Three-dimensional chromatin reorganization regulates B cell development during ageing.

The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs). The gene encoding Ebf1, a key B cell regulator, switches from compartment A to B with age. Genetically reducing Ebf1 recapitulates some features of old pro-B cells. TADs that are most reduced with age contain genes important for B cell development, including the immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD interactions at Igh correlate with altered variable (V), diversity (D) and joining (J) gene recombination. Our observations implicate three-dimensional chromatin reorganization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age.

Effects of aluminum (Al) stress on the isoprenoid metabolism of two Citrus species differing in Al-tolerance.

Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However, how aluminum (Al) stress affects the isoprenoid metabolism and whether isoprenoid metabolism plays a vital role in the Citrus plants in coping with Al stress remain unclear. In this study, we reported that Al-treatment-induced alternation in the volatilization rate of monoterpenes (α-pinene, ß-pinene, limonene, α-terpinene, γ-terpinene and 3-carene) and isoprene were different between Citrus sinensis (Al-tolerant) and C. grandis (Al-sensitive) leaves. The Al-induced decrease of CO2 assimilation, maximum quantum yield of primary PSII photochemistry (Fv/Fm), the lower contents of glucose and starch, and the lowered activities of enzymes involved in the mevalonic acid (MVA) pathway and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway might account for the different volatilization rate of isoprenoids. Furthermore, the altered transcript levels of genes related to isoprenoid precursors and/or derivatives metabolism, such as geranyl diphosphate (GPP) synthase (GPPS) in GPP biosynthesis, geranylgeranyl diphosphate synthase (GGPPS), chlorophyll synthase (CHS) and GGPP reductase (GGPPR) in chlorophyll biosynthesis, limonene synthase (LS) and α-pinene synthase (APS) in limonene and α-pinene synthesis, respectively, might be responsible for the different contents of corresponding products in C. grandis and C. sinensis. Our data suggested that isoprenoid metabolism was involved in Al tolerance response in Citrus, and the alternation of some branches of isoprenoid metabolism could confer different Al-tolerance to Citrus species.

The role of perirenal adipose tissue deposition in chronic kidney disease progression: Mechanisms and therapeutic implications.

Chronic kidney disease (CKD) represents a significant and escalating global health challenge, with morbidity and mortality rates rising steadily. Evidence increasingly implicates perirenal adipose tissue (PRAT) deposition as a contributing factor in the pathogenesis of CKD. This review explores how PRAT deposition may exert deleterious effects on renal structure and function. The anatomical proximity of PRAT to the kidneys not only potentially causes mechanical compression but also leads to the dysregulated secretion of adipokines and inflammatory mediators, such as adiponectin, leptin, visfatin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and exosomes. Additionally, PRAT deposition may contribute to renal lipotoxicity through elevated levels of free fatty acids (FFA), triglycerides (TAG), diacylglycerol (DAG), and ceramides (Cer). PRAT deposition is also linked to the hyperactivation of the renin-angiotensin-aldosterone system (RAAS), which further exacerbates CKD progression. Recognizing PRAT deposition as an independent risk factor for CKD underscores the potential of targeting PRAT as a novel strategy for the prevention and management of CKD. This review further discusses interventions that could include measuring PRAT thickness to establish a baseline, managing metabolic risk factors that promote its deposition, and inhibiting key PRAT-induced signaling pathways.

New-Style Logic Operation and Neuromorphic Computing Enabled by Optoelectronic Artificial Synapses in an MXene/Y:HfO2 Ferroelectric Memristor.

Today's computing systems, to meet the enormous demands of information processing, have driven the development of brain-inspired neuromorphic systems. However, there are relatively few optoelectronic devices in most brain-inspired neuromorphic systems that can simultaneously regulate the conductivity through both optical and electrical signals. In this work, the Au/MXene/Y:HfO2/FTO ferroelectric memristor as an optoelectronic artificial synaptic device exhibited both digital and analog resistance switching (RS) behaviors under different voltages with a good switching ratio (>103). Under optoelectronic conditions, optimal weight update parameters and an enhanced algorithm achieved 97.1% recognition accuracy in convolutional neural networks. A new logic gate circuit specifically designed for optoelectronic inputs was established. Furthermore, the device integrates the impact of relative humidity to develop an innovative three-person voting mechanism with a veto power. These results provide a feasible approach for integrating optoelectronic artificial synapses with logic-based computing devices.

Characterization of a novel adipose tissue located between abdominal lymph nodes and cervix/prostate in mice.

Perigonadal adipose tissue is a homogeneous white adipose tissue (WAT) in adult male mice without any brown adipose tissue (BAT). However, there are congenital differences in the gonads between male and female mice. Whether heterogeneity existed in perigonadal adipose tissues (ATs) in female mice remains unknown. This study reported a perigonadal brown-like AT located between abdominal lymph nodes and the uterine cervix in female mice, termed lymph node-cervical adipose tissue (LNCAT). Its counterpart, lymph node-prostatic adipose tissue (LNPAT), exhibited white phenotype in adult virgin male mice. When exposed to cold, LNCAT/LNPAT increased uncoupling protein 1 (UCP1) expression via activation of tyrosine hydroxylase (TH), in which abdominal lymph nodes were involved. Interestingly, the UCP1 expression in LNCAT/LNPAT varied under different reproductive stages. The UCP1 expression in LNCAT was upregulated at early pregnancy, declined at midlate pregnancy, and reverted in weaning dams. Mating behavior stimulated LNPAT browning in male mice. We found that androgen but not estrogen or progesterone inhibited UCP1 expression in LNCAT. Androgen administration reversed the castration-induced LNPAT browning. Our results identified a perigonadal brown-like AT in female mice and characterized its UCP1 expression patterns under various conditions.NEW & NOTEWORTHY A novel perigonadal brown-like AT (LNCAT) of female mice was identified. Abdominal lymph nodes were involved in cold-induced browning in this newly discovered adipose tissue. The UCP1 expression in LNCAT/LNPAT was also related to ages, sexes, and reproductive stages, in which androgen acted as an inhibitor role.

An adjustable multistage resistance switching behavior of a photoelectric artificial synaptic device with a ferroelectric diode effect for neuromorphic computing.

Neuromorphic computing, which mimics biological neural networks, is widely regarded as the optimal solution for addressing the limitations of traditional von Neumann computing architecture. In this work, an adjustable multistage resistance switching ferroelectric Bi2FeCrO6 diode artificial synaptic device was fabricated using a sol-gel method with a simple process. The device exhibits nonlinearity in its electrical characteristics, demonstrating tunable multistage resistance switching behavior and a strong ferroelectric diode effect through the manipulation of ferroelectric polarization. One of its salient advantages resides in its capacity to dynamically regulate its polarization state in response to an external electric field, thereby facilitating the fine-tuning of synaptic connection strength while maintaining synaptic stability. The device is capable of accurately simulating the fundamental properties of biological synapses, including long/short-term plasticity, paired-pulse facilitation, and spike-timing-dependent plasticity. Additionally, the device exhibits a distinctive photoelectric response and is capable of inducing synaptic plasticity by light signal activation. The utilization of a femtosecond laser for the scrutiny of carrier transport mechanisms imparts profound insights into the intricate dynamics governing the optical memory effect. Furthermore, utilizing a convolutional neural network (CNN) architecture, the recognition accuracy of the MNIST and fashion MNIST datasets was improved to 95.6% and 78%, respectively, through the implementation of improved random adaptive algorithms. These findings present a new opportunity for utilizing Bi2FeCrO6 materials in the development of artificial synapses for neuromorphic computation.

Carexlinanensis (sect. Mitratae), a new species of Cyperaceae from Zhejiang, East China.

Carexlinanensis X.D.Qiu & X.F.Jin, a new species in sect. Mitratae of the sedge family (Cyperaceae) from north-western Zhejiang is described and illustrated. We performed a statistical comparison of the new species with other closely-related species from the same section. Carexlinanensis is similar to Carexsachalinensis F.Schmidt, but differs in having leaf blades 1-2 mm wide (vs. 2.5-3.5 mm wide), utricles longer than pistillate glumes, with beak margin smooth (vs. barbate) and peduncles of lateral spikes enclosed in bract sheaths (vs. exserted from bract sheaths).

Neuromorphic Computing of Optoelectronic Artificial BFCO/AZO Heterostructure Memristors Synapses.

Compared with purely electrical neuromorphic devices, those stimulated by optical signals have gained increasing attention due to their realistic sensory simulation. In this work, an optoelectronic neuromorphic device based on a photoelectric memristor with a Bi2FeCrO6/Al-doped ZnO (BFCO/AZO) heterostructure is fabricated that can respond to both electrical and optical signals and successfully simulate a variety of synaptic behaviors, such as STP, LTP, and PPF. In addition, the photomemory mechanism was identified by analyzing the energy band structures of AZO and BFCO. A convolutional neural network (CNN) architecture for pattern classification at the Mixed National Institute of Standards and Technology (MNIST) was used and improved the recognition accuracy of the MNIST and Fashion-MNIST datasets to 95.21% and 74.19%, respectively, by implementing an improved stochastic adaptive algorithm. These results provide a feasible approach for future implementation of optoelectronic synapses.

Study of the Structure and Bioactivity of Polysaccharides from Different Parts of Stemona tuberosa Lour.

The polysaccharides from Stemona tuberosa Lour, a kind of plant used in Chinese herbal medicine, have various pharmacological activities, such as anti-inflammatory and antioxidant properties. However, the effects of the extraction methods and the activity of polysaccharides from different parts are still unknown. Therefore, this study aimed to evaluate the effects of different extraction methods on the yields, chemical compositions, and bioactivity of polysaccharides extracted from different parts of Stemona tuberosa Lour. Six polysaccharides were extracted from the leaves, roots, and stems of Stemona tuberosa Lour through the use of hot water (i.e., SPS-L1, SPS-R1, and SPS-S1) and an ultrasound-assisted method (i.e., SPS-L2, SPS-R2, and SPS-S2). The results showed that the physicochemical properties, structural properties, and biological activity of the polysaccharides varied with the extraction methods and parts. SPS-R1 and SPS-R2 had higher extraction yields and total sugar contents than those of the other SPSs (SPS-L1, SPS-L2, SPS-S1, and SPS-S2). SPS-L1 had favorable antioxidant activity and the ability to downregulate MUC5AC expression. An investigation of the anti-inflammatory properties showed that SPS-R1 and SPS-R2 had greater anti-inflammatory activities, while SPS-R2 demonstrated the strongest anti-inflammatory potential. The results of this study indicated that SPS-L1 and SPS-L2, which were extracted from non-medicinal parts, may serve as potent natural antioxidants, but further study is necessary to explore their potential applications in the treatment of diseases. The positive anti-inflammatory effects of SPS-R1 and SPS-R2 in the roots may be further exploited in drugs for the treatment of inflammation.

Pathological Characteristics and Classification of Unstable Coronary Atherosclerotic Plaques.

Important forensic diagnostic indicators of sudden death in coronary atherosclerotic heart disease, such as acute or chronic myocardial ischemic changes, sometimes make it difficult to locate the ischemic site due to the short death process, the lack of tissue reaction time. In some cases, the deceased died of sudden death on the first-episode, resulting in difficulty for medical examiners to make an accurate diagnosis. However, clinical studies on coronary instability plaque revealed the key role of coronary spasm and thrombosis caused by their lesions in sudden coronary death process. This paper mainly summarizes the pathological characteristics of unstable coronary plaque based on clinical medical research, including plaque rupture, plaque erosion and calcified nodules, as well as the influencing factors leading to plaque instability, and briefly describes the research progress and technique of the atherosclerotic plaques, in order to improve the study on the mechanism of sudden coronary death and improve the accuracy of the forensic diagnosis of sudden coronary death by diagnosing different pathologic states of coronary atherosclerotic plaques.

Long non-coding RNAFOXD1-AS1 modulated CTCs epithelial-mesenchymal transition and immune escape in hepatocellular carcinoma in vitro by sponging miR-615-3p.

BACKGROUND: Hepatocellular carcinoma (HCC) is widely recognized as a globally prevalent malignancy. Immunotherapy is a promising therapy for HCC patients. Increasing evidence suggests that lncRNAs are involved in HCC progression and immunotherapy. AIM: The study reveals the mechanistic role of long non-coding RNA (lncRNA) FOXD1-AS1 in regulating migration, invasion, circulating tumor cells (CTCs), epithelial-mesenchymal transition (EMT), and immune escape in HCC in vitro. METHODS: This study employed real-time PCR (RT-qPCR) to measure FOXD1-AS1, miR-615-3p, and programmed death-ligand 1 (PD-L1). The interactions of FOXD1-AS1, miR-615-3p, and PD-L1 were validated via dual-luciferase reporter gene and ribonucleoprotein immunoprecipitation (RIP) assay. In vivo experimentation involves BALB/c mice and BALB/c nude mice to investigate the impact of HCC metastasis. RESULTS: The upregulation of lncRNA FOXD1-AS1 in malignant tissues significantly correlates with poor prognosis. The investigation was implemented on the impact of lncRNA FOXD1-AS1 on the migratory, invasive, and EMT of HCC cells. It has been observed that the lncRNA FOXD1-AS1 significantly influences the generation and metastasis of MCTC in vivo analysis. In mechanistic analysis, lncRNA FOXD1-AS1 enhanced immune escape in HCC via upregulation of PD-L1, which acted as a ceRNA by sequestering miR-615-3p. Additionally, lncRNA FOXD1-AS1 was found to modulate the EMT of CTCs through the activation of the PI3K/AKT pathway. CONCLUSION: This study presents compelling evidence supporting the role of lncRNA FOXD1-AS1 as a miRNA sponge that sequesters miR-655-3p and protects PD-L1 from suppression.

Real-time analysis of large-scale neuronal imaging enables closed-loop investigation of neural dynamics.

Large-scale imaging of neuronal activities is crucial for understanding brain functions. However, it is challenging to analyze large-scale imaging data in real time, preventing closed-loop investigation of neural circuitry. Here we develop a real-time analysis system with a field programmable gate array-graphics processing unit design for an up to 500-megabyte-per-second image stream. Adapted to whole-brain imaging of awake larval zebrafish, the system timely extracts activity from up to 100,000 neurons and enables closed-loop perturbations of neural dynamics.

Design of simulated-gas calibration source and self-attenuation correction methods for radioactive noble gas measurement with HPGe detector.

In this study, to achieve accurate measurement of radioactive noble gas and enhance the precision of efficiency calibration, a relatively low-cost and low-density simulated-gas calibration source (SGCS) was produced from polyurethane foam with a density of ρ = 0.098 g cm-3. Using SGCS with a Marinelli beaker geometry, the efficiency calibration was applied to a BE5030, 50.5% relative efficiency HPGe detector in an energy range of 59.54 keV∼1836.06 keV. Then, taking the 81 keV gamma-ray emitted by 133Xe as an example, due to the density difference between the SGCS and the 133Xe gas sample, it is necessary to correct for self-attenuation effects. Therefore, a semi-empirical function for self-attenuation correction was established by using LabSOCS software and XCOM. Upon validation, the relative deviation of efficiency calibration values between the SGCS and the LabSOCS of 133Xe under the density of 0.001 g cm-3 to 0.01 g cm-3 was about 3%. After using the self-attenuation correction method established in this study, the results verified a good consistency of the efficiency calculated by SGCS and LabSOCS software.

[Significance of IgH Gene Rearrangement in Surveillance of Minimal Residual Disease after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma].

OBJECTIVE: To investigate the value of immunoglobulin heavy chain (IgH) gene rearrangement in monitoring minimal residual disease (MRD) in multiple myeloma (MM) received autologous hematopoietic stem cell transplantation(auto-HSCT). METHODS: The clinical data of 26 MM patients who received auto-HSCT in the Department of Hematology, Wuhan First Hospital from 2018 to 2022 were collected. IgH rearrangement was detected by multiplex PCR combined with capillary electrophoresis fragment analysis to evaluate minimal residual disease (MRD), and the outcome of the disease was analyzed statistically. RESULTS: Among the 26 MM patients, 18 were males and 8 were females, with a median age of 59(41-70) years. The median follow-up time after transplantation was 33 (7-52) months. Compared with the IgH rearrangement negative group (n=17), the proportion of CR and sCR of patients with IgH rearrangement positive in bone marrow samples before auto-HSCT at 3 months after transplantation was lower （1/9 vs 14/17）, and the duration of remission (DOR) after transplantation was shorter（10.78±4.35 vs 15.88±5.22 months）, with statistically significant difference in DOR between the two groups(P < 0.05). Compared with IgH rearrangement negative group (n=21), the proportion of CR and sCR of patients with positive IgH rearrangement results from peripheral blood stem cell collection at 3 months after transplantation was lower（0/5 vs 15/21）, the duration of remission (DOR) after transplantation was shorter（9.60±4.83 vs 15.19±5.11 months）, and the difference in DOR between the two groups was statistically significant (P < 0.05). During the follow-up period, 5 patients (5/9) with positive IgH rearrangement results in bone marrow specimens died, and all patients with negative IgH rearrangement results survived. Four patients (4/5) with positive IgH rearrangement results by peripheral blood stem cell samples died, while one patient (1/21) with negative IgH rearrangement results died. In both bone marrow and peripheral blood stem cell samples, the survival time of IgH rearrangement-positive patients after transplantation was shorter than that of IgH rearrangement-negative patients(P < 0.05). Logistic regression analysis showed that gender, disease stage, the proportion of bone marrow smear plasma cells at initial diagnosis, stem cell mobilization plan, efficacy evaluation before transplantation (≥CR and 0.05). CONCLUSION: By detecting IgH rearrangement of MM patients receiving auto-HSCT, the depth of MRD can be further evaluated, which has a certain guiding significance for the efficacy and prognosis of the disease.

Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells.

BACKGROUND: A main obstacle in current valvular heart disease research is the lack of high-quality homogeneous functional heart valve cells. Human induced pluripotent stem cells (hiPSCs)-derived heart valve cells may help with this dilemma. However, there are no well-established protocols to induce hiPSCs to differentiate into functional heart valve cells, and the networks that mediate the differentiation have not been fully elucidated. METHODS: To generate heart valve cells from hiPSCs, we sequentially activated the Wnt, BMP4, VEGF (vascular endothelial growth factor), and NFATc1 signaling pathways using CHIR-99021, BMP4, VEGF-165, and forskolin, respectively. The transcriptional and functional similarity of hiPSC-derived heart valve cells compared with primary heart valve cells were characterized. Longitudinal single-cell RNA sequencing was used to uncover the trajectory, switch genes, pathways, and transcription factors of the differentiation. RESULTS: An efficient protocol was developed to induce hiPSCs to differentiate into functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells. After 6-day differentiation and CD144 magnetic bead sorting, ≈70% CD144+ cells and 30% CD144- cells were obtained. On the basis of single-cell RNA sequencing data, the CD144+ cells and CD144- cells were found to be highly similar to primary heart valve endothelial cells and primary heart valve interstitial cells in gene expression profile. Furthermore, CD144+ cells had the typical function of primary heart valve endothelial cells, including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress. Meanwhile, CD144- cells could secret collagen and matrix metalloproteinases, and differentiate into osteogenic or adipogenic lineages like primary heart valve interstitial cells. Therefore, we identified CD144+ cells and CD144- cells as hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells, respectively. Using single-cell RNA sequencing analysis, we demonstrated that the trajectory of heart valve cell differentiation was consistent with embryonic valve development. We identified the main switch genes (NOTCH1, HEY1, and MEF2C), signaling pathways (TGF-ß, Wnt, and NOTCH), and transcription factors (MSX1, SP5, and MECOM) that mediated the differentiation. Finally, we found that hiPSC-derived valve interstitial-like cells might derive from hiPSC-derived valve endothelial-like cells undergoing endocardial-mesenchymal transition. CONCLUSIONS: In summary, this is the first study to report an efficient strategy to generate functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells from hiPSCs, as well as to elucidate the differentiation trajectory and transcriptional dynamics of hiPSCs differentiated into heart valve cells.

Prospective prenatal cell-free DNA screening for genetic conditions of heterogenous etiologies.

Prenatal cell-free DNA (cfDNA) screening uses extracellular fetal DNA circulating in the peripheral blood of pregnant women to detect prevalent fetal chromosomal anomalies. However, numerous severe conditions with underlying single-gene defects are not included in current prenatal cfDNA screening. In this prospective, multicenter and observational study, pregnant women at elevated risk for fetal genetic conditions were enrolled for a cfDNA screening test based on coordinative allele-aware target enrichment sequencing. This test encompasses the following three of the most frequent pathogenic genetic variations: aneuploidies, microdeletions and monogenic variants. The cfDNA screening results were compared to invasive prenatal or postnatal diagnostic test results for 1,090 qualified participants. The comprehensive cfDNA screening detected a genetic alteration in 135 pregnancies with 98.5% sensitivity and 99.3% specificity relative to standard diagnostics. Of 876 fetuses with suspected structural anomalies on ultrasound examination, comprehensive cfDNA screening identified 55 (56.1%) aneuploidies, 6 (6.1%) microdeletions and 37 (37.8%) single-gene pathogenic variants. The inclusion of targeted monogenic conditions alongside chromosomal aberrations led to a 60.7% increase (from 61 to 98) in the detection rate. Overall, these data provide preliminary evidence that a comprehensive cfDNA screening test can accurately identify fetal pathogenic variants at both the chromosome and single-gene levels in high-risk pregnancies through a noninvasive approach, which has the potential to improve prenatal evaluation of fetal risks for severe genetic conditions arising from heterogenous molecular etiologies. ClinicalTrials.gov registration: ChiCTR2100045739 .

Novel ratio-expressions of genes enables estimation of wound age in contused skeletal muscle.

Given that combination with multiple biomarkers may well raise the predictive value of wound age, it appears critically essential to identify new features under the limited cost. For this purpose, the present study explored whether the gene expression ratios provide unique time information as an additional indicator for wound age estimation not requiring the detection of new biomarkers and allowing full use of the available data. The expression levels of four wound-healing genes (Arid5a, Ier3, Stom, and Lcp1) were detected by real-time polymerase chain reaction, and a total of six expression ratios were calculated among these four genes. The results showed that the expression levels of four genes and six ratios of expression changed time-dependent during wound repair. The six expression ratios provided additional temporal information, distinct from the four genes analyzed separately by principal component analysis. The overall performance metrics for cross-validation and external validation of four typical prediction models were improved when six ratios of expression were added as additional input variables. Overall, expression ratios among genes provide temporal information and have excellent potential as predictive markers for wound age estimation. Combining the expression levels of genes with ratio-expression of genes may allow for more accurate estimates of the time of injury.

Age differences in the impact of dietary salt on metabolism, blood pressure and cognitive function in male rats.

The influence of salt consumption on physiological processes, especially blood pressure (BP), metabolism, and cognition, remains a topical concern. While guidelines endorse reduced salt diets, there are gaps in understanding the age-specific implications and challenges in adherence. The present study delved into the differential effects of salt intake on young adult and aged male rats over a 12-week period, using control, low-, and high-salt diets. Key metrics, such as BP, cognition, and general parameters, were monitored. Our findings revealed significant age-dependent effects of salt intake on survival rates, body weight, blood sodium, blood glucose, blood lipids, BP, heart rates, and cognition. Notably, young adult rats did not show significant sodium level changes on a high-salt diet, whereas aged rats experienced increased sodium levels even on a normal salt diet. Blood glucose levels decreased significantly in aged rats on a high-salt diet but remained stable in young adults. Aged rats had the highest survival rates on low-salt diets. Low-salt diets led to reduced BP in both age groups, more significantly in young adults. Young adult rats displayed increased BP variability on both high- and low-salt diets, while a decrease in BP variability was exclusive to aged rats on a low-salt diet. There were significant differences across age groups in short-term memory, but not in long-term memory. The study provides a nuanced understanding of the age-dependent physiological effects of salt intake, suggesting the necessity of age-specific guidelines for public health.

Exploring the Effect of Compound Glycyrrhizin and Silybinin on the Metabolism of Pexidartinib in Rats Based on CYP3A4 and CYP2C9.

Pexidartinib offered a new therapeutic option for adult patients with symptomatic tenosynovial giant cell tumor (TGCT) who were refractory to surgical treatment and had severe morbidity or functional limitations. Meanwhile, the metabolism of pexidartinib was mainly mediated through the oxidation of cytochrome P450 (CYP) 3A and glucuronidation by uridine glucuronosyltransferase (UGT) 1A4 and attention shall be paid to CYP450-based drug-drug interactions during therapeutic dosing. This study aimed to examine the changes in the pharmacokinetics of pexidartinib by silymarin and compound glycyrrhizin on pexidartinib in vivo in rats by high-performance liquid chromatography (HPLC)-UV approach and to detect its expression in CYP3A4 and CYP2C9 using the western blot. The findings of chromatography experiments revealed that silybinin as well as compound glycyrrhizin increased the exposure of pexidartinib in rats and had a significant inhibitory effect on the metabolism of pexidartinib. The results of immunoblotting assays suggested that silybinin as well as compound glycyrrhizin inhibited the protein expression of CYP3A4 and CYP2C9 in rats. Therefore, the combination of pexidartinib with silybinin and compound glycyrrhizin should be monitored to avoid clinical adverse effects.