OBJECTIVE To predict and validate the potential mechanisms of Kaixinsan （KXS） in ameliorating neuroinflammation in Alzheimer’s disease （AD）. METHODS Network pharmacology was employed to identify core anti- inflammatory components and key inflammatory targets of KXS for AD. Gene ontology （GO） functional annotation， Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment， and molecular docking were performed. Based on these findings， male SD rats were used to establish an AD model via chronic D-galactose induction. The effects of KXS on AD rats were evaluated， including quantitative behavioral score， learning and memory parameters （escape latency， platform crossings， platform quadrant distance and time）， organ indexes （heart， liver， spleen， thymus）， histopathological alterations in the hippocampus， and expressions of inflammation-related pathway proteins and their upstream/downstream regulators. RESULTS Core anti-inflammatory components of KXS for AD included gomisin B， panaxytriol， gomisin A， enhydrin， vulgarin and panaxydol， while key inflammatory targets involved nuclear factor-kappa B subunit 1（ NFKB1）， nuclear factor-κB p65（ NF-κB p65）， interleukin-1β（ IL- 1β）， IL-6， Toll-like receptor 4 （TLR4）， tumor necrosis factor， nucleotide-binding domain leucine-rich repeat and pyrin domain- containing receptor 3 （NLRP3） and caspase-1 （CASP1）. GO and KEGG pathway enrichment involved inflammatory response， phosphorylation and the NF-κB signaling pathway. Molecular docking confirmed strong binding affinities between core components and key targets. Animal experiments demonstrated that， compared to the model group， KXS significantly alleviated histopathological damage （e.g.， neuronal shrinkage， reduced Nissl bodies in hippocampal CA1， CA3， and DG regions）， increased organ indexes （except for liver index） and Nissl-stained positive cells， improved learning and memory performance， and reduced behavioral scores （at the 8 and 12 weeks of the experiment） and protein expression of NF- κB p65， phosphorylated NF- κB p65， TLR4， NLRP3， CASP1 and IL-1β. CONCLUSIONS KXS effectively mitigates neuroinflammation， reduces hippocampal neuronal injury， and enhances learning and memory ability in AD rats， potentially through suppressing the NF-κB signaling pathway and its upstream/ downstream regulators.

Objective To study the chemical constituents of Fallopia aubertii L.Henry Holub. Methods The chemical constituents of Fallopia aubertii L.Henry Holub. were separated and purified by online two-dimensional preparative liquid chromatography and identified by physical and chemical constants and spectral analysis. The inhibitory activities on xanthine oxidase were determined by ultraviolet spectrophotometry. Results Ten compounds were isolated from the extract of Fallopia aubertii L.Henry Holub, including isotachioside（1）, 3,4,5-trimethoxyphenyl-（6'-O-galloyl）-O-β-D-Glucopyranoside（2）, 1-hydroxy-,4,5-1-O-[6'-O-（4''-carboxy-1'',3'',5'trihydrotrimethoxyphenylxy）-phenyl]-β-D-glucopyranoside（3）, myricetrin（4）, myricetin（5）, rutin（6）, quercetin-3-O-β-D-galactoside（7）, quercetin-3-O-β-D-glucopyranoside（8）, lyciumideA（9）, and N-trans-Feruloyltyramine（10）. The inhibitory activity test results showed that the IC₅₀ of compound 5 was 15.92 μmol/L, and the IC₅₀ of compound 6 was 87.36 μmol/L. Conclusion Compounds 1,2,3,4 and 8 were isolated from Medicago polymorpha for the first time. Compounds 5 and 6 had xanthine oxidase inhibitory activity.

The lumbar intervertebral disc exhibits a complex physiological structure with interactions between various segments, and its components are extremely complex. The material properties of different components in the lumbar intervertebral disc, especially the water content (undergoing dynamic change as influenced by age, degeneration, mechanical loading, and proteoglycan content) - critically determine its mechanical properties. When the lumbar intervertebral disc is under continuous pressure, water seeps out, and after the pressure is removed, water re-infiltrates. This dynamic fluid exchange process directly affects the mechanical properties of the lumbar intervertebral disc, while previous isotropic modeling methods have been unable to accurately reflect such solid-liquid phase behaviors. To explore the load-bearing mechanism of the lumbar intervertebral disc and establish a more realistic mechanical model of the lumbar intervertebral disc, this study developed a solid-liquid biphasic, fiber-reinforced finite element model. This model was used to simulate the four movements of the human lumbar spine in daily life, namely flexion, extension, axial rotation, and lateral bending. The fluid pressure, effective solid stress, and liquid pressure-bearing ratio of the annulus fibrosus and nucleus pulposus of different lumbar intervertebral discs were compared and analyzed under the movements. Under all the movements, the fluid pressure distribution was closer to the nucleus pulposus, while the effective solid stress distribution was more concentrated in the outer annulus fibrosus. In terms of fluid pressure, the maximum fluid pressure of the lumbar intervertebral disc during lateral bending was 1.95 MPa, significantly higher than the maximum fluid pressure under other movements. Meanwhile, the maximum effective solid stress of the lumbar intervertebral disc during flexion was 2.43 MPa, markedly higher than the maximum effective solid stress under other movements. Overall, the liquid pressure-bearing ratio under axial rotation was smaller than that under other movements. Based on the solid-liquid biphasic modeling method, this study more accurately revealed the dominant role of the liquid phase in the daily load-bearing process of the lumbar intervertebral disc and the solid-phase mechanical mechanism of the annulus fibrosus load-bearing, and more effectively predicted the solid-liquid phase co-load-bearing mechanism of the lumbar intervertebral disc in daily life.
Humans ; Finite Element Analysis ; Intervertebral Disc/physiology* ; Lumbar Vertebrae/physiology* ; Weight-Bearing/physiology* ; Biomechanical Phenomena ; Stress, Mechanical ; Computer Simulation ; Models, Biological

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To explore the risk factors of apathy and correlations with cognitive function in patients with hypertension combined with cerebral small vessel disease(CSVD).Methods Totally 141 patients with hypertension combined with CSVD were prospectively enrolled and were divided into apathy group(n=43)and non-apathy group(n= 98)according to neuropsychiatric inventory-apathy scale(NPI-Apathy)scores.The general data,imaging marker scores and total imaging burden scores were compared between groups.In hypertension combined with CSVD patients,multivariate logistic regression analysis was performed to screen the independent risk factors of apathy,and Spearman correlation analysis was also performed to observe the correlation of apathy and cognitive function.Results The patients'age,high density lipoprotein cholesterol(HDL-C),Fazekas scores of lateral periventricular white matter hyper-intensity(WMH),cerebral microbleed of depth/infratentorial and total imaging burden scores of apathy group were all higher,while mini-mental state examination(MMSE)and Montreal cognitive assessment(MoCA)scores were both lower than those of non-apathy group(all P＜0.05).HDL-C and Fazekas scores of lateral periventricular WMH were both independent risk factors for apathy(both P＜0.05),while NPI-Apathy scores were moderately negatively correlated with cognitive function in patients with hypertension combined with CSVD(r=-0.543,-0.484,both P＜0.001).Conclusion HDL-C and Fazekas scores of lateral periventricular WMH were both independent risk factors for apathy in patients with hypertension combined with CSVD.The more severe the apathy,the lower the cognitive function.

Background::Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.Methods::We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.Results::The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. Conclusion::The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1. Trial Registration::No. NCT00454519 (https://clinicaltrials.gov/)

The pathogenesis of attention deficit and hyperactive disorder(ADHD)remains unclear.Evidence from epidemiological,biomarker,and genetic studies indicates that inflammation may play a crucial role in ADHD development.Inflammation can influence the onset and progression of ADHD through various mechanisms,such as activation of the hypothalamic-pituitary-adrenal(HPA)axis,alterations in neurotransmitter metabolism,maternal immune activation,disruption of the blood-brain barrier integrity,and impacts on neurodevelopment.A deeper understanding of the relationship between inflammation and ADHD could provide valuable insights into the pathophysiological mechanisms of ADHD and open new perspectives for clinical diagnosis and treatment.

Objective To investigate the efficacy and safety of retroperitoneal single-port laparoscopic (LESS) adrenal tumor resection.Methods The clinical data of 130 patients receiving multi-port and single-port laparoscopic adrenal tumor resection in this hospital from January 2015 to March 2023 were retrospec-tively analyzed.There were 50 cases in the LESS group and 80 cases in the traditional laparoscopic adrenal tumor resection (LA) group.The age,gender,tumor location,complicating underlying diseases and tumor size were collected in the two groups.The related perioperative indicators were compared between the two groups. Results The operation time[(95±52)min vs. (101±58)min],drainage tube indwelling time[(4.9±1.5)d vs. (6.7±1.0)d],postoperative incision satisfaction degree and pain situation had statistically significant differences between the LESS group and LA group (P<0.05).The intraoperative bleeding volume[(20.2±13.2)mL vs. (25.6±11.3)mL]and hospitalization duration[(5.9±1.3)d vs. (7.8±1.0)d]had no statisti-cal differences between the two groups (P>0.05).No intraoperative and postoperative complications oc-curred in the two groups.There was 1 case of conversion to open operation in the LA group.Conclusion The LESS adrenal tumor resection is safe and effective,and the incision is more beautiful compared with multi-port laparoscopic operation.

Objective To explore the pharmacodynamic substances of Simiao Wan for the treatment of hyperuricemia and gout.Methods The pharmacological model of hyperuricemia was established.The chemical components in vivo and in vitro of Simiao Wan were analyzed by UPLC-Q-Exactive-MS.Based on the components absorbed in blood,the"active ingredient-target-pathway"network of Simiao Wan for regulating hyperuricemia and gout was constructed by network pharmacology method.The key ingredients were used for molecular docking with key targets[uricogenase(XDH),uric acid transporter(ABCG2,GLUT9,OAT1,URAT1)and inflammatory targets(PTGS2,TLR2,TLR4)]of hyperuricemia and gout.Finally,experimental verification was conducted according to the results of molecular docking.Our aim is to identify the key pharmacodynamic substances of Simiao Wan for the treatment of hyperuricemia and gout.Results Eighty-nine components of Simiao Wan were identified by UPLC-Q-Exactive-MS analysis,including 74 components absorbed in blood,which were confirmed as candidate ingredients.Network pharmacology was used to constructed"components absorbed in blood-target-pathway"network,and components absorbed in blood were matched with 116 targets of hyperuricemia and 173 targets of gout.It is involved in the regulation of biological processes,such as glucose and lipid metabolism,oxidative stress,inflammatory response,ERK1 and ERK2 cascade,MAPK cascade,PI3K signal transduction.Moreover,Simiao Wan plays a role in regulating the network of hyperuricemia and gout through regulating blood lipids and atherosclerosis,apoptosis,AGE-RAGE,TNF,PI3K-Akt,MAPK,TLRs,JAK-STAT,NF-κB and other signaling pathways.Molecular docking studies showed that berberine,phellodendrine,magnoflorine,jatrorrhizine,palmatine,obacunone,limonin,atractylodin,taxifolin,atractylenolide Ⅲ and β-ecdysterone had good affinity with uric acid synthase,uric acid transporter and inflammatory targets.Western Blot test showed that taxifolin negatively regulates the expression of URAT1.The above-mentioned compounds were the main pharmacodynamic substances of Simiao Wan for the treatment of hyperuricemia and gout.Conclusion This article describes the main pharmacodynamic substances of Simiao Wan in the regulation of hyperuricemia and gout,which can provides a scientific basis for the clinical application,improvement in quality evaluation and standard of Simiao Wan.