Esophageal cancer （EC） is a highly prevalent malignant tumor in China. The phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， as one of the key oncogenic pathways， can promote the cell cycle progression， proliferation， migration， and invasion， induce chemoresistance， and inhibit apoptosis and autophagy of EC cells. Traditional Chinese medicine （TCM）， with the advantages of targeting multiple points with multiple components to delay cancer progression， can target the PI3K/Akt signaling pathway for EC treatment. This article preliminarily discusses the molecular mechanism and role of the PI3K/Akt signaling pathway in EC and elaborates on the specific targets and efficacy of TCM in treating EC through intervention in the PI3K/Akt signaling pathway in the past five years. TCM materials and extracts inhibiting the PI3K/Akt signaling pathway in EC include Borneolum， spore powder of Ganoderma lucidum without spore coat， extract of Celastrus orbiculatus， root extract of Taraxacum， and Bruceae Fructus oil emulsion. TCM active ingredients exerting the effect include flavonoids， terpenoids， saponins， phenols， polysaccharides， alkaloids， and other compounds. TCM compound prescriptions with such effect include Qige San， Huqi San， Xuanfu Daizhetang， Tongyoutang and its decomposed prescriptions， Liujunzi Tang， and Xishenzhi Formula. In addition， TCM injections such as Compound Kushen Injection and Kang'ai injection also inhibit the PI3K/Akt signaling pathway in EC. This paper summarizes the role of the PI3K/Akt signaling pathway in EC and the TCM interventions， aiming to provide reference for the research and clinical application of new drugs for EC.

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

G protein-coupled receptor kinase 2 (GRK2) participates in the phosphorylation and desensitization of G protein-coupled receptor (GPCR), impacting various biological processes such as inflammation and cell proliferation. Dysregulated expression and activity of GRK2 have been reported in multiple cells in rheumatoid arthritis (RA). However, whether and how GRK2 regulates synovial hyperplasia and fibroblast-like synoviocytes (FLSs) proliferation is poorly understood. In this study, we investigated the regulation of GRK2 and its biological function in RA. We found that GRK2 transmembrane activity was increased in FLSs of RA patients and collagen-induced arthritis (CIA) rats. Additionally, we noted a positive correlation between high GRK2 expression on the cell membrane and serological markers associated with RA and CIA. Immunoprecipitation-mass spectrometry and pull-down analyses revealed tumor necrosis factor receptor-associated factor 2 (TRAF2) as a novel substrate of GRK2. Furthermore, surface plasmon resonance (SPR) and molecular docking assays determined that the C-terminus of GRK2 binds to the C-terminus of TRAF2 at the Gln340 residue. GRK2 knockdown and the GRK2 inhibitor CP-25 attenuated synovial hyperplasia and FLS proliferation in CIA both in vitro and in vivo by decreasing GRK2 membrane expression and activity. Mechanistically, increased GRK2 transmembrane activity contributed to the recruitment of TRAF2 on the cell membrane, promoting GRK2-TRAF2 interactions that facilitate the recruitment of the E3 ubiquitin ligase TRIM47 to TRAF2. This enhanced TRAF2 Lys63 polyubiquitylation and induced nuclear factor (NF)-κB activation, leading to synovial hyperplasia and abnormal proliferation of FLSs. Our study provides a mechanistic and preclinical rationale for further evaluation of GRK2 as a therapeutic target for RA.

BACKGROUND:Research has shown that vanillic acid has anti-inflammatory and anti-oxidative stress effects,but it is unclear whether it has a protective effect on endplate chondrocytes.OBJECTIVE:To explore the effect and mechanism of vanillic acid on endplate chondrocytes under inflammatory microenvironment.METHODS:(1)Primary endplate chondrocytes were isolated from the intervertebral disc of SD rats and identified by toluidine blue staining and collagenⅡ immunofluorescence.(2)The CCK-8 assay was employed to detect the effects of interleukin-1β and vanillic acid on the proliferation activity of endplate chondrocytes,in order to determine the concentration of vanillic acid for subsequent cell treatment.(3)An inflammatory microenvironment was simulated by adding 10 ng/mL interleukin-1β to the culture medium,and the endplate chondrocytes were treated with low,medium,and high mass concentrations of vanillic acid.The expression levels of inflammatory markers and extracellular matrix proteins were detected by western blot assay and immunofluorescence.(4)The expression of nuclear factor κB signaling pathway-related proteins was detected by western blot assay.RESULTS AND CONCLUSION:(1)The morphology of endplate chondrocytes in adherent culture was pike or triangular in shape,positive for toluidine blue staining and immunofluorescence for collagen Ⅱ,indicating that the experimentally extracted cells were endplate chondrocytes.(2)The CCK-8 assay results showed that treatment with 2.5,5,10,and 20 μg/mL vanillic acid for 24 hours did not significantly inhibit the proliferation of endplate chondrocytes.Compared with the interleukin-1β group,the viability of endplate chondrocytes treated with 5,10,and 20 μg/mL vanillic acid for 24 hours was significantly increased(P＜0.05).Therefore,5,10,and 20 μg/mL vanillic acid was selected as the low,medium,and high dose groups for subsequent treatment of endplate chondrocytes.(3)Compared with the model group(complete medium containing 10 ng/mL interleukin-1β),the expression of NOD-like receptor thermal domain associated protein 3(NLRP3),matrix metalloproteinase 13,matrix metalloproteinase 3,and tumor necrosis factor alpha protein in the endplate chondrocytes of the low,medium,and high doses of vanillic acid groups were significantly reduced(P＜0.05).(4)Compared with the model group,the protein expression of aggrecan and collagen Ⅱ in the endplate chondrocytes of the low,medium,and high dose groups of vanillic acid significantly increased(P＜0.05).(5)Compared with the model group,the protein expression of phospho-nuclear factor κB and phospho-inhibitor of nuclear factor κB in the endplate chondrocytes of the low,medium,and high dose groups of vanillic acid was significantly reduced(P＜0.05).(6)The above results indicate that vanillic acid may alleviate the inflammatory response and extracellular matrix degradation induced by interleukin-1β in rat endplate chondrocytes by inhibiting the activation of the nuclear factor κB signaling pathway.

Objective To evaluate the efficacy and safety of Qixian Tongluo Formula in the treatment of post-cerebral infarction paralysis with kidney deficiency and blood stasis syndrome,and to preliminarily explore the molecular mechanism of Qixian Tongluo Formula in improving impaired motor function from the perspective of cross-kingdom regulation of Chinese medicine microRNA(miRNA).Methods A pragmatic randomized controlled trial was conducted with 102 patients in the recovery period of post-cerebral infarction paralysis with kidney deficiency and blood stasis syndrome in our hospital.Patients were randomly divided into trial group and control group,with 51 cases in each group.The control group received standard Western medicine standard treatment,while the trial group received Qixian Tongluo Formula in addition to the standard treatment,with one dose per day,boiled in water,and taken warm after breakfast and dinner for a course of 2 months.The disability rate was used as the main efficacy indicator,and the incidence of adverse reactions was used as a safety indicator.miRNA from patient serum and Qixian Tongluo decoction were extracted respectively,and high-throughput sequencing was performed.The two sequences were compared to screen out the cross-kingdom gene transfer of Chinese medicine miRNA.Finally,its target genes of miRNA were predicted,and GO function and KEGG pathway enrichment analysis were carried out.Results A total of 67 patients completed the clinical trial,including 36 cases in the trial group and 31 cases in the control group;The disability rate in the trial group(13.9%)was lower than that in the control group(35.5%)(P<0.05);The incidence of adverse reactions was similar between the trial group(7.69%)and the control group(6.06%)(P>0.05);A total of 9530 Qixian Tongluo decoction miRNA sequences were screened,with 150 potentially involved in cross-kingdom gene transfer,including families such as miR-15 and miR-17;According to the target gene prediction of the top 10 miRNAs in cross-kingdom gene transfer of Chinese medicine,345 overlapping target genes were obtained;GO functional enrichment analysis revealed 16 biological processes,7 cellular components,and 2 molecular functions among the top 25 enriched functions,while KEGG pathway analysis mainly focused on the transforming growth factor-βsignaling pathway,neurotrophin signaling pathway,which are closely related to neural repair and functional recovery processes such as glial scar formation and synaptic plasticity after cerebral ischemia.Conclusion Qixian Tongluo Formula can significantly improve the functional independence level of patients with kidney deficiency and blood stasis syndrome in the recovery period of paralysis after cerebral infarction,offering a safe and effective treatment option for these patients;There were a large number of miRNAs in Qixian Tongluo decoction,some of which could cross-kingdom transferred into the human blood circulation,and promote the recovery of motor function in patients with cerebral infarction through multi-target,multi link and multi pathway gene network regulation.This study provides a new idea for subsequent clinical and basic research.

BACKGROUND:The lower-limb muscle strength shows a significant physiological decline with aging.There may be a certain correlation between sedentary behavior,fear of falling,age and lower-limb muscle strength,but the influence path and effect relationship among them are not yet clear.OBJECTIVE:To examine the relationship between sedentary behavior and lower-limb muscle strength,and to explore the influences of fear of falling and age in such an association among community-dwelling older adults.METHODS:This cross-sectional study recruited 331 community-dwelling older adults(aged≥60 years)in Shanghai.A questionnaire survey was conducted to collect basic information,demographic data,etc.The Short Form of the International Physical Activity Questionnaire was applied to measure sedentary time.Lower-limb muscle strength was assessed by the 30-second chair-stand test.Fear of falling was measured by the Chinese version of Fall Efficacy Scale-International.Descriptive statistics analysis,correlation analysis,regression-based path analysis and mediation analyses were performed on the data.RESULTS AND CONCLUSION:Valid data from 318 community-dwelling older adults[78.9%females,mean age(67.8±5.5)years old]were finally included in the analysis.There were 185 with sedentary time≥3 hours and 133 with sedentary time<3 hours.(1)There was a positive correlation between sedentary behavior and fear of falling(P<0.01),and there were negative correlations between lower-limb muscle strength and sedentary behavior(P<0.01)and between lower-limb muscle strength and fear of falling(P<0.001).(2)Sedentary behavior negatively predicted lower-limb muscle strength(β=-0.125,P<0.05),and positively predicted fear of falling(β=0.182,P<0.01).Fear of falling negatively predicted lower-limb muscle strength(β=-0.293,P<0.001).(3)Fear of falling mediated the relationship between sedentary behavior and lower-limb muscle strength(β=-0.053,95%confidence interval:-0.100 to-0.018).(4)Sedentary behavior had a statistically significant predictive effect on fear of falling(β=0.164,P<0.01),indicating that age moderates the effect of sedentary behavior on fear of falling.

Purpose To investigate the expression of bone sialoprotein(BSP)in the tissues and cells of endome-trial cancer(EC)and its effects on the proliferation and invasion of EC cells.Methods The expression of BSP was assessed by immunohistochemistry in 235 EC tissues and 88 normal endometrial tissues,and its correlation with clinico-pathological features was analyzed.Western blot was used to compare BSP levels between human endometrial carcinoma cell line(HHUA)and normal human endumetial epithelial cells(HEEC).BSP was knocked down in HHUA cells via transient transfection,and the cells were divided into blank control group and BSP-knockdown group.The effects of BSP knockdown on cell cycle,proliferation,migration,invasion,and apoptosis were evaluated using PI staining,CCK-8,scratch,Transwell,and Annexin V-FITC assays,respectively.Protein levels of TGF-β signaling pathway compo-nents were analyzed by Western blot.Results BSP expression was significantly higher in EC tissues than in normal endometrium(P＜0.001)and correlated with lymph node metastasis and advanced FIGO stage(P＜0.05).BSP pro-tein level was also significantly elevated in HHUA cells(2.455 8±0.008 9)compared to HEECs(1.571 2±0.005 4)(P＜0.01).After knockdown,compared with the control group,the proliferation index(74.4±3.33),migration rate(0.48±0.03),and invasion ability(0.36±0.11)of the cells were increased,and the apoptosis rate(25.97％)of the cells was increased(P＜0.05).Furthermore,the expression levels of TGF-β signaling pathway downstream proteins TGF-β1(0.290 4±0.002 3)、TGF-β2(0.292 9±0.001 6)、Smad2(0.469 3±0.001 1)、Smad3(0.247 0±0.001 7)、pAKT(0.382 1±0.001 9)、ATK(0.119 6±0.001 6)and MEK1(0.258 9±0.000 3)in the BSP-knockdown group of EC cells decreased(P＜0.01).Conclusion BSP is highly expressed in endometrial cancer and promotes cancer cell proliferation,invasion,and metastasis by activating the TGF-β signaling pathway.

Objective To analyze the relationship between hypertension combined with obstructive sleep apnea hypopnea syndrome(OSAHS)and intima-media thickness(IMT)and explore the correlation between the risk of IMT and hypertension with OSAHS patients.Methods Select 50 patients with hypertension and OSAHS patients who were treated in Jiaxing Hospital of Traditional Chinese Medicine during January 2020 to February 2024 as observation group,while 50 patients with simple hypertension were used as control groups to collect two groups of patients'sleep respiratory monitoring disorders(AHI),lowest blood oxygen saturation(L-SaO2)at night,average hemodium oxygen saturation(M-SaO2)at night,dynamic blood pressure 24h,daytime and night's average diastolic blood pressure,IMT,conducting relevant statistical analysis,compares correlation between IMT of two groups and the severity of OSAHS.Results Compared with control group,observation group AHI,IMT,average systolic blood pressure voltage and average diastolic blood pressure increased significantly(P＜0.01),L-SaO2,M-SaO2 decreased significantly(P＜0.01).Observation group AHI and average systolic blood voltage and average diastolic pressure of average systolic blood pressure at 24h,daytime,and night were positively correlated(P＜0.01),L-SaO2,24h and daytime average contraction pressure were negatively correlated(P＜0.05).Observation group AHI and IMT were positive,and L-SaO2,M-SaO2 and IMT were negatively related(P＜0.01).Conclusion Severity of the disease of hypertension combined with OSAHS patients is closely related to patient's blood pressure level and change of IMT.Actively controlling blood pressure and IMT may help improve prognosis of patients,reduce the occurrence of cardiovascular events.The prognostic evaluation has certain clinical value.

Objective To investigate the value of artificial intelligence iterative reconstruction(AIIR)in preoperative low-dose CT of ovarian tumor.Methods Seventy patients with ovarian tumor were prospectively enrolled.Routine-dose(120 kVp,200 mAs)and low-dose(120 kVp,40 mAs)contrast-enhanced abdominopelvic CT scanning at portal venous phase were sequentially performed.The routine-dose images were reconstructed with hybrid iterative reconstruction(HIR)(group A),while low-dose images were reconstructed with HIR(group B)and AIIR(group C),respectively.Subjective and objective evaluation of image quality were compared among groups,and the diagnostic accuracy of peripheral organ invasion and peritoneal metastasis based on group A,B and C,as well as radiation dose of routine-and low-dose scanning were recorded.Results In group B,A and C,the subjective scoring of definition of tumor margin and septation,boundary between tumor and surrounding organ,as well as the signal-to-noise ratio and contrast-to-noise ratio of ovarian tumor and psoas muscles,increased successively(all P＜0.017).No significant difference of subjective scoring of tumor feeding vessel clarity was found between group A and C(P=0.435),which were both higher than that in group B(P＜0.017).The accuracy for diagnosing peripheral organ invasion based on group A,B and C was 83.87％ (52/62),72.58％ (45/62)and 83.87％ (52/62),for diagnosing peritoneal metastasis was 85.71％ (60/70),78.57％ (55/70)and 84.29％ (59/70),respectively.Compared to routine-dose CT,the effective dose of low-dose CT was reduced by 79.70％ (2.60 mSv vs.12.81 mSv,P＜0.001).Conclusion AIIR could improve image quality and metastasis diagnostic efficacy in low-dose CT of ovarian tumors.

Objective To investigate the feasibility and efficacy of mindfulness-based stress reduction (MBSR) in the management of chronic pain among military personnel stationed in plateau area of China. Methods Military personnel who had been stationed at an altitude ranging from 3 300 to 3 500 meters for over four months and suffered from chronic pain were selected as the study subjects by the judgment sampling method. A total of 51 individuals were assigned to the control group, and 53 individuals were assigned to the MBSR group using the random number table method. Individuals of the control group received conventional pain management, while the MBSR group received an additional eight-week MBSR training alongside conventional management. Pain, mindfulness levels, mood state, and psychological resilience of individuals were assessed before and 12 weeks after the intervention using the Brief Pain Inventory (BPI), the Five Facet Mindfulness Questionnaire-Short Form, the Profile of Mood States, and the Connor-Davidson Resilience Scale. Results After the intervention, the BPI scores, and the scores of the pain intensity and pain impact dimensions of individuals in the MBSR group were lower than those in the control group (all P<0.01). The reductions in these three scores were greater in the MBSR group than those in the control group (all P<0.01). Meanwhile, individuals in the MBSR group showed superior improvements in the mindfulness level score, the total mood disturbance, and the psychological resilience score compared with the control group (all P<0.05). The multiple linear regression analysis results showed that the pre-intervention BPI score, post-intervention changes in mindfulness levels, headache and lower back pain were influencing factors for the improvement of the BPI score in the MBSR group individuals (all P<0.05). Conclusion Conducting MBSR in military units in plateau areas is an effective approach for alleviating chronic pain. The pain relief effect is more pronounced in individuals with higher initial pain scores, a greater increase in mindfulness scores after training, and those with headache and low back pain.