3-mutated AML with central nervous system (CNS) involvement. We performed gilteritinib to treat a patient with CNS relapsed AML after allogeneic hematopoietic stem cell transplantation. The positive antileukemic effect of gilteritinib may bring new hope for the treatment of FLT3-mutated AML with CNS relapse.

Urinary complement factor D is increased in primary malignant hypertension: a single-center, cross-sectional study.

Kidney injury is one of the detrimental consequences of primary malignant hypertension (pMHTN). There is a paucity of non-invasive biomarkers to enhance diagnosis and elucidate the underlying mechanisms. This study aims to explore urine protein biomarkers for pMHTN associated renal damage. In the discovery phase, urine samples were collected from 8 pMHTN, 19 disease controls (DCs), and 5 healthy controls (HCs). In-gel digestion combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach was used for identification of proteins associated with pMHTN. In the validation phase, the differentially expressed proteins were validated by ELISA assay in cohort with 10 pMHTN patients, 37 DCs, and 30 HCs. Compared to DCs and HCs, a specific band between 15 and 25 kDa was found in 7 out of 8 patients with pMHTN. Further LC-MS/MS analysis revealed 5 differentially expressed proteins. ELISA validation demonstrated that urinary complement factor D (CFD) was significantly up regulated in pMHTN. By receiver operating characteristic curve analysis, urinary CFD/Cr showed moderate potential in discriminating pMHTN from DCs (the area under curve: 0.822, 95% CI 0.618-0.962). Urinary CFD may be a potential biomarker for pMHTN with its elevation indicative of the activation of the alternative complement pathway in pMHTN.

Correlation between serum uric acid to high-density lipoprotein cholesterol ratio and atrial fibrillation in patients with NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has been shown to be closely associated with cardiovascular disease (CVD) and NAFLD. The aim of this study is to clarify whether elevated UHR is associated with the occurrence of AF in patients with NAFLD and to determine whether UHR predicted AF. METHODS: Patients diagnosed with NAFLD in the Department of Cardiovascular Medicine of the Second Hospital of Shanxi Medical University from January 1, 2020, to December 31, 2021, were retrospectively enrolled in this study. The study subjects were categorized into AF group and non-AF group based on the presence or absence of combined AF. Logistic regression was performed to evaluate the correlation between UHR and AF. Sensitivity analysis and subgroup interaction analysis were performed to verify the robustness of the study results. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for UHR to predict the development of AF in patients with NAFLD. RESULTS: A total of 421 patients with NAFLD were included, including 171 in the AF group and 250 in the non-AF group. In the univariate regression analysis, NAFLD patients with higher UHR were more likely to experience AF, and the risk of AF persisted after confounding factors were adjusted for (OR: 1.010, 95%CI: 1.007-1.013, P<0.001). AF risk increased with increasing UHR quartile (P for trend < 0.001). Despite normal serum UA and HDL-C, UHR was still connected with AF in patients with NAFLD. All subgroup variables did not interact significantly with UHR in the subgroup analysis. The ROC curve analysis showed that the areas under the curve for UA, HDL-C, and UHR were 0.702, 0.606, and 0.720, respectively, suggesting that UHR has a higher predictive value for AF occurrence in NAFLD patients compared to HDL-C or UA alone. CONCLUSION: Increased UHR level was independently correlated with a high risk of AF in NAFLD patients.

Urine Proteomic Signatures of Mild Hypothermia Treatment in Cerebral Ischemia-Reperfusion Injury in Rats.

Mild hypothermia (MH) is an effective measure to alleviate cerebral ischemia-reperfusion (I/R) injury. However, the underlying biological mechanisms remain unclear. This study set out to investigate dynamic changes in urinary proteome due to MH in rats with cerebral I/R injury and explore the neuroprotective mechanisms of MH. A Pulsinelli's four-vessel occlusion (4-VO) rat model was used to mimic global cerebral I/R injury. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to profile the urinary proteome of rats with/without MH (32 °C) treatment after I/R injury. Representative differentially expressed proteins (DEPs) associated with MH were validated by western blotting in hippocampus. A total of 597 urinary proteins were identified, among which 119 demonstrated significant changes associated with MH. Gene Ontology (GO) annotation of the DEPs revealed that MH significantly enriched in endopeptidase activity, inflammatory response, aging, response to oxidative stress and reactive oxygen species, blood coagulation, and cell adhesion. Notably, changes in 12 DEPs were significantly reversed by MH treatment. Among them, 8 differential urinary proteins were previously reported to be closely associated with brain disease, including NP, FZD1, B2M, EPCR, ATRN, MB, CA1and VPS4A. Two representative proteins (FZD1, B2M) were further validated by western blotting in the hippocampus and the results were shown to be consistent with urinary proteomic analysis. Overall, this study strengthens the idea that urinary proteome can sensitively reflect pathophysiological changes in the brain, and appears to be the first study to explore the neuroprotective effects of MH by urinary proteomic analysis. FZD1 and B2M may be involved in the most fundamental molecular biological mechanisms of MH neuroprotection.

AI-Enabled Portable E-Nose Regression Predicting Harmful Molecules in a Gas Mixture.

The biomimetic electronic nose (e-nose) technology is a novel technology used for the identification and monitoring of complex gas molecules, and it is gaining significance in this field. However, due to the complexity and multiplicity of gas mixtures, the accuracy of electronic noses in predicting gas concentrations using traditional regression algorithms is not ideal. This paper presents a solution to the difficulty by introducing a fusion network model that utilizes a transformer-based multikernel feature fusion (TMKFF) module combined with a 1DCNN_LSTM network to enhance the accuracy of regression prediction for gas mixture concentrations using a portable electronic nose. The experimental findings demonstrate that the regression prediction performance of the fusion network is significantly superior to that of single models such as convolutional neural network (CNN) and long short-term memory (LSTM). The present study demonstrates the efficacy of our fusion network model in accurately predicting the concentrations of multiple target gases, such as SO2, NO2, and CO, in a gas mixture. Specifically, our algorithm exhibits substantial benefits in enhancing the prediction performance of low-concentration SO2 gas, which is a noteworthy achievement. The determination coefficient (R2) values of 93, 98, and 99% correspondingly demonstrate that the model is very capable of explaining the variation in the concentration of the target gases. The root-mean-square errors (RMSE) are 0.0760, 0.0711, and 3.3825, respectively, while the mean absolute errors (MAE) are 0.0507, 0.0549, and 2.5874, respectively. These results indicate that the model has relatively small prediction errors. The method we have developed holds significant potential for practical applications in detecting atmospheric pollution detection and other molecular detection areas in complex environments.

A joint population pharmacokinetic model to assess the high variability of whole-blood and intracellular tacrolimus in early adult renal transplant recipients.

Tacrolimus (TAC) has high pharmacokinetic (PK) variability during the early transplantation period. The relationships between whole-blood and intracellular TAC concentrations and clinical outcomes remain controversial. This study identifies the factors affecting the PK variability of TAC and characterizes the relationships between whole-blood and intracellular TAC concentrations. Data regarding whole-blood TAC concentrations of 1,787 samples from 215 renal transplant recipients (<90 days postoperative) across two centers and intracellular TAC concentrations (648 samples) digitized from previous studies were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were screened, and the distribution of whole-blood to intracellular TAC concentration ratios (RWB:IC) was estimated. The final model was evaluated using bootstrap, goodness of fit, and prediction-corrected visual predictive checks. The optimal dosing regimens and target ranges for each type of immune cell subsets were determined using Monte Carlo simulations. A two-compartment model adequately described the data, and the estimated mean TAC CL/F was 23.6 L·h-1 (relative standard error: 11.5 %). The hematocrit level, CYP3A5*3 carrier status, co-administration with Wuzhi capsules, and tapering prednisolone dose may contribute to the high variability of TAC PK variability during the early post-transplant period. The estimated RWB:IC of all TAC concentrations in peripheral blood mononuclear cells (PBMCs) was 4940, and inter-center variability of PBMCs was observed. The simulated TAC target range in PBMCs was 20.2-85.9 pg·million cells-1. Inter-center variability in intracellular concentrations should be taken into account in further analyses. TAC dosage adjustments can be guided based on PK/PD variability and simulated intracellular concentrations.

Dynamics and timing of diversification events of ciliated eukaryotes from a large phylogenomic perspective.

Ciliophora, an exceptionally diverse lineage of unicellular eukaryotes, exhibits a remarkable range of species richness across classes in the ciliate Tree of Life. In this study, we have acquired transcriptome and genome data from 40 representative species in seven ciliate classes. Utilizing 247 genes and 105 taxa, we devised a comprehensive phylogenomic tree for Ciliophora, encompassing over 60 % of orders and constituting the most extensive dataset of ciliate species to date. We established a robust phylogenetic framework that encompasses ambiguous taxa and the major classes within the phylum. Our findings support the monophyly of each of two subphyla (Postciliodesmatophora and Intramacronucleata), along with three subclades (Protocruzia, CONTHREEP, and SAPML) nested within Intramacronucleata, and elucidate evolutionary positions among the major classes within the phylum. Drawing on the robust ciliate Tree of Life and three constraints, we estimated the radiation of Ciliophora around 1175 Ma during the middle of the Proterozoic Eon, and most of the ciliate classes diverged from their sister lineage during the latter half of this period. Additionally, based on the time-calibrated tree and species richness pattern, we investigated net diversification rates of Ciliophora and its classes. The global net diversification rate for Ciliophora was estimated at 0.004979 species/Ma. Heterogeneity in net diversification rates was evident at the class level, with faster rates observed in Oligohymenophorea and Spirotrichea than other classes within the subclades CONTHREEP and SAPML, respectively. Notably, our analysis suggests that variations in net diversification rates, rather than clade ages, appear to contribute to the differences in species richness in Ciliophora at the class level.

Recent advances in the applications of DNA frameworks in liquid biopsy: A review.

Cancer is one of the serious threats to public life and health. Early diagnosis, real-time monitoring, and individualized treatment are the keys to improve the survival rate and prolong the survival time of cancer patients. Liquid biopsy is a potential technique for cancer early diagnosis due to its non-invasive and continuous monitoring properties. However, most current liquid biopsy techniques lack the ability to detect cancers at the early stage. Therefore, effective detection of a variety of cancers is expected through the combination of various techniques. Recently, DNA frameworks with tailorable functionality and precise addressability have attracted wide spread attention in biomedical applications, especially in detecting cancer biomarkers such as circulating tumor cells (CTCs), exosomes and circulating tumor nucleic acid (ctNA). Encouragingly, DNA frameworks perform outstanding in detecting these cancer markers, but also face some challenges and opportunities. In this review, we first briefly introduced the development of DNA frameworks and its typical structural characteristics and advantages. Then, we mainly focus on the recent progress of DNA frameworks in detecting commonly used cancer markers in liquid-biopsy. We summarize the advantages and applications of DNA frameworks for detecting CTCs, exosomes and ctNA. Furthermore, we provide an outlook on the possible opportunities and challenges for exploiting the structural advantages of DNA frameworks in the field of cancer diagnosis. Finally, we envision the marriage of DNA frameworks with other emerging materials and technologies to develop the next generation of disease diagnostic biosensors.

Rifampicin synergizes the toxicity of insecticides against the green peach aphid, Myzus persicae.

Myzus persicae is an important pest that has developed resistance to nearly all currently used insecticidal products. The employment of insecticide synergists is one of the effective strategies that need to be developed for the management of this resistance. Our study showed that treatment with a combination of the antibiotic, rifampicin, with imidacloprid, cyantraniliprole, or clothianidin significantly increased their toxicities against M. persicae, by 2.72, 3.59, and 2.41 folds, respectively. Rifampicin treatment led to a noteworthy reduction in the activities of multifunctional oxidases (by 32.64%) and esterases (by 23.80%), along with a decrease in the expression of the CYP6CY3 gene (by 58.57%) in M. persicae. It also negatively impacted the fitness of the aphids, including weight, life span, number of offspring, and elongation of developmental duration. In addition, bioassays showed that the combination of rifampicin and a detoxification enzyme inhibitor, piperonyl butoxide, or dsRNA of CYP6CY3 further significantly improved the toxicity of imidacloprid against M. persicae, by 6.19- and 7.55-fold, respectively. The present study suggests that development of active ingredients such as rifampicin as candidate synergists, show promise to overcome metabolic resistance to insecticides in aphids.

Neuroprotective effects of cordycepin on MPTP-induced Parkinson's disease mice via suppressing PI3K/AKT/mTOR and MAPK-mediated neuroinflammation.

Parkinson's disease (PD) is a prevalent progressive and multifactorial neurodegenerative disorder. Cordycepin is known to exhibit antitumor, anti-inflammatory, antioxidative stress, and neuroprotective effects; however, few studies have explored the neuroprotective mechanism of cordycepin in PD. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model, we investigated the impact of cordycepin on PD and its underlying molecular mechanisms. The findings indicated that cordycepin significantly mitigated MPTP-induced behavior disorder and neuroapoptosis, diminished the loss of dopaminergic neurons in the striatum-substantia nigra pathway, elevated striatal monoamine levels and its metabolites, and inhibited the polarization of microglia and the expression of pro-inflammatory factors. Subsequent proteomic and phosphoproteomic analyses revealed the involvement of the MAPK, mTOR, and PI3K/AKT signaling pathways in the protective mechanism of cordycepin. Cordycepin treatment inhibited the activation of the PI3K/AKT/mTOR signaling pathway and enhanced the expression of autophagy proteins in the striatum and substantia nigra. We also demonstrated the in vivo inhibition of the ERK/JNK signaling pathway by cordycepin treatment. In summary, our investigation reveals that cordycepin exerts neuroprotective effects against PD by promoting autophagy and suppressing neuroinflammation and neuronal apoptosis by inhibiting the PI3K/AKT/mTOR and ERK/JNK signaling pathways. This finding highlights the favorable characteristics of cordycepin in neuroprotection and provides novel molecular insights into the neuroprotective role of natural products in PD.

Effect of electroacupuncture on global cerebral ischemia-reperfusion injury in rats: A urine proteome analysis.

BACKGROUND: This study aimed to investigate dynamic urinary proteome changes of electroacupuncture (EP) on cerebral ischemia-reperfusion (CI/R) injured rats and to explore the therapeutic biological mechanisms of EP. METHODS: First, changed urinary proteins were found in EP stimulation in healthy rats. Then, we used a CI/R injury rat model induced by Pulsinelli's four-vessel occlusion (4-VO) method to explore the function of EP on urinary proteome in CI/R injury. Urine samples were collected for proteome analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. RESULTS: In total, 384 proteins were identified, among which 47 proteins (23 upregulated, 24 downregulated) were differentially expressed with 0.6-log FC and p < .05. Gene ontology analysis revealed that the cell redox homeostasis, acute-phase response, response to lipopolysaccharide, and cellular response to glucocorticoid stimulus were significantly enriched. The partially biologically connected differential proteins were found by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis in the EP group. With the CI/R rat model, 80 proteins (27 upregulated, 53 downregulated) were significantly changed in the CI/R rats compared to the controls. Among these differentially expressed proteins (DEPs), 23 proteins (17 upregulated, six downregulated) showed significant changes after EP treatment (0.6-log FC change, p < .05). The main related biological processes were aging, immune response, acute-phase response, liver regeneration, protein catabolic process, and response to oxidative stress. Many metabolic pathways were enriched by KEGG analysis. CONCLUSION: Our results indicate that the EP could alleviate cerebral damage induced by ischemia-reperfusion through an anti-inflammatory and metabolism regulation mechanism. The urinary proteome might reflect the pathophysiological changes in EP pretreatment in the treatment and prevention of CI/R injury.

AgAu-modified quasi-MIL-53 hybrid nanozymes with triple enzyme-like activities for boosting biocatalytic disinfection.

Metal-organic frameworks (MOFs) have great potential for combating pathogenic bacterial infections and are expected to become an alternative to antibiotics. However, organic linkers obstruct and saturate the inorganic nodes of MOF structures, making it challenging to utilize the applied potential of metal centers. Here, we combined controlled ligand decarboxylation with noble metal nanoparticles to rationally remodel MIL-53, resulting in a hybrid nanozyme (AgAu@QMIL-53, AAQM) with excellent multiple enzyme-like activities that both eradicate bacteria and promote diabetic wound healing. Specifically, benefitting from oxidase (OXD)-like and peroxidase (POD)-like activities, AAQM converts oxygen (O2) and hydrogen peroxide (H2O2) into superoxide anion radicals (O2-) and hydroxyl radicals (OH) to eradicate bacteria. In in vitro antibacterial experiments, AAQM exhibited favorable killing efficacy against Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA) (>99 %). Notably, due to its superoxide (SOD)-like activity and outstanding reactive nitrogen species (RNS) elimination capacity, AAQM can produce adequate O2 and alleviate oxidative stress in diabetic wounds. Benefiting from the rational modification of MIL-53, the synthesized hybrid nanozyme can effectively kill bacteria while alleviating oxidative stress and ultimately promote infected diabetic wound healing. Overall, this biomimetic enzyme-catalyzed strategy will bring enlightenment to the design of self-antibacterial agents for efficient disinfection and wound healing simultaneously.

Dosage-sensitive and simultaneous detection of multiple small-molecule pollutants in environmental water and agriproducts using portable SERS-based lateral flow immunosensor.

The co-contamination of pesticide residues and mycotoxins in agricultural products is a global concern, with the potential for cumulative and synergistic damaging effects, imposing substantial health and economic burdens to the public. The dosage-sensitive and simultaneous detection of multiple pollutants, with a heightened sensitivity in real samples, poses a significant demand and challenge. Herein, we propose a portable detection method integrating surface-enhanced Raman scattering (SERS)-with lateral flow immunoassay (LFIA), offering high sensitivity and multiplex analysis capabilities. This approach enables the simultaneous detection of imidacloprid (IMI), pyraclostrobin (PYR) and aflatoxin B1 (AFB1) through a single test strip. Utilizing the immune-specific binding between antigen and antibodies, we immobilised antibody- conjugated SERS nanotags on three test lines of the strips to generate Raman signal amplification in the proposed biosensor. Accurate quantitative analysis was performed by measuring the SERS signal intensity on the test lines. The limits of detection were 8.6 pg/mL for IMI, 97.4 pg/mL for PYR and 8.9 pg/mL for AFB1, exhibiting sensitivities 12-fold, 102-fold and11-fold higher than the colorimetric signals, respectively. Importantly, the SERS-LFIA immunosensor demonstrated robust performance when applied to real samples, yielding recoveries ranging from 86.16 % to 115.0 %, with relative standard deviation values below 8.67 %. These results underscore the excellent stability, high selectivity and reliability the proposed SERS-LFIA immunosensor. Consequently, it holds promise for the detection of multiple pesticides and mycotoxins in both environmental and agricultural samples.

Transcriptome of Excretory Organs Revealed Potential Targets for the Control of Nilaparvata lugens.

The excretory organs of insects offer potential physiological targets for insect control. In this study, RNA-seq was utilized to identify a set of transporter and receptor genes enriched in the excretory organs of the brown planthopper (BPH), Nilaparvata lugens, which is considered the most important phloem-feeding insect pest in rice. A total of 1565 and 1084 transcripts were upregulated in the excretory organs, Malpighian tubules, and hindgut, respectively, compared to the midgut, which was enriched for transport activity and oxidoreductase activity. Eight potentially important genes were selected for the exploration of biological function, including one sodium/potassium-ATPase (NKA) subunit (ATP1A1), five aquaporins (AQPs), and two neuropeptide receptors. RNA interference (RNAi) assays showed that the knockdown of ATP1A1 and two AQP genes in BPH resulted in significant lethal phenotypes (corrected mortalities = 42.9-63.6%, 7 days after injection) and significantly reduced honeydew amounts. Our findings suggest that several genes enriched in excretory organs were important for BPH survival, which could be new insect control targets.

Modeling the protein binding non-linearity in population pharmacokinetic model of valproic acid in children with epilepsy: a systematic evaluation study.

Background: Several studies have investigated the population pharmacokinetics (popPK) of valproic acid (VPA) in children with epilepsy. However, the predictive performance of these models in the extrapolation to other clinical environments has not been studied. Hence, this study evaluated the predictive abilities of pediatric popPK models of VPA and identified the potential effects of protein binding modeling strategies. Methods: A dataset of 255 trough concentrations in 202 children with epilepsy was analyzed to assess the predictive performance of qualified models, following literature review. The evaluation of external predictive ability was conducted by prediction- and simulation-based diagnostics as well as Bayesian forecasting. Furthermore, five popPK models with different protein binding modeling strategies were developed to investigate the discrepancy among the one-binding site model, Langmuir equation, dose-dependent maximum effect model, linear non-saturable binding equation and the simple exponent model on model predictive ability. Results: Ten popPK models were identified in the literature. Co-medication, body weight, daily dose, and age were the four most commonly involved covariates influencing VPA clearance. The model proposed by Serrano et al. showed the best performance with a median prediction error (MDPE) of 1.40%, median absolute prediction error (MAPE) of 17.38%, and percentages of PE within 20% (F20, 55.69%) and 30% (F30, 76.47%). However, all models performed inadequately in terms of the simulation-based normalized prediction distribution error, indicating unsatisfactory normality. Bayesian forecasting enhanced predictive performance, as prior observations were available. More prior observations are needed for model predictability to reach a stable state. The linear non-saturable binding equation had a higher predictive value than other protein binding models. Conclusion: The predictive abilities of most popPK models of VPA in children with epilepsy were unsatisfactory. The linear non-saturable binding equation is more suitable for modeling non-linearity. Moreover, Bayesian forecasting with prior observations improved model fitness.

Proteome profiling of hippocampus reveals the neuroprotective effect of mild hypothermia on global cerebral ischemia-reperfusion injury in rats.

Cerebral ischemia is one of the leading causes of disability and mortality worldwide. Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (IR) injury. In this study, a rat model of global cerebral I/R injury was established via Pulsinelli's four-vessel occlusion (4-VO) method. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were employed to examine the ipsilateral hippocampus proteome profiles of rats with/without MH (32 °C) treatment after IR injury. Totally 2 122 proteins were identified, among which 153 proteins were significantly changed associated with MH (n = 7 per group, fold change-1.5, p < 0.05). GO annotation of the differentially expressed proteins (DEPs) revealed that cellular oxidant detoxification, response to zinc ions, aging, oxygen transport, negative regulation of catalytic activity, response to hypoxia, regulation of protein phosphorylation, and cellular response to vascular endothelial growth factor stimulus were significantly enriched with MH treatment. The KEGG analysis indicated that metabolic pathways, thermogenesis, pathways of neurodegeneration, chemical carcinogenesis-reactive oxygen species, fluid shear stress and atherosclerosis, and protein processing in endoplasmic reticulum were significantly enriched with MH treatment. Importantly, changes in 16 DEPs were reversed by MH treatment. Among them, VCAM-1, S100A8, CaMKK2 and MKK7 were verified as potential markers associated with MH neuroprotection by Western blot analysis. This study is one of the first to investigate the neuroprotective effects of MH on the hippocampal proteome of experimental models of cerebral IR injury. These DEPs may be involved in the most fundamental molecular mechanisms of MH neuroprotection, and provide a scientific foundation for further promotion of reparative strategies in cerebral IR injury.

Electromagnetic Radiation Exposure and Childhood Leukemia: Meta-Analysis and Systematic Review.

Objective: Leukemia is the most prevalent cancer among children and adolescents. This study investigated the potential association between exposure to magnetic fields and the risk of pediatric leukemia. Methods: We conducted a comprehensive search of electronic databases, including Scopus, EMBASE, Cochrane, Web of Science, and Medline, up to December 15, 2022, to identify relevant studies examining the link between childhood leukemia and magnetic field exposure. Results: The first meta-analysis revealed a statistically significant inverse association between pediatric leukemia and magnetic field strengths ranging from 0.4 µT to 0.2 µT, suggesting a reduced risk associated with this range. The second meta-analysis focused on wiring configuration codes and observed a potential link between residential magnetic field exposure and childhood leukemia. Pooled relative risk estimates were 1.52 (95% CI = 1.05-2.04, P = .021) and 1.58 (95% CI = 1.15-2.23, P = .006) for exposure to 24-hour magnetic field measurements, suggesting a possible causal relationship. In the third meta-analysis, the odds ratios for the exposure groups of 0.1 to 0.2 µT, 0.2 to 0.3 µT, 0.3 to 0.4 µT, and 0.4 µT above 0.2 µT were 1.09 (95% confidence interval = 0.82 to 1.43 µT), 1.14 (95% confidence interval = 0.68 to 1.92 µT), and 1.45 (95% confidence interval = 0.87 to 2.37 µT), respectively. In contrast to the findings of the three meta-analyses, there was no evidence of a statistically significant connection between exposure to 0.2 µT and the risk of juvenile leukemia. A further result showed no discernible difference between the two groups of children who lived less than 100 meters from the source of magnetic fields and those who lived closer (OR = 1.33; 95% CI = 0.98-1.73 µT). Conclusions: The collective results of three meta-analyses, encompassing magnetic field strengths ranging from 0.1 µT to 2.38 µT, underscore a statistically significant association between the intensity of magnetic fields and the occurrence of childhood leukemia. However, one specific analysis concluded that no apparent relationship exists between exposure to 0.1 µT and an elevated risk of leukemia development in children.

Hepatocyte NLRP3 interacts with PKCε to drive hepatic insulin resistance and steatosis.

Hepatic insulin resistance (IR), as a downstream sequela of nonalcoholic fatty liver disease (NAFLD), is strongly associated with liver steatosis. Despite numerous mechanism advancements, the molecular underpinnings and pathogenesis of hepatic IR, especially regarding the pattern recognition receptors in hepatocytes, remain elusive. Here, we identified hepatocyte NLRP3 as a direct and previously-unresolved driver of hepatic IR to promote steatosis response. Under the model of NAFLD, we identified hepatocyte NLRP3 as a crucial inducer of hepatic IR by undertaking multilayer transcriptomic searches and further confirmed that its expression was increased in the liver tissues from NAFLD patients and mouse models (high-fat diet (HFD), leptin-receptor-deficient (db/db) mice), and in palmitic acid (PA)-induced hepatocytes. Loss- or gain-of-function of hepatocyte-specific NLRP3 in HFD-induced mice ameliorated or exacerbated hepatic IR and steatosis, respectively. Mechanistically, NLRP3 directly bound to and promoted protein kinase C epsilon (PKCε) activation to impair insulin signaling and increase liver steatosis, while inhibition of PKCε activation dampened the beneficial effects seen in HFD-induced NLRP3-deficient mice. Moreover, we performed screening and discovered that the transcription factor Yin Yang 1 (YY1) positively controlled NLRP3 expression. In translational potential, adeno-associated virus serotype 8 (AAV8)-mediated NLRP3 knockdown in the liver alleviated hepatic IR and steatosis in db/db mice, and pharmacological inhibition of NLRP3 markedly alleviated diet-induced metabolic disorders. This finding reveals a previously-unexpected regulatory axis from YY1 to PKCε via NLRP3 induction for metabolic diseases and establishes the YY1-NLRP3-PKCε axis as a potential therapeutic target for NAFLD.