Small cell lung cancer (SCLC) is known for its rapid growth and early metastasis, and SCLC patients are highly susceptible to chemoresistance. Studies have shown that the combination of ferroptosis induction and TRX pathway inhibition can significantly inhibit SCLC tumor growth, but the molecular mechanisms underlying ferroptosis in SCLC are poorly understood. In this study, we explored the regulatory role of the ALDH1L2-related metabolic pathway in SCLC chemoresistance by machine learning. We found that ALDH1L2 expression is a poor prognostic factor for SCLC patients and that high ALDH1L2 expression can negatively regulate the level of cellular lipid peroxidation and inhibit ferroptosis, thereby promoting SCLC chemoresistance. Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance.

The clinical utility of histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) in lymphoma is constrained by poor pharmacokinetics and off-target toxicity. To address this, we developed a reactive oxygen species (ROS)-responsive homodimeric SAHA prodrug (SAHA-tk-SAHA) linked via a thioketal bridge, which self-assembled into PEGylated nanoparticles (tk-diSAHA NP). These monodisperse nanoparticles (119.3 ± 4.0 nm) demonstrated excellent stability and ROS-triggered drug release (68.18 ± 2.25% with 10 mM H2O2 vs 6.24% in PBS over 48 h). In vitro, tk-diSAHA NP induced G0/G1 cell cycle arrest and apoptosis in lymphoma cells. In A20 lymphoma-bearing mice, intravenous tk-diSAHA NP achieved superior tumor growth inhibition (615.18 ± 147.88 mm3) compared to oral SAHA (1134.78 ± 311.31 mm3, p < 0.05), with enhanced histone H3 acetylation in tumors and no appreciable systemic toxicity. This ROS-activatable nanoprodrug platform presents a promising strategy to enhance the efficacy and safety of HDACi-based epigenetic therapy for lymphoma.

High expression of Lysine-Specific Demethylase 5B (KDM5B) in lung cancer drives tumorigenesis and immunosuppression. KDM5B is negatively correlated with endoplasmic reticulum (ER)-phagy receptors such as TEX264, indicating that selective induction of ER-phagy may degrade KDM5B. Our work revealed that chemotherapeutic drug Teniposide (Ten) was a potent anti-lung cancer agent, which could increase the stability of TEX264. The present study aims to elucidate the critical target and mechanism by which Ten inhibits KDM5B through TEX264-associated ER-phagy against lung cancer. Ten exhibited potent lung cancer suppression ability, as evidenced by the weakened proliferation of organoids and tumor grafts in mice along with activation of the immune microenvironment. Highly-expressed KDM5B demonstrated down-regulation upon Ten treatment, which may be attributed to its degradation via ER-phagy. Blockage of ER-phagy weakened Ten-mediated KDM5B degradation. Insightful investigations discovered that Ten activated OTUD3, a deubiquitylase, which stabilized TEX264, a crucial receptor for ER-phagy. Notably, genetic knockdown of TOP2A impacted little on the Ten-mediated ER-phagy. OTUD3 silencing dampened Ten-driven ER-phagy and KDM5B inhibition. To summarize, these findings demonstrate that Ten effectively inhibits lung cancer and activates immunocytes by KDM5B inhibition, which is regulated by TEX264-associated ER-phagy. Most importantly, OTUD3 serves as an essential target for enhancement of TEX264 stabilization.

Psammomys obesus, widely known as sand rat, develops obesity during captivity. To assess the role of confinement stress on metabolic alterations and sweet taste perception, the gustatory cue involved in obesity, we administered corticosterone (CORT) intraperitoneally in male Psammomys obesus to yield a stressful condition. CORT administration was found to increase preference for sweet solutions in a two bottle-choice paradigm in these animals. Moreover, CORT administration increased the messenger ribonucleic acid (mRNA) expression of sweet test receptor in fungiform taste bud cells. As regards liver, CORT increased mRNA expression encoding glucose-6-phosphatase (G-6-P), phosphoenolpyruvate carboxykinase 1 (PEPCK1) and stearoyl-CoA desaturase-1 (SCD-1). Interestingly, CORT decreased gut peptide YY (PYY), insulin, and triglyceride levels in the blood. Our study demonstrates that corticosterone, known to be released during the captivity period, might play a key role in the development of obesity by influencing sweet taste perception, release of a gut peptide and modifications in lipid/glucidic metabolic enzymatic pathways in Psammomys obesus.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely used in polycarbonate plastics and epoxy resins, resulting in human exposure primarily through food-contact materials and thermal paper, as well as environmental sources. Studies suggest that BPA has adverse effects on trophoblast cells, which are critical for placental formation, and that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may contribute to BPA-induced cellular dysfunction. However, the mechanisms by which BPA affects placental trophoblast function remain incompletely understood. This study aimed to explore the connection between ER stress/UPR signaling and BPA-induced trophoblast disfunction. BeWo cells were stimulated with forskolin to induce a syncytium formation, a hallmark of trophoblast differentiation, and then exposed to different concentrations of BPA. The effect of BPA on differentiation and secretion capacity, viability, and apoptosis of the trophoblast cells was examined comparing the results with data related to ER stress. Our findings provide evidence that ER stress/UPR activation is involved in BPA-induced trophoblast dysfunction and that BPA-induced apoptosis may be linked to ER stress. In conclusion, this study offers mechanistic insights into how BPA impacts trophoblast cells and may help in understanding the pregnancy-related adverse outcomes associated with BPA exposure.

This study aimed to investigate the effects of soluble epoxide hydrolase (sEH) inhibition on osteoclast differentiation and activity in vitro and in vivo, as well as to elucidate the signaling pathways associated with osteoclastogenesis. Primary murine bone marrow monocytes were stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand to induce osteoclastogenesis and treated with the sEH inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) (0.1-10 μM). Tartrate-resistant acid phosphatase staining, gene expression analyses, and immunofluorescence were used to evaluate osteoclast formation, transcriptional regulation, and cell fusion. A murine model of ligature-induced periodontitis was used to assess in vivo effects of sEH inhibition (TPPU 10 mg/kg). Alveolar bone loss was quantified by histomorphometry, and gingival gene expression was analyzed. In vitro, sEH inhibition significantly reduced tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation, downregulated the expression of key transcription factors and osteoclast activity-related genes. Immunofluorescence analysis revealed attenuation of mitogen-activated protein kinase signaling and reduced dendritic cell-specific transmembrane protein expression, indicating impaired cell fusion. In vivo, TPPU treatment preserved alveolar bone structure, reduced osteoclast-like cell numbers, and decreased the expression of osteoclastic markers in gingival tissues during experimental periodontitis. sEH acts as a crucial regulator of osteoclast differentiation and function. Pharmacological inhibition of sEH suppresses osteoclastogenesis and protects against inflammatory bone loss. Therefore, targeting sEH may represent a novel therapeutic approach to modulate osteoclast activity and prevent bone destruction in periodontitis and other bone-resorptive diseases. SIGNIFICANCE STATEMENT: This study provides direct evidence that soluble epoxide hydrolase inhibition modulates osteoclast differentiation and fusion, contributing to reduced inflammatory bone loss. By demonstrating effects on osteoclast-intrinsic pathways while also influencing the inflammatory microenvironment, our findings support soluble epoxide hydrolase as a pharmacological target for chronic inflammatory bone-resorptive diseases.

Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C14H6N2O8) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.

The expression patterns and potential regulatory correlates of CLDN3 in cancers remain insufficiently characterised, necessitating further investigation. We employed R software alongside bioinformatics platforms to analyse the aberrant expression of CLDN3. Experiments in vitro, including proliferation, wound healing, cell cycle progression and apoptosis assays, were conducted to evaluate the role of CLDN3 in CRC. Co-immunoprecipitation (CO-IP) and immunofluorescence analyses were conducted to investigate the interaction between CLDN3 and TRIM28. Western blotting was employed to evaluate the effect of TRIM28 on CLDN3 SUMOylation and protein stability. CLDN3 was found to be overexpressed in several cancers. Genomic alterations and promoter hypomethylation were identified as key contributors to CLDN3 dysregulation. Bioinformatic analysis suggests that CLDN3 is associated with tumour progression and poor prognosis by influencing pathways, it also contributes to immune dysregulation and chemo-resistance mechanisms. Knockdown of CLDN3 in CRC cells decreased proliferation and migration. CLDN3 overexpression was shown to reduce the sensitivity to 5-FU in CRC cells. CO-IP and immunofluorescence confirmed a direct interaction between CLDN3 and TRIM28. Western blot analysis demonstrated that TRIM28 mediates CLDN3 SUMOylation and degradation. CLDN3 influences the growth and chemotherapy resistance of CRC cells, its interaction with TRIM28 makes the TRIM28/CLDN3 axis as a promising therapeutic target for CRC.

MT mitigates Cd toxicity by enhancing photosystem and antioxidant system activities, and related gene expression in GCC. NAC, HSF, and MYB-related families may play key roles in MT-induced Cd tolerance. Cadmium (Cd), a toxic heavy metal non-essential to plants, has detrimental impacts on both the environment and human health. Melatonin (MT) plays an important protective role in plants against stresses such as heavy metal toxicity. However, the detailed mechanism underlying MT alleviating Cd toxicity remains unclear in ground-cover chrysanthemum (Chrysanthemum morifolium Ramat., GCC). GCC seedlings were pre-treated with MT solution (150 μM) via foliar spraying and subsequently grown under Cd stress, after which the growth, physiological, and transcriptomic responses of the plant were investigated. The results demonstrated that MT pre-treatment inhibited the Cd-induced chlorophyll degradation in GCC seedlings, while it enhanced chlorophyll synthesis and related gene expression by promoting electron transfer efficiency and maintaining the integrity of the oxygen-evolving complex in photosynthesis. Furthermore, MT + Cd treatment upregulated 11 photosystem I (PSI), 13 PSII, eight light-harvesting complex I (LHCI), and 20 LHCII-related genes as compared with Cd treatment alone. MT also alleviated oxidative stress and boosted antioxidant capacity by conserving the activities and gene expression levels of superoxide dismutase, peroxidase, and key enzymes in the ascorbate-glutathione cycle and thioredoxin-peroxiredoxin pathway. In addition, MT reduced the generation rate of O2·- by 27.64%, malondialdehyde by 68.36%, and H2O2 by 44.97%, alleviating the Cd-induced damage. Weighted gene co-expression network analysis provided additional evidence that MT improved GCC tolerance to Cd by modulating the expression of transcription factors (e.g., NAC, HSF, and MYB-related families) related to abiotic stress.

Polyploid rice exhibits superior cadmium tolerance via enhanced antioxidant activity, reduced Cd accumulation, and transporter regulation, with zinc nanoparticles further mitigating toxicity and modulating stress-responsive genes. Cadmium (Cd) contamination poses a serious threat to rice production by impairing plant growth and yield. To investigate the mechanisms of Cd tolerance, we compared diploid rice (E22) and its polyploid counterpart (T42) under Cd stress (50 mg kg-1 soil) with or without zinc supplementation (25 mg kg-1 soil). Upon Cd exposure, E22 exhibited a 7.8% decline in plant weight and seed set, while T42 experienced only a 4.71% reduction in plant weight, demonstrating its enhanced tolerance to Cd toxicity. Consistently, Cd accumulation was markedly lower in T42 across multiple tissues. Under Cd stress, T42 maintained lower levels of H₂O₂ and malondialdehyde while exhibiting enhanced antioxidant activity, including elevated peroxidase, superoxide dismutase, catalase, and glutathione, compared to E22. The more complete organelles in T42 likely contributed to its improved Cd tolerance. Notably, supplementation with ZnO-NPs reduced Cd accumulation in both diploid and polyploid rice. Transcriptomic analysis revealed that starch metabolism-related genes (OsISA1 and OsISA2) were strongly expressed in T42, whereas tubulin genes (OsTB16 and OsTB50) were strongly expressed in T42 under Zn treatment. In contrast, photosynthesis-related genes show remarkable differential expressions between E22 and T42, suggesting different adaptive strategies in E22 and T44, as evidenced by impaired photosynthesis in E22 under stress. Overall, these findings demonstrate that polyploid rice possesses enhanced resilience to Cd stress through coordinated regulation of tubulin, metal transporters, and antioxidant systems, with ZnO-NPs further mitigating Cd toxicity.

Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation.

Aberrant DNA methylation patterns are increasingly recognized as contributors to a wide range of conditions, including metabolic, oncogenic, and neurodevelopmental disorders. Nutritional factors, such as choline, can shape methylation potential via methyl group donation. The purpose of this narrative review is to synthesize current evidence on the DNA methylation landscapes underlying health and disease paradigms, with a focus on the role of choline as a compelling target for modulating epigenetic states. A comprehensive literature review search was conducted in PubMed to identify relevant studies, with additional articles retrieved from review papers.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, increasingly associated with loss of androgen receptor (AR) signaling, and in many cases induction of stemness phenotypes and neuroendocrine features. However, targeted therapies for this stage of the disease are currently lacking. In this study, we demonstrated the critical role of the epigenetic regulator UHRF1 in the enzalutamide resistance development of prostate cancer. We have shown that UHRF1 is highly expressed in enzalutamide-resistant prostate cancer cells and its expression correlates with the loss of AR-dependent glandular features. Knocking down UHRF1 led to increased AR expression and enhanced the activity of canonical AR signaling pathway in prostate cancer cells. The combination of UHRF1 knockdown with enzalutamide treatment demonstrated synergistic tumor inhibitory effects both in vitro and in vivo. Mechanistically, UHRF1 was found to bind to AR and promote its ubiquitination and degradation. Furthermore, inhibition of UHRF1 restored AR pathway activity and re-sensitized resistant prostate cancer cells to enzalutamide. Therefore, our findings elucidate an intracellular molecular mechanism that promotes prostate cancer lineage plasticity and suggest that UHRF1 may serve as a potential therapeutic target for overcoming resistance to AR-targeted therapies.

Endometrial cancer (EC) incidence is increasing globally, highlighting the need for novel therapies targeting molecular drivers of malignancy. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase implicated in tumor progression, is overexpressed in EC; however, its precise role and therapeutic potential remain unclear. In this study, we aimed to investigate EZH2 expression, its functional role, and the efficacy of EZH2 inhibitors in EC cell lines.

Glioblastoma constitutes a major subset of brain cancers and is characterized by a high recurrence rate and a low five-year survival rate. Ginsenoside compound K (GCK), a bioactive component derived from traditional Chinese medicine, exhibits anti-allergic, anti-aging, and notable anti-tumor properties. Although previous studies have shown that GCK can inhibit glioblastoma, its precise role and underlying mechanisms remain unclear. In this study, we demonstrated the effects of GCK on glioma initiation and progression, as well as its associated mechanisms. In vitro experiments revealed that GCK markedly inhibited the proliferation and migration of glioblastoma cells and significantly disrupted their cell cycle. In vivo, intragastric administration of GCK substantially reduced the growth rate of transplanted glioblastoma and prolonged the survival of nude mice. Furthermore, RNA sequencing and Western blot analyses showed that GCK suppresses glioblastoma progression by dephosphorylating p-ERK1/2 via upregulation of DUSP5 expression. These findings highlight the critical role of GCK in glioblastoma inhibition and suggest its potential as a promising therapeutic agent for clinical treatment, underscoring the value of traditional Chinese medicine in modern oncology.

Oxytocin, a neuropeptide predominantly produced in the hypothalamus, has garnered significant attention for its multifaceted roles extending beyond social bonding and reproduction to therapeutic applications in neurodegenerative and neuropsychiatric disorders. This review explores oxytocin's neuroprotective properties, including anti-inflammatory, antioxidant and anti-apoptotic effects, which counteract pathological mechanisms underlying diseases like Alzheimer's, Parkinson's and Epilepsy. Oxytocin's ability to modulate key neurotransmitter systems GABAergic, dopaminergic, and serotonergic pathways enhances synaptic plasticity, neurogenesis, and emotional regulation. These mechanisms have positioned oxytocin as a promising intervention for neuropsychiatric conditions such as autism, schizophrenia, depression, and anxiety. Preclinical and clinical studies have shown that intranasal administration of oxytocin improves social cognition, reduces symptom severity, and is well-tolerated, though challenges remain in standardizing dosages and measuring oxytocin levels due to individual variability. Emerging technologies, such as nanoparticle-based drug delivery systems, offer solutions to enhance oxytocin's bioavailability and brain penetration, making targeted, patient-specific therapies feasible. Epigenetic modifications of the oxytocin receptor gene including DNA methylation have been associated with variability in social and stress-related behaviors. While these findings offer insight into inter-individual differences, their application to precision medicine remains speculative and will require rigorous clinical validation. Combination therapies, integrating oxytocin with agents targeting neuroinflammation and synaptic plasticity, hold potential for synergistic effects. Despite methodological and translational challenges, oxytocin represents a transformative therapeutic agent with broad applications across neurological, psychiatric, and systemic disorders. Future research focusing on nanotechnology, epigenetics, and long-term clinical trials will be pivotal in realizing the full potential of oxytocin-based interventions for complex, multifactorial diseases.

Silicon dioxide nanoparticles (SiO2 NPs) have been shown to alleviate cadmium (Cd) toxicity in plants, but the mechanisms regarding SiO2 NPs-mediated Cd uptake and detoxification on hyperaccumulators are unknown. In this study, physiological and transcriptomic analyses were performed to investigate the impact of SiO2 NPs on the growth and Cd accumulation of the Cd-hyperaccumulator Sedum alfredii. The results showed that SiO2 NPs significantly increased root fresh weight (32.71% to 121.50%) and shoot fresh weight (22.72% to 86.36%). Simultaneously, SiO2 NPs enhanced the Cd uptake and accumulation by S. alfredii (with maximum increases of 232.14%). In the leaves, the Cd content in the phloem of the Si treatment group increased by 1.24 to 1.79-fold, indicating that SiO2 NPs enhanced the transport of Cd to the shoots. Furthermore, SiO2 NPs improved the photosynthetic parameters, with the net photosynthetic rate, transpiration rate and stomatal conductance increasing by 2.86-fold, 1.14-fold, and 1.84-fold of the control, respectively. Furthermore, SiO2 NPs significantly strengthened the antioxidative enzymes activities (SOD, CAT, POD). Transcriptomic analysis revealed that SiO2 NPs enhanced the Cd tolerance and accumulation capacity of S. alfredii by upregulating the expression of genes encoding photosynthesis-related functions (PSI, PSII), antioxidant enzymes, cell wall synthesis functions, heavy metal-responsive transcription factors (WRKY, NAC, bZIP, MYB), and Cd chelation and transport protein functions. Combining physiological and transcriptomic analyses, our findings provide the mechanisms of SiO2 NPs in promoting Cd accumulation and enhancing Cd tolerance in S. alfredii, highlighted the potential of SiO2 NPs to enhance phytoremediation efficiency.

Cytochrome P450s (CYPs) 2C subfamily (eg, 2C8, 2C9, and 2C19) and phase II enzymes such as uridine 5'-diphospho-glucuronosyltransferases (UGTs) are increasingly relevant in drug development and key targets for enzymatic induction. However, for these enzymes, weak induction signals in standard in vitro tools, such as sandwich-cultured human hepatocytes, challenge drug-drug interaction (DDI) risk assessment. This study evaluated an all-human hepatocyte coculture system (TruVivo) as a more sensitive model for CYP2Cs and UGT1A1 induction. After treatment of cells with rifampicin, carbamazepine, and phenytoin, we demonstrated robust mRNA and activity-fold-induction exceeding or meeting the 2-fold threshold in the coculture system, allowing for estimation of CYP2Cs and UGT1A1 induction parameters (IndC50, Indmax), unlike sandwich culture. Using TruVivo IndC50, Indmax of these precipitants in physiologically based pharmacokinetic (PBPK) modeling resulted in high predictive accuracy. In rifampicin studies, using TruVivo mRNA-derived data from the most sensitive donor 1 and average parameters across donors, was essential to properly predict in vivo DDI, particularly for object drugs mainly metabolized by CYP2Cs and UGT1A1, or with moderate to low CYP3A4 contribution (fm ≤ 0.5) in multipathway metabolism. For object drugs metabolized by CYP3A4 beyond 2Cs and UGTs, carbamazepine and phenytoin PBPK predictions highlighted the applicability of TruVivo uncalibrated CYP3A4 data for accurate assessment, whereas parameters calibrated against rifampicin showed a conservative trend in estimating DDI. Overall, the all-human coculture system, paired with PBPK, offers a breakthrough for CYP2Cs and UGT1A1 preclinical DDI induction risk assessment. SIGNIFICANCE STATEMENT: Cryopreserved human hepatocytes in sandwich culture show limited sensitivity toward cytochrome P450s 2C and uridine 5' -diphospho-glucuronosyltransferases induction, challenging in vitro-in vivo translation of the drug-drug interaction risk. This study confirms that TruVivo is a more sensitive in vitro model. By using physiologically based pharmacokinetic modeling, we investigated the impact of the measured induction parameters on predictive accuracy, showing TruVivo as a useful tool for cytochrome P450s 2C and uridine 5' -diphospho-glucuronosyltransferases risk assessment.

The purpose of this study was to investigate whether mitochondrial unfolded protein response (UPRmt) was induced in Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS)-treated osteoblasts and to study the relationship among UPRmt, mitochondrial function and bone resorption in periodontitis.

Postoperative cognitive dysfunction is a type of cognitive impairment that occurs after surgery. Here, this experiment investigated the role of PLCG1 in sevoflurane-induced model and the molecular mechanisms underlying its regulation of ferroptosis. Single-cell RNA sequencing data and bioinformatic analyses were performed using GEO datasets (GSE196239). Mice were exposed to 2.3% sevoflurane for 2 h daily for 3 consecutive days. PLCG1 expression was up-regulation in patients exposed to sevoflurane. Specifically, blood samples from these patients exhibited elevated levels of PLCG1 mRNA. Consistently, in a mouse model of sevoflurane exposure, both mRNA and protein levels of PLCG1 were significantlyincreased in brain tissue. Single-cell RNA sequencing analysis revealed that PLCG1 was predominantly expressed in astrocytes (marked by AQP4, GFAP, LUZP2, and SLC25A28) and neurons (marked by B3GAT2, ENO2, GNG2, and SLC1A1) in sevoflurane-exposed patients. In contrast, PLCG1 expression was undetectable in B cells (CD74, CD79B, CD80, CD86), T cells (CD4, CD8B, CD69, CD247), or macrophages (CD36, CD68, CD83, CD163). In conclusion, PLCG1 drives neuronal ferroptosis in the context of sevoflurane exposure by enhancing mitochondrial oxidative stress and facilitating LAMP2A ubiquitination, thereby impairing the LAMP2A/HSPA8 pathway. These findings position PLCG1 as a promising biomarker and potential therapeutic target for monitoring and mitigating sevoflurane-induced neurotoxicity. In conclusion, PLCG1 drives neuronal in the context of sevoflurane exposure by enhancing mitochondrial oxidative stress and facilitating LAMP2A Ubiquitination, thereby impairing the LAMP2A/HSPA8 pathway. These findings position PLCG1 as a promising biomarker and potential therapeutic target for monitoring and mitigating sevoflurane-induced neurotoxicity.